Flumazenil but not nitrendipine reverses the increased anxiety during ethanol withdrawal in the rat

After 7 day's gradual introduction of ethanol, rats were maintained for a further 4 weeks on a liquid diet containing 10% ethanol (mean daily dose 11.8±0.2 g/kg/day). Control-treated rats received liquid diet alone. Pairs of rats were tested in the social interaction test of anxiety 8 h after withdrawal. Withdrawal from ethanol significantly reduced the time spent in social interaction compared with controls, indicating an anxiogenic withdrawal response. Nitrendipine (50 mg/kg) had no effect on, whereas flumazenil (4 mg/kg) significantly reversed, this withdrawal response. This reversal appeared to be long-lasting as there was still no evidence of increased anxiety when rats were again withdrawn after 3 more days of ethanol diet.     

卡托普利和尼群地平小量联用治疗高血压病

目的　观察卡托普利和尼群地平小量联合用药治疗高血压病的疗效。方法　卡托普利和尼群地平小量联合用药。结果　卡托普利和尼群地平小量联和 ,治疗高血压病总有效率 90 .9% ,单用卡托普利总有效率 63.6% ,单用尼群地平总有效率 62 .5%。卡方检验 ,单一用药与联合用药相比 ,χ2 分别为 4 .59和 4 .16,P<0 .0 5。结论　两药联合用药疗效确切 ,副作用减小 ,可推广使用     

复方尼群洛尔片治疗轻中度原发性高血压的疗效和安全性及剂量配比

目的验证复方尼群洛尔片的有效性和安全性,探讨尼群地平和阿替洛尔的最佳剂量配比。方法2005年2月至7月将上海、南京、苏州7家医院入选275例原发性高血压患者以等比例随机分成3个不同剂量配比的复方尼群洛尔组[每片分别含尼群地平、阿替洛尔：5mg、12．5mg（复方一组）,5mg、10mg（复方二组）,5mg、7．5mg（复方三组）]、单用尼群地平（10mr,／片）组及阿替洛尔（25mg／片）组共5组,进行为期8周治疗。结果治疗8周后5组舒张压的下降值分别为（17±7）、（18±9）、（17±7）、（13±7）和（12±6）mmHg（1mmHg=0．133kPa）。3种不同剂量组合复方组舒张压下降幅度均大于任一单药组。复方一组、复方二组、复方三组、尼群地平组和阿替洛组收缩压的下降值分别为（21±11）、（24±12）、（23±11）、（19±13）和（18±9）mmHg,组间比较,复方二组收缩压下降大于阿替洛尔组。5组的降压总有效率分别为94．4％、98．1％、88．2％、78．4％和71．4％,不同剂量复方组与阿替洛尔组比较,降压疗效的差异有统计学意义（P〈0．01）。第5周时增加剂量比例的组间比较,复方二组低于其他4组。不良反应多数轻微,无需特殊处理,实验室检查无明显改变。结论复方尼群洛尔片治疗轻、中度原发性高血压安全、有效,耐受性好,剂量组合以尼群地平5mg和阿替洛尔10mg为佳。     

临床常用尼群地平片在大鼠体内药代动力学比较研究

目的:研究大鼠灌胃不同厂家尼群地平片后体内药代动力学的一致性.方法:固体灌胃给予SD雄性大鼠尼群地平50 mg/kg,用液质联用的方法测定不同时间的血药浓度,用DAS 3.0数据处理系统对测得的血药浓度数据进行药代动力学参数的计算.结果:三个原料药生产厂家的测定结果显示,晶Ⅳ型尼群地平原料药较常用晶型即晶Ⅰ型有着更好的药物吸收和相对生物利用度,为优势药物晶型;随机抽取的临床常用的16个不同厂家尼群地平产品的大鼠体内药代动力学参数结果呈现差异性,Cmax、tmax、t1-2、AUC(0-t)四个主要参数的最大差异分别可以达到2.5、24.4、4.5和1.6倍之多.结论:不同厂家的尼群地平片在大鼠体内的药代动力学过程存在显著差异,化合物的晶型状态是导致差异的一个重要因素.     

Post-hypoxic changes in rat cortical neuron GABA A receptor function require L-type voltage-gated calcium channel activation

Hypoxia modifies GABA_A receptor (GABA_AR) function and can cause seizures, encephalopathy or myoclonus. To characterize the effects of hypoxia on neuronal GABA_ARs, we subjected rat cortical neurons to 1% O₂ for 2, 4 or 8 h, followed by recovery times of 0-96 h, and used whole-cell and perforated patch-clamp recording to assess GABA_AR currents and pharmacology. Hypoxic exposure for 4 h caused downregulation of maximal GABA current immediately following hypoxia and after 48 h recovery without changing the EC₅₀ for GABA. Two- and eight-hour hypoxic exposures had inconsistent effects on GABA_AR currents. Maximal diazepam potentiation was increased immediately following 4 h hypoxia, while potentiation by zolpidem was increased after 48 h recovery. Pentobarbital enhancement and zinc inhibition of GABA currents were unchanged. Hypoxia also caused a depolarizing shift in the reversal potential of GABA-induced Cl⁻ currents after 24 h recovery. The L-type voltage-gated calcium channel (L-VGCC) blocker, nitrendipine, during hypoxia or control treatment prevented the reduction in GABA_AR currents, and increased control currents over baseline. Nitrendipine also prevented the increase in zolpidem potentiation 48 h after hypoxia, and blocked the depolarizing shift in Cl⁻ reversal potential 24 h after hypoxia. The effects of hypoxia on maximal GABA_AR currents, zolpidem pharmacology and Cl⁻ reversal potential thus require depolarization-induced calcium entry via L-VGCCs, and constitutive L-VGCC activity appears to reduce maximal GABA_AR currents in control neurons via a calcium-dependent process. Calcium-dependent modulation of GABA_AR currents via L-VGCCs may be a fundamental regulatory mechanism for GABA receptor function.     

尼群地平缓释微丸的制备及体外释放影响因素考察

目的:对影响尼群地平缓释微丸中药物体外释放的制备工艺因素进行考察。方法:采用挤出滚圆法制备尼群地平缓释微丸,通过体外释放度试验,对影响缓释微丸中药物释放的润湿剂乙醇浓度及用量、挤出速度、滚圆转速及滚圆时间等因素进行考察,优化制备工艺条件。结果:润湿剂用量及乙醇浓度对药物体外释放影响显著,乙醇浓度应在35%以下,用量宜控制在44mL左右。挤出速度、滚圆转速及滚圆时间等对药物体外释放有一定的影响,分别以48r.min-1、1400r.min-1、5min为宜。结论:采用上述制备工艺,可制得释药速度符合要求的尼群地平缓释微丸。     

钙通道阻滞剂及L－精氨酸对肺动脉高压的影响

采用常压间竭低氧模型，观察了钙通道拮抗剂尼群地平（Ｎｉｔ）、硝苯吡啶（Ｎｉｆ）、内皮依赖性血管舒张因子（ＥＤＲＦ）合成前体Ｌ－精氨酸（Ｌ－Ａ）对大鼠慢性低氧性肺动脉高压的预防作用。结果提示：三者均能预防低氧性肺动脉高压形成和减轻低氧引起的右室肥大；Ｎｉｔ、Ｎｉｆ与Ｌ－Ａ比较无显著性差异（Ｐ＞０．０５）；Ｎｉｔ对低氧性肺动脉高压的降压作用较Ｎｉｆ稍好。     

尼群地平胶囊剂的研制

采用球磨混合粉碎法工艺进行处方设计,试制出尼群地平胶囊剂。将国产片剂(南京制药厂)、自制胶囊剂与西德Bayer公司片剂进行体外溶出、体内血浓测定比较,体内血浆药浓用GC-MS法测定,体内数据按零级溶出、一级吸收口服单室模型经计算机处理求得药动学参数。研制的尼群地平胶囊剂与西德Bayer公司片剂生物等效。     

Acute haemodynamic effects of i.v. nitrendipine in healthy subjects

Summary The haemodynamic effects of an i.v. infusion of 2 mg nitrendipine have been studied in six healthy volunteers.Nitrendipine significantly decreased the systolic (–8.3%) diastolic (–19.9%) and mean arterial (–11.6%) blood pressures and the peripheral vascular resistance (–57.8%), and significantly increased leg blood flow (+128%).Stroke volume did not change. Due to the increase in heart rate (+28.5%), the cardiac output (2.8.2%) rose significantly. The haemodynamic effects were closely related to the serum nitrendipine concentration. The sigmoidal E_max-model was appropriate to describe the data.Pronounced interindividual differences in the serum nitrendipine concentrations required to elicit 50% of the maximum haemodynamic effect (EC₅₀) were observed. The EC₅₀ for the increase in leg blood flow ranged from 2.9 to 30.9 ng/ml and for the reduction in peripheral vascular resistance from 2.1 to 25.7 ng/ml. Interindividual differences in EC₅₀ values were less pronounced if based on unbound serum nitrendipine levels.The fraction of nitrendipine not bound to serum proteins showed a three-fold difference between subjects, with free fractions ranging from 0.011 to 0.036. The unbound EC₅₀ values for the increase in leg blood flow varied between 0.06 and 0.44 ng/ml and for the reduction in peripheral vascular resistance from 0.07 to 0.35 ng/ml.Based on the serum concentrations associated with comparable haemodynamic effects nitrendipine was at least three-times more potent than nifedipine.     

尼群地平固体分散体微丸稳定性的初步研究

目的考察尼群地平固体分散体微丸的稳定性。方法通过影响因素试验和加速试验,考察尼群地平固体分散体微丸的外观,药物和有关物质的含量,以及药物溶出速度（T80）的变化。结果该固体分散体微丸对温度和湿度稳定,对光不稳定,模拟上市包装后稳定性良好。结论尼群地平固体分散体微丸经包装后稳定性较好。