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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/cdn\/css\/http\/css_Xg7z6oCTVgud_Q0huYz9x9iiD5H_2YPSJ5z2ZViSWdY.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EA pharmacokinetic\/pharmacodynamic (PK\/PD) modeling study on the effect of the BK channel blocker GAL021 found that it produced rapid reversal of opioid-induced respiratory depression (OIRD) in a population of healthy male volunteers. This article discusses a study assessing whether GAL21 stimulates breathing in OIRD and evaluated its safety in a proof-of-concept, double-blind crossover study on isohypercapnic ventilation and a subsequent double-blind exploratory study on poikilocapnic ventilation and nonrespiratory end points.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EAnalgesic Drugs\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EAnesthesiology Clinical Trials\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EPain Management\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EAcute \u0026amp; Chronic\u003C\/li\u003E\u003C\/ul\u003E\u003Cul class=\u0022kwd-group clinical-trial\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EAnalgesic Drugs\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EAnesthesiology Clinical Trials\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EPain Management\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EAcute \u0026amp; Chronic\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EAnesthesiology\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EA pharmacokinetic\/pharmacodynamic (PK\/PD) modeling study on the effect of the BK channel blocker GAL021 found that it produced rapid reversal of opioid\u2013induced respiratory depression (OIRD) in a population of healthy male volunteers [Roozekrans M et al. \u003Cem\u003EAnesthesiology\u003C\/em\u003E. 2014].\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003EGAL021\u2014calcium\u2013activated potassium with a stimulatory effect on ventilation at the carotid bodies\u2014reversed OIRD in healthy volunteers without an effect on sedation, analgesia, or hemodynamics [Cotton J. \u003Cem\u003EAnesthesiology\u003C\/em\u003E. 2014]. Margot Roozekrans, MD, Leiden University Medical Center, Leiden, The Netherlands, presented results of the study.\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003EThe research assessed whether GAL21 stimulates breathing in OIRD and evaluated its safety in a proof\u2013of\u2013concept, double\u2013blind crossover study on isohypercapnic ventilation (study 1) and a subsequent double\u2013blind exploratory study on poikilocapnic ventilation and nonrespiratory end points (study 2).\u003C\/p\u003E\u003Cp id=\u0022p-5\u0022\u003ETwelve volunteers were randomized to GAL021 or placebo in the controlled crossover study. Respiratory measurements were obtained under isohypercapnic conditions. The researchers administered intravenous low\u2013 and high\u2013dose GAL021 or placebo on top of low\u2013and high\u2013dose alfentanil\u2013induced respiratory depression. Arterial plasma was collected for measurement of GAL021 and alfentanil concentrations.\u003C\/p\u003E\u003Cp id=\u0022p-6\u0022\u003EData were analyzed with a population PK\/PD model in NONMEM in 2 steps. First, the alfentanil and GAL021 PK data were characterized. Next, the PK models were used as inputs of the sigmoid E\u003Csub\u003EMAX\u003C\/sub\u003E PD model, in which GAL021 was assumed to increase ventilation in a multiplicative fashion so that the degree of reversal depended on the degree of respiratory depression.\u003C\/p\u003E\u003Cp id=\u0022p-7\u0022\u003EThe alfentanil concentration causing 50% respiratory depression was 26.3 \u00b1 3.8 ng\/mL (estimate \u00b1 SE); the alfentanil blood\u2013effect site equilibration half\u2013life was 1.0 \u00b1 0.5 minutes. At a plasma concentration of 1 \u03bcg\/mL, GAL021 reversed the OIRD by 37%; at the maximum dose, it reversed ventilation by 53%. For GAL021, the blood\u2013effect site equilibration half\u2013life was not significantly different from zero.\u003C\/p\u003E\u003Cp id=\u0022p-8\u0022\u003EGAL02 produced rapid reversal of OIRD in the volunteers. The rapid onset of effect supports the findings in animals that GAL021 stimulates respiration at a site close to the vascular bed\u2014namely, the peripheral chemo\u2013receptors of the carotid bodies. In the future, studies should assess whether more complete reversal is possible at varying levels of OIRD.\u003C\/p\u003E\u003Cp id=\u0022p-9\u0022\u003EAnesthesiologists routinely administer drugs that compromise a patient\u0027s ability to breathe, and dealing with the consequences can be a challenge [Cotton J. \u003Cem\u003EAnesthesiology\u003C\/em\u003E. 2014]. Current clinical practice is to treat OIRD with such drugs as the opioid antagonist naloxone, which reverses OIRD as well as analgesia and sometimes has other deleterious side effects [Dahan A et al. \u003Cem\u003EAnesthesiology\u003C\/em\u003E. 2010; van Dorp E et al. \u003Cem\u003EExpert Opin Drug Saf.\u003C\/em\u003E 2007]. Doxapram is another widely used drug that was developed in the 1960s.\u003C\/p\u003E\u003Cp id=\u0022p-10\u0022\u003EHigh\u2013risk powerful opioids such as oxycodone, methadone, propofol, and fentanyl are commonly used by anesthesiologists to manage perioperative and postoperative pain. Less\u2013than\u2013complete relief often takes place due to the fear of OIRD.\u003C\/p\u003E\u003Cp id=\u0022p-11\u0022\u003EThe therapeutic drug GAL021 offers an alternative to naloxone that promises to restore breathing and reduce morbidity and mortality from OIRD without compromising pain relief or increasing sedation.\u003C\/p\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2014 MD Conference Express\u00ae\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/14\/40\/13.2.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzomhp\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}