糖尿病并发症的药物治疗

糖尿病并发症对人类健康造成极大危害，针对各种糖尿病并发症的病因开发其治疗药物已成为人们关注的热点，并取得可喜进展。本文分类概述糖尿病并发症治疗药物的作用机制、临床应用及疗效研究，其药物包括醛糖还原酶抑制剂、糖基化终产物抑制剂、抗氧剂以及血管紧张素转换酶抑制剂。     

治疗糖尿病并发症药物的开发与进展

概述了治疗糖尿病并发症的药物开发与进展,主要包括醛糖还原酶抑制剂,蛋白非酶糖基化阻滞剂,生长因子拮抗剂,血管紧张素转换酶抑制剂,神经营养剂等,简述了其开发思路、临床效果及应用前景。     

肾素-血管紧张素-醛固酮系统阻滞剂在糖尿病心血管并发症中的应用

糖尿病是心血管疾病的独立危险因素，肾素-血管紧张素-醛固酮系统(RAS)在糖尿病心血管并发症的发生和发展中扮演重要的角色。RAS阻滞剂可分为肾素拮抗剂、血管紧张素转化酶抑制剂、血管紧张素Ⅱ受体拮抗剂和醛固酮拮抗剂。这些药物在不同的水平阻断RAS，可以有效地减少糖尿病心血管系统并发症。     

血管紧张素Ⅱ受体拮抗剂在老年患者中临床应用研究进展

血管紧张素Ⅱ受体拮抗剂（ARB）是继血管紧张素转化酶抑制剂（ACEI）后又一类重要的抑制肾素-血管紧张素（RAS）系统的药物,已广泛应用于高血压、心力衰竭、心肌梗死及糖尿病肾病等疾病的治疗。     

2000年～2002年广东省部分医院肾素-血管紧张素系统药物应用调查分析

目的 :了解广东省医院肾素 -血管紧张素系统药物应用情况。方法 :对 2 0 0 0年～ 2 0 0 2年 3年中消耗的血管紧张素转换酶抑制剂 (普利类 )和血管紧张素Ⅱ受体拮抗剂 (沙坦类 )的用药金额、用药频度及日均费用的变化进行统计分析。结果与结论 :2 0 0 0年～ 2 0 0 2年血管紧张素转换酶抑制剂药物销售金额增幅下降 ;血管紧张素Ⅱ受体拮抗剂的年销售总金额则存在迅速上升趋势 ;用药频度最高及用药金额最大的血管紧张素转换酶抑制剂药物为苯那普利 ,血管紧张素Ⅱ受体拮抗剂为氯沙坦 ;日均费用最高的血管紧张素转换酶抑制剂药物为福辛普利 ,血管紧张素Ⅱ受体拮抗剂为氯沙坦 氯噻嗪。     

血管紧张素转换酶抑制剂联合血管紧张素受体拮抗剂治疗糖尿病肾病的临床观察

糖尿病肾病(diabetic nephropathy,DN)是糖尿病常见的微血管并发症,也是糖尿病死亡的主要原因。如何有效地治疗DN,以逆转肾功能或延缓肾功能减退的进展,是临床亟待解决的问题。本研究通过联合血管紧张素转换酶抑制剂(ACEI)及血管紧张素受体拮抗剂(ARB)治疗糖尿病肾病,取得较好的效果。     

AT1受体拮抗剂坎地沙坦的联合用药及不良反应

坎地沙坦是二苯四咪唑类血管紧张素Ⅱ受体AT1亚型拮抗剂[1].血管紧张素Ⅱ受体拮抗剂(ARB)是继血管紧张素转换酶抑制剂(ACEI)之后,对高血压、动脉硬化、心肌肥厚、心力衰竭、糖尿病、肾病等具有良好作用的新一类作用于肾素-血管紧张素系统(RAS)的药物,被世界卫生组织和国际高血压联盟列为6大类抗高血压药物之一.     

高血压合并糖尿病患者的降压用药观察

目的：调查北蔡地区登记在案的老年高血压合并糖尿病患者服用降压药物情况,并加以统计分析,以提高社区治疗水平。方法：通过走访调研,分析250例高血压合并2型糖尿病患者降压治疗情况。结果：250例患者中,单一用药113例（45.2%）,联合用药114例（45.6%）,未服药23例（9.2%）;治疗总有效147例（58.8%）。使用药物中血管紧张素转换酶抑制剂（ACEI）113例（45.2%）,血管紧张素Ⅱ受体拮抗剂（ARB）53例（21.2%）,钙离子拮抗剂（CCB）105例（42.0%）,β受体阻滞剂51例（20.4%）,利尿剂55例（22.0%）,以血管紧张素转换酶抑制剂联合钙离子拮抗剂治疗效果,有效率为73.47%。结论：北蔡地区高血压合并糖尿病患者的降压治疗以钙离子拮抗剂及血管紧张素转换酶抑制剂为主,血管紧张素转换酶抑制剂联合钙离子拮抗剂的治疗方案降压效果更佳。     

罗红霉素联合羧甲司坦治疗慢性阻塞性肺疾病稳定期的临床观察

糖尿病肾病是糖尿病的一种常见慢性并发症,是糖尿病致死致残的重要原因之一.糖尿病肾病的早期缺乏明显的临床症状,而一旦出现蛋白尿,病情已发展至不可逆性,自持续性蛋白尿发展至慢性肾功能衰竭已为期不远[1],因此,对糖尿病肾病的早期诊断和治疗十分重要.本研究比较了血管紧张素受体拮抗剂(AT)坎地沙坦和血管紧张素转换酶抑制剂(ACEI)卡托普利对早期糖尿病肾病的影响,现报告如下.     

血管紧张素转换酶抑制剂和血管紧张素受体拮抗剂治疗糖尿病肾病的临床疗效分析

目的探讨血管紧张素转换酶抑制剂和血管紧张素受体拮抗剂在延缓糖尿病肾病患者肾功能衰竭方面的临床疗效。方法选取笔者所在医院糖尿病肾病患者200例,分别给予血管紧张素转换酶抑制剂、血管紧张素受体拮抗剂治疗以及两者联用,观察三组血压、血肌酐及24h尿蛋白定量,并比较三组疗效。结果 3组血压差异无统计学意义(P>0.05),血肌酐方面,培哚普利组与厄贝沙坦组间差异无统计学意义(P>0.05),联合组与贝那普利组和氯沙坦组差异均有统计学意义(P<0.05),24h尿蛋白定量,培哚普利组与厄贝沙坦组间差异无统计学意义(P>0.05),联合组与另外两组间差异均有统计学意义(P<0.05)。结论血管紧张素转换酶抑制剂和血管紧张素受体拮抗剂在糖尿病肾病患者中能够很好的延缓肾衰竭的进程,保护肾功能,两者联用可以取得更好的疗效。     

肾素血管紧张素系统与糖尿病肾病

肾素血管紧张素系统是生理功能颇为复杂的内分泌系统，广泛存在于机体各个组织。该系统的关键基因决定着个体的糖尿病肾病易感性。血管紧张素Ⅱ通过细胞外基质成分合成增多、降解减少而促使肾小球硬化。血管紧张素转化酶抑制剂及血管紧张素受体拮抗刑具有独立于血压的治疗糖尿病肾病的作用。     

Patent focus on agents affecting cardiovascular and renal functions November 1999 - March 2000

Patent applications relevant to therapy of cardiovascular diseases are reviewed for the period of November 1999 to March 2000. Most of the patents discussed deal with agents affecting blood clotting, membrane ionic currents, hypertension and hypercholesterolaemia. The development and evaluation of several new therapeutic agents for treatment of blood coagulation disorders are discussed, including glycoprotein (GP) IIb/IIIa antagonists, activators of protease-activated receptors, P2T receptor antagonists, adenosine receptor agonists and serine protease inhibitors. Interesting new blockers of the sodium-proton exchange, the N-type calcium channels and the ultrarapid delayed rectifier potassium current (I_Kur) are introduced. Antihypertensive agents are presented including angiotensin II receptor antagonists, vasopressin antagonists and phosphodiesterase inhibitors. Compounds effective against hypercholesterolaemia, especially inhibitors of cholesterol ester transfer protein (CETP) and acyl coenzyme A:cholesterol acyltransferase (ACAT) are also addressed. Agents acting via other mechanisms, like the nitric oxide-cGMP (NO-cGMP) pathway, that are involved in cardiovascular effects are discussed.     

Novel angiotensin II inhibitors in cardiovascular medicine

Blockade of the renin-angiotensin-aldosterone cascade is now recognised as a very effective approach to treat hypertensive, heart failure and high cardiovascular risk patients and to retard the development of renal failure. The purpose of this review is to discuss the state of development of currently available drugs blocking the renin-angiotensin system, such as angiotensin converting enzyme (ACE) inhibitors, renin inhibitors and angiotensin II receptor antagonists, with a special emphasis on the results of the most recent trials conducted with AT₂ receptor antagonists in heart failure and Type 2 diabetes. In addition, the future perspectives of drugs with dual mechanisms of action, such as NEP/ACE inhibitors, also named vasopeptidase inhibitors, are presented.     

血管紧张素Ⅱ受体拮抗剂、血管紧张素转换酶抑制剂、钙拮抗剂对原发性高血压患者血尿酸水平的影响

目的观察血管紧张素Ⅱ受体拮抗剂(AngiotensinⅡreceptor antagonist,ARB)、血管紧张素转换酶抑制剂(Angiotensin converting enzyme inhibitor,ACEI)与钙离子通道拮抗剂(Calcium antagonist,CCB)对高血压患者血尿酸水平的影响。方法入选原发性高血压患者582例,随机分为氯沙坦钾组、替米沙坦组、硝苯地平控释片组、苯磺酸氨氯地平组、培哚普利组、盐酸贝那普利组及对照组,观察患者治疗前及治疗后血尿酸及血压的变化。结果经过8周治疗,与对照组相比,氯沙坦钾组、替米沙坦组、硝苯地平控释片组、培哚普利组、盐酸贝那普利组血尿酸水平均明显下降(P<0.05);与用药前相比,各组患者血压均得到明显控制(P<0.05)。结论对于原发性1~2级高血压患者,ARB类的氯沙坦钾、替米沙坦、ACEI类培哚普利、盐酸贝那普利、CCB类硝苯地平控释片均能降低患者血尿酸水平。     

Evaluation of the angiotensin challenge methodology for assessing the pharmacodynamic profile of antihypertensive drugs acting on the renin-angiotensin system

AIMS: The performance of the experimental paradigm of angiotensin challenges with continuous non-invasive blood pressure measurement was evaluated. Angiotensin dose-response relationships were characterized, along with the influence of clinical covariates. The stability of angiotensin-induced peaks and the variability of the angiotensin doses were assessed. Finally, the predictive value of studies based on angiotensin challenges to determine drug doses effective in therapeutics was evaluated. METHODS: The data were gathered from 13 clinical studies on nine angiotensin II receptor antagonists, one ACE inhibitor and one dual ACE-NEP inhibitor, using Finapres for measuring the response to exogenous angiotensin challenges. Modelling of angiotensin dose-response curves and determination of the inter and intrasubject variability were performed by nonlinear regression (NONMEM). The different sources of variations in angiotensin I and II doses and angiotensin-induced peaks were evaluated by analyses of variance. The dose of ACE inhibitors and angiotensin II receptor antagonists inhibiting blood pressure increase by at least 75%, as measured by this method, was chosen for comparison with the labelled starting dose. RESULTS: Angiotensin challenges exhibited a clear dose-response relationship which can be characterized both by an Emax or a log linear model. The log linear model gave an average systolic/diastolic response of 24+/-6/20+/-5 mmHg for a unit dose of 1 microgram of angiotensin II equivalents, and an increase of 6/6 mmHg for each doubling of the dose. The angiotensin ED50 calculated values were 0.67 microgram for systolic and 0.84 microgram for diastolic blood pressure. The angiotensin doses for eliciting a given response and the angiotensin induced peaks were fairly constant between period and subject, but vary significantly between studies. Based on an inhibition of blood pressure by 75%, the agreement was good between the doses of ACE inhibitors and angiotensin receptor antagonists predicted from studies using the methodology of angiotensin challenges and the doses shown to be clinically efficacious, in spite of high intersubject and intrasubject variabilities. CONCLUSIONS: This experimental method represents a valid surrogate for the therapeutic target and a useful tool for the pharmacokinetic and pharmacodynamic profiling of drugs acting on the renin-angiotensin system.     

Future drug discovery in renin-angiotensin-aldosterone system intervention

Introduction: Renin-angiotensin-aldosterone system inhibitors (RAASIs), including angiotensin-converting enzyme inhibitors, angiotensin AT1 receptor blockers and mineralocorticoid receptor antagonists (MRAs), are the cornerstone for the treatment of cardiovascular and renal diseases.

Areas covered: The authors searched MEDLINE, PubMed and ClinicalTrials.gov to identify eligible full-text English language papers. Herein, the authors discuss AT2-receptor agonists and ACE2/angiotensin-(1–7)/Mas-receptor axis modulators, direct renin inhibitors, brain aminopeptidase A inhibitors, biased AT1R blockers, chymase inhibitors, multitargeted drugs, vaccines and aldosterone receptor antagonists as well as aldosterone synthase inhibitors.

Expert opinion: Preclinical studies have demonstrated that activation of the protective axis of the RAAS represents a novel therapeutic strategy for treating cardiovascular and renal diseases, but there are no clinical trials supporting our expectations. Non-steroidal MRAs might become the third-generation of MRAs for the treatment of heart failure, diabetes mellitus and chronic kidney disease. The main challenge for these new drugs is that conventional RAASIs are safe, effective and cheap generics. Thus, the future of new RAASIs will be directed by economical/strategic reasons.     

Emerging drugs in the management of hypertension

Hypertension is a global health problem, affecting developing and developed countries alike. Most patients with hypertension are undiagnosed, and most diagnosed patients are either untreated or inadequately treated. Randomised controlled trial evidence suggests diuretic therapy for hypertension is as effective as newer drugs in reducing cardiovascular events. There is good evidence for the use of specific classes of drugs in hypertensive patients with a variety of associated clinical conditions, but for uncomplicated cases, the current emphasis in hypertension management is on blood pressure lowering rather than drug class. Individual patients vary in their responses to different drug classes, and optimal therapy for the individual is determined by trial and error. Pharmacogenomics may assist in tailoring therapy for individuals in the future. Emerging drugs include newer members of classes already established in clinical practice, for example, angiotensin II receptor antagonists, aldosterone receptor antagonists, calcium antagonists and centrally acting drugs; newer fixed-dose combination therapies; and more novel therapies, for example, endothelin (ET) receptor antagonists, activators of nitric oxide (NO)-sensitive guanylyl cyclase and vasopeptidase inhibitors.     

Substituted benzimidazole derivatives as angiotensin II-AT1 receptor antagonist: a review

The renin angiotensin system (RAS) plays an important role in regulation of blood pressure and fluid-electrolyte homeostasis. The renin-angiotensin system consists of a cascade of enzymatic reactions producing angiotensin II (Ang II). Ang II is a vasoconstrictive peptide hormone that exerts a wide variety of physiological actions on cardiovascular, renal, endocrine and central nervous systems. The RAS can be inhibited at various points to control pathogenesis of hypertension. Renin inhibitors and angiotensin-converting enzyme (ACE) inhibitors were the earliest RAS blocking agents. A relatively new class of compounds known as Ang II receptor antagonists (SARTANs) is developed for the treatment of hypertension. They exert their action by blocking the binding of Ang II on AT(1) receptor. Angiotensin converting enzyme (ACE) inhibitors are associated with incident of side effects such as cough and angioedema while clinical trials with Ang II receptor antagonists have confirmed that these drugs are safe and efficacious for the treatment of hypertension. Based upon the understanding of molecular interaction of Ang II receptor antagonists with AT(1) receptor some of the common structural features have been identified, such as a heterocyclic (nitrogen atom) ring system, an alkyl side chain and an acidic tetrazole group. Research efforts for development of new molecules with similar structural features have led to the discovery of various non-peptidic Ang II receptor antagonists with different substituted heterocyclic such as imidazole (losartan) and benzimidazole (candesartan and telmisartan). In this study we have critically reviewed various benzimidazole substituted compounds as Ang II-AT(1) receptor antagonists and explored other potential clinical uses for this class of compounds.     

Advances in the design and discovery of drugs for the treatment of prostatic hyperplasia

Introduction: Benign prostatic hyperplasia (BPH) is a common medical problem in nearly 80% of geriatric male population severely affecting the quality of life. Several strategies has been suggested in the past for the management of BPH, but only α-blockers and 5α-reductase inhibitors are in clinical use. This review aims to give deep insight into advances in the design and discovery of newer chemical entities as ‘druggable' molecule for the management of BPH.

Areas covered: In this review, the authors cover various classes of drugs that have shown their potential for management of BPH. These drugs include α-adrenergic antagonists, 5α-reductase inhibitors, phytochemical agents, phosphodiesterase inhibitor, luteinizing hormone releasing hormone antagonists and muscarinic receptor antagonists. Literature searches were carried out using Google Scholar, SciFinder and PubMed.

Expert opinion: The exact etiology of BPH is unknown; however, several mechanisms may be involved in the progression of the disease. Beside surgery and watchful waiting, medical therapies to treat BPH include α-adrenergic antagonist and 5α-reductase inhibitors. Phytotherapeutic agents are also used in some countries. Various other chemical classes of drugs are proposed for the treatment of the disease, but none of them have reached the clinic. Many classes of drugs are currently undergoing clinical trials such as phosphodiesterase inhibitors, luteinizing hormone releasing hormone antagonists and muscarinic receptor antagonists. The current need is to develop a potent, efficacious and highly selective drug for the treatment of BPH.     

Renin-angiotensin system blockade at the level of the angiotensin converting enzyme or the angiotensin type-1 receptor: similarities and differences

The development of drugs which block the renin-angiotensin system (RAS) has been proven a major advance in cardiovascular medicine. Angiotensin converting enzyme (ACE) inhibitors, which block the formation of angiotensin II from the inactive angiotensin I, are widely used as first line treatment in hypertension, heart failure and diabetic nephropathy. More recently, selective antagonists of the angiotensin type-1 receptor (AT1R) have become available for clinical use. Accumulating evidence suggests that AT1R antagonists have similar effects to ACE inhibitors in hypertension, heart failure and diabetic nephropathy. Although ACE inhibitors and AT1R antagonists block the same system, experimental evidence suggest that their mechanisms of action differ in several respects, such as increased bradykinin and angiotensin 1-7 levels with ACE inhibitors and AT2R activation with AT1R antagonists. Nevertheless, the clinical significance of these differences remains largely unknown and, in practice, the only clear advantage of AT1R antagonists over ACE inhibitors is the absence of cough as a side effect. Recent clinical data suggest that combined ACE inhibition and AT1R antagonism offer additive effects in reducing blood pressure in hypertension, in reducing proteinuria in nephropathy and in improving prognosis in heart failure. Further evidence suggests that some hypertensive patients may have a good antihypertensive response with ACE inhibition but not with AT1R antagonism, or the reverse. These data suggest that these two drug classes have important similarities, because they act on the same system, but they also appear to have important differences, which are not only of theoretical but also of clinical importance.