Showa Yakuhin Kako Co., Ltd.

UMIN Clinical Trials Registry (UMIN-CTR) UMIN000011943.

Plasma levels, distribution, excretion and metabolism of acetaminophen (APAP) in rats in relation to age (3, 7 and 49 days old) and dose (10, 50 and 100 mg/kg) were studied.AUC and C_max obtained from plasma level in immature rats (3 and 7 days old) were higher than those in matured rats (49 days old), regardless of the dose.T_max was delayed relatively with an increase of the doses, and there was a marked tendency for the immature rats.Changes of distribution patterns in immature and matured rats, except the gastro-intestinal tract, were similar to that in plasma levels resp., and the elevation of tissue levels in immature rats were delayed in comparison with that of the matured rats.These findings were consistent with the results of the whole body autoradiog.In immature and matured rats, the recovery of APAP and conjugates in urine show no marked differences.However, the glucuronide/sulfate ratio of immature rats was higher than that of matured rats.The percentage of plasma protein binding showed on increase with the age of the rats.

Systemic and intracerebroventricular (i.c.v.) injections of lappaconitine (LA) produced a dose-dependent inhibition of the response to thermal stimulation in sham-operated mice as assayed by the tail-immersion test. After spinal transection, the antinociceptive potencies of s.c.- or i.c.v.-administered LA were markedly reduced. Antinociception induced by systemically administered LA was clearly reduced by pretreatment with 6-hydroxydopamine or 5,7-dihydroxytryptamine through the i.c.v. and intrathecal (i.t.) routes. When LA was administered by i.c.v.-injection, the LA-induced antinociception was reduced by pretreatment with timolol, a beta-adrenergic antagonist, and ketanserin, a 5-HT2 antagonist. Administration of LA by the i.t. route resulted in a significant antinociceptive activity, which was also reduced by pretreatment with phenoxybenzamine, an alpha-adrenergic antagonist, and mianserin, a 5-HT1 antagonist. The results of these studies suggest that the central noradrenergic and serotonergic systems may be involved in the antinociception of systemically administered LA, and these pathways are mediated by beta-adrenoceptors and 5-HT2 receptors in the brain and alpha-adrenoceptors and 5-HT1 receptors in the spinal cord.