Cilostazol

Cilostazol is an antiplatelet agent with vasodilating properties that has been used in the treatment of patients with peripheral ischaemia such as intermittent claudication. The drug inhibits platelet aggregation induced by ADP, collagen and arachidonic acid. Unlike aspirin (acetylsalicylic acid), cilostazol inhibits both primary and secondary aggregation. It also acts as a vascular vasodilator by inhibiting calcium-induced contractions while having no direct effect on contractile proteins. In double-blind randomised trials, patients with intermittent claudication receiving cilostazol showed significant improvements versus placebo in terms of time to initial pain and maximal walking or absolute claudication distance; these findings were confirmed by cilostazol patients' positive responses on subscales measuring physical functioning and quality of life. In a 24-week randomised double-blind trial in patients with intermittent claudication, cilostazol 100mg twice daily produced significant improvements in pain-free and maximum walking distances, compared with pentoxifylline (oxpentifylline) 400mg 3 times daily and placebo. Cilostazol has been well tolerated, with the most common adverse events being headache, diarrhoea, abnormal stools and dizziness.     

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.     

Comparison of the effects of cilostazol and milrinone on intracellular cAMP levels and cellular function in platelets and cardiac cells.

Cilostazol is a potent cyclic nucleotide phosphodiesterase (PDE) type 3 (PDE3) inhibitor that was recently approved by the Food and Drug Administration (FDA) for the treatment of intermittent claudication. Its efficacy is presumed to be due to its vasodilatory and platelet activation inhibitory activities. Compared with those treated with placebo, patients treated with cilostazol showed a minimal increase in cardiac adverse events. Because of its PDE3 inhibitory activity, however, the possibility that cilostazol exerts positive cardiac inotropic effects is a safety concern. Therefore we compared the effects of cilostazol with those of milrinone, a selective PDE3 inhibitor, on intracellular cyclic adenosine monophosphate (cAMP) levels in platelets, cardiac ventricular myocytes, and coronary smooth muscle cells. We also compared the corresponding functional changes in these cells. Cilostazol and milrinone both caused a concentration-dependent increase in the cAMP level in rabbit and human platelets with similar potency. Furthermore, cilostazol and milrinone were equally effective in inhibiting human platelet aggregation with a median inhibitory concentration (IC50) of 0.9 and 2 microM, respectively. In rabbit ventricular myocytes, however, cilostazol elevated cAMP levels to a significantly lesser extent (p < 0.05 vs. milrinone). By using isolated rabbit hearts with a Langendorff preparation, we showed that milrinone is a very potent cardiotonic agent; it concentration-dependently increased left ventricular developed pressure (LVDP) and contractility. Cilostazol was less effective in increasing LVDP and contractility (p < 0.05 vs. milrinone), which is consistent with the cardiac cAMP levels. The cardiac effect of OPC-13015, a metabolite of cilostazol with about sevenfold higher PDE3 inhibition, was similar to cilostazol. Whereas milrinone concentration-dependently increased cAMP in rabbit coronary smooth muscle cells, cilostazol did not have such an effect. However, both compounds increased coronary flow equally in rabbit hearts. Our results show that although cilostazol and milrinone both inhibit PDE3, cilostazol preferentially acts on vascular elements (platelets and flow). This unique profile of cilostazol is consistent with its beneficial and safe clinical outcomes in patients with intermittent claudication.     

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.     

Cilostazol and dipyridamole synergistically inhibit human platelet aggregation

It has been previously shown that cilostazol (Pletal), a drug for relief of symptoms of intermittent claudication, potently inhibits cyclic nucleotide phosphodiesterase type 3 (PDE3) and moderately inhibits adenosine uptake. It elevates extracellular adenosine concentration, by inhibiting adenosine uptake, and combines with PDE3 inhibition to augment inhibition of platelet aggregation and vasodilation while attenuating positive chronotropic and inotropic effects on the heart. In the present study, we tested the hypothesis that cilostazol combined with a more potent adenosine uptake inhibitor, dipyridamole, synergistically inhibited platelet aggregation in human blood. In the presence of exogenous adenosine (1 microM), the combination of cilostazol and dipyridamole synergistically increased intra-platelet cAMP. Furthermore, cilostazol inhibited platelet aggregation in a washed platelet assay concentration-dependently with IC50s of 0.17 +/- 0.04 microM (P < 0.05 versus plus adenosine alone of 0.38 +/- 0.05 microM), 0.11 +/- 0.06 microM (P < 0.05), and 0.01 +/- 0.01 microM (P < 0.005) when combined with 1, 3, or 10 microM dipyridamole, respectively (n = 5). In whole blood, cilostazol (0.3 to 3 microM) and dipyridamole (1 or 3 microM) synergistically inhibited collagen- and ADP-induced platelet aggregation in vitro. Furthermore, the synergism was confirmed in an open-label, sequential study in healthy human subjects using ex vivo whole-blood collagen-induced platelet aggregation. Four hours after oral co-administration of cilostazol (100 mg) and dipyridamole (200 mg), platelet aggregation was inhibited by 45 +/- 17%, while no significant inhibition was observed from subjects treated with either drug alone. The combination may provide a potential treatment of arterial thrombotic disorders.     

Cilostazol down-regulates the height of mural platelet thrombi formed under a high-shear rate flow in the absence of ADAMTS13 activity

Cilostazol is an anti-platelet drug that reversibly inhibits phosphodiesterase III (PDE-III), which is ubiquitously expressed in platelets and various tissues. PDE-III converts cyclic adenosine monophosphate (cAMP) to 5'-AMP and up-regulates the intracellular concentration of cAMP, a potent inhibitor of platelet aggregation. Unlike other anti-platelet drugs, cilostazol is unique because patients receiving this drug do not have a significantly prolonged bleeding time, but the reasons for this difference are still unknown. In this study, we have examined how cilostazol inhibits platelet thrombus formation using anti-coagulated normal whole blood in which the platelets were labeled with a fluorescent dye in comparison with the anti-GPIIb/IIIa agent, tirofiban. We used an in vitro assay to examine mural platelet thrombus growth on a collagen surface under a high-shear rate flow in the absence of ADAMTS13 activity. These experimental conditions mimic the blood flow in patients with thrombotic thrombocytopenic purpura. Using this model, we clearly determined that cilostazol down-regulates the height of mural platelet thrombi formed on a collagen surface in a dose-dependent manner, without affecting the surface coverage. The concentration of cilostazol used in this study was relatively high (60-120μM) compared to clinically relevant concentrations (1-3μM), which may be due to the in vivo synergistic effects of PDE-III present in other tissues aside from platelets. Cilostazol does not affect the initial formation of platelet thrombi, but does inhibit the height of thrombi. These results showed a sharp contrast to tirofiban, and address why cilostazol does not significantly prolong bleeding time, despite its strong anti-platelet activity.     

New mechanism of action for cilostazol: interplay between adenosine and cilostazol in inhibiting platelet activation

Cilostazol, a potent phosphodiesterase 3 inhibitor and anti-thrombotic agent, was recently shown to inhibit adenosine uptake into cardiac myocytes and vascular cells. In the present studies, cilostazol inhibited [ H]-adenosine uptake in both platelets and erythrocytes with a median inhibitory concentration (IC ) of 7 micro M. Next collagen-induced platelet aggregation was studied and it was found that adenosine (1 micro M ), having no effect by itself, shifted the IC of cilostazol from 2.66 micro M to 0.38 micro M (p < 0.01). This shifting was due to an enhanced accumulation of cAMP in platelets and was significantly larger than that by the combination of adenosine and milrinone, which has no effect on adenosine uptake. Similarly, cilostazol, by blocking adenosine uptake, enhanced the adenosine-mediated cAMP increase in Chinese hamster ovary cells that overexpress human A receptor. Furthermore, the inhibitory effect of cilostazol on platelet aggregation in whole blood was significantly reversed by ZM241385 (100 n ), an A adenosine receptor antagonist, and by adenosine deaminase (2 U/ml). These data suggest that the inhibitory effects of cilostazol on adenosine uptake and phosphodiesterase 3 together elevate intracellular cAMP, resulting in greater inhibition of agonist-induced platelet activation.     

Protective effects of cilostazol against transient focal cerebral ischemia and hemorrhagic transformation

Cilostazol, a selective inhibitor of phosphodiesterase III, is an antiplatelet drug and a vasodilator via increased cAMP levels. It has been approved for the treatment of ischemic symptoms in chronic peripheral arterial obstruction or intermittent claudication and for secondary prevention of cerebral infarction (CSPS I). Recently, cilostazol has been reported to be more effective than aspirin in the secondary prevention of all types of stroke in patients and, in particular, prevent the secondary attack of hemorrhagic stroke in patients (CSPS II). Laboratory investigations revealed that cilostazol has a neuroprotective effect against ischemic brain injury. The neuroprotective potential is dependent on its antiinflammatory and antiapoptotic effects mediated by scavenging hydroxyl radicals, decreasing formation of tumor necrosis factor-α, and inhibition of poly (ADP-ribose) polymerase activity. In addition, increasing evidence indicates that cilostazol may offer endothelial protection via both the inhibition of lipopolysaccharide-induced apoptosis and induced nitric oxide (NO) production by endothelial NO synthase activation. The breakdown of the barrier permeability of the blood brain barrier (BBB) often accelerates the progression of diseases such as cerebral ischemia. However, the molecular mechanisms involved in BBB disruption have not been fully determined. Identification of the molecules responsible for the disruption of the endothelial barrier may yield new therapeutic targets in intractable diseases. This article reviews the protective effects of cilostazol against transient focal cerebral ischemia and hemorrhagic transformation and its mechanism of action.     

Cilostazol Decreases Ethanol-Mediated TNFalpha Expression in RAW264.7 Murine Macrophage and in Liver from Binge Drinking Mice

Alcoholic hepatitis is a leading cause of liver failure in which the increased production of tumor necrosis factor α (TNFα) plays a critical role in progression of alcoholic liver disease. In the present study, we investigated the effects of cilostazol, a selective inhibitor of type III phosphodiesterase on ethanol-mediated TNFα production in vitro and in vivo, and the effect of cilostazol was compared with that of pentoxifylline, which is currently used in clinical trial. RAW264.7 murine macrophages were pretreated with ethanol in the presence or absence of cilostazol then, stimulated with lipopolysacchride (LPS). Cilostazol significantly suppressed the level of LPS-stimulated TNFα mRNA and protein with a similar degree to that by pentoxifylline. Cilostazol increased the basal AMP-activated protein kinase (AMPK) activity as well as normalized the decreased AMPK by LPS. AICAR, an AMPK activator and db-cAMP also significantly decreased TNFα production in RAW264.7 cells, but cilostazol did not affect the levels of intracellular cAMP and reactive oxygen species (ROS) production. The in vivo effect of cilostazol was examined using ethanol binge drinking (6 g/kg) mice model. TNFα mRNA and protein decreased in liver from ethanol gavaged mice compared to that from control mice. Pretreatment of mice with cilostazol or pentoxifylline further reduced the TNFα production in liver. These results demonstrated that cilostazol effectively decrease the ethanol-mediated TNFα production both in murine macrophage and in liver from binge drinking mice and AMPK may be responsible for the inhibition of TNFα production by cilostazol.     

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.     

Cost effectiveness of cilostazol compared with naftidrofuryl and pentoxifylline in the treatment of intermittent claudication in the UK

OBJECTIVE: To estimate the cost effectiveness of cilostazol (Pletal) compared to naftidrofuryl and pentoxifylline (Trental) in the treatment of intermittent claudication in the UK. DESIGN AND SETTING: This was a modelling study on the management of patients with intermittent claudication who are 40 years of age or above and have at least six months history of symptomatic intermittent claudication, secondary to lower extremity arterial occlusive disease. The study was performed from the perspective of the UK's National Health Service (NHS). METHODS: Clinical outcomes attributable to managing intermittent claudication were obtained from the published literature and resource utilisation estimates were derived from a panel of vascular surgeons. Using decision analytical techniques, a decision model was constructed depicting the management of intermittent claudication with cilostazol, naftidrofuryl and pentoxifylline over 24 weeks in the UK. The model was used to estimate the cost effectiveness (at 2002/2003 prices) of cilostazol relative to the other treatments. MAIN OUTCOME MEASURES AND RESULTS: Starting treatment with cilostazol instead of naftidrofuryl is expected to increase the percentage improvement in maximal walking distance by 32% (from 57% to 75%) for a 12% increase in NHS costs (from 801 pounds sterling to 895 pounds sterling). Treatment with cilostazol instead of pentoxifylline is expected to increase the percentage improvement in maximal walking distance by 67% (from 45% to 75%) and reduce NHS costs by 2% (from 917 pounds sterling to 895 pounds sterling). Treatment with naftidrofuryl instead of pentoxifylline is expected to increase the percentage improvement in maximal walking distance by 27% (from 45% to 57%) and decrease NHS costs by 14% (from 917 pounds sterling to 801 pounds sterling). CONCLUSION: Within the limitations of our model, starting treatment with cilostazol is expected to be a clinically more effective strategy for improving maximal walking distance at 24 weeks than starting treatment with naftidrofuryl or pentoxifylline and potentially the most cost effective strategy. Moreover, the acquisition cost of a drug should not be used as an indication of the cost effectiveness of a given method of care.     

Cilostazol: therapeutic potential against focal cerebral ischemic damage

Cilostazol was developed as a selective inhibitor of cyclic nucleotide phosphodiesterase 3 (PDE3). The anti-platelet and vasodilator properties of cilostazol have been extensively characterized and considered to contribute to the variety of clinical effects such as intermittent claudication and recurrent stroke. In this review, the novel action mechanism (s) of cilostazol are overviewed with the focus on the action of cilostazol in in vitro and in vivo studies as a maxi-K channel opener targeting anti-apoptotic signaling pathways. Under treatment with cilostazol (10 mg/kg intravenously or 30 mg/kg orally), a significant reduction in cerebral infarct area was evident in rats subjected to ischemia/reperfusion. Increase in cyclic AMP and decrease in TNF-alpha levels were identified in the ipsilateral cortex under treatment with cilostazol accompanied by decreased Bax formation and cytochrome c release with increased Bcl-2 production in the penumbral area as well as in the in vitro human umbilical endothelial cells. Cilostazol suppressed TNF-alpha-induced decrease in viability of SK-N-SH (human neuroblastoma) cells and HCN-1A (human cortical neuron) cells in association with decrease in PTEN phosphorylation and increase in Akt/CREB phosphorylation with suppression of DNA fragmentation, all of which were antagonized by iberiotoxin, a maxi-K(+) channel blocker. Further, cilostazol prevented TNF-alpha-induced PTEN phosphorylation and apoptotic cell death via increased CK2 phosphorylation in the SK-N-SH cells. Cilostazol increased K(+) current in SK-N-SH cells by opening the maxi-K channels. Thus, it was suggested that the action of cilostazol to promote cell survival was ascribed to the maxi-K channel opening-coupled upregulation of CK2 phosphorylation and downregulation of PTEN phosphorylation with resultant increased phosphorylation of Akt and CREB. These in vitro data were confirmed in the in vivo results of rats subjected to focal transient ischemic damage.     

Inhibitory action of cilostazol,a phosphodiesterase III inhibitor,on catecholamine secretion from cultured bovine adrenal chromaffin cells

The effect of cilostazol, a phosphodiesterase III inhibitor, on catecholamine secretion was examined using bovine adrenal chromaffin cells in culture. Catecholamine secretion evoked by acetylcholine was markedly inhibited by cilostazol. In contrast, 56 mM K+-evoked secretion was slightly inhibited by cilostazol. Cilostazol elevated the level of cyclic AMP in the cells. However, a cyclic AMP analog (dibutyryl cAMP) or an adenylate cyclase activator (forskolin) failed to inhibit secretion of catecholamine induced by acetylcholine. Cilostazol decreased the level of intracellular free Ca2+ stimulated by acetylcholine. Cilostazol thus inhibits secretion of catecholamine through its blocking action on Ca2+ movement in the adrenal chromaffin cells.     

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.     

Clinical manifestation of atherosclerotic peripheral arterial disease and the role of cilostazol in treatment of intermittent claudication

Intermittent claudication (IC) is the symptomatic expression of peripheral arterial disease (PAD), which itself is a manifestation of systemic atherosclerosis. Like other forms of atherosclerosis, PAD is associated with elevated rates of cardiovascular and cerebrovascular morbidity and mortality. Until recently, therapeutic options for the treatment of the symptoms of IC have been limited, and the efficacy of available treatment has been questioned. Cilostazol, a selective phosphodiesterase III inhibitor with vasodilator, antiplatelet, and antiproliferative properties, has recently been approved for the treatment of IC symptoms in the United States. Cilostazol significantly improves maximal and pain-free walking distances. Clinical studies have also demonstrated that cilostazol favorably alters plasma lipids (elevates HDL-cholesterol, lowers triglycerides). These properties may contribute to the benefit of this drug in IC and in other diseases secondary to atherosclerosis.     

Cost effectiveness of cilostazol compared with naftidrofuryl and pentoxifylline in the treatment of intermittent claudication in the UK

ABSTRACT

Objective: To estimate the cost effectiveness of cilostazol (Pletal) compared to naftidrofuryl and pentoxifylline (Trental) in the treatment of intermittent claudication in the UK.

Design and setting: This was a modelling study on the management of patients with intermittent claudication who are 40 years of age or above and have at least six months history of symptomatic intermittent claudication, secondary to lower extremity arterial occlusive disease. The study was performed from the perspective of the UK's National Health Service (NHS).

Methods: Clinical outcomes attributable to managing intermittent claudication were obtained from the published literature and resource utilisation estimates were derived from a panel of vascular surgeons. Using decision analytical techniques, a decision model was constructed depicting the management of intermittent claudication with cilostazol, naftidrofuryl and pentoxifylline over 24 weeks in the UK. The model was used to estimate the cost effectiveness (at 2002/2003 prices) of cilostazol relative to the other treatments.

Main outcome measures and results: Starting treatment with cilostazol instead of naftidrofuryl is expected to increase the percentage improvement in maximal walking distance by 32% (from 57% to 75%) for a 12% increase in NHS costs (from £801 to £895). Treatment with cilostazol instead of pentoxifylline is expected to increase the percentage improvement in maximal walking distance by 67% (from 45% to 75%) and reduce NHS costs by 2% (from £917 to £895). Treatment with naftidrofuryl instead of pentoxifylline is expected to increase the percentage improvement in maximal walking distance by 27% (from 45% to 57%) and decrease NHS costs by 14% (from £917 to £801).

Conclusion: Within the limitations of our model, starting treatment with cilostazol is expected to be a clinically more effective strategy for improving maximal walking distance at 24 weeks than starting treatment with naftidrofuryl or pentoxifylline and potentially the most cost effective strategy. Moreover, the acquisition cost of a drug should not be used as an indication of the cost effectiveness of a given method of care.     

Cilostazol and atherogenic dyslipidemia: a clinically relevant effect?

INTRODUCTION: Cilostazol is a reversible, selective inhibitor of PDE3A able to significantly improve walking distance in patients with intermittent claudication. However, beyond its antiplatelet and vasodilator properties, cilostazol seems to have significant effects on atherogenic dyslipidemia. AREAS COVERED: The effects of cilostazol on plasma lipids, lipoproteins, apolipoproteins and postprandial lipemia are reviewed. A literature search (using Medline and Scopus) was performed up to 24 October 2010. The authors also manually reviewed the references of selected articles for any pertinent material. EXPERT OPINION: Cilostazol is able to significantly lower plasma triglyceride levels, with a concomitant increase in high-density lipoprotein (HDL) cholesterol concentrations. Additional effects on pro-atherogenic lipoproteins and apolipoproteins include those on remnant-like particles, HDL subclasses, apolipoprotein B and postprandial lipemia. Cilostazol can improve the pro-atherogenic lipid profile in patients with peripheral arterial disease or type 2 diabetes. Further studies are needed to establish whether cilostazol treatment exerts clinically relevant effects on atherogenic dyslipidemia in high-risk patients.     

Cilostazol treatment of claudication in diabetic patients

OBJECTIVE: To compare the efficacy and safety of cilostazol in diabetic and non-diabetic patients from eight (six placebo- and two active-controlled) randomised, double-blind phase III trials. DESIGN: We only included patients from the trial data set receiving cilostazol 100 mg twice daily (216 diabetic/599 non-diabetic) or placebo (220/616). Efficacy was measured by absolute claudication distance (ACD), using standard treadmill exercise protocols. RESULTS: Among diabetic and non-diabetic patients, cilostazol was superior to placebo (estimated treatment effect 1.15, 95% confidence interval, 1.05-1.25, p = 0.001; and 1.24, 1.18-1.31, p < 0.0001, respectively). There was no statistical difference in response between diabetic and non-diabetic subjects. In the efficacy analysis, cilostazol-treated diabetic subjects with the lowest baseline ACD (but not those with greater baseline ACD) walked approximately 34% farther than at baseline, whereas their non-diabetic counterparts walked 23% farther. There was no significant difference in the adverse event profile of the diabetic and non-diabetic patients on cilostazol. No excess haemorrhagic events occurred in cilostazol-treated diabetic patients. Trial duration varied from 12 to 24 weeks. CONCLUSIONS: Diabetic and non-diabetic patients with intermittent claudication respond favourably to cilostazol, with no significant difference in their overall response. Diabetic individuals with the most severe claudication respond better than those less affected, but the response of non-diabetic patients increases as baseline ACD increases. Adverse event incidence was comparable in the two populations, although diabetic patients might be expected to experience greater morbidity. Cilostazol is a safe and effective treatment for claudication in diabetic and non-diabetic populations.