Measuring treatment effects of Cilostazol on clinical trial endpoints in patients with intermittent claudication

Abstract

Summary: Intermittent claudication (IC) comprises the most common presenting symptoms of peripheral arterial disease (PAD), which itself is a manifestation of systemic atherosclerosis. Typical symptoms of IC are aching pain, numbness, and fatigue in the lower extremities. Symptoms are induced by walking or exercise and usually resolve with rest. The cornerstone of treating IC is risk-factor reduction and a supervised exercise regimen. Pharmacotherapy specifically indicated for the treatment of IC includes a new drug, cilostazol, and the traditional drug, pentoxifylline. Cilostazol also has antiplatelet, antithrombotic, and vasodilatory activity, as well as a positive effect on serum lipids. Eight multicenter clinical trials, seven in the U.S. and one in the U.K., used objective and subjective clinical endpoints to assess the treatment efficacy of cilostazol. Objective endpoints included maximal and pain-free walking distance (MWD and PFWD, respectively), the ankle-brachial index, peripheral hemodynamic measurements, and serum lipid levels. Subjective endpoints, assessed by patient questionnaires, included perceived functional status and healthrelated quality of life. Cilostazol treatment showed statistically significant increases in MWD and PFWD within 4 weeks, as well as improvements in physical functional status at 24 weeks, compared with placebo and pentoxifylline. Increases in high-density lipoprotein cholesterol and decreases in plasma triglycerides were also noted. Subjective assessments appeared to match objective parameters.

Role of Phosphodiesterase 3 in NO/cGMP-Mediated Antiinflammatory Effects in Vascular Smooth Muscle Cells

“…It has already been shown that the PDE3 inhibitor cilostazol (an analogue of cilostamide) is an effective drug for the clinical treatment of symptoms of intermittent claudication due to peripheral arterial disease, which itself, is believed to be a manifestation of systemic atherosclerosis. 30 It has also been reported that PDE3 activity and expression are significantly increased in the aorta of atherosclerosis-prone insulin-resistant rats. 31 Together these findings indicate that PDE3 may play an important role in vascular diseases such as atherosclerosis and therefore suggest that PDE3 inhibitors may be therapeutically useful for the treatment and prevention of atherosclerosis.…”

Approaches for Increasing Cerebral Efflux of Amyloid-β in Experimental Systems

“…A phase 2 trial with cilostazol in patients with MCI (NCT02491268) started in 2015 with an expected completion date of December 1, 2020 but results have not been posted on ClinicalTrials.gov. In a retrospective study, treatment with cilostazol was associated with slowing of cognitive decline in MCI patients but not AD patients [449] while in another retrospective study cilostazol slowed the decrease in MMSE scores in patients with mild dementia but not moderate-to-severe dementia (type of dementia not [445], prevention of deep vein thrombosis after knee or hip replacement surgery [446] Chitin Tissue engineering, wound dressing, drug delivery, cancer diagnosis [447], cancer treatment (used as vehicle for drug delivery [448] Cilostazol MCI a [449], AD b [450], prevention of restenosis and repeat revascularization after percutaneous coronary intervention [451], prevention of vascular mortality and cardiovascular events in patients with stable intermittent claudication [452], ischemic leg ulcers, chronic arterial occlusion, prevention of recurrence of cerebral infarction, chronic atrial fibrillation with episodes of bradycardia [453], prevention of stroke recurrence (NCT00202020), fatty liver disease (NCT04761848), prevention of peripheral neuropathy (NCT05298696), lower extremity revascularization (NCT02374957), Reynaud's (NCT00048776), recurrent stroke with intracranial artery stenosis (NCT00333164)…”

Cilostazol Does not Improve Peripheral Arterial Disease‐Linked Oxidative Stress

“…The result is an increase in cAMP concentrations in blood vessels and platelets, inducing peripheral vasodilaton and inhibiting platelet aggregation. Cilostazol has also been shown to reduce triglycerides and increase high‐density lipoproteins (HDL cholesterol) …”