Cilostazol effects

WARNING Renal impair is the major tox foUow administration instructions Uses CMV retinitis w/ HIV Action Selective inhibition of viral DNA synth Dose Rx 5 mg/kg IV over 1 h once/wk for 2 wk w/ probenecid Maint 5 mg/kg IV once/2 wk w/ probenecid (2 g PO 3 h prior to cidofovir, then 1 g PO at 2 h 8 h after cidofovir) X in renal impair Caution [C, -] Contra Probenecid or sulfa allergy Disp Inj SE Renal tox, chills, fever, HA, NA /D, thrombocytopenia, neutropenia Interactions t Nephrotox W/ aminoglycosides, amphot icin B, foscar-net, IV pentamidine, NSAIDs, vancomycin t effects W/zidovudine EMS Monitor ECG for hypocalcemia (t QT int val) and hypokalemia (flattened T waves) OD May cause renal failure hydration may be effective in reducing drug levels/effects Cilostazol (Pletal) TAntiplatelet, Arterial Vasodilator/ Phosphodiesterase Inhibitor] Uses Reduce Sxs of intermittent claudication Action Phosphodiesterase in inhibitor t s cAMP in pits blood vessels, vasodilation inhibit pit aggregation Dose 100 mg PO bid, 1/2 h before or 2 h after breakfast dinner Caution [C, +/-] Contra CHE, hemostatic disorders. 

Cilostazol is a selective cAMP phosphodiesterase inhibitor. It inhibits platelet aggregation and is a direct arterial vasodilator. It is used for the symptoms of intermittent claudication in individuals with peripheral vascular disease. Side-effects of cilostazol include headache, diarrhea, increased heart rate, and palpitations. Drugs similar to cilostazol have increased the risk of death in patients with congestive heart failure. 

Atarashi H, Endoh Y, Saitoh H, Kiashida H, Hayakawa H. Chronotropic effects of cilostazol, a new antithrombotic agent, in patients with bradyarrhythmias. J Car-diovasc Pharmacol 1998 31 534-9. 

The bioavailability of felodipine was increased approximately twofold when taken with grapefruit juice. Orange juice does not appear to modify the kinetics of PLENDIL Grapefruit juice—Coadministration of felodipine with grapefruit juice resulted in more than twofold increase in the AUC and Cmax, but no prolongation in the half-life of felodipine Grapefruit juice increased the of cilostazol by approximately 50%, but had no effect on AUC... 

A frequently cited mechanism of action for these agents is phosphodiesterase (PDE) inhibition and the associated antiplatelet effects that accompany increases in intracellular cyclic adenosine monophosphate (cAMP). In fact, the effects of these drugs go far beyond their direct effect on PDE inhibition or platelet function. This chapter discusses (/) cyclic nucleotides, PDE, and PDE inhibitors (if) the mechanisms of action of dipyridamole and cilostazol (Hi) drug issues and (iv) current clinical applications for dipyridamole and cilostazol, including recent clinical trials that may have changed our perception of the possible utility of these agents for percutaneous intervention. 

Cilostazol is a PDE3 inhibitor and also is a drug with multiple mechanisms of action (23,24), some of which are directly platelet-related, and others of which exert their effects indirectly via endothelial cells (Figs, 4 and 5), As a PDE inhibitor, it increases the concentration of cyclic nucleotides within platelets and inhibits platelet aggregation in response to shear forces (via ADP) and a variety of agonists. Like other inhibitors of platelet activation, it blocks the expression and release of P-selectin, a key adhesion molecule on the membrane of platelet alpha granules that externalizes with activation, and plays an important role in the interactions between platelets, endothelial cells, and leukocytes, The effect of cilostazol on P-selectin expression appears to be additive to those of aspirin and clopidogrel (25). 

Cilostazol has a number of additional indirect effects. Similar to dipyridamole, it enhances the actions of prostacyclin, although it has not been reported to directly increase prostacyclin release, Cilostazol also affects endothelial cells, specifically the release of cytokines, such as monocytic chemoattractant protein-1 (MCP-1), which appears to play an important role in the development and progression of atherosclerotic lesions (24). Cilostazol, like other PDE3 inhibitors, acts as a vasodilator. 

Lee et al. (50) examined the clinical effect of triple antiplatelet therapy with cilostazol (200 mg load, 100 mg BID), aspirin, and athienopyridine (ticlopidine or clopidogrel) versus... 

The restenosis benefit is also intriguing, but, in all likelihood, has nothing to do with the antiplatelet actions of cilostazol, and may relate more to its effects on cytokine release from endothelial cells and smooth muscle cells, There is also preliminary evidence suggesting that cilostazol may speed the process of endothelialization (53). Again, with DES and their well-documented difficulties with endothelialization (54,55), this is a potentially very important future application that will require prospective testing in clinical trials. 

Goto S. Cilostazol potential mechanism of action for antithrombotic effects accompanied by a low rate of bleeding. Atheroscler Suppl 2006 6 3-1 I,... 

Ahn JC, Song WH, Kwon JA, et al. Effects of cilostazol on platelet activation in coronary stenting patients who already treated with aspirin and clopidogrel. Korean J Int Med 2004 19 230-236. 

Thompson PD, Zimet R, Forbes WR et al. Meta-analysis of results from eight randomized, placebo-controlled trials on hthe effects of cilostazol on patients with intermittent claudication. Am J Cardiol 2002 90 13 14-13 19. 

Comerota AJ. Effect on platelet function of cilostazol, clopidogrel, and aspirin, each alone or in combination. Atheroscler (suppl) 2006 6 13-19. 

As previously mentioned, for SMC proliferation after coronary angioplasty, cell activation and cell-to-cell interaction of platelets and leukocytes mediated by adhesion molecules are considered to be important. Coronary stenting produces the release of an adhesion molecule, P-selectin, from d-granule of activated platelets. P-selectin-mediated platelet-leukocyte interaction has a crucial role in the development of stent restenosis. Cilostazol is an antiplatelet, antithrombotic, phosphodiesterase III inhibitor that by inhibiting P-selectin release has inhibitory effects on SMC migration. In addition, cilostazol may directly act to inhibit intimal hyperplasia. 

Randomized trials conducted with cilostazol 200 mg daily have shown that it is effective in reducing restenosis (45-47). Douglas et al. undertook the Cilostazol for Restenosis Trial (CREST), a randomized, double-blind, placebo-controlled trial to determine whether cilostazol would reduce renarrowing in patients after stent implantation in native coronary arteries. Seven hundred and five patients who had successful coronary stent implantation received, in addition to... 

Kohda N, Tani T Nakayama S, et al. Effect of cilostazol, a phosphodiesterase III inhibitor, on experimental thrombosis in the porcine carotid artery. Thromb Res 1999 96 261-268. 

Dawson DL, Cutler BS, Meissner MH, et al, Cilostazol has beneficial effects in treatment of intermittent claudication results from a multicenter, randomized, prospective, doubleblind trial, Circulation 1998 98 678-686,... 

Money SR, Herd JA, Isaacsohn JL, et al, Effect of cilostazol on walking distances in patients with intermittent claudication caused by peripheral vascular disease, J Vase Surg I 998 27 267-274. 

Strandnessjr DE, Dalman RL, Panian S, et al. Effect of cilostazol in patients with intermittent claudication randomized, double-blind, placebo-controlled study. Vase Endovasc Surg 2002 36 83-91. 

Regensteiner JG, WareJrJE, McCarthy WJ, etal. Effect of cilostazol on treadmill walking, community-based walking ability, and health-related quality of life in patients with intermittent claudication due to peripheral arterial disease meta-analysis of six randomized controlled trials. J Am Geriatr Soc 2002 50 1939-1946. 

Cilostazol is a phosphodiesterase inhibitor that reduces platelet aggregation, vascular smooth muscle proliferation and also has vasodilatory effects. Earlier studies comparing cilostazol and aspirin to ticlodipine and aspirin identified no significant increase in the subacute stent thrombosis rate (21-23). Indeed, the latter has been supported by comparison of this combination to clopidogrel and aspirin (24). Two recent trials, however, have demonstrated that a much higher proportion of patients develop subacute stent thrombosis when taking cilostazol as compared with ticlodipine (25,26). The data from these trials are summarized in Table I. 

Tanabe Y Ito E, Nakagawa I, Suzuki K. Effect of cilostazol on restenosis after coronary angioplasty and stenting in comparison to conventional coronary artery stenting with ticlopidine, IntJ Cardiol 2001 78(3)285-291. 

Sekiguchi M, Hoshizaki H, Adachi H, Ohshima S, Taniguchi K, Kurabayashi M, Effects of antiplatelet agents on subacute thrombosis and restenosis after successful coronary stenting A randomized comparison of ticlopidine and cilostazol. Circ J 2004 68(7) 6I0-6I4,... 

ASPIRIN PERIPHERAL VASODILATORS Possible t risk of bleeding with cilostazol. Low-dose aspirin (<80 mg) appears to be safe Additive effect cilostazol has antiplatelet activity Warn the patient to report any signs oft bleeding... 

CILOSTAZOL ANAGRELIDE Risk of adverse effects Additive effect anagrelide has phosphodiesterase inhibitory activity Avoid co-administration... 

The efficacy and safety data of cilostazol in placebo-controlled clinical trials have been repeatedly subjected to meta-analysis, with the same conclusion (1,2). Cilostazol is well tolerated headache, bowel complaints, and palpitation are the most common but mild adverse effects. 

In another placebo-controUed trial, there were gastrointestinal complaints in 44% of the cilostazol-treated patients and in 15% of the placebo group. The most commonly reported adverse effects included diarrhea, loose stools, flatulence, and nausea they were usually mild and transient but persisted in some patients. Headache occurred in 20% of cilostazol-treated patients but also in 15% of those given placebo (7). 

Kozuma K, Kara K, Yamasaki M, et al. Effects of cilostazol on late lumen loss and repeat revascularization after Palmaz-Schatz coronary stent implantation. Am Heart J 2001 141 124-130. 

Cilostazol (Pletal), a selective inhibitor of PDE III, is used for the treatment of intermittent claudication, an occlusive disease of blood vessels in the legs, which causes pain on walking. It acts as a vasodilator and inhibitor of platelet aggregation. Warfarin, initially developed as a rat poison, and a number of similar compounds, are effective anti-clotting agents by their action as vitamin K antagonists. 

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