Patel S, Chapman A G, Graham J L, Meldrum B S, Frey P
Department of Neurology, Institute of Psychiatry, Denmark Hill, London.
Epilepsy Res. 1990 Sep-Oct;7(1):3-10. doi: 10.1016/0920-1211(90)90049-2.
D-(-)4-(3-phosphonopropyl)piperazine-2-carboxylic acid (D-CPP) and its unsaturated analogue (D(-)(E)-4-(3-phosphonoprop-2-enyl) piperazine-2-carboxylic acid (D-CPPene) have been administered to DBA/2 mice (intracerebroventricularly, i.c.v., intraperitoneally, i.p., and orally, p.o.) and to photosensitive baboons, Papio papio (intravenously, i.v., and orally), and their effects on reflexly induced epileptic responses assessed. In DBA/2 mice the clonic phase of the seizure response to sound is suppressed by D-CPP with an ED50 of 5.5 micrograms/mouse, i.c.v.; 0.69 mg (2.75 mumol)/kg i.p. and 16.6 mg (65.8 mumol)/kg p.o. compared with, for D-CPPene, 2.2 micrograms/mouse i.c.v., 0.41 mg (1.54 mumol)/kg i.p. and 10.8 mg (40.2 mumol)/kg, p.o. In Papio papio myoclonic responses to stroboscopic stimulation are suppressed 24 and 48 h after D-CPP 32 mg (127 mumol)/kg p.o. Administration of D-CPPene 8-16 mg (30-60 mumol)/kg i.v. produces protection against myoclonic responses after 1-2 h, lasting for 48 h. Oral administration of D-CPPene 32-64 mg (119-239 mumol)/kg produces protection beginning after 4 h and sustained for 48 h. Measurements of plasma D-CPPene concentration show rapid clearance after i.v. injection and a low plasma concentration 1.5-5 h after oral administration. The prolonged anticonvulsant action of D-CPP and D-CPPene following oral administration suggests that these compounds merit evaluation as antiepileptic therapy in man.
已将D-(-)4-(3-膦酰基丙基)哌嗪-2-羧酸（D-CPP）及其不饱和类似物（D(-)(E)-4-(3-膦酰基丙-2-烯基)哌嗪-2-羧酸（D-CPPene）经脑室注射（i.c.v.）、腹腔注射（i.p.）和口服（p.o.）给予DBA/2小鼠，并经静脉注射（i.v.）和口服给予光敏狒狒（巴氏狒狒），并评估了它们对反射性诱发癫痫反应的影响。在DBA/2小鼠中，D-CPP对声音诱发癫痫反应的阵挛期有抑制作用，脑室注射时的半数有效剂量（ED50）为5.5微克/小鼠；腹腔注射为0.69毫克（2.75微摩尔）/千克，口服为16.6毫克（65.8微摩尔）/千克。相比之下，D-CPPene脑室注射时为2.2微克/小鼠，腹腔注射为0.41毫克（1.54微摩尔）/千克，口服为10.8毫克（40.2微摩尔）/千克。在巴氏狒狒中，口服32毫克（127微摩尔）/千克D-CPP后24小时和48小时，对频闪刺激的肌阵挛反应受到抑制。静脉注射8 - 16毫克（30 - 60微摩尔）/千克D-CPPene 1 - 2小时后可产生对肌阵挛反应的保护作用，持续48小时。口服32 - 64毫克（119 - 239微摩尔）/千克D-CPPene 4小时后开始产生保护作用，并持续48小时。血浆D-CPPene浓度测量显示，静脉注射后清除迅速，口服给药后1.5 - 5小时血浆浓度较低。口服给药后D-CPP和D-CPPene的抗惊厥作用持续时间延长，表明这些化合物值得作为人类抗癫痫治疗药物进行评估。
