异搏定防治流行性出血热初期急性肾功能衰竭的疗效观察

在综合疗法的基础上加用异搏定3～5天治疗流行性出血热(EHF)发热后期病人41例,在尿蛋白转阴、越期率,特别是越少尿期平明显优于对照组,但对 BUN 水平的影响与对照组无异,异搏定对防治 EHF 急性肾衰具有一定疗效。     

Physiological pharmacokinetics and pharmacodynamics of (+/-)-verapamil in female rats

Tissue distribution and pharmacodynamics of verapamil were evaluated during steady state intravenous (i.v.) infusion and after single dose intraperitoneal (i.p.) drug administration to female Sprague-Dawley rats. In one group of rats, verapamil was infused to a steady state concentration at which time animals were killed. Verapamil-induced decreases in mean arterial pressure (MAP) were monitored during infusion and correlated with concomitantly obtained plasma verapamil concentrations. Tissue (lung, liver, renal medulla, renal cortex, cardiac muscle, skeletal muscle, perirenal fat, brain stem, cerebral cortex, and cerebellum) and plasma samples were obtained immediately after animals were killed and verapamil and norverapamil concentrations determined. Another group of rats, after receiving i.p. verapamil, were killed at 1, 3, 5, 19, and 24 h. Elimination from each tissue evaluated was described by a first order process. Elimination half-life of verapamil was similar among plasma and tissues evaluated (1.5 to 2.2 h). The per cent verapamil not bound to plasma proteins was concentration-independent and similar between rats receiving i.p. (mean +/- S.D.) (2.28 +/- 0.72 per cent) and i.v. (2.08 +/- 0.03 per cent) verapamil. MAP and verapamil concentration in plasma (r = 0.75; p less than 0.01) and cardiac muscle (r = -0.82; p less than 0.01) were inversely correlated in a highly significant fashion during both i.v. and i.p. drug administrations. The tissue-to-plasma distribution ratio for verapamil and norverapamil was similar among animals receiving i.p. verapamil at all points of sampling, suggesting distribution equilibrium had been achieved. After steady state i.v. infusion, both verapamil and norverapamil tissue: plasma concentration ratios were greater than after i.p. administration. Higher tissue: plasma verapamil concentration ratios after i.v. administration than after i.p. administration suggest either only a pseudoequilibrium is attained after i.p. administration or that determinants of tissue distribution of racemic verapamil differ with different routes of drug administration. In these studies, MAP provided a reasonable pharmacodynamic marker for verapamil tissue and plasma concentrations.     

pH值对IFN-α2b、rIL-2、ADM合用维拉帕米对人肝癌细胞杀伤作用的影响

目的　观察培养液在 pH值为 6 .8、7.3、7.6条件下rIL - 2、IFN -α2b、ADM及合用维拉帕米对人肝癌细胞 74 0 4杀伤作用的影响。方法　MTT法于 96孔培养板上进行杀伤实验 ,测定培养液pH值分别为 6 .8、7.3、7.6状态下 ,rIL - 2、IFN -α2b、ADM、及与维拉帕米联合杀伤人肝癌细胞 70 4 0的差异。结果　pH值为 7.6状态下rIL - 2、IFN -α2b、ADM及合用维拉帕米杀伤效果最佳。pH值为 6 .8、7.3、7.6时 ,IFN -α2b都能增加ADM抗肿瘤作用 ,但pH值为 7.6时 ,IFN -α2b +ADM杀伤效果最佳。结论　在偏硷性环境下 ,rIL - 2、IFN -α2b、ADM及合用维拉帕米对肿瘤细胞杀伤效果最佳     

不同血管保存液对人桡动脉血管移植物的抗痉挛作用

目的 研究不同的血管保存液对人离体桡动脉痉挛的缓解与预防能力。方法 非体外循环冠状动脉旁路手术(OPCAB)19例患者,应用“无接触(No Touch)”外科技术获取自体桡动脉,保留未处理的远段0.8～1.5cm。应用血管环灌流技术(Organ Bath)比较不同保存液的抗痉挛作用和预防痉挛作用。结果 血管环灌流实验显示,在对痉挛状态桡动脉的舒张能力方面,PS、VG、DG、NG溶液均可以在10min内100％舒张血管,舒张曲线显示舒张能力依次为VG、DG、NG、PS,但差异无显著性(P>0.05),在预先浸泡处理桡动脉45～60min后,除对照组(Ringer's Solution)外,所有血管保存液均可以有效地预防离体桡动脉的痉挛,各组间差异无显著性(P>0.05)。结论 罂粟碱溶液、VG、DG、NG溶液均有较好的抗血管痉挛作用,单从抗血管痉挛角度考虑可以用作CABG手术中桡动脉的准备液。     

维拉帕米灌注治疗前列腺术后膀胱痉挛性疼痛的临床疗效观察

为探讨前列腺术后膀胱痉挛性疼痛的药物治疗效果，将２６例前列腺增生行耻骨上经膀胱前列腺摘除术后频繁发作膀胱逼尿肌无抑制性收缩导致膀胱痉挛性疼痛者，按随机抽样法分为两组，第１组１５例接受维拉帕米膀胱灌注治疗，第２组１１例作为对照，不用任何可能影响下尿中功能的药物。     

盐酸维拉帕米自乳化缓释片的研制及释药行为的探讨

目的：探索固体自乳化释放药系统，研制自乳化缓释片，考察体外释药行为。方法：以盐酸维拉帕米（Verpamil Hydrochloride,VH)为模型药物，以吐温80（Tween80），豆磷脂（sbpc)为乳化剂，以羟丙甲纤维素（HPMC），卡波普（carbopol)为骨架材料，制备自乳化缓释片。结果：以含吐温80和豆磷脂10％，羟丙甲纤维素和卡波普30％的处方乳化效果好，体外释药符合要求。结论：通过调节乳化剂和骨架材料的比例，可以获得理想的自乳化固体缓释制剂。     

Cytochromes of the P450 2C subfamily are the major enzymes involved in the O-demethylation of verapamil in humans

The calcium channel blocker verapamil [2,8-bis-(3,4-dimethoxyphenyl)-6-methyl-2-isopropyl-6-azaoctanitrile] undergoes extensive biotransformation in man. We have previously demonstrated cytochrome P450 (CYP) 3A4 and 1A2 to be the enzymes responsible for verapamil N-dealkylation (formation of D-617 [2-(3,4-dimethoxyphenyl)-5-methylamino-2-isopropylvaleronitrile]), and verapamil N-demethylation (formation of norverapamil [2,8-bis(3,4-dimethoxyphenyl)-2-isopropyl-6-azaoctanitrile]), while there was no involvement of CYP3A4 and CYP1A2 in the third initial metabolic step of verapamil, which is verapamil O-demethylation. This pathway yields formation of D-703 [2-(4-hydroxy-3-methoxyphenyl)-8-(3,4-dimethoxyphenyl)-6-methyl-2-isopropyl-6-azaoctanitrile] and D-702 [2-(3,4-dimethoxyphenyl)-8-(4-hydroxy-3-methoxyphenyl)6-methyl-2-isopropyl-6-azaoctanitrile]. The enzymes catalyzing verapamil O-demethylation have not been characterized so far. We have therefore identified and characterized the enzymes involved in verapamil O-demethylation in humans by using the following in vitro approaches: (I) characterization of O-demethylation kinetics in the presence of the microsomal fraction of human liver, (II) inhibition of verapamil O-demethylation by specific antibodies and selective inhibitors and (111) investigation of metabolite formation in microsomes obtained from yeast strain Saccharomyces cerevisiae W(R), that was genetically engineered for stable expression of human CYP2C8, 2C9 and 2C18.In human liver microsomes (n=4), the intrinsic clearance (CL_int), as derived from the ratio of V _max/K_m, was significantly higher for O-demethylation to D-703 compared to formation of D-702 following incubation with racemic verapamil (13.9±1.0 vs 2.4±0.6 ml^*min^{-1 *}g^-1 mean±SD; p<0.05), S-Verapamil (16.8±3.3 vs 2.2±1.2 ml^* mini^*g^-1, p<0.05) and R-verapamil (12.1±2.9 vs 3.6 ±1.3 ml^*min^{-1 *} g^-1; p<0.05), thus indicating regioselectivity of verapamil O-demethylation process. The CL_int of D-703 formation in human liver microsomes showed a modest but significant degree of stereo selectivity (p<0.05) with a S/R-ratio of 1.41±0.17. Anti-LKM2 (anti-liver/kidney microsome) autoantibodies (which inhibit CYP2C9 and 2C19) and sulfaphenazole (a specific CYP2C9 inhibitor) reduced the maximum rate of formation of D-703 by 81.5±4.5% and 45%, that of D-702 by 52.7±7.5% and 72.5%, respectively. Both D-703 and D-702 were formed by stably expressed CYP2C9 and CYP2C18, whereas incubation with CYP2C8 selectively yielded D-703.In conclusion, our results show that enzymes of the CYP2C subfamily are mainly involved in verapamil O-demethylation. Verapamil therefore has the potential to interact with other drugs which inhibit or induce these enzymes.     

Effect of peripheral administration of cinnarizine and verapamil on the abstinence syndrome in diazepam-dependent rats

The effects of two calcium channel blockers (verapamil and cinnarizine) were evaluated on diazepam withdrawal symptoms. Rats were made diazepam dependent by chronic treatment with daily injections of the drug, 20 mg/kg IP for 3 weeks. On abrupt termination of the drug, animals showed withdrawal hyperactivity that was assessed by autonomic, behavioural and motor signs. The peak effect was seen 3 days after the withdrawal of diazepam. On IP administration, verapamil and cinnarizine (10, 20 and 40 mg/kg) given on eight occasions at an interval of 12 h reversed the withdrawal-induced increase in spontaneous motor activity. Cinnarizine in higher doses (20 and 40 mg/kg) was found to be effective in suppressing the behavioural signs but verapamil did not show any protective effect against startle response and irritability. These results suggest that modulation of the calcium influx in the CNS might influence withdrawal.This study was presented in XIth International Congress of Pharmacology (IUPHAR) at Amsterdam (July 1–6, 1990)     

十名志愿者口服维拉帕米缓释片药代动力学和心电图研究

对10名男性受试者单剂量po240mgVer缓释片药代动力学及心电图变化进行研究。血药浓度—时间数据用零级吸收过程的一室模型拟合,其药代动力学参数:T_max5.9±1.6h;C_max118.9±37.2μg·L^-1;T₁ 5.4±1.5h;k₀30.5±17.5μg·L^-1·h^-1;T_1/210.8±4.9h。PR间期延长有显著意义,血药浓度与PR间期变化满足S 型模型,其药效学参数:EC₅₀ 64.6±16.9μg·L^-1; E_max54±11ms;s 1.68±0.66。     

异搏定对5-氟脲嘧啶抗肾癌效应的体外增效作用

在体外培养的肾透明细胞癌系中,观察了异搏定(Verapamil,VP)对5-氟脲嘧啶(Fluorouracil,5-Fu)细胞毒作用的影响。结果表明,异搏定在本身无细胞毒性的浓度下,可以显著增强5-氟脲嘧啶的细胞毒性,且增效作用随5-氟脲嘧啶浓度及异搏定浓度的增加及用药时间的延长而增强。