title: Pharmacological evaluation of garenoxacin, a novel des-F(6)-quinolone antimicrobial agent: effects on the central nervous system.
abstract: The effects of garenoxacin (formerly T-3811 or BMS-284756) on the central nervous system (CNS) were compared with various quinolones. Garenoxacin injected intracerebroventricularly into mice caused clonic convulsion at a higher dose (50 micrograms/body) than norfloxacin, ciprofloxacin, sitafloxacin and trovafloxacin. Additionally the convulsant activity of garenoxacin was not potentiated by biphenylacetic acid (BPAA). Garenoxacin did not induce any convulsions at intravenous doses up to 60 mg/kg in combination with 200 mg/kg oral administration of fenbufen in mice, and its convulsant activity was weaker than those of enoxacin, norfloxacin, ciprofloxacin, alatrofloxacin and ofloxacin. In addition, convulsions were not induced by combination administration of garenoxacin (60 mg/kg, i.v.) and any of 9 kinds of nonsteroidal anti-inflammatory drugs (NSAIDs) or BPAA. In a rotarod test, which was performed in order to evaluate the drug-induced dizziness, coordinated locomotor activity of mice was suppressed by alatrofloxacin at an intravenous dose of 60 mg/kg, but not by garenoxacin, ciprofloxacin and norfloxacin at up to 60 mg/kg. In an in vitro study using rat brain synaptic membrane, garenoxacin had no inhibitory effect on GABA binding in the presence or absence of NSAIDs. In conclusion, the effects of garenoxacin on CNS were weaker than those of other quinolones in experimental animals, so it might possess a low potential for CNS adverse reactions such as convulsion and dizziness in clinical use.
authors.affiliation: Drug Safety Research Laboratory, Toyama Chemical Co., Ltd., Research Laboratories, 2-4-1 Simookui, Toyama 930-8508, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Nakamura
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Fukuda
authors.forename: Yukie
authors.initials: Y
authors.lastname: Morita
authors.forename: Keiji
authors.initials: K
authors.lastname: Soumi
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Kawamura
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage*; D002490:Central Nervous System / Q000187:drug effects*; D004347:Drug Interactions; D024841:Fluoroquinolones / Q000008:administration & dosage / Q000009:adverse effects*; D007275:Injections, Intravenous; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D023421:Models, Animal; D015363:Quinolones / Q000008:administration & dosage / Q000009:adverse effects*; D051381:Rats; D017208:Rats, Wistar; D018079:Receptors, GABA / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced*; D005680:gamma-Aminobutyric Acid / Q000187:drug effects / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D024841:Fluoroquinolones; D015363:Quinolones; D018079:Receptors, GABA; D005680:gamma-Aminobutyric Acid; C419689:garenoxacin