钙离子拮抗剂治疗阿尔茨海默氏病的现状

目的：介绍钙离子(Ca2 )拮抗剂治疗阿尔茨海默氏病(AD)的机制和研究进展。方法：查阅近年来国内外相关献。结果：应用Ca2 拮抗剂(如尼莫地平等)治疗AD，可促进受伤神经的再生和感觉运动功能的恢复，并有较好的临床疗效。结论：Ca2 自体平衡失调学说为AD发病机制中的重要组成，应用Ca2 拮抗剂治疗AD具有良好的前景。     

新型钙离子拮抗剂氨氯地平

氨氯地平是一种新型的二氢吡啶类钙离子拮抗剂，有独特的药代动力学特性，作用持续时间长、１次／ｄ，可维持２４ｈ的钙离子拮抗作用，具有降低血压和预防心肌缺血作用。不良反应较少，可用于老年及肾功能不全患者。     

钙离子拮抗剂的不良反应及处理

钙拮抗剂具有抑制Ca2+内流的作用,改变心肌,平滑肌的兴奋-收缩偶联过程,具有松弛血管平滑肌、减轻后负荷、抗血小板凝集、防止动脉粥样硬化的形成、保护血管内膜、改善心肌供氧的作用.其中双氢吡啶类钙拮抗剂有硝苯地平或其缓释或控释制剂、尼群地平、非洛地平、贝尼地平、氨氯地平等,短效的硝苯地平在血压控制时常有波动,长期服用短效硝苯地平致急性心肌梗死的发生率和死亡率随其剂量的增加而增加,因此不能作为首选[1].非双氢吡啶类钙拮抗剂主要有用于心律失常的维拉帕米、冠心病和心绞痛的硫氮卓酮,因其具有负性肌力、负性频率及负性传导作用,很少用于降血压.在临床应用钙拮抗剂时常有不良反应发生,为此笔者对其不良反应和处理方法综述如下,以供参考.     

钙离子拮抗剂在心血管内科的应用

<正> 钙离子拮抗剂自60年代以来逐渐受到基础医学和临床医学工作者的重视,由于它能特异性地作用于细胞膜上的钙通道,阻滞钙离子由细胞外向细胞内转运,故又称为慢通道钙阻滞剂或钙通道阻滞剂(CCB)。常用的CCB有异搏定、硝苯吡啶、硫氮(?)酮、硝苯苄胺啶、甲氧异搏停、双环乙胍啶、心可定、脑益嗪、Nisoldipine等。此外,硝普钠、硝酸甘油、普鲁卡因、苯妥因钠,消炎痛及丹特珞兰等也具有非特性钙通道阻滞作用。     

钙离子通道拮抗剂的临床应用

神经细胞内的Ca^2 与神经递质的释放和中枢神经系统基本电活动和脑的高级功能密切相关，对神经细胞生长、溃变及再生过程具有调节作用。但细胞内钙超载是细胞损伤级联反应的重要环节，是细胞死亡的主要原因(坏死与凋亡)。细胞外钙离子主要通过电压门控性钙通道、受体门控性钙通道和机械激活性钙通道进入细胞内。钙     

钙离子拮抗剂在老年高血压治疗中的益处

高血压是老年人常见的心血管疾病之一,其患病率随着年龄的增长呈明显上升趋势。我国2002年调查数据显示,65岁以上老年人高血压患病率高达50％。然而,我国居民对高血压的知晓率、患者的治疗率和血压控制率却仅分别为30.2％、24.7％和6.1％。我国已成为世界上受高血压危害最严重的国家之一、老年人则是需要重点防治的高危人群,国内外相关儋证医学研究证实,钙离子拮抗剂可明显降低血压与减少心脑血管事件的发生,对于心血管的发病率和死亡率来说,高血压,尤其是收缩性高血压是老年人群的单一最普通而有力的可治疗危险因素。它已成为老年高血压治疗的一线用药。     

钙离子拮抗剂及其微生物来源

综述了来自于微生物的钙离子拮抗剂及其研究进展。     

钙离子拮抗剂使用情况分析

钙离子拮抗剂在临床上多用于治疗心脏和血管系统疾病，如心律失常、高血压、心肌缺血性疾病(冠心病、心绞痛)、脑血管性疾病、慢性心功能不全等。由于本类的各个药物的选择性作用不同而被用于不同的疾病。本文通过对资料的分析，系统地掌握我院门诊部钙离子拮抗剂的使用情况及使用趋势。     

Widening potential for Ca2+ antagonists: non-L-type Ca2+ channel interaction

In addition to their well characterized interaction with the alpha 1 subunit of the voltage-dependent L-type Ca2+ channel, certain Ca2+ antagonists have been reported to modulate an increasing number of cellular functions as diverse as extrusion of cytotoxic substances, or cleavage of cAMP by phosphodiesterase. Some of these interactions (such as the reversal of multidrug resistance by Ca2+ antagonists for the treatment of lymphoma patients) have already been exploited clinically; some (such as protection of ischemic tissue by Ca2+ antagonists interacting with mitochondrial sites) open new therapeutic issues. In this survey of the non-L-type channel Ca2+ antagonist target structures known to date, Gerald Zernig evaluates the available data and emphasizes common characteristics shared by the seemingly diverse target structures. Research on these sites might help to understand yet unexplained effects of Ca2+ antagonists and possibly lead to the development of novel drugs with higher selectivity for non-L-type Ca2+ channel structures.     

New developments in Ca2+ channel antagonists

Toward the beginning of this Perspective we posed a number of questions to be answered concerning the Ca2+ channel antagonists. Biochemical, chemical, clinical, pharmacological, and physiological studies collectively support the conclusion that this important group of molecules does function in specific fashion to inhibit Ca2+ channel function. Major questions of mechanisms and sites of action remain, however, to be resolved. The recent radioligand binding assay supports the conclusion, drawn earlier from the chemical and pharmacological heterogeneity of these agents, that there exists multiple sites and mechanisms of action for the Ca2+ channel antagonists. This is a satisfying conclusion, since, although it makes high demands on future experimentation designed to delineate these sites and mechanisms, it indicates the very real possibility for the development of tissue-selective Ca2+ channel antagonists. Elsewhere in this review we have already addressed the question of tissue selectivity as observed for existing compounds. In our opinion, the structural and pharmacological clues available should bring us closer to the goal of second- and third-generation Ca2+ antagonists with defined tissue selectivity.     

Inhibition of erythrocyte Ca2(+)-pump by Ca2+ antagonists

Inside-out vesicularized membrane fragments from human erythrocytes were prepared to study the effects of various Ca2+ channel entry blockers of plasma membrane Ca2+ transport and (Ca2+ + Mg2+)-ATPase activity concomitantly. Verapamil and diltiazem (0.01 to 5 mM) inhibited both (Ca2+ + Mg2+)-ATPase activity and initial rates of 45Ca2+ net uptake analogously. In general, the parameter affected most by these drugs, using either Ca2+ transport or (Ca2+ + Mg2+)-5'-adenosine-triphospho-hydrolase (EC 3.6.1.3) ([Ca2+ + Mg2+]-ATPase) measurements, was the stimulation by calmodulin. However, the specificity and selectivity of inhibition appeared to be highly concentration and membrane preparation dependent. Verapamil and diltiazem inhibited the calmodulin-Ca2+ transport concentration-effect relationship by changing its apparent affinity as well as the maximal velocity of the process. In a "white ghost" membrane preparation, bepridil inhibited calmodulin activation with a high degree of selectivity as opposed to its effects on calmodulin activation in the vesicular preparation. Nifedipine failed to exhibit any specificity and modestly inhibited basal and calmodulin-activated inside-out vesicular Ca2+ transport and (Ca2+ + Mg2+)-ATPase alike. Our results suggest that verapamil, diltiazem and bepridil (0.01 to 0.3 mM), but not nifedipine (1 nM to 0.01 mM), in relatively high concentrations can antagonize the calmodulin-stimulated Ca2(+)-pump, i.e. the ATPase as well as the transport process. The inhibitors differed with regard to potency, selectivity, and the type of inhibition they produced.     

Differential effects of various Ca2+ antagonists

1. The effects of various Ca antagonists (nicardipine, nifedipine, verapamil, diltiazem, flunarizine, cinnarizine, lidoflazine and papaverine) were studied in one in vitro (inhibition of CaCl2 induced contractions in isolated rat aorta) and two in vivo tests [survival after BaCl2 in the rat and survival after arachidonic acid (AA) in the mouse]. 2. Test substances behave in different ways, thus suggesting varying mechanisms of action. 3. The three tests used are very simple and quick to perform, but taken together give a good preliminary information which allows classification of the products during the screening phase into four subgroups: dihydropyridines, verapamil, diltiazem and diphenylalkylamines.     

Stimulation of canine cardiac sarcoplasmic reticulum Ca2+ uptake by dihydropyridine Ca2+ antagonists

We examined the effects of four Ca2+ antagonists that possess the ability to bind to calmodulin-felodipine, nitrendipine, prenylamine, and verapamil--as well as the effect of the calmodulin antagonist trifluoperazine on Ca2+ uptake and Ca2+ + Mg2+/ATPase activity in canine cardiac sarcoplasmic reticulum. In the presence of 20-30 microM felodipine and 100-200 microM nitrendipine, Ca2+ uptake increased from 69 nmoles X mg-1 X min-1 to 107 and 108 nmoles X mg-1 X min-1, respectively, with half-maximal stimulation occurring at 7.5 and 28 microM respectively. Ca2+ + Mg2+/ATPase activity was unchanged over the same concentration ranges. In contrast, both Ca2+ uptake and Ca2+ + Mg2+/ATPase activities were inhibited in the presence of 10-100 microM trifluoperazine (IC50 = 25 microM), 10-100 microM prenylamine (IC50 = 35 microM) and 100-200 microM verapamil (inhibition insufficient for IC50 determination). None of the drugs affected membrane permeability to Ca2+ as determined by passive 45Ca2+ efflux in the presence of ethyleneglycol bis(beta-amenoethyl ether)N,N,N1-tetraacetic acid (EGTA). Drug inhibition of calmodulin-dependent turkey gizzard myosin light chain kinase activation in a purified protein system was used as a direct measure of calmodulin antagonism, and felodipine, nitrendipine, trifluoperazine, prenylamine, and verapamil blocked this activation at IC50 values of 9.8, 55, 6.4, 31, and 93 microM respectively. None of the drugs studied, however, had any effect upon endogenous phospholamban phosphorylation in our cardiac sarcoplasmic reticulum preparations. These observations indicate that dihydropyridine Ca2+ antagonists stimulate cardiac sarcoplasmic reticulum Ca2+ uptake in vitro either by increasing the efficiency of the transport process or by inhibiting Ca2+-dependent Ca2+ release, and suggest that these effects do not result from interference with calmodulin-mediated processes.     

Partition of Ca2+ antagonists in brain plasma membranes

The partition coefficients (Kp) of three prototype Ca2+ antagonists, nitrendipine, (-)-desmethoxyverapamil and flunarizine were determined in native synaptic plasma membranes (SPM) isolated from sheep brain cortex and in liposomes prepared with the total lipids extracted from the membranes. We found that at 25 degrees and at 5 x 10(-6) M drug concentration the Kp values of the drugs for native SPM are higher than those obtained for liposomes, and are of the order of 334 +/- 53, 257 +/- 36 and 23 X 10(3) for nitrendipine, (-)desmethoxyverapamil and flunarizine, respectively, whereas the Kp values in liposomes are 190 +/- 41, 118 +/- 10 and 6 x 10(3) for the same drugs. The results suggest that the presence of membrane proteins favors the incorporation of the drugs in the membranes. Furthermore, the Kp values of the three Ca2+ antagonists studied increase with temperature in native membranes, but not in liposomes. It is concluded that the physical partitioning in membranes of drugs which act on Ca2+ channels may play some role in the mechanism of interaction of these drugs with the Ca2+ channel proteins.     

Antitussive effects of Ca2+ channel antagonists.

The effects of Ca2+ channel antagonists on the capsaicin-induced cough reflex in guinea pigs were studied. Intraperitoneal injection of nifedipine, verapamil and flunarizine in doses that ranged from 0.3 to 3.0 mg/kg decreased the number of coughs in a dose-dependent manner. These Ca2+ channel antagonists exhibited antitussive effects in the following order of potency: flunarizine = verapamil greater than nifedipine. Pretreatment with a low dose of nifedipine (0.3 mg/kg), which by itself had no significant effect on the number of coughs, markedly increased the antitussive effects of morphine, dihydrocodeine and dextromethorphan. These data suggest that Ca2+ channels play an important role in the regulation of the cough reflex.     

Receptor sites for Ca2+ channel antagonists.

Ca2+ channel antagonist drugs inhibit voltage-gated Ca2+ channels in many different cell types. Inhibition of Ca2+ channels in smooth muscle and cardiac muscle cells by these drugs is valuable in the therapy of a wide range of cardiovascular disorders including hypertension, atrial arrhythmia and angina pectoris. Additional uses under evaluation are protection against ischemic damage during myocardial infarction and stroke and in a wide range of other conditions. Further understanding of the sites and mechanisms of action of Ca2+ channel antagonists, as described in this review by Bill Catterall and J?rg Striessnig, will provide new insight into the design of novel therapeutic agents acting on Ca2+ channels and provide further understanding of Ca2+ channel structure and function.