Smith R D, Brown B S, Maher R W, Matier W L
E.I. du Pont de Nemours and Co., Inc., DuPont Critical Care, Waukegan, IL 60085.
Epilepsia. 1989;30 Suppl 2:S15-21. doi: 10.1111/j.1528-1157.1989.tb05820.x.
ACC-9653, the disodium phosphate ester of 3-hydroxymethyl-5,5-diphenylhydantoin, is a prodrug of phenytoin with advantageous physicochemical properties. ACC-9653 is rapidly converted enzymatically to phenytoin in vivo. ACC-9653 and phenytoin sodium have equivalent anticonvulsant activity against seizures induced by maximal electroshock (MES) in mice following i.p., oral, or i.v. administration. The ED50 doses were 16 mg/kg for i.v. ACC-9653 and 8 mg/kg for i.v. phenytoin sodium. ACC-9653 and phenytoin sodium have similar antiarrhythmic activity against ouabain-induced ventricular tachycardia in anesthetized dogs. The total doses of ACC-9653 or phenytoin sodium necessary to convert the arrhythmia to a normal sinus rhythm were 24 +/- 6 and 14 +/- 3 mg/kg, respectively. Only phenytoin sodium displayed in vitro antiarrhythmic activity against strophanthidin-induced arrhythmias in guinea pig right atria. In anesthetized dogs, a high dose of ACC-9653 (31 mg/kg) was infused over 15, 20, and 30 min and the responses were compared to an equimolar dose of phenytoin sodium (21 mg/kg). The ACC-9653 and phenytoin sodium treatments produced similar marked reductions in diastolic blood pressure and contractile force (LVdP/dt). The maximum effects of each treatment occurred at the time of maximum phenytoin sodium levels. Acute toxicity studies of ACC-9653 and phenytoin sodium were carried out in mice, rats, rabbits, and dogs by i.v., i.m., and i.p. routes of administration. The systemic toxic signs of both agents were similar and occurred at approximately equivalent doses. Importantly, the local irritation of ACC-9653 was markedly less than phenytoin sodium following i.m. administration.(ABSTRACT TRUNCATED AT 250 WORDS)
ACC - 9653，即3 - 羟甲基 - 5,5 - 二苯基乙内酰脲的磷酸二钠酯，是苯妥英的前药，具有有利的物理化学性质。ACC - 9653在体内可被酶快速转化为苯妥英。ACC - 9653和苯妥英钠经腹腔注射、口服或静脉注射给药后，对小鼠最大电休克（MES）诱导的癫痫发作具有等效的抗惊厥活性。静脉注射ACC - 9653的半数有效剂量（ED50）为16mg/kg，静脉注射苯妥英钠的ED50为8mg/kg。ACC - 9653和苯妥英钠对麻醉犬哇巴因诱导的室性心动过速具有相似的抗心律失常活性。将心律失常转为正常窦性心律所需的ACC - 9653或苯妥英钠的总剂量分别为24±6mg/kg和14±3mg/kg。仅苯妥英钠在体外对豚鼠右心房毒毛花苷诱导的心律失常具有抗心律失常活性。在麻醉犬中，在15、20和30分钟内输注高剂量的ACC - 9653（31mg/kg），并将反应与等摩尔剂量的苯妥英钠（21mg/kg）进行比较。ACC - 9653和苯妥英钠治疗使舒张压和收缩力（左室内压变化率，LVdP/dt）显著降低的程度相似。每种治疗的最大效应出现在苯妥英钠水平最高时。通过静脉注射、肌肉注射和腹腔注射途径，在小鼠、大鼠、兔子和犬中进行了ACC - 9653和苯妥英钠的急性毒性研究。两种药物的全身毒性体征相似，且在大致等效的剂量下出现。重要的是，肌肉注射后ACC - 9653的局部刺激性明显小于苯妥英钠。（摘要截断于250字）
