Tantisira B, Tantisira M H, Patarapanich C, Sooksawate T, Chunngam T
Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand.
Res Commun Mol Pathol Pharmacol. 1997 Aug;97(2):151-64.
Anticonvulsant activity, lethality and neurotoxicity of a valproic acid (VPA) analog, N-(2-propylpentanoyl) urea (VPU) in comparison to its parent compound were investigated in mice. Intraperitoneally administered VPU demonstrated a higher protection than VPA in both the maximal electroshock seizure (MES) and the pentylenetetrazole (PTZ) tests exhibiting a median effective dose (ED50) of 66 and 57 mg/kg, respectively. VPU weakly blocked the effect of bicuculline and was ineffective in strychnine test. Furthermore, VPU was also active orally demonstrating an ED50 approximately 6 times higher than its ED50 by the intraperitoneal route. Based on the relatively high median lethal dose (LD50), 1553 mg/kg, VPU possesses a greater margin of safety (LD50/ED50) than did VPA. Unwanted (side) effects in terms of impairment of motor activity and neurotoxicity were assessed by the rotorod test, locomotor activity test as well as potentiation of barbiturate sleeping time. The median neurotoxic dose (TD50) as measured by rotorod test were 625 mg/kg for intraperitoneally given VPU. This finding results in higher protective index (PI = TD50/ED50) of VPU (PI = 9.5) than that of VPA (PI = 1.1) implying that, in therapeutic dose, VPU may produce less neurological side effects than did VPA. Superiority of VPU in terms of higher potency in parallel with minimal neurological deficit as assessed by rotorod test was evident throughout the observation period of 12 hours. Similar results on locomotor activity as well as potentiation of barbiturate sleeping time were obtained with VPU and VPA. Thus, VPU is preferably expected to exert minor degree of CNS depression. Taken altogether, our findings demonstrate greater anticovulsant activity for VPU than for VPA. In addition, this compound is also orally active and seems to offer a greater safety margin in parallel with lower unwanted effects in relation to its parent compound. As indicated by the animal data obtained, VPU is an attractive anticonvulsant candidate for further investigation.
在小鼠中研究了丙戊酸（VPA）类似物N-（2-丙基戊酰基）脲（VPU）与其母体化合物相比的抗惊厥活性、致死性和神经毒性。腹腔注射VPU在最大电休克惊厥（MES）和戊四氮（PTZ）试验中均表现出比VPA更高的保护作用，其半数有效剂量（ED50）分别为66和57mg/kg。VPU对荷包牡丹碱的作用有微弱阻断作用，在士的宁试验中无效。此外，VPU口服也有活性，其ED50比腹腔注射途径高约6倍。基于相对较高的半数致死剂量（LD50），即1553mg/kg，VPU比VPA具有更大的安全范围（LD50/ED50）。通过转棒试验、自发活动试验以及巴比妥类睡眠时间延长试验评估了VPU在运动活动受损和神经毒性方面的不良（副作用）效应。通过转棒试验测得腹腔注射VPU的半数神经毒性剂量（TD50）为625mg/kg。这一发现导致VPU的保护指数（PI = TD50/ED50）（PI = 9.5）高于VPA（PI = 1.1），这意味着在治疗剂量下，VPU可能比VPA产生更少的神经副作用。在12小时的观察期内，通过转棒试验评估，VPU在效力更高且神经功能缺损最小方面的优势明显。VPU和VPA在自发活动以及巴比妥类睡眠时间延长方面得到了类似的结果。因此，预计VPU引起的中枢神经系统抑制程度较轻。综上所述，我们的研究结果表明VPU比VPA具有更强的抗惊厥活性。此外，该化合物口服也有活性，并且与其母体化合物相比，似乎具有更大的安全范围以及更低的不良效应。正如所获得的动物数据所示，VPU是一个有吸引力的抗惊厥候选物，有待进一步研究。
