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.     

Cilostazol (pletal): a dual inhibitor of cyclic nucleotide phosphodiesterase type 3 and adenosine uptake

Cilostazol (Pletal), a quinolinone derivative, has been approved in the U.S. for the treatment of symptoms of intermittent claudication (IC) since 1999 and for related indications since 1988 in Japan and other Asian countries. The vasodilatory and antiplatelet actions of cilostazol are due mainly to the inhibition of phosphodiesterase 3 (PDE3) and subsequent elevation of intracellular cAMP levels. Recent preclinical studies have demonstrated that cilostazol also possesses the ability to inhibit adenosine uptake, a property that may distinguish it from other PDE3 inhibitors, such as milrinone. Elevation of interstitial and circulating adenosine levels by cilostazol has been found to potentiate the cAMP-elevating effect of PDE3 inhibition in platelets and smooth muscle, thereby augmenting antiplatelet and vasodilatory effects of the drug. In contrast, elevation of interstitial adenosine by cilostazol in the heart has been shown to reduce increases in cAMP caused by the PDE3-inhibitory action of cilostazol, thus attenuating the cardiotonic effects. Cilostazol has also been reported to inhibit smooth muscle cell proliferation in vitro and has been demonstrated in a clinical study to favorably alter plasma lipids: to decrease triglyceride and to increase HDL-cholesterol levels. One, or a combination of several of these effects may contribute to the clinical benefits and safety of this drug in IC and other disease conditions secondary to atherosclerosis. In eight double-blind randomized placebo-controlled trials, cilostazol significantly increased maximal walking distance, or absolute claudication distance on a treadmill. In addition, cilostazol improved quality of life indices as assessed by patient questionnaire. One large randomized, double-blinded, placebo-controlled, multicenter competitor trial demonstrated the superiority of cilostazol over pentoxifylline, the only other drug approved for IC. Cilostazol has been generally well-tolerated, with the most common adverse events being headache, diarrhea, abnormal stools and dizziness. Studies involving off-label use of cilostazol for prevention of coronary thrombosis/restenosis and stroke recurrence have also recently been reported.     

Treatment of intermittent claudication with pentoxifylline and cilostazol.

The pathophysiology of intermittent claudication (IC) and the role of pentoxifylline and cilostazol for treating IC are discussed. IC, a result of inadequate blood flow to the musculature, is the primary symptom of occlusive peripheral vascular disease (PVD). Patients with IC often have a decreased quality of life because of mobility limitations. PVD is a sign of generalized atherosclerosis and increases the risk of cardiac morbidity and mortality. Smoking, hypertension, diabetes mellitus, and increasing age may hasten the progression of PVD. Strategies for treating IC are aimed at improving symptoms and reducing the progression of atherosclerosis and include risk-factor modification, exercise, and antiplatelet therapy. Cilostazol and pentoxifylline are the only two drugs with FDA-approved labeling for use in treating IC. Both drugs have been shown to increase pain-free walking time and total distance walked, although there is some conflicting evidence for pentoxifylline. Cilostazol and pentoxi-fylline are fairly well tolerated; the most common adverse effects involve the gastrointestinal tract and central nervous system. Inhibitors of cytochrome P-450 isoenzymes 3A4 and 2C19 should be used cautiously in patients taking cilostazol, and this drug is contraindicated in patients with congestive heart failure. Cilostazol is more costly than pentoxifylline. Initiation of therapy with either pentoxifylline or cilostazol may be reasonable if risk-factor modifications, lifestyle changes, and antiplatelet therapy are not effective. The mainstays of therapy for IC are risk-factor modification, exercise, and antiplatelet therapy. If these prove inadequate, treatment with pentoxifylline or cilostazol may be reasonable.     

Treatment of chronic peripheral arterial disease

Peripheral arterial disease (PAD) is a common but under-recognized problem. Intermittent claudication is the most frequent symptom of PAD, although the diagnosis of PAD is often overlooked until the patient is presented with limb-threatening ischemia. Importantly, PAD is a marker of generalized atherosclerosis and is closely associated with coronary and cerebrovascular disease. The primary causes of death in patients with PAD are myocardial infarction and stroke. Reducing risk factors is an integral and aggressive part of the treatment regimen. The recognition and diagnosis of PAD, combined with its appropriate medical management, may well reduce the overall risk of cardiovascular morbidity. When diagnosed early, both exercise and pharmacotherapy can ameliorate symptoms of claudication. augment functional performance, and improve quality of life. This review focuses on the general medical management and specific therapeutic options. Because PAD is a manifestation of generalized atherosclerosis, the principal issue in medical management of PAD is a treatment plan that modifies known risk factors for atherosclerosis and its atherothrombotic complications. All patients with PAD should be receiving antiplatelet therapy to prevent ischemic events and ACE inhibitors should be used if appropriate. Medical treatment for patients with claudication includes exercise in rehabilitation and drug therapy. It is also recognized that selected patients with claudication symptoms may benefit from catheter-based interventions, and most PAD patients with critical leg ischemia require revascularization procedures. Although many therapies for claudication have been thoroughly investigated, research continues on new treatments. In contrast, more prospective, randomized trials are needed to evaluate various therapies for treating patients with PAD.     

Phosphodiesterases as targets for intermittent claudication

Intermittent claudication (IC) is one of the most frequent forms of lower extremity peripheral arterial disease (PAD) and is most commonly caused by arterial atherosclerosis. Its clinical manifestation includes fatigue, discomfort, or pain occurring in limb muscles due to exercise-induced ischemia, thus limiting the ability of IC patients to walk and exercise. In addition to lifestyle changes (diet, exercise, and smoking cessation), pharmacological treatments are needed. Pathologically, atherosclerotic lesions cause a mismatch in oxygen supply and metabolic demand in the leg muscles during walking/exercise. This subjects the muscles to repeated ischemia and reperfusion injury that can alter structure and oxidative metabolism, resulting in insufficient utilization of oxygen supply. Despite extensive research efforts, cilostazol and pentoxifylline are the only drugs indicated for relieving the symptoms of IC, with cilostazol demonstrating significant improvement in walking distance and quality of life in these patients. Originally developed as a PDE3 inhibitor, cilostazol was later found to have several other pharmacological actions, and its success has been attributed to its multifactorial actions on platelets, endothelium, smooth muscle, and lipid profiles. Using cilostazol as an example, we discuss the rationales and pitfalls of targeting PDEs in IC, and potential strategies for the development of new and more effective pharmacological treatments.     

Propionyl l-carnitine: intermittent claudication and peripheral arterial disease

Peripheral arterial disease (PAD) is a clinical manifestation of underlying aorto-iliac and leg atherosclerosis that is characterized by different stages of stenosis and obstruction. It affects approximately 12% of the adult population and about 20% of people over the age of 70 years, and is associated with increased cardiovascular (CV) and cerebrovascular morbidity. Intermittent claudication (IC) is the major symptom of PAD; it is defined as cramping leg pain (in the buttock, thigh, or calf) while/after clim bing one or two flights of stairs, or during walking. The goals of IC management are to: slow the progression of local and systemic atherosclerosis, prevent major fatal and nonfatal CV events (myocardial infarction and stroke), improve walking capacity, prevent and reduce resting pain and cutaneous lesions. Propionyl L-carnitine is an acyl derivative of levocarnitine (L-carnitine) and is indicated for patients with peripheral arterial occlusive disease. It corrects secondary muscle carnitine deficiency in patients with PAD, significantly improving the walking capacity; it is a free radical that produces positive effects on endothelial function; it protects from oxidative stress; and it enhances most measures of quality of life. The recent Trans-Atlantic Inter-Society Consensus II update recommends the use of propionyl L-carnitine in combination with physical training to improve the symptoms associated with PAD.     

Efficacy of ruxolitinib for myelofibrosis

Peripheral arterial disease (PAD) encompasses the vascular diseases caused primarily by atherosclerosis and thromboembolic pathophysiological processes that alter the normal structure and function of the aorta, its visceral arterial branches and the arteries of the upper and lower extremities. PAD is associated with an increased risk for cardiovascular morbidity and mortality. The goals for pharmacological therapy in PAD should focus on reducing cardiovascular risk, improving walking distance and preventing critical limb ischaemia. Exercise training plays a key role in the therapeutic assessment, as well stopping smoking. Antiplatelet therapy (aspirin) should be given to every PAD patient if there are no contraindications. Neither their combination nor anticoagulant therapy has shown additional benefit in PAD patients. Several pharmacological agents have been developed to improve the functional state of the claudicant and to relieve the symptoms. Many studied drugs have shown either no, a small or a potential benefit. With future development of new drugs for PAD, there is an absolute need for very strict well-designed protocols in order to evaluate the claudication distance, the progression of the disease and the reduction in cardiovascular morbidity and mortality. New developments should focus on improvement of endothelial function, vascular repair and enhancement of collateral circulation.     

Antiplatelet therapy in peripheral artery disease

Peripheral artery disease (PAD) is a term that relates to atherosclerosis and narrowing of the arteries in the lower extremities. The prevalence of PAD is approximately 12% of the adult population. Despite the low rate of peripheral complications and amputation, PAD is complicated by a high rate of cardiovascular events including myocardial infarction, stroke, and vascular death with an annual incidence of about 5%.The detection of PAD is initially based on the appearance of typical symptoms (claudication and critical limb ischemia) related to peripheral arterial insufficiency. However, PAD may also be present in the absence of clinical symptoms (asymptomatic PAD). Accordingly, asymptomatic disease may occur in up to 50% of all patients with PAD. Ankle brachial index (ABI) is a diagnostic test used to evaluate the presence of PAD, defined by an ABI ≤0.90. The ABI is also demonstrated to be useful in the assessment of vascular risk in asymptomatic and symptomatic patients. Antiplatelet therapy remains a key intervention to reduce cardiovascular risk in PAD. Data from Antithrombotic Trialists' Collaboration showed that antiplatelet treatment was associated with a 23% risk reduction of vascular events in overall population with PAD. However, closer scrutiny of these data reveals that nonaspirin antiplatelet drugs, including ticlopidine, clopidogrel, picotamide, and dipyridamole largely drove the benefits in the PAD subgroup. It remains an open issue if PAD represents an atherosclerotic clinical model where aspirin, differently from coronary heart disease, is less effective in reducing atherosclerotic progression. Based on the reported results further trials with aspirin should be done in asymptomatic (ABI ≤0.90) and symptomatic PAD patients. Finally, the role of new antiplatelet drugs such as prasugrel and ticagrelor has not yet been studied in PAD.     

Cilostazol as a unique antithrombotic agent

Cilostazol (CLZ) was originally developed as a selective inhibitor of cyclic nucleotide phosphodiesterase 3 (PDE3). PDE3 inhibition in platelets and vascular smooth muscle cells (VSMC) was expected to provide an antiplatelet effect and vasodilation. Recent preclinical studies have demonstrated that CLZ also possesses the ability to inhibit adenosine uptake by various cells, a property that distinguishes CLZ from other PDE3 inhibitors, such as milrinone. After extensive preclinical and clinical studies, CLZ has been shown to have unique antithrombotic and vasodilatory properties based upon these novel mechanisms of action. CLZ was approved in 1988 for the treatment of symptoms related to peripheral arterial occlusive disease in Japan (Pletaal) and in 1999 in the U.S. and in 2001 in the U.K. (Pletal) for the treatment of intermittent claudication symptoms. Despite its remarkable antiplatelet properties, CLZ is not generally considered an antithrombotic agent in Western countries, perhaps due to the bulk of its antithrombotic preclinical and clinical development being conducted in Japan. In this review, the unique properties of CLZ are reviewed with the focus on CLZ as a unique antiplatelet agent targeting platelets and VSMC, demonstrating synergy with endogenous mediators and showing lowered risk of bleeding risk compared to other antiplatelet drugs.     

Pharmacological interventions for peripheral artery disease

Peripheral arterial disease (PAD) encompasses the vascular diseases caused primarily by atherosclerosis and thromboembolic pathophysiological processes that alter the normal structure and function of the aorta, its visceral arterial branches and the arteries of the upper and lower extremities. PAD is associated with an increased risk for cardiovascular morbidity and mortality. The goals for pharmacological therapy in PAD should focus on reducing cardiovascular risk, improving walking distance and preventing critical limb ischaemia. Exercise training plays a key role in the therapeutic assessment, as well stopping smoking. Antiplatelet therapy (aspirin) should be given to every PAD patient if there are no contraindications. Neither their combination nor anticoagulant therapy has shown additional benefit in PAD patients. Several pharmacological agents have been developed to improve the functional state of the claudicant and to relieve the symptoms. Many studied drugs have shown either no, a small or a potential benefit. With future development of new drugs for PAD, there is an absolute need for very strict well-designed protocols in order to evaluate the claudication distance, the progression of the disease and the reduction in cardiovascular morbidity and mortality. New developments should focus on improvement of endothelial function, vascular repair and enhancement of collateral circulation.     

Pharmacological treatment of the psychosis of Alzheimer's disease: what is the best approach?

Psychosis of Alzheimer's disease (PAD) forms part of the behavioural and psychological symptoms of dementia (BPSD). PAD includes symptoms of psychosis such as hallucinations or delusions, and may be associated with agitation, negative symptoms or depression. Even though the US FDA has not approved any medication for the treatment of PAD, atypical antipsychotics have been widely used and favoured by geriatric experts in the management of the condition in view of their modest efficacy and relative safety. However, the recent FDA warnings regarding the cardiac, metabolic, cerebrovascular and mortality risks associated with the use of these drugs in elderly patients with dementia have caused serious concerns regarding their use. Nevertheless, until an effective and safe medication is approved by the regulatory agencies for PAD, clinicians do not have a better choice than atypical antipsychotics for the management of the serious symptoms of this condition.     

Emerging drugs in peripheral arterial disease

Peripheral arterial disease (PAD) is the manifestation of atherosclerotic occlusion within a peripheral vascular bed. This can occur in any noncoronary arterial bed, but PAD most commonly refers to atherosclerosis in the aorto-iliac system and infrainguinal vessels that lead to symptoms in the lower extremities. The disease most often becomes clinically apparent in elderly individuals, commonly presenting as intermittent claudication. More advanced, or multisegmental disease, may present with ischaemic rest pain or tissue loss. Although the limb manifestations of PAD can be disabling, PAD is also a marker of coronary or cerebrovascular atherosclerosis. In fact, approximately 80% of mortality in PAD patients is secondary to a cardiovascular event. In accordance with this, initial medical management of this disease focuses on preventative and risk reduction strategies to minimise the risk of cardiovascular morbidity and mortality. At present, the majority of recommendations with respect to risk reduction therapy in PAD patients are extrapolated from the coronary and cerebrovascular literature. Limb-directed therapy in PAD intends to minimise symptoms and serve as an adjunct to surgical intervention. However, existing data on the efficacy of these agents suggests that they are only partially effective. In addition, the effect of existing nonoperative intervention on the progression of disease has not been completely elucidated. As such, new therapies are under development, which target various goals, including minimising local progression of disease, minimising disability, reducing systemic cardiovascular morbidity/mortality and augmenting the durability of surgical intervention.     

Emerging drugs in peripheral arterial disease

Peripheral arterial disease (PAD) is the manifestation of atherosclerotic occlusion within a peripheral vascular bed. This can occur in any noncoronary arterial bed, but PAD most commonly refers to atherosclerosis in the aorto–iliac system and infrainguinal vessels that lead to symptoms in the lower extremities. The disease most often becomes clinically apparent in elderly individuals, commonly presenting as intermittent claudication. More advanced, or multisegmental disease, may present with ischaemic rest pain or tissue loss. Although the limb manifestations of PAD can be disabling, PAD is also a marker of coronary or cerebrovascular atherosclerosis. In fact, ~ 80% of mortality in PAD patients is secondary to a cardiovascular event. In accordance with this, initial medical management of this disease focuses on preventative and risk reduction strategies to minimise the risk of cardiovascular morbidity and mortality. At present, the majority of recommendations with respect to risk reduction therapy in PAD patients are extrapolated from the coronary and cerebrovascular literature. Limb-directed therapy in PAD intends to minimise symptoms and serve as an adjunct to surgical intervention. However, existing data on the efficacy of these agents suggests that they are only partially effective. In addition, the effect of existing nonoperative intervention on the progression of disease has not been completely elucidated. As such, new therapies are under development, which target various goals, including minimising local progression of disease, minimising disability, reducing systemic cardiovascular morbidity/mortality and augmenting the durability of surgical intervention.     

The effect of risk factor changes on peripheral arterial disease and cardiovascular risk

Peripheral arterial disease (PAD) due to atherosclerosis, although frequently ignored in clinical practice, results in significant cardiovascular morbidity and mortality and may progress due to uncontrolled atherosclerotic risk factors. Although treatment of claudication symptoms is important for improved lifestyle, treatment of risk factors will prolong life. Smoking cessation, blood pressure control, lipid modification and strict control of diabetes mellitus will reduce the risk of both macro and micro vascular disease progression. Risk factor modification in conjunction with antiplatelet treatment results in decreased heart attack, stroke and peripheral vascular events in patients with PAD.     

Endothelin-1 in peripheral arterial disease: A potential role in muscle damage

The evidence for the role of endothelin-1 (ET-1) in endothelial dysfunction and atherosclerosis has been growing since its discovery. However most studies have focussed on cardiac disease and its role in peripheral arterial disease (PAD) is less clear. In addition to its role in the development and progression of atherosclerotic lesions in lower limb arteries, there is evidence that ET-1 adversely affects microvessels within the muscle and the viability of the ischemic muscle itself. This review summarises some of these findings which underscore the potential use of ET antagonists as an adjunct in the treatment of PAD.     

Inhibition of adenosine uptake and augmentation of ischemia-induced increase of interstitial adenosine by cilostazol, an agent to treat intermittent claudication

Cilostazol (Pletal), a quinolinone derivative with a cyclic nucleotide phosphodiesterase type 3 (PDE3) inhibitory activity, was recently approved by the Food and Drug Administration for treatment of symptoms of intermittent claudication (IC). However, the underlying mechanisms of action are not entirely clear. In this study, we showed that cilostazol inhibited adenosine uptake into cardiac ventricular myocytes, coronary artery smooth muscle, and endothelial cells with a median effective concentration (EC50) approximately 10 microM. In vivo, cilostazol increased cardiac interstitial adenosine levels after a 2-min ischemia in rabbit hearts (329 +/- 92% increase vs. 102 +/- 29% ischemia alone). The combination of cilostazol and 2-min ischemia reduced infarction from subsequent 30-min regional ischemia and 3 h of reperfusion (infarct size was 18 +/- 4% vs. 53 +/- 3% in the hearts with 2-min ischemia alone or 48 +/- 2% in the hearts treated with cilostazol alone). In contrast, milrinone had no effect on either adenosine uptake or interstitial adenosine levels. These data show that cilostazol, unlike milrinone, inhibits adenosine uptake, and thus potentiates adenosine accumulation from a 2-min ischemia. Future studies are needed to investigate the role of adenosine in the treatment of IC by cilostazol.     

Developing pharmaceutical treatments for peripheral artery disease

Peripheral artery disease (PAD) is a debilitating atherosclerotic disease of the lower limbs and is associated with an increased risk of cardiovascular morbidity and mortality. Treatment goals should be aimed at providing symptom relief (claudication) and reducing the risk of systemic cardiovascular morbidity and mortality. In the development of pharmaceutical treatment for PAD, aggressive non-pharmacological intervention and pharmacological treatment of the risk factors associated with PAD should be given. Antiplatelet therapy, aspirin, should be given to every PAD patient if there are no contraindications. Should symptoms worsen or intolerance to aspirin develop, ticlopidine or clopidogrel would be the alternative. Several pharmacological agents have been developed to improve the functional state of the claudicant and to relieve the symptoms. Many studied drugs have shown either no, small or potential benefit. With future development of new drugs for PAD, there is an absolute need for very strict, well-designed protocols in order to evaluate the claudication distance and progression of the disease, as well as the reduction in cardiovascular morbidity and mortality.     

Developing pharmaceutical treatments for peripheral artery disease

Peripheral artery disease (PAD) is a debilitating atherosclerotic disease of the lower limbs and is associated with an increased risk of cardiovascular morbidity and mortality. Treatment goals should be aimed at providing symptom relief (claudication) and reducing the risk of systemic cardiovascular morbidity and mortality. In the development of pharmaceutical treatment for PAD, aggressive non-pharmacological intervention and pharmacological treatment of the risk factors associated with PAD should be given. Antiplatelet therapy, aspirin, should be given to every PAD patient if there are no contraindications. Should symptoms worsen or intolerance to aspirin develop, ticlopidine or clopidogrel would be the alternative. Several pharmacological agents have been developed to improve the functional state of the claudicant and to relieve the symptoms. Many studied drugs have shown either no, small or potential benefit. With future development of new drugs for PAD, there is an absolute need for very strict, well-designed protocols in order to evaluate the claudication distance and progression of the disease, as well as the reduction in cardiovascular morbidity and mortality.     

Cardiovascular morbidity and mortality in peripheral arterial disease

The term peripheral arterial disease (PAD) is often used to describe atherosclerosis involving the arteries supplying the lower extremities. Potentially modifiable factors that predispose to the development and progression of both symptomatic and asymptomatic PAD include smoking, diabetes mellitus, hyperlipidemia, and hypertension. Since the same risk factors for PAD predispose to the development of systemic atherosclerosis, identification of PAD increases the likelihood of coexistent coronary heart and cerebrovascular disease. Even after adjustment for risk factors, PAD appears to increase the risk for ischemic manifestations involving these other vascular territories with about a 2-fold increase in myocardial infarction and perhaps stroke. The most dramatic consequence of PAD is impaired survival with a 2- to 3-fold increased risk of 5- to 10-year mortality. While the adverse cardiovascular and cerebrovascular complications are highest for persons with more severe PAD, there is still a significant risk in persons with mild and even asymptomatic disease. The focus in the management of PAD should be on early diagnosis and efforts to reduce the risk of adverse events including risk factor modification and antiplatelet therapy.