RP-HPLC法测定西尼地平有关物质

目的 建立西尼地平有关物质检测方法.方法 采用十八烷基硅烷键合硅胶柱,流动相为乙腈:0.025 mol·L-1磷酸二氢铵溶液:环己烷=60:39:1,柱温40℃,流速1.5 ml·min-1,检测波长为240 nm.结果 通过破坏性试验,用此条件检测,主峰和杂质峰均能很好的得到分离,不受干扰,专属性强,线性范围:1～...     

Ambulatory Blood Pressure Monitoring in Patients with Essential Hypertension Treated with a New Calcium Antagonist, Cilnidipine

Cilnidipine (FRC-8653), a new dihydropyridine calcium antagonist, was given to 14 hospitalized patients with essential hypertension, and 24-hour ambulatory blood pressure (BP) monitoring was performed. Once-daily administration of cilnidipine (5–20 mg) for 1–3 weeks decreased the 24-hour average BP significantly from 149 ± 4/88 ± 2 mmHg to 141 ± 3/82 ± 2 mmHg without any change in the pulse rate. The decrease in ambulatory BP by cilnidipine was evident during the daytime (156 ± 4/93 ± 2 mmHg to 143 ± 5/84 ± 2 mmHg, p > 0.01 for systolic BP and p > 0.01 for diastolic BP), while it was mild during nighttime (141 ± 4/80 ± 2 mmHg to 133 ± 4/76 ± 3 mmHg, p > 0.05 for systolic and ns for diastolic BP). The decrease in the ambulatory BP over the whole day and during the nighttime was significantly correlated with the basal ambulatory BP levels. When the subjects were divided into the high ambulatory BP (n = 7) and low ambulatory BP (n = 7) groups, the BP reduction by cilnidipine was evident throughout 24 hours in the high ambulatory BP group, while it was mild and significant only during daytime in the low ambulatory BP group. In summary, once-daily cilnidipine exerts a sufficient and prolonged reduction of BP without an increase in the pulse rate in patients with hypertension. The potency of cilnidipine to decrease ambulatory BP may depend on the basal ambulatory BP level. Cilnidipine is thus a useful antihypertensive drug that may not cause an excessive decrease in BP or a reflex tachycardia.     

Investigational calcium channel blockers for the treatment of hypertension

Introduction: Voltage-gated Ca²⁺ channels are the primary route of Ca²⁺ entry in vascular smooth muscle cells, playing a key role in the regulation of arterial tone and blood pressure. Since the 60´s, L-type Ca²⁺ channel blockers (CCBs) have been widely used for the treatment of hypertension.

Areas covered: T-type Ca²⁺ channels regulate vascular tone in small-resistance vessels and aldosterone secretion, and N-type channels expressed in sympathetic nerve terminals regulate the release of neurotransmitters. We performed a literature search in MEDLINE, PubMed and ClinicalTrials.gov to identify eligible studies published between January 2001 and March 2016 and reviewed the antihypertensive and renoprotective effects of four CCBs with different pharmacological profiles: azelnidipine (L-type), cilnidipine (L-/N-type) and benidipine and efonidipine (L-/T-type CCBs). Despite similar blood pressure lowering effects, L/N- and L/T-type CCBs, compared with L-type CCBs, decreased intraglomerular pressure, improved renal hemodynamics and provided a greater decrease in proteinuria even in patients already treated with renin-angiotensin-aldosterone inhibitors.

Expert opinion: Dual L/N- and L/T-type CCBs may exhibit therapeutic advantages over L-type blockers in hypertensive patients with chronic kidney disease. Because clinical trials supporting these advantages present important biases, further large-scale, long-term comparative trials are needed to confirm that these differences translate into improved clinical outcomes.     

The evaluation of the N-type channel blocking properties of cilnidipine and other voltage-dependent calcium antagonists

Sympathetic neurotransmission in tissues with intact sympathetic nerve arborization is extensively dependent on calcium influx via N-type calcium-channels. It was the objective of the present study to assess and compare the claimed sympatholytic effect of the 1,4-dihydropyridine compound cilnidipine with other voltage-dependent calcium-channel (VDCC) antagonists. We studied these compounds by means of three different models. In the rabbit isolated thoracic aorta, the alleged sympatholytic properties displayed by these compounds were evaluated in the noradrenaline spillover model. Additionally, the influence of cilnidipine on stimulation-induced constrictor responses was studied in the rat isolated tail artery (male Wistar rats, 250-300 g) in addition to its effect on noradrenaline-induced contractions. Finally, we studied the influence of cilnidipine and other calcium-channel blockers on stimulation-induced chronotropic responses, in order to address N- or L-type selectivity, in the pithed rat model (male Wistar rats, 260-320 g). Furthermore, we evaluated their effect on noradrenaline-induced tachycardia. In the isolated rabbit thoracic aorta preparation omega-conotoxin GVIA (0.1 microM) nearly abolished the sympathetic outflow caused by stimulation, whereas nifedipine (0.1 microM) and amlodipine (1 microM) did not influence the evoked noradrenaline release. Cilnidipine (1 microM) significantly attenuated the response by nearly 18% and mibefradil (1 microM) by c. 42%. The stimulation-induced constrictor response (prejunctional effect) in the rat isolated tail artery could be blocked by omega-conotoxin GVIA (0.5 and 1 microM). Cilnidipine (10 nm and 0.1 microM) significantly attenuated responses to stimulation by maximally 20%, whereas it did not influence the constrictor response to noradrenaline (postjunctional effect). The mean heart rate in the pithed rat model amounted to 309.3 +/- 3.6 beats/min (bpm). Electrical stimulation of the cardio-accelerator nerves (C7-Th1) resulted in an increase by 106.7 +/- 2.2 bpm. All antagonists studied, except for nifedipine, attenuated the chronotropic response to stimulation (P < 0.05). The rank order of sympatholytic efficacy was: omega-conotoxin GVIA (84.8%), mibefradil (75.1%), cilnidipine (43.0%) and amlodipine (34.8%). Noradrenaline (10 nmol/kg) increased the heart rate by 117.8 +/- 2.7 bpm. This chronotropic response was influenced equally well by the calcium-channels blockers as observed in the stimulation (prejunctional) experiment. In conclusion, the N-type channel blocking properties and thus sympatholytic effect of cilnidipine could be demonstrated in some (vascular) but not all (cardiac) models studied. At the level of the vasculature cilnidipine reduced the neurotransmitter release to electrical stimulation in both the noradrenaline spillover model and in the model of the rat isolated tail artery, respectively. For amlodipine and nifedipine no sympatholytic activity could be demonstrated. In the pithed rat model, we were unable to demonstrate a selective N-type blocking effect for the VDCC-antagonists.     

西尼地平的合成

以双烯酮为原料，分别与乙二醇单甲醚和肉桂醇进行酯化反应制得乙酰乙酸-2-甲氧基乙酯和乙酰乙酸肉桂酯，前者与间硝基苯甲醛缩合生成的2-（3-硝基亚苄基）乙酰乙酸2-甲氧基乙酸和后者的氨化产物3-氨基-2-丁烯酸肉桂酯再进行Hantzsch环化反应制得新型钙拮抗剂西尼地平。方法条件温和，反应总收率68.3%(以肉桂酯计）。     

Long-term blockade of L/N-type Ca2+ channels by cilnidipine ameliorates repolarization abnormality of the canine hypertrophied heart

Background and purpose:

The heart of the canine model of chronic atrioventricular block is known to have a ventricular electrical remodelling, which mimics the pathophysiology of long QT syndrome. Using this model, we explored a new pharmacological therapeutic strategy for the prevention of cardiac sudden death.

Experimental approach:

The L-type Ca²⁺ channel blocker amlodipine (2.5 mg·day⁻¹), L/N-type Ca²⁺ channel blocker cilnidipine (5 mg·day⁻¹), or the angiotensin II receptor blocker candesartan (12 mg·day⁻¹) was administered orally to the dogs with chronic atrioventricular block for 4 weeks. Electropharmacological assessments with the monophasic action potential (MAP) recordings and blood sample analyses were performed before and 4 weeks after the start of drug administration.

Key results:

Amlodipine and cilnidipine decreased the blood pressure, while candesartan hardly affected it. The QT interval, MAP duration and beat-to-beat variability of the ventricular repolarization period were shortened only in the cilnidipine group, but such effects were not observed in the amlodipine or candesartan group. Plasma concentrations of adrenaline, angiotensin II and aldosterone decreased in the cilnidipine group. In contrast, plasma concentrations of angiotensin II and aldosterone were elevated in the amlodipine group, whereas in the candesartan group an increase in plasma levels of angiotensin II and a decrease in noradrenaline and adrenaline concentrations were observed.

Conclusions and implications:

Long-term blockade of L/N-type Ca²⁺ channels ameliorated the ventricular electrical remodelling in the hypertrophied heart which causes the prolongation of the QT interval. This could provide a novel therapeutic strategy for the treatment of cardiovascular diseases.     

西尼地平的合成工艺改进

目的改进二氢吡啶类钙拮抗剂西尼地平的合成工艺。方法以肉桂醇为原料,经酯化、氨化和缩合-环合而得。结果所得产物结构经红外光谱、核磁共振氢谱及质谱确证,总收率57.3%。结论改进后的合成工艺简单、合理可行。     

国产西尼地平治疗原发性轻中度高血压的疗效和安全性

目的:评价西尼地平治疗原发性轻中度高血压的疗效和安全性.方法:采用随机、双盲、前瞻性平行对照试验,64例原发性轻中度高血压患者分为试验组和对照组各32例,两组分别口服西尼地平和氨氯地平5mg·d -1 ,4周时如血压未达到有效标准则两组都增加剂量至10mg·d -1 至8周结束.检测两组治疗前后的血压、心率、心电图和血、尿实验室检查的变化.结果:63例完成全部试验,治疗8周末,经ITT分析,试验组平均坐位收缩压和舒张压降低程度与对照组比较差异无显著性[收缩压降低(17.63±12.06)mmHg vs(21.18±13.67)mmHg,P=0.1695;舒张压降低(13.06±6.73)mmHg vs(15.67±6.80)mmHg,P=0.1564];对照组降压的总有效率为90.63%,试验组为90.63%,两组差异无显著性(P=0.427);两组患者不良事件发生率也差异无显著性.结论:国产西尼地平治疗轻中度高血压安全有效.     

西尼地平片治疗轻中度高血压的有效性和安全性

目的评价西尼地平治疗轻中度原发性高血压的有效性和安全性。方法用随机双盲对照试验设计,入选病人共48例,西尼地平(试验组)24例,氨氯地平(对照组)24例。结果与治疗前相比,治疗8周后试验组收缩压和舒张压分别下降19.26和14.68mmHg(P<0.01),对照组分别下降为18.22和12.91mmHg(P<0.01),均有统计学意义。试验组和对照组药物不良反应的例数分别为0和2例,2组比较无统计学差异(P>0.05),均无严重不良反应发生。结论西尼地平片每日服用1次,降低血压,安全有效。