人肝微粒体中西尼地平及其代谢物的HPLC测定法及代谢动力学

目的　建立人肝微粒体中西尼地平及其脱氢代谢物的 HPLC测定法 ,并用本法研究西尼地平在人肝微粒体中代谢的动力学。方法　色谱柱为 Hypersil C1 8柱 (2 5 0 mm× 4.6mm ID,5μm) ,流动相为乙腈 -甲醇 -0 .0 1 mol/ L四丁基溴化铵溶液 (5 5∶ 5∶ 40 ,V/ V/ V) ,柱温 5 0℃ ,检测波长 UV 2 3 8nm,样品用乙醚 -正己烷 (1∶ 1 ,V/ V)提取。用人肝微粒体研究西尼地平的代谢。结果　本法的回收率为 90 .62 %～ 1 0 9.90 % ,西尼地平和其脱氢代谢物的日间、日内 RSD分别为 4.70 %～ 8.3 5 %和 3 .88%～ 8.1 1 % ,西尼地平及其脱氢代谢物的浓度分别在 0 .77μg/ ml～ 98.2 4μg/ ml和 0 .1 3 μg/ ml～ 5 .3 6μg/ ml范围内与峰面积呈良好的线性相关性。在温孵时间为1 0～ 60 min,微粒体蛋白浓度为 1 mg/ ml时 ,西尼地平呈线性消除 ,而其脱氢代谢物呈线性增加。结论　西尼地平在人肝微粒体内被迅速代谢 ,人肝 P45 0酶参与了西尼地平的脱氢氧化     

动态血压监测评价西尼地平治疗原发性高血压的疗效

目的 应用动态血压监测(ABPM) 的方法评价西尼地平胶囊治疗原发性高血压的疗效. 方法 采用开放的方法, 22 例原发性高血压患者经2周洗脱期, 服用西尼地平胶囊5 mg, qd, 2 周末坐位舒张压(DBP) ≥90 mmHg 者加量至10 mg, qd, 继续服用6周. 于洗脱期末及治疗8周末各行ABPM 和实验室检查1次. 结果 ABPM 显示8 周末24 h 平均血压、日间平均血压、夜间平均血压、白昼平均收缩压（SBP）负荷、夜间平均DBP负荷均比治疗前明显降低, 差异有显著性或极显著性( P<0.05或P<0.01). 降低SBP和DBP谷峰比分别为0.61和0.50. 不良反应发生率低. 结论 西尼地平胶囊每天5～10 mg治疗原发性高血压安全有效.     

西尼地平和氨氯地平降压有效性和安全性比较

目的　评价西尼地平和氨氯地平降压的疗效和安全性。方法　采用随机双盲双模拟研究方法。西尼地平组 (A组 ) 2 7例 ,氨氯地平组 (B组 ) 2 7例。起始剂量为 5mg ,活性药物治疗 4周后未达到有效标准则药物剂量加倍继续治疗 4周 ,有效者原药量继续服用 4周。总疗程为 8周。结果　两组患者治疗 4周和 8周血压均比用药前下降 (P <0 .0 5 )。A、B两组总有效率分别为 85 .1 9%和 88.89%。两组间总有效率无显著性差异 (P >0 .0 5 )。A、B两组不良反应发生率分别为 1 1 .1 1 %和 1 4 .81 % ,试验过程中不良反应均能耐受 ,无一例退出试验。结论　西尼地平和氨氯地平均是治疗轻、中度高血压的有效药物 ,药物不良反应少     

Influence of cilnidipine or nisoldipine on sympathetic activity in healthy male subjects

The aim of this study was to investigate whether cilnidipine, an N- and L-type calcium channel blocker, and nisoldipine, an L-type calcium channel blocker, have different effects on sympathetic activity, using an identical group of healthy male subjects. Eight healthy men (22–28 years) were given 10 mg of cilnidipine or 10 mg of nisoldipine in a randomized crossover design. In each trial, in subjects without medication on day 1 (control) and with medication on day 2, we measured heart rate (HR), low frequency (LF)/high frequency (HF) of HR variability, and plasma noradrenaline (NA) in a resting supine position and during head-up tilt, and palmar sweating during a mental arithmetic test, before and at 1, 2, 4, 6, and 8 h after administration. Time-plasma concentration profiles of the two drugs were similar. Measurements in controls on the two days showed no significant difference in any of these parameters. Nisoldipine, but not cilnidipine, slightly increased HR and LF/HF at rest. Head-up tilt increased HR, LF/HF, and plasma NA. As evaluated with repeated-measures analysis of variance, head-up tilt induced a significant increase in LF/HF, but not HR or plasma NA, and the effect of cilnidipine was significantly less than that of nisoldipine (P = 0.017). Postural hypotension was not observed. There was no difference in mental arithmetic-induced sweating between the two drugs. Cilnidipine, but not nisoldipine, might have a weak inhibitory effect on reflex sympathetic activity.     

HPLC法测定西尼地平及其片剂的含量

目的 建立起西尼地平有关物质检查及其片剂含量测定的RP-HPLC方法。方法 色谱柱：ShimpackODS柱，流动相：甲醇-0.03mol/L磷酸二氢钾水溶液（pH=3.5,81:19)，检测波长：240nm，流速：1.0ml/min。结果 西尼地平与有关物质完全分离。西尼地平在1.6-300μg/mL范围内，峰面积与浓度线性关系良好，r=0.9999。平均回收率；99.78%(n=9),RSD=0.5%。结论 可用于西尼地平的有关物质检查及其片剂的含量测定。     

西尼地平治疗轻、中度原发性高血压临床疗效及安全性观察

目的 :评价西尼地平治疗高血压的有效性和安全性。方法 :16例原发性轻、中度高血压患者入组本研究 ,应用西尼地平治疗 2 4wk。西尼地平起始剂量为 5mg,1日 1次 ,1mo后根据舒张压情况可将西尼地平剂量调整至 10mg,1日 1次。结果 :与治疗前相比 ,收缩压和舒张压的下降均具有显著性差异。 2 4wk时收缩压和舒张压分别下降了 13.38mmHg和 12 75mmHg。心率无改变。不良反应轻微。结论 :西尼地平是新型第三代双通道二氢吡啶类钙通道阻滞剂 ,在治疗轻、中度高血压过程中安全有效 ,不良反应轻微 ,患者能很好耐受。     

Antinociceptive effect of cilnidipine, a novel N-type calcium channel antagonist

We investigated the antinociceptic effects of cilnidipine, a dihydropyridine derivative which acts on both L- and N-type voltage-dependent calcium channels, in mice. Intrathecally injected cilnidipine showed significant analgesic effect in formalin test. Cilnidipine significantly suppressed N-type currents in dorsal root ganglion (DRG) cells. Our findings apparently support the idea that cilnidipine attenuates synaptic neurotransmission by inhibiting N-type calcium channels in DRG neurons.     

Preferential inhibition of L- and N-type calcium channels in the rat hippocampal neurons by cilnidipine

The effect of a dihydropyridine Ca²⁺ antagonist, cilnidipine, on voltage-dependent Ca²⁺ channels was studied in acutely dissociated rat CA1 pyramidal neurons using the nystatin-perforated patch recording configuration under voltage-clamp conditions. Cilnidipine had no effect on low-voltage-activated (LVA) Ca²⁺ channels at the low concentrations under 10⁻⁶ M. On the other hand, cilnidipine inhibited the high-voltage-activated (HVA) Ca²⁺ current (I_Ca) in a concentration-dependent manner and the inhibition curve showed a step-wise pattern; cilnidipine selectively reduced only L-type HVA I_Ca at the low concentrations under 10⁻⁷ and 10⁻⁶ M cilnidipine blocked not only L- but also N-type HVA I_Ca. At the high concentration over 10⁻⁶ M cilnidipine non-selectively blocked the T-type LVA and P/Q- and R-type HVA Ca²⁺ channels. This is the first report that cilnidipine at lower concentration of 10⁻⁶ M blocks both L- and N-type HVA I_Ca in the hippocampal neurons.     

Inhibitory effects of cilnidipine on peripheral and brain N-type Ca2+ channels expressed in BHK cells

We investigated differences in electrophysiological characteristics between peripheral and central N-type Ca²⁺ channels, containing _1B-a and a_1B-c, respectively. In addition, we examined the inhibitory effects of cilnidipine, a dihydropyridine (DHP) derivative, on both channels. Both _1B subunits were transiently expressed in BHK cells, and then analyzed using the whole-cell patch-clamp technique. The current–voltage relationship showed that _1B-c currents were activated at more negative potentials than _1B-a currents. The voltage-dependent steady-state inactivation and activation showed that the V_1/2 values for inactivation and activation of _1B-c (−88.5±1.3 and −33.2±1.3 mV) were both significantly more negative than those for _1B-a (−83.3±1.3 and −27.9±2.3 mV). Despite the different electrophysiological characteristics of these two N-type channels, cilnidipine blocked both with similar potency within the range 0.1 to 10 μM. Furthermore, cilnidipine had no effect on the I–V relationships or the steady-state inactivation curves. Our data indicate that the spliced positions of _1B-a and a_1B-c may affect not only their voltage-sensing abilities but also the kinetics of channel activation and inactivation. The data also suggest that cilnidipine binds to sites independent of those controlling voltage-sensing and channel kinetics in these _1B subunits.     

西尼地平片剂的工艺研究

通过对西尼地平片不同处方工艺的比较研究,以片面外观、硬度、崩解时间及溶出度作为主要考察指标,确定了其最佳工艺。