Cilostazol for Secondary Stroke Prevention: History, Evidence, Limitations, and Possibilities

Cilostazol is a PDE3 (phosphodiesterase III) inhibitor with a long track record of safety that is Food and Drug Administration and European Medicines Agency approved for the treatment of claudication in patients with peripheral arterial disease. In addition, cilostazol has been approved for secondary stroke prevention in several Asian countries based on trials that have demonstrated a reduction in stroke recurrence among patients with noncardioembolic stroke. The onset of benefit appears after 60 to 90 days of treatment, which is consistent with cilostazol’s pleiotropic effects on platelet aggregation, vascular remodeling, blood flow, and plasma lipids. Cilostazol appears safe and does not increase the risk of major bleeding when given alone or in combination with aspirin or clopidogrel. Adverse effects such as headache, gastrointestinal symptoms, and palpitations, however, contributed to a 6% increase in drug discontinuation among patients randomized to cilostazol in a large secondary stroke prevention trial (CSPS.com [Cilostazol Stroke Prevention Study for Antiplatelet Combination]). Due to limitations of prior trials, such as open-label design, premature trial termination, large loss to follow-up, lack of functional or cognitive outcome data, and exclusive enrollment in Asia, the existing trials have not led to a change in clinical practice or guidelines in Western countries. These limitations could be addressed by a double-blind placebo-controlled randomized trial conducted in a broader population. If positive, it would increase the evidence in support of long-term treatment with cilostazol for secondary prevention in the millions of patients worldwide who have experienced a noncardioembolic ischemic stroke.

Evaluation of the anticonvulsant activity of the phosphodiesterase III inhibitor cilostazol in the animal model of epilepsy

The present study is objected to evaluate the anticonvulsant activity of the phosphodiesterase III inhibitor cilostazol in the animal model of epilepsy. Conventional anti-epileptic rodent models like Maximal Electric Shock (MES)- induced convulsions and Pentylenetetrazol (PTZ) induced convulsions were used. The animals were randomly divided into six groups, with six rats in every group. Here anti-epileptic activity of cilostazol with two different doses (10 mg/kg i.p and 20 mg/kg i.p) was compared with standard drug and standard drug + Cilostazol two different doses (10 mg/kg i.p and 20 mg/kg i.p). Cilostazol (20 mg/kg i.p) exhibited an anticonvulsant effect in MES-induced and PTZ induced convulsion models over the Control group and cilostazol (10 mg/kg i.p). Standard drugs were shown superiority in seizure suppression activity than cilostazol (20 mg/kg i.p). The time duration of onset of clonic convulsion and period of clonic convulsions in PTZ induced convulsion were increased and decreased respectively when compared to Standard drug + cilostazol both doses and standard drug alone. Phenytoin abolished convulsions induced by MES- convulsion model. So the present study established that cilostazol has low anticonvulsant efficacy in comparison with conventional drugs (Phenytoin and Sodium Valproate). The potentiating effect of cilostazol with standard drugs was also demonstrated.

The Protective Effect of Cilostazol in Genotoxicity Induced by Methotrexate in Human Cultured Lymphocytes

Background: Methotrexate is an antagonist of folic acid that has been shown to be genotoxic to healthy body cells via induction of oxidative stress. Cilostazol is a phosphodiesterase III inhibitor and a potent antioxidant drug. Objectives: To evaluate the potential protective effect of cilostazol on methotrexate genotoxicity. Results: Methotrexate significantly increased the frequency of CAs and SCEs (p < 0.0001) as compared to control cultures. This chromosomal damage induced by methotrexate was considerably decreased by pretreatment of the cells with cilostazol (P < 0.01). Moreover, the results showed that methotrexate resulted in a notable reduction (P < 0.01) in cells kinetic parameters, the mitotic index (MI) and the proliferative index (PI). Similarly, cilostazol significantly reduced the mitotic index, which could be related to the anti-proliferative effect (P < 0.01). Conclusion: Methotrexate is genotoxic, and cilostazol could prevent the methotrexate-induced chromosomal damage with no modulation of methotrexate-induced cytotoxicity.

Low-Dose Phosphodiesterase III Inhibitor Reduces the Vascular Amyloid Burden in Amyloid-β Protein Precursor Transgenic Mice

A previous study reported that relatively high-dose cilostazol (0.3%) promoted the drainage of cerebrovascular amyloid-β (Aβ) protein in Aβ Precursor Protein (APP) transgenic mice overexpressing vasculotropic Aβ. We investigated whether lower-dose cilostazol can decrease micro-hemorrhages and Aβ deposition in the brain using APP transgenic mice. At baseline, 14-month-old female Tg2576 mice were randomly assigned to a control group (vehicle), aspirin group (0.01% aspirin), or cilostazol group (0.01% cilostazol). The severity of cerebral micro-hemorrhages (i.e., number), area of senile plaque, and severity of vascular amyloid burden (quantified with cerebral amyloid angiopathy (CAA) score (=number of Aβ-positive vessels × severity of amyloid burden of Aβ-positive vessels) were evaluated in the brain of mice aged 15 and 21–23 months. At 15 months, no differences were shown in each pathological change among the three groups. At 21–23 months, there were no differences in the severity of cerebral micro-hemorrhages or area of senile plaque among the three groups. However, the CAA score was significantly lower in the cilostazol compared to the control group (p = 0.046, Mann–Whitney U test), although no difference was seen between the control and aspirin group. Our study showed that lower-dose cilostazol could reduce the vascular amyloid burden without increasing cerebral micro-hemorrhages in APP transgenic mice.

Preparation and in-vitro evaluation of cilostazol self-emulsifying drug delivery system

This work reported a first liquid self-nanoemulsifying drug delivery system (SEDD) of cilostazol using oleic acid as oil phase, tween 80 as surfactant, and transcutol as co-surfactant. Cilostazol is a poor water-soluble phosphodiesterase III inhibitor, which has antiplatelet and vasodilator effect used to relief intermittent claudication symptoms. Cilostazol solubility was determined in various oils, surfactants and co-surfactants and phase diagram was constructed at different oil: surfactant: co-surfactant ratios to determine the existence of nano-emulsion region. The in-vitro dissolution profile showed an optimized cilostazol SEDD formula (LT1) containing oleic acid (10%) as oil, tween 80 (45%) as surfactant, and transcutol (45%) as co-surfactant in comparison with the commercial conventionally Tablets. The LT1 formula was thermodynamically sTable, with a zeta potential of -30.48 mV and droplet size 154 nm. The LT1 capsule showed a superior dissolution profile (100%) when compared to the commercial Tablet (64%) of cilostazol. The objective of the present study is to formulate cilostazol as an oral liquid SEDD with better solubility and drug release to overcome a variable bioavailability of the commercial Tablet in which a high-fat meal increases absorption to approximately 90%.

Is Milrinone Effective for Infants with Mild-to-Moderate Congenital Diaphragmatic Hernia?

Objective Pulmonary hypertension with left ventricular dysfunction commonly occurs in congenital diaphragmatic hernia (CDH). Milrinone, a phosphodiesterase-III inhibitor with lusitropic and vasodilator effects, is used in up to 30% of CDH infants across the United States. No randomized trials have tested the efficacy or safety of milrinone in CDH neonates. Study Design We performed a paired retrospective analysis of CDH infants to assess the efficacy of milrinone treatment (N = 24 pairs). Efficacy was assessed by change in oxygenation index (OI) and calculated pulmonary artery pressure (PAP). We evaluated safety on the basis of risks factors such as nonoperative bleeding, dysrhythmia, hypokalemia, and thrombocytopenia. Results The median age of milrinone initiation was 18 hours (interquartile range [IQR]: 9–38) and the median duration was 127 hours (IQR: 95–194). PAP did not change from the baseline of 49 ± 11 mm Hg (milrinone) and 53 ± 11 mm Hg (no milrinone; p = 0.327). Baseline OI was 9.6 ± 6.5. There was a similar decrease in OI (median [IQR]; milrinone: 58% [16–74]; vs. no milrinone: 65% [50–71]; p = 0.221 between groups; p < 0.005 within groups). Baseline left ventricle measurements were similar. Both groups showed significant improvement over time. No adverse events were noted. Conclusion In OI-matched untreated neonates with mild-to-moderate CDH, milrinone use was associated with neither improved OI, PAP, or left ventricular measurements, nor adverse events. Study limitations warrant prospective randomized controlled trials.

IONOTROPIC TRAPPING LECITHIN BASED CILOSTAZOL NANOCOCHLEATES FOR DRUG DELIVERY APPLICATIONS

The nanocochleate drug delivery is based on encapsulating drugs in multilayered lipid crystal matrix (a cochleate) to potentially deliver the drug safely and effectively through the lipoidal membrane. Cilostazol is approved for the treatment of intermittent claudication and used as fibrinolytic agent, platelet aggregation inhibitor, bronchodilator agent, phosphodiesterase III Inhibitor and vasodilator agent. therefore, this drug delivery is suitable to deliver drug molecules into blood vessels. Formulations with lecithin showed good in vitro drug release, drug entrapment study results and the drug in formulations was found to be intact and compatible with lipids used. Two optimized formulations containing cilostazol lecithin-cholesterol showed Korsemayer peppas model perfect zero order release and showed better sustained and controlled drug release. Lecithin-cholesterol nanocochleates prepared by external ionotropic trapping method was found to be better ionic cross linking of drug-lipids particles. Therefore, ionotropic cross-linked particles are promising carriers for oral controlled release dosage forms.