title: Oseltamivir produces hypothermic and neuromuscular effects by inhibition of nicotinic acetylcholine receptor functions: comparison to procaine and bupropion.
abstract: Oseltamivir, an anti-influenza virus drug, induces marked hypothermia in normal mice. We have proposed that the hypothermic effect arises from inhibition of the nicotinic acetylcholine receptor function of sympathetic ganglion neurons which innervate the brown adipose tissue (a heat generator). It has been reported that local anesthetics inhibit nicotinic acetylcholine receptor function by acting on its ionic channels, and that bupropion, a nicotinic antagonist, induces hypothermia. In this study, we compared the effects of oseltamivir, procaine and bupropion on body temperature, cardiovascular function and neuromuscular transmission. Intraperitoneal administration of oseltamivir (100mg/kg), procaine (86.6mg/kg) and bupropion (86.7mg/kg) lowered the core body temperature of normal mice. At lower doses (10-30mg/kg oseltamivir, 8.7-26mg/kg procaine and bupropion), when administered subcutaneously, the three drugs antagonized the hypothermia induced by intraperitoneal injection of nicotine (1mg/kg). In anesthetized rats, intravenous oseltamivir (30-100mg/kg), procaine (10mg/kg) and bupropion (10mg/kg) induced hypotension and bradycardia. Oseltamivir alone (100mg/kg) did not inhibit neuromuscular twitch contraction of rats, but at 3-30mg/kg it augmented the muscle-relaxing effect of d-tubocurarine. Similar effects were observed when lower doses of procaine (10-30mg/kg) and bupropion (3-10mg/kg) were administered, suggesting that systemic administration of oseltamivir inhibits muscular nicotinic acetylcholine receptors. These results support the idea that the hypothermic effect of oseltamivir is due to its effects on sympathetic ganglia which innervate the brown adipose tissue, and suggest that oseltamivir may exert non-selective ion channel blocking effects like those of ester-type local anesthetics.
authors.affiliation: Laboratory of Clinical Pharmacy and Pharmacology, Faculty of Pharmacy and Research Institute of Pharmaceutical Sciences, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo 202-8585, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Fukushima
authors.affiliation: Laboratory of CNS Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Chazono
authors.affiliation: Laboratory of CNS Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hashimoto
authors.affiliation: Laboratory of CNS Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan.
authors.forename: Yui
authors.initials: Y
authors.lastname: Iwajima
authors.affiliation: Laboratory of CNS Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan.
authors.forename: Shohei
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Laboratory of Hospital Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Maeda
authors.affiliation: Laboratory of CNS Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ohsawa
authors.affiliation: Laboratory of Clinical Pharmacy and Pharmacology, Faculty of Pharmacy and Research Institute of Pharmaceutical Sciences, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo 202-8585, Japan. Electronic address: hi_ono@musashino-u.ac.jp.
authors.forename: Hideki
authors.initials: H
authors.lastname: Ono
mesh_terms: D000818:Animals; D001919:Bradycardia / Q000139:chemically induced; D016642:Bupropion / Q000494:pharmacology*; D004357:Drug Synergism; D005334:Fever / Q000139:chemically induced*; D007022:Hypotension / Q000139:chemically induced; D008297:Male; D051379:Mice; D009126:Muscle Relaxation / Q000187:drug effects; D009465:Neuromuscular Agents / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D053139:Oseltamivir / Q000494:pharmacology*; D011343:Procaine / Q000494:pharmacology*; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*
chemical_list: D009465:Neuromuscular Agents; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D016642:Bupropion; D053139:Oseltamivir; D011343:Procaine
keywords: Bupropion; Hypothermia; Neuromuscular junction; Nicotinic acetylcholine receptor; Oseltamivir; Procaine