tetano
Editor, Senior Moderator
Basic Clin Pharmacol Toxicol. 2012 Feb 6. doi: 10.1111/j.1742-7843.2012.00861.x. [Epub ahead of print]
Absence of Central Nervous System and Hypothermic Effects Following Single Oral Administration of High Doses of Oseltamivir in the Rat.
Freichel C, Breidenbach A, Hoffmann G, K?rner A, Gatti S, Donner B, Bansod S, Bellot M, Gand L, Weiser T, Singer T, Prinssen EP.
Source
F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Abstract
Oseltamivir is widely used for the treatment and prophylaxis of influenza. Renewed interest in the central nervous system (CNS) tolerability profile of oseltamivir has been triggered by reports of neuropsychiatric adverse events in influenza patients. In addition, a recent preclinical study in rodents suggested a hypothermic effect of oseltamivir. The current studies investigated the CNS effects, body temperature effect and toxicokinetic profile of oseltamivir in rats. The CNS/temperature study included three groups receiving oseltamivir (500, 763 and 1,000 mg/kg free base by oral gavage), one vehicle/control group and one reference group (D-amphetamine, 10 mg/kg). CNS parameters (behaviour, motor activity and co-ordination, and sensory/motor reflex responses) and rectal temperature were measured at baseline and at five intervals until 8 hr post-dose. In the toxicokinetic study, rats received oseltamivir by oral gavage at 763 or 1,000 mg/kg free base. Plasma, cerebrospinal fluid (CSF) and perfused brain concentrations of oseltamivir and its active metabolite, oseltamivir carboxylate (OC), were measured until 8 hr post-dose. Median scores for CNS parameters were similar in controls and animals receiving oseltamivir at all time points. Oseltamivir had no physiologically relevant effect on body temperature, but induced a short-lived and small dose-independent decrease in temperature in all active treatment groups at 1 hr post-dose only. Plasma concentrations of OC were higher than of oseltamivir, but the reverse was true in CSF and brain. CNS penetration was low for both moieties. In rats, oseltamivir at supratherapeutic doses up to 1,000 mg/kg free base did not exert any effects on CNS function or hypothermic effects and led to limited CNS exposure, resulting in large safety margins.
? 2012 The Authors Basic & Clinical Pharmacology & Toxicology ? 2012 Nordic Pharmacological Society.
PMID:
22309322
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/22309322
Absence of Central Nervous System and Hypothermic Effects Following Single Oral Administration of High Doses of Oseltamivir in the Rat.
Freichel C, Breidenbach A, Hoffmann G, K?rner A, Gatti S, Donner B, Bansod S, Bellot M, Gand L, Weiser T, Singer T, Prinssen EP.
Source
F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Abstract
Oseltamivir is widely used for the treatment and prophylaxis of influenza. Renewed interest in the central nervous system (CNS) tolerability profile of oseltamivir has been triggered by reports of neuropsychiatric adverse events in influenza patients. In addition, a recent preclinical study in rodents suggested a hypothermic effect of oseltamivir. The current studies investigated the CNS effects, body temperature effect and toxicokinetic profile of oseltamivir in rats. The CNS/temperature study included three groups receiving oseltamivir (500, 763 and 1,000 mg/kg free base by oral gavage), one vehicle/control group and one reference group (D-amphetamine, 10 mg/kg). CNS parameters (behaviour, motor activity and co-ordination, and sensory/motor reflex responses) and rectal temperature were measured at baseline and at five intervals until 8 hr post-dose. In the toxicokinetic study, rats received oseltamivir by oral gavage at 763 or 1,000 mg/kg free base. Plasma, cerebrospinal fluid (CSF) and perfused brain concentrations of oseltamivir and its active metabolite, oseltamivir carboxylate (OC), were measured until 8 hr post-dose. Median scores for CNS parameters were similar in controls and animals receiving oseltamivir at all time points. Oseltamivir had no physiologically relevant effect on body temperature, but induced a short-lived and small dose-independent decrease in temperature in all active treatment groups at 1 hr post-dose only. Plasma concentrations of OC were higher than of oseltamivir, but the reverse was true in CSF and brain. CNS penetration was low for both moieties. In rats, oseltamivir at supratherapeutic doses up to 1,000 mg/kg free base did not exert any effects on CNS function or hypothermic effects and led to limited CNS exposure, resulting in large safety margins.
? 2012 The Authors Basic & Clinical Pharmacology & Toxicology ? 2012 Nordic Pharmacological Society.
PMID:
22309322
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/22309322