Hypothermic Action of Oseltamivir Not Dependent on Its Anti-influenza Virus Action

Although the anti-influenza virus drug oseltamivir ameliorates the fever of influenza, adverse events related to its hypothermic effect have been reported. We found that oseltamivir causes dose-dependent hypothermia in normal mice, and have been studying the pharmacological mechanisms responsible for 12 years. Oseltamivir blocks nicotinic cholinergic transmission at sympathetic ganglia and reduces sympathetic modulation of brown adipose tissue (BAT), a heat generator. Oseltamivir was found to target the ion channels of nicotinic acetylcholine receptors, as demonstrated by patch clamp experiments with cells expressing the human alpha 3 beta 4 nicotinic receptor. Metabolized oseltamivir carboxylate, which inhibits the influenza virus neuraminidase, did not elicit hypothermia and ion channel suppression. Body temperature was decreased by intracerebroventricular administration of oseltamivir. Because this hypothermic effect was inhibited by dopamine D-2 receptor blockade, it was suggested that oseltamivir centrally stimulates the D-2 receptor. In Japan, the package inserts for oseltamivir and amantadine indicate very similar adverse neuropsychiatric reactions for the two drugs (abnormal behavior, consciousness disturbance, convulsion, delirium, delusion, hallucination). A literature search revealed that in some previous studies, oseltamivir and amantadine were shown to block the ion channel systems and activate the dopaminergic nervous system via several mechanisms. Therefore the similarity of the adverse reactions elicited by oseltamivir and amantadine was considered attributable to their similar pharmacological effects.