Akio Ozaki

Improvement of cisplatin-induced emesis and delayed gastric emptying by KB-R6933, a novel 5-HT3 receptor antagonist

The effects of a novel 5-hydroxytryptamine3 (5-HT3) receptor antagonist, KB-R6933, 6-amino-5-chloro-1-isopropyl-2-(4-methyl-1-piperazinyl)-benzimidazole dimaleate, on emesis and delayed gastric emptying induced by cisplatin were assessed in experimental models. Prophylactic intravenous or oral treatment with KB-R6933 prolonged the latent period until the first emetic episode and decreased the number of emetic episodes induced by cisplatin in ferrets. KB-R6933 immediately inhibited the subsequent emesis when administered to the ferrets which exhibited established vomiting after administration of cisplatin. In rats treated with cisplatin, the gastric emptying rate was significantly reduced. KB-R6933 reversed the reduction of gastric emptying induced by cisplatin. These results suggest that KB-R6933 is an antiemetic agent, and could improve the cisplatin-induced delay of gastric emptying.

Effects of a new diphenylpiperazine calcium antagonist, KB-2796, on cerebral ischemic neuronal damage in rats

1. The effects of KB-2796, a new diphenylpiperazine calcium antagonist, on the mitochondrial dysfunction and energy metabolism deficits were examined in the ischemic rat brain. 2. KB-2796 (30 mg/kg, p.o.), administered 60 min prior to decapitation, improved the reduced respiratory activity of mitochondria obtained from rat brain 5 min after decapitative ischemia. 3. KB-2796 (30 mg/kg, p.o.), administered 60 min prior to ischemic insult, improved both the reductions in pyruvate and ATP and prevented increases in the lactate/pyruvate ratio induced by 30-min forebrain ischemia in rats with 4-vessel occlusion (4-VO). 4. The effect of KB-2796 on local cerebral glucose utilization (LCGU) was examined by a quantitative autoradiographic 2-[14C]deoxyglucose method in normal and 4-VO rats. 5. Postischemic LCGU measured 24 hr after reperfusion in the forebrain, in particular in the cortex, thalamus, geniculate body, hippocampus, caudate-putamen, nucleus accumbens, colliculus, and corpus callosum, was below the normal control value. 6. KB-2796 (1 mg/kg, i.v.), administered 1 min prior to the injection of 2-[14C]deoxyglucose, improved the reductions in LCGU that were produced by cerebral ischemia in the cortex, thalamus, geniculate body, caudate-putamen, nucleus accumbens and substantia nigra, but did not affect LCGU in normal rats. 7. These findings suggest that KB-2796 minimized the deficits in brain energy metabolism produced by ischemia; this agent may therefore be a valuable therapeutic drug in cerebrovascular-related disorders.