Disease relevance of Pletaal

• The US experience with cilostazol in treating intermittent claudication [1].
• In addition, cilostazol achieved significant risk reductions on a number of combined endpoints (e.g., cerebral infarction, intracranial hemorrhage, myocardial infarction, or vascular death), and was associated with benefits in intent-to-treat analyses [2].
• The greatest risk reduction (43.4% in cilostazol versus placebo, P = 0.0373) was found in patients who initially had a lacunar infarction, suggesting that cilostazol has a specific effect against small-vessel disease [2].
• Cilostazol, by contrast, has been shown to significantly reduce the risk of recurrent strokes without affecting the occurrence of intracranial hemorrhage [2].
• At present, management strategies for secondary prevention of stroke include aggressive treatment of cardiovascular risk factors (i.e., hypertension, smoking cessation, etc.). Antiplatelet drugs in Japan, namely aspirin and cilostazol, are utilized regularly for the prevention of secondary stroke [2].
• The present study demonstrates that cilostazol attenuates retinal injury after transient ischemia via inhibition of leukocyte-endothelial cell interactions [3].

Psychiatry related information on Pletaal

• METHODS AND RESULTS: In the present study 642 patients who underwent stenting were randomized to treatment either with cilostazol + aspirin (C group, 321 patients) or ticlopidine + aspirin (T group, 321 patients) [4].

High impact information on Pletaal

• Cilostazol decreases the activity of phosphodiesterase type 3, leading to the accumulation of cyclic adenosine monophosphate, which initiates a cascade of events including upregulation of anti-oncogenes p53 and p21 and upregulation of hepatocyte growth factor (HGF) [5].
• Unlike other antiplatelet agents cilostazol not only inhibits platelet function but also improves endothelial cell function [6].
• The Cilostazol for RESTenosis (CREST) clinical trial was initiated to evaluate the efficacy of cilostazol, an antiplatelet drug, in inhibiting restenosis after stent implantation in a native coronary artery as evaluated by quantitative coronary angiography [5].
• The combination of aspirin and clopidogrel had a greater effect on increasing bleeding time than either monotherapy, and no further bleeding time prolongation was observed, when cilostazol was added to any aspirin/clopidogrel regimen [7].
• BACKGROUND: Cilostazol is a new phosphodiesterase inhibitor that suppresses platelet aggregation and also acts as a direct arterial vasodilator [8].

Chemical compound and disease context of Pletaal

• The effects of cilostazol, a dual inhibitor of type 3 phosphodiesterase and adenosine uptake, on ion currents were investigated in pituitary GH(3) cells and pheochromocytoma PC12 cells [9].
• In addition to pentoxifylline and cilostazol, clinical trials indicate many other drugs may relieve the symptoms of intermittent claudication [10].
• Cyclic AMP level was significantly elevated in the cortex of 4- and 12-h reperfusion (P < 0.01) following treatment with cilostazol (10 mg/kg, 5 min after 2-h ischemia) accompanied by decreased tumor necrosis factor-alpha level [11].
• Thus, there was no synergism between the effects of epalrestat and cilostazol on the development of experimental diabetic neuropathy [12].
• The aim of this study is to elucidate the difference in effect between cilostazol (CZ) and acetylsalicylic acid (ASA) on microcirculatory disturbance in ischemia/reperfusion injury [13].

Biological context of Pletaal

• Cilostazol is a potent inhibitor of platelet aggregation with vasodilation effects [14].
• CONCLUSIONS: Cilostazol may have effects on suppression of P-selectin-mediated platelet activation, platelet-leukocyte interaction, and subsequent Mac-1-mediated leukocyte activation, which might lead to a reduced restenosis rate after coronary stent implantation [15].
• In diabetic neuropathy, a cilostazol-supplemented diet improved both NBF and nerve conduction in a dose- and time-dependent fashion [16].
• Consistent with nuclear staining, DNA fragmentation in VSMCs treated with forskolin as well as 8-bromo-cAMP and cilostazol was significantly increased compared with DNA fragmentation in VSMCs treated with vehicle, whereas PDGF significantly decreased the rate of DNA fragmentation (P<0.01) [17].
• Upregulation of p53 protein by cAMP was further confirmed by the observation that the decrease in p21, a p53-inducible protein, by PDGF was significantly attenuated by cilostazol in a dose-dependent manner (P<0.01) [17].

Anatomical context of Pletaal

• AIMS/HYPOTHESIS: Cilostazol, a well-known phosphodiesterase type 3 (PDE3) inhibitor for the treatment of peripheral arterial disease, has vasodilator properties and an anti-proliferative action on the growth of vascular smooth muscle cells [18].
• OBJECTIVES: The aim of this study was to confirm clinically a hypothesis that cilostazol inhibits leukocyte Mac-1, leading to prevention of post-stent restenosis [15].
• Cilostazol increased nerve blood flow (NBF) in a dose-dependent fashion with an EC50 of 10(-5.74) mol/l. Cilostazol also normalized NBF in experimental diabetic neuropathy with a 10(-4) mol/l local application on the sciatic nerve [16].
• We examined whether epineurally applied cilostazol acted as a vasodilator on the peripheral nerve of normal and diabetic rats, and whether feeding the rats a cilostazol-supplemented diet could improve diabetic neuropathy [16].
• We evaluated the effects of cilostazol, a selective inhibitor of cyclic adenosine monophosphate phosphodiesterase, on the pial vessels of adult cats subjected to endothelial damage followed by middle cerebral artery occlusion [19].

Associations of Pletaal with other chemical compounds

• After treatment with Cilostazol, prostaglandin I2 analog, and LDL apheresis, the rheological indexes were significantly improved, while the API did not change [20].
• Studies do demonstrate improvement in walking ability resulting from exercise rehabilitation programs, as well as from use of cilostazol and, to a more modest degree, pentoxifylline [21].
• However, the decrease in local HGF production by high D-glucose was significantly attenuated by addition of PGI2 analogue or cilostazol [22].
• Identification of interaction sites of cyclic nucleotide phosphodiesterase type 3A with milrinone and cilostazol using molecular modeling and site-directed mutagenesis [23].
• CONCLUSION: Elevation of cAMP may be responsible for the inhibitory effect of beta-agonists, rolipram, and cilostazol on chemical mediator release and cytokine production by cultured human mast cells [24].

Gene context of Pletaal

• Our study implies that highly conserved residuals Y751, D950 and F1004 in the PDE families are key residues for binding of both substrate and inhibitors, and nonconserved T844 may be responsible for the cilostazol selectivity of PDE3A [23].
• In contrast, the increase in blood perfusion induced by topical administration of cilostazol, which induces vasodilation via cyclic adenosine monophosphate, was not different between 7.5-month-old Apoe(-/-) mice and controls [25].
• In conclusion, increased cAMP level by cilostazol is directly coupled to its maxi-K channel opening action via protein kinase activation in human endothelial cells, thereby suppressing TNF-alpha-stimulated superoxide production and expression of adhesion molecules [26].
• In the human endothelial cells transfected with siRNA-targeting maxi-K channels, cilostazol did not suppress the superoxide generation, VCAM-1 and MCP-1 expressions, and monocyte adhesion as contrasted with the wild-type cells [26].
• Further, cilostazol prevented TNF-alpha-induced PTEN phosphorylation and apoptotic cell death via increased CK2 phosphorylation in the SK-N-SH cells [27].

Analytical, diagnostic and therapeutic context of Pletaal

• Data will be presented regarding the safety and efficacy demonstrated by cilostazol in clinical trials, as well as the effects of risk-factor control, exercise therapy, revascularization, and experimental drugs on the treatment of claudication in the PAD population [1].
• Recently, results of the Cilostazol for Restenosis (CREST) trial, a randomized, double-blind study, show that cilostazol reduces the risk of restenosis in patients who receive bare-metal stents, including high-risk patients [28].
• METHODS: A total of 89 subjects were allocated at random to the cilostazol group ( n = 43) or the control group ( n = 46) [29].
• The findings suggest that cilostazol is an interesting candidate for future clinical trials of delayed cerebral vasospasm [30].
• The plasma concentration of cilostazol was measured with a validated HPLC method that entailed ultraviolet detection [31].

References