Search

The effects of oseltamivir, a neuraminidase inhibitor, were tested on the function of neuronal nicotinic acetylcholine receptors (nAChRs) in a neuroblastoma cell line IMR32 derived from human peripheral neurons and on recombinant human α3β4 nAChRs expressed in HEK cells. IMR32 cells predominately express α3β4 nAChRs. Nicotine (nic, 30 μm)-evoked currents recorded at -90 mV in IMR32 cells using the whole-cell patch clamp technique were reversibly blocked by oseltamivir in a concentration-dependent manner. In contrast, an active metabolite of oseltamivir, oseltamivir carboxylate (OC) at 30 μm had little effect on the nic-evoked currents. Oseltamivir also blocked nic-evoked currents derived from HEK cells with recombinant α3β4 nAChRs. This blockade was voltage-dependent with 10, 30 and 100 μm oseltamivir inhibiting ~50% at -100, -60 and -40 mV, respectively. Non-inactivating currents in IMR32 cells and in HEK cells with α3β4 nAChRs, which were evoked by an endogenous nicotinic agonist, ACh (5 μm), were reversibly blocked by oseltamivir. These data demonstrate that oseltamivir blocks nAChRs, presumably via binding to a site in the channel pore., (© 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Oseltamivir, an anti-influenza virus drug, has strong antipyretic effects in mice (Biological and Pharmaceutical Bulletin, 31, 2008, 638) and patients with influenza. In addition, hypothermia has been reported as an adverse event. The prodrug oseltamivir is converted to oseltamivir carboxylate (OC), an active metabolite of influenza virus neuraminidase. In this study, core body temperature was measured in mice, and oseltamivir and OC were administered intracerebroventricularly (i.c.v.) or intraperitoneally (i.p). Low i.c.v. doses of oseltamivir and OC dose-dependently produced hypothermia. Zanamivir (i.c.v.), another neuraminidase inhibitor, did not produce hypothermia. These results suggested that the hypothermic effects of oseltamivir (i.p. and i.c.v.) and OC (i.c.v.) are not due to neuraminidase inhibition. OC (i.p.) did not lower body temperature. Although mecamylamine (i.c.v.) blocked the hypothermic effect of nicotine-administered i.c.v., the hypothermic effects of oseltamivir and OC (i.c.v.) were not blocked by mecamylamine (i.c.v.). The effect of oseltamivir (i.p.) was markedly increased by s.c.-pre-administered mecamylamine and also hexamethonium, a peripherally acting ganglionic blocker, suggesting their potentiating interaction at peripheral sites. The hypothermic effect of nicotine (i.c.v.) was decreased by lower doses of oseltamivir (i.c.v.), suggesting the anti-nicotinic action of oseltamivir. These results suggest that oseltamivir (i.p.) causes hypothermia through depression of sympathetic temperature regulatory mechanisms via inhibition of nicotinic receptor function and through unknown central mechanisms., (© 2013 Nordic Pharmacological Society. Published by John Wiley & Sons Ltd.)

It has been reported that one of the serious adverse events after the treatment of oseltamivir phosphate (OP) for influenza patients is sudden death resulting from cardiorespiratory arrest. To investigate the aetiology of such an adverse consequence, we examined effects of OP (expressed as free base) on blood pressure and ventilation in anaesthetized rats with vagotomy. Intravenous OP (30-200 mg/kg) caused dose-dependent hypotension and bradycardia in spontaneously breathing animals. Concomitantly with changes in blood pressure, the tracheal airflow increased. The ventilatory rate hastened during the injection and then transiently slowed around 1 min. after the administration (transient hypopnea). Thereafter, it gradually returned to control. The hypopnea increased with increasing dose and ventilatory arrest occurred at 200 mg/kg. Intraduodenal OP (500-1000 mg/kg) provoked cardioventilatory arrest 72-218 min. after the injection. Oseltamivir carboxylate (100-200 mg/kg, i.v.), an active metabolite of OP, had no significant effect on ventilation and blood pressure. In artificially ventilated animals, intravenous OP caused slowing of the respiratory rate around 1 min. after the injection in a dose-dependent manner. This effect of OP waned in 5 min. after the administration. The amplitude of phrenic nerve discharge was not changed at lower doses (30-100 mg/kg). The phrenic nerve stopped to discharge immediately after higher doses (150-200 mg/kg). We demonstrated that OP causes central suppression of the respiratory function in rats and suggest a relationship between the OP-induced cardiorespiratory arrest and sudden death observed in influenza patients after taking OP., (© 2012 The Authors Basic & Clinical Pharmacology & Toxicology © 2012 Nordic Pharmacological Society.)

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 the reports of neuropsychiatric adverse events in patients with influenza. In addition, a recent pre-clinical 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 1000 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 after dosing. In the toxicokinetic study, rats received oseltamivir by oral gavage at 763 or 1000 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 after dosing. 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 after dosing 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 1000 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.)