阿折地平片工艺验证

目的通过本试验来验证阿折地平片中试工艺的可行性、可靠性。方法采用同步验证法,包括多种测试手段,对阿折地平片中试工艺各步骤进行验证。结果验证批次的阿折地平片各项指标符合质量标准要求。结论阿折地平片中试工艺生产可行,工艺流程及工艺参数能够保证产品质量;工艺可靠、稳定。     

阿折地平的合成

目的：合成阿折地平。方法：以二苯基甲胺为原料,经加成、酯化、酸化、氨化、缩合等反应合成阿折地平。结果：经元素分析、Ms,IR,NMR等测试确定了化学结构,总收率21％。结论：本方法原料易得,便于工业化生产。     

阿折地平的合成工艺改进

目的 改进抗高血压药物阿折地平的合成工艺。方法 以二苯甲胺和环氧氯丙烷为起始原料,经取代,酯化, 酸化,缩合等反应制得抗高血压药物阿折地平。结果与结论 目标化合物的结构经¹H-NMR、质谱确证。总收率为30.88%,比文献收率提高了10.62%。改进后的方法操作简便,有利于工业化生产。     

LC-MS/MS法测定人血浆中阿折地平的浓度

目的:建立测定人血浆中阿折地平浓度的方法。方法:人血浆样本经乙腈沉淀蛋白后采用液相色谱-串联质谱(LC-MS/MS)法进样测定,色谱柱为Zorbax Eclipse XDB-C18,流动相为甲醇-10 mmol/L乙酸铵(含1%甲酸)(80∶20,V/V)。选用多重反应监测扫描方式进行质谱监测,监测离子反应分别为m/z 583.3→167.1(阿折地平)、m/z 285.1→154.0(内标地西泮)。结果:阿折地平的血药浓度在0.05~40 ng/ml范围内线性关系良好,定量下限为0.05 ng/ml。日内、日间RSD分别为3.01%~7.75%,0.99%~12.08%;平均提取回收率为110.20%~111.99%。结论:该方法简便、快速、灵敏、专属性强、重现性好,适用于人血浆中阿折地平浓度的测定。     

HPLC测定阿折地平及其制剂的含量和有关物质

目的测定阿折地平、阿折地平片及胶囊的含量和有关物质。方法采用HPLC法,用D iamonsilTMC18色谱柱(250 mm×4.6 mm,5μm);流动相为乙腈-10 mmol.L-1磷酸二氢铵溶液(三乙胺调pH6.5)(82:18);流速1.0 m l.m in-1;检测波长254nm;柱温30℃;进样20μl。结果阿折地平与其相邻杂质峰能完全分离;在16.84~336.80μg.m l-1范围内,其线性关系良好(r2=0.9999)。结论所用方法简便、准确、专属性好,可作为阿折地平及其片剂和胶囊剂的含量测定及有关物质的检查。     

阿折地平片在健康人体内的药动学研究

目的:建立测定人血浆中阿折地平浓度的方法,并进行人体药动学研究。方法:20名健康受试者随机分成2组,分别单剂量口服阿折地平片8mg和16mg,8mg剂量组同时参与完成多剂量给药试验。采用液-质联用法测定人血浆中阿折地平浓度,并计算单剂量及多剂量给药后的药动学参数。结果:单剂量口服阿折地平片8mg和16mg后,阿折地平的药动学参数分别为:cmax(1.66±0.45)、(4.25±1.38)μg·L-1,tma(x3.50±1.08)、(4.00±1.16)h,t1/(221.3±8.1)、(19.5±4.0)h,AUC0～7(217.9±6.0)、(49.9±17.5)μg·h·L-1。多剂量口服阿折地平片8mg后,阿折地平的药动学参数为:cma(x2.63±1.41)μg·L-1,tma(x3.50±1.08)h,t1/(232.5±9.2)h,AUC0～7(243.8±26.4)μg·h·L-1,ca(v1.19±0.671)μg·L-1,AUCs(s28.4±16.1)μg·h·L-1,波动度(DF)为(1.78±0.49),稳态蓄积比(Rs)为(1.56±0.95)。结论:本试验建立的测定方法灵敏、准确、简便。阿折地平片单剂量给药的药动学参数cmax和AUC0～72随剂量的增加而增加,多剂量给药后阿折地平在体内有一定的蓄积。     

阿折地平和苯磺酸氨氯地平片对老年轻中度原发性高血压动态血压的影响

目的比较阿折地平片和苯磺酸氨氯地平片对老年轻中度原发性高血压患者血压和血压变异性（BPV）的影响。方法将60例老年轻中度原发性高血压患者随机分为2组,每组30例,分别服用阿折地平片（8mg／d）和苯磺酸氨氯地平片（5mg／d）12用,分别监测患者治疗前后24h动态血压的变化,比较两种药物对血压和BPV的影响。结果与治疗前比较,阿折地平和苯磺酸氨氯地平片治疗后均能有效地降低24h收压缩（SBP）、24h舒张压（DBP）、24hSBPV和24hDBPV,差异均有统计学意义（P〈0．05）。治疗后,阿折地平片和苯磺酸氨氯地平片在降低24hSBP和24hDBP的疗效差异无统计学意义（P〉0．05）：但在控制BPV方面,阿折地平片优于苯磺酸氨氯地平片（P〈0．05）。结论阿折地平片和苯磺酸氨氯地平片均是理想的控制血压和BPV的长效钙离子拮抗剂,阿折地平片在控制BPV方面优于苯磺酸氨氯地平片,更适用于老年轻中度原发性高血压患者。     

阿折地平片的人体药动学研究

目的:考察阿折地平片在人体内的药动学特性。方法:采用液-质联用(LC-MS)法,测定24名健康受试者口服受试制剂(单剂量含阿折地平8、16mg和多剂量)后血浆中阿折地平浓度。结果:单剂量口服阿折地平片8、16mg后,阿折地平的t1/2分别为(20.338±7.601)、(27.995±7.724)h,tmax分别为(3.333±1.303)、(3.667±0.985)h,cmax分别为(5.908±2.827)、(10.61±3.929)μg·L-1,AUC0～96h分别为(61.167±33.777)、(139.502±72.898)μg·h·L-1,AUC0～∞分别为(63.363±35.314)、(147.395±78.21)μg·h·L-1;多剂量口服阿折地平片8mg后,阿折地平的t1/2为(28.168±7.926)h,tmax为(3.167±0.718)h,cmax为(5.882±1.895)μg·L-1,AUC0～96h为(86.723±41.588)μg·h·L-1,AUC0～∞为(93.948±50.957)μg·h·L-1。结论:阿折地平片在8～16mg剂量范围内呈线性动力学特征,不同性别间药动学参数总体上差异不大,多剂量给药与单剂量给药的药动学参数基本一致。     

丁酸氯维地平的合成

目的研究短效二氢吡啶类钙通道阻滞剂--丁酸氯维地平的合成工艺.方法双乙烯酮和3-羟基丙腈经加成、胺化、然后与2,3-二氯亚苄基乙酰乙酸甲酯闭环缩合、水解,最后与正丁酸氯甲酯反应制得丁酸氯维地平.结果本工艺所得丁酸氯维地平总收率约为48%.结论本合成工艺稳定,条件温和,操作简便,适合丁酸氯维地平工业化生产.     

丁酸氯维地平的合成工艺

摘 要：目的 研究适合工业化生产的丁酸氯维地平合成方法。方法 采用2,3-二氯苯甲醛、β-氨基巴豆酸甲酯与乙酰乙酸乙酯环化缩合,选择性水解得到4-(2,3-二氯苯基)-1,4-二氢-2,6-二甲基-3,5-吡啶二羧酸单甲酯钾盐,再同丁酸氯甲酯反应得到丁酸氯维地平。结果 该合成工艺的丁酸氯维地平总收率为48%。结论 该工艺稳定,操作简单,适合工业化生产丁酸氯维地平。     

阿折地平胶囊溶出度方法研究

目的建立一种合适的阿折地平胶囊溶出度的测定方法。方法以0.1 mol.L-1盐酸溶液(含0.3%十二烷基硫酸钠)1 000 mL为溶出介质,转速为100 r.min-1,紫外检测波长269 nm。结果在4.0~24.0μg.mL-1范围内阿折地平浓度与吸光度呈良好线性关系,r=0.999 6;平均回收率98.16%,RSD=0.62%(n=9)。结论该方法准确可靠,重复性好,可作为阿折地平胶囊溶出度检验和质量控制的方法。     

HPLC法测定阿折地平片含量

目的建立高效液相色谱法测定阿折地平片的含量.方法采用Diamonsil C18柱(250mm×4.6mm,5μm),以磷酸盐缓冲液(磷酸二氢钠0.005mol·L-1,磷酸氢二钠0.004mol L-1)-乙腈(30∶70)为流动相,流速1.0mL· min-1;检测波长256nm;柱温30℃.结果阿折地平在2.50~40.0μg·mL-1范围内线性关系良好,r=0.9995,高、中、低3种不同浓度的平均回收率分别为99.8%、100.2%、100.5%,RSD为0.49%、0.57%、0.64%.结论所用方法简便、准确,可用于阿折地平片剂的质量控制.     

阿折地平:一种新型二氢吡啶类钙拮抗药

阿折地平是日本Sankyo公司与Ube公司联合开发的一种新型二氢吡啶类钙拮抗药,选择性作用于L-型钙通道,在日本已被批准用于治疗高血压,其降压疗效与肾上腺素β受体阻断剂和血管紧张肽转换酶抑制药相当。本文对该药的药效学、药动学和临床应用等研究作一综述。     

阿折地平的药动学和临床研究进展

阿折地平作为第3代二氢吡啶类钙拮抗剂,不仅显示出独特的降压优势,还具有减慢心率、抗动脉粥样硬化、心肾保护、改善胰岛素耐受、降低尿酸、减轻肝硬化等药理作用,具有较高的临床应用价值。查阅国内外相关文献,综述阿折地平的结构特征、药动学和临床研究进展,以期为临床合理用药及深入研究提供依据。     

Validated Stability-Indicating RP-HPLC Method for the Simultaneous Determination of Azelnidipine and Olmesartan in Their Combined Dosage Form

A simple, rapid, and highly selective RP-HPLC method was developed for the simultaneous determination of Azelnidipine (AZL) and Olmesartan (OLM) drug substances in the fixed dosage strength of 16 mg and 20 mg, respectively. Effective chromatographic separation was achieved using a Hypersil GOLD C18 column (150 mm × 4.6 mm internal diameter, 5 µm particle size) with a mobile phase composed of methanol, acetonitrile, and water in the ratio of 40:40:20 (by volume). The mobile phase was pumped using a gradient HPLC system at a flow rate of 0.5 mL/min, and quantification of the analytes was based on measuring their peak areas at 260 nm. The retention times for Azelnidipine and Olmesartan were about 8.56 and 3.04 min, respectively. The reliability and analytical performance of the proposed HPLC procedure were statistically validated with respect to system suitability, linearity, ranges, precision, accuracy, specificity, robustness, detection, and quantification limits. Calibration curves were linear in the ranges of 2–48 μg/mL for Azelnidipine and 2.5–60 μg/mL for Olmesartan with correlation coefficients >0.990. The proposed method proved to be selective and stability-indicating by the resolution of the two analytes from the forced degradation (hydrolysis, oxidation, and photolysis) products. The validated HPLC method was successfully applied to the analysis of AZL and OLM in their combined dosage form.     

Comparative effects of azelnidipine and other Ca2+-channel blockers on the induction of inducible nitric oxide synthase in vascular smooth muscle cells

Overproduction of nitric oxide by inducible nitric oxide synthase contributes to the progression of cardiovascular disease. We investigated the effects of azelnidipine and other Ca2+-channel blockers on nitric oxide production by cultured aortic smooth muscle cells isolated from Wistar rats and human umbilical vein endothelial cells (HUVECs), using the Griess reaction and oxyhemoglobin method. Release of lactic dehydrogenase (LDH) was measured to evaluate cell damage, and immunohistochemistry was performed to examine the expression of inducible nitric oxide synthase and nitrotyrosine protein. Azelnidipine and other Ca2+-channel blockers inhibited the release of nitric oxide induced by lipopolysaccharide plus interferon-gamma. Azelnidipine inhibited it most potently among the Ca2+-channel blockers tested (azelnidipine, amlodipine, nifedipine, diltiazem, verapamil, and nicardipine) at a concentration of 10 microM. Longer stimulation with these agents induced the expression of inducible nitric oxide synthase and nitrotyrosine, with an increase of lactic dehydrogenase release, whereas azelnidipine suppressed these changes. In human umbilical vein endothelial cells, azelnidipine enhanced basal nitric oxide production by endothelial nitric oxide synthase. In conclusion, azelnidipine potently inhibited the induction of inducible nitric oxide synthase and then nitric oxide production in vascular smooth muscle cells, while enhancing constitutive nitric oxide production by endothelial cells. Azelnidipine may inhibit nitrotyrosine expression and cell damage caused by overproduction of nitric oxide, suggesting a mechanism for its cardiovascular protective effect.     

Azelnidipine

Azelnidipine is a new dihydropyridine calcium channel antagonist with selectivity for L-type calcium channels that has recently been approved in Japan for the treatment of patients with hypertension. Results from clinical trials showed that, in 95 patients with mild-to-moderate hypertension, long-term treatment with azelnidipine effectively controls blood pressure (BP). The mean reduction from baseline in sitting systolic/diastolic BP after 1 year of treatment was 27.8/16.6 mm Hg. Among 172 patients with uncontrolled hypertension receiving non-calcium channel antagonist antihypertensive agents, the addition of azelnidipine therapy significantly reduced mean BP in a noncomparative, 1-year study (a reduction from 165.7/95.4 mm Hg at baseline to 138.2/79.9 mm Hg at study end). The antihypertensive efficacy of azelnidipine in patients with mild-to-moderate hypertension was shown to be similar to that of amlodipine or nitrendipine in randomised, double-blind studies. Azelnidipine and amlodipine controlled 24-hour BP to a similar extent. Azelnidipine is generally well tolerated; vasodilator adverse events such as as headache and hot facial flushes account for most of the adverse events. Its use is not associated with reflex tachycardia.