CINXE.COM

<!doctype html> <html data-n-head-ssr lang="en" data-n-head="%7B%22lang%22:%7B%22ssr%22:%22en%22%7D%7D"> <head > <link data-n-head="ssr" rel="icon" type="image/png" sizes="16x16" href="https://brand.frontiersin.org/m/ed3f9ce840a03d7/favicon_16-tenantFavicon-Frontiers.png"> <link data-n-head="ssr" rel="icon" type="image/png" sizes="32x32" href="https://brand.frontiersin.org/m/ed3f9ce840a03d7/favicon_32-tenantFavicon-Frontiers.png"> <link data-n-head="ssr" rel="apple-touch-icon" type="image/png" sizes="180x180" href="https://brand.frontiersin.org/m/ed3f9ce840a03d7/favicon_180-tenantFavicon-Frontiers.png"> <title>Frontiers | Determination of α1-acid glycoprotein (AGP) concentration by HPLC in patients following local infiltration analgesia for primary total hip arthroplasty and its relation to ropivacaine (total and unbound)</title><meta data-n-head="ssr" charset="utf-8"><meta data-n-head="ssr" name="viewport" content="width=device-width, initial-scale=1"><meta data-n-head="ssr" data-hid="charset" charset="utf-8"><meta data-n-head="ssr" data-hid="mobile-web-app-capable" name="mobile-web-app-capable" content="yes"><meta data-n-head="ssr" data-hid="apple-mobile-web-app-title" name="apple-mobile-web-app-title" content="Frontiers | Articles"><meta data-n-head="ssr" data-hid="theme-color" name="theme-color" content="#0C4DED"><meta data-n-head="ssr" data-hid="description" property="description" name="description" content="Introduction: This study was performed to determine the levels of α1-acid glycoprotein (AGP) in old-age patients undergoing total hip arthroplasty. AGP is co..."><meta data-n-head="ssr" data-hid="og:title" property="og:title" name="title" content="Frontiers | Determination of α1-acid glycoprotein (AGP) concentration by HPLC in patients following local infiltration analgesia for primary total hip arthroplasty and its relation to ropivacaine (total and unbound)"><meta data-n-head="ssr" data-hid="og:description" property="og:description" name="description" content="Introduction: This study was performed to determine the levels of α1-acid glycoprotein (AGP) in old-age patients undergoing total hip arthroplasty. AGP is co..."><meta data-n-head="ssr" data-hid="keywords" name="keywords" content="HPLC,α1-acid glycoprotein,human plasma,Hip joint surgery patients,Protein Binding"><meta data-n-head="ssr" data-hid="og:site_name" property="og:site_name" name="site_name" content="Frontiers"><meta data-n-head="ssr" data-hid="og:image" property="og:image" name="image" content="https://images-provider.frontiersin.org/api/ipx/w=1200&f=png/https://www.frontiersin.org/files/Articles/1145962/fphar-14-1145962-HTML-r3/image_m/fphar-14-1145962-g001.jpg"><meta data-n-head="ssr" data-hid="og:type" property="og:type" name="type" content="article"><meta data-n-head="ssr" data-hid="og:url" property="og:url" name="url" content="https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1145962/full"><meta data-n-head="ssr" data-hid="twitter:card" name="twitter:card" content="summary_large_image"><meta data-n-head="ssr" data-hid="citation_volume" name="citation_volume" content="14"><meta data-n-head="ssr" data-hid="citation_journal_title" name="citation_journal_title" content="Frontiers in Pharmacology"><meta data-n-head="ssr" data-hid="citation_publisher" name="citation_publisher" content="Frontiers"><meta data-n-head="ssr" data-hid="citation_journal_abbrev" name="citation_journal_abbrev" content="Front. Pharmacol."><meta data-n-head="ssr" data-hid="citation_issn" name="citation_issn" content="1663-9812"><meta data-n-head="ssr" data-hid="citation_doi" name="citation_doi" content="10.3389/fphar.2023.1145962"><meta data-n-head="ssr" data-hid="citation_firstpage" name="citation_firstpage" content="1145962"><meta data-n-head="ssr" data-hid="citation_language" name="citation_language" content="English"><meta data-n-head="ssr" data-hid="citation_title" name="citation_title" content="Determination of α1-acid glycoprotein (AGP) concentration by HPLC in patients following local infiltration analgesia for primary total hip arthroplasty and its relation to ropivacaine (total and unbound)"><meta data-n-head="ssr" data-hid="citation_keywords" name="citation_keywords" content="HPLC; α1-acid glycoprotein; human plasma; Hip joint surgery patients; Protein Binding"><meta data-n-head="ssr" data-hid="citation_abstract" name="citation_abstract" content="<p><bold>Introduction:</bold> This study was performed to determine the levels of α1-acid glycoprotein (AGP) in old-age patients undergoing total hip arthroplasty. AGP is considered an acute phase protein produced during the acute phase reaction in the body to various stimuli; their proper monitoring is thus important.</p><p><bold>Methods:</bold> In order to study how AGP concentrations in old age patients change in response to surgical stress (total hip arthroplasty), a high-performance liquid chromatography assay was performed to measure AGP levels. AGP was isolated from the plasma by adding perchloric acid and was analyzed using PLRP-S 4000°A column. The mobile phase consisted of 1 mL TFA/L of water (Solvent A pH 2) and 1 mL TFA/L of acetonitrile (Solvent B). The gradient used was as follows: 0 min 18% B and 82% A, 15 min 60% B and 40% A, and 17 min 60% B and 40% A followed by column re-equilibration for 7 min before the next injection. AGP peak was obtained between 8.8 and 8.9 min. The method was fully optimised according to established guidelines.</p><p><bold>Results:</bold> The data obtained were analyzed on ChromQuest software. AGP concentrations were determined in all samples, including baseline and samples taken at different timed intervals. The peak for AGP was obtained between 8.8 and 8.9 min for both standard AGP and patient plasma. The graphs indicate that AGP concentration in almost all patient samples increased considerably, especially after 4 h and 24 h—for example, initial concentration in patient 1 was 10.36 mg/100 mL but, after 24 h, increased to 23.50 mg/100 mL. There was thus almost a 13 mg/100 mL increase in 24 h, which is confirmed by AGP concentration increasing after various conditions, including surgery. The increased plasma protein binding was comparatively associated with the unchanged free fraction of the drug.</p><p><bold>Conclusion:</bold> This surgically induced increase in AGP concentration resulted in increased plasma protein binding of the drug (ropivacaine), which in turn kept the free portion of ropivacaine stable during the postoperative period.</p>"><meta data-n-head="ssr" data-hid="citation_pdf_url" name="citation_pdf_url" content="https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1145962/pdf"><meta data-n-head="ssr" data-hid="citation_online_date" name="citation_online_date" content="2023/05/16"><meta data-n-head="ssr" data-hid="citation_publication_date" name="citation_publication_date" content="2023/06/26"><meta data-n-head="ssr" data-hid="citation_author_0" name="citation_author" content="Abbas, Muhammad"><meta data-n-head="ssr" data-hid="citation_author_institution_0" name="citation_author_institution" content="Department of Pharmacy, Pakistan"><meta data-n-head="ssr" data-hid="citation_author_1" name="citation_author" content="Alossaimi, Manal A."><meta data-n-head="ssr" data-hid="citation_author_institution_1" name="citation_author_institution" content="Department of Pharmaceutical Chemistry, Saudi Arabia"><meta data-n-head="ssr" data-hid="citation_author_2" name="citation_author" content="Altamimi, Abdulmalik S. A."><meta data-n-head="ssr" data-hid="citation_author_institution_2" name="citation_author_institution" content="Department of Pharmaceutical Chemistry, Saudi Arabia"><meta data-n-head="ssr" data-hid="citation_author_3" name="citation_author" content="Alajaji, Mai"><meta data-n-head="ssr" data-hid="citation_author_institution_3" name="citation_author_institution" content="College of Pharmacy, Saudi Arabia"><meta data-n-head="ssr" data-hid="citation_author_4" name="citation_author" content="Watson, David G."><meta data-n-head="ssr" data-hid="citation_author_institution_4" name="citation_author_institution" content="Strathclyde Institute of Pharmacy and Biomedical Sciences, United Kingdom"><meta data-n-head="ssr" data-hid="citation_author_5" name="citation_author" content="Shah, Sayyed I."><meta data-n-head="ssr" data-hid="citation_author_institution_5" name="citation_author_institution" content="Department of Pharmacy, Pakistan"><meta data-n-head="ssr" data-hid="citation_author_6" name="citation_author" content="Shah, Yasar"><meta data-n-head="ssr" data-hid="citation_author_institution_6" name="citation_author_institution" content="Department of Pharmacy, Pakistan"><meta data-n-head="ssr" data-hid="citation_author_7" name="citation_author" content="Anwar, Mohammad S."><meta data-n-head="ssr" data-hid="citation_author_institution_7" name="citation_author_institution" content="Department of Pharmacy, Pakistan"><meta data-n-head="ssr" data-hid="dc.identifier" name="dc.identifier" content="doi:10.3389/fphar.2023.1145962"><link data-n-head="ssr" rel="manifest" href="/article-pages/_nuxt/manifest.c499fc0a.json" data-hid="manifest"><link data-n-head="ssr" rel="canonical" href="https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1145962/full"><script data-n-head="ssr" data-hid="newrelic-browser-script" type="text/javascript">window.NREUM||(NREUM={});NREUM.info = {"agent":"","beacon":"bam.nr-data.net","errorBeacon":"bam.nr-data.net","licenseKey":"598a124f17","applicationID":"588603994","agentToken":null,"applicationTime":2.06482,"transactionName":"MQcDMkECCkNSW0YMWghNIgldDQFTRxd1IGFJTQ==","queueTime":0,"ttGuid":"501c4af784b5a76a"}; (window.NREUM||(NREUM={})).init={privacy:{cookies_enabled:true},ajax:{deny_list:["bam.nr-data.net"]},distributed_tracing:{enabled:true}};(window.NREUM||(NREUM={})).loader_config={agentID:"594400880",accountID:"230385",trustKey:"230385",xpid:"VgUHUl5WGwYIXFdSBAgOUg==",licenseKey:"598a124f17",applicationID:"588603994"};;/*! For license information please see nr-loader-spa-1.283.2.min.js.LICENSE.txt */ (()=>{var e,t,r={8122:(e,t,r)=>{"use strict";r.d(t,{a:()=>i});var n=r(944);function i(e,t){try{if(!e||"object"!=typeof e)return(0,n.R)(3);if(!t||"object"!=typeof t)return(0,n.R)(4);const r=Object.create(Object.getPrototypeOf(t),Object.getOwnPropertyDescriptors(t)),o=0===Object.keys(r).length?e:r;for(let a in o)if(void 0!==e[a])try{if(null===e[a]){r[a]=null;continue}Array.isArray(e[a])&&Array.isArray(t[a])?r[a]=Array.from(new Set([...e[a],...t[a]])):"object"==typeof e[a]&&"object"==typeof t[a]?r[a]=i(e[a],t[a]):r[a]=e[a]}catch(e){(0,n.R)(1,e)}return r}catch(e){(0,n.R)(2,e)}}},2555:(e,t,r)=>{"use strict";r.d(t,{Vp:()=>c,fn:()=>s,x1:()=>u});var n=r(384),i=r(8122);const o={beacon:n.NT.beacon,errorBeacon:n.NT.errorBeacon,licenseKey:void 0,applicationID:void 0,sa:void 0,queueTime:void 0,applicationTime:void 0,ttGuid:void 0,user:void 0,account:void 0,product:void 0,extra:void 0,jsAttributes:{},userAttributes:void 0,atts:void 0,transactionName:void 0,tNamePlain:void 0},a={};function s(e){try{const t=c(e);return!!t.licenseKey&&!!t.errorBeacon&&!!t.applicationID}catch(e){return!1}}function c(e){if(!e)throw new Error("All info objects require an agent identifier!");if(!a[e])throw new Error("Info for ".concat(e," was never set"));return a[e]}function u(e,t){if(!e)throw new Error("All info objects require an agent identifier!");a[e]=(0,i.a)(t,o);const r=(0,n.nY)(e);r&&(r.info=a[e])}},9417:(e,t,r)=>{"use strict";r.d(t,{D0:()=>h,gD:()=>g,xN:()=>p});var n=r(3333);const i=e=>{if(!e||"string"!=typeof e)return!1;try{document.createDocumentFragment().querySelector(e)}catch{return!1}return!0};var o=r(2614),a=r(944),s=r(384),c=r(8122);const u="[data-nr-mask]",d=()=>{const e={feature_flags:[],experimental:{marks:!1,measures:!1,resources:!1},mask_selector:"*",block_selector:"[data-nr-block]",mask_input_options:{color:!1,date:!1,"datetime-local":!1,email:!1,month:!1,number:!1,range:!1,search:!1,tel:!1,text:!1,time:!1,url:!1,week:!1,textarea:!1,select:!1,password:!0}};return{ajax:{deny_list:void 0,block_internal:!0,enabled:!0,autoStart:!0},distributed_tracing:{enabled:void 0,exclude_newrelic_header:void 0,cors_use_newrelic_header:void 0,cors_use_tracecontext_headers:void 0,allowed_origins:void 0},get feature_flags(){return e.feature_flags},set feature_flags(t){e.feature_flags=t},generic_events:{enabled:!0,autoStart:!0},harvest:{interval:30},jserrors:{enabled:!0,autoStart:!0},logging:{enabled:!0,autoStart:!0},metrics:{enabled:!0,autoStart:!0},obfuscate:void 0,page_action:{enabled:!0},page_view_event:{enabled:!0,autoStart:!0},page_view_timing:{enabled:!0,autoStart:!0},performance:{get capture_marks(){return e.feature_flags.includes(n.$v.MARKS)||e.experimental.marks},set capture_marks(t){e.experimental.marks=t},get capture_measures(){return e.feature_flags.includes(n.$v.MEASURES)||e.experimental.measures},set capture_measures(t){e.experimental.measures=t},capture_detail:!0,resources:{get enabled(){return e.feature_flags.includes(n.$v.RESOURCES)||e.experimental.resources},set enabled(t){e.experimental.resources=t},asset_types:[],first_party_domains:[],ignore_newrelic:!0}},privacy:{cookies_enabled:!0},proxy:{assets:void 0,beacon:void 0},session:{expiresMs:o.wk,inactiveMs:o.BB},session_replay:{autoStart:!0,enabled:!1,preload:!1,sampling_rate:10,error_sampling_rate:100,collect_fonts:!1,inline_images:!1,fix_stylesheets:!0,mask_all_inputs:!0,get mask_text_selector(){return e.mask_selector},set mask_text_selector(t){i(t)?e.mask_selector="".concat(t,",").concat(u):""===t||null===t?e.mask_selector=u:(0,a.R)(5,t)},get block_class(){return"nr-block"},get ignore_class(){return"nr-ignore"},get mask_text_class(){return"nr-mask"},get block_selector(){return e.block_selector},set block_selector(t){i(t)?e.block_selector+=",".concat(t):""!==t&&(0,a.R)(6,t)},get mask_input_options(){return e.mask_input_options},set mask_input_options(t){t&&"object"==typeof t?e.mask_input_options={...t,password:!0}:(0,a.R)(7,t)}},session_trace:{enabled:!0,autoStart:!0},soft_navigations:{enabled:!0,autoStart:!0},spa:{enabled:!0,autoStart:!0},ssl:void 0,user_actions:{enabled:!0,elementAttributes:["id","className","tagName","type"]}}},l={},f="All configuration objects require an agent identifier!";function h(e){if(!e)throw new Error(f);if(!l[e])throw new Error("Configuration for ".concat(e," was never set"));return l[e]}function p(e,t){if(!e)throw new Error(f);l[e]=(0,c.a)(t,d());const r=(0,s.nY)(e);r&&(r.init=l[e])}function g(e,t){if(!e)throw new Error(f);var r=h(e);if(r){for(var n=t.split("."),i=0;i<n.length-1;i++)if("object"!=typeof(r=r[n[i]]))return;r=r[n[n.length-1]]}return r}},5603:(e,t,r)=>{"use strict";r.d(t,{a:()=>c,o:()=>s});var n=r(384),i=r(8122);const o={accountID:void 0,trustKey:void 0,agentID:void 0,licenseKey:void 0,applicationID:void 0,xpid:void 0},a={};function s(e){if(!e)throw new Error("All loader-config objects require an agent identifier!");if(!a[e])throw new Error("LoaderConfig for ".concat(e," was never set"));return a[e]}function c(e,t){if(!e)throw new Error("All loader-config objects require an agent identifier!");a[e]=(0,i.a)(t,o);const r=(0,n.nY)(e);r&&(r.loader_config=a[e])}},3371:(e,t,r)=>{"use strict";r.d(t,{V:()=>f,f:()=>l});var n=r(8122),i=r(384),o=r(6154),a=r(9324);let s=0;const c={buildEnv:a.F3,distMethod:a.Xs,version:a.xv,originTime:o.WN},u={customTransaction:void 0,disabled:!1,isolatedBacklog:!1,loaderType:void 0,maxBytes:3e4,onerror:void 0,ptid:void 0,releaseIds:{},appMetadata:{},session:void 0,denyList:void 0,timeKeeper:void 0,obfuscator:void 0,harvester:void 0},d={};function l(e){if(!e)throw new Error("All runtime objects require an agent identifier!");if(!d[e])throw new Error("Runtime for ".concat(e," was never set"));return d[e]}function f(e,t){if(!e)throw new Error("All runtime objects require an agent identifier!");d[e]={...(0,n.a)(t,u),...c},Object.hasOwnProperty.call(d[e],"harvestCount")||Object.defineProperty(d[e],"harvestCount",{get:()=>++s});const r=(0,i.nY)(e);r&&(r.runtime=d[e])}},9324:(e,t,r)=>{"use strict";r.d(t,{F3:()=>i,Xs:()=>o,Yq:()=>a,xv:()=>n});const n="1.283.2",i="PROD",o="CDN",a="^2.0.0-alpha.17"},6154:(e,t,r)=>{"use strict";r.d(t,{A4:()=>s,OF:()=>d,RI:()=>i,WN:()=>h,bv:()=>o,gm:()=>a,lR:()=>f,m:()=>u,mw:()=>c,sb:()=>l});var n=r(1863);const i="undefined"!=typeof window&&!!window.document,o="undefined"!=typeof WorkerGlobalScope&&("undefined"!=typeof self&&self instanceof WorkerGlobalScope&&self.navigator instanceof WorkerNavigator||"undefined"!=typeof globalThis&&globalThis instanceof WorkerGlobalScope&&globalThis.navigator instanceof WorkerNavigator),a=i?window:"undefined"!=typeof WorkerGlobalScope&&("undefined"!=typeof self&&self instanceof WorkerGlobalScope&&self||"undefined"!=typeof globalThis&&globalThis instanceof WorkerGlobalScope&&globalThis),s="complete"===a?.document?.readyState,c=Boolean("hidden"===a?.document?.visibilityState),u=""+a?.location,d=/iPad|iPhone|iPod/.test(a.navigator?.userAgent),l=d&&"undefined"==typeof SharedWorker,f=(()=>{const e=a.navigator?.userAgent?.match(/Firefox[/\s](\d+\.\d+)/);return Array.isArray(e)&&e.length>=2?+e[1]:0})(),h=Date.now()-(0,n.t)()},7295:(e,t,r)=>{"use strict";r.d(t,{Xv:()=>a,gX:()=>i,iW:()=>o});var n=[];function i(e){if(!e||o(e))return!1;if(0===n.length)return!0;for(var t=0;t<n.length;t++){var r=n[t];if("*"===r.hostname)return!1;if(s(r.hostname,e.hostname)&&c(r.pathname,e.pathname))return!1}return!0}function o(e){return void 0===e.hostname}function a(e){if(n=[],e&&e.length)for(var t=0;t<e.length;t++){let r=e[t];if(!r)continue;0===r.indexOf("http://")?r=r.substring(7):0===r.indexOf("https://")&&(r=r.substring(8));const i=r.indexOf("/");let o,a;i>0?(o=r.substring(0,i),a=r.substring(i)):(o=r,a="");let[s]=o.split(":");n.push({hostname:s,pathname:a})}}function s(e,t){return!(e.length>t.length)&&t.indexOf(e)===t.length-e.length}function c(e,t){return 0===e.indexOf("/")&&(e=e.substring(1)),0===t.indexOf("/")&&(t=t.substring(1)),""===e||e===t}},1687:(e,t,r)=>{"use strict";r.d(t,{Ak:()=>c,Ze:()=>l,x3:()=>u});var n=r(7836),i=r(3606),o=r(860),a=r(2646);const s={};function c(e,t){const r={staged:!1,priority:o.P3[t]||0};d(e),s[e].get(t)||s[e].set(t,r)}function u(e,t){e&&s[e]&&(s[e].get(t)&&s[e].delete(t),h(e,t,!1),s[e].size&&f(e))}function d(e){if(!e)throw new Error("agentIdentifier required");s[e]||(s[e]=new Map)}function l(e="",t="feature",r=!1){if(d(e),!e||!s[e].get(t)||r)return h(e,t);s[e].get(t).staged=!0,f(e)}function f(e){const t=Array.from(s[e]);t.every((([e,t])=>t.staged))&&(t.sort(((e,t)=>e[1].priority-t[1].priority)),t.forEach((([t])=>{s[e].delete(t),h(e,t)})))}function h(e,t,r=!0){const o=e?n.ee.get(e):n.ee,s=i.i.handlers;if(!o.aborted&&o.backlog&&s){if(r){const e=o.backlog[t],r=s[t];if(r){for(let t=0;e&&t<e.length;++t)p(e[t],r);Object.entries(r).forEach((([e,t])=>{Object.values(t||{}).forEach((t=>{t[0]?.on&&t[0]?.context()instanceof a.y&&t[0].on(e,t[1])}))}))}}o.isolatedBacklog||delete s[t],o.backlog[t]=null,o.emit("drain-"+t,[])}}function p(e,t){var r=e[1];Object.values(t[r]||{}).forEach((t=>{var r=e[0];if(t[0]===r){var n=t[1],i=e[3],o=e[2];n.apply(i,o)}}))}},7836:(e,t,r)=>{"use strict";r.d(t,{P:()=>c,ee:()=>u});var n=r(384),i=r(8990),o=r(3371),a=r(2646),s=r(5607);const c="nr@context:".concat(s.W),u=function e(t,r){var n={},s={},d={},l=!1;try{l=16===r.length&&(0,o.f)(r).isolatedBacklog}catch(e){}var f={on:p,addEventListener:p,removeEventListener:function(e,t){var r=n[e];if(!r)return;for(var i=0;i<r.length;i++)r[i]===t&&r.splice(i,1)},emit:function(e,r,n,i,o){!1!==o&&(o=!0);if(u.aborted&&!i)return;t&&o&&t.emit(e,r,n);for(var a=h(n),c=g(e),d=c.length,l=0;l<d;l++)c[l].apply(a,r);var p=v()[s[e]];p&&p.push([f,e,r,a]);return a},get:m,listeners:g,context:h,buffer:function(e,t){const r=v();if(t=t||"feature",f.aborted)return;Object.entries(e||{}).forEach((([e,n])=>{s[n]=t,t in r||(r[t]=[])}))},abort:function(){f._aborted=!0,Object.keys(f.backlog).forEach((e=>{delete f.backlog[e]}))},isBuffering:function(e){return!!v()[s[e]]},debugId:r,backlog:l?{}:t&&"object"==typeof t.backlog?t.backlog:{},isolatedBacklog:l};return Object.defineProperty(f,"aborted",{get:()=>{let e=f._aborted||!1;return e||(t&&(e=t.aborted),e)}}),f;function h(e){return e&&e instanceof a.y?e:e?(0,i.I)(e,c,(()=>new a.y(c))):new a.y(c)}function p(e,t){n[e]=g(e).concat(t)}function g(e){return n[e]||[]}function m(t){return d[t]=d[t]||e(f,t)}function v(){return f.backlog}}(void 0,"globalEE"),d=(0,n.Zm)();d.ee||(d.ee=u)},2646:(e,t,r)=>{"use strict";r.d(t,{y:()=>n});class n{constructor(e){this.contextId=e}}},9908:(e,t,r)=>{"use strict";r.d(t,{d:()=>n,p:()=>i});var n=r(7836).ee.get("handle");function i(e,t,r,i,o){o?(o.buffer([e],i),o.emit(e,t,r)):(n.buffer([e],i),n.emit(e,t,r))}},3606:(e,t,r)=>{"use strict";r.d(t,{i:()=>o});var n=r(9908);o.on=a;var i=o.handlers={};function o(e,t,r,o){a(o||n.d,i,e,t,r)}function a(e,t,r,i,o){o||(o="feature"),e||(e=n.d);var a=t[o]=t[o]||{};(a[r]=a[r]||[]).push([e,i])}},3878:(e,t,r)=>{"use strict";function n(e,t){return{capture:e,passive:!1,signal:t}}function i(e,t,r=!1,i){window.addEventListener(e,t,n(r,i))}function o(e,t,r=!1,i){document.addEventListener(e,t,n(r,i))}r.d(t,{DD:()=>o,jT:()=>n,sp:()=>i})},5607:(e,t,r)=>{"use strict";r.d(t,{W:()=>n});const n=(0,r(9566).bz)()},9566:(e,t,r)=>{"use strict";r.d(t,{LA:()=>s,ZF:()=>c,bz:()=>a,el:()=>u});var n=r(6154);const i="xxxxxxxx-xxxx-4xxx-yxxx-xxxxxxxxxxxx";function o(e,t){return e?15&e[t]:16*Math.random()|0}function a(){const e=n.gm?.crypto||n.gm?.msCrypto;let t,r=0;return e&&e.getRandomValues&&(t=e.getRandomValues(new Uint8Array(30))),i.split("").map((e=>"x"===e?o(t,r++).toString(16):"y"===e?(3&o()|8).toString(16):e)).join("")}function s(e){const t=n.gm?.crypto||n.gm?.msCrypto;let r,i=0;t&&t.getRandomValues&&(r=t.getRandomValues(new Uint8Array(e)));const a=[];for(var s=0;s<e;s++)a.push(o(r,i++).toString(16));return a.join("")}function c(){return s(16)}function u(){return s(32)}},2614:(e,t,r)=>{"use strict";r.d(t,{BB:()=>a,H3:()=>n,g:()=>u,iL:()=>c,tS:()=>s,uh:()=>i,wk:()=>o});const n="NRBA",i="SESSION",o=144e5,a=18e5,s={STARTED:"session-started",PAUSE:"session-pause",RESET:"session-reset",RESUME:"session-resume",UPDATE:"session-update"},c={SAME_TAB:"same-tab",CROSS_TAB:"cross-tab"},u={OFF:0,FULL:1,ERROR:2}},1863:(e,t,r)=>{"use strict";function n(){return Math.floor(performance.now())}r.d(t,{t:()=>n})},7485:(e,t,r)=>{"use strict";r.d(t,{D:()=>i});var n=r(6154);function i(e){if(0===(e||"").indexOf("data:"))return{protocol:"data"};try{const t=new URL(e,location.href),r={port:t.port,hostname:t.hostname,pathname:t.pathname,search:t.search,protocol:t.protocol.slice(0,t.protocol.indexOf(":")),sameOrigin:t.protocol===n.gm?.location?.protocol&&t.host===n.gm?.location?.host};return r.port&&""!==r.port||("http:"===t.protocol&&(r.port="80"),"https:"===t.protocol&&(r.port="443")),r.pathname&&""!==r.pathname?r.pathname.startsWith("/")||(r.pathname="/".concat(r.pathname)):r.pathname="/",r}catch(e){return{}}}},944:(e,t,r)=>{"use strict";function n(e,t){"function"==typeof console.debug&&console.debug("New Relic Warning: https://github.com/newrelic/newrelic-browser-agent/blob/main/docs/warning-codes.md#".concat(e),t)}r.d(t,{R:()=>n})},5284:(e,t,r)=>{"use strict";r.d(t,{t:()=>c,B:()=>s});var n=r(7836),i=r(6154);const o="newrelic";const a=new Set,s={};function c(e,t){const r=n.ee.get(t);s[t]??={},e&&"object"==typeof e&&(a.has(t)||(r.emit("rumresp",[e]),s[t]=e,a.add(t),function(e={}){try{i.gm.dispatchEvent(new CustomEvent(o,{detail:e}))}catch(e){}}({loaded:!0})))}},8990:(e,t,r)=>{"use strict";r.d(t,{I:()=>i});var n=Object.prototype.hasOwnProperty;function i(e,t,r){if(n.call(e,t))return e[t];var i=r();if(Object.defineProperty&&Object.keys)try{return Object.defineProperty(e,t,{value:i,writable:!0,enumerable:!1}),i}catch(e){}return e[t]=i,i}},6389:(e,t,r)=>{"use strict";function n(e,t=500,r={}){const n=r?.leading||!1;let i;return(...r)=>{n&&void 0===i&&(e.apply(this,r),i=setTimeout((()=>{i=clearTimeout(i)}),t)),n||(clearTimeout(i),i=setTimeout((()=>{e.apply(this,r)}),t))}}function i(e){let t=!1;return(...r)=>{t||(t=!0,e.apply(this,r))}}r.d(t,{J:()=>i,s:()=>n})},3304:(e,t,r)=>{"use strict";r.d(t,{A:()=>o});var n=r(7836);const i=()=>{const e=new WeakSet;return(t,r)=>{if("object"==typeof r&&null!==r){if(e.has(r))return;e.add(r)}return r}};function o(e){try{return JSON.stringify(e,i())??""}catch(e){try{n.ee.emit("internal-error",[e])}catch(e){}return""}}},5289:(e,t,r)=>{"use strict";r.d(t,{GG:()=>o,sB:()=>a});var n=r(3878);function i(){return"undefined"==typeof document||"complete"===document.readyState}function o(e,t){if(i())return e();(0,n.sp)("load",e,t)}function a(e){if(i())return e();(0,n.DD)("DOMContentLoaded",e)}},384:(e,t,r)=>{"use strict";r.d(t,{NT:()=>o,US:()=>d,Zm:()=>a,bQ:()=>c,dV:()=>s,nY:()=>u,pV:()=>l});var n=r(6154),i=r(1863);const o={beacon:"bam.nr-data.net",errorBeacon:"bam.nr-data.net"};function a(){return n.gm.NREUM||(n.gm.NREUM={}),void 0===n.gm.newrelic&&(n.gm.newrelic=n.gm.NREUM),n.gm.NREUM}function s(){let e=a();return e.o||(e.o={ST:n.gm.setTimeout,SI:n.gm.setImmediate,CT:n.gm.clearTimeout,XHR:n.gm.XMLHttpRequest,REQ:n.gm.Request,EV:n.gm.Event,PR:n.gm.Promise,MO:n.gm.MutationObserver,FETCH:n.gm.fetch,WS:n.gm.WebSocket}),e}function c(e,t){let r=a();r.initializedAgents??={},t.initializedAt={ms:(0,i.t)(),date:new Date},r.initializedAgents[e]=t}function u(e){let t=a();return t.initializedAgents?.[e]}function d(e,t){a()[e]=t}function l(){return function(){let e=a();const t=e.info||{};e.info={beacon:o.beacon,errorBeacon:o.errorBeacon,...t}}(),function(){let e=a();const t=e.init||{};e.init={...t}}(),s(),function(){let e=a();const t=e.loader_config||{};e.loader_config={...t}}(),a()}},2843:(e,t,r)=>{"use strict";r.d(t,{u:()=>i});var n=r(3878);function i(e,t=!1,r,i){(0,n.DD)("visibilitychange",(function(){if(t)return void("hidden"===document.visibilityState&&e());e(document.visibilityState)}),r,i)}},8139:(e,t,r)=>{"use strict";r.d(t,{u:()=>f});var n=r(7836),i=r(3434),o=r(8990),a=r(6154);const s={},c=a.gm.XMLHttpRequest,u="addEventListener",d="removeEventListener",l="nr@wrapped:".concat(n.P);function f(e){var t=function(e){return(e||n.ee).get("events")}(e);if(s[t.debugId]++)return t;s[t.debugId]=1;var r=(0,i.YM)(t,!0);function f(e){r.inPlace(e,[u,d],"-",p)}function p(e,t){return e[1]}return"getPrototypeOf"in Object&&(a.RI&&h(document,f),c&&h(c.prototype,f),h(a.gm,f)),t.on(u+"-start",(function(e,t){var n=e[1];if(null!==n&&("function"==typeof n||"object"==typeof n)){var i=(0,o.I)(n,l,(function(){var e={object:function(){if("function"!=typeof n.handleEvent)return;return n.handleEvent.apply(n,arguments)},function:n}[typeof n];return e?r(e,"fn-",null,e.name||"anonymous"):n}));this.wrapped=e[1]=i}})),t.on(d+"-start",(function(e){e[1]=this.wrapped||e[1]})),t}function h(e,t,...r){let n=e;for(;"object"==typeof n&&!Object.prototype.hasOwnProperty.call(n,u);)n=Object.getPrototypeOf(n);n&&t(n,...r)}},3434:(e,t,r)=>{"use strict";r.d(t,{Jt:()=>o,YM:()=>c});var n=r(7836),i=r(5607);const o="nr@original:".concat(i.W);var a=Object.prototype.hasOwnProperty,s=!1;function c(e,t){return e||(e=n.ee),r.inPlace=function(e,t,n,i,o){n||(n="");const a="-"===n.charAt(0);for(let s=0;s<t.length;s++){const c=t[s],u=e[c];d(u)||(e[c]=r(u,a?c+n:n,i,c,o))}},r.flag=o,r;function r(t,r,n,s,c){return d(t)?t:(r||(r=""),nrWrapper[o]=t,function(e,t,r){if(Object.defineProperty&&Object.keys)try{return Object.keys(e).forEach((function(r){Object.defineProperty(t,r,{get:function(){return e[r]},set:function(t){return e[r]=t,t}})})),t}catch(e){u([e],r)}for(var n in e)a.call(e,n)&&(t[n]=e[n])}(t,nrWrapper,e),nrWrapper);function nrWrapper(){var o,a,d,l;try{a=this,o=[...arguments],d="function"==typeof n?n(o,a):n||{}}catch(t){u([t,"",[o,a,s],d],e)}i(r+"start",[o,a,s],d,c);try{return l=t.apply(a,o)}catch(e){throw i(r+"err",[o,a,e],d,c),e}finally{i(r+"end",[o,a,l],d,c)}}}function i(r,n,i,o){if(!s||t){var a=s;s=!0;try{e.emit(r,n,i,t,o)}catch(t){u([t,r,n,i],e)}s=a}}}function u(e,t){t||(t=n.ee);try{t.emit("internal-error",e)}catch(e){}}function d(e){return!(e&&"function"==typeof e&&e.apply&&!e[o])}},9414:(e,t,r)=>{"use strict";r.d(t,{J:()=>c});var n=r(7836),i=r(2646),o=r(944),a=r(3434);const s=new Map;function c(e,t,r,c){if("object"!=typeof t||!t||"string"!=typeof r||!r||"function"!=typeof t[r])return(0,o.R)(29);const u=function(e){return(e||n.ee).get("logger")}(e),d=(0,a.YM)(u),l=new i.y(n.P);l.level=c.level,l.customAttributes=c.customAttributes;const f=t[r]?.[a.Jt]||t[r];return s.set(f,l),d.inPlace(t,[r],"wrap-logger-",(()=>s.get(f))),u}},9300:(e,t,r)=>{"use strict";r.d(t,{T:()=>n});const n=r(860).K7.ajax},3333:(e,t,r)=>{"use strict";r.d(t,{$v:()=>u,TZ:()=>n,Zp:()=>i,kd:()=>c,mq:()=>s,nf:()=>a,qN:()=>o});const n=r(860).K7.genericEvents,i=["auxclick","click","copy","keydown","paste","scrollend"],o=["focus","blur"],a=4,s=1e3,c=["PageAction","UserAction","BrowserPerformance"],u={MARKS:"experimental.marks",MEASURES:"experimental.measures",RESOURCES:"experimental.resources"}},6774:(e,t,r)=>{"use strict";r.d(t,{T:()=>n});const n=r(860).K7.jserrors},993:(e,t,r)=>{"use strict";r.d(t,{A$:()=>o,ET:()=>a,TZ:()=>s,p_:()=>i});var n=r(860);const i={ERROR:"ERROR",WARN:"WARN",INFO:"INFO",DEBUG:"DEBUG",TRACE:"TRACE"},o={OFF:0,ERROR:1,WARN:2,INFO:3,DEBUG:4,TRACE:5},a="log",s=n.K7.logging},3785:(e,t,r)=>{"use strict";r.d(t,{R:()=>c,b:()=>u});var n=r(9908),i=r(1863),o=r(860),a=r(8154),s=r(993);function c(e,t,r={},c=s.p_.INFO){(0,n.p)(a.xV,["API/logging/".concat(c.toLowerCase(),"/called")],void 0,o.K7.metrics,e),(0,n.p)(s.ET,[(0,i.t)(),t,r,c],void 0,o.K7.logging,e)}function u(e){return"string"==typeof e&&Object.values(s.p_).some((t=>t===e.toUpperCase().trim()))}},8154:(e,t,r)=>{"use strict";r.d(t,{z_:()=>o,XG:()=>s,TZ:()=>n,rs:()=>i,xV:()=>a});r(6154),r(9566),r(384);const n=r(860).K7.metrics,i="sm",o="cm",a="storeSupportabilityMetrics",s="storeEventMetrics"},6630:(e,t,r)=>{"use strict";r.d(t,{T:()=>n});const n=r(860).K7.pageViewEvent},782:(e,t,r)=>{"use strict";r.d(t,{T:()=>n});const n=r(860).K7.pageViewTiming},6344:(e,t,r)=>{"use strict";r.d(t,{BB:()=>d,G4:()=>o,Qb:()=>l,TZ:()=>i,Ug:()=>a,_s:()=>s,bc:()=>u,yP:()=>c});var n=r(2614);const i=r(860).K7.sessionReplay,o={RECORD:"recordReplay",PAUSE:"pauseReplay",REPLAY_RUNNING:"replayRunning",ERROR_DURING_REPLAY:"errorDuringReplay"},a=.12,s={DomContentLoaded:0,Load:1,FullSnapshot:2,IncrementalSnapshot:3,Meta:4,Custom:5},c={[n.g.ERROR]:15e3,[n.g.FULL]:3e5,[n.g.OFF]:0},u={RESET:{message:"Session was reset",sm:"Reset"},IMPORT:{message:"Recorder failed to import",sm:"Import"},TOO_MANY:{message:"429: Too Many Requests",sm:"Too-Many"},TOO_BIG:{message:"Payload was too large",sm:"Too-Big"},CROSS_TAB:{message:"Session Entity was set to OFF on another tab",sm:"Cross-Tab"},ENTITLEMENTS:{message:"Session Replay is not allowed and will not be started",sm:"Entitlement"}},d=5e3,l={API:"api"}},5270:(e,t,r)=>{"use strict";r.d(t,{Aw:()=>c,CT:()=>u,SR:()=>s});var n=r(384),i=r(9417),o=r(7767),a=r(6154);function s(e){return!!(0,n.dV)().o.MO&&(0,o.V)(e)&&!0===(0,i.gD)(e,"session_trace.enabled")}function c(e){return!0===(0,i.gD)(e,"session_replay.preload")&&s(e)}function u(e,t){const r=t.correctAbsoluteTimestamp(e);return{originalTimestamp:e,correctedTimestamp:r,timestampDiff:e-r,originTime:a.WN,correctedOriginTime:t.correctedOriginTime,originTimeDiff:Math.floor(a.WN-t.correctedOriginTime)}}},3738:(e,t,r)=>{"use strict";r.d(t,{He:()=>i,Kp:()=>s,Lc:()=>u,Rz:()=>d,TZ:()=>n,bD:()=>o,d3:()=>a,jx:()=>l,uP:()=>c});const n=r(860).K7.sessionTrace,i="bstResource",o="resource",a="-start",s="-end",c="fn"+a,u="fn"+s,d="pushState",l=1e3},3962:(e,t,r)=>{"use strict";r.d(t,{AM:()=>o,O2:()=>c,Qu:()=>u,TZ:()=>s,ih:()=>d,pP:()=>a,tC:()=>i});var n=r(860);const i=["click","keydown","submit","popstate"],o="api",a="initialPageLoad",s=n.K7.softNav,c={INITIAL_PAGE_LOAD:"",ROUTE_CHANGE:1,UNSPECIFIED:2},u={INTERACTION:1,AJAX:2,CUSTOM_END:3,CUSTOM_TRACER:4},d={IP:"in progress",FIN:"finished",CAN:"cancelled"}},7378:(e,t,r)=>{"use strict";r.d(t,{$p:()=>x,BR:()=>b,Kp:()=>R,L3:()=>y,Lc:()=>c,NC:()=>o,SG:()=>d,TZ:()=>i,U6:()=>p,UT:()=>m,d3:()=>w,dT:()=>f,e5:()=>A,gx:()=>v,l9:()=>l,oW:()=>h,op:()=>g,rw:()=>u,tH:()=>T,uP:()=>s,wW:()=>E,xq:()=>a});var n=r(384);const i=r(860).K7.spa,o=["click","submit","keypress","keydown","keyup","change"],a=999,s="fn-start",c="fn-end",u="cb-start",d="api-ixn-",l="remaining",f="interaction",h="spaNode",p="jsonpNode",g="fetch-start",m="fetch-done",v="fetch-body-",b="jsonp-end",y=(0,n.dV)().o.ST,w="-start",R="-end",x="-body",E="cb"+R,A="jsTime",T="fetch"},4234:(e,t,r)=>{"use strict";r.d(t,{W:()=>o});var n=r(7836),i=r(1687);class o{constructor(e,t){this.agentIdentifier=e,this.ee=n.ee.get(e),this.featureName=t,this.blocked=!1}deregisterDrain(){(0,i.x3)(this.agentIdentifier,this.featureName)}}},7767:(e,t,r)=>{"use strict";r.d(t,{V:()=>o});var n=r(9417),i=r(6154);const o=e=>i.RI&&!0===(0,n.gD)(e,"privacy.cookies_enabled")},8969:(e,t,r)=>{"use strict";r.d(t,{j:()=>O});var n=r(860),i=r(2555),o=r(3371),a=r(9908),s=r(7836),c=r(1687),u=r(5289),d=r(6154),l=r(944),f=r(8154),h=r(384),p=r(6344);const g=["setErrorHandler","finished","addToTrace","addRelease","recordCustomEvent","addPageAction","setCurrentRouteName","setPageViewName","setCustomAttribute","interaction","noticeError","setUserId","setApplicationVersion","start",p.G4.RECORD,p.G4.PAUSE,"log","wrapLogger"],m=["setErrorHandler","finished","addToTrace","addRelease"];var v=r(1863),b=r(2614),y=r(993),w=r(3785),R=r(9414);function x(){const e=(0,h.pV)();g.forEach((t=>{e[t]=(...r)=>function(t,...r){let n=[];return Object.values(e.initializedAgents).forEach((e=>{e&&e.api?e.exposed&&e.api[t]&&n.push(e.api[t](...r)):(0,l.R)(38,t)})),n.length>1?n:n[0]}(t,...r)}))}const E={};var A=r(9417),T=r(5603),N=r(5284);const S=e=>{const t=e.startsWith("http");e+="/",r.p=t?e:"https://"+e};let _=!1;function O(e,t={},g,O){let{init:I,info:P,loader_config:j,runtime:C={},exposed:k=!0}=t;C.loaderType=g;const L=(0,h.pV)();P||(I=L.init,P=L.info,j=L.loader_config),(0,A.xN)(e.agentIdentifier,I||{}),(0,T.a)(e.agentIdentifier,j||{}),P.jsAttributes??={},d.bv&&(P.jsAttributes.isWorker=!0),(0,i.x1)(e.agentIdentifier,P);const H=(0,A.D0)(e.agentIdentifier),M=[P.beacon,P.errorBeacon];_||(H.proxy.assets&&(S(H.proxy.assets),M.push(H.proxy.assets)),H.proxy.beacon&&M.push(H.proxy.beacon),x(),(0,h.US)("activatedFeatures",N.B),e.runSoftNavOverSpa&&=!0===H.soft_navigations.enabled&&H.feature_flags.includes("soft_nav")),C.denyList=[...H.ajax.deny_list||[],...H.ajax.block_internal?M:[]],C.ptid=e.agentIdentifier,(0,o.V)(e.agentIdentifier,C),e.ee=s.ee.get(e.agentIdentifier),void 0===e.api&&(e.api=function(e,t,h=!1){t||(0,c.Ak)(e,"api");const g={};var x=s.ee.get(e),A=x.get("tracer");E[e]=b.g.OFF,x.on(p.G4.REPLAY_RUNNING,(t=>{E[e]=t}));var T="api-",N=T+"ixn-";function S(t,r,n,o){const a=(0,i.Vp)(e);return null===r?delete a.jsAttributes[t]:(0,i.x1)(e,{...a,jsAttributes:{...a.jsAttributes,[t]:r}}),I(T,n,!0,o||null===r?"session":void 0)(t,r)}function _(){}g.log=function(e,{customAttributes:t={},level:r=y.p_.INFO}={}){(0,a.p)(f.xV,["API/log/called"],void 0,n.K7.metrics,x),(0,w.R)(x,e,t,r)},g.wrapLogger=(e,t,{customAttributes:r={},level:i=y.p_.INFO}={})=>{(0,a.p)(f.xV,["API/wrapLogger/called"],void 0,n.K7.metrics,x),(0,R.J)(x,e,t,{customAttributes:r,level:i})},m.forEach((e=>{g[e]=I(T,e,!0,"api")})),g.addPageAction=I(T,"addPageAction",!0,n.K7.genericEvents),g.recordCustomEvent=I(T,"recordCustomEvent",!0,n.K7.genericEvents),g.setPageViewName=function(t,r){if("string"==typeof t)return"/"!==t.charAt(0)&&(t="/"+t),(0,o.f)(e).customTransaction=(r||"http://custom.transaction")+t,I(T,"setPageViewName",!0)()},g.setCustomAttribute=function(e,t,r=!1){if("string"==typeof e){if(["string","number","boolean"].includes(typeof t)||null===t)return S(e,t,"setCustomAttribute",r);(0,l.R)(40,typeof t)}else(0,l.R)(39,typeof e)},g.setUserId=function(e){if("string"==typeof e||null===e)return S("enduser.id",e,"setUserId",!0);(0,l.R)(41,typeof e)},g.setApplicationVersion=function(e){if("string"==typeof e||null===e)return S("application.version",e,"setApplicationVersion",!1);(0,l.R)(42,typeof e)},g.start=()=>{try{(0,a.p)(f.xV,["API/start/called"],void 0,n.K7.metrics,x),x.emit("manual-start-all")}catch(e){(0,l.R)(23,e)}},g[p.G4.RECORD]=function(){(0,a.p)(f.xV,["API/recordReplay/called"],void 0,n.K7.metrics,x),(0,a.p)(p.G4.RECORD,[],void 0,n.K7.sessionReplay,x)},g[p.G4.PAUSE]=function(){(0,a.p)(f.xV,["API/pauseReplay/called"],void 0,n.K7.metrics,x),(0,a.p)(p.G4.PAUSE,[],void 0,n.K7.sessionReplay,x)},g.interaction=function(e){return(new _).get("object"==typeof e?e:{})};const O=_.prototype={createTracer:function(e,t){var r={},i=this,o="function"==typeof t;return(0,a.p)(f.xV,["API/createTracer/called"],void 0,n.K7.metrics,x),h||(0,a.p)(N+"tracer",[(0,v.t)(),e,r],i,n.K7.spa,x),function(){if(A.emit((o?"":"no-")+"fn-start",[(0,v.t)(),i,o],r),o)try{return t.apply(this,arguments)}catch(e){const t="string"==typeof e?new Error(e):e;throw A.emit("fn-err",[arguments,this,t],r),t}finally{A.emit("fn-end",[(0,v.t)()],r)}}}};function I(e,t,r,i){return function(){return(0,a.p)(f.xV,["API/"+t+"/called"],void 0,n.K7.metrics,x),i&&(0,a.p)(e+t,[r?(0,v.t)():performance.now(),...arguments],r?null:this,i,x),r?void 0:this}}function P(){r.e(478).then(r.bind(r,8778)).then((({setAPI:t})=>{t(e),(0,c.Ze)(e,"api")})).catch((e=>{(0,l.R)(27,e),x.abort()}))}return["actionText","setName","setAttribute","save","ignore","onEnd","getContext","end","get"].forEach((e=>{O[e]=I(N,e,void 0,h?n.K7.softNav:n.K7.spa)})),g.setCurrentRouteName=h?I(N,"routeName",void 0,n.K7.softNav):I(T,"routeName",!0,n.K7.spa),g.noticeError=function(t,r){"string"==typeof t&&(t=new Error(t)),(0,a.p)(f.xV,["API/noticeError/called"],void 0,n.K7.metrics,x),(0,a.p)("err",[t,(0,v.t)(),!1,r,!!E[e]],void 0,n.K7.jserrors,x)},d.RI?(0,u.GG)((()=>P()),!0):P(),g}(e.agentIdentifier,O,e.runSoftNavOverSpa)),void 0===e.exposed&&(e.exposed=k),_=!0}},8374:(e,t,r)=>{r.nc=(()=>{try{return document?.currentScript?.nonce}catch(e){}return""})()},860:(e,t,r)=>{"use strict";r.d(t,{$J:()=>u,K7:()=>s,P3:()=>c,XX:()=>i,qY:()=>n,v4:()=>a});const n="events",i="jserrors",o="browser/blobs",a="rum",s={ajax:"ajax",genericEvents:"generic_events",jserrors:i,logging:"logging",metrics:"metrics",pageAction:"page_action",pageViewEvent:"page_view_event",pageViewTiming:"page_view_timing",sessionReplay:"session_replay",sessionTrace:"session_trace",softNav:"soft_navigations",spa:"spa"},c={[s.pageViewEvent]:1,[s.pageViewTiming]:2,[s.metrics]:3,[s.jserrors]:4,[s.spa]:5,[s.ajax]:6,[s.sessionTrace]:7,[s.softNav]:8,[s.sessionReplay]:9,[s.logging]:10,[s.genericEvents]:11},u={[s.pageViewEvent]:a,[s.pageViewTiming]:n,[s.ajax]:n,[s.spa]:n,[s.softNav]:n,[s.metrics]:i,[s.jserrors]:i,[s.sessionTrace]:o,[s.sessionReplay]:o,[s.logging]:"browser/logs",[s.genericEvents]:"ins"}}},n={};function i(e){var t=n[e];if(void 0!==t)return t.exports;var o=n[e]={exports:{}};return r[e](o,o.exports,i),o.exports}i.m=r,i.d=(e,t)=>{for(var r in t)i.o(t,r)&&!i.o(e,r)&&Object.defineProperty(e,r,{enumerable:!0,get:t[r]})},i.f={},i.e=e=>Promise.all(Object.keys(i.f).reduce(((t,r)=>(i.f[r](e,t),t)),[])),i.u=e=>({212:"nr-spa-compressor",249:"nr-spa-recorder",478:"nr-spa"}[e]+"-1.283.2.min.js"),i.o=(e,t)=>Object.prototype.hasOwnProperty.call(e,t),e={},t="NRBA-1.283.2.PROD:",i.l=(r,n,o,a)=>{if(e[r])e[r].push(n);else{var s,c;if(void 0!==o)for(var u=document.getElementsByTagName("script"),d=0;d<u.length;d++){var l=u[d];if(l.getAttribute("src")==r||l.getAttribute("data-webpack")==t+o){s=l;break}}if(!s){c=!0;var f={478:"sha512-2oN05BjxuObKuOX8E0vq/zS51M+2HokmNPBRUrIC1fw3hpJqoI18/nckSFiqV11KxT7ag3C+FunKrR8n0PD9Ig==",249:"sha512-Zs5nIHr/khH6G8IhAEdnngg+P7y/IfmjU0PQmXABpCEtSTeKV22OYdaa9lENrW9uxI0lZ6O5e5dCnEMsTS0onA==",212:"sha512-LPKde7A1ZxIHzoSqWKxn5uWVhM9u76Vtmp9DMBf+Ry3mnn2jpsfyfigMYD5Yka2RG3NeIBqOwNYuPrWL39qn6w=="};(s=document.createElement("script")).charset="utf-8",s.timeout=120,i.nc&&s.setAttribute("nonce",i.nc),s.setAttribute("data-webpack",t+o),s.src=r,0!==s.src.indexOf(window.location.origin+"/")&&(s.crossOrigin="anonymous"),f[a]&&(s.integrity=f[a])}e[r]=[n];var h=(t,n)=>{s.onerror=s.onload=null,clearTimeout(p);var i=e[r];if(delete e[r],s.parentNode&&s.parentNode.removeChild(s),i&&i.forEach((e=>e(n))),t)return t(n)},p=setTimeout(h.bind(null,void 0,{type:"timeout",target:s}),12e4);s.onerror=h.bind(null,s.onerror),s.onload=h.bind(null,s.onload),c&&document.head.appendChild(s)}},i.r=e=>{"undefined"!=typeof Symbol&&Symbol.toStringTag&&Object.defineProperty(e,Symbol.toStringTag,{value:"Module"}),Object.defineProperty(e,"__esModule",{value:!0})},i.p="https://js-agent.newrelic.com/",(()=>{var e={38:0,788:0};i.f.j=(t,r)=>{var n=i.o(e,t)?e[t]:void 0;if(0!==n)if(n)r.push(n[2]);else{var o=new Promise(((r,i)=>n=e[t]=[r,i]));r.push(n[2]=o);var a=i.p+i.u(t),s=new Error;i.l(a,(r=>{if(i.o(e,t)&&(0!==(n=e[t])&&(e[t]=void 0),n)){var o=r&&("load"===r.type?"missing":r.type),a=r&&r.target&&r.target.src;s.message="Loading chunk "+t+" failed.\n("+o+": "+a+")",s.name="ChunkLoadError",s.type=o,s.request=a,n[1](s)}}),"chunk-"+t,t)}};var t=(t,r)=>{var n,o,[a,s,c]=r,u=0;if(a.some((t=>0!==e[t]))){for(n in s)i.o(s,n)&&(i.m[n]=s[n]);if(c)c(i)}for(t&&t(r);u<a.length;u++)o=a[u],i.o(e,o)&&e[o]&&e[o][0](),e[o]=0},r=self["webpackChunk:NRBA-1.283.2.PROD"]=self["webpackChunk:NRBA-1.283.2.PROD"]||[];r.forEach(t.bind(null,0)),r.push=t.bind(null,r.push.bind(r))})(),(()=>{"use strict";i(8374);var e=i(944),t=i(6344),r=i(9566);class n{agentIdentifier;constructor(){this.agentIdentifier=(0,r.LA)(16)}#e(t,...r){if("function"==typeof this.api?.[t])return this.api[t](...r);(0,e.R)(35,t)}addPageAction(e,t){return this.#e("addPageAction",e,t)}recordCustomEvent(e,t){return this.#e("recordCustomEvent",e,t)}setPageViewName(e,t){return this.#e("setPageViewName",e,t)}setCustomAttribute(e,t,r){return this.#e("setCustomAttribute",e,t,r)}noticeError(e,t){return this.#e("noticeError",e,t)}setUserId(e){return this.#e("setUserId",e)}setApplicationVersion(e){return this.#e("setApplicationVersion",e)}setErrorHandler(e){return this.#e("setErrorHandler",e)}addRelease(e,t){return this.#e("addRelease",e,t)}log(e,t){return this.#e("log",e,t)}}class o extends n{#e(t,...r){if("function"==typeof this.api?.[t])return this.api[t](...r);(0,e.R)(35,t)}start(){return this.#e("start")}finished(e){return this.#e("finished",e)}recordReplay(){return this.#e(t.G4.RECORD)}pauseReplay(){return this.#e(t.G4.PAUSE)}addToTrace(e){return this.#e("addToTrace",e)}setCurrentRouteName(e){return this.#e("setCurrentRouteName",e)}interaction(){return this.#e("interaction")}wrapLogger(e,t,r){return this.#e("wrapLogger",e,t,r)}}var a=i(860),s=i(9417);const c=Object.values(a.K7);function u(e){const t={};return c.forEach((r=>{t[r]=function(e,t){return!0===(0,s.gD)(t,"".concat(e,".enabled"))}(r,e)})),t}var d=i(8969);var l=i(1687),f=i(4234),h=i(5289),p=i(6154),g=i(5270),m=i(7767),v=i(6389);class b extends f.W{constructor(e,t,r=!0){super(e.agentIdentifier,t),this.auto=r,this.abortHandler=void 0,this.featAggregate=void 0,this.onAggregateImported=void 0,!1===e.init[this.featureName].autoStart&&(this.auto=!1),this.auto?(0,l.Ak)(e.agentIdentifier,t):this.ee.on("manual-start-all",(0,v.J)((()=>{(0,l.Ak)(e.agentIdentifier,this.featureName),this.auto=!0,this.importAggregator(e)})))}importAggregator(t,r={}){if(this.featAggregate||!this.auto)return;let n;this.onAggregateImported=new Promise((e=>{n=e}));const o=async()=>{let o;try{if((0,m.V)(this.agentIdentifier)){const{setupAgentSession:e}=await i.e(478).then(i.bind(i,6526));o=e(t)}}catch(t){(0,e.R)(20,t),this.ee.emit("internal-error",[t]),this.featureName===a.K7.sessionReplay&&this.abortHandler?.()}try{if(!this.#t(this.featureName,o))return(0,l.Ze)(this.agentIdentifier,this.featureName),void n(!1);const{lazyFeatureLoader:e}=await i.e(478).then(i.bind(i,6103)),{Aggregate:a}=await e(this.featureName,"aggregate");this.featAggregate=new a(t,r),t.runtime.harvester.initializedAggregates.push(this.featAggregate),n(!0)}catch(t){(0,e.R)(34,t),this.abortHandler?.(),(0,l.Ze)(this.agentIdentifier,this.featureName,!0),n(!1),this.ee&&this.ee.abort()}};p.RI?(0,h.GG)((()=>o()),!0):o()}#t(e,t){switch(e){case a.K7.sessionReplay:return(0,g.SR)(this.agentIdentifier)&&!!t;case a.K7.sessionTrace:return!!t;default:return!0}}}var y=i(6630);class w extends b{static featureName=y.T;constructor(e,t=!0){super(e,y.T,t),this.importAggregator(e)}}var R=i(384);var x=i(9908),E=i(2843),A=i(3878),T=i(782),N=i(1863);class S extends b{static featureName=T.T;constructor(e,t=!0){super(e,T.T,t),p.RI&&((0,E.u)((()=>(0,x.p)("docHidden",[(0,N.t)()],void 0,T.T,this.ee)),!0),(0,A.sp)("pagehide",(()=>(0,x.p)("winPagehide",[(0,N.t)()],void 0,T.T,this.ee))),this.importAggregator(e))}}var _=i(8154);class O extends b{static featureName=_.TZ;constructor(e,t=!0){super(e,_.TZ,t),this.importAggregator(e)}}var I=i(6774),P=i(3304);class j{constructor(e,t,r,n,i){this.name="UncaughtError",this.message="string"==typeof e?e:(0,P.A)(e),this.sourceURL=t,this.line=r,this.column=n,this.__newrelic=i}}function C(e){return H(e)?e:new j(void 0!==e?.message?e.message:e,e?.filename||e?.sourceURL,e?.lineno||e?.line,e?.colno||e?.col,e?.__newrelic)}function k(e){const t="Unhandled Promise Rejection";if(!e?.reason)return;if(H(e.reason))try{return e.reason.message=t+": "+e.reason.message,C(e.reason)}catch(t){return C(e.reason)}const r=C(e.reason);return r.message=t+": "+r?.message,r}function L(e){if(e.error instanceof SyntaxError&&!/:\d+$/.test(e.error.stack?.trim())){const t=new j(e.message,e.filename,e.lineno,e.colno,e.error.__newrelic);return t.name=SyntaxError.name,t}return H(e.error)?e.error:C(e)}function H(e){return e instanceof Error&&!!e.stack}class M extends b{static featureName=I.T;#r=!1;constructor(e,r=!0){super(e,I.T,r);try{this.removeOnAbort=new AbortController}catch(e){}this.ee.on("internal-error",((e,t)=>{this.abortHandler&&(0,x.p)("ierr",[C(e),(0,N.t)(),!0,{},this.#r,t],void 0,this.featureName,this.ee)})),this.ee.on(t.G4.REPLAY_RUNNING,(e=>{this.#r=e})),p.gm.addEventListener("unhandledrejection",(e=>{this.abortHandler&&(0,x.p)("err",[k(e),(0,N.t)(),!1,{unhandledPromiseRejection:1},this.#r],void 0,this.featureName,this.ee)}),(0,A.jT)(!1,this.removeOnAbort?.signal)),p.gm.addEventListener("error",(e=>{this.abortHandler&&(0,x.p)("err",[L(e),(0,N.t)(),!1,{},this.#r],void 0,this.featureName,this.ee)}),(0,A.jT)(!1,this.removeOnAbort?.signal)),this.abortHandler=this.#n,this.importAggregator(e)}#n(){this.removeOnAbort?.abort(),this.abortHandler=void 0}}var D=i(8990);let K=1;const U="nr@id";function V(e){const t=typeof e;return!e||"object"!==t&&"function"!==t?-1:e===p.gm?0:(0,D.I)(e,U,(function(){return K++}))}function G(e){if("string"==typeof e&&e.length)return e.length;if("object"==typeof e){if("undefined"!=typeof ArrayBuffer&&e instanceof ArrayBuffer&&e.byteLength)return e.byteLength;if("undefined"!=typeof Blob&&e instanceof Blob&&e.size)return e.size;if(!("undefined"!=typeof FormData&&e instanceof FormData))try{return(0,P.A)(e).length}catch(e){return}}}var F=i(8139),B=i(7836),W=i(3434);const z={},q=["open","send"];function Z(t){var r=t||B.ee;const n=function(e){return(e||B.ee).get("xhr")}(r);if(void 0===p.gm.XMLHttpRequest)return n;if(z[n.debugId]++)return n;z[n.debugId]=1,(0,F.u)(r);var i=(0,W.YM)(n),o=p.gm.XMLHttpRequest,a=p.gm.MutationObserver,s=p.gm.Promise,c=p.gm.setInterval,u="readystatechange",d=["onload","onerror","onabort","onloadstart","onloadend","onprogress","ontimeout"],l=[],f=p.gm.XMLHttpRequest=function(t){const r=new o(t),a=n.context(r);try{n.emit("new-xhr",[r],a),r.addEventListener(u,(s=a,function(){var e=this;e.readyState>3&&!s.resolved&&(s.resolved=!0,n.emit("xhr-resolved",[],e)),i.inPlace(e,d,"fn-",y)}),(0,A.jT)(!1))}catch(t){(0,e.R)(15,t);try{n.emit("internal-error",[t])}catch(e){}}var s;return r};function h(e,t){i.inPlace(t,["onreadystatechange"],"fn-",y)}if(function(e,t){for(var r in e)t[r]=e[r]}(o,f),f.prototype=o.prototype,i.inPlace(f.prototype,q,"-xhr-",y),n.on("send-xhr-start",(function(e,t){h(e,t),function(e){l.push(e),a&&(g?g.then(b):c?c(b):(m=-m,v.data=m))}(t)})),n.on("open-xhr-start",h),a){var g=s&&s.resolve();if(!c&&!s){var m=1,v=document.createTextNode(m);new a(b).observe(v,{characterData:!0})}}else r.on("fn-end",(function(e){e[0]&&e[0].type===u||b()}));function b(){for(var e=0;e<l.length;e++)h(0,l[e]);l.length&&(l=[])}function y(e,t){return t}return n}var Y="fetch-",J=Y+"body-",X=["arrayBuffer","blob","json","text","formData"],Q=p.gm.Request,ee=p.gm.Response,te="prototype";const re={};function ne(e){const t=function(e){return(e||B.ee).get("fetch")}(e);if(!(Q&&ee&&p.gm.fetch))return t;if(re[t.debugId]++)return t;function r(e,r,n){var i=e[r];"function"==typeof i&&(e[r]=function(){var e,r=[...arguments],o={};t.emit(n+"before-start",[r],o),o[B.P]&&o[B.P].dt&&(e=o[B.P].dt);var a=i.apply(this,r);return t.emit(n+"start",[r,e],a),a.then((function(e){return t.emit(n+"end",[null,e],a),e}),(function(e){throw t.emit(n+"end",[e],a),e}))})}return re[t.debugId]=1,X.forEach((e=>{r(Q[te],e,J),r(ee[te],e,J)})),r(p.gm,"fetch",Y),t.on(Y+"end",(function(e,r){var n=this;if(r){var i=r.headers.get("content-length");null!==i&&(n.rxSize=i),t.emit(Y+"done",[null,r],n)}else t.emit(Y+"done",[e],n)})),t}var ie=i(7485),oe=i(5603);class ae{constructor(e){this.agentIdentifier=e}generateTracePayload(e){if(!this.shouldGenerateTrace(e))return null;var t=(0,oe.o)(this.agentIdentifier);if(!t)return null;var n=(t.accountID||"").toString()||null,i=(t.agentID||"").toString()||null,o=(t.trustKey||"").toString()||null;if(!n||!i)return null;var a=(0,r.ZF)(),s=(0,r.el)(),c=Date.now(),u={spanId:a,traceId:s,timestamp:c};return(e.sameOrigin||this.isAllowedOrigin(e)&&this.useTraceContextHeadersForCors())&&(u.traceContextParentHeader=this.generateTraceContextParentHeader(a,s),u.traceContextStateHeader=this.generateTraceContextStateHeader(a,c,n,i,o)),(e.sameOrigin&&!this.excludeNewrelicHeader()||!e.sameOrigin&&this.isAllowedOrigin(e)&&this.useNewrelicHeaderForCors())&&(u.newrelicHeader=this.generateTraceHeader(a,s,c,n,i,o)),u}generateTraceContextParentHeader(e,t){return"00-"+t+"-"+e+"-01"}generateTraceContextStateHeader(e,t,r,n,i){return i+"@nr=0-1-"+r+"-"+n+"-"+e+"----"+t}generateTraceHeader(e,t,r,n,i,o){if(!("function"==typeof p.gm?.btoa))return null;var a={v:[0,1],d:{ty:"Browser",ac:n,ap:i,id:e,tr:t,ti:r}};return o&&n!==o&&(a.d.tk=o),btoa((0,P.A)(a))}shouldGenerateTrace(e){return this.isDtEnabled()&&this.isAllowedOrigin(e)}isAllowedOrigin(e){var t=!1,r={};if((0,s.gD)(this.agentIdentifier,"distributed_tracing")&&(r=(0,s.D0)(this.agentIdentifier).distributed_tracing),e.sameOrigin)t=!0;else if(r.allowed_origins instanceof Array)for(var n=0;n<r.allowed_origins.length;n++){var i=(0,ie.D)(r.allowed_origins[n]);if(e.hostname===i.hostname&&e.protocol===i.protocol&&e.port===i.port){t=!0;break}}return t}isDtEnabled(){var e=(0,s.gD)(this.agentIdentifier,"distributed_tracing");return!!e&&!!e.enabled}excludeNewrelicHeader(){var e=(0,s.gD)(this.agentIdentifier,"distributed_tracing");return!!e&&!!e.exclude_newrelic_header}useNewrelicHeaderForCors(){var e=(0,s.gD)(this.agentIdentifier,"distributed_tracing");return!!e&&!1!==e.cors_use_newrelic_header}useTraceContextHeadersForCors(){var e=(0,s.gD)(this.agentIdentifier,"distributed_tracing");return!!e&&!!e.cors_use_tracecontext_headers}}var se=i(9300),ce=i(7295),ue=["load","error","abort","timeout"],de=ue.length,le=(0,R.dV)().o.REQ,fe=(0,R.dV)().o.XHR;class he extends b{static featureName=se.T;constructor(e,t=!0){super(e,se.T,t),this.dt=new ae(e.agentIdentifier),this.handler=(e,t,r,n)=>(0,x.p)(e,t,r,n,this.ee);try{const e={xmlhttprequest:"xhr",fetch:"fetch",beacon:"beacon"};p.gm?.performance?.getEntriesByType("resource").forEach((t=>{if(t.initiatorType in e&&0!==t.responseStatus){const r={status:t.responseStatus},n={rxSize:t.transferSize,duration:Math.floor(t.duration),cbTime:0};pe(r,t.name),this.handler("xhr",[r,n,t.startTime,t.responseEnd,e[t.initiatorType]],void 0,a.K7.ajax)}}))}catch(e){}ne(this.ee),Z(this.ee),function(e,t,r,n){function i(e){var t=this;t.totalCbs=0,t.called=0,t.cbTime=0,t.end=R,t.ended=!1,t.xhrGuids={},t.lastSize=null,t.loadCaptureCalled=!1,t.params=this.params||{},t.metrics=this.metrics||{},e.addEventListener("load",(function(r){E(t,e)}),(0,A.jT)(!1)),p.lR||e.addEventListener("progress",(function(e){t.lastSize=e.loaded}),(0,A.jT)(!1))}function o(e){this.params={method:e[0]},pe(this,e[1]),this.metrics={}}function s(t,r){e.loader_config.xpid&&this.sameOrigin&&r.setRequestHeader("X-NewRelic-ID",e.loader_config.xpid);var i=n.generateTracePayload(this.parsedOrigin);if(i){var o=!1;i.newrelicHeader&&(r.setRequestHeader("newrelic",i.newrelicHeader),o=!0),i.traceContextParentHeader&&(r.setRequestHeader("traceparent",i.traceContextParentHeader),i.traceContextStateHeader&&r.setRequestHeader("tracestate",i.traceContextStateHeader),o=!0),o&&(this.dt=i)}}function c(e,r){var n=this.metrics,i=e[0],o=this;if(n&&i){var a=G(i);a&&(n.txSize=a)}this.startTime=(0,N.t)(),this.body=i,this.listener=function(e){try{"abort"!==e.type||o.loadCaptureCalled||(o.params.aborted=!0),("load"!==e.type||o.called===o.totalCbs&&(o.onloadCalled||"function"!=typeof r.onload)&&"function"==typeof o.end)&&o.end(r)}catch(e){try{t.emit("internal-error",[e])}catch(e){}}};for(var s=0;s<de;s++)r.addEventListener(ue[s],this.listener,(0,A.jT)(!1))}function u(e,t,r){this.cbTime+=e,t?this.onloadCalled=!0:this.called+=1,this.called!==this.totalCbs||!this.onloadCalled&&"function"==typeof r.onload||"function"!=typeof this.end||this.end(r)}function d(e,t){var r=""+V(e)+!!t;this.xhrGuids&&!this.xhrGuids[r]&&(this.xhrGuids[r]=!0,this.totalCbs+=1)}function l(e,t){var r=""+V(e)+!!t;this.xhrGuids&&this.xhrGuids[r]&&(delete this.xhrGuids[r],this.totalCbs-=1)}function f(){this.endTime=(0,N.t)()}function h(e,r){r instanceof fe&&"load"===e[0]&&t.emit("xhr-load-added",[e[1],e[2]],r)}function g(e,r){r instanceof fe&&"load"===e[0]&&t.emit("xhr-load-removed",[e[1],e[2]],r)}function m(e,t,r){t instanceof fe&&("onload"===r&&(this.onload=!0),("load"===(e[0]&&e[0].type)||this.onload)&&(this.xhrCbStart=(0,N.t)()))}function v(e,r){this.xhrCbStart&&t.emit("xhr-cb-time",[(0,N.t)()-this.xhrCbStart,this.onload,r],r)}function b(e){var t,r=e[1]||{};if("string"==typeof e[0]?0===(t=e[0]).length&&p.RI&&(t=""+p.gm.location.href):e[0]&&e[0].url?t=e[0].url:p.gm?.URL&&e[0]&&e[0]instanceof URL?t=e[0].href:"function"==typeof e[0].toString&&(t=e[0].toString()),"string"==typeof t&&0!==t.length){t&&(this.parsedOrigin=(0,ie.D)(t),this.sameOrigin=this.parsedOrigin.sameOrigin);var i=n.generateTracePayload(this.parsedOrigin);if(i&&(i.newrelicHeader||i.traceContextParentHeader))if(e[0]&&e[0].headers)s(e[0].headers,i)&&(this.dt=i);else{var o={};for(var a in r)o[a]=r[a];o.headers=new Headers(r.headers||{}),s(o.headers,i)&&(this.dt=i),e.length>1?e[1]=o:e.push(o)}}function s(e,t){var r=!1;return t.newrelicHeader&&(e.set("newrelic",t.newrelicHeader),r=!0),t.traceContextParentHeader&&(e.set("traceparent",t.traceContextParentHeader),t.traceContextStateHeader&&e.set("tracestate",t.traceContextStateHeader),r=!0),r}}function y(e,t){this.params={},this.metrics={},this.startTime=(0,N.t)(),this.dt=t,e.length>=1&&(this.target=e[0]),e.length>=2&&(this.opts=e[1]);var r,n=this.opts||{},i=this.target;"string"==typeof i?r=i:"object"==typeof i&&i instanceof le?r=i.url:p.gm?.URL&&"object"==typeof i&&i instanceof URL&&(r=i.href),pe(this,r);var o=(""+(i&&i instanceof le&&i.method||n.method||"GET")).toUpperCase();this.params.method=o,this.body=n.body,this.txSize=G(n.body)||0}function w(e,t){if(this.endTime=(0,N.t)(),this.params||(this.params={}),(0,ce.iW)(this.params))return;let n;this.params.status=t?t.status:0,"string"==typeof this.rxSize&&this.rxSize.length>0&&(n=+this.rxSize);const i={txSize:this.txSize,rxSize:n,duration:(0,N.t)()-this.startTime};r("xhr",[this.params,i,this.startTime,this.endTime,"fetch"],this,a.K7.ajax)}function R(e){const t=this.params,n=this.metrics;if(!this.ended){this.ended=!0;for(let t=0;t<de;t++)e.removeEventListener(ue[t],this.listener,!1);t.aborted||(0,ce.iW)(t)||(n.duration=(0,N.t)()-this.startTime,this.loadCaptureCalled||4!==e.readyState?null==t.status&&(t.status=0):E(this,e),n.cbTime=this.cbTime,r("xhr",[t,n,this.startTime,this.endTime,"xhr"],this,a.K7.ajax))}}function E(e,r){e.params.status=r.status;var n=function(e,t){var r=e.responseType;return"json"===r&&null!==t?t:"arraybuffer"===r||"blob"===r||"json"===r?G(e.response):"text"===r||""===r||void 0===r?G(e.responseText):void 0}(r,e.lastSize);if(n&&(e.metrics.rxSize=n),e.sameOrigin){var i=r.getResponseHeader("X-NewRelic-App-Data");i&&((0,x.p)(_.rs,["Ajax/CrossApplicationTracing/Header/Seen"],void 0,a.K7.metrics,t),e.params.cat=i.split(", ").pop())}e.loadCaptureCalled=!0}t.on("new-xhr",i),t.on("open-xhr-start",o),t.on("open-xhr-end",s),t.on("send-xhr-start",c),t.on("xhr-cb-time",u),t.on("xhr-load-added",d),t.on("xhr-load-removed",l),t.on("xhr-resolved",f),t.on("addEventListener-end",h),t.on("removeEventListener-end",g),t.on("fn-end",v),t.on("fetch-before-start",b),t.on("fetch-start",y),t.on("fn-start",m),t.on("fetch-done",w)}(e,this.ee,this.handler,this.dt),this.importAggregator(e)}}function pe(e,t){var r=(0,ie.D)(t),n=e.params||e;n.hostname=r.hostname,n.port=r.port,n.protocol=r.protocol,n.host=r.hostname+":"+r.port,n.pathname=r.pathname,e.parsedOrigin=r,e.sameOrigin=r.sameOrigin}const ge={},me=["pushState","replaceState"];function ve(e){const t=function(e){return(e||B.ee).get("history")}(e);return!p.RI||ge[t.debugId]++||(ge[t.debugId]=1,(0,W.YM)(t).inPlace(window.history,me,"-")),t}var be=i(3738);const{He:ye,bD:we,d3:Re,Kp:xe,TZ:Ee,Lc:Ae,uP:Te,Rz:Ne}=be;class Se extends b{static featureName=Ee;constructor(e,t=!0){super(e,Ee,t);if(!(0,m.V)(this.agentIdentifier))return void this.deregisterDrain();const r=this.ee;let n;ve(r),this.eventsEE=(0,F.u)(r),this.eventsEE.on(Te,(function(e,t){this.bstStart=(0,N.t)()})),this.eventsEE.on(Ae,(function(e,t){(0,x.p)("bst",[e[0],t,this.bstStart,(0,N.t)()],void 0,a.K7.sessionTrace,r)})),r.on(Ne+Re,(function(e){this.time=(0,N.t)(),this.startPath=location.pathname+location.hash})),r.on(Ne+xe,(function(e){(0,x.p)("bstHist",[location.pathname+location.hash,this.startPath,this.time],void 0,a.K7.sessionTrace,r)}));try{n=new PerformanceObserver((e=>{const t=e.getEntries();(0,x.p)(ye,[t],void 0,a.K7.sessionTrace,r)})),n.observe({type:we,buffered:!0})}catch(e){}this.importAggregator(e,{resourceObserver:n})}}var _e=i(2614);class Oe extends b{static featureName=t.TZ;#i;#o;constructor(e,r=!0){let n;super(e,t.TZ,r),this.replayRunning=!1,this.#o=e;try{n=JSON.parse(localStorage.getItem("".concat(_e.H3,"_").concat(_e.uh)))}catch(e){}(0,g.SR)(e.agentIdentifier)&&this.ee.on(t.G4.RECORD,(()=>this.#a())),this.#s(n)?(this.#i=n?.sessionReplayMode,this.#c()):this.importAggregator(e),this.ee.on("err",(e=>{this.replayRunning&&(this.errorNoticed=!0,(0,x.p)(t.G4.ERROR_DURING_REPLAY,[e],void 0,this.featureName,this.ee))})),this.ee.on(t.G4.REPLAY_RUNNING,(e=>{this.replayRunning=e}))}#s(e){return e&&(e.sessionReplayMode===_e.g.FULL||e.sessionReplayMode===_e.g.ERROR)||(0,g.Aw)(this.agentIdentifier)}#u=!1;async#c(e){if(!this.#u){this.#u=!0;try{const{Recorder:t}=await Promise.all([i.e(478),i.e(249)]).then(i.bind(i,8589));this.recorder??=new t({mode:this.#i,agentIdentifier:this.agentIdentifier,trigger:e,ee:this.ee,agentRef:this.#o}),this.recorder.startRecording(),this.abortHandler=this.recorder.stopRecording}catch(e){}this.importAggregator(this.#o,{recorder:this.recorder,errorNoticed:this.errorNoticed})}}#a(){this.featAggregate?this.featAggregate.mode!==_e.g.FULL&&this.featAggregate.initializeRecording(_e.g.FULL,!0):(this.#i=_e.g.FULL,this.#c(t.Qb.API),this.recorder&&this.recorder.parent.mode!==_e.g.FULL&&(this.recorder.parent.mode=_e.g.FULL,this.recorder.stopRecording(),this.recorder.startRecording(),this.abortHandler=this.recorder.stopRecording))}}var Ie=i(3962);class Pe extends b{static featureName=Ie.TZ;constructor(e,t=!0){if(super(e,Ie.TZ,t),!p.RI||!(0,R.dV)().o.MO)return;const r=ve(this.ee);Ie.tC.forEach((e=>{(0,A.sp)(e,(e=>{a(e)}),!0)}));const n=()=>(0,x.p)("newURL",[(0,N.t)(),""+window.location],void 0,this.featureName,this.ee);r.on("pushState-end",n),r.on("replaceState-end",n);try{this.removeOnAbort=new AbortController}catch(e){}(0,A.sp)("popstate",(e=>(0,x.p)("newURL",[e.timeStamp,""+window.location],void 0,this.featureName,this.ee)),!0,this.removeOnAbort?.signal);let i=!1;const o=new((0,R.dV)().o.MO)(((e,t)=>{i||(i=!0,requestAnimationFrame((()=>{(0,x.p)("newDom",[(0,N.t)()],void 0,this.featureName,this.ee),i=!1})))})),a=(0,v.s)((e=>{(0,x.p)("newUIEvent",[e],void 0,this.featureName,this.ee),o.observe(document.body,{attributes:!0,childList:!0,subtree:!0,characterData:!0})}),100,{leading:!0});this.abortHandler=function(){this.removeOnAbort?.abort(),o.disconnect(),this.abortHandler=void 0},this.importAggregator(e,{domObserver:o})}}var je=i(7378);const Ce={},ke=["appendChild","insertBefore","replaceChild"];function Le(e){const t=function(e){return(e||B.ee).get("jsonp")}(e);if(!p.RI||Ce[t.debugId])return t;Ce[t.debugId]=!0;var r=(0,W.YM)(t),n=/[?&](?:callback|cb)=([^&#]+)/,i=/(.*)\.([^.]+)/,o=/^(\w+)(\.|$)(.*)$/;function a(e,t){if(!e)return t;const r=e.match(o),n=r[1];return a(r[3],t[n])}return r.inPlace(Node.prototype,ke,"dom-"),t.on("dom-start",(function(e){!function(e){if(!e||"string"!=typeof e.nodeName||"script"!==e.nodeName.toLowerCase())return;if("function"!=typeof e.addEventListener)return;var o=(s=e.src,c=s.match(n),c?c[1]:null);var s,c;if(!o)return;var u=function(e){var t=e.match(i);if(t&&t.length>=3)return{key:t[2],parent:a(t[1],window)};return{key:e,parent:window}}(o);if("function"!=typeof u.parent[u.key])return;var d={};function l(){t.emit("jsonp-end",[],d),e.removeEventListener("load",l,(0,A.jT)(!1)),e.removeEventListener("error",f,(0,A.jT)(!1))}function f(){t.emit("jsonp-error",[],d),t.emit("jsonp-end",[],d),e.removeEventListener("load",l,(0,A.jT)(!1)),e.removeEventListener("error",f,(0,A.jT)(!1))}r.inPlace(u.parent,[u.key],"cb-",d),e.addEventListener("load",l,(0,A.jT)(!1)),e.addEventListener("error",f,(0,A.jT)(!1)),t.emit("new-jsonp",[e.src],d)}(e[0])})),t}const He={};function Me(e){const t=function(e){return(e||B.ee).get("promise")}(e);if(He[t.debugId])return t;He[t.debugId]=!0;var r=t.context,n=(0,W.YM)(t),i=p.gm.Promise;return i&&function(){function e(r){var o=t.context(),a=n(r,"executor-",o,null,!1);const s=Reflect.construct(i,[a],e);return t.context(s).getCtx=function(){return o},s}p.gm.Promise=e,Object.defineProperty(e,"name",{value:"Promise"}),e.toString=function(){return i.toString()},Object.setPrototypeOf(e,i),["all","race"].forEach((function(r){const n=i[r];e[r]=function(e){let i=!1;[...e||[]].forEach((e=>{this.resolve(e).then(a("all"===r),a(!1))}));const o=n.apply(this,arguments);return o;function a(e){return function(){t.emit("propagate",[null,!i],o,!1,!1),i=i||!e}}}})),["resolve","reject"].forEach((function(r){const n=i[r];e[r]=function(e){const r=n.apply(this,arguments);return e!==r&&t.emit("propagate",[e,!0],r,!1,!1),r}})),e.prototype=i.prototype;const o=i.prototype.then;i.prototype.then=function(...e){var i=this,a=r(i);a.promise=i,e[0]=n(e[0],"cb-",a,null,!1),e[1]=n(e[1],"cb-",a,null,!1);const s=o.apply(this,e);return a.nextPromise=s,t.emit("propagate",[i,!0],s,!1,!1),s},i.prototype.then[W.Jt]=o,t.on("executor-start",(function(e){e[0]=n(e[0],"resolve-",this,null,!1),e[1]=n(e[1],"resolve-",this,null,!1)})),t.on("executor-err",(function(e,t,r){e[1](r)})),t.on("cb-end",(function(e,r,n){t.emit("propagate",[n,!0],this.nextPromise,!1,!1)})),t.on("propagate",(function(e,r,n){this.getCtx&&!r||(this.getCtx=function(){if(e instanceof Promise)var r=t.context(e);return r&&r.getCtx?r.getCtx():this})}))}(),t}const De={},Ke="setTimeout",Ue="setInterval",Ve="clearTimeout",Ge="-start",Fe=[Ke,"setImmediate",Ue,Ve,"clearImmediate"];function Be(e){const t=function(e){return(e||B.ee).get("timer")}(e);if(De[t.debugId]++)return t;De[t.debugId]=1;var r=(0,W.YM)(t);return r.inPlace(p.gm,Fe.slice(0,2),Ke+"-"),r.inPlace(p.gm,Fe.slice(2,3),Ue+"-"),r.inPlace(p.gm,Fe.slice(3),Ve+"-"),t.on(Ue+Ge,(function(e,t,n){e[0]=r(e[0],"fn-",null,n)})),t.on(Ke+Ge,(function(e,t,n){this.method=n,this.timerDuration=isNaN(e[1])?0:+e[1],e[0]=r(e[0],"fn-",this,n)})),t}const We={};function ze(e){const t=function(e){return(e||B.ee).get("mutation")}(e);if(!p.RI||We[t.debugId])return t;We[t.debugId]=!0;var r=(0,W.YM)(t),n=p.gm.MutationObserver;return n&&(window.MutationObserver=function(e){return this instanceof n?new n(r(e,"fn-")):n.apply(this,arguments)},MutationObserver.prototype=n.prototype),t}const{TZ:qe,d3:Ze,Kp:Ye,$p:Je,wW:Xe,e5:$e,tH:Qe,uP:et,rw:tt,Lc:rt}=je;class nt extends b{static featureName=qe;constructor(e,t=!0){if(super(e,qe,t),!p.RI)return;try{this.removeOnAbort=new AbortController}catch(e){}let r,n=0;const i=this.ee.get("tracer"),o=Le(this.ee),a=Me(this.ee),s=Be(this.ee),c=Z(this.ee),u=this.ee.get("events"),d=ne(this.ee),l=ve(this.ee),f=ze(this.ee);function h(e,t){l.emit("newURL",[""+window.location,t])}function g(){n++,r=window.location.hash,this[et]=(0,N.t)()}function m(){n--,window.location.hash!==r&&h(0,!0);var e=(0,N.t)();this[$e]=~~this[$e]+e-this[et],this[rt]=e}function v(e,t){e.on(t,(function(){this[t]=(0,N.t)()}))}this.ee.on(et,g),a.on(tt,g),o.on(tt,g),this.ee.on(rt,m),a.on(Xe,m),o.on(Xe,m),this.ee.on("fn-err",((...t)=>{t[2]?.__newrelic?.[e.agentIdentifier]||(0,x.p)("function-err",[...t],void 0,this.featureName,this.ee)})),this.ee.buffer([et,rt,"xhr-resolved"],this.featureName),u.buffer([et],this.featureName),s.buffer(["setTimeout"+Ye,"clearTimeout"+Ze,et],this.featureName),c.buffer([et,"new-xhr","send-xhr"+Ze],this.featureName),d.buffer([Qe+Ze,Qe+"-done",Qe+Je+Ze,Qe+Je+Ye],this.featureName),l.buffer(["newURL"],this.featureName),f.buffer([et],this.featureName),a.buffer(["propagate",tt,Xe,"executor-err","resolve"+Ze],this.featureName),i.buffer([et,"no-"+et],this.featureName),o.buffer(["new-jsonp","cb-start","jsonp-error","jsonp-end"],this.featureName),v(d,Qe+Ze),v(d,Qe+"-done"),v(o,"new-jsonp"),v(o,"jsonp-end"),v(o,"cb-start"),l.on("pushState-end",h),l.on("replaceState-end",h),window.addEventListener("hashchange",h,(0,A.jT)(!0,this.removeOnAbort?.signal)),window.addEventListener("load",h,(0,A.jT)(!0,this.removeOnAbort?.signal)),window.addEventListener("popstate",(function(){h(0,n>1)}),(0,A.jT)(!0,this.removeOnAbort?.signal)),this.abortHandler=this.#n,this.importAggregator(e)}#n(){this.removeOnAbort?.abort(),this.abortHandler=void 0}}var it=i(3333);class ot extends b{static featureName=it.TZ;constructor(e,t=!0){super(e,it.TZ,t);const r=[e.init.page_action.enabled,e.init.performance.capture_marks,e.init.performance.capture_measures,e.init.user_actions.enabled,e.init.performance.resources.enabled];if(p.RI&&(e.init.user_actions.enabled&&(it.Zp.forEach((e=>(0,A.sp)(e,(e=>(0,x.p)("ua",[e],void 0,this.featureName,this.ee)),!0))),it.qN.forEach((e=>{const t=(0,v.s)((e=>{(0,x.p)("ua",[e],void 0,this.featureName,this.ee)}),500,{leading:!0});(0,A.sp)(e,t)}))),e.init.performance.resources.enabled&&p.gm.PerformanceObserver?.supportedEntryTypes.includes("resource"))){new PerformanceObserver((e=>{e.getEntries().forEach((e=>{(0,x.p)("browserPerformance.resource",[e],void 0,this.featureName,this.ee)}))})).observe({type:"resource",buffered:!0})}r.some((e=>e))?this.importAggregator(e):this.deregisterDrain()}}var at=i(993),st=i(3785),ct=i(9414);class ut extends b{static featureName=at.TZ;constructor(e,t=!0){super(e,at.TZ,t);const r=this.ee;(0,ct.J)(r,p.gm.console,"log",{level:"info"}),(0,ct.J)(r,p.gm.console,"error",{level:"error"}),(0,ct.J)(r,p.gm.console,"warn",{level:"warn"}),(0,ct.J)(r,p.gm.console,"info",{level:"info"}),(0,ct.J)(r,p.gm.console,"debug",{level:"debug"}),(0,ct.J)(r,p.gm.console,"trace",{level:"trace"}),this.ee.on("wrap-logger-end",(function([e]){const{level:t,customAttributes:n}=this;(0,st.R)(r,e,n,t)})),this.importAggregator(e)}}new class extends o{constructor(t){super(),p.gm?(this.features={},(0,R.bQ)(this.agentIdentifier,this),this.desiredFeatures=new Set(t.features||[]),this.desiredFeatures.add(w),this.runSoftNavOverSpa=[...this.desiredFeatures].some((e=>e.featureName===a.K7.softNav)),(0,d.j)(this,t,t.loaderType||"agent"),this.run()):(0,e.R)(21)}get config(){return{info:this.info,init:this.init,loader_config:this.loader_config,runtime:this.runtime}}run(){try{const t=u(this.agentIdentifier),r=[...this.desiredFeatures];r.sort(((e,t)=>a.P3[e.featureName]-a.P3[t.featureName])),r.forEach((r=>{if(!t[r.featureName]&&r.featureName!==a.K7.pageViewEvent)return;if(this.runSoftNavOverSpa&&r.featureName===a.K7.spa)return;if(!this.runSoftNavOverSpa&&r.featureName===a.K7.softNav)return;const n=function(e){switch(e){case a.K7.ajax:return[a.K7.jserrors];case a.K7.sessionTrace:return[a.K7.ajax,a.K7.pageViewEvent];case a.K7.sessionReplay:return[a.K7.sessionTrace];case a.K7.pageViewTiming:return[a.K7.pageViewEvent];default:return[]}}(r.featureName).filter((e=>!(e in this.features)));n.length>0&&(0,e.R)(36,{targetFeature:r.featureName,missingDependencies:n}),this.features[r.featureName]=new r(this)}))}catch(t){(0,e.R)(22,t);for(const e in this.features)this.features[e].abortHandler?.();const r=(0,R.Zm)();delete r.initializedAgents[this.agentIdentifier]?.api,delete r.initializedAgents[this.agentIdentifier]?.features,delete this.sharedAggregator;return r.ee.get(this.agentIdentifier).abort(),!1}}}({features:[he,w,S,Se,Oe,O,M,ot,ut,Pe,nt],loaderType:"spa"})})()})();</script><link rel="preload" href="/article-pages/_nuxt/e397d1a.js" as="script"><link rel="preload" href="/article-pages/_nuxt/2abb6c5.js" as="script"><link rel="preload" href="/article-pages/_nuxt/css/66101cf.css" as="style"><link rel="preload" href="/article-pages/_nuxt/701e3a3.js" as="script"><link rel="preload" href="/article-pages/_nuxt/css/dac93f2.css" as="style"><link rel="preload" href="/article-pages/_nuxt/71728a1.js" as="script"><link rel="preload" href="/article-pages/_nuxt/a5e7651.js" as="script"><link rel="preload" href="/article-pages/_nuxt/css/e5cdfa1.css" as="style"><link rel="preload" href="/article-pages/_nuxt/f548f7f.js" as="script"><link rel="preload" href="/article-pages/_nuxt/css/868b092.css" as="style"><link rel="preload" href="/article-pages/_nuxt/e3c5a8f.js" as="script"><link rel="preload" href="/article-pages/_nuxt/css/97e04e3.css" as="style"><link rel="preload" href="/article-pages/_nuxt/0d6d8e5.js" as="script"><link rel="preload" href="/article-pages/_nuxt/ed7fc59.js" as="script"><link rel="stylesheet" href="/article-pages/_nuxt/css/66101cf.css"><link rel="stylesheet" href="/article-pages/_nuxt/css/dac93f2.css"><link rel="stylesheet" href="/article-pages/_nuxt/css/e5cdfa1.css"><link rel="stylesheet" href="/article-pages/_nuxt/css/868b092.css"><link rel="stylesheet" href="/article-pages/_nuxt/css/97e04e3.css"> <meta property="fb:admins" content="1841006843"> </head> <body > <button class="BypassBlock__firstEl"></button> <a href="#main-content" class="BypassBlock__wrapper"> <span class="BypassBlock__button">Skip to main content</span> </a>  <noscript> <iframe src="https://tag-manager.frontiersin.org/ns.html?id=GTM-M322FV2&gtm_auth=owVbWxfaJr21yQv1fe1cAQ&gtm_preview=env-1&gtm_cookies_win=x" height="0" width="0" style="display:none;visibility:hidden"></iframe> </noscript>  <div data-server-rendered="true" id="__nuxt"><div id="__layout"><div theme="purple" class="ArticleLayout"><nav class="Ibar"><div class="Ibar__main"><div class="Ibar__wrapper"><button aria-label="Open Menu" data-event="iBar-btn-openMenu" class="Ibar__burger"></button> <div class="Ibar__logo"><a href="//www.frontiersin.org/" aria-label="Frontiershome" data-event="iBar-a-home" class="Ibar__logo__link"><svg viewBox="0 0 2811 590" fill="none" xmlns="http://www.w3.org/2000/svg" class="Ibar__logo__svg"><path d="M633.872 234.191h-42.674v-57.246h42.674c0-19.776 2.082-35.389 5.204-48.92 4.164-13.53 9.368-23.939 17.695-31.225 8.326-8.326 18.735-13.53 32.266-16.653 13.531-3.123 29.143-5.204 47.878-5.204h21.858c7.286 0 14.572 1.04 21.857 1.04v62.451c-8.326-1.041-16.653-2.082-23.939-2.082-10.408 0-17.694 1.041-23.939 4.164-6.245 3.122-9.368 10.408-9.368 22.898v13.531h53.083v57.246h-53.083v213.372h-89.512V234.191zM794.161 176.945h86.39v47.879h1.041c6.245-17.694 16.653-30.185 31.225-39.552 14.572-9.368 31.225-13.531 49.96-13.531h10.409c3.122 0 7.286 1.041 10.408 2.082v81.185c-6.245-2.082-11.449-3.122-16.653-4.163-5.204-1.041-11.449-1.041-16.654-1.041-11.449 0-20.816 2.082-29.143 5.204-8.327 3.123-15.613 8.327-20.817 14.572-5.204 6.245-10.408 12.49-12.49 20.817-3.123 8.326-4.163 15.612-4.163 23.939v133.228h-88.472V176.945h-1.041zM989.84 312.254c0-19.776 3.122-39.552 10.41-56.205 7.28-17.695 16.65-32.266 29.14-45.797 12.49-13.531 27.06-22.899 44.76-30.185 17.69-7.285 36.43-11.449 57.24-11.449 20.82 0 39.56 4.164 57.25 11.449 17.69 7.286 32.27 17.695 45.8 30.185 12.49 12.49 22.9 28.102 29.14 45.797 7.29 17.694 10.41 36.429 10.41 56.205 0 20.817-3.12 39.552-10.41 57.246-7.29 17.695-16.65 32.266-29.14 44.756-12.49 12.49-28.11 22.899-45.8 30.185-17.69 7.286-36.43 11.449-57.25 11.449-20.81 0-40.59-4.163-57.24-11.449-17.7-7.286-32.27-17.695-44.76-30.185-12.49-12.49-21.86-28.102-29.14-44.756-7.288-17.694-10.41-36.429-10.41-57.246zm88.47 0c0 8.327 1.04 17.694 3.12 26.021 2.09 9.368 5.21 16.653 9.37 23.939 4.16 7.286 9.37 13.531 16.65 17.695 7.29 4.163 15.62 7.285 26.03 7.285 10.4 0 18.73-2.081 26.02-7.285 7.28-4.164 12.49-10.409 16.65-17.695 4.16-7.286 7.29-15.612 9.37-23.939 2.08-9.368 3.12-17.694 3.12-26.021 0-8.327-1.04-17.694-3.12-26.021-2.08-9.368-5.21-16.653-9.37-23.939-4.16-7.286-9.37-13.531-16.65-17.695-7.29-5.204-15.62-7.285-26.02-7.285-10.41 0-18.74 2.081-26.03 7.285-7.28 5.205-12.49 10.409-16.65 17.695-4.16 7.286-7.28 15.612-9.37 23.939-2.08 9.368-3.12 17.694-3.12 26.021zM1306.25 176.945h86.39v37.47h1.04c4.17-7.286 9.37-13.531 15.62-18.735 6.24-5.204 13.53-10.408 20.81-14.572 7.29-4.163 15.62-7.286 23.94-9.367 8.33-2.082 16.66-3.123 24.98-3.123 22.9 0 40.6 4.164 53.09 11.449 13.53 7.286 22.89 16.654 29.14 27.062 6.24 10.409 10.41 21.858 12.49 34.348 2.08 12.49 2.08 22.898 2.08 33.307v172.779h-88.47V316.417v-27.061c0-9.368-1.04-16.654-4.16-23.94-3.13-7.286-7.29-12.49-13.53-16.653-6.25-4.164-15.62-6.245-27.07-6.245-8.32 0-15.61 2.081-21.85 5.204-6.25 3.122-11.45 7.286-14.58 13.531-4.16 5.204-6.24 11.449-8.32 18.735s-3.12 14.572-3.12 21.858v145.717h-88.48V176.945zM1780.88 234.19h-55.17v122.819c0 10.408 3.12 17.694 8.33 20.817 6.24 3.122 13.53 5.204 22.9 5.204 4.16 0 7.28 0 11.45-1.041h11.45v65.573c-8.33 0-15.62 1.041-23.94 2.082-8.33 1.04-16.66 1.041-23.94 1.041-18.74 0-34.35-2.082-46.84-5.205-12.49-3.122-21.86-8.326-29.14-15.612-7.29-7.286-12.49-16.654-14.58-29.144-3.12-12.49-4.16-27.062-4.16-45.797V234.19h-44.76v-57.246h44.76V94.717h88.47v82.227h55.17v57.246zM1902.66 143.639h-88.48V75.984h88.48v67.655zm-89.52 33.307h88.48v270.618h-88.48V176.946zM2024.43 334.111c1.04 18.735 6.25 33.307 16.66 44.756 10.4 11.449 24.98 16.653 43.71 16.653 10.41 0 20.82-2.081 30.19-7.286 9.36-5.204 16.65-12.49 20.81-22.898h83.27c-4.16 15.613-10.41 29.144-19.78 40.593-9.36 11.449-19.77 20.817-31.22 28.102-12.49 7.286-24.98 12.491-39.55 16.654-14.57 3.122-29.15 5.204-43.72 5.204-21.86 0-41.63-3.122-60.37-9.367-18.73-6.246-34.34-15.613-46.83-28.103-12.49-12.49-22.9-27.062-30.19-45.797-7.28-17.694-10.41-38.511-10.41-60.369 0-20.817 4.17-39.552 11.45-57.246 7.29-17.694 17.7-32.266 31.23-44.756 13.53-12.49 29.14-21.858 46.83-29.144 17.7-7.286 36.43-10.408 56.21-10.408 23.94 0 45.8 4.163 63.49 12.49 17.7 8.327 33.31 19.776 44.76 35.389 11.45 15.612 20.81 32.266 26.02 52.042 5.2 19.776 8.33 41.633 7.28 64.532h-199.84v-1.041zm110.33-49.961c-1.04-15.612-6.24-28.102-15.61-39.551-9.37-10.409-21.86-16.654-37.47-16.654s-28.1 5.204-38.51 15.613c-10.41 10.408-16.66 23.939-18.74 40.592h110.33zM2254.46 176.945h86.39v47.879h1.04c6.25-17.694 16.65-30.185 31.23-39.552 14.57-9.368 31.22-13.531 49.96-13.531h10.4c3.13 0 7.29 1.041 10.41 2.082v81.185c-6.24-2.082-11.45-3.122-16.65-4.163-5.21-1.041-11.45-1.041-16.65-1.041-11.45 0-20.82 2.082-29.15 5.204-8.32 3.123-15.61 8.327-20.81 14.572-6.25 6.245-10.41 12.49-12.49 20.817-3.13 8.326-4.17 15.612-4.17 23.939v133.228h-88.47V176.945h-1.04zM2534.45 359.091c0 7.286 1.04 12.49 4.16 17.694 3.12 5.204 6.24 9.368 10.41 12.49 4.16 3.123 9.36 5.204 14.57 7.286 6.24 2.082 11.45 2.082 17.69 2.082 4.17 0 8.33 0 13.53-2.082 5.21-1.041 9.37-3.123 13.53-5.204 4.17-2.082 7.29-5.204 10.41-9.368 3.13-4.163 4.17-8.327 4.17-13.531 0-5.204-2.09-9.367-5.21-12.49-3.12-3.122-7.28-6.245-11.45-8.327-4.16-2.081-9.36-4.163-14.57-5.204-5.2-1.041-9.37-2.081-13.53-3.122-13.53-3.123-28.1-6.245-42.67-9.368-14.58-3.122-28.11-7.286-40.6-12.49-12.49-6.245-22.9-13.531-30.18-23.939-8.33-10.409-11.45-23.94-11.45-42.675 0-16.653 4.16-30.184 11.45-40.592 8.33-10.409 17.69-18.736 30.18-24.981 12.49-6.245 26.02-10.408 40.6-13.53 14.57-3.123 28.1-4.164 41.63-4.164 14.57 0 29.14 1.041 43.71 4.164 14.58 2.081 27.07 7.285 39.56 13.53 12.49 6.245 21.85 15.613 29.14 27.062 7.29 11.45 11.45 26.021 12.49 43.716h-82.23c0-10.409-4.16-18.736-11.45-23.94-7.28-4.163-16.65-7.286-28.1-7.286-4.16 0-8.32 0-12.49 1.041-4.16 1.041-8.32 1.041-12.49 2.082-4.16 1.041-7.28 3.122-9.37 6.245-2.08 3.122-4.16 6.245-4.16 11.449 0 6.245 3.12 11.449 10.41 15.613 6.24 4.163 14.57 7.286 24.98 10.408 10.41 2.082 20.82 5.204 32.27 7.286 11.44 2.082 22.89 4.163 33.3 6.245 13.53 3.123 24.98 7.286 33.31 13.531 9.37 6.245 15.61 12.49 20.82 19.776 5.2 7.286 9.36 14.572 11.45 21.858 2.08 7.285 3.12 13.53 3.12 19.776 0 17.694-4.17 33.306-11.45 45.796-8.33 12.491-17.7 21.858-30.19 30.185-12.49 7.286-26.02 12.49-41.63 16.653-15.61 3.123-31.22 5.204-45.8 5.204-15.61 0-32.26-1.04-47.87-4.163-15.62-3.122-29.15-8.327-41.64-15.612a83.855 83.855 0 01-30.18-30.185c-8.33-12.49-12.49-28.102-12.49-46.838h84.31v-2.081z" fill="#FFFFFF" class="Ibar__logo__text"></path> <path d="M0 481.911V281.028l187.351-58.287v200.882L0 481.911z" fill="#8BC53F"></path> <path d="M187.351 423.623V222.741l126.983 87.431v200.882l-126.983-87.431z" fill="#EBD417"></path> <path d="M126.982 569.341L0 481.911l187.351-58.287 126.983 87.43-187.352 58.287z" fill="#034EA1"></path> <path d="M183.188 212.331l51.001-116.574 65.573 155.085-51.001 116.574-65.573-155.085z" fill="#712E74"></path> <path d="M248.761 367.415l51.001-116.574 171.739-28.102-49.96 115.533-172.78 29.143z" fill="#009FD1"></path> <path d="M299.762 250.842L234.189 95.757l171.739-28.103 65.573 155.085-171.739 28.103z" fill="#F6921E"></path> <path d="M187.352 222.741L59.328 198.802 44.757 71.819 172.78 95.76l14.572 126.982z" fill="#DA2128"></path> <path d="M172.78 95.758L44.757 71.818l70.777-70.776 128.023 23.94-70.777 70.776z" fill="#25BCBD"></path> <path d="M258.129 153.005l-70.777 69.736-14.571-126.982 70.777-70.778 14.571 128.024z" fill="#00844A"></path></svg></a></div> <a aria-label="Frontiers in Pharmacology" href="//www.frontiersin.org/journals/pharmacology" data-event="iBar-a-journalHome" class="Ibar__journalName"><div logoClass="Ibar__logo--mixed" class="Ibar__journalName__container"><div class="Ibar__journal__maskLogo" style="display:none;"><img src="" class="Ibar__journal__logo"></div> <div class="Ibar__journalName"><span>Frontiers in</span> <span> Pharmacology</span></div></div></a> <div parent-data-event="iBar" class="Ibar__dropdown Ibar__dropdown--aboutUs"><button class="Ibar__dropdown__trigger"> About us </button> <div class="Ibar__dropdown__menu"><div class="Ibar__dropdown__menu__header"><button aria-label="Close Dropdown" class="Ibar__dropdown__menu__header__title"> About us </button> <button aria-label="Close Dropdown" class="Ibar__close"></button></div> <div class="Ibar__dropdown__about"><ul class="Ibar__dropdown__about__block"><li class="Ibar__dropdown__about__block__title">Who we are</li> <li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/about/mission" target="_self" data-event="iBar-aboutUs_0-a_whoWeAre">Mission and values</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/about/history" target="_self" data-event="iBar-aboutUs_0-a_whoWeAre">History</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/about/leadership" target="_self" data-event="iBar-aboutUs_0-a_whoWeAre">Leadership</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/about/awards" target="_self" data-event="iBar-aboutUs_0-a_whoWeAre">Awards</a></li></ul><ul class="Ibar__dropdown__about__block"><li class="Ibar__dropdown__about__block__title">Impact and progress</li> <li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/about/impact" target="_self" data-event="iBar-aboutUs_1-a_impactAndProgress">Frontiers' impact</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://progressreport.frontiersin.org/?utm_source=fweb&utm_medium=frep&utm_campaign=pr20" target="_blank" data-event="iBar-aboutUs_1-a_impactAndProgress">Progress Report 2022</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/about/annual-reports" target="_self" data-event="iBar-aboutUs_1-a_impactAndProgress">All annual reports</a></li></ul><ul class="Ibar__dropdown__about__block"><li class="Ibar__dropdown__about__block__title">Publishing model</li> <li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/about/how-we-publish" target="_self" data-event="iBar-aboutUs_2-a_publishingModel">How we publish</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/about/open-access" target="_self" data-event="iBar-aboutUs_2-a_publishingModel">Open access</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/about/fee-policy" target="_self" data-event="iBar-aboutUs_2-a_publishingModel">Fee policy</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/about/peer-review" target="_self" data-event="iBar-aboutUs_2-a_publishingModel">Peer review</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/about/research-integrity" target="_self" data-event="iBar-aboutUs_2-a_publishingModel">Research integrity</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/about/research-topics" target="_self" data-event="iBar-aboutUs_2-a_publishingModel">Research Topics</a></li></ul><ul class="Ibar__dropdown__about__block"><li class="Ibar__dropdown__about__block__title">Services</li> <li class="Ibar__dropdown__about__block__item"><a href="https://publishingpartnerships.frontiersin.org/" target="_blank" data-event="iBar-aboutUs_3-a_services">Societies</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/open-access-agreements/consortia" target="_self" data-event="iBar-aboutUs_3-a_services">National consortia</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/about/open-access-agreements" target="_self" data-event="iBar-aboutUs_3-a_services">Institutional partnerships</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/about/collaborators" target="_self" data-event="iBar-aboutUs_3-a_services">Collaborators</a></li></ul><ul class="Ibar__dropdown__about__block"><li class="Ibar__dropdown__about__block__title">More from Frontiers</li> <li class="Ibar__dropdown__about__block__item"><a href="https://forum.frontiersin.org/" target="_blank" data-event="iBar-aboutUs_4-a_moreFromFrontiers">Frontiers Forum</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersplanetprize.org/" target="_blank" data-event="iBar-aboutUs_4-a_moreFromFrontiers">Frontiers Planet Prize</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://pressoffice.frontiersin.org/" target="_blank" data-event="iBar-aboutUs_4-a_moreFromFrontiers">Press office</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.orgabout/sustainability" target="_self" data-event="iBar-aboutUs_4-a_moreFromFrontiers">Sustainability</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://careers.frontiersin.org/" target="_blank" data-event="iBar-aboutUs_4-a_moreFromFrontiers">Career opportunities</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/about/contact" target="_self" data-event="iBar-aboutUs_4-a_moreFromFrontiers">Contact us</a></li></ul></div></div></div> <a href="https://www.frontiersin.org/journals" data-event="iBar-a-allJournals" class="Ibar__link">All journals</a><a href="https://www.frontiersin.org/articles" data-event="iBar-a-allArticles" class="Ibar__link">All articles</a> <a href="https://www.frontiersin.org/submission/submit?domainid=1&fieldid=62&specialtyid=0&entitytype=2&entityid=176" data-event="iBar-a-submit" class="Ibar__button Ibar__submit">Submit your research</a> <div class="Ibar__spacer"></div> <a href="/search" aria-label="Search" data-event="iBar-a-search" class="Ibar__icon Ibar__icon--search"><span>Search</span></a>    <div class="Ibar__userArea"></div></div></div> <div class="Ibar__menu Ibar__menu--journal"><div class="Ibar__menu__header"><div class="Ibar__logo"><div class="Ibar__logo"><a href="//www.frontiersin.org/" aria-label="Frontiershome" data-event="iBar-a-home" class="Ibar__logo__link"><svg viewBox="0 0 2811 590" fill="none" xmlns="http://www.w3.org/2000/svg" class="Ibar__logo__svg"><path d="M633.872 234.191h-42.674v-57.246h42.674c0-19.776 2.082-35.389 5.204-48.92 4.164-13.53 9.368-23.939 17.695-31.225 8.326-8.326 18.735-13.53 32.266-16.653 13.531-3.123 29.143-5.204 47.878-5.204h21.858c7.286 0 14.572 1.04 21.857 1.04v62.451c-8.326-1.041-16.653-2.082-23.939-2.082-10.408 0-17.694 1.041-23.939 4.164-6.245 3.122-9.368 10.408-9.368 22.898v13.531h53.083v57.246h-53.083v213.372h-89.512V234.191zM794.161 176.945h86.39v47.879h1.041c6.245-17.694 16.653-30.185 31.225-39.552 14.572-9.368 31.225-13.531 49.96-13.531h10.409c3.122 0 7.286 1.041 10.408 2.082v81.185c-6.245-2.082-11.449-3.122-16.653-4.163-5.204-1.041-11.449-1.041-16.654-1.041-11.449 0-20.816 2.082-29.143 5.204-8.327 3.123-15.613 8.327-20.817 14.572-5.204 6.245-10.408 12.49-12.49 20.817-3.123 8.326-4.163 15.612-4.163 23.939v133.228h-88.472V176.945h-1.041zM989.84 312.254c0-19.776 3.122-39.552 10.41-56.205 7.28-17.695 16.65-32.266 29.14-45.797 12.49-13.531 27.06-22.899 44.76-30.185 17.69-7.285 36.43-11.449 57.24-11.449 20.82 0 39.56 4.164 57.25 11.449 17.69 7.286 32.27 17.695 45.8 30.185 12.49 12.49 22.9 28.102 29.14 45.797 7.29 17.694 10.41 36.429 10.41 56.205 0 20.817-3.12 39.552-10.41 57.246-7.29 17.695-16.65 32.266-29.14 44.756-12.49 12.49-28.11 22.899-45.8 30.185-17.69 7.286-36.43 11.449-57.25 11.449-20.81 0-40.59-4.163-57.24-11.449-17.7-7.286-32.27-17.695-44.76-30.185-12.49-12.49-21.86-28.102-29.14-44.756-7.288-17.694-10.41-36.429-10.41-57.246zm88.47 0c0 8.327 1.04 17.694 3.12 26.021 2.09 9.368 5.21 16.653 9.37 23.939 4.16 7.286 9.37 13.531 16.65 17.695 7.29 4.163 15.62 7.285 26.03 7.285 10.4 0 18.73-2.081 26.02-7.285 7.28-4.164 12.49-10.409 16.65-17.695 4.16-7.286 7.29-15.612 9.37-23.939 2.08-9.368 3.12-17.694 3.12-26.021 0-8.327-1.04-17.694-3.12-26.021-2.08-9.368-5.21-16.653-9.37-23.939-4.16-7.286-9.37-13.531-16.65-17.695-7.29-5.204-15.62-7.285-26.02-7.285-10.41 0-18.74 2.081-26.03 7.285-7.28 5.205-12.49 10.409-16.65 17.695-4.16 7.286-7.28 15.612-9.37 23.939-2.08 9.368-3.12 17.694-3.12 26.021zM1306.25 176.945h86.39v37.47h1.04c4.17-7.286 9.37-13.531 15.62-18.735 6.24-5.204 13.53-10.408 20.81-14.572 7.29-4.163 15.62-7.286 23.94-9.367 8.33-2.082 16.66-3.123 24.98-3.123 22.9 0 40.6 4.164 53.09 11.449 13.53 7.286 22.89 16.654 29.14 27.062 6.24 10.409 10.41 21.858 12.49 34.348 2.08 12.49 2.08 22.898 2.08 33.307v172.779h-88.47V316.417v-27.061c0-9.368-1.04-16.654-4.16-23.94-3.13-7.286-7.29-12.49-13.53-16.653-6.25-4.164-15.62-6.245-27.07-6.245-8.32 0-15.61 2.081-21.85 5.204-6.25 3.122-11.45 7.286-14.58 13.531-4.16 5.204-6.24 11.449-8.32 18.735s-3.12 14.572-3.12 21.858v145.717h-88.48V176.945zM1780.88 234.19h-55.17v122.819c0 10.408 3.12 17.694 8.33 20.817 6.24 3.122 13.53 5.204 22.9 5.204 4.16 0 7.28 0 11.45-1.041h11.45v65.573c-8.33 0-15.62 1.041-23.94 2.082-8.33 1.04-16.66 1.041-23.94 1.041-18.74 0-34.35-2.082-46.84-5.205-12.49-3.122-21.86-8.326-29.14-15.612-7.29-7.286-12.49-16.654-14.58-29.144-3.12-12.49-4.16-27.062-4.16-45.797V234.19h-44.76v-57.246h44.76V94.717h88.47v82.227h55.17v57.246zM1902.66 143.639h-88.48V75.984h88.48v67.655zm-89.52 33.307h88.48v270.618h-88.48V176.946zM2024.43 334.111c1.04 18.735 6.25 33.307 16.66 44.756 10.4 11.449 24.98 16.653 43.71 16.653 10.41 0 20.82-2.081 30.19-7.286 9.36-5.204 16.65-12.49 20.81-22.898h83.27c-4.16 15.613-10.41 29.144-19.78 40.593-9.36 11.449-19.77 20.817-31.22 28.102-12.49 7.286-24.98 12.491-39.55 16.654-14.57 3.122-29.15 5.204-43.72 5.204-21.86 0-41.63-3.122-60.37-9.367-18.73-6.246-34.34-15.613-46.83-28.103-12.49-12.49-22.9-27.062-30.19-45.797-7.28-17.694-10.41-38.511-10.41-60.369 0-20.817 4.17-39.552 11.45-57.246 7.29-17.694 17.7-32.266 31.23-44.756 13.53-12.49 29.14-21.858 46.83-29.144 17.7-7.286 36.43-10.408 56.21-10.408 23.94 0 45.8 4.163 63.49 12.49 17.7 8.327 33.31 19.776 44.76 35.389 11.45 15.612 20.81 32.266 26.02 52.042 5.2 19.776 8.33 41.633 7.28 64.532h-199.84v-1.041zm110.33-49.961c-1.04-15.612-6.24-28.102-15.61-39.551-9.37-10.409-21.86-16.654-37.47-16.654s-28.1 5.204-38.51 15.613c-10.41 10.408-16.66 23.939-18.74 40.592h110.33zM2254.46 176.945h86.39v47.879h1.04c6.25-17.694 16.65-30.185 31.23-39.552 14.57-9.368 31.22-13.531 49.96-13.531h10.4c3.13 0 7.29 1.041 10.41 2.082v81.185c-6.24-2.082-11.45-3.122-16.65-4.163-5.21-1.041-11.45-1.041-16.65-1.041-11.45 0-20.82 2.082-29.15 5.204-8.32 3.123-15.61 8.327-20.81 14.572-6.25 6.245-10.41 12.49-12.49 20.817-3.13 8.326-4.17 15.612-4.17 23.939v133.228h-88.47V176.945h-1.04zM2534.45 359.091c0 7.286 1.04 12.49 4.16 17.694 3.12 5.204 6.24 9.368 10.41 12.49 4.16 3.123 9.36 5.204 14.57 7.286 6.24 2.082 11.45 2.082 17.69 2.082 4.17 0 8.33 0 13.53-2.082 5.21-1.041 9.37-3.123 13.53-5.204 4.17-2.082 7.29-5.204 10.41-9.368 3.13-4.163 4.17-8.327 4.17-13.531 0-5.204-2.09-9.367-5.21-12.49-3.12-3.122-7.28-6.245-11.45-8.327-4.16-2.081-9.36-4.163-14.57-5.204-5.2-1.041-9.37-2.081-13.53-3.122-13.53-3.123-28.1-6.245-42.67-9.368-14.58-3.122-28.11-7.286-40.6-12.49-12.49-6.245-22.9-13.531-30.18-23.939-8.33-10.409-11.45-23.94-11.45-42.675 0-16.653 4.16-30.184 11.45-40.592 8.33-10.409 17.69-18.736 30.18-24.981 12.49-6.245 26.02-10.408 40.6-13.53 14.57-3.123 28.1-4.164 41.63-4.164 14.57 0 29.14 1.041 43.71 4.164 14.58 2.081 27.07 7.285 39.56 13.53 12.49 6.245 21.85 15.613 29.14 27.062 7.29 11.45 11.45 26.021 12.49 43.716h-82.23c0-10.409-4.16-18.736-11.45-23.94-7.28-4.163-16.65-7.286-28.1-7.286-4.16 0-8.32 0-12.49 1.041-4.16 1.041-8.32 1.041-12.49 2.082-4.16 1.041-7.28 3.122-9.37 6.245-2.08 3.122-4.16 6.245-4.16 11.449 0 6.245 3.12 11.449 10.41 15.613 6.24 4.163 14.57 7.286 24.98 10.408 10.41 2.082 20.82 5.204 32.27 7.286 11.44 2.082 22.89 4.163 33.3 6.245 13.53 3.123 24.98 7.286 33.31 13.531 9.37 6.245 15.61 12.49 20.82 19.776 5.2 7.286 9.36 14.572 11.45 21.858 2.08 7.285 3.12 13.53 3.12 19.776 0 17.694-4.17 33.306-11.45 45.796-8.33 12.491-17.7 21.858-30.19 30.185-12.49 7.286-26.02 12.49-41.63 16.653-15.61 3.123-31.22 5.204-45.8 5.204-15.61 0-32.26-1.04-47.87-4.163-15.62-3.122-29.15-8.327-41.64-15.612a83.855 83.855 0 01-30.18-30.185c-8.33-12.49-12.49-28.102-12.49-46.838h84.31v-2.081z" fill="#FFFFFF" class="Ibar__logo__text"></path> <path d="M0 481.911V281.028l187.351-58.287v200.882L0 481.911z" fill="#8BC53F"></path> <path d="M187.351 423.623V222.741l126.983 87.431v200.882l-126.983-87.431z" fill="#EBD417"></path> <path d="M126.982 569.341L0 481.911l187.351-58.287 126.983 87.43-187.352 58.287z" fill="#034EA1"></path> <path d="M183.188 212.331l51.001-116.574 65.573 155.085-51.001 116.574-65.573-155.085z" fill="#712E74"></path> <path d="M248.761 367.415l51.001-116.574 171.739-28.102-49.96 115.533-172.78 29.143z" fill="#009FD1"></path> <path d="M299.762 250.842L234.189 95.757l171.739-28.103 65.573 155.085-171.739 28.103z" fill="#F6921E"></path> <path d="M187.352 222.741L59.328 198.802 44.757 71.819 172.78 95.76l14.572 126.982z" fill="#DA2128"></path> <path d="M172.78 95.758L44.757 71.818l70.777-70.776 128.023 23.94-70.777 70.776z" fill="#25BCBD"></path> <path d="M258.129 153.005l-70.777 69.736-14.571-126.982 70.777-70.778 14.571 128.024z" fill="#00844A"></path></svg></a></div></div> <button aria-label="Close Menu" data-event="iBarMenu-btn-closeMenu" class="Ibar__close"></button></div> <div class="Ibar__menu__wrapper"><div class="Ibar__menu__journal"><a href="//www.frontiersin.org/journals/pharmacology" data-event="iBarMenu-a-journalHome"><div class="Ibar__journalName__container"><div class="Ibar__journal__maskLogo" style="display:none;"><img src="" class="Ibar__journal__logo"></div> <div class="Ibar__journalName"><span>Frontiers in</span> <span> Pharmacology</span></div></div></a> <div parent-data-event="iBarMenu" class="Ibar__dropdown"><button class="Ibar__dropdown__trigger"> Sections </button> <div class="Ibar__dropdown__menu"><div class="Ibar__dropdown__menu__header"><button aria-label="Close Dropdown" class="Ibar__dropdown__menu__header__title"> Sections </button> <button aria-label="Close Dropdown" class="Ibar__close"></button></div> <ul class="Ibar__dropdown__sections"><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/cardiovascular-and-smooth-muscle-pharmacology" data-event="iBarJournal-sections-a_id_182">Cardiovascular and Smooth Muscle Pharmacology</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/drug-metabolism-and-transport" data-event="iBarJournal-sections-a_id_199">Drug Metabolism and Transport</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/drugs-outcomes-research-and-policies" data-event="iBarJournal-sections-a_id_202">Drugs Outcomes Research and Policies</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/elsi-in-science-and-genetics" data-event="iBarJournal-sections-a_id_650">ELSI in Science and Genetics</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/ethnopharmacology" data-event="iBarJournal-sections-a_id_184">Ethnopharmacology</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/experimental-pharmacology-and-drug-discovery" data-event="iBarJournal-sections-a_id_183">Experimental Pharmacology and Drug Discovery</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/gastrointestinal-and-hepatic-pharmacology" data-event="iBarJournal-sections-a_id_186">Gastrointestinal and Hepatic Pharmacology</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/inflammation-pharmacology" data-event="iBarJournal-sections-a_id_188">Inflammation Pharmacology</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/integrative-and-regenerative-pharmacology" data-event="iBarJournal-sections-a_id_178">Integrative and Regenerative Pharmacology</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/neuropharmacology" data-event="iBarJournal-sections-a_id_26">Neuropharmacology</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/obstetric-and-pediatric-pharmacology" data-event="iBarJournal-sections-a_id_196">Obstetric and Pediatric Pharmacology</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/pharmacoepidemiology" data-event="iBarJournal-sections-a_id_2186">Pharmacoepidemiology</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/pharmacogenetics-and-pharmacogenomics" data-event="iBarJournal-sections-a_id_198">Pharmacogenetics and Pharmacogenomics</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/pharmacology-of-anti-cancer-drugs" data-event="iBarJournal-sections-a_id_192">Pharmacology of Anti-Cancer Drugs</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/pharmacology-of-infectious-diseases" data-event="iBarJournal-sections-a_id_2216">Pharmacology of Infectious Diseases</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/pharmacology-of-ion-channels-and-channelopathies" data-event="iBarJournal-sections-a_id_179">Pharmacology of Ion Channels and Channelopathies</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/predictive-toxicology" data-event="iBarJournal-sections-a_id_195">Predictive Toxicology</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/renal-pharmacology" data-event="iBarJournal-sections-a_id_1357">Renal Pharmacology</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/respiratory-pharmacology" data-event="iBarJournal-sections-a_id_190">Respiratory Pharmacology</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/translational-pharmacology" data-event="iBarJournal-sections-a_id_1251">Translational Pharmacology</a></li></ul></div></div> <a href="//www.frontiersin.org/journals/pharmacology/articles" data-event="iBar-a-articles" class="Ibar__link">Articles</a><a href="//www.frontiersin.org/journals/pharmacology/research-topics" data-event="iBar-a-researchTopics" class="Ibar__link">Research Topics</a><a href="//www.frontiersin.org/journals/pharmacology/editors" data-event="iBar-a-editorialBoard" class="Ibar__link">Editorial board</a> <div parent-data-event="iBarMenu" class="Ibar__dropdown"><button class="Ibar__dropdown__trigger"> About journal </button> <div class="Ibar__dropdown__menu"><div class="Ibar__dropdown__menu__header"><button aria-label="Close Dropdown" class="Ibar__dropdown__menu__header__title"> About journal </button> <button aria-label="Close Dropdown" class="Ibar__close"></button></div> <div class="Ibar__dropdown__about"><ul class="Ibar__dropdown__about__block"><li class="Ibar__dropdown__about__block__title">Scope</li> <li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/journals/pharmacology/about#about-editors" target="_self" data-event="iBar-aboutJournal_0-a_scope">Field chief editors</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/journals/pharmacology/about#about-scope" target="_self" data-event="iBar-aboutJournal_0-a_scope">Mission & scope</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/journals/pharmacology/about#about-facts" target="_self" data-event="iBar-aboutJournal_0-a_scope">Facts</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/journals/pharmacology/about#about-submission" target="_self" data-event="iBar-aboutJournal_0-a_scope">Journal sections</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/journals/pharmacology/about#about-open" target="_self" data-event="iBar-aboutJournal_0-a_scope">Open access statement</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/journals/pharmacology/about#copyright-statement" target="_self" data-event="iBar-aboutJournal_0-a_scope">Copyright statement</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/journals/pharmacology/about#about-quality" target="_self" data-event="iBar-aboutJournal_0-a_scope">Quality</a></li></ul><ul class="Ibar__dropdown__about__block"><li class="Ibar__dropdown__about__block__title">For authors</li> <li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/journals/pharmacology/for-authors/why-submit" target="_self" data-event="iBar-aboutJournal_1-a_forAuthors">Why submit?</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/journals/pharmacology/for-authors/article-types" target="_self" data-event="iBar-aboutJournal_1-a_forAuthors">Article types</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/journals/pharmacology/for-authors/author-guidelines" target="_self" data-event="iBar-aboutJournal_1-a_forAuthors">Author guidelines</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/journals/pharmacology/for-authors/editor-guidelines" target="_self" data-event="iBar-aboutJournal_1-a_forAuthors">Editor guidelines</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/journals/pharmacology/for-authors/publishing-fees" target="_self" data-event="iBar-aboutJournal_1-a_forAuthors">Publishing fees</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/journals/pharmacology/for-authors/submission-checklist" target="_self" data-event="iBar-aboutJournal_1-a_forAuthors">Submission checklist</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/journals/pharmacology/for-authors/contact-editorial-office" target="_self" data-event="iBar-aboutJournal_1-a_forAuthors">Contact editorial office</a></li></ul></div></div></div></div> <div parent-data-event="iBarMenu" class="Ibar__dropdown Ibar__dropdown--aboutUs"><button class="Ibar__dropdown__trigger"> About us </button> <div class="Ibar__dropdown__menu"><div class="Ibar__dropdown__menu__header"><button aria-label="Close Dropdown" class="Ibar__dropdown__menu__header__title"> About us </button> <button aria-label="Close Dropdown" class="Ibar__close"></button></div> <div class="Ibar__dropdown__about"><ul class="Ibar__dropdown__about__block"><li class="Ibar__dropdown__about__block__title">Who we are</li> <li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/about/mission" target="_self" data-event="iBar-aboutUs_0-a_whoWeAre">Mission and values</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/about/history" target="_self" data-event="iBar-aboutUs_0-a_whoWeAre">History</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/about/leadership" target="_self" data-event="iBar-aboutUs_0-a_whoWeAre">Leadership</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/about/awards" target="_self" data-event="iBar-aboutUs_0-a_whoWeAre">Awards</a></li></ul><ul class="Ibar__dropdown__about__block"><li class="Ibar__dropdown__about__block__title">Impact and progress</li> <li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/about/impact" target="_self" data-event="iBar-aboutUs_1-a_impactAndProgress">Frontiers' impact</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://progressreport.frontiersin.org/?utm_source=fweb&utm_medium=frep&utm_campaign=pr20" target="_blank" data-event="iBar-aboutUs_1-a_impactAndProgress">Progress Report 2022</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/about/annual-reports" target="_self" data-event="iBar-aboutUs_1-a_impactAndProgress">All annual reports</a></li></ul><ul class="Ibar__dropdown__about__block"><li class="Ibar__dropdown__about__block__title">Publishing model</li> <li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/about/how-we-publish" target="_self" data-event="iBar-aboutUs_2-a_publishingModel">How we publish</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/about/open-access" target="_self" data-event="iBar-aboutUs_2-a_publishingModel">Open access</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/about/fee-policy" target="_self" data-event="iBar-aboutUs_2-a_publishingModel">Fee policy</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/about/peer-review" target="_self" data-event="iBar-aboutUs_2-a_publishingModel">Peer review</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/about/research-integrity" target="_self" data-event="iBar-aboutUs_2-a_publishingModel">Research integrity</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/about/research-topics" target="_self" data-event="iBar-aboutUs_2-a_publishingModel">Research Topics</a></li></ul><ul class="Ibar__dropdown__about__block"><li class="Ibar__dropdown__about__block__title">Services</li> <li class="Ibar__dropdown__about__block__item"><a href="https://publishingpartnerships.frontiersin.org/" target="_blank" data-event="iBar-aboutUs_3-a_services">Societies</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/open-access-agreements/consortia" target="_self" data-event="iBar-aboutUs_3-a_services">National consortia</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/about/open-access-agreements" target="_self" data-event="iBar-aboutUs_3-a_services">Institutional partnerships</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/about/collaborators" target="_self" data-event="iBar-aboutUs_3-a_services">Collaborators</a></li></ul><ul class="Ibar__dropdown__about__block"><li class="Ibar__dropdown__about__block__title">More from Frontiers</li> <li class="Ibar__dropdown__about__block__item"><a href="https://forum.frontiersin.org/" target="_blank" data-event="iBar-aboutUs_4-a_moreFromFrontiers">Frontiers Forum</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersplanetprize.org/" target="_blank" data-event="iBar-aboutUs_4-a_moreFromFrontiers">Frontiers Planet Prize</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://pressoffice.frontiersin.org/" target="_blank" data-event="iBar-aboutUs_4-a_moreFromFrontiers">Press office</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.orgabout/sustainability" target="_self" data-event="iBar-aboutUs_4-a_moreFromFrontiers">Sustainability</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://careers.frontiersin.org/" target="_blank" data-event="iBar-aboutUs_4-a_moreFromFrontiers">Career opportunities</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/about/contact" target="_self" data-event="iBar-aboutUs_4-a_moreFromFrontiers">Contact us</a></li></ul></div></div></div> <a href="https://www.frontiersin.org/journals" data-event="iBar-a-allJournals" class="Ibar__link">All journals</a><a href="https://www.frontiersin.org/articles" data-event="iBar-a-allArticles" class="Ibar__link">All articles</a>    <a href="https://www.frontiersin.org/submission/submit?domainid=1&fieldid=62&specialtyid=0&entitytype=2&entityid=176" data-event="iBarMenu-a-submit" class="Ibar__button Ibar__submit">Submit your research</a></div></div> <div class="Ibar__journal"><div class="Ibar__wrapper Ibar__wrapper--journal"><a aria-label="Frontiers in Pharmacology" href="//www.frontiersin.org/journals/pharmacology" data-event="iBarJournal-a-journalHome" class="Ibar__journalName"><div class="Ibar__journalName__container"><div class="Ibar__journal__maskLogo" style="display:none;"><img src="" class="Ibar__journal__logo"></div> <div class="Ibar__journalName"><span>Frontiers in</span> <span> Pharmacology</span></div></div></a> <div parent-data-event="iBarJournal" class="Ibar__dropdown"><button class="Ibar__dropdown__trigger"> Sections </button> <div class="Ibar__dropdown__menu"><div class="Ibar__dropdown__menu__header"><button aria-label="Close Dropdown" class="Ibar__dropdown__menu__header__title"> Sections </button> <button aria-label="Close Dropdown" class="Ibar__close"></button></div> <ul class="Ibar__dropdown__sections"><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/cardiovascular-and-smooth-muscle-pharmacology" data-event="iBarJournal-sections-a_id_182">Cardiovascular and Smooth Muscle Pharmacology</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/drug-metabolism-and-transport" data-event="iBarJournal-sections-a_id_199">Drug Metabolism and Transport</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/drugs-outcomes-research-and-policies" data-event="iBarJournal-sections-a_id_202">Drugs Outcomes Research and Policies</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/elsi-in-science-and-genetics" data-event="iBarJournal-sections-a_id_650">ELSI in Science and Genetics</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/ethnopharmacology" data-event="iBarJournal-sections-a_id_184">Ethnopharmacology</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/experimental-pharmacology-and-drug-discovery" data-event="iBarJournal-sections-a_id_183">Experimental Pharmacology and Drug Discovery</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/gastrointestinal-and-hepatic-pharmacology" data-event="iBarJournal-sections-a_id_186">Gastrointestinal and Hepatic Pharmacology</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/inflammation-pharmacology" data-event="iBarJournal-sections-a_id_188">Inflammation Pharmacology</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/integrative-and-regenerative-pharmacology" data-event="iBarJournal-sections-a_id_178">Integrative and Regenerative Pharmacology</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/neuropharmacology" data-event="iBarJournal-sections-a_id_26">Neuropharmacology</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/obstetric-and-pediatric-pharmacology" data-event="iBarJournal-sections-a_id_196">Obstetric and Pediatric Pharmacology</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/pharmacoepidemiology" data-event="iBarJournal-sections-a_id_2186">Pharmacoepidemiology</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/pharmacogenetics-and-pharmacogenomics" data-event="iBarJournal-sections-a_id_198">Pharmacogenetics and Pharmacogenomics</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/pharmacology-of-anti-cancer-drugs" data-event="iBarJournal-sections-a_id_192">Pharmacology of Anti-Cancer Drugs</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/pharmacology-of-infectious-diseases" data-event="iBarJournal-sections-a_id_2216">Pharmacology of Infectious Diseases</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/pharmacology-of-ion-channels-and-channelopathies" data-event="iBarJournal-sections-a_id_179">Pharmacology of Ion Channels and Channelopathies</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/predictive-toxicology" data-event="iBarJournal-sections-a_id_195">Predictive Toxicology</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/renal-pharmacology" data-event="iBarJournal-sections-a_id_1357">Renal Pharmacology</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/respiratory-pharmacology" data-event="iBarJournal-sections-a_id_190">Respiratory Pharmacology</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/translational-pharmacology" data-event="iBarJournal-sections-a_id_1251">Translational Pharmacology</a></li></ul></div></div> <a href="//www.frontiersin.org/journals/pharmacology/articles" data-event="iBar-a-articles" class="Ibar__link">Articles</a><a href="//www.frontiersin.org/journals/pharmacology/research-topics" data-event="iBar-a-researchTopics" class="Ibar__link">Research Topics</a><a href="//www.frontiersin.org/journals/pharmacology/editors" data-event="iBar-a-editorialBoard" class="Ibar__link">Editorial board</a> <div parent-data-event="iBarJournal" class="Ibar__dropdown"><button class="Ibar__dropdown__trigger"> About journal </button> <div class="Ibar__dropdown__menu"><div class="Ibar__dropdown__menu__header"><button aria-label="Close Dropdown" class="Ibar__dropdown__menu__header__title"> About journal </button> <button aria-label="Close Dropdown" class="Ibar__close"></button></div> <div class="Ibar__dropdown__about"><ul class="Ibar__dropdown__about__block"><li class="Ibar__dropdown__about__block__title">Scope</li> <li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/journals/pharmacology/about#about-editors" target="_self" data-event="iBar-aboutJournal_0-a_scope">Field chief editors</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/journals/pharmacology/about#about-scope" target="_self" data-event="iBar-aboutJournal_0-a_scope">Mission & scope</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/journals/pharmacology/about#about-facts" target="_self" data-event="iBar-aboutJournal_0-a_scope">Facts</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/journals/pharmacology/about#about-submission" target="_self" data-event="iBar-aboutJournal_0-a_scope">Journal sections</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/journals/pharmacology/about#about-open" target="_self" data-event="iBar-aboutJournal_0-a_scope">Open access statement</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/journals/pharmacology/about#copyright-statement" target="_self" data-event="iBar-aboutJournal_0-a_scope">Copyright statement</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/journals/pharmacology/about#about-quality" target="_self" data-event="iBar-aboutJournal_0-a_scope">Quality</a></li></ul><ul class="Ibar__dropdown__about__block"><li class="Ibar__dropdown__about__block__title">For authors</li> <li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/journals/pharmacology/for-authors/why-submit" target="_self" data-event="iBar-aboutJournal_1-a_forAuthors">Why submit?</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/journals/pharmacology/for-authors/article-types" target="_self" data-event="iBar-aboutJournal_1-a_forAuthors">Article types</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/journals/pharmacology/for-authors/author-guidelines" target="_self" data-event="iBar-aboutJournal_1-a_forAuthors">Author guidelines</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/journals/pharmacology/for-authors/editor-guidelines" target="_self" data-event="iBar-aboutJournal_1-a_forAuthors">Editor guidelines</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/journals/pharmacology/for-authors/publishing-fees" target="_self" data-event="iBar-aboutJournal_1-a_forAuthors">Publishing fees</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/journals/pharmacology/for-authors/submission-checklist" target="_self" data-event="iBar-aboutJournal_1-a_forAuthors">Submission checklist</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/journals/pharmacology/for-authors/contact-editorial-office" target="_self" data-event="iBar-aboutJournal_1-a_forAuthors">Contact editorial office</a></li></ul></div></div></div> <div class="Ibar__spacer"></div></div></div> <div class="Ibar__journal Ibar__journal--mix"><div class="Ibar__wrapper Ibar__wrapper--journal"><div class="Ibar__logo"><a href="//www.frontiersin.org/" aria-label="Frontiershome" data-event="iBar-a-home" class="Ibar__logo__link"><svg viewBox="0 0 2811 590" fill="none" xmlns="http://www.w3.org/2000/svg" class="Ibar__logo__svg"><path d="M633.872 234.191h-42.674v-57.246h42.674c0-19.776 2.082-35.389 5.204-48.92 4.164-13.53 9.368-23.939 17.695-31.225 8.326-8.326 18.735-13.53 32.266-16.653 13.531-3.123 29.143-5.204 47.878-5.204h21.858c7.286 0 14.572 1.04 21.857 1.04v62.451c-8.326-1.041-16.653-2.082-23.939-2.082-10.408 0-17.694 1.041-23.939 4.164-6.245 3.122-9.368 10.408-9.368 22.898v13.531h53.083v57.246h-53.083v213.372h-89.512V234.191zM794.161 176.945h86.39v47.879h1.041c6.245-17.694 16.653-30.185 31.225-39.552 14.572-9.368 31.225-13.531 49.96-13.531h10.409c3.122 0 7.286 1.041 10.408 2.082v81.185c-6.245-2.082-11.449-3.122-16.653-4.163-5.204-1.041-11.449-1.041-16.654-1.041-11.449 0-20.816 2.082-29.143 5.204-8.327 3.123-15.613 8.327-20.817 14.572-5.204 6.245-10.408 12.49-12.49 20.817-3.123 8.326-4.163 15.612-4.163 23.939v133.228h-88.472V176.945h-1.041zM989.84 312.254c0-19.776 3.122-39.552 10.41-56.205 7.28-17.695 16.65-32.266 29.14-45.797 12.49-13.531 27.06-22.899 44.76-30.185 17.69-7.285 36.43-11.449 57.24-11.449 20.82 0 39.56 4.164 57.25 11.449 17.69 7.286 32.27 17.695 45.8 30.185 12.49 12.49 22.9 28.102 29.14 45.797 7.29 17.694 10.41 36.429 10.41 56.205 0 20.817-3.12 39.552-10.41 57.246-7.29 17.695-16.65 32.266-29.14 44.756-12.49 12.49-28.11 22.899-45.8 30.185-17.69 7.286-36.43 11.449-57.25 11.449-20.81 0-40.59-4.163-57.24-11.449-17.7-7.286-32.27-17.695-44.76-30.185-12.49-12.49-21.86-28.102-29.14-44.756-7.288-17.694-10.41-36.429-10.41-57.246zm88.47 0c0 8.327 1.04 17.694 3.12 26.021 2.09 9.368 5.21 16.653 9.37 23.939 4.16 7.286 9.37 13.531 16.65 17.695 7.29 4.163 15.62 7.285 26.03 7.285 10.4 0 18.73-2.081 26.02-7.285 7.28-4.164 12.49-10.409 16.65-17.695 4.16-7.286 7.29-15.612 9.37-23.939 2.08-9.368 3.12-17.694 3.12-26.021 0-8.327-1.04-17.694-3.12-26.021-2.08-9.368-5.21-16.653-9.37-23.939-4.16-7.286-9.37-13.531-16.65-17.695-7.29-5.204-15.62-7.285-26.02-7.285-10.41 0-18.74 2.081-26.03 7.285-7.28 5.205-12.49 10.409-16.65 17.695-4.16 7.286-7.28 15.612-9.37 23.939-2.08 9.368-3.12 17.694-3.12 26.021zM1306.25 176.945h86.39v37.47h1.04c4.17-7.286 9.37-13.531 15.62-18.735 6.24-5.204 13.53-10.408 20.81-14.572 7.29-4.163 15.62-7.286 23.94-9.367 8.33-2.082 16.66-3.123 24.98-3.123 22.9 0 40.6 4.164 53.09 11.449 13.53 7.286 22.89 16.654 29.14 27.062 6.24 10.409 10.41 21.858 12.49 34.348 2.08 12.49 2.08 22.898 2.08 33.307v172.779h-88.47V316.417v-27.061c0-9.368-1.04-16.654-4.16-23.94-3.13-7.286-7.29-12.49-13.53-16.653-6.25-4.164-15.62-6.245-27.07-6.245-8.32 0-15.61 2.081-21.85 5.204-6.25 3.122-11.45 7.286-14.58 13.531-4.16 5.204-6.24 11.449-8.32 18.735s-3.12 14.572-3.12 21.858v145.717h-88.48V176.945zM1780.88 234.19h-55.17v122.819c0 10.408 3.12 17.694 8.33 20.817 6.24 3.122 13.53 5.204 22.9 5.204 4.16 0 7.28 0 11.45-1.041h11.45v65.573c-8.33 0-15.62 1.041-23.94 2.082-8.33 1.04-16.66 1.041-23.94 1.041-18.74 0-34.35-2.082-46.84-5.205-12.49-3.122-21.86-8.326-29.14-15.612-7.29-7.286-12.49-16.654-14.58-29.144-3.12-12.49-4.16-27.062-4.16-45.797V234.19h-44.76v-57.246h44.76V94.717h88.47v82.227h55.17v57.246zM1902.66 143.639h-88.48V75.984h88.48v67.655zm-89.52 33.307h88.48v270.618h-88.48V176.946zM2024.43 334.111c1.04 18.735 6.25 33.307 16.66 44.756 10.4 11.449 24.98 16.653 43.71 16.653 10.41 0 20.82-2.081 30.19-7.286 9.36-5.204 16.65-12.49 20.81-22.898h83.27c-4.16 15.613-10.41 29.144-19.78 40.593-9.36 11.449-19.77 20.817-31.22 28.102-12.49 7.286-24.98 12.491-39.55 16.654-14.57 3.122-29.15 5.204-43.72 5.204-21.86 0-41.63-3.122-60.37-9.367-18.73-6.246-34.34-15.613-46.83-28.103-12.49-12.49-22.9-27.062-30.19-45.797-7.28-17.694-10.41-38.511-10.41-60.369 0-20.817 4.17-39.552 11.45-57.246 7.29-17.694 17.7-32.266 31.23-44.756 13.53-12.49 29.14-21.858 46.83-29.144 17.7-7.286 36.43-10.408 56.21-10.408 23.94 0 45.8 4.163 63.49 12.49 17.7 8.327 33.31 19.776 44.76 35.389 11.45 15.612 20.81 32.266 26.02 52.042 5.2 19.776 8.33 41.633 7.28 64.532h-199.84v-1.041zm110.33-49.961c-1.04-15.612-6.24-28.102-15.61-39.551-9.37-10.409-21.86-16.654-37.47-16.654s-28.1 5.204-38.51 15.613c-10.41 10.408-16.66 23.939-18.74 40.592h110.33zM2254.46 176.945h86.39v47.879h1.04c6.25-17.694 16.65-30.185 31.23-39.552 14.57-9.368 31.22-13.531 49.96-13.531h10.4c3.13 0 7.29 1.041 10.41 2.082v81.185c-6.24-2.082-11.45-3.122-16.65-4.163-5.21-1.041-11.45-1.041-16.65-1.041-11.45 0-20.82 2.082-29.15 5.204-8.32 3.123-15.61 8.327-20.81 14.572-6.25 6.245-10.41 12.49-12.49 20.817-3.13 8.326-4.17 15.612-4.17 23.939v133.228h-88.47V176.945h-1.04zM2534.45 359.091c0 7.286 1.04 12.49 4.16 17.694 3.12 5.204 6.24 9.368 10.41 12.49 4.16 3.123 9.36 5.204 14.57 7.286 6.24 2.082 11.45 2.082 17.69 2.082 4.17 0 8.33 0 13.53-2.082 5.21-1.041 9.37-3.123 13.53-5.204 4.17-2.082 7.29-5.204 10.41-9.368 3.13-4.163 4.17-8.327 4.17-13.531 0-5.204-2.09-9.367-5.21-12.49-3.12-3.122-7.28-6.245-11.45-8.327-4.16-2.081-9.36-4.163-14.57-5.204-5.2-1.041-9.37-2.081-13.53-3.122-13.53-3.123-28.1-6.245-42.67-9.368-14.58-3.122-28.11-7.286-40.6-12.49-12.49-6.245-22.9-13.531-30.18-23.939-8.33-10.409-11.45-23.94-11.45-42.675 0-16.653 4.16-30.184 11.45-40.592 8.33-10.409 17.69-18.736 30.18-24.981 12.49-6.245 26.02-10.408 40.6-13.53 14.57-3.123 28.1-4.164 41.63-4.164 14.57 0 29.14 1.041 43.71 4.164 14.58 2.081 27.07 7.285 39.56 13.53 12.49 6.245 21.85 15.613 29.14 27.062 7.29 11.45 11.45 26.021 12.49 43.716h-82.23c0-10.409-4.16-18.736-11.45-23.94-7.28-4.163-16.65-7.286-28.1-7.286-4.16 0-8.32 0-12.49 1.041-4.16 1.041-8.32 1.041-12.49 2.082-4.16 1.041-7.28 3.122-9.37 6.245-2.08 3.122-4.16 6.245-4.16 11.449 0 6.245 3.12 11.449 10.41 15.613 6.24 4.163 14.57 7.286 24.98 10.408 10.41 2.082 20.82 5.204 32.27 7.286 11.44 2.082 22.89 4.163 33.3 6.245 13.53 3.123 24.98 7.286 33.31 13.531 9.37 6.245 15.61 12.49 20.82 19.776 5.2 7.286 9.36 14.572 11.45 21.858 2.08 7.285 3.12 13.53 3.12 19.776 0 17.694-4.17 33.306-11.45 45.796-8.33 12.491-17.7 21.858-30.19 30.185-12.49 7.286-26.02 12.49-41.63 16.653-15.61 3.123-31.22 5.204-45.8 5.204-15.61 0-32.26-1.04-47.87-4.163-15.62-3.122-29.15-8.327-41.64-15.612a83.855 83.855 0 01-30.18-30.185c-8.33-12.49-12.49-28.102-12.49-46.838h84.31v-2.081z" fill="#FFFFFF" class="Ibar__logo__text"></path> <path d="M0 481.911V281.028l187.351-58.287v200.882L0 481.911z" fill="#8BC53F"></path> <path d="M187.351 423.623V222.741l126.983 87.431v200.882l-126.983-87.431z" fill="#EBD417"></path> <path d="M126.982 569.341L0 481.911l187.351-58.287 126.983 87.43-187.352 58.287z" fill="#034EA1"></path> <path d="M183.188 212.331l51.001-116.574 65.573 155.085-51.001 116.574-65.573-155.085z" fill="#712E74"></path> <path d="M248.761 367.415l51.001-116.574 171.739-28.102-49.96 115.533-172.78 29.143z" fill="#009FD1"></path> <path d="M299.762 250.842L234.189 95.757l171.739-28.103 65.573 155.085-171.739 28.103z" fill="#F6921E"></path> <path d="M187.352 222.741L59.328 198.802 44.757 71.819 172.78 95.76l14.572 126.982z" fill="#DA2128"></path> <path d="M172.78 95.758L44.757 71.818l70.777-70.776 128.023 23.94-70.777 70.776z" fill="#25BCBD"></path> <path d="M258.129 153.005l-70.777 69.736-14.571-126.982 70.777-70.778 14.571 128.024z" fill="#00844A"></path></svg></a></div> <a aria-label="Frontiers in Pharmacology" href="//www.frontiersin.org/journals/pharmacology" data-event="iBarJournal-a-journalHome" class="Ibar__journalName"><div logoClass="Ibar__logo--mixed" class="Ibar__journalName__container"><div class="Ibar__journal__maskLogo" style="display:none;"><img src="" class="Ibar__journal__logo"></div> <div class="Ibar__journalName"><span>Frontiers in</span> <span> Pharmacology</span></div></div></a> <div class="Ibar__spacer"></div> <div parent-data-event="iBarJournal" class="Ibar__dropdown"><button class="Ibar__dropdown__trigger"> Sections </button> <div class="Ibar__dropdown__menu"><div class="Ibar__dropdown__menu__header"><button aria-label="Close Dropdown" class="Ibar__dropdown__menu__header__title"> Sections </button> <button aria-label="Close Dropdown" class="Ibar__close"></button></div> <ul class="Ibar__dropdown__sections"><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/cardiovascular-and-smooth-muscle-pharmacology" data-event="iBarJournal-sections-a_id_182">Cardiovascular and Smooth Muscle Pharmacology</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/drug-metabolism-and-transport" data-event="iBarJournal-sections-a_id_199">Drug Metabolism and Transport</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/drugs-outcomes-research-and-policies" data-event="iBarJournal-sections-a_id_202">Drugs Outcomes Research and Policies</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/elsi-in-science-and-genetics" data-event="iBarJournal-sections-a_id_650">ELSI in Science and Genetics</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/ethnopharmacology" data-event="iBarJournal-sections-a_id_184">Ethnopharmacology</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/experimental-pharmacology-and-drug-discovery" data-event="iBarJournal-sections-a_id_183">Experimental Pharmacology and Drug Discovery</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/gastrointestinal-and-hepatic-pharmacology" data-event="iBarJournal-sections-a_id_186">Gastrointestinal and Hepatic Pharmacology</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/inflammation-pharmacology" data-event="iBarJournal-sections-a_id_188">Inflammation Pharmacology</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/integrative-and-regenerative-pharmacology" data-event="iBarJournal-sections-a_id_178">Integrative and Regenerative Pharmacology</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/neuropharmacology" data-event="iBarJournal-sections-a_id_26">Neuropharmacology</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/obstetric-and-pediatric-pharmacology" data-event="iBarJournal-sections-a_id_196">Obstetric and Pediatric Pharmacology</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/pharmacoepidemiology" data-event="iBarJournal-sections-a_id_2186">Pharmacoepidemiology</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/pharmacogenetics-and-pharmacogenomics" data-event="iBarJournal-sections-a_id_198">Pharmacogenetics and Pharmacogenomics</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/pharmacology-of-anti-cancer-drugs" data-event="iBarJournal-sections-a_id_192">Pharmacology of Anti-Cancer Drugs</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/pharmacology-of-infectious-diseases" data-event="iBarJournal-sections-a_id_2216">Pharmacology of Infectious Diseases</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/pharmacology-of-ion-channels-and-channelopathies" data-event="iBarJournal-sections-a_id_179">Pharmacology of Ion Channels and Channelopathies</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/predictive-toxicology" data-event="iBarJournal-sections-a_id_195">Predictive Toxicology</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/renal-pharmacology" data-event="iBarJournal-sections-a_id_1357">Renal Pharmacology</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/respiratory-pharmacology" data-event="iBarJournal-sections-a_id_190">Respiratory Pharmacology</a></li><li class="Ibar__dropdown__sections__item"><a href="/journals/pharmacology/sections/translational-pharmacology" data-event="iBarJournal-sections-a_id_1251">Translational Pharmacology</a></li></ul></div></div> <a href="//www.frontiersin.org/journals/pharmacology/articles" data-event="iBar-a-articles" class="Ibar__link">Articles</a><a href="//www.frontiersin.org/journals/pharmacology/research-topics" data-event="iBar-a-researchTopics" class="Ibar__link">Research Topics</a><a href="//www.frontiersin.org/journals/pharmacology/editors" data-event="iBar-a-editorialBoard" class="Ibar__link">Editorial board</a> <div parent-data-event="iBarJournal" class="Ibar__dropdown"><button class="Ibar__dropdown__trigger"> About journal </button> <div class="Ibar__dropdown__menu"><div class="Ibar__dropdown__menu__header"><button aria-label="Close Dropdown" class="Ibar__dropdown__menu__header__title"> About journal </button> <button aria-label="Close Dropdown" class="Ibar__close"></button></div> <div class="Ibar__dropdown__about"><ul class="Ibar__dropdown__about__block"><li class="Ibar__dropdown__about__block__title">Scope</li> <li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/journals/pharmacology/about#about-editors" target="_self" data-event="iBar-aboutJournal_0-a_scope">Field chief editors</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/journals/pharmacology/about#about-scope" target="_self" data-event="iBar-aboutJournal_0-a_scope">Mission & scope</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/journals/pharmacology/about#about-facts" target="_self" data-event="iBar-aboutJournal_0-a_scope">Facts</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/journals/pharmacology/about#about-submission" target="_self" data-event="iBar-aboutJournal_0-a_scope">Journal sections</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/journals/pharmacology/about#about-open" target="_self" data-event="iBar-aboutJournal_0-a_scope">Open access statement</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/journals/pharmacology/about#copyright-statement" target="_self" data-event="iBar-aboutJournal_0-a_scope">Copyright statement</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/journals/pharmacology/about#about-quality" target="_self" data-event="iBar-aboutJournal_0-a_scope">Quality</a></li></ul><ul class="Ibar__dropdown__about__block"><li class="Ibar__dropdown__about__block__title">For authors</li> <li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/journals/pharmacology/for-authors/why-submit" target="_self" data-event="iBar-aboutJournal_1-a_forAuthors">Why submit?</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/journals/pharmacology/for-authors/article-types" target="_self" data-event="iBar-aboutJournal_1-a_forAuthors">Article types</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/journals/pharmacology/for-authors/author-guidelines" target="_self" data-event="iBar-aboutJournal_1-a_forAuthors">Author guidelines</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/journals/pharmacology/for-authors/editor-guidelines" target="_self" data-event="iBar-aboutJournal_1-a_forAuthors">Editor guidelines</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/journals/pharmacology/for-authors/publishing-fees" target="_self" data-event="iBar-aboutJournal_1-a_forAuthors">Publishing fees</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/journals/pharmacology/for-authors/submission-checklist" target="_self" data-event="iBar-aboutJournal_1-a_forAuthors">Submission checklist</a></li><li class="Ibar__dropdown__about__block__item"><a href="https://www.frontiersin.org/journals/pharmacology/for-authors/contact-editorial-office" target="_self" data-event="iBar-aboutJournal_1-a_forAuthors">Contact editorial office</a></li></ul></div></div></div> <div class="Ibar__spacer"></div> <a href="https://www.frontiersin.org/submission/submit?domainid=1&fieldid=62&specialtyid=0&entitytype=2&entityid=176" data-event="iBarJournal-a-submit" class="Ibar__button Ibar__submit"><span>Submit</span> <span> your research</span></a> <a href="/search" aria-label="Search" data-event="iBar-a-search" class="Ibar__icon Ibar__icon--search"><span>Search</span></a>    <div class="Ibar__userArea"></div></div></div></nav> <div class="ArticlePage"><div><div class="Layout Layout--withAside Layout--withIbarMix ArticleDetails"> <main class="Layout__main"> <div class="ArticleDetails__main"><div class="ArticleLayoutHeader"><div class="ArticleLayoutHeader__info"><p class="ArticleLayoutHeader__info__title"> ORIGINAL RESEARCH article </p> <p class="ArticleLayoutHeader__info__journalDate"><span>Front. Pharmacol.</span> <span>, 26 June 2023</span></p> <p class="ArticleLayoutHeader__info__journalDate"> Sec. Translational Pharmacology </p> <p class="ArticleLayoutHeader__info__doiVolume"><span> Volume 14 - 2023 | </span> <a href="https://doi.org/10.3389/fphar.2023.1145962" class="ArticleLayoutHeader__info__doi"> https://doi.org/10.3389/fphar.2023.1145962 </a></p> </div>  <p class="ArticleLayoutHeader__isPartOfRT"><span class="ArticleLayoutHeader__isPartOfRT__label">This article is part of the Research Topic</span> <span class="ArticleLayoutHeader__isPartOfRT__title">The Practical Implication of Clinical Pharmacokinetics in Drug Development, Pharmaceuticals Analysis, and Clinical Research</span> <span class="Link__wrapper"><a aria-label="View all 6 articles" href="https://www.frontiersin.org/research-topics/45495/the-practical-implication-of-clinical-pharmacokinetics-in-drug-development-pharmaceuticals-analysis-and-clinical-research/magazine" target="_self" data-event="customLink-link-a_viewAll6Articles" class="Link Link--linkType Link--maincolor Link--medium Link--icon Link--chevronRight Link--right"><span>View all 6 articles</span></a></span></p></div> <div class="ArticleDetails__main__content"><div class="ArticleDetails__main__content__main ArticleDetails__main__content__main--fullArticle"><div class="JournalAbstract"><div class="JournalAbstract__titleWrapper"><h1>Determination of α1-acid glycoprotein (AGP) concentration by HPLC in patients following local infiltration analgesia for primary total hip arthroplasty and its relation to ropivacaine (total and unbound)</h1> </div> </div> <div class="JournalFullText"><div class="JournalAbstract"><a id="h1" name="h1"></a><div class="authors"><span class="author-wrapper notranslate"><a href="https://loop.frontiersin.org/people/1417926" class="user-id-1417926"><img class="pr5" src="https://loop.frontiersin.org/images/profile/1417926/74" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';" alt="Muhammad Abbas
">Muhammad Abbas</a><sup>1</sup>*</span><span class="author-wrapper notranslate"><a href="https://loop.frontiersin.org/people/1109038" class="user-id-1109038"><img class="pr5" src="https://loop.frontiersin.org/images/profile/1109038/74" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';" alt="Manal A. Alossaimi">Manal A. Alossaimi</a><sup>2</sup></span><span class="author-wrapper notranslate"><img class="pr5" src="https://loop.frontiersin.org/cdn/images/profile/default_32.jpg" alt="Abdulmalik S. A. Altamimi" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';">Abdulmalik S. A. Altamimi<sup>2</sup></span><span class="author-wrapper notranslate"><img class="pr5" src="https://loop.frontiersin.org/cdn/images/profile/default_32.jpg" alt="Mai Alajaji" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';">Mai Alajaji<sup>3</sup></span><span class="author-wrapper notranslate"><a href="https://loop.frontiersin.org/people/2176267" class="user-id-2176267"><img class="pr5" src="https://loop.frontiersin.org/images/profile/2176267/74" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';" alt="David G. Watson">David G. Watson</a><sup>4</sup></span><span class="author-wrapper notranslate"><img class="pr5" src="https://loop.frontiersin.org/cdn/images/profile/default_32.jpg" alt="Sayyed I. Shah" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';">Sayyed I. Shah<sup>1</sup></span><span class="author-wrapper notranslate"><img class="pr5" src="https://loop.frontiersin.org/cdn/images/profile/default_32.jpg" alt="Yasar Shah" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';">Yasar Shah<sup>1</sup></span><span class="author-wrapper notranslate"><img class="pr5" src="https://loop.frontiersin.org/cdn/images/profile/default_32.jpg" alt="Mohammad S. Anwar" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';">Mohammad S. Anwar<sup>5</sup></span></div><ul class="notes"><li><span><sup>1</sup></span>Department of Pharmacy, Abdul Wali Khan University Mardan, Mardan, Pakistan</li><li><span><sup>2</sup></span>Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdul Aziz University, Al-Kharj, Saudi Arabia</li><li><span><sup>3</sup></span>College of Pharmacy, King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia</li><li><span><sup>4</sup></span>Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom</li><li><span><sup>5</sup></span>Department of Pharmacy, University of Swabi, Swabi, Pakistan</li></ul><p class="mb15"><b>Introduction:</b> This study was performed to determine the levels of α1-acid glycoprotein (AGP) in old-age patients undergoing total hip arthroplasty. AGP is considered an acute phase protein produced during the acute phase reaction in the body to various stimuli; their proper monitoring is thus important.</p><p class="mb15"><b>Methods:</b> In order to study how AGP concentrations in old age patients change in response to surgical stress (total hip arthroplasty), a high-performance liquid chromatography assay was performed to measure AGP levels. AGP was isolated from the plasma by adding perchloric acid and was analyzed using PLRP-S 4000°A column. The mobile phase consisted of 1 mL TFA/L of water (Solvent A pH 2) and 1 mL TFA/L of acetonitrile (Solvent B). The gradient used was as follows: 0 min 18% B and 82% A, 15 min 60% B and 40% A, and 17 min 60% B and 40% A followed by column re-equilibration for 7 min before the next injection. AGP peak was obtained between 8.8 and 8.9 min. The method was fully optimised according to established guidelines.</p><p class="mb15"><b>Results:</b> The data obtained were analyzed on ChromQuest software. AGP concentrations were determined in all samples, including baseline and samples taken at different timed intervals. The peak for AGP was obtained between 8.8 and 8.9 min for both standard AGP and patient plasma. The graphs indicate that AGP concentration in almost all patient samples increased considerably, especially after 4 h and 24 h—for example, initial concentration in patient 1 was 10.36 mg/100 mL but, after 24 h, increased to 23.50 mg/100 mL. There was thus almost a 13 mg/100 mL increase in 24 h, which is confirmed by AGP concentration increasing after various conditions, including surgery. The increased plasma protein binding was comparatively associated with the unchanged free fraction of the drug.</p><p class="mb15"><b>Conclusion:</b> This surgically induced increase in AGP concentration resulted in increased plasma protein binding of the drug (ropivacaine), which in turn kept the free portion of ropivacaine stable during the postoperative period.</p><div class="clear"></div></div><div class="JournalFullText"><a id="h2" name="h2"></a><h2>1 Introduction</h2><p class="mb15">Drug binding to different proteins in plasma may be significantly important in drug therapy because drug protein binding serves as a depot for the drug and has an influence on the pharmacokinetic and pharmacodynamic parameters and metabolism of the compound (<a href="#B25">Zeitlinger et al., 2011</a>). The pharmacological action of the drug is only due to the unbound portion of the drug and not to the total drug present in the plasma (<a href="#B13">Kratochwil et al., 2002</a>; <a href="#B2">Banker et al., 2003</a>). Thus, the effect of plasma protein binding on the pharmacokinetic and pharmacodynamic parameters needs careful attention. Many cases have been reported where a small change in plasma protein binding resulted in clinically vital changes in the pharmacokinetic parameters of the drug (<a href="#B19">Schmidt et al., 2010</a>). “Unbound fraction” is the concentration of a drug which is not bound to plasma proteins, and only this concentration of the drug produces the pharmacological effect. This unbound concentration varies during the dosing interval and must be accurately and correctly explained to determine the drug's effect (<a href="#B18">Roberts et al., 2013</a>). Drug binding to plasma proteins plays a vital role in determining the diffusion rate of the drug between extracellular and intracellular space; therefore, any change in this diffusion affects pharmacokinetic parameters, including the distribution volume and the clearance rate of the drug (<a href="#B3">Bohnert and Gan, 2013</a>). Generally, in cases of highly protein-bound drugs, a little change in protein binding is responsible for significant changes in the unbound concentration of drug, thereby increasing the clearance and volume of distribution (<a href="#B3">Bohnert and Gan, 2013</a>; <a href="#B18">Roberts et al., 2013</a>).</p><p class="mb15">Acute phase proteins (α1-acid glycoprotein—AGP or AAP) are produced during the acute phase reaction in the body to various stimuli and play a role in the defence response shown by the body. The initiation of acute phase reactions in the body prevents any further injury by removing any harmful material and initiating the repair process to restore the organ to normal function. Their levels also inform us about the progression of the disease or inflammatory response by monitoring their concentrations in the blood. The changes in the plasma concentration of these proteins lead to altered drug binding and ultimately affect the pharmacokinetic and pharmacodynamic parameters of the drug (<a href="#B22">Tesseromatis et al., 2011</a>).</p><p class="mb15">Among the acute phase proteins, AGP is the most important (<a href="#B17">Rice et al., 1997</a>; <a href="#B22">Tesseromatis et al., 2011</a>). It is also called orosomucoid (ORM) and is the main protein responsible for binding basic drugs (<a href="#B23">Wood and Wood, 1981</a>; <a href="#B14">Kremer et al., 1988</a>; <a href="#B4">Booker et al., 1996</a>; <a href="#B7">Fournier et al., 2000</a>; <a href="#B9">Hochepied et al., 2003</a>; <a href="#B22">Tesseromatis et al., 2011</a>; <a href="#B10">Huang and Ung, 2013</a>; <a href="#B21">Taguchi et al., 2013</a>). AGP was first described by Karl Schmid and Richard J. Winzler and their colleagues in 1950; they considered it an unusual protein because of its low p<em>I</em> value, which ranges from 2.8–3.8 and has a comparatively high content of carbohydrate (45% w/w) (<a href="#B12">Kishino and Miyazaki, 1997</a>; <a href="#B15">Kremmer et al., 2004</a>). AGP was considered as having the highest carbohydrate content of any protein until the characterisation of galactoglycoprotein in 1980, which has a 76% carbohydrate content (<a href="#B8">Hellerstein et al., 1985</a>; <a href="#B7">Fournier et al., 2000</a>; <a href="#B24">Xuan and Hage, 2005</a>). AGP is also reported as playing a role in drug–drug interactions due to the displacement of drugs and other endogenous molecules from their binding sites, resulting in significant clinical implications (<a href="#B22">Tesseromatis et al., 2011</a>).</p><p class="mb15">The concentration of AGP in serum increases in various conditions, like post-surgical inflammation due to burn injury, cancer, and various other conditions (<a href="#B8">Hellerstein et al., 1985</a>; <a href="#B12">Kishino and Miyazaki, 1997</a>; <a href="#B16">Larsson et al., 1997</a>; <a href="#B9">Hochepied et al., 2003</a>; <a href="#B10">Huang and Ung, 2013</a>; <a href="#B6">Eckersall and Schmidt, 2014</a>). AGP synthesis mostly occurs in the liver, and then it is secreted by hepatocytes (<a href="#B22">Tesseromatis et al., 2011</a>; <a href="#B11">Keser et al., 2021</a>). However, there is also evidence of extra hepatic synthesis, which is production of AGP in places apart from hepatic tissue like human breast epithelial cells, the kidney, adipose tissue, and the spleen, thymus, and heart (<a href="#B9">Hochepied et al., 2003</a>). There is also variation in the levels of AGP among healthy individuals depending on age, sex, and hormonal variations (<a href="#B10">Huang and Ung, 2013</a>). The effectiveness of a drug in these cases depends on whether it is acidic in nature or a basic drug, as well on whether the drug binds to the albumin, to which acidic drugs normally bind, or to AGP, to which basic drugs bind. Drug displacement from protein binding sites by another strongly binding drug will also have a significant effect on the concentration of the displaced drug; dose adjustment should be taken into consideration in the use of such drugs (<a href="#B18">Roberts et al., 2013</a>; <a href="#B5">Bteich, 2019</a>).</p><a id="h3" name="h3"></a><h2>2 Methodology</h2><h3 class="pt0">2.1 Patients</h3><p class="mb0">We measured AGP in 20 patients (12 male and 8 female patients) aged 65 years or over undergoing unilateral total hip arthroplasty following high-volume, high-dose local infiltration analgesia. The study protocol was approved by the Regional Ethics Committee and conducted in accordance with the Helsinki Declaration (NCT01873313) from August 2012 to March 2013 in Golden Jubilee Hospital, Glasgow Scotland. Ten blood samples at different timed intervals were taken from each patient, and AGP was determined. A total of 200 samples were thus analysed for AGP. (20*10 = 200). Local anaesthetic infiltration was performed intra-operatively by the surgeon using 180 mL plain ropivacaine 0.2%. Circumferential infiltration of the deep and peri-capsular tissues with up to 80 mL was followed by infiltration of the gluteal muscles and fascia lata with approximately 70 mL. Finally, 30 mL was used to infiltrate the subcutaneous tissues and skin, completing the total of 180 mL.</p><h3 class="pt0">2.2 Chemicals and blood plasma for AGP analysis</h3><p class="mb0">Human AGP (standard), trifluoroacetic acid, and perchloric acid (70%) were purchased from Sigma Aldrich (UK). HPLC-grade water was produced by a Direct-Q 3 Ultrapure Water System from Millipore, UK. HPLC-grade acetonitrile (ACN) was purchased from Fisher Scientific, United Kingdom. Blank plasma was provided by the Blood Transfusion Service of Gartnavel Hospital, Glasgow. Plasma samples were obtained from Dr Mike Gill from patients undergoing hip joint surgery at the Golden Jubilee Hospital in Clydebank. The samples were stored at −20°C until analysis.</p><h3 class="pt0">2.3 HPLC analysis</h3><p class="mb0">A high-performance liquid chromatographic (HPLC) system was used in the analysis and consisted of a SpectraSYSTEM P2000 gradient pump, a SpectraSYSTEM AS3000 autosampler (equipped with a Type 7010-150 Rheodyne injection valve (20 µL loop)), and a SpectraSYSTEM UV 1000 detector. The column used in the analysis was a PLRP-S 4000°A column (50 mm × 4.6 mm I.D., 5 µm particle size, Agilent Technologies). The pressure maintained at the column head was about 9,000 psi. The mobile phase consisted of 1 mL TFA/L of water (Solvent A pH 2) and 1 mL TFA/L of acetonitrile (Solvent B). The gradient used was as follows: 0 min 18% B and 82% A, 15 min 60% B and 40% A, and 17 min 60% B and 40% A followed by column re-equilibration for 7 min before the next injection. The flow rate of the mobile phase was 1 mL/min. The detection wavelength was set to 220 nm. The column was kept at room temperature. The data acquired were processed using ChromQuest software.</p><a id="h3-1" name="h3-1"></a><h3 class="pt0">2.4 Standards preparation</h3><p class="mb0">Stock solution of AGP was prepared at a concentration of 2 mg/mL in water. Different calibration solutions were then prepared from the stock solution by diluting it in 0.5 M perchloric acid. Different standards at concentrations of 6.25 mg/100 mL (0.0625 mg/mL), 12.5 mg/100 mL (0.125 mg/mL), 25 mg/100 mL (0.25 mg/mL), 50 mg/100 mL (0.5 mg/mL), and 100 mg/100 mL (1 mg/mL) were prepared and directly injected into the chromatographic system.</p><a id="h3-2" name="h3-2"></a><h3 class="pt0">2.5 Sample preparation</h3><p class="mb0">Venous blood samples from each patient participating in the study were taken at 5, 10, 15, 20, 25, and 30 min, then 1, 4, and 24 h following the injection of local anaesthetic, at the Golden Jubilee Hospital in Clydebank. The samples were then transferred to the University of Strathclyde, Glasgow, for analysis.</p><p class="mb0">The concentrations of AGP in all the patient plasma were then determined as follows: to 50 µL of patient or control plasma, 100 µL of 0.5 M of perchloric acid was added and was vortexed for 20 S in an Eppendorf tube to mix it thoroughly. The acidified plasma was then centrifuged at 9,000 rpm for 5 min at room temperature. The supernatant was then transferred to the insert in the HPLC vial for analysis. Both the extracted standards and samples were stored at 4°C before being chromatographed.</p><p class="mb0">The AGP concentration was then calculated from its linear correlation versus the values of peak areas obtained from the perchloric acid extract, expressed as mg/100 mL of plasma.</p><h3 class="pt0">2.6 Method validation</h3><p class="mb0">The method was validated according to ICH guidelines.</p><h4>2.6.1 Linearity</h4><p class="mb0">The method’s linearity was established using the standards for AGP dissolved in perchloric acid as described in <a href="#h3-1">Section 2.4</a>.</p><h4>2.6.2 Recovery</h4><p class="mb0">In order to determine the accuracy of the extraction procedure, the recovery of AGP by perchloric acid extraction was determined. AGP was added to a constant volume of plasma (50 μL) in two different concentrations (25 and 50 mg/100 mL) and then mixed with perchloric acid as before in order to prepare a standard addition curve.</p><h4>2.6.3 Accuracy and precision</h4><p class="mb0">The within-run reproducibility of retention time and peak area was examined by repeated injection (<em>n</em> = 3) of an AGP standard (50 mg/100 mL). Three replicates prepared from the 50 μL amounts of the pooled plasma QC sample were run on three different occasions to calculate within- and between-run precision.</p><h4>2.6.4 Reproducibility</h4><p class="mb0">Replicates of the same QC samples (50 mg/100 mL) were run alongside the patient samples to monitor the performance of each assay.</p><h4>2.6.5 Sensitivity</h4><p class="mb0">The sensitivity of the method was determined in standard solutions and blank plasma spiked with the analyte. The limit of detection was defined as the minimum concentration for which a signal-to-noise ratio of 3 was obtained; for LOQ, a signal-to-noise ratio of 10 was considered.</p><h4>2.6.6 Application of the method to patient plasma</h4><p class="mb0">To determine the clinical relevance of the method, the concentration of AGP was identified and determined in the plasma of old-age hip joint surgery patients. The procedure was discussed in <a href="#h3-2">Section 2.5</a>.</p><h3 class="pt0">2.7 Ropivacaine determination</h3><p class="mb0">A fully validated method was developed on LC-MS to determine the free and bound portions of ropivacaine and published in <a href="#B1">Abbas et al. (2013</a>).</p><a id="h4" name="h4"></a><h2>3 Results</h2><p class="mb15">The normal mean value for AGP concentration in the plasma is 77 mg/100 mL (<a href="#B4">Booker et al., 1996</a>). However, there is great variation of this value among individuals. The results we obtained in our analysis gave concentrations which were generally below those specified by previous studies.</p><h3 class="pt0">3.1 Results of standard AGP samples and patient plasma</h3><p class="mb0">The AGP concentrations were analysed in the plasma of 20 hip joint surgery patients. These samples were taken at 5 min, 10 min, 15 min, 20 min, 25 min, 30 min, 1 h, 4 h, and 24 h. <a href="#F1">Figure 1</a> shows a typical chromatogram of the AGP standard injected directly into the chromatographic system, and <a href="#F2">Figure 2</a> shows a chromatogram of the AGP in patient plasma following removal of the rest of the protein with 0.5 M perchloric acid. The peak for AGP was obtained between 8.8 and 8.9 min. This method works very well for determining AGP, and there is minimal interference from other serum proteins like HSA, which is precipitated out almost completely by the perchloric acid; AGP remains in solution because of its high water solubility, which is due to its 40% carbohydrate content (<a href="#B20">Stumpe et al., 2006</a>).</p><div class="DottedLine"></div><div class="Imageheaders">FIGURE 1</div><div class="FigureDesc"><a href="https://www.frontiersin.org/files/Articles/1145962/fphar-14-1145962-HTML-r3/image_m/fphar-14-1145962-g001.jpg" name="Figure1" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/1145962/fphar-14-1145962-HTML-r3/image_m/fphar-14-1145962-g001.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/1145962/fphar-14-1145962-HTML-r3/image_m/fphar-14-1145962-g001.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/1145962/fphar-14-1145962-HTML-r3/image_m/fphar-14-1145962-g001.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/1145962/fphar-14-1145962-HTML-r3/image_m/fphar-14-1145962-g001.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/1145962/fphar-14-1145962-HTML-r3/image_m/fphar-14-1145962-g001.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/1145962/fphar-14-1145962-HTML-r3/image_m/fphar-14-1145962-g001.jpg" alt="www.frontiersin.org" id="F1" loading="lazy"> </picture> </a><p><b>FIGURE 1</b>. Typical chromatogram of an unextracted aqueous standard containing 50 mg/100 mL of AGP. The elution was performed on a PLRP-S 4000°A column (50 mm × 4.6 mm I.D., 5 µm particle size, Agilent Technologies). The mobile phase consisted of 1 mL TFA/L of water (Solvent A) and 1 mL TFA/L of acetonitrile (Solvent B). The gradient used was 0 min 18% B, 15 min 60% B, and 17 min 60% B followed by column re-equilibration for 7 min before the next injection. The flow rate of the mobile phase was 1 mL/min. The detection wavelength was set to 220 nm. Retention time observed was 8.9 min.</p></div><div class="clear"></div><div class="DottedLine"></div><div class="Imageheaders">FIGURE 2</div><div class="FigureDesc"><a href="https://www.frontiersin.org/files/Articles/1145962/fphar-14-1145962-HTML-r3/image_m/fphar-14-1145962-g002.jpg" name="Figure2" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/1145962/fphar-14-1145962-HTML-r3/image_m/fphar-14-1145962-g002.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/1145962/fphar-14-1145962-HTML-r3/image_m/fphar-14-1145962-g002.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/1145962/fphar-14-1145962-HTML-r3/image_m/fphar-14-1145962-g002.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/1145962/fphar-14-1145962-HTML-r3/image_m/fphar-14-1145962-g002.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/1145962/fphar-14-1145962-HTML-r3/image_m/fphar-14-1145962-g002.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/1145962/fphar-14-1145962-HTML-r3/image_m/fphar-14-1145962-g002.jpg" alt="www.frontiersin.org" id="F2" loading="lazy"> </picture> </a><p><b>FIGURE 2</b>. Typical chromatogram of AGP extracted from 50 µL of patient plasma. Analysis was performed on PLRP-S 4000°A column (50 mm × 4.6 mm I.D., 5 µm particle size, Agilent Technologies). The mobile phase consisted of 1 mL TFA/L of water (Solvent A) and 1 mL TFA/L of acetonitrile (Solvent B). The gradient used was 0 min 18% B, 15 min 60% B, and 17 min 60% B followed by column re-equilibration for 7 min before the next injection. The flow rate of the mobile phase was 1 mL/min. The detection wavelength was set to 220 nm. Retention time observed was 8.89 min.</p></div><div class="clear"></div><div class="DottedLine"></div><h3 class="pt0">3.2 Method validation</h3><h4>3.2.1 Linearity</h4><p class="mb0">The calibration curve obtained by plotting the areas of the AGP peaks versus AGP concentration on different days was linear (calibration curve added in <a href="#SM1">Supplementary Material</a>). The data were obtained for the calibration curve on three different days, and the average of these data was used for the calibration curve. The curve covered the concentration range from 6 mg/100 mL to 100 mg/100 mL, which also covered the concentration of AGP in the patient plasma.</p><h4>3.2.2 Recovery</h4><p class="mb0">In the recovery test, the recovery after liquid–liquid extraction with perchloric acid of 25 mg/100 mL spiking of AGP into plasma was 91.7% ± 8.9% (<em>n</em> = 6), and, for 50 mg/100 mL spiking, the recovery was 90.1% ± 3.7% (<em>n</em> = 6).</p><h4>3.2.3 Accuracy and precision</h4><p class="mb0">The within-run precision of the extraction/HPLC procedure ranged from ±1.2% to ±3.8%, and the between-run precision was ±6.1%.</p><h4>3.2.4 Reproducibility</h4><p class="mb0">Having established linearity, a single-point standard of 50 mg/100 mL was run every day with the patient samples, and results were always well within limits.</p><h4>3.2.5 Sensitivity</h4><p class="mb0">The method was sensitive enough to determine the lowest level of AGP 5 mg/100 mL (LOD), while LOQ was found to be 10 mg/100 mL.</p><h4>3.2.6 Application of the method to patient plasma</h4><p class="mb0">The results for the AGP concentrations in patients receiving a continuous infusion of a local anaesthetic ropivacaine following total hip arthroplasty are presented in <a href="#F4">Figure 4</a>.</p><a id="h5" name="h5"></a><h2>4 Discussion</h2><p class="mb15">The margin of therapeutic safety for many drugs like anaesthetics should be considered in older age because the body's ageing process may result in toxicity of the drugs. Very little data have been published regarding the binding of local anaesthetics to plasma proteins. This study was performed to determine the level of AGP in the plasma of old-aged hip joint surgery patients.</p><p class="mb15">The level of AGP in the plasma increased during the study period, which indicated that the level of AGP increases during or following surgical procedures. Similar results were shown in a previous study (<a href="#B3">Bohnert and Gan, 2013</a>) which determined the concentration of AGP in neonates and also by two other studies <a href="#B8">Hellerstein et al. (1985</a>) and <a href="#B22">Tesseromatis et al. (2011</a>).</p><p class="mb15">As can be seen from graphs of the results (<a href="#F4">Figure 4</a>), nearly all patients had AGP levels which were higher after 4 h and 24 h than early timed samples. This increase in AGP level is directly related to plasma protein binding, which increases in the samples taken after 24 h. The increased plasma protein binding was comparatively associated with the unchanged free fraction of the drug. As the effect of the drug is mainly due to its free or unbound portion, any altered concentration of AGP will ultimately affect the level of the unbound portion of the drug and its subsequent effect. This surgically related increase in AGP concentration resulted in increased plasma protein binding of the drug (ropivacaine), which in turn kept the free portion of ropivacaine stable and within limits during the postoperative period, as shown in <a href="#F3">Figure 3</a>. A detailed method regarding ropivacaine determination was published in <a href="#B1">Abbas et al. (2013</a>).</p><div class="DottedLine"></div><div class="Imageheaders">FIGURE 3</div><div class="FigureDesc"><a href="https://www.frontiersin.org/files/Articles/1145962/fphar-14-1145962-HTML-r3/image_m/fphar-14-1145962-g003.jpg" name="Figure3" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/1145962/fphar-14-1145962-HTML-r3/image_m/fphar-14-1145962-g003.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/1145962/fphar-14-1145962-HTML-r3/image_m/fphar-14-1145962-g003.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/1145962/fphar-14-1145962-HTML-r3/image_m/fphar-14-1145962-g003.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/1145962/fphar-14-1145962-HTML-r3/image_m/fphar-14-1145962-g003.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/1145962/fphar-14-1145962-HTML-r3/image_m/fphar-14-1145962-g003.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/1145962/fphar-14-1145962-HTML-r3/image_m/fphar-14-1145962-g003.jpg" alt="www.frontiersin.org" id="F3" loading="lazy"> </picture> </a><p><b>FIGURE 3</b>. Mean plasma concentration of ropivacaine following local infiltration analgesia <b>(A)</b> total concentration i.e., bound to AGP <b>(B)</b> free concentration of ropivacaine. The error bars indicates SD.</p></div><div class="clear"></div><div class="DottedLine"></div><p class="mb15">The data and graphs in <a href="#F4">Figure 4</a> clearly show a significant increase in AGP concentration after surgery, especially in samples taken after 4 h and 24 h. In patient 1, the initial concentration is 10.36 mg/100 mL, but, after 24 h, it increases to 23.50 mg/100 mL. There is thus almost a 13 mg/100 mL increase in 24 h. In patient 2H, there is also a significant increase in initial concentration and after 24 h, as seen in the table and from the graph, of 8.8 mg/100 mL and, after 24 h, 26.44 mg/100 mL. In patient 3H, there is also a considerable increase in the initial concentration of 5.19 mg/100 mL and, after 24 h, 27.05 mg/100 mL. There is likewise an increase in the concentration of AGP in all 20 patients. This confirms that there is an increase in AGP concentration after surgical conditions as well as in stress conditions as shown in different studies.</p><div class="DottedLine"></div><div class="Imageheaders">FIGURE 4</div><div class="FigureDesc"><a href="https://www.frontiersin.org/files/Articles/1145962/fphar-14-1145962-HTML-r3/image_m/fphar-14-1145962-g004.jpg" name="Figure4" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/1145962/fphar-14-1145962-HTML-r3/image_m/fphar-14-1145962-g004.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/1145962/fphar-14-1145962-HTML-r3/image_m/fphar-14-1145962-g004.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/1145962/fphar-14-1145962-HTML-r3/image_m/fphar-14-1145962-g004.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/1145962/fphar-14-1145962-HTML-r3/image_m/fphar-14-1145962-g004.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/1145962/fphar-14-1145962-HTML-r3/image_m/fphar-14-1145962-g004.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/1145962/fphar-14-1145962-HTML-r3/image_m/fphar-14-1145962-g004.jpg" alt="www.frontiersin.org" id="F4" loading="lazy"> </picture> </a><p><b>FIGURE 4</b>. Concentrations of AGP at different time intervals in 20 hip joint patients. The graphs indicate a significant increase in AGP concentration after surgery, especially in samples taken after 4 h and 24 h. In patient 1, initial concentration is 10.36 mg/100 mL, but, after 24 h, it increases to 23.50 mg/100 mL. There is thus almost a 13 mg/100 mL increase in 24 h. In patient 2H, there is also a significant increase in the initial concentration, and, after 24 h, the table and from graph show it as 8.8 mg/100 mL and, after 24 h, 26.44 mg/100 mL. In patient 3H, there is also a considerable increase in initial concentration of 5.19 mg/100 mL; after 24 h, it is 27.05 mg/100 mL. Likewise, there is an increase in AGP concentration in all 20 patients.</p></div><div class="clear"></div><div class="DottedLine"></div><p class="mb15">It is also clear from the data that there is considerable inter-individual variation in the level of AGP. It was found by <a href="#B4">Booker et al. (1996</a>) that the mean concentration is 77 mg/100 mL; however, based on our results, it is difficult to determine any exact concentration because of this inter-individual variability in AGP concentration. Therefore, this is a solid base for any dose adjustment in the case of surgical condition because of increased levels of AGP.</p><a id="h6" name="h6"></a><h2>5 Conclusion</h2><p class="mb15">The results confirmed that AGP concentration in almost all patients increased considerably in all samples, especially after 4 h and 24 h, which confirms that AGP concentration increases after surgical conditions. Therefore, dose adjustment should be considered in the use of drugs which bind to AGP.</p><a id="h7" name="h7"></a><h2>Data availability statement</h2><p class="mb15">The original contributions presented in the study are included in the article/<a href="#SM1">Supplementary Material</a>; further inquiries can be directed to the corresponding authors.</p><a id="h8" name="h8"></a><h2>Ethics statement</h2><p class="mb0">The studies involving human participants were reviewed and approved by the Regional Ethics Committee and conducted in accordance with the Declaration of Helsinki (NCT01873313). The patients/participants provided their written informed consent to participate in this study.</p><a id="h9" name="h9"></a><h2>Author contributions</h2><p class="mb0">MuA: sample preparation and sample analysis, data interpretation, and manuscript preparation. DW: project design. YS: sample analysis. SS: data interpretation. MoA: manuscript preparation. MaA: manuscript preparation and data analysis. LM: manuscript preparation and data analysis<em>.</em> All authors contributed to the article and approved the submitted version.</p><a id="h10" name="h10"></a><h2>Acknowledgments</h2><p class="mb03">The authors are thankful to the University of Strathclyde, Glasgow, and Abdul Wali Khan University, Mardan, Pakistan, for facilitating the study<b>.</b> This study is supported via funding from Prince sattam bin Abdulaziz University project number (PSAU/2023/R/1444).</p><a id="h11" name="h11"></a><h2>Conflict of interest</h2><p class="mb0">The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p><a id="h12" name="h12"></a><h2>Publisher’s note</h2><p class="mb15">All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors, and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.</p><a id="h13" name="h13"></a><h2>Supplementary material</h2><p class="mb15" id="SM1">The Supplementary Material for this article can be found online at: <a href="https://www.frontiersin.org/articles/10.3389/fphar.2023.1145962/full#supplementary-material">https://www.frontiersin.org/articles/10.3389/fphar.2023.1145962/full#supplementary-material</a></p><a id="h14" name="h14"></a><h2>References</h2><div class="References"><p class="ReferencesCopy1"><a name="B1" id="B1"></a>Abbas, M., Ahmad, L., Shah, Y., Gill, M., and Watson, D. G. (2013). Development of a method to measure free and bound ropivacaine in human plasma using equilibrium dialysis and Hydrophilic interaction chromatography coupled to high resolution mass spectrometry. <em>Talanta</em> 117, 60–63. doi:10.1016/j.talanta.2013.08.049</p><p class="ReferencesCopy2"><a href="https://pubmed.ncbi.nlm.nih.gov/24209310/">PubMed Abstract</a> | <a href="https://doi.org/10.1016/j.talanta.2013.08.049">CrossRef Full Text</a> | <a href="https://scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=Development+of+a+method+to+measure+free+and+bound+ropivacaine+in+human+plasma+using+equilibrium+dialysis+and+Hydrophilic+interaction+chromatography+coupled+to+high+resolution+mass+spectrometry&btnG=">Google Scholar</a></p></div><div class="References"><p class="ReferencesCopy1"><a name="B2" id="B2"></a>Banker, M. J., Clark, T. H., and Williams, J. A. (2003). Development and validation of a 96-well equilibrium dialysis apparatus for measuring plasma protein binding. <em>J. Pharm. Sci.</em> 92, 967–974. doi:10.1002/jps.10332</p><p class="ReferencesCopy2"><a href="https://pubmed.ncbi.nlm.nih.gov/12712416/">PubMed Abstract</a> | <a href="https://doi.org/10.1002/jps.10332">CrossRef Full Text</a> | <a href="https://scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=Development+and+validation+of+a+96-well+equilibrium+dialysis+apparatus+for+measuring+plasma+protein+binding&btnG=">Google Scholar</a></p></div><div class="References"><p class="ReferencesCopy1"><a name="B3" id="B3"></a>Bohnert, T., and Gan, L.-S. (2013). Plasma protein binding: From discovery to development. <em>J. Pharm. Sci.</em> 102, 2953–2994. doi:10.1002/jps.23614</p><p class="ReferencesCopy2"><a href="https://pubmed.ncbi.nlm.nih.gov/23798314/">PubMed Abstract</a> | <a href="https://doi.org/10.1002/jps.23614">CrossRef Full Text</a> | <a href="https://scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=Plasma+protein+binding:+From+discovery+to+development&btnG=">Google Scholar</a></p></div><div class="References"><p class="ReferencesCopy1"><a name="B4" id="B4"></a>Booker, P., Taylor, C., and Saba, G. (1996). Perioperative changes in alpha 1-acid glycoprotein concentrations in infants undergoing major surgery. <em>Br. J. Anaesth.</em> 76, 365–368. doi:10.1093/bja/76.3.365</p><p class="ReferencesCopy2"><a href="https://pubmed.ncbi.nlm.nih.gov/8785135/">PubMed Abstract</a> | <a href="https://doi.org/10.1093/bja/76.3.365">CrossRef Full Text</a> | <a href="https://scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=Perioperative+changes+in+alpha+1-acid+glycoprotein+concentrations+in+infants+undergoing+major+surgery&btnG=">Google Scholar</a></p></div><div class="References"><p class="ReferencesCopy1"><a name="B5" id="B5"></a>Bteich, M. (2019). An overview of albumin and alpha-1-acid glycoprotein main characteristics: Highlighting the roles of amino acids in binding kinetics and molecular interactions. <em>Heliyon</em> 5, e02879. doi:10.1016/j.heliyon.2019.e02879</p><p class="ReferencesCopy2"><a href="https://pubmed.ncbi.nlm.nih.gov/31844752/">PubMed Abstract</a> | <a href="https://doi.org/10.1016/j.heliyon.2019.e02879">CrossRef Full Text</a> | <a href="https://scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=An+overview+of+albumin+and+alpha-1-acid+glycoprotein+main+characteristics:+Highlighting+the+roles+of+amino+acids+in+binding+kinetics+and+molecular+interactions&btnG=">Google Scholar</a></p></div><div class="References"><p class="ReferencesCopy1"><a name="B6" id="B6"></a>Eckersall, P. D., and Schmidt, E. M. D. S. (2014). The final hurdles for acute phase protein analysis in small animal practice. <em>J. Small Anim. Pract.</em> 55, 1–3. Wiley Online Library. doi:10.1111/jsap.12168</p><p class="ReferencesCopy2"><a href="https://pubmed.ncbi.nlm.nih.gov/24387103/">PubMed Abstract</a> | <a href="https://doi.org/10.1111/jsap.12168">CrossRef Full Text</a> | <a href="https://scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=The+final+hurdles+for+acute+phase+protein+analysis+in+small+animal+practice&btnG=">Google Scholar</a></p></div><div class="References"><p class="ReferencesCopy1"><a name="B7" id="B7"></a>Fournier, T., Medjoubi-N, N., and Porquet, D. (2000). Alpha-1-acid glycoprotein. <em>Biochim. Biophys. Acta</em> 1482, 157–171. doi:10.1016/s0167-4838(00)00153-9</p><p class="ReferencesCopy2"><a href="https://pubmed.ncbi.nlm.nih.gov/11058758/">PubMed Abstract</a> | <a href="https://doi.org/10.1016/s0167-4838(00)00153-9">CrossRef Full Text</a> | <a href="https://scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=Alpha-1-acid+glycoprotein&btnG=">Google Scholar</a></p></div><div class="References"><p class="ReferencesCopy1"><a name="B8" id="B8"></a>Hellerstein, M., Sasak, V., Ordovas, J., and Munro, H. (1985). Isolation of alpha 1-acid glycoprotein from human plasma using high-performance liquid chromatography. <em>Anal. Biochem.</em> 146, 366–371. doi:10.1016/0003-2697(85)90553-6</p><p class="ReferencesCopy2"><a href="https://pubmed.ncbi.nlm.nih.gov/4025802/">PubMed Abstract</a> | <a href="https://doi.org/10.1016/0003-2697(85)90553-6">CrossRef Full Text</a> | <a href="https://scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=Isolation+of+alpha+1-acid+glycoprotein+from+human+plasma+using+high-performance+liquid+chromatography&btnG=">Google Scholar</a></p></div><div class="References"><p class="ReferencesCopy1"><a name="B9" id="B9"></a>Hochepied, T., Berger, F. G., Baumann, H., and Libert, C. (2003). Alpha(1)-acid glycoprotein: An acute phase protein with inflammatory and immunomodulating properties. <em>Cytokine & growth factor Rev.</em> 14, 25–34. doi:10.1016/s1359-6101(02)00054-0</p><p class="ReferencesCopy2"><a href="https://doi.org/10.1016/s1359-6101(02)00054-0">CrossRef Full Text</a> | <a href="https://scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=Alpha(1)-acid+glycoprotein:+An+acute+phase+protein+with+inflammatory+and+immunomodulating+properties&btnG=">Google Scholar</a></p></div><div class="References"><p class="ReferencesCopy1"><a name="B10" id="B10"></a>Huang, Z., and Ung, T. (2013). Effect of alpha-1-acid glycoprotein binding on pharmacokinetics and pharmacodynamics. <em>Curr. drug Metab.</em> 14, 226–238. doi:10.2174/1389200211314020011</p><p class="ReferencesCopy2"><a href="https://pubmed.ncbi.nlm.nih.gov/23092311/">PubMed Abstract</a> | <a href="https://doi.org/10.2174/1389200211314020011">CrossRef Full Text</a> | <a href="https://scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=Effect+of+alpha-1-acid+glycoprotein+binding+on+pharmacokinetics+and+pharmacodynamics&btnG=">Google Scholar</a></p></div><div class="References"><p class="ReferencesCopy1"><a name="B11" id="B11"></a>Keser, T., Tijardović, M., Gornik, I., Lukić, E., Lauc, G., Gornik, O., et al. (2021). High-throughput and site-specific N-glycosylation analysis of human alpha-1-acid glycoprotein offers a great potential for new biomarker discovery. <em>Mol. Cell. Proteomics</em> 20, 100044. doi:10.1074/mcp.RA120.002433</p><p class="ReferencesCopy2"><a href="https://pubmed.ncbi.nlm.nih.gov/33493676/">PubMed Abstract</a> | <a href="https://doi.org/10.1074/mcp.RA120.002433">CrossRef Full Text</a> | <a href="https://scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=High-throughput+and+site-specific+N-glycosylation+analysis+of+human+alpha-1-acid+glycoprotein+offers+a+great+potential+for+new+biomarker+discovery&btnG=">Google Scholar</a></p></div><div class="References"><p class="ReferencesCopy1"><a name="B12" id="B12"></a>Kishino, S., and Miyazaki, K. (1997). Separation methods for glycoprotein analysis and preparation. <em>J. Chromatogr. B Biomed. Sci. Appl.</em> 699, 371–381. doi:10.1016/s0378-4347(97)00155-2</p><p class="ReferencesCopy2"><a href="https://pubmed.ncbi.nlm.nih.gov/9392383/">PubMed Abstract</a> | <a href="https://doi.org/10.1016/s0378-4347(97)00155-2">CrossRef Full Text</a> | <a href="https://scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=Separation+methods+for+glycoprotein+analysis+and+preparation&btnG=">Google Scholar</a></p></div><div class="References"><p class="ReferencesCopy1"><a name="B13" id="B13"></a>Kratochwil, N. A., Huber, W., Müller, F., Kansy, M., and Gerber, P. R. (2002). Predicting plasma protein binding of drugs: A new approach. <em>Biochem. Pharmacol.</em> 64, 1355–1374. doi:10.1016/s0006-2952(02)01074-2</p><p class="ReferencesCopy2"><a href="https://pubmed.ncbi.nlm.nih.gov/12392818/">PubMed Abstract</a> | <a href="https://doi.org/10.1016/s0006-2952(02)01074-2">CrossRef Full Text</a> | <a href="https://scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=Predicting+plasma+protein+binding+of+drugs:+A+new+approach&btnG=">Google Scholar</a></p></div><div class="References"><p class="ReferencesCopy1"><a name="B14" id="B14"></a>Kremer, J. M., Wilting, J., and Janssen, L. (1988). Drug binding to human alpha-1-acid glycoprotein in health and disease. <em>Pharmacol. Rev.</em> 40, 1–47.</p><p class="ReferencesCopy2"><a href="https://pubmed.ncbi.nlm.nih.gov/3064105/">PubMed Abstract</a> | <a href="https://scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=Drug+binding+to+human+alpha-1-acid+glycoprotein+in+health+and+disease&btnG=">Google Scholar</a></p></div><div class="References"><p class="ReferencesCopy1"><a name="B15" id="B15"></a>Kremmer, T., Szöllösi, É., Boldizsár, M., Vincze, B., Ludányi, K., Imre, T., et al. (2004). Liquid chromatographic and mass spectrometric analysis of human serum acid alpha-1-glycoprotein. <em>Biomed. Chromatogr.</em> 18, 323–329. doi:10.1002/bmc.324</p><p class="ReferencesCopy2"><a href="https://pubmed.ncbi.nlm.nih.gov/15236441/">PubMed Abstract</a> | <a href="https://doi.org/10.1002/bmc.324">CrossRef Full Text</a> | <a href="https://scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=Liquid+chromatographic+and+mass+spectrometric+analysis+of+human+serum+acid+alpha-1-glycoprotein&btnG=">Google Scholar</a></p></div><div class="References"><p class="ReferencesCopy1"><a name="B16" id="B16"></a>Larsson, B., Lonnqvist, P., and Olsson, G. (1997). Plasma concentrations of bupivacaine in neonates after continuous epidural infusion. <em>Anesth. Analgesia</em> 84, 501–505. doi:10.1097/00000539-199703000-00006</p><p class="ReferencesCopy2"><a href="https://doi.org/10.1097/00000539-199703000-00006">CrossRef Full Text</a> | <a href="https://scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=Plasma+concentrations+of+bupivacaine+in+neonates+after+continuous+epidural+infusion&btnG=">Google Scholar</a></p></div><div class="References"><p class="ReferencesCopy1"><a name="B17" id="B17"></a>Rice, A., Grimshaw, J., Trocha-Grimshaw, J., Mccarron, P., and Wisdom, G. B. (1997). Identification of alpha 1-acid glycoprotein (orosomucoid) in human synovial fluid by capillary electrophoresis. <em>J. Chromatogr. A</em> 772, 305–311. doi:10.1016/s0021-9673(96)00990-9</p><p class="ReferencesCopy2"><a href="https://pubmed.ncbi.nlm.nih.gov/9226930/">PubMed Abstract</a> | <a href="https://doi.org/10.1016/s0021-9673(96)00990-9">CrossRef Full Text</a> | <a href="https://scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=Identification+of+alpha+1-acid+glycoprotein+(orosomucoid)+in+human+synovial+fluid+by+capillary+electrophoresis&btnG=">Google Scholar</a></p></div><div class="References"><p class="ReferencesCopy1"><a name="B18" id="B18"></a>Roberts, J. A., Pea, F., and Lipman, J. (2013). The clinical relevance of plasma protein binding changes. <em>Clin. Pharmacokinet.</em> 52, 1–8. doi:10.1007/s40262-012-0018-5</p><p class="ReferencesCopy2"><a href="https://pubmed.ncbi.nlm.nih.gov/23150213/">PubMed Abstract</a> | <a href="https://doi.org/10.1007/s40262-012-0018-5">CrossRef Full Text</a> | <a href="https://scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=The+clinical+relevance+of+plasma+protein+binding+changes&btnG=">Google Scholar</a></p></div><div class="References"><p class="ReferencesCopy1"><a name="B19" id="B19"></a>Schmidt, S., Gonzalez, D., and Derendorf, H. (2010). Significance of protein binding in pharmacokinetics and pharmacodynamics. <em>J. Pharm. Sci.</em> 99, 1107–1122. doi:10.1002/jps.21916</p><p class="ReferencesCopy2"><a href="https://pubmed.ncbi.nlm.nih.gov/19852037/">PubMed Abstract</a> | <a href="https://doi.org/10.1002/jps.21916">CrossRef Full Text</a> | <a href="https://scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=Significance+of+protein+binding+in+pharmacokinetics+and+pharmacodynamics&btnG=">Google Scholar</a></p></div><div class="References"><p class="ReferencesCopy1"><a name="B20" id="B20"></a>Stumpe, M., Miller, C., Morton, N., Bell, G., and Watson, D. (2006). High-performance liquid chromatography determination of alpha1-acid glycoprotein in small volumes of plasma from neonates. <em>J. Chromatogr. B</em> 831, 81–84. doi:10.1016/j.jchromb.2005.11.039</p><p class="ReferencesCopy2"><a href="https://doi.org/10.1016/j.jchromb.2005.11.039">CrossRef Full Text</a> | <a href="https://scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=High-performance+liquid+chromatography+determination+of+alpha1-acid+glycoprotein+in+small+volumes+of+plasma+from+neonates&btnG=">Google Scholar</a></p></div><div class="References"><p class="ReferencesCopy1"><a name="B21" id="B21"></a>Taguchi, K., Nishi, K., Chuang, V. G., Maruyama, T., and Otagiri, M. (2013). “Molecular aspects of human alpha-1 acid glycoprotein—Structure and function,” in <em>Acute phase proteins</em> (London: <span class="publisher-name">IntechOpen</span>), 139–162. </p><p class="ReferencesCopy2"><a href="https://scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=Molecular+aspects+of+human+alpha-1+acid+glycoprotein—Structure+and+function&btnG=">Google Scholar</a></p></div><div class="References"><p class="ReferencesCopy1"><a name="B22" id="B22"></a>Tesseromatis, C., Alevizou, A., Tigka, E., and Kotsiou, A. (2011). <em>Acute-phase proteins: alpha-1-acid glycoprotein</em>. London: <span class="publisher-name">IntechOpen</span>. </p><p class="ReferencesCopy2"><a href="https://scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=Acute-phase+proteins:+alpha-1-acid+glycoprotein&btnG=">Google Scholar</a></p></div><div class="References"><p class="ReferencesCopy1"><a name="B23" id="B23"></a>Wood, M., and Wood, A. J. (1981). Changes in plasma drug binding and alpha 1-acid glycoprotein in mother and newborn infant. <em>Clin. Pharmacol. Ther.</em> 29, 522–526. doi:10.1038/clpt.1981.73</p><p class="ReferencesCopy2"><a href="https://pubmed.ncbi.nlm.nih.gov/7471620/">PubMed Abstract</a> | <a href="https://doi.org/10.1038/clpt.1981.73">CrossRef Full Text</a> | <a href="https://scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=Changes+in+plasma+drug+binding+and+alpha+1-acid+glycoprotein+in+mother+and+newborn+infant&btnG=">Google Scholar</a></p></div><div class="References"><p class="ReferencesCopy1"><a name="B24" id="B24"></a>Xuan, H., and Hage, D. S. (2005). Immobilization of alpha(1)-acid glycoprotein for chromatographic studies of drug-protein binding. <em>Anal. Biochem.</em> 346, 300–310. doi:10.1016/j.ab.2005.08.025</p><p class="ReferencesCopy2"><a href="https://pubmed.ncbi.nlm.nih.gov/16225836/">PubMed Abstract</a> | <a href="https://doi.org/10.1016/j.ab.2005.08.025">CrossRef Full Text</a> | <a href="https://scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=Immobilization+of+alpha(1)-acid+glycoprotein+for+chromatographic+studies+of+drug-protein+binding&btnG=">Google Scholar</a></p></div><div class="References"><p class="ReferencesCopy1"><a name="B25" id="B25"></a>Zeitlinger, M. A., Derendorf, H., Mouton, J. W., Cars, O., Craig, W. A., Andes, D., et al. (2011). Protein binding: Do we ever learn? <em>Antimicrob. agents Chemother.</em> 55, 3067–3074. doi:10.1128/AAC.01433-10</p><p class="ReferencesCopy2"><a href="https://pubmed.ncbi.nlm.nih.gov/21537013/">PubMed Abstract</a> | <a href="https://doi.org/10.1128/AAC.01433-10">CrossRef Full Text</a> | <a href="https://scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=Protein+binding:+Do+we+ever+learn?&btnG=">Google Scholar</a></p></div></div><div class="thinLineM20"></div><div class="AbstractSummary"><p><span>Keywords:</span> HPLC, α1-acid glycoprotein, human plasma, hip joint surgery patients, protein binding</p><p><span>Citation:</span> Abbas M, Alossaimi MA, Altamimi ASA, Alajaji M, Watson DG, Shah SI, Shah Y and Anwar MS (2023) Determination of α1-acid glycoprotein (AGP) concentration by HPLC in patients following local infiltration analgesia for primary total hip arthroplasty and its relation to ropivacaine (total and unbound). <em>Front. Pharmacol.</em> 14:1145962. doi: 10.3389/fphar.2023.1145962</p><p id="timestamps"><span>Received:</span> 16 January 2023; <span>Accepted:</span> 16 May 2023;<br><span>Published:</span> 26 June 2023.</p><div><p>Edited by:</p> <a href="https://loop.frontiersin.org/people/243834/overview">Tahir Ali</a>, University of Calgary, Canada</div><div><p>Reviewed by:</p> <a href="https://loop.frontiersin.org/people/1943882/overview">Swati Jaiswal</a>, University of Massachusetts Medical School, United States<br><a href="https://loop.frontiersin.org/people/542593/overview">Mohammed Abdessadek</a>Université Ibn Zohr, Morocco</div><p><span>Copyright</span> © 2023 Abbas, Alossaimi, Altamimi, Alajaji, Watson, Shah, Shah and Anwar. This is an open-access article distributed under the terms of the <a rel="license" href="http://creativecommons.org/licenses/by/4.0/" target="_blank">Creative Commons Attribution License (CC BY).</a> The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</p><p><span>*Correspondence:</span> Muhammad Abbas, <a id="encmail">bXVoYW1tYWRhYmJhc0Bhd2t1bS5lZHUucGs=</a></p><div class="clear"></div></div> </div></div> <p class="AbstractSummary__disclaimer"><span>Disclaimer: </span> All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. </p></div></div></main> <aside class="Layout__aside"><div class="ArticleDetails__wrapper"><div class="ArticleDetails__aside"><div class="ArticleDetails__aside__responsiveButtons"><div id="FloatingButtonsEl" class="ActionsDropDown"><button aria-label="Open dropdown" data-event="actionsDropDown-button-toggle" class="ActionsDropDown__button ActionsDropDown__button--type ActionsDropDown__button--icon"><span class="ActionsDropDown__button__label">Download article</span></button> <div class="ActionsDropDown__menuWrapper"> <ul class="ActionsDropDown__menu"><li><a href="/journals/pharmacology/articles/10.3389/fphar.2023.1145962/pdf" target="_blank" rel="noopener noreferrer" data-event="actionsDropDown-a-pdf" class="ActionsDropDown__option"> Download PDF </a></li><li><a href="http://www.readcube.com/articles/10.3389/fphar.2023.1145962" target="_blank" rel="noopener noreferrer" data-event="actionsDropDown-a-readCube" class="ActionsDropDown__option"> ReadCube </a></li><li><a href="/journals/pharmacology/articles/10.3389/fphar.2023.1145962/epub" target="_blank" rel="noopener noreferrer" data-event="actionsDropDown-a-epub" class="ActionsDropDown__option"> EPUB </a></li><li><a href="/journals/pharmacology/articles/10.3389/fphar.2023.1145962/xml/nlm" target="_blank" rel="noopener noreferrer" data-event="actionsDropDown-a-nlmXml" class="ActionsDropDown__option"> XML (NLM) </a></li></ul> <button aria-label="Close modal" data-event="actionsDropDown-button-close" class="ActionsDropDown__mobileClose"></button></div></div> <div class="ArticleDetails__aside__responsiveButtons__items"> <div class="ArticleDetailsShare__responsive"><button aria-label="Open share options" class="ArticleDetailsShare__trigger"></button> <div class="ArticleDetailsShare"><p class="ArticleDetailsShare__title">Share on</p> <ul class="ArticleDetailsShare__list"><li class="ArticleDetailsShare__item"><a href="https://www.twitter.com/share?url=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1145962/full" target="_blank" title="Share on X" aria-label="Share on X" class="ArticleDetailsShare__link ArticleDetailsShare__link--x"></a></li><li class="ArticleDetailsShare__item"><a href="https://www.linkedin.com/share?url=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1145962/full" target="_blank" title="Share on Linkedin" aria-label="Share on Linkedin" class="ArticleDetailsShare__link ArticleDetailsShare__link--linkedin"></a></li><li class="ArticleDetailsShare__item"><a href="https://www.facebook.com/sharer/sharer.php?u=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1145962/full" target="_blank" title="Share on Facebook" aria-label="Share on Facebook" class="ArticleDetailsShare__link ArticleDetailsShare__link--facebook"></a></li></ul></div></div> <div class="ActionsDropDown"><button aria-label="Open dropdown" data-event="actionsDropDown-button-toggle" class="ActionsDropDown__button ActionsDropDown__button--typeIconButton ActionsDropDown__button--iconQuote"></button> <div class="ActionsDropDown__menuWrapper"><div class="ActionsDropDown__mobileTitle"> Export citation </div> <ul class="ActionsDropDown__menu"><li><a href="/journals/pharmacology/articles/10.3389/fphar.2023.1145962/endNote" target="_blank" rel="noopener noreferrer" data-event="actionsDropDown-a-endNote" class="ActionsDropDown__option"> EndNote </a></li><li><a href="/journals/pharmacology/articles/10.3389/fphar.2023.1145962/reference" target="_blank" rel="noopener noreferrer" data-event="actionsDropDown-a-referenceManager" class="ActionsDropDown__option"> Reference Manager </a></li><li><a href="/journals/pharmacology/articles/10.3389/fphar.2023.1145962/text" target="_blank" rel="noopener noreferrer" data-event="actionsDropDown-a-simpleTextFile" class="ActionsDropDown__option"> Simple Text file </a></li><li><a href="/journals/pharmacology/articles/10.3389/fphar.2023.1145962/bibTex" target="_blank" rel="noopener noreferrer" data-event="actionsDropDown-a-bibTex" class="ActionsDropDown__option"> BibTex </a></li></ul> <button aria-label="Close modal" data-event="actionsDropDown-button-close" class="ActionsDropDown__mobileClose"></button></div></div></div></div> <div class="TotalViews"><div class="TotalViews__data"><div class="TotalViews__data__metrics"><div class="TotalViews__data__metrics__number"> 1,8K </div> <div class="TotalViews__data__metrics__text"><div class="TotalViews__data__metrics__label">Total views</div></div></div> <div class="TotalViews__data__metrics"><div class="TotalViews__data__metrics__number"> 417 </div> <div class="TotalViews__data__metrics__text"><div class="TotalViews__data__metrics__label">Downloads</div></div></div> <div class="TotalViews__data__metrics"><div class="TotalViews__data__metrics__number"> 2 </div> <div class="TotalViews__data__metrics__text"><div class="TotalViews__data__metrics__label">Citations</div></div></div> <div class="ImpactMetricsInfoPopover"><button aria-label="Open impact metrics info" class="ImpactMetricsInfoPopover__button"></button> <div class="ImpactMetricsInfoPopover__tooltip"><button aria-label="Close impact metrics info" class="ImpactMetricsInfoPopover__tooltip__closeButton"></button> <div class="ImpactMetricsInfoPopover__tooltip__text"> Citation numbers are available from Dimensions </div></div></div></div> <div class="TotalViews__viewImpactLink"><span class="Link__wrapper"><a aria-label="View article impact" href="http://loop-impact.frontiersin.org/impact/article/1145962#totalviews/views" target="_blank" data-event="customLink-link-a_viewArticleImpact" class="Link Link--linkType Link--maincolor Link--medium Link--icon Link--chevronRight Link--right"><span>View article impact</span></a></span></div> <div class="TotalViews__altmetric"><div data-badge-popover="bottom" data-badge-type="donut" data-doi="10.3389/fphar.2023.1145962" data-condensed="true" data-link-target="new" class="altmetric-embed"></div> <span class="Link__wrapper"><a aria-label="View altmetric score" href="https://www.altmetric.com/details/doi/10.3389/fphar.2023.1145962" target="_blank" data-event="customLink-link-a_viewAltmetricScore" class="Link Link--linkType Link--maincolor Link--medium Link--icon Link--chevronRight Link--right"><span>View altmetric score</span></a></span></div></div> <div class="ArticleDetailsShare"><p class="ArticleDetailsShare__title">Share on</p> <ul class="ArticleDetailsShare__list"><li class="ArticleDetailsShare__item"><a href="https://www.twitter.com/share?url=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1145962/full" target="_blank" title="Share on X" aria-label="Share on X" class="ArticleDetailsShare__link ArticleDetailsShare__link--x"></a></li><li class="ArticleDetailsShare__item"><a href="https://www.linkedin.com/share?url=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1145962/full" target="_blank" title="Share on Linkedin" aria-label="Share on Linkedin" class="ArticleDetailsShare__link ArticleDetailsShare__link--linkedin"></a></li><li class="ArticleDetailsShare__item"><a href="https://www.facebook.com/sharer/sharer.php?u=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1145962/full" target="_blank" title="Share on Facebook" aria-label="Share on Facebook" class="ArticleDetailsShare__link ArticleDetailsShare__link--facebook"></a></li></ul></div> <div class="ArticleDetailsEditors"><div class="ArticleDetailsEditors__editors"><div class="ArticleDetailsEditors__title">Edited by</div> <a href="https://loop.frontiersin.org/people/243834/overview" data-event="editorInfo-a-tahirAli" class="ArticleDetailsEditors__ediorInfo"><figure class="Avatar Avatar--size-32"><img src="https://loop.frontiersin.org/images/profile/243834/32" alt="Tahir Ali" class="Avatar__img is-inside-mask"></figure> <div class="ArticleDetailsEditors__ediorInfo__info"><div class="ArticleDetailsEditors__ediorInfo__name notranslate"> Tahir Ali </div> <div class="ArticleDetailsEditors__ediorInfo__affiliation notranslate"> University of Calgary, Canada </div></div></a></div></div> <div class="ArticleDetailsEditors"><div class="ArticleDetailsEditors__editors"><div class="ArticleDetailsEditors__title">Reviewed by</div> <a href="https://loop.frontiersin.org/people/542593/overview" data-event="editorInfo-a-mohammedAbdessadek" class="ArticleDetailsEditors__ediorInfo"><figure class="Avatar Avatar--size-32"><img src="https://loop.frontiersin.org/images/profile/542593/32" alt="Mohammed Abdessadek" class="Avatar__img is-inside-mask"></figure> <div class="ArticleDetailsEditors__ediorInfo__info"><div class="ArticleDetailsEditors__ediorInfo__name notranslate"> Mohammed Abdessadek </div> <div class="ArticleDetailsEditors__ediorInfo__affiliation notranslate"> Université Ibn Zohr, Morocco </div></div></a><a href="https://loop.frontiersin.org/people/1943882/overview" data-event="editorInfo-a-swatiJaiswal" class="ArticleDetailsEditors__ediorInfo"><figure class="Avatar Avatar--size-32"><img src="https://loop.frontiersin.org/images/profile/1943882/32" alt="Swati Jaiswal" class="Avatar__img is-inside-mask"></figure> <div class="ArticleDetailsEditors__ediorInfo__info"><div class="ArticleDetailsEditors__ediorInfo__name notranslate"> Swati Jaiswal </div> <div class="ArticleDetailsEditors__ediorInfo__affiliation notranslate"> University of Massachusetts Medical School, United States </div></div></a></div></div> <div class="ArticleDetailsGlossary ArticleDetailsGlossary--open"><button class="ArticleDetailsGlossary__header"><div class="ArticleDetailsGlossary__header__title">Table of contents</div> <div class="ArticleDetailsGlossary__header__arrow"></div></button> <div class="ArticleDetailsGlossary__content"><ul class="flyoutJournal"><li><a href="#h1">Abstract</a></li><li><a href="#h2">1 Introduction</a></li><li><a href="#h3">2 Methodology</a></li><li><a href="#h4">3 Results</a></li><li><a href="#h5">4 Discussion</a></li><li><a href="#h6">5 Conclusion</a></li><li><a href="#h7">Data availability statement</a></li><li><a href="#h8">Ethics statement</a></li><li><a href="#h9">Author contributions</a></li><li><a href="#h10">Acknowledgments</a></li><li><a href="#h11">Conflict of interest</a></li><li><a href="#h12">Publisher’s note</a></li><li><a href="#h13">Supplementary material</a></li><li><a href="#h14">References</a></li></ul></div></div>  <div class="ActionsDropDown"><button aria-label="Open dropdown" data-event="actionsDropDown-button-toggle" class="ActionsDropDown__button ActionsDropDown__button--typeOutline ActionsDropDown__button--iconQuote"><span class="ActionsDropDown__button__label">Export citation</span></button> <div class="ActionsDropDown__menuWrapper"> <ul class="ActionsDropDown__menu"><li><a href="/journals/pharmacology/articles/10.3389/fphar.2023.1145962/endNote" target="_blank" rel="noopener noreferrer" data-event="actionsDropDown-a-endNote" class="ActionsDropDown__option"> EndNote </a></li><li><a href="/journals/pharmacology/articles/10.3389/fphar.2023.1145962/reference" target="_blank" rel="noopener noreferrer" data-event="actionsDropDown-a-referenceManager" class="ActionsDropDown__option"> Reference Manager </a></li><li><a href="/journals/pharmacology/articles/10.3389/fphar.2023.1145962/text" target="_blank" rel="noopener noreferrer" data-event="actionsDropDown-a-simpleTextFile" class="ActionsDropDown__option"> Simple Text file </a></li><li><a href="/journals/pharmacology/articles/10.3389/fphar.2023.1145962/bibTex" target="_blank" rel="noopener noreferrer" data-event="actionsDropDown-a-bibTex" class="ActionsDropDown__option"> BibTex </a></li></ul> <button aria-label="Close modal" data-event="actionsDropDown-button-close" class="ActionsDropDown__mobileClose"></button></div></div> <div class="CheckForUpdates"><button data-target="crossmark" data-event="checkForUpdates-btn-openModal" class="CheckForUpdates__link"><img src="/article-pages/_nuxt/img/crossmark.5c8ec60.svg" alt="Crossmark icon" class="CheckForUpdates__link__img"> <div class="CheckForUpdates__link__text">Check for updates</div></button></div> <div class="Announcement"><p class="Announcement__title"> Research integrity at Frontiers </p> <article class="CardA"><div class="CardA__wrapper CardA__wrapper--vertical"><figure class="FrontiersImage CardA__img"><picture class="FrontiersImage"><source srcset="https://images-provider.frontiersin.org/api/ipx/w=440&f=webp/https://d2csxpduxe849s.cloudfront.net/media/E32629C6-9347-4F84-81FEAEF7BFA342B3/0B4B1380-42EB-4FD5-9D7E2DBC603E79F8/webimage-C4875379-1478-416F-B03DF68FE3D8DBB5.png" media="(max-width: 563px)"><source srcset="https://images-provider.frontiersin.org/api/ipx/s=320x400&fit=outside&f=webp/https://d2csxpduxe849s.cloudfront.net/media/E32629C6-9347-4F84-81FEAEF7BFA342B3/0B4B1380-42EB-4FD5-9D7E2DBC603E79F8/webimage-C4875379-1478-416F-B03DF68FE3D8DBB5.png" media="(max-width: 1024px)"><source srcset="https://images-provider.frontiersin.org/api/ipx/s=268x280&fit=outside&f=webp/https://d2csxpduxe849s.cloudfront.net/media/E32629C6-9347-4F84-81FEAEF7BFA342B3/0B4B1380-42EB-4FD5-9D7E2DBC603E79F8/webimage-C4875379-1478-416F-B03DF68FE3D8DBB5.png" media="(max-width: 1441px)"><source srcset="https://images-provider.frontiersin.org/api/ipx/s=366x408&fit=outside&f=webp/https://d2csxpduxe849s.cloudfront.net/media/E32629C6-9347-4F84-81FEAEF7BFA342B3/0B4B1380-42EB-4FD5-9D7E2DBC603E79F8/webimage-C4875379-1478-416F-B03DF68FE3D8DBB5.png" media=""><source srcset="https://d2csxpduxe849s.cloudfront.net/media/E32629C6-9347-4F84-81FEAEF7BFA342B3/0B4B1380-42EB-4FD5-9D7E2DBC603E79F8/webimage-C4875379-1478-416F-B03DF68FE3D8DBB5.png" media=""> <img src="https://d2csxpduxe849s.cloudfront.net/media/E32629C6-9347-4F84-81FEAEF7BFA342B3/0B4B1380-42EB-4FD5-9D7E2DBC603E79F8/webimage-C4875379-1478-416F-B03DF68FE3D8DBB5.png" alt="Man ultramarathon runner in the mountains he trains at sunset" loading="lazy" class="is-inside-mask"></picture> </figure> <div class="CardA__info"><h2 class="CardA__title">94% of researchers rate our articles as excellent or good</h2> <p class="CardA__text">Learn more about the work of our research integrity team to safeguard the quality of each article we publish.</p> <br> <span class="Link__wrapper"><a aria-label="About our research integrity team" href="https://www.frontiersin.org/about/research-integrity" target="_self" data-event="customLink-link-a_findOutMore" class="Link Link--linkType Link--maincolor Link--small Link--icon Link--chevronRight Link--right"><span>Find out more </span></a></span></div></div></article></div>  </div>  <div><div class="FloatingButtons"> <div class="ActionsDropDown"><button aria-label="Open dropdown" data-event="actionsDropDown-button-toggle" class="ActionsDropDown__button ActionsDropDown__button--type ActionsDropDown__button--iconDownload"><span class="ActionsDropDown__button__label">Download article</span></button> <div class="ActionsDropDown__menuWrapper"><div class="ActionsDropDown__mobileTitle"> Download </div> <ul class="ActionsDropDown__menu"><li><a href="/journals/pharmacology/articles/10.3389/fphar.2023.1145962/pdf" target="_blank" rel="noopener noreferrer" data-event="actionsDropDown-a-pdf" class="ActionsDropDown__option"> Download PDF </a></li><li><a href="http://www.readcube.com/articles/10.3389/fphar.2023.1145962" target="_blank" rel="noopener noreferrer" data-event="actionsDropDown-a-readCube" class="ActionsDropDown__option"> ReadCube </a></li><li><a href="/journals/pharmacology/articles/10.3389/fphar.2023.1145962/epub" target="_blank" rel="noopener noreferrer" data-event="actionsDropDown-a-epub" class="ActionsDropDown__option"> EPUB </a></li><li><a href="/journals/pharmacology/articles/10.3389/fphar.2023.1145962/xml/nlm" target="_blank" rel="noopener noreferrer" data-event="actionsDropDown-a-nlmXml" class="ActionsDropDown__option"> XML (NLM) </a></li></ul> <button aria-label="Close modal" data-event="actionsDropDown-button-close" class="ActionsDropDown__mobileClose"></button></div></div></div> </div></div></aside></div> <div class="Announcement Announcement--Responsive"><p class="Announcement__title"> Research integrity at Frontiers </p> <article class="CardA"><div class="CardA__wrapper CardA__wrapper--vertical"><figure class="FrontiersImage CardA__img"><picture class="FrontiersImage"><source srcset="https://images-provider.frontiersin.org/api/ipx/w=440&f=webp/https://d2csxpduxe849s.cloudfront.net/media/E32629C6-9347-4F84-81FEAEF7BFA342B3/0B4B1380-42EB-4FD5-9D7E2DBC603E79F8/webimage-C4875379-1478-416F-B03DF68FE3D8DBB5.png" media="(max-width: 563px)"><source srcset="https://images-provider.frontiersin.org/api/ipx/s=320x400&fit=outside&f=webp/https://d2csxpduxe849s.cloudfront.net/media/E32629C6-9347-4F84-81FEAEF7BFA342B3/0B4B1380-42EB-4FD5-9D7E2DBC603E79F8/webimage-C4875379-1478-416F-B03DF68FE3D8DBB5.png" media="(max-width: 1024px)"><source srcset="https://images-provider.frontiersin.org/api/ipx/s=268x280&fit=outside&f=webp/https://d2csxpduxe849s.cloudfront.net/media/E32629C6-9347-4F84-81FEAEF7BFA342B3/0B4B1380-42EB-4FD5-9D7E2DBC603E79F8/webimage-C4875379-1478-416F-B03DF68FE3D8DBB5.png" media="(max-width: 1441px)"><source srcset="https://images-provider.frontiersin.org/api/ipx/s=366x408&fit=outside&f=webp/https://d2csxpduxe849s.cloudfront.net/media/E32629C6-9347-4F84-81FEAEF7BFA342B3/0B4B1380-42EB-4FD5-9D7E2DBC603E79F8/webimage-C4875379-1478-416F-B03DF68FE3D8DBB5.png" media=""><source srcset="https://d2csxpduxe849s.cloudfront.net/media/E32629C6-9347-4F84-81FEAEF7BFA342B3/0B4B1380-42EB-4FD5-9D7E2DBC603E79F8/webimage-C4875379-1478-416F-B03DF68FE3D8DBB5.png" media=""> <img src="https://d2csxpduxe849s.cloudfront.net/media/E32629C6-9347-4F84-81FEAEF7BFA342B3/0B4B1380-42EB-4FD5-9D7E2DBC603E79F8/webimage-C4875379-1478-416F-B03DF68FE3D8DBB5.png" alt="Man ultramarathon runner in the mountains he trains at sunset" loading="lazy" class="is-inside-mask"></picture> </figure> <div class="CardA__info"><h2 class="CardA__title">94% of researchers rate our articles as excellent or good</h2> <p class="CardA__text">Learn more about the work of our research integrity team to safeguard the quality of each article we publish.</p> <br> <span class="Link__wrapper"><a aria-label="About our research integrity team" href="https://www.frontiersin.org/about/research-integrity" target="_self" data-event="customLink-link-a_findOutMore" class="Link Link--linkType Link--maincolor Link--small Link--icon Link--chevronRight Link--right"><span>Find out more </span></a></span></div></div></article></div> <div></div></div></div>  <footer class="Footer"><div class="Footer__wrapper"><div class="Footer__sections"><ul class="Accordion"><li class="Accordion__item"><button class="Accordion__headline"> <div class="Accordion__title">Guidelines</div> <div class="Accordion__space"></div> <div class="Accordion__arrow"></div></button> <div class="Accordion__content Accordion__content--fadeOut" style="height:0px;"><ul><li><a href="https://www.frontiersin.org/guidelines/author-guidelines" target="_self" data-event="footer-block_0-a_authorGuidelines">Author guidelines</a></li><li><a href="https://www.frontiersin.org/guidelines/editor-guidelines" target="_self" data-event="footer-block_0-a_editorGuidelines">Editor guidelines</a></li><li><a href="https://www.frontiersin.org/guidelines/policies-and-publication-ethics" target="_self" data-event="footer-block_0-a_policiesAndPublicationE">Policies and publication ethics</a></li><li><a href="https://www.frontiersin.org/about/fee-policy" target="_self" data-event="footer-block_0-a_feePolicy">Fee policy</a></li></ul></div></li><li class="Accordion__item"><button class="Accordion__headline"> <div class="Accordion__title">Explore</div> <div class="Accordion__space"></div> <div class="Accordion__arrow"></div></button> <div class="Accordion__content Accordion__content--fadeOut" style="height:0px;"><ul><li><a href="https://www.frontiersin.org/articles" target="_self" data-event="footer-block_1-a_articles">Articles</a></li><li><a href="https://www.frontiersin.org/research-topics" target="_self" data-event="footer-block_1-a_researchTopics">Research Topics </a></li><li><a href="https://www.frontiersin.org/journals" target="_self" data-event="footer-block_1-a_journals">Journals</a></li><li><a href="https://www.frontiersin.org/about/how-we-publish" target="_self" data-event="footer-block_1-a_howWePublish">How we publish</a></li></ul></div></li><li class="Accordion__item"><button class="Accordion__headline"> <div class="Accordion__title">Outreach</div> <div class="Accordion__space"></div> <div class="Accordion__arrow"></div></button> <div class="Accordion__content Accordion__content--fadeOut" style="height:0px;"><ul><li><a href="https://forum.frontiersin.org/" target="_blank" data-event="footer-block_2-a_frontiersForum">Frontiers Forum </a></li><li><a href="https://policylabs.frontiersin.org/" target="_blank" data-event="footer-block_2-a_frontiersPolicyLabs">Frontiers Policy Labs </a></li><li><a href="https://kids.frontiersin.org/" target="_blank" data-event="footer-block_2-a_frontiersForYoungMinds">Frontiers for Young Minds</a></li><li><a href="https://www.frontiersplanetprize.org/" target="_blank" data-event="footer-block_2-a_frontiersPlanetPrize">Frontiers Planet Prize</a></li></ul></div></li><li class="Accordion__item"><button class="Accordion__headline"> <div class="Accordion__title">Connect</div> <div class="Accordion__space"></div> <div class="Accordion__arrow"></div></button> <div class="Accordion__content Accordion__content--fadeOut" style="height:0px;"><ul><li><a href="https://helpcenter.frontiersin.org" target="_blank" data-event="footer-block_3-a_helpCenter">Help center</a></li><li><a href="https://loop.frontiersin.org/settings/email-preferences?a=publishers" target="_blank" data-event="footer-block_3-a_emailsAndAlerts">Emails and alerts </a></li><li><a href="https://www.frontiersin.org/about/contact" target="_self" data-event="footer-block_3-a_contactUs">Contact us </a></li><li><a href="https://www.frontiersin.org/submission/submit" target="_self" data-event="footer-block_3-a_submit">Submit</a></li><li><a href="https://careers.frontiersin.org/" target="_blank" data-event="footer-block_3-a_careerOpportunities">Career opportunities</a></li></ul></div></li></ul> <div class="Footer__socialLinks"><div class="Footer__socialLinks__title">Follow us</div> <span class="Link__wrapper"><a aria-label="Frontiers Facebook" href="https://www.facebook.com/Frontiersin" target="_blank" data-event="footer-facebook-a_" class="Link Link--linkType Link--grey Link--medium Link--icon Link--facebook Link--right"><span></span></a></span><span class="Link__wrapper"><a aria-label="Frontiers Twitter" href="https://twitter.com/frontiersin" target="_blank" data-event="footer-twitter-a_" class="Link Link--linkType Link--grey Link--medium Link--icon Link--twitter Link--right"><span></span></a></span><span class="Link__wrapper"><a aria-label="Frontiers LinkedIn" href="https://www.linkedin.com/company/frontiers" target="_blank" data-event="footer-linkedIn-a_" class="Link Link--linkType Link--grey Link--medium Link--icon Link--linkedin Link--right"><span></span></a></span><span class="Link__wrapper"><a aria-label="Frontiers Instagram" href="https://www.instagram.com/frontiersin_" target="_blank" data-event="footer-instagram-a_" class="Link Link--linkType Link--grey Link--medium Link--icon Link--instagram Link--right"><span></span></a></span></div></div> <div class="Footer__copyright"><div><span>© 2025 Frontiers Media S.A. All rights reserved</span></div> <div><a href="https://www.frontiersin.org/legal/privacy-policy" target="_blank">Privacy policy</a> <span>|</span> <a href="https://www.frontiersin.org/legal/terms-and-conditions" target="_blank">Terms and conditions</a></div></div></div></footer> <div class="SnackbarWrapper"><ul class="SnackbarContainer"></ul></div></div></div></div><script>window.__NUXT__=(function(a,b,c,d,e,f,g,h,i,j,k,l,m,n,o,p,q,r,s,t,u,v,w,x,y,z,A,B,C,D,E,F,G,H,I,J,K,L,M,N,O,P,Q,R,S,T,U,V,W,X,Y,Z,_,$,aa,ab,ac,ad,ae,af,ag,ah,ai,aj,ak,al,am,an,ao,ap,aq,ar,as,at,au,av,aw,ax,ay,az,aA,aB,aC,aD,aE,aF,aG,aH,aI,aJ,aK,aL,aM,aN,aO,aP,aQ,aR,aS,aT,aU,aV,aW,aX,aY,aZ,a_,a$,ba,bb,bc,bd,be,bf,bg,bh,bi,bj,bk,bl,bm,bn,bo,bp,bq,br,bs,bt,bu,bv,bw,bx,by,bz,bA,bB,bC,bD,bE,bF,bG,bH,bI,bJ,bK,bL,bM,bN,bO,bP,bQ,bR,bS,bT,bU,bV,bW,bX,bY,bZ,b_,b$,ca,cb,cc,cd,ce,cf,cg,ch,ci,cj,ck,cl,cm,cn,co,cp,cq,cr,cs,ct,cu,cv,cw,cx,cy,cz,cA,cB,cC,cD,cE,cF,cG,cH,cI,cJ,cK,cL,cM,cN,cO){av.id=aw;av.name=ax;av.slug=ay;av.specialtyId=1730;av.__typename="journal_section";return {layout:"ArticleLayout",data:[{}],fetch:{},error:e,state:{currentJournal:{identifier:t,name:p,slug:u,banner:[{id:"754E12A9-443F-4EA8-AB01E0811E45131D",src:V,name:"FPHAR_Main Visual_Purple_Website",tags:["pain","medical","pharmaceutical","antibiotic","concept","capsule","treatment"],type:H,width:5844,height:3896,idHash:"79b643019a2651e0",archive:l,brandId:W,limited:l,fileSize:8675243,isPublic:c,original:"https:\u002F\u002Fbrand.frontiersin.org\u002Fm\u002F79b643019a2651e0\u002Foriginal\u002FFPHAR_Main-Visual_Purple_Website.jpeg",copyright:"Copyright (c) 2017 Marian Weyo\u002FShutterstock. No use without permission.",extension:["jpeg"],thumbnails:{mini:"https:\u002F\u002Fd2csxpduxe849s.cloudfront.net\u002Fmedia\u002FE32629C6-9347-4F84-81FEAEF7BFA342B3\u002F754E12A9-443F-4EA8-AB01E0811E45131D\u002Fmini-97EEF455-249B-43BD-9D8F02FEE86046D3.jpg",thul:"https:\u002F\u002Fd2csxpduxe849s.cloudfront.net\u002Fmedia\u002FE32629C6-9347-4F84-81FEAEF7BFA342B3\u002F754E12A9-443F-4EA8-AB01E0811E45131D\u002Fthul-B2DBD910-1DDF-4ED3-B1500DF973953144.jpg",webimage:V,Guidelines:"https:\u002F\u002Fd2csxpduxe849s.cloudfront.net\u002Fmedia\u002FE32629C6-9347-4F84-81FEAEF7BFA342B3\u002F754E12A9-443F-4EA8-AB01E0811E45131D\u002FF3882BDE-513E-4D16-8DB695504865E7B8\u002FGuidelines-FPHAR_Main Visual_Purple_Website.png",WebsiteJpg_XL:"https:\u002F\u002Fd2csxpduxe849s.cloudfront.net\u002Fmedia\u002FE32629C6-9347-4F84-81FEAEF7BFA342B3\u002F754E12A9-443F-4EA8-AB01E0811E45131D\u002FF3882BDE-513E-4D16-8DB695504865E7B8\u002FWebsiteJpg_XL-FPHAR_Main Visual_Purple_Website.jpg",WebsiteWebP_L:"https:\u002F\u002Fd2csxpduxe849s.cloudfront.net\u002Fmedia\u002FE32629C6-9347-4F84-81FEAEF7BFA342B3\u002F754E12A9-443F-4EA8-AB01E0811E45131D\u002FF3882BDE-513E-4D16-8DB695504865E7B8\u002FWebsiteWebP_L-FPHAR_Main Visual_Purple_Website.webp",WebsiteWebP_M:"https:\u002F\u002Fd2csxpduxe849s.cloudfront.net\u002Fmedia\u002FE32629C6-9347-4F84-81FEAEF7BFA342B3\u002F754E12A9-443F-4EA8-AB01E0811E45131D\u002FF3882BDE-513E-4D16-8DB695504865E7B8\u002FWebsiteWebP_M-FPHAR_Main Visual_Purple_Website.webp",WebsiteWebP_XL:"https:\u002F\u002Fd2csxpduxe849s.cloudfront.net\u002Fmedia\u002FE32629C6-9347-4F84-81FEAEF7BFA342B3\u002F754E12A9-443F-4EA8-AB01E0811E45131D\u002FF3882BDE-513E-4D16-8DB695504865E7B8\u002FWebsiteWebP_XL-FPHAR_Main Visual_Purple_Website.webp"},dateCreated:X,description:"Pills Tablets Capsule or Medicament freely laid on glass background.",orientation:I,userCreated:"Caroline Sutter",watermarked:l,dateModified:X,datePublished:"2022-06-27T09:27:09Z",ecsArchiveFiles:[],propertyOptions:["414FB2D4-2283-43FD-BE14E534ECA67928","6C18119B-14BD-4951-B437696F4357BD33","7C692885-DB25-4858-B1FB4FF47B241E9B","D88C0047-EC30-4506-A7DF28A4D765E1CF"],property_Channel:["frontiersin_org"],"property_Sub-Type":["Main_Visual"],property_Asset_Type:["Photography"],activeOriginalFocusPoint:{x:2922,y:1948},property_Office_Department:["Publishing"]}],description:"The most cited pharmacology and pharmacy journal advances access to pharmacological discoveries to prevent and treat human disease.",mission:"\u003Cp\u003EFrontiers in Pharmacology is an interdisciplinary journal that publishes research on the interactions between drugs and living beings to prevent and cure human disease.\u003C\u002Fp\u003E\n\n\u003Cp\u003ELed by Field Chief Editor Heike Wulff (University of California, Davis, US), Frontiers in Pharmacology explores basic and clinical pharmacology, medicinal chemistry, pharmacy, and toxicology to clarify the fundamental processes of disease treatment and drug effects. Indexed in PubMed Central (PMC), Scopus, Web of Science (SCIE), and the DOAJ, the journal welcomes academic, industrial, and clinical work focused on pharmacology.\u003C\u002Fp\u003E\n\n\u003Cp\u003ETopics include, but are not limited to:\u003C\u002Fp\u003E\n\u003Cul\u003E\n \u003Cli\u003Ecardiovascular and smooth muscle pharmacology\u003C\u002Fli\u003E\n \u003Cli\u003Edrug metabolism and transport\u003C\u002Fli\u003E\n \u003Cli\u003Edrugs outcomes research and policies\u003C\u002Fli\u003E\n \u003Cli\u003EELSI in science and genetics\u003C\u002Fli\u003E\n \u003Cli\u003Eethnopharmacology\u003C\u002Fli\u003E\n \u003Cli\u003Eexperimental pharmacology and drug discovery\u003C\u002Fli\u003E\n \u003Cli\u003Egastrointestinal and hepatic pharmacology\u003C\u002Fli\u003E\n \u003Cli\u003Einflammation pharmacology\u003C\u002Fli\u003E\n \u003Cli\u003Eintegrative and regenerative pharmacology\u003C\u002Fli\u003E\n \u003Cli\u003Eneuropharmacology\u003C\u002Fli\u003E\n \u003Cli\u003Eobstetric and pediatric pharmacology\u003C\u002Fli\u003E\n \u003Cli\u003Epharmacoepidemiology\u003C\u002Fli\u003E\n \u003Cli\u003Epharmacogenetics and pharmacogenomics\u003C\u002Fli\u003E\n \u003Cli\u003Epharmacology of anti-cancer drugs\u003C\u002Fli\u003E\n \u003Cli\u003Epharmacology of infectious diseases\u003C\u002Fli\u003E\n \u003Cli\u003Epharmacology of ion channels and channelopathies\u003C\u002Fli\u003E\n \u003Cli\u003Epredictive toxicology\u003C\u002Fli\u003E\n \u003Cli\u003Erenal pharmacology\u003C\u002Fli\u003E\n \u003Cli\u003Erespiratory pharmacology\u003C\u002Fli\u003E\n \u003Cli\u003Etranslational pharmacology.\u003C\u002Fli\u003E\n\u003C\u002Ful\u003E\n\n\u003Cp\u003EAll submissions to the journal involving natural products, including plant extracts or preparations, must adhere to \u003Ci\u003E'The Four Pillars of Ethnopharmacology'\u003C\u002Fi\u003E to be considered for peer review, regardless of the specialty section, as a baseline standard for sample characterization. These are a set of mandatory guidelines designed to maintain the scientific, cultural, and ethical integrity of the Journal, and describe what the leading journals in the field consider as the basic aspects of good research (full ConPhyMP statement available \u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Fjournals\u002Fpharmacology\u002Farticles\u002F10.3389\u002Ffphar.2022.953205\u002Ffull\" target=\"_blank\"\u003Ehere\u003C\u002Fa\u003E, ConPhyMP statement overview \u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Fjournals\u002Fpharmacology\u002Farticles\u002F10.3389\u002Ffphar.2023.1338710\u002Ffull\" target=\"_blank\"\u003Ehere\u003C\u002Fa\u003E, and GA-tool \u003Ca href=\"https:\u002F\u002Fga-online.org\u002Fbest-practice\u002F\" target=\"_blank\"\u003Ehere\u003C\u002Fa\u003E). Please refer to the \u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002Fpdf\u002F4_pillars_FULL_TEXT.pdf\" target=\"_blank\"\u003EFULL VERSION\u003C\u002Fa\u003E of these guidelines before submitting a manuscript to the journal.\u003C\u002Fp\u003E \n\u003Cp\u003ETo be considered for publication in Frontiers in Pharmacology, studies incorporating complementary or alternative medicine must be based on a set of data linked to local or traditional uses that can be evaluated pharmacologically. A clear and plausible set of pharmacological data must be generated in these studies. Similarly, the journal endorses protocols including a minimum of 2 cell-lines in vitro as an evidential basis to demonstrate proposed anti-cancer effects in all relevant studies submitted to all specialty sections in the journal.\u003C\u002Fp\u003E\n\u003Cp\u003EIsolated data mining studies using disproportionality analyses of databases containing spontaneously reported adverse events, frequently lead to misinterpretation due to various reporting biases, lack of structured control, and insufficient demographic details. Presenting such analyses in isolation typically does not yield clinically actionable safety findings without the broader context of a comprehensive signal evaluation. To ensure rigor and relevance, all submissions to the journal must be complemented by a proper systematic review and\u002For thorough analyses of reported cases, and adhere to the READUS-PV guidelines (\u003Ca href=\"https:\u002F\u002Fwww.equator-network.org\u002Freporting-guidelines\u002Fthe-reporting-of-a-disproportionality-analysis-for-drug-safety-signal-detection-using-individual-case-safety-reports-in-pharmacovigilance-readus-pv-development-and-statement\u002F\" target=\"_blank\"\u003EThe Reporting of a Disproportionality Analysis for Drug Safety Signal Detection Using Individual Case Safety Reports in PharmacoVigilance\u003C\u002Fa\u003E). Authors are expected to ensure compliance with the corresponding \u003Ca href=\"https:\u002F\u002Freadus-statement.org\u002Fwp-content\u002Fuploads\u002F2024\u002F03\u002Freadus-checklist.pdf\" target=\"_blank\"\u003Echecklist\u003C\u002Fa\u003E before proceeding with submission to the journal. Full publication of the READUS-PV guidelines is available \u003Ca href=\"https:\u002F\u002Fpmc.ncbi.nlm.nih.gov\u002Farticles\u002FPMC11116242\u002Fpdf\u002F40264_2024_Article_1421.pdf\" target=\"_blank\"\u003Ehere\u003C\u002Fa\u003E.\u003C\u002Fp\u003E\n\n\u003Cp\u003EFurther unique criteria for the conception and review of submissions may apply, where appropriate, for individual specialty sections.\u003C\u002Fp\u003E\n\n\u003Cp\u003EThe journal welcomes submissions that support and advance the \u003Ca href=\"https:\u002F\u002Fwww.globalgoals.org\u002Fgoals\u002F\" target=\"_blank\"\u003EUN Sustainable Development Goals\u003C\u002Fa\u003E (SDGs), notably the \u003Ca href=\"https:\u002F\u002Fwww.globalgoals.org\u002Fgoals\u002F3-good-health-and-well-being\u002F\" target=\"_blank\"\u003ESDG 3: Good Health and Well-being\u003C\u002Fa\u003E.\u003C\u002Fp\u003E\n\n\u003Cp\u003EManuscripts that focus solely on clinical trials, patient management, or conventional therapies without a focus on pharmacological research are not suitable for publication in this journal. Additionally, studies that are purely statistical or predictive in nature, without providing novel insights into pharmacological mechanisms or drug development, are not within the scope of this journal.\u003C\u002Fp\u003E\n\n\u003Cp\u003EFrontiers in Pharmacology is committed to advancing developments in the field of pharmacological discoveries by allowing unrestricted access to articles and communicating scientific knowledge to researchers and the public alike, to enable the scientific breakthroughs of the future.\u003C\u002Fp\u003E\n\n\u003Cb\u003E\u003Cp\u003EEthics Information\u003C\u002Fp\u003E\u003C\u002Fb\u003E\n\u003Cp\u003EResearch involving human subjects should comply with the ethical guidelines outlined in the \u003Ca href= https:\u002F\u002Fwww.wma.net\u002Fpolicies-post\u002Fwma-declaration-of-helsinki\u002F” target=”_blank”\u003EWorld Medical Association’s Declaration of Helsinki\u003C\u002Fa\u003E.\u003C\u002Fp\u003E\n\u003Cp\u003ESimilarly, authors are required to specify the institutional and national standards adhered to for the care and use of laboratory animals. Transparent and accurate reporting of animal studies is required, with references to guidelines such as \u003Ca href=\"https:\u002F\u002Farriveguidelines.org\u002Farrive-guidelines\" target=\"_blank\"\u003EARRIVE\u003C\u002Fa\u003E and \u003Ca href=\"https:\u002F\u002Fnc3rs.org.uk\u002Fsites\u002Fdefault\u002Ffiles\u002F2022-01\u002FThe%20IMPROVE%20Guidelines%20%28poster%29.pdf\" target=\"_blank\"\u003E IMPROVE\u003C\u002Fa\u003E.\u003C\u002Fp\u003E\n\u003Cp\u003EExtended information on research ethics can be found under the Frontiers Policies and Publication Ethics page.\u003C\u002Fp\u003E",palette:"purple",impactFactor:"5.6",citeScore:"6.3",citations:"356000",showTagline:e,twitter:"@FrontPharmacol",__typename:"Journal"},currentFrontiersJournal:{id:t,name:p,slug:u,printISSN:e,shortName:J,electronicISSN:K,abbreviation:Y,specialtyId:e,publicationDate:e,isOnline:h,isOpenForSubmissions:h,spaceId:c,field:{id:Z,domainId:c,__typename:_},__typename:a},articleHubSlug:g,articleHubPage:L,currentArticle:{id:1145962,doi:$,title:aa,acceptanceDate:new Date(1684214740000),receptionDate:new Date(1673889744000),publicationDate:new Date(1687737600000),isPublished:h,abstract:ab,researchTopic:{id:45495,title:"The Practical Implication of Clinical Pharmacokinetics in Drug Development, Pharmaceuticals Analysis, and Clinical Research",articlesCount:M,isMagazinePage:h,slug:"the-practical-implication-of-clinical-pharmacokinetics-in-drug-development-pharmaceuticals-analysis-and-clinical-research",isOpenForSubmission:j},articleType:{id:24,name:"Original Research"},stage:{id:N,name:g},keywords:["HPLC","α1-acid glycoprotein","human plasma","Hip joint surgery patients","Protein Binding"],authors:[{id:ac,firstName:ad,lastName:"Abbas",givenNames:ad,isCorresponding:j,isProfilePublic:h,userId:ac,affiliations:[{organizationName:x,countryName:y,cityName:g,stateName:g,zipCode:g}]},{id:ae,firstName:af,lastName:"Alossaimi",givenNames:af,isCorresponding:j,isProfilePublic:h,userId:ae,affiliations:[{organizationName:ag,countryName:O,cityName:g,stateName:g,zipCode:g}]},{id:l,firstName:ah,lastName:"Altamimi",givenNames:ah,isCorresponding:j,isProfilePublic:j,userId:l,affiliations:[{organizationName:ag,countryName:O,cityName:g,stateName:g,zipCode:g}]},{id:l,firstName:ai,lastName:"Alajaji",givenNames:ai,isCorresponding:j,isProfilePublic:j,userId:l,affiliations:[{organizationName:"College of Pharmacy",countryName:O,cityName:g,stateName:g,zipCode:g}]},{id:aj,firstName:ak,lastName:"Watson",givenNames:ak,isCorresponding:j,isProfilePublic:h,userId:aj,affiliations:[{organizationName:"Strathclyde Institute of Pharmacy and Biomedical Sciences",countryName:"United Kingdom",cityName:g,stateName:g,zipCode:g}]},{id:l,firstName:al,lastName:am,givenNames:al,isCorresponding:j,isProfilePublic:j,userId:l,affiliations:[{organizationName:x,countryName:y,cityName:g,stateName:g,zipCode:g}]},{id:l,firstName:an,lastName:am,givenNames:an,isCorresponding:j,isProfilePublic:j,userId:l,affiliations:[{organizationName:x,countryName:y,cityName:g,stateName:g,zipCode:g}]},{id:l,firstName:ao,lastName:"Anwar",givenNames:ao,isCorresponding:j,isProfilePublic:j,userId:l,affiliations:[{organizationName:x,countryName:y,cityName:g,stateName:g,zipCode:g}]}],editors:[{id:ap,firstName:aq,lastName:"Ali",givenNames:aq,isCorresponding:j,isProfilePublic:h,userId:ap,affiliations:[{organizationName:"University of Calgary",countryName:"Canada",cityName:g,stateName:g,zipCode:g}]}],reviewers:[{id:ar,firstName:as,lastName:"Abdessadek",givenNames:as,isCorresponding:j,isProfilePublic:h,userId:ar,affiliations:[{organizationName:"Université Ibn Zohr",countryName:"Morocco",cityName:g,stateName:g,zipCode:g}]},{id:at,firstName:au,lastName:"Jaiswal",givenNames:au,isCorresponding:j,isProfilePublic:h,userId:at,affiliations:[{organizationName:"University of Massachusetts Medical School",countryName:"United States",cityName:g,stateName:g,zipCode:g}]}],journal:{id:t,slug:u,name:p,shortName:J,electronicISSN:K,field:{id:Z,domainId:c,__typename:_},specialtyId:e,journalSectionPaths:[{section:av,__typename:"journal_journalSectionPath"}],__typename:a},section:av,impactMetrics:{views:1811,downloads:417,citations:q},volume:az,articleVolume:"Volume 14 - 2023",relatedArticles:[],isPublishedV2:j,contents:{titleHtml:"Determination of α1-acid glycoprotein (AGP) concentration by HPLC in patients following local infiltration analgesia for primary total hip arthroplasty and its relation to ropivacaine (total and unbound)",fullTextHtml:"\u003Cdiv class=\"JournalAbstract\"\u003E\u003Ca id=\"h1\" name=\"h1\"\u003E\u003C\u002Fa\u003E\u003Cdiv class=\"authors\"\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Ca href=\"https:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F1417926\" class=\"user-id-1417926\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fimages\u002Fprofile\u002F1417926\u002F74\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\" alt=\"Muhammad Abbas
\"\u003EMuhammad Abbas\u003C\u002Fa\u003E\u003Csup\u003E1\u003C\u002Fsup\u003E*\u003C\u002Fspan\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Ca href=\"https:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F1109038\" class=\"user-id-1109038\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fimages\u002Fprofile\u002F1109038\u002F74\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\" alt=\"Manal A. Alossaimi\"\u003EManal A. Alossaimi\u003C\u002Fa\u003E\u003Csup\u003E2\u003C\u002Fsup\u003E\u003C\u002Fspan\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg\" alt=\"Abdulmalik S. A. Altamimi\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\"\u003EAbdulmalik S. A. Altamimi\u003Csup\u003E2\u003C\u002Fsup\u003E\u003C\u002Fspan\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg\" alt=\"Mai Alajaji\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\"\u003EMai Alajaji\u003Csup\u003E3\u003C\u002Fsup\u003E\u003C\u002Fspan\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Ca href=\"https:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F2176267\" class=\"user-id-2176267\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fimages\u002Fprofile\u002F2176267\u002F74\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\" alt=\"David G. Watson\"\u003EDavid G. Watson\u003C\u002Fa\u003E\u003Csup\u003E4\u003C\u002Fsup\u003E\u003C\u002Fspan\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg\" alt=\"Sayyed I. Shah\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\"\u003ESayyed I. Shah\u003Csup\u003E1\u003C\u002Fsup\u003E\u003C\u002Fspan\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg\" alt=\"Yasar Shah\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\"\u003EYasar Shah\u003Csup\u003E1\u003C\u002Fsup\u003E\u003C\u002Fspan\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg\" alt=\"Mohammad S. Anwar\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\"\u003EMohammad S. Anwar\u003Csup\u003E5\u003C\u002Fsup\u003E\u003C\u002Fspan\u003E\u003C\u002Fdiv\u003E\u003Cul class=\"notes\"\u003E\u003Cli\u003E\u003Cspan\u003E\u003Csup\u003E1\u003C\u002Fsup\u003E\u003C\u002Fspan\u003EDepartment of Pharmacy, Abdul Wali Khan University Mardan, Mardan, Pakistan\u003C\u002Fli\u003E\u003Cli\u003E\u003Cspan\u003E\u003Csup\u003E2\u003C\u002Fsup\u003E\u003C\u002Fspan\u003EDepartment of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdul Aziz University, Al-Kharj, Saudi Arabia\u003C\u002Fli\u003E\u003Cli\u003E\u003Cspan\u003E\u003Csup\u003E3\u003C\u002Fsup\u003E\u003C\u002Fspan\u003ECollege of Pharmacy, King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia\u003C\u002Fli\u003E\u003Cli\u003E\u003Cspan\u003E\u003Csup\u003E4\u003C\u002Fsup\u003E\u003C\u002Fspan\u003EStrathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom\u003C\u002Fli\u003E\u003Cli\u003E\u003Cspan\u003E\u003Csup\u003E5\u003C\u002Fsup\u003E\u003C\u002Fspan\u003EDepartment of Pharmacy, University of Swabi, Swabi, Pakistan\u003C\u002Fli\u003E\u003C\u002Ful\u003E\u003Cp class=\"mb15\"\u003E\u003Cb\u003EIntroduction:\u003C\u002Fb\u003E This study was performed to determine the levels of α1-acid glycoprotein (AGP) in old-age patients undergoing total hip arthroplasty. AGP is considered an acute phase protein produced during the acute phase reaction in the body to various stimuli; their proper monitoring is thus important.\u003C\u002Fp\u003E\u003Cp class=\"mb15\"\u003E\u003Cb\u003EMethods:\u003C\u002Fb\u003E In order to study how AGP concentrations in old age patients change in response to surgical stress (total hip arthroplasty), a high-performance liquid chromatography assay was performed to measure AGP levels. AGP was isolated from the plasma by adding perchloric acid and was analyzed using PLRP-S 4000°A column. The mobile phase consisted of 1 mL TFA\u002FL of water (Solvent A pH 2) and 1 mL TFA\u002FL of acetonitrile (Solvent B). The gradient used was as follows: 0 min 18% B and 82% A, 15 min 60% B and 40% A, and 17 min 60% B and 40% A followed by column re-equilibration for 7 min before the next injection. AGP peak was obtained between 8.8 and 8.9 min. The method was fully optimised according to established guidelines.\u003C\u002Fp\u003E\u003Cp class=\"mb15\"\u003E\u003Cb\u003EResults:\u003C\u002Fb\u003E The data obtained were analyzed on ChromQuest software. AGP concentrations were determined in all samples, including baseline and samples taken at different timed intervals. The peak for AGP was obtained between 8.8 and 8.9 min for both standard AGP and patient plasma. The graphs indicate that AGP concentration in almost all patient samples increased considerably, especially after 4 h and 24 h—for example, initial concentration in patient 1 was 10.36 mg\u002F100 mL but, after 24 h, increased to 23.50 mg\u002F100 mL. There was thus almost a 13 mg\u002F100 mL increase in 24 h, which is confirmed by AGP concentration increasing after various conditions, including surgery. The increased plasma protein binding was comparatively associated with the unchanged free fraction of the drug.\u003C\u002Fp\u003E\u003Cp class=\"mb15\"\u003E\u003Cb\u003EConclusion:\u003C\u002Fb\u003E This surgically induced increase in AGP concentration resulted in increased plasma protein binding of the drug (ropivacaine), which in turn kept the free portion of ropivacaine stable during the postoperative period.\u003C\u002Fp\u003E\u003Cdiv class=\"clear\"\u003E\u003C\u002Fdiv\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"JournalFullText\"\u003E\u003Ca id=\"h2\" name=\"h2\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003E1 Introduction\u003C\u002Fh2\u003E\u003Cp class=\"mb15\"\u003EDrug binding to different proteins in plasma may be significantly important in drug therapy because drug protein binding serves as a depot for the drug and has an influence on the pharmacokinetic and pharmacodynamic parameters and metabolism of the compound (\u003Ca href=\"#B25\"\u003EZeitlinger et al., 2011\u003C\u002Fa\u003E). The pharmacological action of the drug is only due to the unbound portion of the drug and not to the total drug present in the plasma (\u003Ca href=\"#B13\"\u003EKratochwil et al., 2002\u003C\u002Fa\u003E; \u003Ca href=\"#B2\"\u003EBanker et al., 2003\u003C\u002Fa\u003E). Thus, the effect of plasma protein binding on the pharmacokinetic and pharmacodynamic parameters needs careful attention. Many cases have been reported where a small change in plasma protein binding resulted in clinically vital changes in the pharmacokinetic parameters of the drug (\u003Ca href=\"#B19\"\u003ESchmidt et al., 2010\u003C\u002Fa\u003E). “Unbound fraction” is the concentration of a drug which is not bound to plasma proteins, and only this concentration of the drug produces the pharmacological effect. This unbound concentration varies during the dosing interval and must be accurately and correctly explained to determine the drug's effect (\u003Ca href=\"#B18\"\u003ERoberts et al., 2013\u003C\u002Fa\u003E). Drug binding to plasma proteins plays a vital role in determining the diffusion rate of the drug between extracellular and intracellular space; therefore, any change in this diffusion affects pharmacokinetic parameters, including the distribution volume and the clearance rate of the drug (\u003Ca href=\"#B3\"\u003EBohnert and Gan, 2013\u003C\u002Fa\u003E). Generally, in cases of highly protein-bound drugs, a little change in protein binding is responsible for significant changes in the unbound concentration of drug, thereby increasing the clearance and volume of distribution (\u003Ca href=\"#B3\"\u003EBohnert and Gan, 2013\u003C\u002Fa\u003E; \u003Ca href=\"#B18\"\u003ERoberts et al., 2013\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\u003Cp class=\"mb15\"\u003EAcute phase proteins (α1-acid glycoprotein—AGP or AAP) are produced during the acute phase reaction in the body to various stimuli and play a role in the defence response shown by the body. The initiation of acute phase reactions in the body prevents any further injury by removing any harmful material and initiating the repair process to restore the organ to normal function. Their levels also inform us about the progression of the disease or inflammatory response by monitoring their concentrations in the blood. The changes in the plasma concentration of these proteins lead to altered drug binding and ultimately affect the pharmacokinetic and pharmacodynamic parameters of the drug (\u003Ca href=\"#B22\"\u003ETesseromatis et al., 2011\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\u003Cp class=\"mb15\"\u003EAmong the acute phase proteins, AGP is the most important (\u003Ca href=\"#B17\"\u003ERice et al., 1997\u003C\u002Fa\u003E; \u003Ca href=\"#B22\"\u003ETesseromatis et al., 2011\u003C\u002Fa\u003E). It is also called orosomucoid (ORM) and is the main protein responsible for binding basic drugs (\u003Ca href=\"#B23\"\u003EWood and Wood, 1981\u003C\u002Fa\u003E; \u003Ca href=\"#B14\"\u003EKremer et al., 1988\u003C\u002Fa\u003E; \u003Ca href=\"#B4\"\u003EBooker et al., 1996\u003C\u002Fa\u003E; \u003Ca href=\"#B7\"\u003EFournier et al., 2000\u003C\u002Fa\u003E; \u003Ca href=\"#B9\"\u003EHochepied et al., 2003\u003C\u002Fa\u003E; \u003Ca href=\"#B22\"\u003ETesseromatis et al., 2011\u003C\u002Fa\u003E; \u003Ca href=\"#B10\"\u003EHuang and Ung, 2013\u003C\u002Fa\u003E; \u003Ca href=\"#B21\"\u003ETaguchi et al., 2013\u003C\u002Fa\u003E). AGP was first described by Karl Schmid and Richard J. Winzler and their colleagues in 1950; they considered it an unusual protein because of its low p\u003Cem\u003EI\u003C\u002Fem\u003E value, which ranges from 2.8–3.8 and has a comparatively high content of carbohydrate (45% w\u002Fw) (\u003Ca href=\"#B12\"\u003EKishino and Miyazaki, 1997\u003C\u002Fa\u003E; \u003Ca href=\"#B15\"\u003EKremmer et al., 2004\u003C\u002Fa\u003E). AGP was considered as having the highest carbohydrate content of any protein until the characterisation of galactoglycoprotein in 1980, which has a 76% carbohydrate content (\u003Ca href=\"#B8\"\u003EHellerstein et al., 1985\u003C\u002Fa\u003E; \u003Ca href=\"#B7\"\u003EFournier et al., 2000\u003C\u002Fa\u003E; \u003Ca href=\"#B24\"\u003EXuan and Hage, 2005\u003C\u002Fa\u003E). AGP is also reported as playing a role in drug–drug interactions due to the displacement of drugs and other endogenous molecules from their binding sites, resulting in significant clinical implications (\u003Ca href=\"#B22\"\u003ETesseromatis et al., 2011\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\u003Cp class=\"mb15\"\u003EThe concentration of AGP in serum increases in various conditions, like post-surgical inflammation due to burn injury, cancer, and various other conditions (\u003Ca href=\"#B8\"\u003EHellerstein et al., 1985\u003C\u002Fa\u003E; \u003Ca href=\"#B12\"\u003EKishino and Miyazaki, 1997\u003C\u002Fa\u003E; \u003Ca href=\"#B16\"\u003ELarsson et al., 1997\u003C\u002Fa\u003E; \u003Ca href=\"#B9\"\u003EHochepied et al., 2003\u003C\u002Fa\u003E; \u003Ca href=\"#B10\"\u003EHuang and Ung, 2013\u003C\u002Fa\u003E; \u003Ca href=\"#B6\"\u003EEckersall and Schmidt, 2014\u003C\u002Fa\u003E). AGP synthesis mostly occurs in the liver, and then it is secreted by hepatocytes (\u003Ca href=\"#B22\"\u003ETesseromatis et al., 2011\u003C\u002Fa\u003E; \u003Ca href=\"#B11\"\u003EKeser et al., 2021\u003C\u002Fa\u003E). However, there is also evidence of extra hepatic synthesis, which is production of AGP in places apart from hepatic tissue like human breast epithelial cells, the kidney, adipose tissue, and the spleen, thymus, and heart (\u003Ca href=\"#B9\"\u003EHochepied et al., 2003\u003C\u002Fa\u003E). There is also variation in the levels of AGP among healthy individuals depending on age, sex, and hormonal variations (\u003Ca href=\"#B10\"\u003EHuang and Ung, 2013\u003C\u002Fa\u003E). The effectiveness of a drug in these cases depends on whether it is acidic in nature or a basic drug, as well on whether the drug binds to the albumin, to which acidic drugs normally bind, or to AGP, to which basic drugs bind. Drug displacement from protein binding sites by another strongly binding drug will also have a significant effect on the concentration of the displaced drug; dose adjustment should be taken into consideration in the use of such drugs (\u003Ca href=\"#B18\"\u003ERoberts et al., 2013\u003C\u002Fa\u003E; \u003Ca href=\"#B5\"\u003EBteich, 2019\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\u003Ca id=\"h3\" name=\"h3\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003E2 Methodology\u003C\u002Fh2\u003E\u003Ch3 class=\"pt0\"\u003E2.1 Patients\u003C\u002Fh3\u003E\u003Cp class=\"mb0\"\u003EWe measured AGP in 20 patients (12 male and 8 female patients) aged 65 years or over undergoing unilateral total hip arthroplasty following high-volume, high-dose local infiltration analgesia. The study protocol was approved by the Regional Ethics Committee and conducted in accordance with the Helsinki Declaration (NCT01873313) from August 2012 to March 2013 in Golden Jubilee Hospital, Glasgow Scotland. Ten blood samples at different timed intervals were taken from each patient, and AGP was determined. A total of 200 samples were thus analysed for AGP. (20*10 = 200). Local anaesthetic infiltration was performed intra-operatively by the surgeon using 180 mL plain ropivacaine 0.2%. Circumferential infiltration of the deep and peri-capsular tissues with up to 80 mL was followed by infiltration of the gluteal muscles and fascia lata with approximately 70 mL. Finally, 30 mL was used to infiltrate the subcutaneous tissues and skin, completing the total of 180 mL.\u003C\u002Fp\u003E\u003Ch3 class=\"pt0\"\u003E2.2 Chemicals and blood plasma for AGP analysis\u003C\u002Fh3\u003E\u003Cp class=\"mb0\"\u003EHuman AGP (standard), trifluoroacetic acid, and perchloric acid (70%) were purchased from Sigma Aldrich (UK). HPLC-grade water was produced by a Direct-Q 3 Ultrapure Water System from Millipore, UK. HPLC-grade acetonitrile (ACN) was purchased from Fisher Scientific, United Kingdom. Blank plasma was provided by the Blood Transfusion Service of Gartnavel Hospital, Glasgow. Plasma samples were obtained from Dr Mike Gill from patients undergoing hip joint surgery at the Golden Jubilee Hospital in Clydebank. The samples were stored at −20°C until analysis.\u003C\u002Fp\u003E\u003Ch3 class=\"pt0\"\u003E2.3 HPLC analysis\u003C\u002Fh3\u003E\u003Cp class=\"mb0\"\u003EA high-performance liquid chromatographic (HPLC) system was used in the analysis and consisted of a SpectraSYSTEM P2000 gradient pump, a SpectraSYSTEM AS3000 autosampler (equipped with a Type 7010-150 Rheodyne injection valve (20 µL loop)), and a SpectraSYSTEM UV 1000 detector. The column used in the analysis was a PLRP-S 4000°A column (50 mm × 4.6 mm I.D., 5 µm particle size, Agilent Technologies). The pressure maintained at the column head was about 9,000 psi. The mobile phase consisted of 1 mL TFA\u002FL of water (Solvent A pH 2) and 1 mL TFA\u002FL of acetonitrile (Solvent B). The gradient used was as follows: 0 min 18% B and 82% A, 15 min 60% B and 40% A, and 17 min 60% B and 40% A followed by column re-equilibration for 7 min before the next injection. The flow rate of the mobile phase was 1 mL\u002Fmin. The detection wavelength was set to 220 nm. The column was kept at room temperature. The data acquired were processed using ChromQuest software.\u003C\u002Fp\u003E\u003Ca id=\"h3-1\" name=\"h3-1\"\u003E\u003C\u002Fa\u003E\u003Ch3 class=\"pt0\"\u003E2.4 Standards preparation\u003C\u002Fh3\u003E\u003Cp class=\"mb0\"\u003EStock solution of AGP was prepared at a concentration of 2 mg\u002FmL in water. Different calibration solutions were then prepared from the stock solution by diluting it in 0.5 M perchloric acid. Different standards at concentrations of 6.25 mg\u002F100 mL (0.0625 mg\u002FmL), 12.5 mg\u002F100 mL (0.125 mg\u002FmL), 25 mg\u002F100 mL (0.25 mg\u002FmL), 50 mg\u002F100 mL (0.5 mg\u002FmL), and 100 mg\u002F100 mL (1 mg\u002FmL) were prepared and directly injected into the chromatographic system.\u003C\u002Fp\u003E\u003Ca id=\"h3-2\" name=\"h3-2\"\u003E\u003C\u002Fa\u003E\u003Ch3 class=\"pt0\"\u003E2.5 Sample preparation\u003C\u002Fh3\u003E\u003Cp class=\"mb0\"\u003EVenous blood samples from each patient participating in the study were taken at 5, 10, 15, 20, 25, and 30 min, then 1, 4, and 24 h following the injection of local anaesthetic, at the Golden Jubilee Hospital in Clydebank. The samples were then transferred to the University of Strathclyde, Glasgow, for analysis.\u003C\u002Fp\u003E\u003Cp class=\"mb0\"\u003EThe concentrations of AGP in all the patient plasma were then determined as follows: to 50 µL of patient or control plasma, 100 µL of 0.5 M of perchloric acid was added and was vortexed for 20 S in an Eppendorf tube to mix it thoroughly. The acidified plasma was then centrifuged at 9,000 rpm for 5 min at room temperature. The supernatant was then transferred to the insert in the HPLC vial for analysis. Both the extracted standards and samples were stored at 4°C before being chromatographed.\u003C\u002Fp\u003E\u003Cp class=\"mb0\"\u003EThe AGP concentration was then calculated from its linear correlation versus the values of peak areas obtained from the perchloric acid extract, expressed as mg\u002F100 mL of plasma.\u003C\u002Fp\u003E\u003Ch3 class=\"pt0\"\u003E2.6 Method validation\u003C\u002Fh3\u003E\u003Cp class=\"mb0\"\u003EThe method was validated according to ICH guidelines.\u003C\u002Fp\u003E\u003Ch4\u003E2.6.1 Linearity\u003C\u002Fh4\u003E\u003Cp class=\"mb0\"\u003EThe method’s linearity was established using the standards for AGP dissolved in perchloric acid as described in \u003Ca href=\"#h3-1\"\u003ESection 2.4\u003C\u002Fa\u003E.\u003C\u002Fp\u003E\u003Ch4\u003E2.6.2 Recovery\u003C\u002Fh4\u003E\u003Cp class=\"mb0\"\u003EIn order to determine the accuracy of the extraction procedure, the recovery of AGP by perchloric acid extraction was determined. AGP was added to a constant volume of plasma (50 μL) in two different concentrations (25 and 50 mg\u002F100 mL) and then mixed with perchloric acid as before in order to prepare a standard addition curve.\u003C\u002Fp\u003E\u003Ch4\u003E2.6.3 Accuracy and precision\u003C\u002Fh4\u003E\u003Cp class=\"mb0\"\u003EThe within-run reproducibility of retention time and peak area was examined by repeated injection (\u003Cem\u003En\u003C\u002Fem\u003E = 3) of an AGP standard (50 mg\u002F100 mL). Three replicates prepared from the 50 μL amounts of the pooled plasma QC sample were run on three different occasions to calculate within- and between-run precision.\u003C\u002Fp\u003E\u003Ch4\u003E2.6.4 Reproducibility\u003C\u002Fh4\u003E\u003Cp class=\"mb0\"\u003EReplicates of the same QC samples (50 mg\u002F100 mL) were run alongside the patient samples to monitor the performance of each assay.\u003C\u002Fp\u003E\u003Ch4\u003E2.6.5 Sensitivity\u003C\u002Fh4\u003E\u003Cp class=\"mb0\"\u003EThe sensitivity of the method was determined in standard solutions and blank plasma spiked with the analyte. The limit of detection was defined as the minimum concentration for which a signal-to-noise ratio of 3 was obtained; for LOQ, a signal-to-noise ratio of 10 was considered.\u003C\u002Fp\u003E\u003Ch4\u003E2.6.6 Application of the method to patient plasma\u003C\u002Fh4\u003E\u003Cp class=\"mb0\"\u003ETo determine the clinical relevance of the method, the concentration of AGP was identified and determined in the plasma of old-age hip joint surgery patients. The procedure was discussed in \u003Ca href=\"#h3-2\"\u003ESection 2.5\u003C\u002Fa\u003E.\u003C\u002Fp\u003E\u003Ch3 class=\"pt0\"\u003E2.7 Ropivacaine determination\u003C\u002Fh3\u003E\u003Cp class=\"mb0\"\u003EA fully validated method was developed on LC-MS to determine the free and bound portions of ropivacaine and published in \u003Ca href=\"#B1\"\u003EAbbas et al. (2013\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\u003Ca id=\"h4\" name=\"h4\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003E3 Results\u003C\u002Fh2\u003E\u003Cp class=\"mb15\"\u003EThe normal mean value for AGP concentration in the plasma is 77 mg\u002F100 mL (\u003Ca href=\"#B4\"\u003EBooker et al., 1996\u003C\u002Fa\u003E). However, there is great variation of this value among individuals. The results we obtained in our analysis gave concentrations which were generally below those specified by previous studies.\u003C\u002Fp\u003E\u003Ch3 class=\"pt0\"\u003E3.1 Results of standard AGP samples and patient plasma\u003C\u002Fh3\u003E\u003Cp class=\"mb0\"\u003EThe AGP concentrations were analysed in the plasma of 20 hip joint surgery patients. These samples were taken at 5 min, 10 min, 15 min, 20 min, 25 min, 30 min, 1 h, 4 h, and 24 h. \u003Ca href=\"#F1\"\u003EFigure 1\u003C\u002Fa\u003E shows a typical chromatogram of the AGP standard injected directly into the chromatographic system, and \u003Ca href=\"#F2\"\u003EFigure 2\u003C\u002Fa\u003E shows a chromatogram of the AGP in patient plasma following removal of the rest of the protein with 0.5 M perchloric acid. The peak for AGP was obtained between 8.8 and 8.9 min. This method works very well for determining AGP, and there is minimal interference from other serum proteins like HSA, which is precipitated out almost completely by the perchloric acid; AGP remains in solution because of its high water solubility, which is due to its 40% carbohydrate content (\u003Ca href=\"#B20\"\u003EStumpe et al., 2006\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"Imageheaders\"\u003EFIGURE 1\u003C\u002Fdiv\u003E\u003Cdiv class=\"FigureDesc\"\u003E\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F1145962\u002Ffphar-14-1145962-HTML-r3\u002Fimage_m\u002Ffphar-14-1145962-g001.jpg\" name=\"Figure1\" target=\"_blank\"\u003E\n \u003Cpicture\u003E\n \u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=480&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F1145962\u002Ffphar-14-1145962-HTML-r3\u002Fimage_m\u002Ffphar-14-1145962-g001.jpg\" media=\"(max-width: 563px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=370&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F1145962\u002Ffphar-14-1145962-HTML-r3\u002Fimage_m\u002Ffphar-14-1145962-g001.jpg\" media=\"(max-width: 1024px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=290&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F1145962\u002Ffphar-14-1145962-HTML-r3\u002Fimage_m\u002Ffphar-14-1145962-g001.jpg\" media=\"(max-width: 1441px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=410&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F1145962\u002Ffphar-14-1145962-HTML-r3\u002Fimage_m\u002Ffphar-14-1145962-g001.jpg\" media=\"\"\u003E\u003Csource type=\"image\u002Fjpg\" srcset=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F1145962\u002Ffphar-14-1145962-HTML-r3\u002Fimage_m\u002Ffphar-14-1145962-g001.jpg\" media=\"\"\u003E \u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F1145962\u002Ffphar-14-1145962-HTML-r3\u002Fimage_m\u002Ffphar-14-1145962-g001.jpg\" alt=\"www.frontiersin.org\" id=\"F1\" loading=\"lazy\"\u003E\n \u003C\u002Fpicture\u003E\n\u003C\u002Fa\u003E\u003Cp\u003E\u003Cb\u003EFIGURE 1\u003C\u002Fb\u003E. Typical chromatogram of an unextracted aqueous standard containing 50 mg\u002F100 mL of AGP. The elution was performed on a PLRP-S 4000°A column (50 mm × 4.6 mm I.D., 5 µm particle size, Agilent Technologies). The mobile phase consisted of 1 mL TFA\u002FL of water (Solvent A) and 1 mL TFA\u002FL of acetonitrile (Solvent B). The gradient used was 0 min 18% B, 15 min 60% B, and 17 min 60% B followed by column re-equilibration for 7 min before the next injection. The flow rate of the mobile phase was 1 mL\u002Fmin. The detection wavelength was set to 220 nm. Retention time observed was 8.9 min.\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"clear\"\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"Imageheaders\"\u003EFIGURE 2\u003C\u002Fdiv\u003E\u003Cdiv class=\"FigureDesc\"\u003E\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F1145962\u002Ffphar-14-1145962-HTML-r3\u002Fimage_m\u002Ffphar-14-1145962-g002.jpg\" name=\"Figure2\" target=\"_blank\"\u003E\n \u003Cpicture\u003E\n \u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=480&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F1145962\u002Ffphar-14-1145962-HTML-r3\u002Fimage_m\u002Ffphar-14-1145962-g002.jpg\" media=\"(max-width: 563px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=370&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F1145962\u002Ffphar-14-1145962-HTML-r3\u002Fimage_m\u002Ffphar-14-1145962-g002.jpg\" media=\"(max-width: 1024px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=290&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F1145962\u002Ffphar-14-1145962-HTML-r3\u002Fimage_m\u002Ffphar-14-1145962-g002.jpg\" media=\"(max-width: 1441px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=410&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F1145962\u002Ffphar-14-1145962-HTML-r3\u002Fimage_m\u002Ffphar-14-1145962-g002.jpg\" media=\"\"\u003E\u003Csource type=\"image\u002Fjpg\" srcset=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F1145962\u002Ffphar-14-1145962-HTML-r3\u002Fimage_m\u002Ffphar-14-1145962-g002.jpg\" media=\"\"\u003E \u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F1145962\u002Ffphar-14-1145962-HTML-r3\u002Fimage_m\u002Ffphar-14-1145962-g002.jpg\" alt=\"www.frontiersin.org\" id=\"F2\" loading=\"lazy\"\u003E\n \u003C\u002Fpicture\u003E\n\u003C\u002Fa\u003E\u003Cp\u003E\u003Cb\u003EFIGURE 2\u003C\u002Fb\u003E. Typical chromatogram of AGP extracted from 50 µL of patient plasma. Analysis was performed on PLRP-S 4000°A column (50 mm × 4.6 mm I.D., 5 µm particle size, Agilent Technologies). The mobile phase consisted of 1 mL TFA\u002FL of water (Solvent A) and 1 mL TFA\u002FL of acetonitrile (Solvent B). The gradient used was 0 min 18% B, 15 min 60% B, and 17 min 60% B followed by column re-equilibration for 7 min before the next injection. The flow rate of the mobile phase was 1 mL\u002Fmin. The detection wavelength was set to 220 nm. Retention time observed was 8.89 min.\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"clear\"\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\u003Ch3 class=\"pt0\"\u003E3.2 Method validation\u003C\u002Fh3\u003E\u003Ch4\u003E3.2.1 Linearity\u003C\u002Fh4\u003E\u003Cp class=\"mb0\"\u003EThe calibration curve obtained by plotting the areas of the AGP peaks versus AGP concentration on different days was linear (calibration curve added in \u003Ca href=\"#SM1\"\u003ESupplementary Material\u003C\u002Fa\u003E). The data were obtained for the calibration curve on three different days, and the average of these data was used for the calibration curve. The curve covered the concentration range from 6 mg\u002F100 mL to 100 mg\u002F100 mL, which also covered the concentration of AGP in the patient plasma.\u003C\u002Fp\u003E\u003Ch4\u003E3.2.2 Recovery\u003C\u002Fh4\u003E\u003Cp class=\"mb0\"\u003EIn the recovery test, the recovery after liquid–liquid extraction with perchloric acid of 25 mg\u002F100 mL spiking of AGP into plasma was 91.7% ± 8.9% (\u003Cem\u003En\u003C\u002Fem\u003E = 6), and, for 50 mg\u002F100 mL spiking, the recovery was 90.1% ± 3.7% (\u003Cem\u003En\u003C\u002Fem\u003E = 6).\u003C\u002Fp\u003E\u003Ch4\u003E3.2.3 Accuracy and precision\u003C\u002Fh4\u003E\u003Cp class=\"mb0\"\u003EThe within-run precision of the extraction\u002FHPLC procedure ranged from ±1.2% to ±3.8%, and the between-run precision was ±6.1%.\u003C\u002Fp\u003E\u003Ch4\u003E3.2.4 Reproducibility\u003C\u002Fh4\u003E\u003Cp class=\"mb0\"\u003EHaving established linearity, a single-point standard of 50 mg\u002F100 mL was run every day with the patient samples, and results were always well within limits.\u003C\u002Fp\u003E\u003Ch4\u003E3.2.5 Sensitivity\u003C\u002Fh4\u003E\u003Cp class=\"mb0\"\u003EThe method was sensitive enough to determine the lowest level of AGP 5 mg\u002F100 mL (LOD), while LOQ was found to be 10 mg\u002F100 mL.\u003C\u002Fp\u003E\u003Ch4\u003E3.2.6 Application of the method to patient plasma\u003C\u002Fh4\u003E\u003Cp class=\"mb0\"\u003EThe results for the AGP concentrations in patients receiving a continuous infusion of a local anaesthetic ropivacaine following total hip arthroplasty are presented in \u003Ca href=\"#F4\"\u003EFigure 4\u003C\u002Fa\u003E.\u003C\u002Fp\u003E\u003Ca id=\"h5\" name=\"h5\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003E4 Discussion\u003C\u002Fh2\u003E\u003Cp class=\"mb15\"\u003EThe margin of therapeutic safety for many drugs like anaesthetics should be considered in older age because the body's ageing process may result in toxicity of the drugs. Very little data have been published regarding the binding of local anaesthetics to plasma proteins. This study was performed to determine the level of AGP in the plasma of old-aged hip joint surgery patients.\u003C\u002Fp\u003E\u003Cp class=\"mb15\"\u003EThe level of AGP in the plasma increased during the study period, which indicated that the level of AGP increases during or following surgical procedures. Similar results were shown in a previous study (\u003Ca href=\"#B3\"\u003EBohnert and Gan, 2013\u003C\u002Fa\u003E) which determined the concentration of AGP in neonates and also by two other studies \u003Ca href=\"#B8\"\u003EHellerstein et al. (1985\u003C\u002Fa\u003E) and \u003Ca href=\"#B22\"\u003ETesseromatis et al. (2011\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\u003Cp class=\"mb15\"\u003EAs can be seen from graphs of the results (\u003Ca href=\"#F4\"\u003EFigure 4\u003C\u002Fa\u003E), nearly all patients had AGP levels which were higher after 4 h and 24 h than early timed samples. This increase in AGP level is directly related to plasma protein binding, which increases in the samples taken after 24 h. The increased plasma protein binding was comparatively associated with the unchanged free fraction of the drug. As the effect of the drug is mainly due to its free or unbound portion, any altered concentration of AGP will ultimately affect the level of the unbound portion of the drug and its subsequent effect. This surgically related increase in AGP concentration resulted in increased plasma protein binding of the drug (ropivacaine), which in turn kept the free portion of ropivacaine stable and within limits during the postoperative period, as shown in \u003Ca href=\"#F3\"\u003EFigure 3\u003C\u002Fa\u003E. A detailed method regarding ropivacaine determination was published in \u003Ca href=\"#B1\"\u003EAbbas et al. (2013\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"Imageheaders\"\u003EFIGURE 3\u003C\u002Fdiv\u003E\u003Cdiv class=\"FigureDesc\"\u003E\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F1145962\u002Ffphar-14-1145962-HTML-r3\u002Fimage_m\u002Ffphar-14-1145962-g003.jpg\" name=\"Figure3\" target=\"_blank\"\u003E\n \u003Cpicture\u003E\n \u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=480&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F1145962\u002Ffphar-14-1145962-HTML-r3\u002Fimage_m\u002Ffphar-14-1145962-g003.jpg\" media=\"(max-width: 563px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=370&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F1145962\u002Ffphar-14-1145962-HTML-r3\u002Fimage_m\u002Ffphar-14-1145962-g003.jpg\" media=\"(max-width: 1024px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=290&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F1145962\u002Ffphar-14-1145962-HTML-r3\u002Fimage_m\u002Ffphar-14-1145962-g003.jpg\" media=\"(max-width: 1441px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=410&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F1145962\u002Ffphar-14-1145962-HTML-r3\u002Fimage_m\u002Ffphar-14-1145962-g003.jpg\" media=\"\"\u003E\u003Csource type=\"image\u002Fjpg\" srcset=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F1145962\u002Ffphar-14-1145962-HTML-r3\u002Fimage_m\u002Ffphar-14-1145962-g003.jpg\" media=\"\"\u003E \u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F1145962\u002Ffphar-14-1145962-HTML-r3\u002Fimage_m\u002Ffphar-14-1145962-g003.jpg\" alt=\"www.frontiersin.org\" id=\"F3\" loading=\"lazy\"\u003E\n \u003C\u002Fpicture\u003E\n\u003C\u002Fa\u003E\u003Cp\u003E\u003Cb\u003EFIGURE 3\u003C\u002Fb\u003E. Mean plasma concentration of ropivacaine following local infiltration analgesia \u003Cb\u003E(A)\u003C\u002Fb\u003E total concentration i.e., bound to AGP \u003Cb\u003E(B)\u003C\u002Fb\u003E free concentration of ropivacaine. The error bars indicates SD.\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"clear\"\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\u003Cp class=\"mb15\"\u003EThe data and graphs in \u003Ca href=\"#F4\"\u003EFigure 4\u003C\u002Fa\u003E clearly show a significant increase in AGP concentration after surgery, especially in samples taken after 4 h and 24 h. In patient 1, the initial concentration is 10.36 mg\u002F100 mL, but, after 24 h, it increases to 23.50 mg\u002F100 mL. There is thus almost a 13 mg\u002F100 mL increase in 24 h. In patient 2H, there is also a significant increase in initial concentration and after 24 h, as seen in the table and from the graph, of 8.8 mg\u002F100 mL and, after 24 h, 26.44 mg\u002F100 mL. In patient 3H, there is also a considerable increase in the initial concentration of 5.19 mg\u002F100 mL and, after 24 h, 27.05 mg\u002F100 mL. There is likewise an increase in the concentration of AGP in all 20 patients. This confirms that there is an increase in AGP concentration after surgical conditions as well as in stress conditions as shown in different studies.\u003C\u002Fp\u003E\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"Imageheaders\"\u003EFIGURE 4\u003C\u002Fdiv\u003E\u003Cdiv class=\"FigureDesc\"\u003E\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F1145962\u002Ffphar-14-1145962-HTML-r3\u002Fimage_m\u002Ffphar-14-1145962-g004.jpg\" name=\"Figure4\" target=\"_blank\"\u003E\n \u003Cpicture\u003E\n \u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=480&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F1145962\u002Ffphar-14-1145962-HTML-r3\u002Fimage_m\u002Ffphar-14-1145962-g004.jpg\" media=\"(max-width: 563px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=370&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F1145962\u002Ffphar-14-1145962-HTML-r3\u002Fimage_m\u002Ffphar-14-1145962-g004.jpg\" media=\"(max-width: 1024px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=290&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F1145962\u002Ffphar-14-1145962-HTML-r3\u002Fimage_m\u002Ffphar-14-1145962-g004.jpg\" media=\"(max-width: 1441px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=410&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F1145962\u002Ffphar-14-1145962-HTML-r3\u002Fimage_m\u002Ffphar-14-1145962-g004.jpg\" media=\"\"\u003E\u003Csource type=\"image\u002Fjpg\" srcset=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F1145962\u002Ffphar-14-1145962-HTML-r3\u002Fimage_m\u002Ffphar-14-1145962-g004.jpg\" media=\"\"\u003E \u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F1145962\u002Ffphar-14-1145962-HTML-r3\u002Fimage_m\u002Ffphar-14-1145962-g004.jpg\" alt=\"www.frontiersin.org\" id=\"F4\" loading=\"lazy\"\u003E\n \u003C\u002Fpicture\u003E\n\u003C\u002Fa\u003E\u003Cp\u003E\u003Cb\u003EFIGURE 4\u003C\u002Fb\u003E. Concentrations of AGP at different time intervals in 20 hip joint patients. The graphs indicate a significant increase in AGP concentration after surgery, especially in samples taken after 4 h and 24 h. In patient 1, initial concentration is 10.36 mg\u002F100 mL, but, after 24 h, it increases to 23.50 mg\u002F100 mL. There is thus almost a 13 mg\u002F100 mL increase in 24 h. In patient 2H, there is also a significant increase in the initial concentration, and, after 24 h, the table and from graph show it as 8.8 mg\u002F100 mL and, after 24 h, 26.44 mg\u002F100 mL. In patient 3H, there is also a considerable increase in initial concentration of 5.19 mg\u002F100 mL; after 24 h, it is 27.05 mg\u002F100 mL. Likewise, there is an increase in AGP concentration in all 20 patients.\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"clear\"\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\u003Cp class=\"mb15\"\u003EIt is also clear from the data that there is considerable inter-individual variation in the level of AGP. It was found by \u003Ca href=\"#B4\"\u003EBooker et al. (1996\u003C\u002Fa\u003E) that the mean concentration is 77 mg\u002F100 mL; however, based on our results, it is difficult to determine any exact concentration because of this inter-individual variability in AGP concentration. Therefore, this is a solid base for any dose adjustment in the case of surgical condition because of increased levels of AGP.\u003C\u002Fp\u003E\u003Ca id=\"h6\" name=\"h6\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003E5 Conclusion\u003C\u002Fh2\u003E\u003Cp class=\"mb15\"\u003EThe results confirmed that AGP concentration in almost all patients increased considerably in all samples, especially after 4 h and 24 h, which confirms that AGP concentration increases after surgical conditions. Therefore, dose adjustment should be considered in the use of drugs which bind to AGP.\u003C\u002Fp\u003E\u003Ca id=\"h7\" name=\"h7\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EData availability statement\u003C\u002Fh2\u003E\u003Cp class=\"mb15\"\u003EThe original contributions presented in the study are included in the article\u002F\u003Ca href=\"#SM1\"\u003ESupplementary Material\u003C\u002Fa\u003E; further inquiries can be directed to the corresponding authors.\u003C\u002Fp\u003E\u003Ca id=\"h8\" name=\"h8\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EEthics statement\u003C\u002Fh2\u003E\u003Cp class=\"mb0\"\u003EThe studies involving human participants were reviewed and approved by the Regional Ethics Committee and conducted in accordance with the Declaration of Helsinki (NCT01873313). The patients\u002Fparticipants provided their written informed consent to participate in this study.\u003C\u002Fp\u003E\u003Ca id=\"h9\" name=\"h9\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EAuthor contributions\u003C\u002Fh2\u003E\u003Cp class=\"mb0\"\u003EMuA: sample preparation and sample analysis, data interpretation, and manuscript preparation. DW: project design. YS: sample analysis. SS: data interpretation. MoA: manuscript preparation. MaA: manuscript preparation and data analysis. LM: manuscript preparation and data analysis\u003Cem\u003E.\u003C\u002Fem\u003E All authors contributed to the article and approved the submitted version.\u003C\u002Fp\u003E\u003Ca id=\"h10\" name=\"h10\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EAcknowledgments\u003C\u002Fh2\u003E\u003Cp class=\"mb03\"\u003EThe authors are thankful to the University of Strathclyde, Glasgow, and Abdul Wali Khan University, Mardan, Pakistan, for facilitating the study\u003Cb\u003E.\u003C\u002Fb\u003E This study is supported via funding from Prince sattam bin Abdulaziz University project number (PSAU\u002F2023\u002FR\u002F1444).\u003C\u002Fp\u003E\u003Ca id=\"h11\" name=\"h11\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EConflict of interest\u003C\u002Fh2\u003E\u003Cp class=\"mb0\"\u003EThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003C\u002Fp\u003E\u003Ca id=\"h12\" name=\"h12\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EPublisher’s note\u003C\u002Fh2\u003E\u003Cp class=\"mb15\"\u003EAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors, and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.\u003C\u002Fp\u003E\u003Ca id=\"h13\" name=\"h13\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003ESupplementary material\u003C\u002Fh2\u003E\u003Cp class=\"mb15\" id=\"SM1\"\u003EThe Supplementary Material for this article can be found online at: \u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Farticles\u002F10.3389\u002Ffphar.2023.1145962\u002Ffull#supplementary-material\"\u003Ehttps:\u002F\u002Fwww.frontiersin.org\u002Farticles\u002F10.3389\u002Ffphar.2023.1145962\u002Ffull#supplementary-material\u003C\u002Fa\u003E\u003C\u002Fp\u003E\u003Ca id=\"h14\" name=\"h14\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EReferences\u003C\u002Fh2\u003E\u003Cdiv class=\"References\"\u003E\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B1\" id=\"B1\"\u003E\u003C\u002Fa\u003EAbbas, M., Ahmad, L., Shah, Y., Gill, M., and Watson, D. G. (2013). Development of a method to measure free and bound ropivacaine in human plasma using equilibrium dialysis and Hydrophilic interaction chromatography coupled to high resolution mass spectrometry. \u003Cem\u003ETalanta\u003C\u002Fem\u003E 117, 60–63. doi:10.1016\u002Fj.talanta.2013.08.049\u003C\u002Fp\u003E\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F24209310\u002F\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1016\u002Fj.talanta.2013.08.049\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fscholar.google.com\u002Fscholar?hl=en&as_sdt=0%2C5&q=Development+of+a+method+to+measure+free+and+bound+ropivacaine+in+human+plasma+using+equilibrium+dialysis+and+Hydrophilic+interaction+chromatography+coupled+to+high+resolution+mass+spectrometry&btnG=\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"References\"\u003E\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B2\" id=\"B2\"\u003E\u003C\u002Fa\u003EBanker, M. J., Clark, T. H., and Williams, J. A. (2003). Development and validation of a 96-well equilibrium dialysis apparatus for measuring plasma protein binding. \u003Cem\u003EJ. Pharm. Sci.\u003C\u002Fem\u003E 92, 967–974. doi:10.1002\u002Fjps.10332\u003C\u002Fp\u003E\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F12712416\u002F\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1002\u002Fjps.10332\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fscholar.google.com\u002Fscholar?hl=en&as_sdt=0%2C5&q=Development+and+validation+of+a+96-well+equilibrium+dialysis+apparatus+for+measuring+plasma+protein+binding&btnG=\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"References\"\u003E\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B3\" id=\"B3\"\u003E\u003C\u002Fa\u003EBohnert, T., and Gan, L.-S. (2013). Plasma protein binding: From discovery to development. \u003Cem\u003EJ. Pharm. Sci.\u003C\u002Fem\u003E 102, 2953–2994. doi:10.1002\u002Fjps.23614\u003C\u002Fp\u003E\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F23798314\u002F\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1002\u002Fjps.23614\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fscholar.google.com\u002Fscholar?hl=en&as_sdt=0%2C5&q=Plasma+protein+binding:+From+discovery+to+development&btnG=\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"References\"\u003E\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B4\" id=\"B4\"\u003E\u003C\u002Fa\u003EBooker, P., Taylor, C., and Saba, G. (1996). Perioperative changes in alpha 1-acid glycoprotein concentrations in infants undergoing major surgery. \u003Cem\u003EBr. J. Anaesth.\u003C\u002Fem\u003E 76, 365–368. doi:10.1093\u002Fbja\u002F76.3.365\u003C\u002Fp\u003E\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F8785135\u002F\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1093\u002Fbja\u002F76.3.365\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fscholar.google.com\u002Fscholar?hl=en&as_sdt=0%2C5&q=Perioperative+changes+in+alpha+1-acid+glycoprotein+concentrations+in+infants+undergoing+major+surgery&btnG=\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"References\"\u003E\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B5\" id=\"B5\"\u003E\u003C\u002Fa\u003EBteich, M. (2019). An overview of albumin and alpha-1-acid glycoprotein main characteristics: Highlighting the roles of amino acids in binding kinetics and molecular interactions. \u003Cem\u003EHeliyon\u003C\u002Fem\u003E 5, e02879. doi:10.1016\u002Fj.heliyon.2019.e02879\u003C\u002Fp\u003E\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F31844752\u002F\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1016\u002Fj.heliyon.2019.e02879\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fscholar.google.com\u002Fscholar?hl=en&as_sdt=0%2C5&q=An+overview+of+albumin+and+alpha-1-acid+glycoprotein+main+characteristics:+Highlighting+the+roles+of+amino+acids+in+binding+kinetics+and+molecular+interactions&btnG=\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"References\"\u003E\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B6\" id=\"B6\"\u003E\u003C\u002Fa\u003EEckersall, P. D., and Schmidt, E. M. D. S. (2014). The final hurdles for acute phase protein analysis in small animal practice. \u003Cem\u003EJ. Small Anim. Pract.\u003C\u002Fem\u003E 55, 1–3. Wiley Online Library. doi:10.1111\u002Fjsap.12168\u003C\u002Fp\u003E\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F24387103\u002F\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1111\u002Fjsap.12168\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fscholar.google.com\u002Fscholar?hl=en&as_sdt=0%2C5&q=The+final+hurdles+for+acute+phase+protein+analysis+in+small+animal+practice&btnG=\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"References\"\u003E\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B7\" id=\"B7\"\u003E\u003C\u002Fa\u003EFournier, T., Medjoubi-N, N., and Porquet, D. (2000). Alpha-1-acid glycoprotein. \u003Cem\u003EBiochim. Biophys. Acta\u003C\u002Fem\u003E 1482, 157–171. doi:10.1016\u002Fs0167-4838(00)00153-9\u003C\u002Fp\u003E\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F11058758\u002F\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1016\u002Fs0167-4838(00)00153-9\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fscholar.google.com\u002Fscholar?hl=en&as_sdt=0%2C5&q=Alpha-1-acid+glycoprotein&btnG=\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"References\"\u003E\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B8\" id=\"B8\"\u003E\u003C\u002Fa\u003EHellerstein, M., Sasak, V., Ordovas, J., and Munro, H. (1985). Isolation of alpha 1-acid glycoprotein from human plasma using high-performance liquid chromatography. \u003Cem\u003EAnal. Biochem.\u003C\u002Fem\u003E 146, 366–371. doi:10.1016\u002F0003-2697(85)90553-6\u003C\u002Fp\u003E\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F4025802\u002F\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1016\u002F0003-2697(85)90553-6\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fscholar.google.com\u002Fscholar?hl=en&as_sdt=0%2C5&q=Isolation+of+alpha+1-acid+glycoprotein+from+human+plasma+using+high-performance+liquid+chromatography&btnG=\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"References\"\u003E\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B9\" id=\"B9\"\u003E\u003C\u002Fa\u003EHochepied, T., Berger, F. G., Baumann, H., and Libert, C. (2003). Alpha(1)-acid glycoprotein: An acute phase protein with inflammatory and immunomodulating properties. \u003Cem\u003ECytokine & growth factor Rev.\u003C\u002Fem\u003E 14, 25–34. doi:10.1016\u002Fs1359-6101(02)00054-0\u003C\u002Fp\u003E\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1016\u002Fs1359-6101(02)00054-0\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fscholar.google.com\u002Fscholar?hl=en&as_sdt=0%2C5&q=Alpha(1)-acid+glycoprotein:+An+acute+phase+protein+with+inflammatory+and+immunomodulating+properties&btnG=\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"References\"\u003E\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B10\" id=\"B10\"\u003E\u003C\u002Fa\u003EHuang, Z., and Ung, T. (2013). Effect of alpha-1-acid glycoprotein binding on pharmacokinetics and pharmacodynamics. \u003Cem\u003ECurr. drug Metab.\u003C\u002Fem\u003E 14, 226–238. doi:10.2174\u002F1389200211314020011\u003C\u002Fp\u003E\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F23092311\u002F\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.2174\u002F1389200211314020011\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fscholar.google.com\u002Fscholar?hl=en&as_sdt=0%2C5&q=Effect+of+alpha-1-acid+glycoprotein+binding+on+pharmacokinetics+and+pharmacodynamics&btnG=\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"References\"\u003E\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B11\" id=\"B11\"\u003E\u003C\u002Fa\u003EKeser, T., Tijardović, M., Gornik, I., Lukić, E., Lauc, G., Gornik, O., et al. (2021). High-throughput and site-specific N-glycosylation analysis of human alpha-1-acid glycoprotein offers a great potential for new biomarker discovery. \u003Cem\u003EMol. Cell. Proteomics\u003C\u002Fem\u003E 20, 100044. doi:10.1074\u002Fmcp.RA120.002433\u003C\u002Fp\u003E\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F33493676\u002F\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1074\u002Fmcp.RA120.002433\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fscholar.google.com\u002Fscholar?hl=en&as_sdt=0%2C5&q=High-throughput+and+site-specific+N-glycosylation+analysis+of+human+alpha-1-acid+glycoprotein+offers+a+great+potential+for+new+biomarker+discovery&btnG=\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"References\"\u003E\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B12\" id=\"B12\"\u003E\u003C\u002Fa\u003EKishino, S., and Miyazaki, K. (1997). Separation methods for glycoprotein analysis and preparation. \u003Cem\u003EJ. Chromatogr. B Biomed. Sci. Appl.\u003C\u002Fem\u003E 699, 371–381. doi:10.1016\u002Fs0378-4347(97)00155-2\u003C\u002Fp\u003E\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F9392383\u002F\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1016\u002Fs0378-4347(97)00155-2\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fscholar.google.com\u002Fscholar?hl=en&as_sdt=0%2C5&q=Separation+methods+for+glycoprotein+analysis+and+preparation&btnG=\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"References\"\u003E\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B13\" id=\"B13\"\u003E\u003C\u002Fa\u003EKratochwil, N. A., Huber, W., Müller, F., Kansy, M., and Gerber, P. R. (2002). Predicting plasma protein binding of drugs: A new approach. \u003Cem\u003EBiochem. Pharmacol.\u003C\u002Fem\u003E 64, 1355–1374. doi:10.1016\u002Fs0006-2952(02)01074-2\u003C\u002Fp\u003E\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F12392818\u002F\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1016\u002Fs0006-2952(02)01074-2\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fscholar.google.com\u002Fscholar?hl=en&as_sdt=0%2C5&q=Predicting+plasma+protein+binding+of+drugs:+A+new+approach&btnG=\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"References\"\u003E\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B14\" id=\"B14\"\u003E\u003C\u002Fa\u003EKremer, J. M., Wilting, J., and Janssen, L. (1988). Drug binding to human alpha-1-acid glycoprotein in health and disease. \u003Cem\u003EPharmacol. Rev.\u003C\u002Fem\u003E 40, 1–47.\u003C\u002Fp\u003E\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F3064105\u002F\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fscholar.google.com\u002Fscholar?hl=en&as_sdt=0%2C5&q=Drug+binding+to+human+alpha-1-acid+glycoprotein+in+health+and+disease&btnG=\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"References\"\u003E\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B15\" id=\"B15\"\u003E\u003C\u002Fa\u003EKremmer, T., Szöllösi, É., Boldizsár, M., Vincze, B., Ludányi, K., Imre, T., et al. (2004). Liquid chromatographic and mass spectrometric analysis of human serum acid alpha-1-glycoprotein. \u003Cem\u003EBiomed. Chromatogr.\u003C\u002Fem\u003E 18, 323–329. doi:10.1002\u002Fbmc.324\u003C\u002Fp\u003E\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F15236441\u002F\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1002\u002Fbmc.324\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fscholar.google.com\u002Fscholar?hl=en&as_sdt=0%2C5&q=Liquid+chromatographic+and+mass+spectrometric+analysis+of+human+serum+acid+alpha-1-glycoprotein&btnG=\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"References\"\u003E\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B16\" id=\"B16\"\u003E\u003C\u002Fa\u003ELarsson, B., Lonnqvist, P., and Olsson, G. (1997). Plasma concentrations of bupivacaine in neonates after continuous epidural infusion. \u003Cem\u003EAnesth. Analgesia\u003C\u002Fem\u003E 84, 501–505. doi:10.1097\u002F00000539-199703000-00006\u003C\u002Fp\u003E\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1097\u002F00000539-199703000-00006\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fscholar.google.com\u002Fscholar?hl=en&as_sdt=0%2C5&q=Plasma+concentrations+of+bupivacaine+in+neonates+after+continuous+epidural+infusion&btnG=\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"References\"\u003E\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B17\" id=\"B17\"\u003E\u003C\u002Fa\u003ERice, A., Grimshaw, J., Trocha-Grimshaw, J., Mccarron, P., and Wisdom, G. B. (1997). Identification of alpha 1-acid glycoprotein (orosomucoid) in human synovial fluid by capillary electrophoresis. \u003Cem\u003EJ. Chromatogr. A\u003C\u002Fem\u003E 772, 305–311. doi:10.1016\u002Fs0021-9673(96)00990-9\u003C\u002Fp\u003E\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F9226930\u002F\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1016\u002Fs0021-9673(96)00990-9\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fscholar.google.com\u002Fscholar?hl=en&as_sdt=0%2C5&q=Identification+of+alpha+1-acid+glycoprotein+(orosomucoid)+in+human+synovial+fluid+by+capillary+electrophoresis&btnG=\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"References\"\u003E\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B18\" id=\"B18\"\u003E\u003C\u002Fa\u003ERoberts, J. A., Pea, F., and Lipman, J. (2013). The clinical relevance of plasma protein binding changes. \u003Cem\u003EClin. Pharmacokinet.\u003C\u002Fem\u003E 52, 1–8. doi:10.1007\u002Fs40262-012-0018-5\u003C\u002Fp\u003E\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F23150213\u002F\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1007\u002Fs40262-012-0018-5\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fscholar.google.com\u002Fscholar?hl=en&as_sdt=0%2C5&q=The+clinical+relevance+of+plasma+protein+binding+changes&btnG=\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"References\"\u003E\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B19\" id=\"B19\"\u003E\u003C\u002Fa\u003ESchmidt, S., Gonzalez, D., and Derendorf, H. (2010). Significance of protein binding in pharmacokinetics and pharmacodynamics. \u003Cem\u003EJ. Pharm. Sci.\u003C\u002Fem\u003E 99, 1107–1122. doi:10.1002\u002Fjps.21916\u003C\u002Fp\u003E\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F19852037\u002F\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1002\u002Fjps.21916\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fscholar.google.com\u002Fscholar?hl=en&as_sdt=0%2C5&q=Significance+of+protein+binding+in+pharmacokinetics+and+pharmacodynamics&btnG=\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"References\"\u003E\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B20\" id=\"B20\"\u003E\u003C\u002Fa\u003EStumpe, M., Miller, C., Morton, N., Bell, G., and Watson, D. (2006). High-performance liquid chromatography determination of alpha1-acid glycoprotein in small volumes of plasma from neonates. \u003Cem\u003EJ. Chromatogr. B\u003C\u002Fem\u003E 831, 81–84. doi:10.1016\u002Fj.jchromb.2005.11.039\u003C\u002Fp\u003E\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1016\u002Fj.jchromb.2005.11.039\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fscholar.google.com\u002Fscholar?hl=en&as_sdt=0%2C5&q=High-performance+liquid+chromatography+determination+of+alpha1-acid+glycoprotein+in+small+volumes+of+plasma+from+neonates&btnG=\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"References\"\u003E\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B21\" id=\"B21\"\u003E\u003C\u002Fa\u003ETaguchi, K., Nishi, K., Chuang, V. G., Maruyama, T., and Otagiri, M. (2013). “Molecular aspects of human alpha-1 acid glycoprotein—Structure and function,” in \u003Cem\u003EAcute phase proteins\u003C\u002Fem\u003E (London: \u003Cspan class=\"publisher-name\"\u003EIntechOpen\u003C\u002Fspan\u003E), 139–162. \u003C\u002Fp\u003E\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fscholar.google.com\u002Fscholar?hl=en&as_sdt=0%2C5&q=Molecular+aspects+of+human+alpha-1+acid+glycoprotein—Structure+and+function&btnG=\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"References\"\u003E\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B22\" id=\"B22\"\u003E\u003C\u002Fa\u003ETesseromatis, C., Alevizou, A., Tigka, E., and Kotsiou, A. (2011). \u003Cem\u003EAcute-phase proteins: alpha-1-acid glycoprotein\u003C\u002Fem\u003E. London: \u003Cspan class=\"publisher-name\"\u003EIntechOpen\u003C\u002Fspan\u003E. \u003C\u002Fp\u003E\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fscholar.google.com\u002Fscholar?hl=en&as_sdt=0%2C5&q=Acute-phase+proteins:+alpha-1-acid+glycoprotein&btnG=\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"References\"\u003E\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B23\" id=\"B23\"\u003E\u003C\u002Fa\u003EWood, M., and Wood, A. J. (1981). Changes in plasma drug binding and alpha 1-acid glycoprotein in mother and newborn infant. \u003Cem\u003EClin. Pharmacol. Ther.\u003C\u002Fem\u003E 29, 522–526. doi:10.1038\u002Fclpt.1981.73\u003C\u002Fp\u003E\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F7471620\u002F\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1038\u002Fclpt.1981.73\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fscholar.google.com\u002Fscholar?hl=en&as_sdt=0%2C5&q=Changes+in+plasma+drug+binding+and+alpha+1-acid+glycoprotein+in+mother+and+newborn+infant&btnG=\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"References\"\u003E\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B24\" id=\"B24\"\u003E\u003C\u002Fa\u003EXuan, H., and Hage, D. S. (2005). Immobilization of alpha(1)-acid glycoprotein for chromatographic studies of drug-protein binding. \u003Cem\u003EAnal. Biochem.\u003C\u002Fem\u003E 346, 300–310. doi:10.1016\u002Fj.ab.2005.08.025\u003C\u002Fp\u003E\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F16225836\u002F\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1016\u002Fj.ab.2005.08.025\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fscholar.google.com\u002Fscholar?hl=en&as_sdt=0%2C5&q=Immobilization+of+alpha(1)-acid+glycoprotein+for+chromatographic+studies+of+drug-protein+binding&btnG=\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"References\"\u003E\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B25\" id=\"B25\"\u003E\u003C\u002Fa\u003EZeitlinger, M. A., Derendorf, H., Mouton, J. W., Cars, O., Craig, W. A., Andes, D., et al. (2011). Protein binding: Do we ever learn? \u003Cem\u003EAntimicrob. agents Chemother.\u003C\u002Fem\u003E 55, 3067–3074. doi:10.1128\u002FAAC.01433-10\u003C\u002Fp\u003E\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F21537013\u002F\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1128\u002FAAC.01433-10\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fscholar.google.com\u002Fscholar?hl=en&as_sdt=0%2C5&q=Protein+binding:+Do+we+ever+learn?&btnG=\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"thinLineM20\"\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"AbstractSummary\"\u003E\u003Cp\u003E\u003Cspan\u003EKeywords:\u003C\u002Fspan\u003E HPLC, α1-acid glycoprotein, human plasma, hip joint surgery patients, protein binding\u003C\u002Fp\u003E\u003Cp\u003E\u003Cspan\u003ECitation:\u003C\u002Fspan\u003E Abbas M, Alossaimi MA, Altamimi ASA, Alajaji M, Watson DG, Shah SI, Shah Y and Anwar MS (2023) Determination of α1-acid glycoprotein (AGP) concentration by HPLC in patients following local infiltration analgesia for primary total hip arthroplasty and its relation to ropivacaine (total and unbound). \u003Cem\u003EFront. Pharmacol.\u003C\u002Fem\u003E 14:1145962. doi: 10.3389\u002Ffphar.2023.1145962\u003C\u002Fp\u003E\u003Cp id=\"timestamps\"\u003E\u003Cspan\u003EReceived:\u003C\u002Fspan\u003E 16 January 2023; \u003Cspan\u003EAccepted:\u003C\u002Fspan\u003E 16 May 2023;\u003Cbr\u003E\u003Cspan\u003EPublished:\u003C\u002Fspan\u003E 26 June 2023.\u003C\u002Fp\u003E\u003Cdiv\u003E\u003Cp\u003EEdited by:\u003C\u002Fp\u003E \u003Ca href=\"https:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F243834\u002Foverview\"\u003ETahir Ali\u003C\u002Fa\u003E, University of Calgary, Canada\u003C\u002Fdiv\u003E\u003Cdiv\u003E\u003Cp\u003EReviewed by:\u003C\u002Fp\u003E \u003Ca href=\"https:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F1943882\u002Foverview\"\u003ESwati Jaiswal\u003C\u002Fa\u003E, University of Massachusetts Medical School, United States\u003Cbr\u003E\u003Ca href=\"https:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F542593\u002Foverview\"\u003EMohammed Abdessadek\u003C\u002Fa\u003EUniversité Ibn Zohr, Morocco\u003C\u002Fdiv\u003E\u003Cp\u003E\u003Cspan\u003ECopyright\u003C\u002Fspan\u003E © 2023 Abbas, Alossaimi, Altamimi, Alajaji, Watson, Shah, Shah and Anwar. This is an open-access article distributed under the terms of the \u003Ca rel=\"license\" href=\"http:\u002F\u002Fcreativecommons.org\u002Flicenses\u002Fby\u002F4.0\u002F\" target=\"_blank\"\u003ECreative Commons Attribution License (CC BY).\u003C\u002Fa\u003E The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\u003C\u002Fp\u003E\u003Cp\u003E\u003Cspan\u003E*Correspondence:\u003C\u002Fspan\u003E Muhammad Abbas, \u003Ca id=\"encmail\"\u003EbXVoYW1tYWRhYmJhc0Bhd2t1bS5lZHUucGs=\u003C\u002Fa\u003E\u003C\u002Fp\u003E\u003Cdiv class=\"clear\"\u003E\u003C\u002Fdiv\u003E\u003C\u002Fdiv\u003E\r\n",menuHtml:"\u003Cul class=\"flyoutJournal\"\u003E\u003Cli\u003E\u003Ca href=\"#h1\"\u003EAbstract\u003C\u002Fa\u003E\u003C\u002Fli\u003E\u003Cli\u003E\u003Ca href=\"#h2\"\u003E1 Introduction\u003C\u002Fa\u003E\u003C\u002Fli\u003E\u003Cli\u003E\u003Ca href=\"#h3\"\u003E2 Methodology\u003C\u002Fa\u003E\u003C\u002Fli\u003E\u003Cli\u003E\u003Ca href=\"#h4\"\u003E3 Results\u003C\u002Fa\u003E\u003C\u002Fli\u003E\u003Cli\u003E\u003Ca href=\"#h5\"\u003E4 Discussion\u003C\u002Fa\u003E\u003C\u002Fli\u003E\u003Cli\u003E\u003Ca href=\"#h6\"\u003E5 Conclusion\u003C\u002Fa\u003E\u003C\u002Fli\u003E\u003Cli\u003E\u003Ca href=\"#h7\"\u003EData availability statement\u003C\u002Fa\u003E\u003C\u002Fli\u003E\u003Cli\u003E\u003Ca href=\"#h8\"\u003EEthics statement\u003C\u002Fa\u003E\u003C\u002Fli\u003E\u003Cli\u003E\u003Ca href=\"#h9\"\u003EAuthor contributions\u003C\u002Fa\u003E\u003C\u002Fli\u003E\u003Cli\u003E\u003Ca href=\"#h10\"\u003EAcknowledgments\u003C\u002Fa\u003E\u003C\u002Fli\u003E\u003Cli\u003E\u003Ca href=\"#h11\"\u003EConflict of interest\u003C\u002Fa\u003E\u003C\u002Fli\u003E\u003Cli\u003E\u003Ca href=\"#h12\"\u003EPublisher’s note\u003C\u002Fa\u003E\u003C\u002Fli\u003E\u003Cli\u003E\u003Ca href=\"#h13\"\u003ESupplementary material\u003C\u002Fa\u003E\u003C\u002Fli\u003E\u003Cli\u003E\u003Ca href=\"#h14\"\u003EReferences\u003C\u002Fa\u003E\u003C\u002Fli\u003E\u003C\u002Ful\u003E"},files:[{name:"EPUB.epub",fileServerPackageEntryId:g,type:{code:aA,name:aA}},{name:aB,fileServerPackageEntryId:"fphar-14-1145962-r3\u002Ffphar-14-1145962.pdf",type:{code:r,name:r}},{name:aB,fileServerPackageEntryId:g,type:{code:r,name:r}},{name:"fphar-14-1145962.xml",fileServerPackageEntryId:"fphar-14-1145962-r3\u002Ffphar-14-1145962.xml",type:{code:"NLM_XML",name:"XML"}},{name:"Provisional PDF.pdf",fileServerPackageEntryId:g,type:{code:r,name:r}}]},currentArticlePageMetaInfo:{title:aC,link:[{rel:"canonical",href:aD}],meta:[{hid:z,property:z,name:z,content:aE},{hid:aF,property:aF,name:"title",content:aC},{hid:aG,property:aG,name:z,content:aE},{hid:aH,name:aH,content:"HPLC,α1-acid glycoprotein,human plasma,Hip joint surgery patients,Protein Binding"},{hid:aI,property:aI,name:"site_name",content:A},{hid:aJ,property:aJ,name:H,content:"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=1200&f=png\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F1145962\u002Ffphar-14-1145962-HTML-r3\u002Fimage_m\u002Ffphar-14-1145962-g001.jpg"},{hid:aK,property:aK,name:"type",content:"article"},{hid:aL,property:aL,name:"url",content:aD},{hid:aM,name:aM,content:"summary_large_image"},{hid:aN,name:aN,content:"14"},{hid:aO,name:aO,content:p},{hid:aP,name:aP,content:A},{hid:aQ,name:aQ,content:J},{hid:aR,name:aR,content:K},{hid:aS,name:aS,content:$},{hid:aT,name:aT,content:"1145962"},{hid:aU,name:aU,content:"English"},{hid:aV,name:aV,content:aa},{hid:aW,name:aW,content:"HPLC; α1-acid glycoprotein; human plasma; Hip joint surgery patients; Protein Binding"},{hid:aX,name:aX,content:ab},{hid:aY,name:aY,content:"https:\u002F\u002Fwww.frontiersin.org\u002Fjournals\u002Fpharmacology\u002Farticles\u002F10.3389\u002Ffphar.2023.1145962\u002Fpdf"},{hid:aZ,name:aZ,content:"2023\u002F05\u002F16"},{hid:a_,name:a_,content:"2023\u002F06\u002F26"},{hid:"citation_author_0",name:n,content:"Abbas, Muhammad"},{hid:"citation_author_institution_0",name:o,content:B},{hid:"citation_author_1",name:n,content:"Alossaimi, Manal A."},{hid:"citation_author_institution_1",name:o,content:a$},{hid:"citation_author_2",name:n,content:"Altamimi, Abdulmalik S. A."},{hid:"citation_author_institution_2",name:o,content:a$},{hid:"citation_author_3",name:n,content:"Alajaji, Mai"},{hid:"citation_author_institution_3",name:o,content:"College of Pharmacy, Saudi Arabia"},{hid:"citation_author_4",name:n,content:"Watson, David G."},{hid:"citation_author_institution_4",name:o,content:"Strathclyde Institute of Pharmacy and Biomedical Sciences, United Kingdom"},{hid:"citation_author_5",name:n,content:"Shah, Sayyed I."},{hid:"citation_author_institution_5",name:o,content:B},{hid:"citation_author_6",name:n,content:"Shah, Yasar"},{hid:"citation_author_institution_6",name:o,content:B},{hid:"citation_author_7",name:n,content:"Anwar, Mohammad S."},{hid:"citation_author_institution_7",name:o,content:B},{hid:ba,name:ba,content:"doi:10.3389\u002Ffphar.2023.1145962"}],script:[{src:"https:\u002F\u002Fcdnjs.cloudflare.com\u002Fpolyfill\u002Fv3\u002Fpolyfill.min.js?features=es6",body:h,async:h},{src:"https:\u002F\u002Fcdnjs.cloudflare.com\u002Fajax\u002Flibs\u002Fmathjax\u002F2.7.1\u002FMathJax.js?config=TeX-MML-AM_CHTML",body:h,async:h},{src:"https:\u002F\u002Fd1bxh8uas1mnw7.cloudfront.net\u002Fassets\u002Faltmetric_badges-f0bc9b243ff5677d05460c1eb71834ca998946d764eb3bc244ab4b18ba50d21e.js",body:h,async:h},{src:"https:\u002F\u002Fapi.altmetric.com\u002Fv1\u002Fdoi\u002F10.3389\u002Ffphar.2023.1145962?callback=_altmetric.embed_callback&domain=www.frontiersin.org&key=3c130976ca2b8f2e88f8377633751ba1&cache_until=14-15",body:h,async:h},{src:"https:\u002F\u002Fcrossmark-cdn.crossref.org\u002Fwidget\u002Fv2.0\u002Fwidget.js",body:h,async:h}]},articleHubArticlesList:[],showCrossmarkWidget:h,hasSupplementalData:j,isPreviewArticlePage:j,settingsFeaturesSwitchers:{displayTitlePillLabels:h,displayRelatedArticlesBox:h,showEditors:h,showReviewers:h,showLoopImpactLink:h,enableFigshare:j},tenantConfig:{spaceId:c,name:A,availableJournalPages:[bb,bc,bd,"volumes","about"],announcement:{sys:{id:"2tE5oIdYfULBQILAgR2OSx",__typename:"Sys"},preHeader:"Research integrity at Frontiers",title:"94% of researchers rate our articles as excellent or good",description:"Learn more about the work of our research integrity team to safeguard the quality of each article we publish.",image:[{id:"0B4B1380-42EB-4FD5-9D7E2DBC603E79F8",src:be,name:bf,tags:["ultra","sunset","achieving","summer","challenge","winning","extreme","workout","hike","path","action","uphill","effort","athlete","physical","height","activity","mountaineering","endurance","mount","runner","nordic","race","male","achieve","nature","run","adventure",I,"perseverance","freedom","fitness","backcountry","altitude","sports","man","hill","mountain","outdoor","exercise","energetic","trail","climb","skyrunning","lifestyle"],type:H,width:7100,height:4733,archive:l,brandId:W,limited:l,fileSize:16838862,isPublic:l,original:e,copyright:e,extension:["jpg"],thumbnails:{mini:"https:\u002F\u002Fd2csxpduxe849s.cloudfront.net\u002Fmedia\u002FE32629C6-9347-4F84-81FEAEF7BFA342B3\u002F0B4B1380-42EB-4FD5-9D7E2DBC603E79F8\u002Fmini-C4875379-1478-416F-B03DF68FE3D8DBB5.png",thul:"https:\u002F\u002Fd2csxpduxe849s.cloudfront.net\u002Fmedia\u002FE32629C6-9347-4F84-81FEAEF7BFA342B3\u002F0B4B1380-42EB-4FD5-9D7E2DBC603E79F8\u002Fthul-C4875379-1478-416F-B03DF68FE3D8DBB5.png",webimage:be,Guidelines:"https:\u002F\u002Fd2csxpduxe849s.cloudfront.net\u002Fmedia\u002FE32629C6-9347-4F84-81FEAEF7BFA342B3\u002F0B4B1380-42EB-4FD5-9D7E2DBC603E79F8\u002FGuidelines-C4875379-1478-416F-B03DF68FE3D8DBB5.png",WebsiteJpg_XL:"https:\u002F\u002Fd2csxpduxe849s.cloudfront.net\u002Fmedia\u002FE32629C6-9347-4F84-81FEAEF7BFA342B3\u002F0B4B1380-42EB-4FD5-9D7E2DBC603E79F8\u002FWebsiteJpg_XL-C4875379-1478-416F-B03DF68FE3D8DBB5.jpg",WebsiteWebP_L:"https:\u002F\u002Fd2csxpduxe849s.cloudfront.net\u002Fmedia\u002FE32629C6-9347-4F84-81FEAEF7BFA342B3\u002F0B4B1380-42EB-4FD5-9D7E2DBC603E79F8\u002FWebsiteWebP_L-C4875379-1478-416F-B03DF68FE3D8DBB5.webp",WebsiteWebP_M:"https:\u002F\u002Fd2csxpduxe849s.cloudfront.net\u002Fmedia\u002FE32629C6-9347-4F84-81FEAEF7BFA342B3\u002F0B4B1380-42EB-4FD5-9D7E2DBC603E79F8\u002FWebsiteWebP_M-C4875379-1478-416F-B03DF68FE3D8DBB5.webp",WebsiteWebP_XL:"https:\u002F\u002Fd2csxpduxe849s.cloudfront.net\u002Fmedia\u002FE32629C6-9347-4F84-81FEAEF7BFA342B3\u002F0B4B1380-42EB-4FD5-9D7E2DBC603E79F8\u002FWebsiteWebP_XL-C4875379-1478-416F-B03DF68FE3D8DBB5.webp"},dateCreated:"2022-12-14T15:44:00Z",description:bf,orientation:I,watermarked:l,dateModified:"2023-01-26T09:08:47Z",datePublished:"2022-12-14T16:40:06Z",videoPreviewURLs:[],textMetaproperties:[]}],link:{text:"Find out more ",url:bg,target:f,ariaLabel:"About our research integrity team",__typename:v},__typename:"Announcement"}},components:{ibar:{tenantLogo:g,journalLogo:g,aboutUs:[{title:"Who we are",links:[{text:"Mission and values",url:"https:\u002F\u002Fwww.frontiersin.org\u002Fabout\u002Fmission",target:f,ariaLabel:e},{text:"History",url:"https:\u002F\u002Fwww.frontiersin.org\u002Fabout\u002Fhistory",target:f,ariaLabel:e},{text:"Leadership",url:"https:\u002F\u002Fwww.frontiersin.org\u002Fabout\u002Fleadership",target:f,ariaLabel:e},{text:"Awards",url:"https:\u002F\u002Fwww.frontiersin.org\u002Fabout\u002Fawards",target:f,ariaLabel:e}]},{title:"Impact and progress",links:[{text:"Frontiers' impact",url:"https:\u002F\u002Fwww.frontiersin.org\u002Fabout\u002Fimpact",target:f,ariaLabel:e},{text:"Progress Report 2022",url:"https:\u002F\u002Fprogressreport.frontiersin.org\u002F?utm_source=fweb&utm_medium=frep&utm_campaign=pr20",target:m,ariaLabel:e},{text:"All annual reports",url:"https:\u002F\u002Fwww.frontiersin.org\u002Fabout\u002Fannual-reports",target:f,ariaLabel:e}]},{title:"Publishing model",links:[{text:bh,url:bi,target:f,ariaLabel:e},{text:"Open access",url:"https:\u002F\u002Fwww.frontiersin.org\u002Fabout\u002Fopen-access",target:f,ariaLabel:e},{text:bj,url:bk,target:f,ariaLabel:e},{text:"Peer review",url:"https:\u002F\u002Fwww.frontiersin.org\u002Fabout\u002Fpeer-review",target:f,ariaLabel:e},{text:"Research integrity",url:bg,target:f,ariaLabel:e},{text:bl,url:"https:\u002F\u002Fwww.frontiersin.org\u002Fabout\u002Fresearch-topics",target:f,ariaLabel:e}]},{title:"Services",links:[{text:"Societies",url:"https:\u002F\u002Fpublishingpartnerships.frontiersin.org\u002F",target:m,ariaLabel:e},{text:"National consortia",url:"https:\u002F\u002Fwww.frontiersin.org\u002Fopen-access-agreements\u002Fconsortia",target:f,ariaLabel:e},{text:"Institutional partnerships",url:"https:\u002F\u002Fwww.frontiersin.org\u002Fabout\u002Fopen-access-agreements",target:f,ariaLabel:e},{text:"Collaborators",url:"https:\u002F\u002Fwww.frontiersin.org\u002Fabout\u002Fcollaborators",target:f,ariaLabel:e}]},{title:"More from Frontiers",links:[{text:"Frontiers Forum",url:bm,target:m,ariaLabel:"this link will take you to the Frontiers Forum website"},{text:bn,url:bo,target:m,ariaLabel:bp},{text:"Press office",url:"https:\u002F\u002Fpressoffice.frontiersin.org\u002F",target:m,ariaLabel:"this link will take you to the Frontiers press office website"},{text:"Sustainability",url:"https:\u002F\u002Fwww.frontiersin.orgabout\u002Fsustainability",target:f,ariaLabel:"link to information about Frontiers' sustainability"},{text:bq,url:br,target:m,ariaLabel:"this link will take you to the Frontiers careers website"},{text:"Contact us",url:bs,target:f,ariaLabel:"this link will take you to the help pages to contact our support team"}]}],submitUrl:"https:\u002F\u002Fwww.frontiersin.org\u002Fsubmission\u002Fsubmit?domainid=1&fieldid=62&specialtyid=0&entitytype=2&entityid=176",showSubmitButton:h,journal:{id:t,name:p,slug:u,sections:[{id:182,name:"Cardiovascular and Smooth Muscle Pharmacology",slug:"cardiovascular-and-smooth-muscle-pharmacology"},{id:199,name:"Drug Metabolism and Transport",slug:"drug-metabolism-and-transport"},{id:202,name:"Drugs Outcomes Research and Policies",slug:"drugs-outcomes-research-and-policies"},{id:650,name:"ELSI in Science and Genetics",slug:"elsi-in-science-and-genetics"},{id:184,name:"Ethnopharmacology",slug:"ethnopharmacology"},{id:183,name:"Experimental Pharmacology and Drug Discovery",slug:"experimental-pharmacology-and-drug-discovery"},{id:186,name:"Gastrointestinal and Hepatic Pharmacology",slug:"gastrointestinal-and-hepatic-pharmacology"},{id:188,name:"Inflammation Pharmacology",slug:"inflammation-pharmacology"},{id:178,name:"Integrative and Regenerative Pharmacology",slug:"integrative-and-regenerative-pharmacology"},{id:26,name:"Neuropharmacology",slug:"neuropharmacology"},{id:196,name:"Obstetric and Pediatric Pharmacology",slug:"obstetric-and-pediatric-pharmacology"},{id:2186,name:"Pharmacoepidemiology",slug:"pharmacoepidemiology"},{id:198,name:"Pharmacogenetics and Pharmacogenomics",slug:"pharmacogenetics-and-pharmacogenomics"},{id:192,name:"Pharmacology of Anti-Cancer Drugs",slug:"pharmacology-of-anti-cancer-drugs"},{id:2216,name:"Pharmacology of Infectious Diseases",slug:"pharmacology-of-infectious-diseases"},{id:179,name:"Pharmacology of Ion Channels and Channelopathies",slug:"pharmacology-of-ion-channels-and-channelopathies"},{id:195,name:"Predictive Toxicology",slug:"predictive-toxicology"},{id:1357,name:"Renal Pharmacology",slug:"renal-pharmacology"},{id:190,name:"Respiratory Pharmacology",slug:"respiratory-pharmacology"},{id:aw,name:ax,slug:ay}]},sectionTerm:"Sections",aboutJournal:[{title:"Scope",links:[{text:"Field chief editors",url:"https:\u002F\u002Fwww.frontiersin.org\u002Fjournals\u002Fpharmacology\u002Fabout#about-editors",target:f,ariaLabel:e},{text:"Mission & scope",url:"https:\u002F\u002Fwww.frontiersin.org\u002Fjournals\u002Fpharmacology\u002Fabout#about-scope",target:f,ariaLabel:e},{text:"Facts",url:"https:\u002F\u002Fwww.frontiersin.org\u002Fjournals\u002Fpharmacology\u002Fabout#about-facts",target:f,ariaLabel:e},{text:"Journal sections",url:"https:\u002F\u002Fwww.frontiersin.org\u002Fjournals\u002Fpharmacology\u002Fabout#about-submission",target:f,ariaLabel:e},{text:"Open access statement",url:"https:\u002F\u002Fwww.frontiersin.org\u002Fjournals\u002Fpharmacology\u002Fabout#about-open",target:f,ariaLabel:e},{text:"Copyright statement",url:"https:\u002F\u002Fwww.frontiersin.org\u002Fjournals\u002Fpharmacology\u002Fabout#copyright-statement",target:f,ariaLabel:e},{text:"Quality",url:"https:\u002F\u002Fwww.frontiersin.org\u002Fjournals\u002Fpharmacology\u002Fabout#about-quality",target:f,ariaLabel:e}]},{title:"For authors",links:[{text:"Why submit?",url:"https:\u002F\u002Fwww.frontiersin.org\u002Fjournals\u002Fpharmacology\u002Ffor-authors\u002Fwhy-submit",target:f,ariaLabel:e},{text:"Article types",url:"https:\u002F\u002Fwww.frontiersin.org\u002Fjournals\u002Fpharmacology\u002Ffor-authors\u002Farticle-types",target:f,ariaLabel:e},{text:bt,url:"https:\u002F\u002Fwww.frontiersin.org\u002Fjournals\u002Fpharmacology\u002Ffor-authors\u002Fauthor-guidelines",target:f,ariaLabel:e},{text:bu,url:"https:\u002F\u002Fwww.frontiersin.org\u002Fjournals\u002Fpharmacology\u002Ffor-authors\u002Feditor-guidelines",target:f,ariaLabel:e},{text:"Publishing fees",url:"https:\u002F\u002Fwww.frontiersin.org\u002Fjournals\u002Fpharmacology\u002Ffor-authors\u002Fpublishing-fees",target:f,ariaLabel:e},{text:"Submission checklist",url:"https:\u002F\u002Fwww.frontiersin.org\u002Fjournals\u002Fpharmacology\u002Ffor-authors\u002Fsubmission-checklist",target:f,ariaLabel:e},{text:"Contact editorial office",url:"https:\u002F\u002Fwww.frontiersin.org\u002Fjournals\u002Fpharmacology\u002Ffor-authors\u002Fcontact-editorial-office",target:f,ariaLabel:e}]}],mainLinks:[{text:"All journals",url:bv,target:f,ariaLabel:e},{text:"All articles",url:bw,target:f,ariaLabel:e}],journalLinks:[{text:bx,url:bb,target:f,ariaLabel:e},{text:bl,url:bd,target:f,ariaLabel:e},{text:"Editorial board",url:bc,target:f,ariaLabel:e}],helpCenterLink:{text:C,url:by,target:m,ariaLabel:C}},footer:{blocks:[{title:"Guidelines",links:[{text:bt,url:"https:\u002F\u002Fwww.frontiersin.org\u002Fguidelines\u002Fauthor-guidelines",target:f,ariaLabel:e},{text:bu,url:"https:\u002F\u002Fwww.frontiersin.org\u002Fguidelines\u002Feditor-guidelines",target:f,ariaLabel:e},{text:"Policies and publication ethics",url:"https:\u002F\u002Fwww.frontiersin.org\u002Fguidelines\u002Fpolicies-and-publication-ethics",target:f,ariaLabel:e},{text:bj,url:bk,target:f,ariaLabel:e}]},{title:"Explore",links:[{text:bx,url:bw,target:f,ariaLabel:e},{text:"Research Topics ",url:"https:\u002F\u002Fwww.frontiersin.org\u002Fresearch-topics",target:f,ariaLabel:e},{text:"Journals",url:bv,target:f,ariaLabel:e},{text:bh,url:bi,target:f,ariaLabel:e}]},{title:"Outreach",links:[{text:"Frontiers Forum ",url:bm,target:m,ariaLabel:"Frontiers Forum website"},{text:"Frontiers Policy Labs ",url:"https:\u002F\u002Fpolicylabs.frontiersin.org\u002F",target:m,ariaLabel:e},{text:bz,url:"https:\u002F\u002Fkids.frontiersin.org\u002F",target:m,ariaLabel:"Frontiers for Young Minds journal"},{text:bn,url:bo,target:m,ariaLabel:bp}]},{title:"Connect",links:[{text:C,url:by,target:m,ariaLabel:C},{text:"Emails and alerts ",url:"https:\u002F\u002Floop.frontiersin.org\u002Fsettings\u002Femail-preferences?a=publishers",target:m,ariaLabel:"Subscribe to Frontiers emails"},{text:"Contact us ",url:bs,target:f,ariaLabel:"Subscribe to newsletter"},{text:"Submit",url:"https:\u002F\u002Fwww.frontiersin.org\u002Fsubmission\u002Fsubmit",target:f,ariaLabel:e},{text:bq,url:br,target:m,ariaLabel:e}]}],socialLinks:[{link:{text:bA,url:"https:\u002F\u002Fwww.facebook.com\u002FFrontiersin",target:m,ariaLabel:bA},type:v,color:D,icon:"Facebook",size:E,hiddenText:h},{link:{text:"Frontiers Twitter",url:"https:\u002F\u002Ftwitter.com\u002Ffrontiersin",target:m,ariaLabel:e},type:v,color:D,icon:"Twitter",size:E,hiddenText:h},{link:{text:"Frontiers LinkedIn",url:"https:\u002F\u002Fwww.linkedin.com\u002Fcompany\u002Ffrontiers",target:m,ariaLabel:e},type:v,color:D,icon:"LinkedIn",size:E,hiddenText:h},{link:{text:"Frontiers Instagram",url:"https:\u002F\u002Fwww.instagram.com\u002Ffrontiersin_",target:m,ariaLabel:e},type:v,color:D,icon:"Instagram",size:E,hiddenText:h}],copyright:"Frontiers Media S.A. All rights reserved",termsAndConditionsUrl:"https:\u002F\u002Fwww.frontiersin.org\u002Flegal\u002Fterms-and-conditions",privacyPolicyUrl:"https:\u002F\u002Fwww.frontiersin.org\u002Flegal\u002Fprivacy-policy"},newsletterComponent:e,snackbarItems:[]},mainHeader:{title:g,image:L,breadcrumbs:[],linksCollection:{total:l,items:[]},metricsCollection:{total:l,items:[]}},user:{loggedUserInfo:L},journals:[{id:bB,name:bC,slug:bD,abbreviation:bE,space:{id:i,domainName:k,__typename:b},__typename:a},{id:2445,name:bC,slug:bD,abbreviation:bE,space:{id:c,domainName:d,__typename:b},__typename:a},{id:P,name:"Test SSPH Journal",slug:"test-ssph-journal",abbreviation:"testjournal",space:{id:s,domainName:F,__typename:b},__typename:a},{id:bF,name:"TEST ALF Journal",slug:"test-alf-journal",abbreviation:"talfj",space:{id:w,domainName:Q,__typename:b},__typename:a},{id:i,name:bG,slug:bH,abbreviation:bI,space:{id:i,domainName:k,__typename:b},__typename:a},{id:2360,name:bG,slug:bH,abbreviation:bI,space:{id:c,domainName:d,__typename:b},__typename:a},{id:c,name:"Smoke Test Field",slug:"smoke-test-field",abbreviation:"FJST",space:{id:R,domainName:bJ,__typename:b},__typename:a},{id:bF,name:bK,slug:bL,abbreviation:bM,space:{id:s,domainName:F,__typename:b},__typename:a},{id:2077,name:bK,slug:bL,abbreviation:bM,space:{id:c,domainName:d,__typename:b},__typename:a},{id:P,name:bN,slug:bO,abbreviation:bP,space:{id:w,domainName:Q,__typename:b},__typename:a},{id:P,name:bN,slug:bO,abbreviation:bP,space:{id:c,domainName:d,__typename:b},__typename:a},{id:bQ,name:bR,slug:bS,abbreviation:bT,space:{id:i,domainName:k,__typename:b},__typename:a},{id:3776,name:bR,slug:bS,abbreviation:bT,space:{id:c,domainName:d,__typename:b},__typename:a},{id:bU,name:bV,slug:bW,abbreviation:bX,space:{id:i,domainName:k,__typename:b},__typename:a},{id:3765,name:bV,slug:bW,abbreviation:bX,space:{id:c,domainName:d,__typename:b},__typename:a},{id:az,name:bY,slug:bZ,abbreviation:b_,space:{id:i,domainName:k,__typename:b},__typename:a},{id:3414,name:bY,slug:bZ,abbreviation:b_,space:{id:c,domainName:d,__typename:b},__typename:a},{id:20,name:b$,slug:ca,abbreviation:cb,space:{id:i,domainName:k,__typename:b},__typename:a},{id:3754,name:b$,slug:ca,abbreviation:cb,space:{id:c,domainName:d,__typename:b},__typename:a},{id:R,name:cc,slug:cd,abbreviation:ce,space:{id:i,domainName:k,__typename:b},__typename:a},{id:2444,name:cc,slug:cd,abbreviation:ce,space:{id:c,domainName:d,__typename:b},__typename:a},{id:cf,name:cg,slug:ch,abbreviation:ci,space:{id:s,domainName:F,__typename:b},__typename:a},{id:cf,name:cg,slug:ch,abbreviation:ci,space:{id:c,domainName:d,__typename:b},__typename:a},{id:i,name:"GSL Test",slug:"gsl-test",abbreviation:"gslt",space:{id:q,domainName:S,__typename:b},__typename:a},{id:2356,name:"Frontiers in the Internet of Things",slug:"the-internet-of-things",abbreviation:"friot",space:{id:c,domainName:d,__typename:b},__typename:a},{id:656,name:"Frontiers in Zoological Science",slug:"zoological-science",abbreviation:"fzoos",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1720,name:"Frontiers in Zoological Research",slug:"zoological-research",abbreviation:"fzolr",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3162,name:"Frontiers in Wound Care",slug:"wound-care",abbreviation:"fwoca",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3136,name:"Frontiers in Worm Science",slug:"worm-science",abbreviation:"fwors",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3583,name:"Frontiers in Wind Energy",slug:"wind-energy",abbreviation:"fwinde",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1451,name:"Frontiers in Water",slug:"water",abbreviation:"frwa",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1561,name:"Frontiers in Virtual Reality",slug:"virtual-reality",abbreviation:"frvir",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2000,name:"Frontiers in Virology",slug:"virology",abbreviation:"fviro",space:{id:c,domainName:d,__typename:b},__typename:a},{id:649,name:"Frontiers in Veterinary Science",slug:"veterinary-science",abbreviation:"fvets",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2176,name:"Frontiers in Urology",slug:"urology",abbreviation:"fruro",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3099,name:"Frontiers in Tuberculosis",slug:"tuberculosis",abbreviation:"ftubr",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1843,name:"Frontiers in Tropical Diseases",slug:"tropical-diseases",abbreviation:"fitd",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2417,name:"Frontiers in Transplantation",slug:"transplantation",abbreviation:"frtra",space:{id:c,domainName:d,__typename:b},__typename:a},{id:473,name:"Frontiers in Toxicology",slug:"toxicology",abbreviation:"ftox",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2105,name:"Frontiers in Thermal Engineering",slug:"thermal-engineering",abbreviation:"fther",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3190,name:"Frontiers in The Neurobiology of Pain",slug:"the-neurobiology-of-pain",abbreviation:g,space:{id:c,domainName:d,__typename:b},__typename:a},{id:1967,name:"Frontiers in Test_Field_Science_Archive",slug:"testfieldsciencearchive",abbreviation:"fntesc",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1347,name:"Frontiers in Test_Field_Humanities_Archive",slug:"testfieldhumanitiesarchive",abbreviation:"fntes",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3573,name:"Frontiers in Taxonomy",slug:"taxonomy",abbreviation:"Front. Taxon.",space:{id:c,domainName:d,__typename:b},__typename:a},{id:s,name:"Frontiers in Systems Neuroscience",slug:"systems-neuroscience",abbreviation:"fnsys",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1721,name:"Frontiers in Systems Biology",slug:"systems-biology",abbreviation:"fsysb",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3381,name:"Frontiers in Synthetic Biology",slug:"synthetic-biology",abbreviation:"fsybi",space:{id:c,domainName:d,__typename:b},__typename:a},{id:22,name:"Frontiers in Synaptic Neuroscience",slug:"synaptic-neuroscience",abbreviation:"fnsyn",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2299,name:"Frontiers in Sustainable Tourism",slug:"sustainable-tourism",abbreviation:"frsut",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2483,name:"Frontiers in Sustainable Resource Management",slug:"sustainable-resource-management",abbreviation:"fsrma",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1335,name:"Frontiers in Sustainable Food Systems",slug:"sustainable-food-systems",abbreviation:"fsufs",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2726,name:"Frontiers in Sustainable Energy Policy",slug:"sustainable-energy-policy",abbreviation:"fsuep",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1468,name:"Frontiers in Sustainable Cities",slug:"sustainable-cities",abbreviation:"frsc",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1397,name:"Frontiers in Sustainable Business",slug:"sustainable-business",abbreviation:"fisb",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1547,name:"Frontiers in Sustainability",slug:"sustainability",abbreviation:"frsus",space:{id:c,domainName:d,__typename:b},__typename:a},{id:604,name:"Frontiers in Surgery",slug:"surgery",abbreviation:"fsurg",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2504,name:"Frontiers in Structural Biology",slug:"structural-biology",abbreviation:"frsbi",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2497,name:"Frontiers in Stroke",slug:"stroke",abbreviation:"fstro",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3434,name:"Frontiers in Stem Cells",slug:"stem-cells",abbreviation:"fstce",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1482,name:"Frontiers in Sports and Active Living",slug:"sports-and-active-living",abbreviation:"fspor",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1695,name:"Frontiers in Space Technologies",slug:"space-technologies",abbreviation:"frspt",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3519,name:"Frontiers in Solar Energy",slug:"solar-energy",abbreviation:"fsoln",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1718,name:"Frontiers in Soil Science",slug:"soil-science",abbreviation:"fsoil",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2346,name:"Frontiers in Soft Matter",slug:"soft-matter",abbreviation:"frsfm",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1213,name:"Frontiers in Sociology",slug:"sociology",abbreviation:"fsoc",space:{id:c,domainName:d,__typename:b},__typename:a},{id:T,name:"Frontiers in Society Journal Archive",slug:"society-journal-archive",abbreviation:U,space:{id:c,domainName:d,__typename:b},__typename:a},{id:2690,name:"Frontiers in Social Psychology",slug:"social-psychology",abbreviation:"frsps",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2819,name:"Frontiers in Smart Grids",slug:"smart-grids",abbreviation:"frsgr",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2288,name:"Frontiers in Sleep",slug:"sleep",abbreviation:"frsle",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2552,name:"Frontiers in Skin Cancer",slug:"skin-cancer",abbreviation:"fskcr",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1786,name:"Frontiers in Signal Processing",slug:"signal-processing",abbreviation:"frsip",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1704,name:"Frontiers in Sensors",slug:"sensors",abbreviation:"fsens",space:{id:c,domainName:d,__typename:b},__typename:a},{id:s,name:"Frontiers in Science archive",slug:"science-archive",abbreviation:G,space:{id:i,domainName:k,__typename:b},__typename:a},{id:3737,name:"Frontiers in Science Diplomacy",slug:"science-diplomacy",abbreviation:"fsdip",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2766,name:"Frontiers in Science",slug:"science",abbreviation:"fsci",space:{id:c,domainName:d,__typename:b},__typename:a},{id:657,name:"Frontiers in Robotics and AI",slug:"robotics-and-ai",abbreviation:"frobt",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1606,name:"Frontiers in Research Metrics and Analytics",slug:"research-metrics-and-analytics",abbreviation:"frma",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1479,name:"Frontiers in Reproductive Health",slug:"reproductive-health",abbreviation:"frph",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1830,name:"Frontiers in Remote Sensing",slug:"remote-sensing",abbreviation:"frsen",space:{id:c,domainName:d,__typename:b},__typename:a},{id:659,name:"Frontiers in Rehabilitation Sciences",slug:"rehabilitation-sciences",abbreviation:"fresc",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3550,name:"Frontiers in Regenerative Medicine",slug:"regenerative-medicine",abbreviation:"fregm",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1949,name:"Frontiers in Radiology",slug:"radiology",abbreviation:"fradi",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3189,name:"Frontiers in RNA Research",slug:"rna-research",abbreviation:"frnar",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2306,name:"Frontiers in Quantum Science and Technology",slug:"quantum-science-and-technology",abbreviation:"frqst",space:{id:c,domainName:d,__typename:b},__typename:a},{id:T,name:"Frontiers in Public Health Archive",slug:"public-health-archive",abbreviation:U,space:{id:s,domainName:F,__typename:b},__typename:a},{id:609,name:"Frontiers in Public Health",slug:"public-health",abbreviation:"fpubh",space:{id:c,domainName:d,__typename:b},__typename:a},{id:36,name:"Frontiers in Psychology",slug:"psychology",abbreviation:"fpsyg",space:{id:c,domainName:d,__typename:b},__typename:a},{id:71,name:"Frontiers in Psychiatry",slug:"psychiatry",abbreviation:"fpsyt",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3267,name:"Frontiers in Protistology",slug:"protistology",abbreviation:"frpro",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2452,name:"Frontiers in Proteomics",slug:"proteomics",abbreviation:"fprot",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3171,name:"Frontiers in Prosthetics and Orthotics",slug:"prosthetics-and-orthotics",abbreviation:"fpror ",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3643,name:"Frontiers in Polymer Science",slug:"polymer-science",abbreviation:"fplms",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1558,name:"Frontiers in Political Science",slug:"political-science",abbreviation:"fpos",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3615,name:"Frontiers in Polar Science",slug:"polar-science",abbreviation:"fposc",space:{id:c,domainName:d,__typename:b},__typename:a},{id:373,name:"Frontiers in Plant Science",slug:"plant-science",abbreviation:"fpls",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3477,name:"Frontiers in Plant Physiology",slug:"plant-physiology",abbreviation:"fphgy",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3589,name:"Frontiers in Plant Genomics",slug:"plant-genomics",abbreviation:"fpgen",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3579,name:"Frontiers in Plant Ecology",slug:"plant-ecology",abbreviation:"fpley",space:{id:c,domainName:d,__typename:b},__typename:a},{id:210,name:"Frontiers in Physiology",slug:"physiology",abbreviation:"fphys",space:{id:c,domainName:d,__typename:b},__typename:a},{id:616,name:"Frontiers in Physics",slug:"physics",abbreviation:"fphy",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1803,name:"Frontiers in Photonics",slug:"photonics",abbreviation:"fphot",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3604,name:"Frontiers in Photobiology",slug:"photobiology",abbreviation:"fphbi",space:{id:c,domainName:d,__typename:b},__typename:a},{id:t,name:p,slug:u,abbreviation:Y,space:{id:c,domainName:d,__typename:b},__typename:a},{id:3388,name:"Frontiers in Personality Disorders",slug:"personality-disorders",abbreviation:"fprsd",space:{id:c,domainName:d,__typename:b},__typename:a},{id:606,name:"Frontiers in Pediatrics",slug:"pediatrics",abbreviation:"fped",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2554,name:"Frontiers in Pediatric Dermatology",slug:"pediatric-dermatology",abbreviation:"fpdm",space:{id:c,domainName:d,__typename:b},__typename:a},{id:T,name:"Frontiers in Pathology and Oncology Archive",slug:"pathology-and-oncology-archive",abbreviation:U,space:{id:w,domainName:Q,__typename:b},__typename:a},{id:610,name:cj,slug:ck,abbreviation:cl,space:{id:c,domainName:d,__typename:b},__typename:a},{id:3351,name:cj,slug:ck,abbreviation:cl,space:{id:c,domainName:d,__typename:b},__typename:a},{id:2705,name:"Frontiers in Parasitology",slug:"parasitology",abbreviation:"fpara",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1727,name:"Frontiers in Pain Research",slug:"pain-research",abbreviation:"fpain",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2679,name:"Frontiers in Organizational Psychology",slug:"organizational-psychology",abbreviation:"forgp",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1702,name:"Frontiers in Oral Health",slug:"oral-health",abbreviation:"froh",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2232,name:"Frontiers in Ophthalmology",slug:"ophthalmology",abbreviation:"fopht",space:{id:c,domainName:d,__typename:b},__typename:a},{id:451,name:"Frontiers in Oncology",slug:"oncology",abbreviation:"fonc",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3123,name:"Frontiers in Ocean Sustainability",slug:"ocean-sustainability",abbreviation:"focsu",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2612,name:"Frontiers in Occupational Therapy",slug:"occupational-therapy",abbreviation:"froct",space:{id:c,domainName:d,__typename:b},__typename:a},{id:628,name:"Frontiers in Nutrition",slug:"nutrition",abbreviation:"fnut",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2062,name:"Frontiers in Nuclear Medicine",slug:"nuclear-medicine",abbreviation:"fnume",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2172,name:"Frontiers in Nuclear Engineering",slug:"nuclear-engineering",abbreviation:"fnuen",space:{id:c,domainName:d,__typename:b},__typename:a},{id:c,name:"Frontiers in Neuroscience",slug:"neuroscience",abbreviation:"fnins",space:{id:c,domainName:d,__typename:b},__typename:a},{id:cm,name:"Frontiers in Neurorobotics",slug:"neurorobotics",abbreviation:"fnbot",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3056,name:"Frontiers in Neuropsychiatry",slug:"neuropsychiatry",abbreviation:"fnpsy",space:{id:c,domainName:d,__typename:b},__typename:a},{id:141,name:"Frontiers in Neurology",slug:"neurology",abbreviation:"fneur",space:{id:c,domainName:d,__typename:b},__typename:a},{id:cn,name:"Frontiers in Neuroinformatics",slug:"neuroinformatics",abbreviation:"fninf",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3283,name:"Frontiers in Neuroinflammation",slug:"neuroinflammation",abbreviation:"fnein",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1973,name:"Frontiers in Neuroimaging",slug:"neuroimaging",abbreviation:"fnimg",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1833,name:"Frontiers in Neuroergonomics",slug:"neuroergonomics",abbreviation:"fnrgo",space:{id:c,domainName:d,__typename:b},__typename:a},{id:N,name:"Frontiers in Neuroengineering",slug:"neuroengineering",abbreviation:"fneng",space:{id:c,domainName:d,__typename:b},__typename:a},{id:co,name:"Frontiers in Neuroenergetics",slug:"neuroenergetics",abbreviation:"fnene",space:{id:c,domainName:d,__typename:b},__typename:a},{id:w,name:"Frontiers in Neuroanatomy",slug:"neuroanatomy",abbreviation:"fnana",space:{id:c,domainName:d,__typename:b},__typename:a},{id:bU,name:"Frontiers in Neural Circuits",slug:"neural-circuits",abbreviation:"fncir",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2021,name:"Frontiers in Network Physiology",slug:"network-physiology",abbreviation:"fnetp",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3130,name:"Frontiers in Network Neuroscience",slug:"network-neuroscience",abbreviation:"fnnsc",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2357,name:"Frontiers in Nephrology",slug:"nephrology",abbreviation:"fneph",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2320,name:"Frontiers in Natural Products",slug:"natural-products",abbreviation:"fntpr",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1528,name:"Frontiers in Nanotechnology",slug:"nanotechnology",abbreviation:"fnano",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2882,name:"Frontiers in Musculoskeletal Disorders",slug:"musculoskeletal-disorders",abbreviation:"fmscd",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3275,name:"Frontiers in Multiple Sclerosis",slug:"multiple-sclerosis",abbreviation:"fmscr",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3152,name:"Frontiers in Mollusk Science",slug:"mollusk-science",abbreviation:"fmlsc",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2031,name:"Frontiers in Molecular Neuroscience",slug:"molecular-neuroscience",abbreviation:"fnmol",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2086,name:"Frontiers in Molecular Medicine",slug:"molecular-medicine",abbreviation:"fmmed",space:{id:c,domainName:d,__typename:b},__typename:a},{id:698,name:"Frontiers in Molecular Biosciences",slug:"molecular-biosciences",abbreviation:"fmolb",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2807,name:"Frontiers in Microbiomes",slug:"microbiomes",abbreviation:"frmbi",space:{id:c,domainName:d,__typename:b},__typename:a},{id:310,name:"Frontiers in Microbiology",slug:"microbiology",abbreviation:"fmicb",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2327,name:"Frontiers in Metals and Alloys",slug:"metals-and-alloys",abbreviation:"ftmal",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2307,name:"Frontiers in Membrane Science and Technology",slug:"membrane-science-and-technology",abbreviation:"frmst",space:{id:c,domainName:d,__typename:b},__typename:a},{id:602,name:"Frontiers in Medicine",slug:"medicine",abbreviation:"fmed",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1573,name:"Frontiers in Medical Technology",slug:"medical-technology",abbreviation:"fmedt",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3135,name:"Frontiers in Medical Engineering",slug:"medical-engineering",abbreviation:"fmede",space:{id:c,domainName:d,__typename:b},__typename:a},{id:950,name:"Frontiers in Mechanical Engineering",slug:"mechanical-engineering",abbreviation:"fmech",space:{id:c,domainName:d,__typename:b},__typename:a},{id:608,name:"Frontiers in Materials",slug:"materials",abbreviation:"fmats",space:{id:c,domainName:d,__typename:b},__typename:a},{id:655,name:"Frontiers in Marine Science",slug:"marine-science",abbreviation:"fmars",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2100,name:"Frontiers in Manufacturing Technology",slug:"manufacturing-technology",abbreviation:"fmtec",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2931,name:"Frontiers in Mammal Science",slug:"mammal-science",abbreviation:"fmamm",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2896,name:"Frontiers in Malaria",slug:"malaria",abbreviation:"fmala",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3107,name:"Frontiers in Lupus",slug:"lupus",abbreviation:"flupu",space:{id:c,domainName:d,__typename:b},__typename:a},{id:435,name:"Frontiers in Linguistics",slug:"linguistics",abbreviation:"fling",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2636,name:"Frontiers in Language Sciences",slug:"language-sciences",abbreviation:"flang",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2670,name:"Frontiers in Lab on a Chip Technologies",slug:"lab-on-a-chip-technologies",abbreviation:"frlct",space:{id:c,domainName:d,__typename:b},__typename:a},{id:M,name:"Frontiers in Integrative Neuroscience",slug:"integrative-neuroscience",abbreviation:"fnint",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1723,name:"Frontiers in Insect Science",slug:"insect-science",abbreviation:"finsc",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3093,name:"Frontiers in Influenza",slug:"influenza",abbreviation:"finfl",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3073,name:"Frontiers in Inflammation",slug:"inflammation",abbreviation:"finmn",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3200,name:"Frontiers in Industrial Microbiology",slug:"industrial-microbiology",abbreviation:"finmi",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3291,name:"Frontiers in Industrial Engineering",slug:"industrial-engineering",abbreviation:"fieng",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2765,name:"Frontiers in Impact Journals",slug:"impact-journals",abbreviation:g,space:{id:c,domainName:d,__typename:b},__typename:a},{id:3078,name:"Frontiers in Immunotherapeutics",slug:"immunotherapeutics",abbreviation:"fimms",space:{id:c,domainName:d,__typename:b},__typename:a},{id:276,name:"Frontiers in Immunology",slug:"immunology",abbreviation:"fimmu",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2379,name:"Frontiers in Imaging",slug:"imaging",abbreviation:"fimag",space:{id:c,domainName:d,__typename:b},__typename:a},{id:629,name:"Frontiers in ICT",slug:"ict",abbreviation:"fict",space:{id:c,domainName:d,__typename:b},__typename:a},{id:16,name:"Frontiers in Humanities and Social Sciences Archive",slug:"humanities-and-social-sciences-archive",abbreviation:G,space:{id:i,domainName:k,__typename:b},__typename:a},{id:3759,name:"Frontiers in Human Rights",slug:"human-rights",abbreviation:g,space:{id:c,domainName:d,__typename:b},__typename:a},{id:1588,name:"Frontiers in Human Neuroscience",slug:"human-neuroscience",abbreviation:"fnhum",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1533,name:"Frontiers in Human Dynamics",slug:"human-dynamics",abbreviation:"fhumd",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2733,name:"Frontiers in Horticulture",slug:"horticulture",abbreviation:"fhort",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3316,name:"Frontiers in Histology",slug:"histology",abbreviation:"frhis",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2378,name:"Frontiers in High Performance Computing",slug:"high-performance-computing",abbreviation:"fhpcp",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2456,name:"Frontiers in Hematology",slug:"hematology",abbreviation:"frhem",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2063,name:"Frontiers in Health Services",slug:"health-services",abbreviation:"frhs",space:{id:c,domainName:d,__typename:b},__typename:a},{id:w,name:"Frontiers in Health Archive",slug:"health-archive",abbreviation:G,space:{id:i,domainName:k,__typename:b},__typename:a},{id:3508,name:"Frontiers in Green Chemistry",slug:"green-chemistry",abbreviation:"fgrch",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1728,name:"Frontiers in Global Women's Health",slug:"global-womens-health",abbreviation:"fgwh",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2918,name:"Frontiers in Geochemistry",slug:"geochemistry",abbreviation:"fgeoc",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1540,name:"Frontiers in Genome Editing",slug:"genome-editing",abbreviation:"fgeed",space:{id:c,domainName:d,__typename:b},__typename:a},{id:240,name:"Frontiers in Genetics",slug:"genetics",abbreviation:"fgene",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3496,name:"Frontiers in Genetic Microbiology",slug:"genetic-microbiology",abbreviation:"fgemi",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3227,name:"Frontiers in Genetic Disorders",slug:"genetic-disorders",abbreviation:"frged",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2333,name:"Frontiers in Gastroenterology",slug:"gastroenterology",abbreviation:"fgstr",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1529,name:"Frontiers in Future Transportation",slug:"future-transportation",abbreviation:"ffutr",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1725,name:"Frontiers in Fungal Biology",slug:"fungal-biology",abbreviation:"ffunb",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2826,name:"Frontiers in Fuels",slug:"fuels",abbreviation:"ffuel",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3207,name:"Frontiers in Freshwater Science",slug:"freshwater-science",abbreviation:"ffwsc",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1366,name:"Frontiers in Forests and Global Change",slug:"forests-and-global-change",abbreviation:"ffgc",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2689,name:"Frontiers in Forensic Science",slug:"forensic-science",abbreviation:g,space:{id:c,domainName:d,__typename:b},__typename:a},{id:2289,name:"Frontiers in Food Science and Technology",slug:"food-science-and-technology",abbreviation:"frfst",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3559,name:"Frontiers in Fluorescence",slug:"fluorescence",abbreviation:"fflur",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2987,name:"Frontiers in Fish Science",slug:"fish-science",abbreviation:"frish",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3489,name:"Frontiers in Fire Science and Technology",slug:"fire-science-and-technology",abbreviation:"firtc",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2749,name:"Frontiers in Financial Economics",slug:"financial-economics",abbreviation:"ffecn",space:{id:c,domainName:d,__typename:b},__typename:a},{id:c,name:"Frontiers in FSHIP Test Journal",slug:"fship-test-journal",abbreviation:"ftest",space:{id:i,domainName:k,__typename:b},__typename:a},{id:bQ,name:"Frontiers in Evolutionary Neuroscience",slug:"evolutionary-neuroscience",abbreviation:"fnevo",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2955,name:"Frontiers in Ethology",slug:"ethology",abbreviation:"fetho",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3032,name:"Frontiers in Epigenetics and Epigenomics",slug:"epigenetics-and-epigenomics",abbreviation:"freae",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2394,name:"Frontiers in Epidemiology",slug:"epidemiology",abbreviation:"fepid",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3450,name:"Frontiers in Environmental Toxicology",slug:"environmental-toxicology",abbreviation:"fentx",space:{id:c,domainName:d,__typename:b},__typename:a},{id:627,name:"Frontiers in Environmental Science",slug:"environmental-science",abbreviation:"fenvs",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2888,name:"Frontiers in Environmental Health",slug:"environmental-health",abbreviation:"fenvh",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2851,name:"Frontiers in Environmental Engineering",slug:"environmental-engineering",abbreviation:"fenve",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2547,name:"Frontiers in Environmental Economics",slug:"environmental-economics",abbreviation:"frevc",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1697,name:"Frontiers in Environmental Chemistry",slug:"environmental-chemistry",abbreviation:"fenvc",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2756,name:"Frontiers in Environmental Archaeology",slug:"environmental-archaeology",abbreviation:"fearc",space:{id:c,domainName:d,__typename:b},__typename:a},{id:15,name:"Frontiers in Engineering archive",slug:"engineering-archive",abbreviation:G,space:{id:i,domainName:k,__typename:b},__typename:a},{id:626,name:"Frontiers in Energy Research",slug:"energy-research",abbreviation:"fenrg",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3115,name:"Frontiers in Energy Efficiency",slug:"energy-efficiency",abbreviation:"fenef",space:{id:c,domainName:d,__typename:b},__typename:a},{id:106,name:"Frontiers in Endocrinology",slug:"endocrinology",abbreviation:"fendo",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1696,name:"Frontiers in Electronics",slug:"electronics",abbreviation:"felec",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1800,name:"Frontiers in Electronic Materials",slug:"electronic-materials",abbreviation:"femat",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2998,name:"Frontiers in Educational Psychology",slug:"educational-psychology",abbreviation:"fepys",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1239,name:"Frontiers in Education",slug:"education",abbreviation:"feduc",space:{id:c,domainName:d,__typename:b},__typename:a},{id:625,name:"Frontiers in Economics",slug:"economics",abbreviation:"fecon",space:{id:c,domainName:d,__typename:b},__typename:a},{id:471,name:"Frontiers in Ecology and Evolution",slug:"ecology-and-evolution",abbreviation:"fevo",space:{id:c,domainName:d,__typename:b},__typename:a},{id:c,name:"Frontiers in Earth Science Archive",slug:"earth-science-archive",abbreviation:"gslfj",space:{id:q,domainName:S,__typename:b},__typename:a},{id:654,name:"Frontiers in Earth Science",slug:"earth-science",abbreviation:"feart",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3309,name:"Frontiers in Earth Observation and Land Monitoring",slug:"earth-observation-and-land-monitoring",abbreviation:"feolm",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2161,name:"Frontiers in Drug Safety and Regulation",slug:"drug-safety-and-regulation",abbreviation:"fdsfr",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2137,name:"Frontiers in Drug Discovery",slug:"drug-discovery",abbreviation:"fddsv",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2136,name:"Frontiers in Drug Delivery",slug:"drug-delivery",abbreviation:"fddev",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2775,name:"Frontiers in Disaster and Emergency Medicine",slug:"disaster-and-emergency-medicine",abbreviation:"femer",space:{id:c,domainName:d,__typename:b},__typename:a},{id:788,name:"Frontiers in Digital Humanities",slug:"digital-humanities",abbreviation:"fdigh",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1534,name:"Frontiers in Digital Health",slug:"digital-health",abbreviation:"fdgth",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2999,name:"Frontiers in Developmental Psychology",slug:"developmental-psychology",abbreviation:"fdpys",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2873,name:"Frontiers in Detector Science and Technology",slug:"detector-science-and-technology",abbreviation:"fdest",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3611,name:"Frontiers in Design Engineering",slug:"design-engineering",abbreviation:"fdese",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2550,name:"Frontiers in Dermatological Research",slug:"dermatological-research",abbreviation:"fdmre",space:{id:c,domainName:d,__typename:b},__typename:a},{id:607,name:"Frontiers in Dental Medicine",slug:"dental-medicine",abbreviation:"fdmed",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2597,name:"Frontiers in Dementia",slug:"dementia",abbreviation:"frdem",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1785,name:"Frontiers in Control Engineering",slug:"control-engineering",abbreviation:"fcteg",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1724,name:"Frontiers in Conservation Science",slug:"conservation-science",abbreviation:"fcosc",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3454,name:"Frontiers in Condensed Matter",slug:"condensed-matter",abbreviation:"fconm",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1511,name:"Frontiers in Computer Science",slug:"computer-science",abbreviation:"fcomp",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3566,name:"Frontiers in Computational Physiology",slug:"computational-physiology",abbreviation:"fcphy",space:{id:c,domainName:d,__typename:b},__typename:a},{id:bB,name:"Frontiers in Computational Neuroscience",slug:"computational-neuroscience",abbreviation:"fncom",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3234,name:"Frontiers in Complex Systems",slug:"complex-systems",abbreviation:"fcpxs",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1787,name:"Frontiers in Communications and Networks",slug:"communications-and-networks",abbreviation:"frcmn",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1238,name:"Frontiers in Communication",slug:"communication",abbreviation:"fcomm",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2535,name:"Frontiers in Cognition",slug:"cognition",abbreviation:"fcogn",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2857,name:"Frontiers in Coatings, Dyes and Interface Engineering",slug:"coatings-dyes-and-interface-engineering",abbreviation:"frcdi",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3222,name:"Frontiers in Clinical Microbiology",slug:"clinical-microbiology",abbreviation:"fclmi",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1729,name:"Frontiers in Clinical Diabetes and Healthcare",slug:"clinical-diabetes-and-healthcare",abbreviation:"fcdhc",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2551,name:"Frontiers in Clinical Dermatology",slug:"clinical-dermatology",abbreviation:"fcldm",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1490,name:"Frontiers in Climate",slug:"climate",abbreviation:"fclim",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3338,name:"Frontiers in Chromosome Research",slug:"chromosome-research",abbreviation:g,space:{id:c,domainName:d,__typename:b},__typename:a},{id:2587,name:"Frontiers in Child and Adolescent Psychiatry",slug:"child-and-adolescent-psychiatry",abbreviation:"frcha",space:{id:c,domainName:d,__typename:b},__typename:a},{id:601,name:"Frontiers in Chemistry",slug:"chemistry",abbreviation:"fchem",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1532,name:"Frontiers in Chemical Engineering",slug:"chemical-engineering",abbreviation:"fceng",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3038,name:"Frontiers in Chemical Biology",slug:"chemical-biology",abbreviation:"fchbi",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3322,name:"Frontiers in Ceramics",slug:"ceramics",abbreviation:"fceic",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1440,name:"Frontiers in Cellular and Infection Microbiology",slug:"cellular-and-infection-microbiology",abbreviation:"fcimb",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1523,name:"Frontiers in Cellular Neuroscience",slug:"cellular-neuroscience",abbreviation:"fncel",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3084,name:"Frontiers in Cellular Immunology",slug:"cellular-immunology",abbreviation:"fcimy",space:{id:c,domainName:d,__typename:b},__typename:a},{id:403,name:"Frontiers in Cell and Developmental Biology",slug:"cell-and-developmental-biology",abbreviation:"fcell",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3178,name:"Frontiers in Cell Signaling",slug:"cell-signaling",abbreviation:"fcsig",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2655,name:"Frontiers in Cell Death",slug:"cell-death",abbreviation:"fceld",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1901,name:"Frontiers in Catalysis",slug:"catalysis",abbreviation:"fctls",space:{id:c,domainName:d,__typename:b},__typename:a},{id:755,name:"Frontiers in Cardiovascular Medicine",slug:"cardiovascular-medicine",abbreviation:"fcvm",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2662,name:"Frontiers in Carbon",slug:"carbon",abbreviation:"frcrb",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3513,name:"Frontiers in Cancer Interception",slug:"cancer-interception",abbreviation:"fcint",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3433,name:"Frontiers in Cancer Control and Society",slug:"cancer-control-and-society",abbreviation:"fcacs",space:{id:c,domainName:d,__typename:b},__typename:a},{id:921,name:"Frontiers in Built Environment",slug:"built-environment",abbreviation:"fbuil",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1418,name:"Frontiers in Blockchain",slug:"blockchain",abbreviation:"fbloc",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2971,name:"Frontiers in Bird Science",slug:"bird-science",abbreviation:"fbirs",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3300,name:"Frontiers in Biophysics",slug:"biophysics",abbreviation:"frbis",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2222,name:"Frontiers in Biomaterials Science",slug:"biomaterials-science",abbreviation:"fbiom",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1722,name:"Frontiers in Bioinformatics",slug:"bioinformatics",abbreviation:"fbinf",space:{id:c,domainName:d,__typename:b},__typename:a},{id:452,name:"Frontiers in Bioengineering and Biotechnology",slug:"bioengineering-and-biotechnology",abbreviation:"fbioe",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1380,name:"Frontiers in Big Data",slug:"big-data",abbreviation:"fdata",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1589,name:"Frontiers in Behavioral Neuroscience",slug:"behavioral-neuroscience",abbreviation:"fnbeh",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2432,name:"Frontiers in Behavioral Economics",slug:"behavioral-economics",abbreviation:"frbhe",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2796,name:"Frontiers in Bee Science",slug:"bee-science",abbreviation:"frbee",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3214,name:"Frontiers in Batteries and Electrochemistry",slug:"batteries-and-electrochemistry",abbreviation:"fbael",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3011,name:"Frontiers in Bacteriology",slug:"bacteriology",abbreviation:"fbrio",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3040,name:"Frontiers in Audiology and Otology",slug:"audiology-and-otology",abbreviation:"fauot",space:{id:c,domainName:d,__typename:b},__typename:a},{id:603,name:"Frontiers in Astronomy and Space Sciences",slug:"astronomy-and-space-sciences",abbreviation:"fspas",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1437,name:"Frontiers in Artificial Intelligence",slug:"artificial-intelligence",abbreviation:"frai",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2940,name:"Frontiers in Arachnid Science",slug:"arachnid-science",abbreviation:"frchs",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2834,name:"Frontiers in Aquaculture",slug:"aquaculture",abbreviation:"faquc",space:{id:c,domainName:d,__typename:b},__typename:a},{id:981,name:"Frontiers in Applied Mathematics and Statistics",slug:"applied-mathematics-and-statistics",abbreviation:"fams",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3417,name:"Frontiers in Applied Environmental Microbiology",slug:"applied-environmental-microbiology",abbreviation:"faemi",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2714,name:"Frontiers in Antibiotics",slug:"antibiotics",abbreviation:"frabi",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3443,name:"Frontiers in Anti-Cancer Therapies",slug:"anti-cancer-therapies",abbreviation:"facth",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3253,name:"Frontiers in Antennas and Propagation",slug:"antennas-and-propagation",abbreviation:"fanpr",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1719,name:"Frontiers in Animal Science",slug:"animal-science",abbreviation:"fanim",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2513,name:"Frontiers in Anesthesiology",slug:"anesthesiology",abbreviation:"fanes",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1989,name:"Frontiers in Analytical Science",slug:"analytical-science",abbreviation:"frans",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2909,name:"Frontiers in Amphibian and Reptile Science",slug:"amphibian-and-reptile-science",abbreviation:"famrs",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1705,name:"Frontiers in Allergy",slug:"allergy",abbreviation:"falgy",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1541,name:"Frontiers in Agronomy",slug:"agronomy",abbreviation:"fagro",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3631,name:"Frontiers in Agricultural Engineering",slug:"agricultural-engineering",abbreviation:"faeng",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2477,name:"Frontiers in Aging Neuroscience",slug:"aging-neuroscience",abbreviation:"fnagi",space:{id:c,domainName:d,__typename:b},__typename:a},{id:1566,name:"Frontiers in Aging",slug:"aging",abbreviation:"fragi",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2449,name:"Frontiers in Aerospace Engineering",slug:"aerospace-engineering",abbreviation:"fpace",space:{id:c,domainName:d,__typename:b},__typename:a},{id:2195,name:"Frontiers in Adolescent Medicine",slug:"adolescent-medicine",abbreviation:"fradm",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3426,name:"Frontiers in Acoustics",slug:"acoustics",abbreviation:"facou",space:{id:c,domainName:d,__typename:b},__typename:a},{id:979,name:bz,slug:"frontiers-for-young-minds",abbreviation:"frym",space:{id:c,domainName:d,__typename:b},__typename:a},{id:3260,name:"Frontiers In Ocean Engineering",slug:"frontiers-in-ocean-engineering",abbreviation:"focen",space:{id:c,domainName:d,__typename:b},__typename:a},{id:cm,name:"FSHIP Test Journal 2",slug:"fship-test-journal-2",abbreviation:"FTJ2",space:{id:i,domainName:k,__typename:b},__typename:a},{id:i,name:cp,slug:cq,abbreviation:cr,space:{id:R,domainName:bJ,__typename:b},__typename:a},{id:3746,name:cp,slug:cq,abbreviation:cr,space:{id:c,domainName:d,__typename:b},__typename:a},{id:cn,name:cs,slug:ct,abbreviation:cu,space:{id:i,domainName:k,__typename:b},__typename:a},{id:3231,name:cs,slug:ct,abbreviation:cu,space:{id:c,domainName:d,__typename:b},__typename:a},{id:q,name:cv,slug:cw,abbreviation:cx,space:{id:q,domainName:S,__typename:b},__typename:a},{id:2078,name:cv,slug:cw,abbreviation:cx,space:{id:c,domainName:d,__typename:b},__typename:a},{id:M,name:cy,slug:cz,abbreviation:cA,space:{id:i,domainName:k,__typename:b},__typename:a},{id:2359,name:cy,slug:cz,abbreviation:cA,space:{id:c,domainName:d,__typename:b},__typename:a},{id:8,name:cB,slug:cC,abbreviation:cD,space:{id:i,domainName:k,__typename:b},__typename:a},{id:2446,name:cB,slug:cC,abbreviation:cD,space:{id:c,domainName:d,__typename:b},__typename:a},{id:10,name:cE,slug:cF,abbreviation:cG,space:{id:i,domainName:k,__typename:b},__typename:a},{id:3230,name:cE,slug:cF,abbreviation:cG,space:{id:c,domainName:d,__typename:b},__typename:a},{id:q,name:cH,slug:cI,abbreviation:cJ,space:{id:i,domainName:k,__typename:b},__typename:a},{id:2358,name:cH,slug:cI,abbreviation:cJ,space:{id:c,domainName:d,__typename:b},__typename:a},{id:3660,name:"Advanced Optical Technologies",slug:"advanced-optical-technologies",abbreviation:"aot",space:{id:c,domainName:d,__typename:b},__typename:a},{id:co,name:cK,slug:cL,abbreviation:cM,space:{id:i,domainName:k,__typename:b},__typename:a},{id:3659,name:cK,slug:cL,abbreviation:cM,space:{id:c,domainName:d,__typename:b},__typename:a},{id:N,name:cN,slug:cO,abbreviation:"abp",space:{id:i,domainName:k,__typename:b},__typename:a},{id:3695,name:cN,slug:cO,abbreviation:"ABP",space:{id:c,domainName:d,__typename:b},__typename:a}]},serverRendered:h,routePath:"\u002Fjournals\u002Fpharmacology\u002Farticles\u002F10.3389\u002Ffphar.2023.1145962\u002Ffull",config:{baseUrl:"https:\u002F\u002Fwww.frontiersin.org",appName:"article-pages-2022",spaceId:c,spaceName:A,domain:d,loopUrl:"https:\u002F\u002Floop.frontiersin.org",ssMainDomain:d,googleRecaptchaKeyName:"FrontiersRecaptchaV2",googleRecaptchaSiteKey:"6LdG3i0UAAAAAOC4qUh35ubHgJotEHp_STXHgr_v",linkedArticleCopyText:"'{\"articleTypeCopyText\":[{\"articleTypeId\":0,\"originalArticleCopyText\":\"Part of this article's content has been mentioned in:\",\"linkedArticleCopyText\":\"This article mentions parts of:\"},{\"articleTypeId\":122,\"originalArticleCopyText\":\"Parts of this article's content have been modified or rectified in:\",\"linkedArticleCopyText\":\"This article is an erratum on:\"},{\"articleTypeId\":129,\"originalArticleCopyText\":\"Parts of this article's content have been modified or rectified in:\",\"linkedArticleCopyText\":\"This article is an addendum to:\"},{\"articleTypeId\":128,\"originalArticleCopyText\":\"A correction has been applied to this article in:\",\"linkedArticleCopyText\":\"This article is a correction to:\"},{\"articleTypeId\":134,\"originalArticleCopyText\":\"A retraction of this article was approved in:\",\"linkedArticleCopyText\":\"This article is a retraction of:\"},{\"articleTypeId\":29,\"originalArticleCopyText\":\"A commentary has been posted on this article:\",\"linkedArticleCopyText\":\"This article is a commentary on:\"},{\"articleTypeId\":30,\"originalArticleCopyText\":\"A commentary has been posted on this article:\",\"linkedArticleCopyText\":\"This article is a commentary on:\"}],\"articleIdCopyText\":[]}'\n",articleTypeConfigurableLabel:"\u003C\u003Carticle-type:uppercase\u003E\u003E article",terminologySettings:"'{\"terms\":[{\"sequenceNumber\":1,\"key\":\"frontiers\",\"tenantTerm\":\"Frontiers\",\"frontiersDefaultTerm\":\"Frontiers\",\"category\":\"Customer\"},{\"sequenceNumber\":2,\"key\":\"submission_system\",\"tenantTerm\":\"submission system\",\"frontiersDefaultTerm\":\"submission system\",\"category\":\"Product\"},{\"sequenceNumber\":3,\"key\":\"public_pages\",\"tenantTerm\":\"public pages\",\"frontiersDefaultTerm\":\"public pages\",\"category\":\"Product\"},{\"sequenceNumber\":4,\"key\":\"my_frontiers\",\"tenantTerm\":\"my frontiers\",\"frontiersDefaultTerm\":\"my frontiers\",\"category\":\"Product\"},{\"sequenceNumber\":5,\"key\":\"digital_editorial_office\",\"tenantTerm\":\"digital editorial office\",\"frontiersDefaultTerm\":\"digital editorial office\",\"category\":\"Product\"},{\"sequenceNumber\":6,\"key\":\"deo\",\"tenantTerm\":\"DEO\",\"frontiersDefaultTerm\":\"DEO\",\"category\":\"Product\"},{\"sequenceNumber\":7,\"key\":\"digital_editorial_office_for_chiefs\",\"tenantTerm\":\"digital editorial office for chiefs\",\"frontiersDefaultTerm\":\"digital editorial office for chiefs\",\"category\":\"Product\"},{\"sequenceNumber\":8,\"key\":\"digital_editorial_office_for_eof\",\"tenantTerm\":\"digital editorial office for eof\",\"frontiersDefaultTerm\":\"digital editorial office for eof\",\"category\":\"Product\"},{\"sequenceNumber\":9,\"key\":\"editorial_office\",\"tenantTerm\":\"editorial office\",\"frontiersDefaultTerm\":\"editorial office\",\"category\":\"Product\"},{\"sequenceNumber\":10,\"key\":\"eof\",\"tenantTerm\":\"EOF\",\"frontiersDefaultTerm\":\"EOF\",\"category\":\"Product\"},{\"sequenceNumber\":11,\"key\":\"research_topic_management\",\"tenantTerm\":\"research topic management\",\"frontiersDefaultTerm\":\"research topic management\",\"category\":\"Product\"},{\"sequenceNumber\":12,\"key\":\"review_forum\",\"tenantTerm\":\"review forum\",\"frontiersDefaultTerm\":\"review forum\",\"category\":\"Product\"},{\"sequenceNumber\":13,\"key\":\"accounting_office\",\"tenantTerm\":\"accounting office\",\"frontiersDefaultTerm\":\"accounting office\",\"category\":\"Product\"},{\"sequenceNumber\":14,\"key\":\"aof\",\"tenantTerm\":\"AOF\",\"frontiersDefaultTerm\":\"AOF\",\"category\":\"Product\"},{\"sequenceNumber\":15,\"key\":\"publishing_office\",\"tenantTerm\":\"publishing office\",\"frontiersDefaultTerm\":\"publishing office\",\"category\":\"Product\"},{\"sequenceNumber\":16,\"key\":\"production_office\",\"tenantTerm\":\"production office forum\",\"frontiersDefaultTerm\":\"production office forum\",\"category\":\"Product\"},{\"sequenceNumber\":17,\"key\":\"pof\",\"tenantTerm\":\"POF\",\"frontiersDefaultTerm\":\"POF\",\"category\":\"Product\"},{\"sequenceNumber\":18,\"key\":\"book_office_forum\",\"tenantTerm\":\"book office forum\",\"frontiersDefaultTerm\":\"book office forum\",\"category\":\"Product\"},{\"sequenceNumber\":19,\"key\":\"bof\",\"tenantTerm\":\"BOF\",\"frontiersDefaultTerm\":\"BOF\",\"category\":\"Product\"},{\"sequenceNumber\":20,\"key\":\"aira\",\"tenantTerm\":\"AIRA\",\"frontiersDefaultTerm\":\"AIRA\",\"category\":\"Product\"},{\"sequenceNumber\":21,\"key\":\"editorial_board_management\",\"tenantTerm\":\"editorial board management\",\"frontiersDefaultTerm\":\"editorial board management\",\"category\":\"Product\"},{\"sequenceNumber\":22,\"key\":\"ebm\",\"tenantTerm\":\"EBM\",\"frontiersDefaultTerm\":\"EBM\",\"category\":\"Product\"},{\"sequenceNumber\":23,\"key\":\"domain\",\"tenantTerm\":\"domain\",\"frontiersDefaultTerm\":\"domain\",\"category\":\"Taxonomy\"},{\"sequenceNumber\":24,\"key\":\"journal\",\"tenantTerm\":\"journal\",\"frontiersDefaultTerm\":\"journal\",\"category\":\"Taxonomy\"},{\"sequenceNumber\":25,\"key\":\"section\",\"tenantTerm\":\"section\",\"frontiersDefaultTerm\":\"section\",\"category\":\"Taxonomy\"},{\"sequenceNumber\":26,\"key\":\"domains\",\"tenantTerm\":\"domains\",\"frontiersDefaultTerm\":\"domains\",\"category\":\"Taxonomy\"},{\"sequenceNumber\":27,\"key\":\"specialty_section\",\"tenantTerm\":\"specialty section\",\"frontiersDefaultTerm\":\"specialty section\",\"category\":\"Taxonomy\"},{\"sequenceNumber\":28,\"key\":\"specialty_journal\",\"tenantTerm\":\"specialty journal\",\"frontiersDefaultTerm\":\"specialty journal\",\"category\":\"Taxonomy\"},{\"sequenceNumber\":29,\"key\":\"journals\",\"tenantTerm\":\"journals\",\"frontiersDefaultTerm\":\"journals\",\"category\":\"Taxonomy\"},{\"sequenceNumber\":30,\"key\":\"sections\",\"tenantTerm\":\"sections\",\"frontiersDefaultTerm\":\"sections\",\"category\":\"Taxonomy\"},{\"sequenceNumber\":31,\"key\":\"specialty_sections\",\"tenantTerm\":\"specialty sections\",\"frontiersDefaultTerm\":\"specialty sections\",\"category\":\"Taxonomy\"},{\"sequenceNumber\":32,\"key\":\"specialty_journals\",\"tenantTerm\":\"specialty journals\",\"frontiersDefaultTerm\":\"specialty journals\",\"category\":\"Taxonomy\"},{\"sequenceNumber\":33,\"key\":\"manuscript\",\"tenantTerm\":\"manuscript\",\"frontiersDefaultTerm\":\"manuscript\",\"category\":\"Core\"},{\"sequenceNumber\":34,\"key\":\"manuscripts\",\"tenantTerm\":\"manuscripts\",\"frontiersDefaultTerm\":\"manuscripts\",\"category\":\"Core\"},{\"sequenceNumber\":35,\"key\":\"article\",\"tenantTerm\":\"article\",\"frontiersDefaultTerm\":\"article\",\"category\":\"Core\"},{\"sequenceNumber\":36,\"key\":\"articles\",\"tenantTerm\":\"articles\",\"frontiersDefaultTerm\":\"articles\",\"category\":\"Core\"},{\"sequenceNumber\":37,\"key\":\"article_type\",\"tenantTerm\":\"article type\",\"frontiersDefaultTerm\":\"article type\",\"category\":\"Core\"},{\"sequenceNumber\":38,\"key\":\"article_types\",\"tenantTerm\":\"article types\",\"frontiersDefaultTerm\":\"article types\",\"category\":\"Core\"},{\"sequenceNumber\":39,\"key\":\"author\",\"tenantTerm\":\"author\",\"frontiersDefaultTerm\":\"author\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":40,\"key\":\"authors\",\"tenantTerm\":\"authors\",\"frontiersDefaultTerm\":\"authors\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":41,\"key\":\"authoring\",\"tenantTerm\":\"authoring\",\"frontiersDefaultTerm\":\"authoring\",\"category\":\"Core\"},{\"sequenceNumber\":42,\"key\":\"authored\",\"tenantTerm\":\"authored\",\"frontiersDefaultTerm\":\"authored\",\"category\":\"Core\"},{\"sequenceNumber\":43,\"key\":\"accept\",\"tenantTerm\":\"accept\",\"frontiersDefaultTerm\":\"accept\",\"category\":\"Process\"},{\"sequenceNumber\":44,\"key\":\"accepted\",\"tenantTerm\":\"accepted\",\"frontiersDefaultTerm\":\"accepted\",\"category\":\"Process\"},{\"sequenceNumber\":45,\"key\":\"assistant_field_chief_editor\",\"tenantTerm\":\"Assistant Field Chief Editor\",\"frontiersDefaultTerm\":\"Assistant Field Chief Editor\",\"description\":\"An editorial role on a Field Journal that a Registered User may hold. This gives them rights to different functionality and parts of the platform\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":46,\"key\":\"assistant_specialty_chief_editor\",\"tenantTerm\":\"Assistant Specialty Chief Editor\",\"frontiersDefaultTerm\":\"Assistant Specialty Chief Editor\",\"description\":\"An editorial role on a specialty that a Registered User may hold. This gives them rights to different functionality and parts of the platform\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":47,\"key\":\"assistant_specialty_chief_editors\",\"tenantTerm\":\"Assistant Specialty Chief Editors\",\"frontiersDefaultTerm\":\"Assistant Specialty Chief Editors\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":48,\"key\":\"associate_editor\",\"tenantTerm\":\"Associate Editor\",\"frontiersDefaultTerm\":\"Associate Editor\",\"description\":\"An editorial role on a specialty that a Registered User may hold. This gives them rights to different functionality and parts of the platform\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":49,\"key\":\"specialty_chief_editor\",\"tenantTerm\":\"Specialty Chief Editor\",\"frontiersDefaultTerm\":\"Specialty Chief Editor\",\"description\":\"An editorial role on a specialty that a Registered User may hold. This gives them rights to different functionality and parts of the platform\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":50,\"key\":\"specialty_chief_editors\",\"tenantTerm\":\"Specialty Chief Editors\",\"frontiersDefaultTerm\":\"Specialty Chief Editors\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":51,\"key\":\"chief_editor\",\"tenantTerm\":\"Chief Editor\",\"frontiersDefaultTerm\":\"Chief Editor\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":52,\"key\":\"chief_editors\",\"tenantTerm\":\"Chief Editors\",\"frontiersDefaultTerm\":\"Chief Editors\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":53,\"key\":\"call_for_participation\",\"tenantTerm\":\"call for participation\",\"frontiersDefaultTerm\":\"call for participation\",\"category\":\"Process\"},{\"sequenceNumber\":54,\"key\":\"citation\",\"tenantTerm\":\"citation\",\"frontiersDefaultTerm\":\"citation\",\"category\":\"Misc.\"},{\"sequenceNumber\":55,\"key\":\"citations\",\"tenantTerm\":\"citations\",\"frontiersDefaultTerm\":\"citations\",\"category\":\"Misc.\"},{\"sequenceNumber\":56,\"key\":\"contributor\",\"tenantTerm\":\"contributor\",\"frontiersDefaultTerm\":\"contributor\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":57,\"key\":\"contributors\",\"tenantTerm\":\"contributors\",\"frontiersDefaultTerm\":\"contributors\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":58,\"key\":\"corresponding_author\",\"tenantTerm\":\"corresponding author\",\"frontiersDefaultTerm\":\"corresponding author\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":59,\"key\":\"corresponding_authors\",\"tenantTerm\":\"corresponding authors\",\"frontiersDefaultTerm\":\"corresponding authors\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":60,\"key\":\"decline\",\"tenantTerm\":\"decline\",\"frontiersDefaultTerm\":\"decline\",\"category\":\"Process\"},{\"sequenceNumber\":61,\"key\":\"declined\",\"tenantTerm\":\"declined\",\"frontiersDefaultTerm\":\"declined\",\"category\":\"Process\"},{\"sequenceNumber\":62,\"key\":\"reject\",\"tenantTerm\":\"reject\",\"frontiersDefaultTerm\":\"reject\",\"category\":\"Process\"},{\"sequenceNumber\":63,\"key\":\"rejected\",\"tenantTerm\":\"rejected\",\"frontiersDefaultTerm\":\"rejected\",\"category\":\"Process\"},{\"sequenceNumber\":64,\"key\":\"publish\",\"tenantTerm\":\"publish\",\"frontiersDefaultTerm\":\"publish\",\"category\":\"Core\"},{\"sequenceNumber\":65,\"key\":\"published\",\"tenantTerm\":\"published\",\"frontiersDefaultTerm\":\"published\",\"category\":\"Core\"},{\"sequenceNumber\":66,\"key\":\"publication\",\"tenantTerm\":\"publication\",\"frontiersDefaultTerm\":\"publication\",\"category\":\"Core\"},{\"sequenceNumber\":67,\"key\":\"peer_review\",\"tenantTerm\":\"peer review\",\"frontiersDefaultTerm\":\"peer review\",\"category\":\"Peer Review Process\"},{\"sequenceNumber\":68,\"key\":\"peer_reviewed\",\"tenantTerm\":\"peer reviewed\",\"frontiersDefaultTerm\":\"peer reviewed\",\"category\":\"Peer Review Process\"},{\"sequenceNumber\":69,\"key\":\"initial_validation\",\"tenantTerm\":\"initial validation\",\"frontiersDefaultTerm\":\"initial validation\",\"category\":\"Peer Review Process\"},{\"sequenceNumber\":70,\"key\":\"editorial_assignment\",\"tenantTerm\":\"editorial assignment\",\"frontiersDefaultTerm\":\"editorial assignment\",\"category\":\"Peer Review Process\"},{\"sequenceNumber\":71,\"key\":\"independent_review\",\"tenantTerm\":\"independent review\",\"frontiersDefaultTerm\":\"independent review\",\"category\":\"Peer Review Process\"},{\"sequenceNumber\":72,\"key\":\"interactive_review\",\"tenantTerm\":\"interactive review\",\"frontiersDefaultTerm\":\"interactive review\",\"category\":\"Peer Review Process\"},{\"sequenceNumber\":73,\"key\":\"review\",\"tenantTerm\":\"review\",\"frontiersDefaultTerm\":\"review\",\"category\":\"Peer Review Process\"},{\"sequenceNumber\":74,\"key\":\"reviewing\",\"tenantTerm\":\"reviewing\",\"frontiersDefaultTerm\":\"reviewing\",\"category\":\"Peer Review Process\"},{\"sequenceNumber\":75,\"key\":\"reviewer\",\"tenantTerm\":\"reviewer\",\"frontiersDefaultTerm\":\"reviewer\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":76,\"key\":\"reviewers\",\"tenantTerm\":\"reviewers\",\"frontiersDefaultTerm\":\"reviewers\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":77,\"key\":\"review_finalized\",\"tenantTerm\":\"review finalized\",\"frontiersDefaultTerm\":\"review finalized\",\"category\":\"Peer Review Process\"},{\"sequenceNumber\":78,\"key\":\"final_decision\",\"tenantTerm\":\"final decision\",\"frontiersDefaultTerm\":\"final decision\",\"category\":\"Peer Review Process\"},{\"sequenceNumber\":79,\"key\":\"final_validation\",\"tenantTerm\":\"final validation\",\"frontiersDefaultTerm\":\"final validation\",\"category\":\"Peer Review Process\"},{\"sequenceNumber\":80,\"key\":\"ae_accept_manuscript\",\"tenantTerm\":\"recommend to accept manuscript\",\"frontiersDefaultTerm\":\"accept manuscript\",\"category\":\"Process\"},{\"sequenceNumber\":81,\"key\":\"fee\",\"tenantTerm\":\"fee\",\"frontiersDefaultTerm\":\"fee\",\"category\":\"Accounting\"},{\"sequenceNumber\":82,\"key\":\"fees\",\"tenantTerm\":\"fees\",\"frontiersDefaultTerm\":\"fees\",\"category\":\"Accounting\"},{\"sequenceNumber\":83,\"key\":\"guest_associate_editor\",\"tenantTerm\":\"Guest Associate Editor\",\"frontiersDefaultTerm\":\"Guest Associate Editor\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":84,\"key\":\"guest_associate_editors\",\"tenantTerm\":\"Guest Associate Editors\",\"frontiersDefaultTerm\":\"Guest Associate Editors\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":85,\"key\":\"in_review\",\"tenantTerm\":\"in review\",\"frontiersDefaultTerm\":\"in review\",\"category\":\"Peer Review Process\"},{\"sequenceNumber\":86,\"key\":\"institutional_member\",\"tenantTerm\":\"institutional partner\",\"frontiersDefaultTerm\":\"institutional partner\",\"category\":\"Accounting\"},{\"sequenceNumber\":87,\"key\":\"institutional_membership\",\"tenantTerm\":\"institutional partnership\",\"frontiersDefaultTerm\":\"institutional partnership\",\"category\":\"Accounting\"},{\"sequenceNumber\":88,\"key\":\"article_processing_charge\",\"tenantTerm\":\"article processing charge\",\"frontiersDefaultTerm\":\"article processing charge\",\"category\":\"Accounting\"},{\"sequenceNumber\":89,\"key\":\"article_processing_charges\",\"tenantTerm\":\"article processing charges\",\"frontiersDefaultTerm\":\"article processing charges\",\"category\":\"Accounting\"},{\"sequenceNumber\":90,\"key\":\"apcs\",\"tenantTerm\":\"APCs\",\"frontiersDefaultTerm\":\"APCs\",\"category\":\"Accounting\"},{\"sequenceNumber\":91,\"key\":\"apc\",\"tenantTerm\":\"APC\",\"frontiersDefaultTerm\":\"APC\",\"category\":\"Accounting\"},{\"sequenceNumber\":92,\"key\":\"received\",\"tenantTerm\":\"received\",\"frontiersDefaultTerm\":\"received\",\"description\":\"Date manuscript was received on.\",\"category\":\"Core\"},{\"sequenceNumber\":93,\"key\":\"transferred\",\"tenantTerm\":\"transferred\",\"frontiersDefaultTerm\":\"transferred\",\"category\":\"Core\"},{\"sequenceNumber\":94,\"key\":\"transfer\",\"tenantTerm\":\"transfer\",\"frontiersDefaultTerm\":\"transfer\",\"category\":\"Core\"},{\"sequenceNumber\":95,\"key\":\"research_topic\",\"tenantTerm\":\"research topic\",\"frontiersDefaultTerm\":\"research topic\",\"category\":\"Core\"},{\"sequenceNumber\":96,\"key\":\"research_topics\",\"tenantTerm\":\"research topics\",\"frontiersDefaultTerm\":\"research topics\",\"category\":\"Core\"},{\"sequenceNumber\":97,\"key\":\"topic_editor\",\"tenantTerm\":\"Topic Editor\",\"frontiersDefaultTerm\":\"Topic Editor\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":98,\"key\":\"review_editor\",\"tenantTerm\":\"Review Editor\",\"frontiersDefaultTerm\":\"Review Editor\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":99,\"key\":\"title\",\"tenantTerm\":\"title\",\"frontiersDefaultTerm\":\"title\",\"category\":\"Manuscript Metadata\"},{\"sequenceNumber\":100,\"key\":\"running_title\",\"tenantTerm\":\"running title\",\"frontiersDefaultTerm\":\"running title\",\"category\":\"Manuscript Metadata\"},{\"sequenceNumber\":101,\"key\":\"submit\",\"tenantTerm\":\"submit\",\"frontiersDefaultTerm\":\"submit\",\"category\":\"Process\"},{\"sequenceNumber\":102,\"key\":\"submitted\",\"tenantTerm\":\"submitted\",\"frontiersDefaultTerm\":\"submitted\",\"category\":\"Process\"},{\"sequenceNumber\":103,\"key\":\"submitting\",\"tenantTerm\":\"submitting\",\"frontiersDefaultTerm\":\"submitting\",\"category\":\"Process\"},{\"sequenceNumber\":104,\"key\":\"t_e\",\"tenantTerm\":\"TE\",\"frontiersDefaultTerm\":\"TE\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":105,\"key\":\"topic\",\"tenantTerm\":\"topic\",\"frontiersDefaultTerm\":\"topic\",\"category\":\"Process\"},{\"sequenceNumber\":106,\"key\":\"topic_summary\",\"tenantTerm\":\"topic summary\",\"frontiersDefaultTerm\":\"topic summary\",\"category\":\"Process\"},{\"sequenceNumber\":107,\"key\":\"figure\",\"tenantTerm\":\"figure\",\"frontiersDefaultTerm\":\"figure\",\"category\":\"Manuscript Metadata\"},{\"sequenceNumber\":108,\"key\":\"figures\",\"tenantTerm\":\"figures\",\"frontiersDefaultTerm\":\"figures\",\"category\":\"Manuscript Metadata\"},{\"sequenceNumber\":109,\"key\":\"editorial_file\",\"tenantTerm\":\"editorial file\",\"frontiersDefaultTerm\":\"editorial file\",\"category\":\"Core\"},{\"sequenceNumber\":110,\"key\":\"editorial_files\",\"tenantTerm\":\"editorial files\",\"frontiersDefaultTerm\":\"editorial files\",\"category\":\"Core\"},{\"sequenceNumber\":111,\"key\":\"e_book\",\"tenantTerm\":\"e-book\",\"frontiersDefaultTerm\":\"e-book\",\"category\":\"Core\"},{\"sequenceNumber\":112,\"key\":\"organization\",\"tenantTerm\":\"organization\",\"frontiersDefaultTerm\":\"organization\",\"category\":\"Core\"},{\"sequenceNumber\":113,\"key\":\"institution\",\"tenantTerm\":\"institution\",\"frontiersDefaultTerm\":\"institution\",\"category\":\"Core\"},{\"sequenceNumber\":114,\"key\":\"reference\",\"tenantTerm\":\"reference\",\"frontiersDefaultTerm\":\"reference\",\"category\":\"Manuscript Metadata\"},{\"sequenceNumber\":115,\"key\":\"references\",\"tenantTerm\":\"references\",\"frontiersDefaultTerm\":\"references\",\"category\":\"Manuscript Metadata\"},{\"sequenceNumber\":116,\"key\":\"sce\",\"tenantTerm\":\"SCE\",\"frontiersDefaultTerm\":\"SCE\",\"description\":\"Abbreviation for Specialty Chief Editor\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":117,\"key\":\"submission\",\"tenantTerm\":\"submission\",\"frontiersDefaultTerm\":\"submission\",\"category\":\"Process\"},{\"sequenceNumber\":118,\"key\":\"submissions\",\"tenantTerm\":\"submissions\",\"frontiersDefaultTerm\":\"submissions\",\"category\":\"Process\"},{\"sequenceNumber\":119,\"key\":\"editing\",\"tenantTerm\":\"editing\",\"frontiersDefaultTerm\":\"editing\",\"category\":\"Process\"},{\"sequenceNumber\":120,\"key\":\"in_preparation\",\"tenantTerm\":\"in preparation\",\"frontiersDefaultTerm\":\"in preparation\",\"category\":\"Process\"},{\"sequenceNumber\":121,\"key\":\"country_region\",\"tenantTerm\":\"country\u002Fregion\",\"frontiersDefaultTerm\":\"country\u002Fregion\",\"description\":\"Because of political issues, some of the country listings are actually classified as `regions` and we need to include this. However other clients may not want to do this.\",\"category\":\"Manuscript Metadata\"},{\"sequenceNumber\":122,\"key\":\"countries_regions\",\"tenantTerm\":\"countries\u002Fregions\",\"frontiersDefaultTerm\":\"countries\u002Fregions\",\"description\":\"Because of political issues, some of the country listings are actually classified as `regions` and we need to include this. However other clients may not want to do this.\",\"category\":\"Manuscript Metadata\"},{\"sequenceNumber\":123,\"key\":\"specialty\",\"tenantTerm\":\"specialty\",\"frontiersDefaultTerm\":\"specialty\",\"category\":\"Core\"},{\"sequenceNumber\":124,\"key\":\"specialties\",\"tenantTerm\":\"specialties\",\"frontiersDefaultTerm\":\"specialties\",\"category\":\"Core\"},{\"sequenceNumber\":125,\"key\":\"associate_editors\",\"tenantTerm\":\"Associate Editors\",\"frontiersDefaultTerm\":\"Associate Editors\",\"description\":\"An editorial role on a specialty that a Registered User may hold. This gives them rights to different functionality and parts of the platform\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":126,\"key\":\"reviewed\",\"tenantTerm\":\"reviewed\",\"frontiersDefaultTerm\":\"reviewed\",\"category\":\"Peer Review Process\"},{\"sequenceNumber\":127,\"key\":\"institutional_members\",\"tenantTerm\":\"institutional partners\",\"frontiersDefaultTerm\":\"institutional partners\",\"category\":\"Accounting\"},{\"sequenceNumber\":128,\"key\":\"institutional_memberships\",\"tenantTerm\":\"institutional partnerships\",\"frontiersDefaultTerm\":\"institutional partnerships\",\"category\":\"Accounting\"},{\"sequenceNumber\":129,\"key\":\"assistant_field_chief_editors\",\"tenantTerm\":\"Assistant Field Chief Editors\",\"frontiersDefaultTerm\":\"Assistant Field Chief Editors\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":130,\"key\":\"publications\",\"tenantTerm\":\"publications\",\"frontiersDefaultTerm\":\"publications\",\"category\":\"Process\"},{\"sequenceNumber\":131,\"key\":\"ae_accepted\",\"tenantTerm\":\"recommended acceptance\",\"frontiersDefaultTerm\":\"accepted\",\"category\":\"Process\"},{\"sequenceNumber\":132,\"key\":\"field_journal\",\"tenantTerm\":\"field journal\",\"frontiersDefaultTerm\":\"field journal\",\"category\":\"Taxonomy\"},{\"sequenceNumber\":133,\"key\":\"field_journals\",\"tenantTerm\":\"field journals\",\"frontiersDefaultTerm\":\"field journals\",\"category\":\"Taxonomy\"},{\"sequenceNumber\":134,\"key\":\"program_manager\",\"tenantTerm\":\"program manager\",\"frontiersDefaultTerm\":\"program manager\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":135,\"key\":\"journal_manager\",\"tenantTerm\":\"journal manager\",\"frontiersDefaultTerm\":\"journal manager\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":136,\"key\":\"journal_specialist\",\"tenantTerm\":\"journal specialist\",\"frontiersDefaultTerm\":\"journal specialist\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":137,\"key\":\"program_managers\",\"tenantTerm\":\"program managers\",\"frontiersDefaultTerm\":\"program managers\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":138,\"key\":\"journal_managers\",\"tenantTerm\":\"journal managers\",\"frontiersDefaultTerm\":\"journal managers\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":139,\"key\":\"journal_specialists\",\"tenantTerm\":\"journal specialists\",\"frontiersDefaultTerm\":\"journal specialists\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":140,\"key\":\"cover_letter\",\"tenantTerm\":\"manuscript contribution to the field\",\"frontiersDefaultTerm\":\"manuscript contribution to the field\",\"category\":\"Process\"},{\"sequenceNumber\":141,\"key\":\"ae_accepted_manuscript\",\"tenantTerm\":\"recommended to accept manuscript\",\"frontiersDefaultTerm\":\"accepted manuscript\",\"category\":\"Process\"},{\"sequenceNumber\":142,\"key\":\"recommend_for_rejection\",\"tenantTerm\":\"recommend for rejection\",\"frontiersDefaultTerm\":\"recommend for rejection\",\"category\":\"Process\"},{\"sequenceNumber\":143,\"key\":\"recommended_for_rejection\",\"tenantTerm\":\"recommended for rejection\",\"frontiersDefaultTerm\":\"recommended for rejection\",\"category\":\"Process\"},{\"sequenceNumber\":144,\"key\":\"ae\",\"tenantTerm\":\"AE\",\"frontiersDefaultTerm\":\"AE\",\"description\":\"Associate Editor - board member\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":145,\"key\":\"re\",\"tenantTerm\":\"RE\",\"frontiersDefaultTerm\":\"RE\",\"description\":\"Review Editor\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":146,\"key\":\"rev\",\"tenantTerm\":\"REV\",\"frontiersDefaultTerm\":\"REV\",\"description\":\"Reviewer\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":147,\"key\":\"aut\",\"tenantTerm\":\"AUT\",\"frontiersDefaultTerm\":\"AUT\",\"description\":\"Author\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":148,\"key\":\"coraut\",\"tenantTerm\":\"CORAUT\",\"frontiersDefaultTerm\":\"CORAUT\",\"description\":\"Corresponding author\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":149,\"key\":\"saut\",\"tenantTerm\":\"SAUT\",\"frontiersDefaultTerm\":\"SAUT\",\"description\":\"Submitting author\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":150,\"key\":\"coaut\",\"tenantTerm\":\"COAUT\",\"frontiersDefaultTerm\":\"COAUT\",\"description\":\"co-author\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":151,\"key\":\"tsof\",\"tenantTerm\":\"TSOF\",\"frontiersDefaultTerm\":\"TSOF\",\"description\":\"Typesetter\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":152,\"key\":\"typesetting_office\",\"tenantTerm\":\"typesetting office\",\"frontiersDefaultTerm\":\"typesetting office\",\"category\":\"Product\"},{\"sequenceNumber\":153,\"key\":\"config\",\"tenantTerm\":\"CONFIG\",\"frontiersDefaultTerm\":\"CONFIG\",\"description\":\"Configuration office role\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":154,\"key\":\"jm\",\"tenantTerm\":\"JM\",\"frontiersDefaultTerm\":\"JM\",\"description\":\"Journal Manager\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":155,\"key\":\"rte\",\"tenantTerm\":\"RTE\",\"frontiersDefaultTerm\":\"RTE\",\"description\":\"Research topic editor\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":156,\"key\":\"organizations\",\"tenantTerm\":\"organizations\",\"frontiersDefaultTerm\":\"organizations\",\"category\":\"Core\"},{\"sequenceNumber\":157,\"key\":\"publishing\",\"tenantTerm\":\"publishing\",\"frontiersDefaultTerm\":\"publishing\",\"category\":\"Core\"},{\"sequenceNumber\":158,\"key\":\"acceptance\",\"tenantTerm\":\"acceptance\",\"frontiersDefaultTerm\":\"acceptance\",\"category\":\"Process\"},{\"sequenceNumber\":159,\"key\":\"preferred_associate_editor\",\"tenantTerm\":\"preferred associate editor\",\"frontiersDefaultTerm\":\"preferred associate editor\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":160,\"key\":\"topic_editors\",\"tenantTerm\":\"Topic Editors\",\"frontiersDefaultTerm\":\"Topic Editors\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":161,\"key\":\"institutions\",\"tenantTerm\":\"institutions\",\"frontiersDefaultTerm\":\"institutions\",\"category\":\"Core\"},{\"sequenceNumber\":162,\"key\":\"author(s)\",\"tenantTerm\":\"author(s)\",\"frontiersDefaultTerm\":\"author(s)\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":163,\"key\":\"figure(s)\",\"tenantTerm\":\"figure(s)\",\"frontiersDefaultTerm\":\"figure(s)\",\"category\":\"Manuscript Metadata\"},{\"sequenceNumber\":164,\"key\":\"co-authors\",\"tenantTerm\":\"co-authors\",\"frontiersDefaultTerm\":\"co-authors\",\"description\":\"co-authors\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":165,\"key\":\"editorial_board_members\",\"tenantTerm\":\"editorial board members\",\"frontiersDefaultTerm\":\"editorial board members\",\"description\":\"editorial board members\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":166,\"key\":\"editorial_board\",\"tenantTerm\":\"editorial board\",\"frontiersDefaultTerm\":\"editorial board\",\"description\":\"editorial board\",\"category\":\"Product\"},{\"sequenceNumber\":167,\"key\":\"co-authorship\",\"tenantTerm\":\"co-authorship\",\"frontiersDefaultTerm\":\"co-authorship\",\"description\":\"co-authorship\",\"category\":\"Misc.\"},{\"sequenceNumber\":168,\"key\":\"role_id_1\",\"tenantTerm\":\"registration office\",\"frontiersDefaultTerm\":\"registration office\",\"category\":\"User Role\"},{\"sequenceNumber\":169,\"key\":\"role_id_2\",\"tenantTerm\":\"editorial office\",\"frontiersDefaultTerm\":\"editorial office\",\"category\":\"User Role\"},{\"sequenceNumber\":170,\"key\":\"role_id_7\",\"tenantTerm\":\"field chief editor\",\"frontiersDefaultTerm\":\"field chief editor\",\"category\":\"User Role\"},{\"sequenceNumber\":171,\"key\":\"role_id_8\",\"tenantTerm\":\"assistant field chief editor\",\"frontiersDefaultTerm\":\"assistant field chief editor\",\"category\":\"User Role\"},{\"sequenceNumber\":172,\"key\":\"role_id_9\",\"tenantTerm\":\"specialty chief editor\",\"frontiersDefaultTerm\":\"specialty chief editor\",\"category\":\"User Role\"},{\"sequenceNumber\":173,\"key\":\"role_id_10\",\"tenantTerm\":\"assistant specialty chief editor\",\"frontiersDefaultTerm\":\"assistant specialty chief editor\",\"category\":\"User Role\"},{\"sequenceNumber\":174,\"key\":\"role_id_11\",\"tenantTerm\":\"associate editor\",\"frontiersDefaultTerm\":\"associate editor\",\"category\":\"User Role\"},{\"sequenceNumber\":175,\"key\":\"role_id_12\",\"tenantTerm\":\"guest associate editor\",\"frontiersDefaultTerm\":\"guest associate editor\",\"category\":\"User Role\"},{\"sequenceNumber\":176,\"key\":\"role_id_13\",\"tenantTerm\":\"review editor\",\"frontiersDefaultTerm\":\"review editor\",\"category\":\"User Role\"},{\"sequenceNumber\":177,\"key\":\"role_id_14\",\"tenantTerm\":\"reviewer\",\"frontiersDefaultTerm\":\"reviewer\",\"category\":\"User Role\"},{\"sequenceNumber\":178,\"key\":\"role_id_15\",\"tenantTerm\":\"author\",\"frontiersDefaultTerm\":\"author\",\"category\":\"User Role\"},{\"sequenceNumber\":179,\"key\":\"role_id_16\",\"tenantTerm\":\"corresponding author\",\"frontiersDefaultTerm\":\"corresponding author\",\"category\":\"User Role\"},{\"sequenceNumber\":180,\"key\":\"role_id_17\",\"tenantTerm\":\"submitting author\",\"frontiersDefaultTerm\":\"submitting author\",\"category\":\"User Role\"},{\"sequenceNumber\":181,\"key\":\"role_id_18\",\"tenantTerm\":\"co-author\",\"frontiersDefaultTerm\":\"co-author\",\"category\":\"User Role\"},{\"sequenceNumber\":182,\"key\":\"role_id_20\",\"tenantTerm\":\"production office\",\"frontiersDefaultTerm\":\"production office\",\"category\":\"User Role\"},{\"sequenceNumber\":183,\"key\":\"role_id_22\",\"tenantTerm\":\"typesetting office (typesetter)\",\"frontiersDefaultTerm\":\"typesetting office (typesetter)\",\"category\":\"User Role\"},{\"sequenceNumber\":184,\"key\":\"role_id_24\",\"tenantTerm\":\"registered user\",\"frontiersDefaultTerm\":\"registered user\",\"category\":\"User Role\"},{\"sequenceNumber\":185,\"key\":\"role_id_35\",\"tenantTerm\":\"job office\",\"frontiersDefaultTerm\":\"job office\",\"category\":\"User Role\"},{\"sequenceNumber\":186,\"key\":\"role_id_41\",\"tenantTerm\":\"special event administrator\",\"frontiersDefaultTerm\":\"special event administrator\",\"category\":\"User Role\"},{\"sequenceNumber\":187,\"key\":\"role_id_42\",\"tenantTerm\":\"special event reviewer\",\"frontiersDefaultTerm\":\"special event reviewer\",\"category\":\"User Role\"},{\"sequenceNumber\":188,\"key\":\"role_id_43\",\"tenantTerm\":\"submit abstract\",\"frontiersDefaultTerm\":\"submit abstract\",\"category\":\"User Role\"},{\"sequenceNumber\":189,\"key\":\"role_id_52\",\"tenantTerm\":\"events office\",\"frontiersDefaultTerm\":\"events office\",\"category\":\"User Role\"},{\"sequenceNumber\":190,\"key\":\"role_id_53\",\"tenantTerm\":\"event administrator\",\"frontiersDefaultTerm\":\"event administrator\",\"category\":\"User Role\"},{\"sequenceNumber\":191,\"key\":\"role_id_89\",\"tenantTerm\":\"content management office\",\"frontiersDefaultTerm\":\"content management office\",\"category\":\"User Role\"},{\"sequenceNumber\":192,\"key\":\"role_id_98\",\"tenantTerm\":\"accounting office\",\"frontiersDefaultTerm\":\"accounting office\",\"category\":\"User Role\"},{\"sequenceNumber\":193,\"key\":\"role_id_99\",\"tenantTerm\":\"projects\",\"frontiersDefaultTerm\":\"projects\",\"category\":\"User Role\"},{\"sequenceNumber\":194,\"key\":\"role_id_103\",\"tenantTerm\":\"configuration office\",\"frontiersDefaultTerm\":\"configuration office\",\"category\":\"User Role\"},{\"sequenceNumber\":195,\"key\":\"role_id_104\",\"tenantTerm\":\"beta user\",\"frontiersDefaultTerm\":\"beta user\",\"category\":\"User Role\"},{\"sequenceNumber\":196,\"key\":\"role_id_106\",\"tenantTerm\":\"wfconf\",\"frontiersDefaultTerm\":\"wfconf\",\"category\":\"User Role\"},{\"sequenceNumber\":197,\"key\":\"role_id_107\",\"tenantTerm\":\"rt management beta user\",\"frontiersDefaultTerm\":\"rt management beta user\",\"category\":\"User Role\"},{\"sequenceNumber\":198,\"key\":\"role_id_108\",\"tenantTerm\":\"deo beta user\",\"frontiersDefaultTerm\":\"deo beta user\",\"category\":\"User Role\"},{\"sequenceNumber\":199,\"key\":\"role_id_109\",\"tenantTerm\":\"search beta user\",\"frontiersDefaultTerm\":\"search beta user\",\"category\":\"User Role\"},{\"sequenceNumber\":200,\"key\":\"role_id_110\",\"tenantTerm\":\"journal manager\",\"frontiersDefaultTerm\":\"journal manager\",\"category\":\"User Role\"},{\"sequenceNumber\":201,\"key\":\"role_id_111\",\"tenantTerm\":\"myfrontiers beta user\",\"frontiersDefaultTerm\":\"myfrontiers beta user\",\"category\":\"User Role\"},{\"sequenceNumber\":202,\"key\":\"role_id_21\",\"tenantTerm\":\"copy editor\",\"frontiersDefaultTerm\":\"copy editor\",\"category\":\"User Role\"},{\"sequenceNumber\":203,\"key\":\"role_id_1_abr\",\"tenantTerm\":\"ROF\",\"frontiersDefaultTerm\":\"ROF\",\"category\":\"User Role\"},{\"sequenceNumber\":204,\"key\":\"role_id_2_abr\",\"tenantTerm\":\"EOF\",\"frontiersDefaultTerm\":\"EOF\",\"category\":\"User Role\"},{\"sequenceNumber\":205,\"key\":\"role_id_7_abr\",\"tenantTerm\":\"FCE\",\"frontiersDefaultTerm\":\"FCE\",\"category\":\"User Role\"},{\"sequenceNumber\":206,\"key\":\"role_id_8_abr\",\"tenantTerm\":\"AFCE\",\"frontiersDefaultTerm\":\"AFCE\",\"category\":\"User Role\"},{\"sequenceNumber\":207,\"key\":\"role_id_9_abr\",\"tenantTerm\":\"SCE\",\"frontiersDefaultTerm\":\"SCE\",\"category\":\"User Role\"},{\"sequenceNumber\":208,\"key\":\"role_id_10_abr\",\"tenantTerm\":\"ASCE\",\"frontiersDefaultTerm\":\"ASCE\",\"category\":\"User Role\"},{\"sequenceNumber\":209,\"key\":\"role_id_11_abr\",\"tenantTerm\":\"AE\",\"frontiersDefaultTerm\":\"AE\",\"category\":\"User Role\"},{\"sequenceNumber\":210,\"key\":\"role_id_12_abr\",\"tenantTerm\":\"GAE\",\"frontiersDefaultTerm\":\"GAE\",\"category\":\"User Role\"},{\"sequenceNumber\":211,\"key\":\"role_id_13_abr\",\"tenantTerm\":\"RE\",\"frontiersDefaultTerm\":\"RE\",\"category\":\"User Role\"},{\"sequenceNumber\":212,\"key\":\"role_id_14_abr\",\"tenantTerm\":\"REV\",\"frontiersDefaultTerm\":\"REV\",\"category\":\"User Role\"},{\"sequenceNumber\":213,\"key\":\"role_id_15_abr\",\"tenantTerm\":\"AUT\",\"frontiersDefaultTerm\":\"AUT\",\"category\":\"User Role\"},{\"sequenceNumber\":214,\"key\":\"role_id_16_abr\",\"tenantTerm\":\"CORAUT\",\"frontiersDefaultTerm\":\"CORAUT\",\"category\":\"User Role\"},{\"sequenceNumber\":215,\"key\":\"role_id_17_abr\",\"tenantTerm\":\"SAUT\",\"frontiersDefaultTerm\":\"SAUT\",\"category\":\"User Role\"},{\"sequenceNumber\":216,\"key\":\"role_id_18_abr\",\"tenantTerm\":\"COAUT\",\"frontiersDefaultTerm\":\"COAUT\",\"category\":\"User Role\"},{\"sequenceNumber\":217,\"key\":\"role_id_20_abr\",\"tenantTerm\":\"POF\",\"frontiersDefaultTerm\":\"POF\",\"category\":\"User Role\"},{\"sequenceNumber\":218,\"key\":\"role_id_22_abr\",\"tenantTerm\":\"TSOF\",\"frontiersDefaultTerm\":\"TSOF\",\"category\":\"User Role\"},{\"sequenceNumber\":219,\"key\":\"role_id_24_abr\",\"tenantTerm\":\"RU\",\"frontiersDefaultTerm\":\"RU\",\"category\":\"User Role\"},{\"sequenceNumber\":220,\"key\":\"role_id_35_abr\",\"tenantTerm\":\"JOF\",\"frontiersDefaultTerm\":\"JOF\",\"category\":\"User Role\"},{\"sequenceNumber\":221,\"key\":\"role_id_41_abr\",\"tenantTerm\":\"SE-ADM\",\"frontiersDefaultTerm\":\"SE-ADM\",\"category\":\"User Role\"},{\"sequenceNumber\":222,\"key\":\"role_id_42_abr\",\"tenantTerm\":\"SE-REV\",\"frontiersDefaultTerm\":\"SE-REV\",\"category\":\"User Role\"},{\"sequenceNumber\":223,\"key\":\"role_id_43_abr\",\"tenantTerm\":\"SE-AUT\",\"frontiersDefaultTerm\":\"SE-AUT\",\"category\":\"User Role\"},{\"sequenceNumber\":224,\"key\":\"role_id_52_abr\",\"tenantTerm\":\"EVOF\",\"frontiersDefaultTerm\":\"EVOF\",\"category\":\"User Role\"},{\"sequenceNumber\":225,\"key\":\"role_id_53_abr\",\"tenantTerm\":\"EV-ADM\",\"frontiersDefaultTerm\":\"EV-ADM\",\"category\":\"User Role\"},{\"sequenceNumber\":226,\"key\":\"role_id_89_abr\",\"tenantTerm\":\"COMOF\",\"frontiersDefaultTerm\":\"COMOF\",\"category\":\"User Role\"},{\"sequenceNumber\":227,\"key\":\"role_id_98_abr\",\"tenantTerm\":\"AOF\",\"frontiersDefaultTerm\":\"AOF\",\"category\":\"User Role\"},{\"sequenceNumber\":228,\"key\":\"role_id_99_abr\",\"tenantTerm\":\"Projects\",\"frontiersDefaultTerm\":\"Projects\",\"category\":\"User Role\"},{\"sequenceNumber\":229,\"key\":\"role_id_103_abr\",\"tenantTerm\":\"CONFIG\",\"frontiersDefaultTerm\":\"CONFIG\",\"category\":\"User Role\"},{\"sequenceNumber\":230,\"key\":\"role_id_104_abr\",\"tenantTerm\":\"BETA\",\"frontiersDefaultTerm\":\"BETA\",\"category\":\"User Role\"},{\"sequenceNumber\":231,\"key\":\"role_id_106_abr\",\"tenantTerm\":\"WFCONF\",\"frontiersDefaultTerm\":\"WFCONF\",\"category\":\"User Role\"},{\"sequenceNumber\":232,\"key\":\"role_id_107_abr\",\"tenantTerm\":\"RTBETA\",\"frontiersDefaultTerm\":\"RTBETA\",\"category\":\"User Role\"},{\"sequenceNumber\":233,\"key\":\"role_id_108_abr\",\"tenantTerm\":\"DEOBETA\",\"frontiersDefaultTerm\":\"DEOBETA\",\"category\":\"User Role\"},{\"sequenceNumber\":234,\"key\":\"role_id_109_abr\",\"tenantTerm\":\"SEARCHBETA\",\"frontiersDefaultTerm\":\"SEARCHBETA\",\"category\":\"User Role\"},{\"sequenceNumber\":235,\"key\":\"role_id_110_abr\",\"tenantTerm\":\"JM\",\"frontiersDefaultTerm\":\"JM\",\"category\":\"User Role\"},{\"sequenceNumber\":236,\"key\":\"role_id_111_abr\",\"tenantTerm\":\"MFBETA\",\"frontiersDefaultTerm\":\"MFBETA\",\"category\":\"User Role\"},{\"sequenceNumber\":237,\"key\":\"role_id_21_abr\",\"tenantTerm\":\"COPED\",\"frontiersDefaultTerm\":\"COPED\",\"category\":\"User Role\"},{\"sequenceNumber\":238,\"key\":\"reviewer_editorial_board\",\"tenantTerm\":\"editorial board\",\"frontiersDefaultTerm\":\"editorial board\",\"description\":\"This is the label for the review editorial board\",\"category\":\"Label\"},{\"sequenceNumber\":239,\"key\":\"field_chief_editor\",\"tenantTerm\":\"Field Chief Editor\",\"frontiersDefaultTerm\":\"Field Chief Editor\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":240,\"key\":\"field_chief_editors\",\"tenantTerm\":\"Field Chief Editors\",\"frontiersDefaultTerm\":\"Field Chief Editors\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":241,\"key\":\"editor\",\"tenantTerm\":\"editor\",\"frontiersDefaultTerm\":\"editor\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":242,\"key\":\"editors\",\"tenantTerm\":\"editors\",\"frontiersDefaultTerm\":\"editors\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":243,\"key\":\"board\",\"tenantTerm\":\"board\",\"frontiersDefaultTerm\":\"board\",\"category\":\"Label\"},{\"sequenceNumber\":244,\"key\":\"boards\",\"tenantTerm\":\"boards\",\"frontiersDefaultTerm\":\"boards\",\"category\":\"Label\"},{\"sequenceNumber\":245,\"key\":\"article_collection\",\"tenantTerm\":\"article collection\",\"frontiersDefaultTerm\":\"article collection\",\"category\":\"Label\"},{\"sequenceNumber\":246,\"key\":\"article_collections\",\"tenantTerm\":\"article collections\",\"frontiersDefaultTerm\":\"article collections\",\"category\":\"Label\"},{\"sequenceNumber\":247,\"key\":\"handling_editor\",\"tenantTerm\":\"handling editor\",\"frontiersDefaultTerm\":\"associate editor\",\"description\":\"This terminology key is for the person assigned to edit a manuscript. It is a label for the temporary handling editor assignment.\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":248,\"key\":\"handling_editors\",\"tenantTerm\":\"handling editors\",\"frontiersDefaultTerm\":\"associate editors\",\"description\":\"This terminology key is for the person assigned to edit a manuscript. It is a label for the temporary handling editor assignment.\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":249,\"key\":\"ae_accept\",\"tenantTerm\":\"recommend acceptance\",\"frontiersDefaultTerm\":\"accept\",\"category\":\"Process\"},{\"sequenceNumber\":250,\"key\":\"rtm\",\"tenantTerm\":\"RTM\",\"frontiersDefaultTerm\":\"RTM\",\"category\":\"Product\"},{\"sequenceNumber\":251,\"key\":\"frontiers_media_sa\",\"tenantTerm\":\"Frontiers Media S.A\",\"frontiersDefaultTerm\":\"Frontiers Media S.A\",\"category\":\"Customer\"},{\"sequenceNumber\":252,\"key\":\"review_editors\",\"tenantTerm\":\"Review Editors\",\"frontiersDefaultTerm\":\"Review Editors\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":253,\"key\":\"journal_card_chief_editor\",\"tenantTerm\":\"Chief Editor\",\"frontiersDefaultTerm\":\"Chief Editor\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":254,\"key\":\"journal_card_chief_editors\",\"tenantTerm\":\"Chief Editors\",\"frontiersDefaultTerm\":\"Chief Editors\",\"category\":\"Label (Role)\"},{\"sequenceNumber\":255,\"key\":\"call_for_papers\",\"tenantTerm\":\"Call for papers\",\"frontiersDefaultTerm\":\"Call for papers\",\"category\":\"Label\"},{\"sequenceNumber\":256,\"key\":\"calls_for_papers\",\"tenantTerm\":\"Calls for papers\",\"frontiersDefaultTerm\":\"Calls for papers\",\"category\":\"Label\"},{\"sequenceNumber\":257,\"key\":\"supervising_editor\",\"tenantTerm\":\"Supervising Editor\",\"frontiersDefaultTerm\":\"Supervising Editor\",\"description\":\"A Chief or Assistant Chief editor who is assigned to a manuscript to supervise.\",\"category\":\"Role\",\"externalKey\":\"supervising_editor\"},{\"sequenceNumber\":258,\"key\":\"supervising_editors\",\"tenantTerm\":\"Supervising Editors\",\"frontiersDefaultTerm\":\"Supervising Editors\",\"description\":\"A Chief or Assistant Chief editor who is assigned to a manuscript to supervise.\",\"category\":\"Role\",\"externalKey\":\"supervising_editors\"},{\"sequenceNumber\":259,\"key\":\"reviewer_endorse\",\"tenantTerm\":\"endorse\",\"frontiersDefaultTerm\":\"endorse\",\"category\":\"Label\"},{\"sequenceNumber\":260,\"key\":\"reviewer_endorsed\",\"tenantTerm\":\"endorsed\",\"frontiersDefaultTerm\":\"endorsed\",\"category\":\"Label\"},{\"sequenceNumber\":261,\"key\":\"reviewer_endorse_publication\",\"tenantTerm\":\"endorse publication\",\"frontiersDefaultTerm\":\"endorse publication\",\"category\":\"Label\"},{\"sequenceNumber\":262,\"key\":\"reviewer_endorsed_publication\",\"tenantTerm\":\"endorsed publication\",\"frontiersDefaultTerm\":\"endorsed publication\",\"category\":\"Label\"},{\"sequenceNumber\":263,\"key\":\"editor_role\",\"tenantTerm\":\"editor role\",\"frontiersDefaultTerm\":\"Editor Role\",\"category\":\"Label\"},{\"sequenceNumber\":264,\"key\":\"editor_roles\",\"tenantTerm\":\"editor roles\",\"frontiersDefaultTerm\":\"Editor Roles\",\"category\":\"Label\"},{\"sequenceNumber\":265,\"key\":\"editorial_role\",\"tenantTerm\":\"editorial role\",\"frontiersDefaultTerm\":\"Editorial Role\",\"category\":\"Label\"},{\"sequenceNumber\":266,\"key\":\"editorial_roles\",\"tenantTerm\":\"editorial roles\",\"frontiersDefaultTerm\":\"Editorial Roles\",\"category\":\"Label\"},{\"sequenceNumber\":267,\"key\":\"call_for_paper\",\"tenantTerm\":\"Call for paper\",\"frontiersDefaultTerm\":\"Call for paper\",\"category\":\"Label\"},{\"sequenceNumber\":268,\"key\":\"research_topic_abstract\",\"tenantTerm\":\"manuscript summary\",\"frontiersDefaultTerm\":\"manuscript summary\",\"category\":\"Process\"},{\"sequenceNumber\":269,\"key\":\"research_topic_abstracts\",\"tenantTerm\":\"manuscript summaries\",\"frontiersDefaultTerm\":\"manuscript summaries\",\"category\":\"Process\"},{\"sequenceNumber\":270,\"key\":\"submissions_team_manager\",\"tenantTerm\":\"Journal Manager\",\"frontiersDefaultTerm\":\"Content Manager\",\"category\":\"Process\"},{\"sequenceNumber\":271,\"key\":\"submissions_team\",\"tenantTerm\":\"Journal Team\",\"frontiersDefaultTerm\":\"Content Team\",\"category\":\"Process\"},{\"sequenceNumber\":272,\"key\":\"topic_coordinator\",\"tenantTerm\":\"topic coordinator\",\"frontiersDefaultTerm\":\"topic coordinator\",\"category\":\"Process\"},{\"sequenceNumber\":273,\"key\":\"topic_coordinators\",\"tenantTerm\":\"topic coordinators\",\"frontiersDefaultTerm\":\"topic coordinators\",\"category\":\"Process\"}]}'\n",gtmId:"GTM-M322FV2",gtmAuth:"owVbWxfaJr21yQv1fe1cAQ",gtmServerUrl:"https:\u002F\u002Ftag-manager.frontiersin.org",gtmPreview:"env-1",faviconSize512:"https:\u002F\u002Fbrand.frontiersin.org\u002Fm\u002Fed3f9ce840a03d7\u002Ffavicon_512-tenantFavicon-Frontiers.png",socialMediaImg:"https:\u002F\u002Fbrand.frontiersin.org\u002Fm\u002F1c8bcb536c789e11\u002FGuidelines-Frontiers_Logo_1200x628_1-91to1.png",_app:{basePath:"\u002F",assetsPath:"\u002Farticle-pages\u002F_nuxt\u002F",cdnURL:e}},apollo:{contentfulJournalsDelivery:Object.create(null),contentfulJournalsPreview:Object.create(null),contentfulHomeDelivery:Object.create(null),contentfulHomePreview:Object.create(null),frontiersGraph:Object.create(null)}}}("journal_journal","public_space",1,"frontiersin.org",null,"_self","",true,3,false,"frontierspartnerships.org",0,"_blank","citation_author","citation_author_institution","Frontiers in Pharmacology",2,"PDF",5,176,"pharmacology","Link",4,"Department of Pharmacy","Pakistan","description","Frontiers","Department of Pharmacy, Pakistan","Help center","Grey","Medium","ssph-journal.org","fship","image","landscape","Front. Pharmacol.","1663-9812",void 0,6,18,"Saudi Arabia",1920,"por-journal.com",7,"escubed.org",1918,"fipp","https:\u002F\u002Fd2csxpduxe849s.cloudfront.net\u002Fmedia\u002FE32629C6-9347-4F84-81FEAEF7BFA342B3\u002F754E12A9-443F-4EA8-AB01E0811E45131D\u002Fwebimage-9D720582-24AD-4D2E-9205AB9D241919DA.jpg","22C10171-81B3-4DA6-99342F272A32E8BB","2022-06-27T10:00:45Z","fphar",62,"journal_field","10.3389\u002Ffphar.2023.1145962","Determination of α1-acid glycoprotein (AGP) concentration by HPLC in patients following local infiltration analgesia for primary total hip arthroplasty and its relation to ropivacaine (total and unbound)","\u003Cp\u003E\u003Cbold\u003EIntroduction:\u003C\u002Fbold\u003E This study was performed to determine the levels of α1-acid glycoprotein (AGP) in old-age patients undergoing total hip arthroplasty. AGP is considered an acute phase protein produced during the acute phase reaction in the body to various stimuli; their proper monitoring is thus important.\u003C\u002Fp\u003E\u003Cp\u003E\u003Cbold\u003EMethods:\u003C\u002Fbold\u003E In order to study how AGP concentrations in old age patients change in response to surgical stress (total hip arthroplasty), a high-performance liquid chromatography assay was performed to measure AGP levels. AGP was isolated from the plasma by adding perchloric acid and was analyzed using PLRP-S 4000°A column. The mobile phase consisted of 1 mL TFA\u002FL of water (Solvent A pH 2) and 1 mL TFA\u002FL of acetonitrile (Solvent B). The gradient used was as follows: 0 min 18% B and 82% A, 15 min 60% B and 40% A, and 17 min 60% B and 40% A followed by column re-equilibration for 7 min before the next injection. AGP peak was obtained between 8.8 and 8.9 min. The method was fully optimised according to established guidelines.\u003C\u002Fp\u003E\u003Cp\u003E\u003Cbold\u003EResults:\u003C\u002Fbold\u003E The data obtained were analyzed on ChromQuest software. AGP concentrations were determined in all samples, including baseline and samples taken at different timed intervals. The peak for AGP was obtained between 8.8 and 8.9 min for both standard AGP and patient plasma. The graphs indicate that AGP concentration in almost all patient samples increased considerably, especially after 4 h and 24 h—for example, initial concentration in patient 1 was 10.36 mg\u002F100 mL but, after 24 h, increased to 23.50 mg\u002F100 mL. There was thus almost a 13 mg\u002F100 mL increase in 24 h, which is confirmed by AGP concentration increasing after various conditions, including surgery. The increased plasma protein binding was comparatively associated with the unchanged free fraction of the drug.\u003C\u002Fp\u003E\u003Cp\u003E\u003Cbold\u003EConclusion:\u003C\u002Fbold\u003E This surgically induced increase in AGP concentration resulted in increased plasma protein binding of the drug (ropivacaine), which in turn kept the free portion of ropivacaine stable during the postoperative period.\u003C\u002Fp\u003E",1417926,"Muhammad",1109038,"Manal A.","Department of Pharmaceutical Chemistry","Abdulmalik S. A.","Mai",2176267,"David G.","Sayyed I.","Shah","Yasar","Mohammad S.",243834,"Tahir",542593,"Mohammed",1943882,"Swati",{},1251,"Translational Pharmacology","translational-pharmacology",14,"EPUB","fphar-14-1145962.pdf","Frontiers | Determination of α1-acid glycoprotein (AGP) concentration by HPLC in patients following local infiltration analgesia for primary total hip arthroplasty and its relation to ropivacaine (total and unbound)","https:\u002F\u002Fwww.frontiersin.org\u002Fjournals\u002Fpharmacology\u002Farticles\u002F10.3389\u002Ffphar.2023.1145962\u002Ffull","Introduction: This study was performed to determine the levels of α1-acid glycoprotein (AGP) in old-age patients undergoing total hip arthroplasty. AGP is co...","og:title","og:description","keywords","og:site_name","og:image","og:type","og:url","twitter:card","citation_volume","citation_journal_title","citation_publisher","citation_journal_abbrev","citation_issn","citation_doi","citation_firstpage","citation_language","citation_title","citation_keywords","citation_abstract","citation_pdf_url","citation_online_date","citation_publication_date","Department of Pharmaceutical Chemistry, Saudi Arabia","dc.identifier","articles","editors","research-topics","https:\u002F\u002Fd2csxpduxe849s.cloudfront.net\u002Fmedia\u002FE32629C6-9347-4F84-81FEAEF7BFA342B3\u002F0B4B1380-42EB-4FD5-9D7E2DBC603E79F8\u002Fwebimage-C4875379-1478-416F-B03DF68FE3D8DBB5.png","Man ultramarathon runner in the mountains he trains at sunset","https:\u002F\u002Fwww.frontiersin.org\u002Fabout\u002Fresearch-integrity","How we publish","https:\u002F\u002Fwww.frontiersin.org\u002Fabout\u002Fhow-we-publish","Fee policy","https:\u002F\u002Fwww.frontiersin.org\u002Fabout\u002Ffee-policy","Research Topics","https:\u002F\u002Fforum.frontiersin.org\u002F","Frontiers Planet Prize","https:\u002F\u002Fwww.frontiersplanetprize.org\u002F","this link will take you to the Frontiers Planet Prize website","Career opportunities","https:\u002F\u002Fcareers.frontiersin.org\u002F","https:\u002F\u002Fwww.frontiersin.org\u002Fabout\u002Fcontact","Author guidelines","Editor guidelines","https:\u002F\u002Fwww.frontiersin.org\u002Fjournals","https:\u002F\u002Fwww.frontiersin.org\u002Farticles","Articles","https:\u002F\u002Fhelpcenter.frontiersin.org","Frontiers for Young Minds","Frontiers Facebook",9,"Transplant International","transplant-international","ti",1921,"Spanish Journal of Soil Science","spanish-journal-of-soil-science","sjss","ebm-journal.org","Public Health Reviews","public-health-reviews","phrs","Pathology and Oncology Research","pathology-and-oncology-research","pore",21,"Pastoralism: Research, Policy and Practice","pastoralism-research-policy-and-practice","past",11,"Oncology Reviews","oncology-reviews","or","Journal of Pharmacy & Pharmaceutical Sciences","journal-of-pharmacy-pharmaceutical-sciences","jpps","Journal of Cutaneous Immunology and Allergy","journal-of-cutaneous-immunology-and-allergy","JCIA","Journal of Abdominal Wall Surgery","journal-of-abdominal-wall-surgery","jaws",1919,"International Journal of Public Health","international-journal-of-public-health","ijph","Frontiers in Pathology","pathology","fpath",13,12,17,"Experimental Biology and Medicine","experimental-biology-and-medicine","EBM","European Journal of Cultural Management and Policy","european-journal-of-cultural-management-and-policy","ejcmp","Earth Science, Systems and Society","earth-science-systems-and-society","esss","Dystonia","dystonia","dyst","British Journal of Biomedical Science","british-journal-of-biomedical-science","bjbs","Aerospace Research Communications","aerospace-research-communications","arc","Advances in Drug and Alcohol Research","advances-in-drug-and-alcohol-research","adar","Acta Virologica","acta-virologica","av","Acta Biochimica Polonica","acta-biochimica-polonica"));</script><script src="/article-pages/_nuxt/e397d1a.js" defer></script><script src="/article-pages/_nuxt/a5e7651.js" defer></script><script src="/article-pages/_nuxt/f548f7f.js" defer></script><script src="/article-pages/_nuxt/e3c5a8f.js" defer></script><script src="/article-pages/_nuxt/0d6d8e5.js" defer></script><script src="/article-pages/_nuxt/ed7fc59.js" defer></script><script src="/article-pages/_nuxt/2abb6c5.js" defer></script><script src="/article-pages/_nuxt/701e3a3.js" defer></script><script src="/article-pages/_nuxt/71728a1.js" defer></script><script data-n-head="ssr" src="https://cdnjs.cloudflare.com/polyfill/v3/polyfill.min.js?features=es6" data-body="true" async></script><script data-n-head="ssr" src="https://cdnjs.cloudflare.com/ajax/libs/mathjax/2.7.1/MathJax.js?config=TeX-MML-AM_CHTML" data-body="true" async></script><script data-n-head="ssr" src="https://d1bxh8uas1mnw7.cloudfront.net/assets/altmetric_badges-f0bc9b243ff5677d05460c1eb71834ca998946d764eb3bc244ab4b18ba50d21e.js" data-body="true" async></script><script data-n-head="ssr" src="https://api.altmetric.com/v1/doi/10.3389/fphar.2023.1145962?callback=_altmetric.embed_callback&domain=www.frontiersin.org&key=3c130976ca2b8f2e88f8377633751ba1&cache_until=14-15" data-body="true" async></script><script data-n-head="ssr" src="https://crossmark-cdn.crossref.org/widget/v2.0/widget.js" data-body="true" async></script> </body> </html>