Cilostazol: a new drug in the treatment intermittent claudication

The most common symptom of lower extremity peripheral arterial disease (PAD) is intermittent claudication. The severity of PAD is closely related with the risk of myocardial infarction, ischaemic stroke, and death from vascular causes. Despite the higher prevalence of PAD, far less importance is given to its diagnosis and management. Patients with peripheral arterial disease should be offered secondary prevention strategies including aggressive risk factor modification and anti-platelet drug therapy. Cilostazol, a reversible, selective inhibitor of PDE III with antiplatelet, antithrombotic and vasodilatory effects, was approved by the FDA in 1999 for the treatment of Intermittent Claudication. It is believed that the collective pharmacology effect of cilostazol actually improves blood flow to the lower extremities. The efficacy of cilistazol has been demonstrated in eight Phase three clinical trials. Cilostazol is the first drug to consistently demonstrate clinical efficacy in many double-blind randomised control trials. It is indicated for the improvement of the maximal and pain-free walking distances in patients with IC, who do not have rest pain and who do not have evidence of peripheral tissue necrosis. In this review we highlight the role of Cilostazol in the management of peripheral arterial disease. The combined effect of aspirin with Cilostazol was recently patented.     

Intermittent claudication in older patients. Practical treatment guidelines.

The prevalence of intermittent claudication (IC) increases with age; when questioned, older patients consider increased difficulty in walking to be a normal consequence of aging. Although the prognosis for the involved limb with IC is relatively good, IC is an important clinical predictor of increased cardiovascular mortality. It is important to effect a minimal strategy for determining the presence of lesions in different vascular regions: carotids, coronaries, aorta and renal arteries. The goals for the treatment of IC in the elderly are to improve the walking distance and quality of life and to increase survival. Practical guidelines for the treatment of IC are to first establish a correct diagnosis. Then, patients have to apply life-style modifications and participate in an exercise programme, with the next treatment step involving the use of antiplatelet drugs. However, it must be remembered that older patients could have limitations on exercise; in such cases, a vasoactive drug should be considered. The third guideline consists of multifocal evaluation of the arteries, specifically the coronaries, carotids and abdominal aorta. The existence of an iliac obstruction or stenosis requires consideration of the 2 last guidelines. In more than 75% of cases, elderly patients have femoropopliteal or distal arterial obstructions: exercise and a vasoactive drug should be employed in these instances. The presence of iliac lesions has to be discussed in the presence of a multidisciplinary team in a vascular centre, and should consider the usefulness of percutaneous transluminal angioplasty or surgery.     

西洛他唑降低链脲佐菌素诱发糖尿病大鼠肾脏VCAM-1表达

目的　探讨西洛他唑对高糖大鼠肾组织VCAM - 1的影响及对肾脏的可能保护作用。方法　雄性SD大鼠,链脲佐菌素(STZ)制备糖尿病大鼠模型。观察西洛他唑12周后对血糖、糖化血红蛋白、肾重/体重比值、肾脏VCAM - 1mRNA及蛋白表达的影响。结果　糖尿病对照组及各治疗组肾重/体重比值均明显增加(P <0 . 0 1);VCAM - 1mRNA表达在糖尿病组明显升高,药物治疗后有显著改善( P <0. 0 1);Westernblot各组均有VCAM - 1表达,糖尿病组较正常组表达增强,药物治疗后呈下降趋势。结论　STZ诱发的糖尿病大鼠肾脏VCAM - 1表达增加,西洛他唑降可低糖尿病大鼠肾组织VCAM - 1mRNA和蛋白表达,对糖尿病肾脏具有保护作用。     

Cilostazol for treatment of cerebral infarction

ABSTRACT

Introduction: Stroke not only causes critical disability and death but is also a cause of anxiety with the possibility of secondary cardiovascular events including secondary ischemic stroke. Indeed, patients with a history of previous stroke have a high rate of stroke recurrence, indicating the clinical importance of secondary stroke prevention.

Area of covered: This review provides an overview of the pooled evidence for cilostazol’s use in the management of secondary stroke prevention. Among the various antiplatelet agents that are available, aspirin is the most frequently used agent worldwide for the prevention of secondary stroke. Cilostazol, a selective phosphodiesterase (PDE) 3A inhibitor, is used worldwide for the treatment of patients with intermittent claudication. However, in Asia, cilostazol is recommended and used in practice for secondary stroke prevention.

Expert opinion: The authors believe that cilostazol could be used for secondary stroke prevention not only in Asia but worldwide. However, further randomized trials on cilostazol are needed, especially in the US and Europe to better support its case.     

Drug treatment of intermittent claudication

The US FDA has approved two drugs for the management of intermittent claudication: pentoxifylline and cilostazol. The mechanism of action that provides symptom relief with pentoxifylline is poorly understood but is thought to involve red blood cell deformability as well as a reduction in fibrinogen concentration, platelet adhesiveness and whole blood viscosity. The recommended dose of pentoxifylline is 400 mg three times daily with meals. Cilostazol is a potent, reversible, phosphodiesterase III inhibitor. The inhibition of phosphodiesterase allows for the increased availability of cyclic adenosine monophosphate (cAMP). cAMP mediates many agonist-induced platelet inhibitory, vasodilatory and vascular antiproliferative responses. Cilostazol, at a dose of 100 mg twice daily, is recommended to be taken 30 minutes before or 2 hours after breakfast and dinner. In addition to pentoxifylline and cilostazol, clinical trials indicate many other drugs may relieve the symptoms of intermittent claudication. Ginkgo biloba, available as an over-the-counter extract, provides symptom relief comparable to pentoxifylline. Two European agents, naftidrofuryl and buflomedil, also have efficacy that is reported to be similar to pentoxifylline. Policosanol is a mixture of fatty alcohols derived from honeybee wax which, according to very limited data, reduces symptoms of claudication. Amino acids, certain peptides and prostaglandins may have a therapeutic role. Finally, novel approaches including angiogenesis mediated by growth factors, are currently under investigation.     

Prevention and treatment of diabetic nephropathy in older patients

Renal disease in older diabetic patients is costly in terms of morbidity, mortality and expenditure. Therefore, prevention and treatment of diabetic nephropathy has become a prominent goal in the treatment of patients with diabetes mellitus. Preventive treatment should begin no later than at the stage of microalbuminuria, and regular screening for microalbuminuria is recommended for all patients with diabetes, irrespective of age. Improved metabolic control has been demonstrated to lower urinary albumin excretion. Target glycosylated haemoglobin levels should be below 7%, or 1% above the upper limit of normal of non-diabetic subjects. The use of an intensified treatment regimen is recommended. Insulin therapy has no adverse effects on renal indexes. To preserve renal function in older diabetic patients, blood pressure should be kept at or below 130/80 mm Hg. Treatment with ACE inhibitors or angiotensin II receptor antagonists (angiotensin II receptor blockers; ARBs) is superior to other pharmacological therapy, and should be initiated as first-line treatment. Most of the calcium channel antagonists have been found to increase or to have no effect on microalbuminuria despite blood pressure reduction. Moreover, there is substantial controversy as to whether they may be associated with increased cardiovascular morbidity. Non-dihydropyridine derivatives and calcium channel antagonists, such as nitrendipine, may be nephroprotective and have favourable effects on patients outcomes. A renoprotective action of diuretics may be confined to indapamide. Although beta-adrenoreceptor blockers are effective antihypertensive agents, they may not adequately preserve kidney function in older diabetic patients. However, as add-on treatment to ACE inhibitors or ARBs, they are particularly beneficial in nephropathic patients at risk of cardiovascular disease or with arrhythmias, in whom they may prove life-saving.     

Saroglitazar for the treatment of dyslipidemia in diabetic patients

Introduction: Diabetes and dyslipidemia are commonly associated modifiable risk factors for cardiovascular diseases. Majority of patients with diabetes also suffer from dyslipidemia (diabetic dyslipidemia). Diabetic dyslipidemia is more atherogenic as it is commonly associated with high triglyceride (TG) levels, high proportion of small dense low-density lipoprotein cholesterol and low high-density lipoprotein cholesterol (HDL-C) level (atherogenic dyslipidemia). Currently used pharmacotherapies for the management of diabetes and dyslipidemia like thiazolidinediones (PPAR-γ agonist; for insulin resistance) and fibrates (PPAR-α agonist; for hypertriglyceridemia) have many limitations and side effects. Saroglitazar, a dual PPAR-α/γ agonists, is an emerging therapeutic option with its dual benefit on glycemic and lipid parameters.

Areas covered: This paper reviews the clinical development of saroglitazar for the management of diabetic dyslipidemia. The efficacy and safety profile of saroglitazar is reviewed in context to currently available therapy like pioglitazone for diabetes and fibrates for hypertriglyceridemia. In addition, this paper also reviews the association between diabetes and dyslipidemia and the role of TG in reducing cardiovascular events.

Expert opinion: Saroglitazar, a dual PPAR-α/γ agonist, is a potential therapeutic option for the management of diabetic dyslipidemia. It has dual benefit of significant improvement in glycemic parameters (glycated hemoglobin and fasting blood glucose) and significant improvement in dyslipidemia (TGs, apolipoprotein B, non-HDL-C). The results of Phase III clinical trials indicate that saroglitazar is devoid of conventional side effects of fibrates and pioglitazone. Future clinical trials of saroglitazar will further establish its place in the management of diabetes, dyslipidemia and associated cardiovascular risk.     

Acebutolol in the treatment of diabetic patients with hypertension

A double-blind, parallel group comparison study was carried out in 20 diabetic patients with mild to moderate hypertension to assess the effectiveness and tolerance of acebutolol compared with placebo. After a 4-week wash-out period on placebo, patients received either 400 mg acebutolol or placebo once daily for 12 weeks and then placebo for a further 4 weeks. The results showed that acebutolol was more effective than placebo in lowering raised blood pressure in these patients. No deterioration in diabetic control occurred during the study and no significant side-effects of the drug were observed compared with placebo. In particular, the previously described side-effects of beta-blocker therapy in diabetic patients were not observed as a clinical problem in this study.     

Acebutolol in the treatment of diabetic patients with hypertension

Summary

A double-blind, parallel group comparison study was carried out in 20 diabetic patients with mild to moderate hypertension to assess the effectiveness and tolerance of acebutolol compared with placebo. After a 4-week wash-out period on placebo, patients received either 400?mg acebutolol or placebo once daily for 12 weeks and then placebo for a further 4 weeks. The results showed that acebutolol was more effective than placebo in lowering raised blood pressure in these patients. No deterioration in diabetic control occurred during the study and no significant side-effects of the drug were observed compared with placebo. In particular, the previously described side-effects of beta-blocker therapy in diabetic patients were not observed as a clinical problem in this study.     

The role of cilostazol in the treatment of intermittent claudication

SUMMARY

This paper represents a review, by experts, of current opinion and information on intermittent claudication (IC) and the role that cilostazol plays in its treatment. IC is a common and debilitating condition that has a significant adverse impact on health-related quality of life (HR-QoL). It is currently under-recognised as a powerful marker of increased cardiovascular (CV) risk. The clinical priority is secondary prevention – sometimes referred to as best medical therapy aimed at reducing CV risk. However, the priority for most patients (often overlooked by clinicians) is symptom relief: an increase in walking distance leading to an improvement in HR-QoL. The symptoms of IC may be improved by exercise, pharmacotherapy, and when these are unsuitable or unsuccessful, endovascular or surgical intervention.     

The impact of statin treatment on diabetic patients

Retrospective analysis of secondary prevention trials indicates that 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors (statins) reduce the risk of recurrent coronary heart disease events in individuals with diabetes. Diabetic individuals may receive greater benefit from statin treatment than non-diabetic individuals, because of a higher absolute risk. Available data are limited, although several randomized trials of primary prevention with diabetic patients are ongoing. The low-density lipoprotein cholesterol goal is now considered to be < 100 mg/dl for individuals with diabetes. Pleiotropic effects of statins may be involved in anti-atherogenic or other actions of statin.     

吡格列酮治疗2型糖尿病的疗效观察

目的评价吡格列酮治疗2型糖尿病的有效性和安全性。方法将60例未接受胰岛素治疗的2型糖尿病人随机分成两组,观察组(30例)予吡格列酮30mg/d,对照组(30例)予二甲双胍0.75g/d,治疗12周。对两组患者的疗效和安全性进行比较。结果两种药物均使空腹和餐后血糖、HbA1C明显下降(P<0.05),两组疗效相似。两组不良事件发生率相似。结论吡格列酮治疗2型糖尿病安全、有效。     

Clinical effects of intravenous iloprost in patients with intermittent claudication

Summary In a randomized patient-blind study iloprost or hydroxy-ethyl starch 200/0.5 were given i.v. 5 h daily for 2 weeks to 24 patients suffering from severe intermittent claudication due to peripheral vascular disease. An increase in pain-free walking distance of more than 50% occurred in 6 of 11 patients after the iloprost infusions and in 7 of 12 patients after HES treatment. No significant effects on haemodynamic or clinical chemistry tests were observed.