Repinotan hydrochloride (repinotan) is a highly potent and selective 5-HT(1A) full receptor agonist. The ability of repinotan to cross the blood-brain barrier (BBB) and penetrate into rat brain tissue was investigated, because rapid penetration into brain tissue is thought to be essential for neuroprotective efficacy. Intravenous (i.v.) repinotan was rapidly distributed into brain, and the distribution equilibrium between blood and brain was reached immediately after the start of infusion. Free concentrations of repinotan were identical in brain and plasma, indicating that repinotan crosses the BBB freely in both directions with diffusion as a driving force. The brain concentration of repinotan was determined by the free plasma concentration. Thus, the total plasma concentration of repinotan (sum of bound and unbound compound) is only indicative for the brain concentration as long as the unbound fraction remains constant. Metabolites of repinotan do not penetrate the BBB and are retained in the perfusing blood due to their increased polarity. The penetration of [14C] repinotan into ischemic areas of the brain was dependent on time. In studies using injured animals (pMCAO), high levels of [14C] repinotan could be detected in ischemic areas when the compound was administered up to 5 h post injury. [14C] repinotan radioactivity could no longer be detected in ischemic areas when administered 18 h after pMCA-O. After the end of infusion, repinotan was rapidly and completely eliminated from rat brains. Elimination occurred in parallel from plasma and brain with half-lives of about 1 h. In conclusion, repinotan rapidly and to a considerable extent penetrates into brain tissue of healthy and injured animals.
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Article Synopsis
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Selective 5-HT(1A)-R-agonist repinotan prevents remifentanil-induced ventilatory depression and prolongs antinociception.
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January 2012
Clinic of Anesthesiology and Intensive Care Medicine, Bonn University Hospital, Bonn, Germany.
Background: 5-HT(1A)-R-agonist repinotan was shown to counteract a morphine-induced ventilatory depression but had pronociceptive effects at small doses (0.2 μg/kg). It remained to be clarified (1) whether a moderate dose of repinotan, sufficient to stimulate spontaneous breathing, impairs antinociception if plasma concentration decreases over time, and if (2) moderate doses prevent ventilatory depression if given before the opioid.
View Article and Find Full Text PDFRepinotan, a selective 5-HT1A-R-agonist, antagonizes morphine-induced ventilatory depression in anesthetized rats.
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University Hospital of Bonn, Clinic of Anaesthesiology and Intensive Care Medicine, Bonn, Germany.
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November 2009
University of British Columbia, Vancouver, British Columbia, Canada.
Background And Purpose: Repinotan hydrochloride is a serotonin (5-HT)(1A) receptor full agonist with evidence of neuroprotection in animal models of permanent and transient focal ischemia. The purpose of this Phase IIb study was to investigate the efficacy, safety, and tolerability of a targeted exposure to repinotan in patients with acute ischemic stroke.
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Effect of gender and age on the pharmacokinetics of repinotan.
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Institute of Clinical Pharmacology, Bayer HealthCare AG, Wuppertal, Germany.
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