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Cilostazol

A Review of its Use in Intermittent Claudication

American Journal of Cardiovascular Drugs volume 3, pages 117–138 (2003)Cite this article

Summary

Abstract

Cilostazol (Pletal®) is a selective inhibitor of phosphodiesterase-III with antiplatelet, antithrombotic and vasodilating properties. It also exhibits antiproliferative effects on smooth muscle cells and has beneficial effects on high density lipoprotein-cholesterol and triglyceride levels.

Randomized, double-blind, placebo-controlled 12- to 24-week trials in >2000 patients with moderate to severe intermittent claudication demonstrated that cilostazol generally significantly increased walking distances and improved quality of life compared with placebo. Additionally, a large comparative 24-week trial showed that cilostazol 100mg twice daily was significantly more effective than pentoxifylline 400mg three times daily (pentoxifylline was not significantly different from placebo).

Cilostazol was generally well tolerated. Adverse events reported significantly more often with cilostazol than with placebo included headache, diarrhea, abnormal stools, infection, rhinitis and peripheral edema and in comparison with pentoxifylline were headache, diarrhea, abnormal stools and palpitations. Adverse events were generally mild to moderate in intensity, transient or resolved after symptomatic treatment and rarely required treatment withdrawal.

Significant drug interactions are observed when cilostazol is coadministered with other agents that inhibit cytochrome P450 (CYP) 3A4 (e. g. erythromycin or diltiazem) or CYP2C19 (e. g. omeprazole). As a result, in Europe cilostazol is contraindicated in patients receiving CYP3A4 or CYP2C19 inhibitors and in the US it is recommended that dosage reduction for cilostazol be considered during coadministration of cilostazol and CYP3A4 or CYP2C19 inhibitors. Conversely, cilostazol itself does not appear to inhibit CYP3A4. Coadministration of cilostazol with aspirin or warfarin did not result in any clinically significant changes to coagulation parameters, bleeding time or platelet aggregation.

Conclusion: In six of eight well designed clinical trials, cilostazol was significantly more effective than placebo in increasing walking distances and improving the quality of life of patients with moderate to severe intermittent claudication. In addition, limited comparative data have shown that cilostazol has superior efficacy compared with pentoxifylline. Cilostazol is also generally well tolerated. Additional comparative trials are required to confirm these results, to determine the place of cilostazol in relation to other agents or exercise therapy and risk factor reduction alone, and to establish the effects of long-term treatment with cilostazol in patients with intermittent claudication. Cilostazol is contraindicated in several subpopulations of patients, particularly those with congestive heart failure and severe hepatic or renal impairment. Nonetheless, current data support the choice of cilostazol as a promising therapy amongst the limited options available for patients with intermittent claudication.

Pharmacodynamic Profile

Cilostazol has antiplatelet, antithrombotic and vasodilating properties. In vitro, ex vivo and in vivo studies have shown that cilostazol inhibits both primary and secondary platelet aggregation induced by ADP, collagen, arachidonic acid, epinephrine (adrenaline), thrombin, remnant-like lipoprotein and shear stress without affecting bleeding time. In animal models, cilostazol inhibited thrombus formation induced by various stimuli.

Cilostazol causes vasodilation by inhibiting calcium-induced contractions of smooth muscle cells (SMCs) while having no direct effect on contractile proteins. Cilostazol 100mg twice daily for 6 weeks significantly increased skin temperature, ankle blood flow and skin blood flow in the legs of patients with intermittent claudication (p < 0.05).

The drug also inhibits proliferation of vascular SMCs induced by a variety of growth factors in animal models and human cells in vitro and demonstrates beneficial effects on certain plasma lipids. High density lipoprotein-cholesterol levels increased and levels of triglycerides decreased relative to placebo or baseline after 8–12 weeks’ treatment with cilostazol 100mg twice daily in two randomized, double-blind trials.

The precise mechanism by which cilostazol improves the symptoms of intermittent claudication is not fully known, but is thought to be multifactorial. Cilostazol is a selective inhibitor of phosphodiesterase-III (PDE-III), thereby suppressing cyclic adenosine monophosphate (cAMP) degradation. Cilostazol also inhibits adenosine uptake into cells which augments the cAMP-elevating effect of PDE-III inhibition.

Pharmacokinetic Profile

In patients with intermittent claudication, steady state was reached within 4 days following multiple doses of cilostazol. The peak plasma concentration (Cmax) at steady state was 1331.5 μg/L with a regimen of 100mg twice daily and occurred 2.7 hours after the final dose. The high apparent volume of distribution of cilostazol (2.76 L/kg) suggests extensive tissue binding. Cilostazol is extensively bound to plasma proteins with a free fraction of 2–5%.

Coadministration of cilostazol with food (a high fat meal) increased the rate and also the extent of cilostazol absorption.

Cilostazol is extensively metabolized (oxidative metabolism) to dehydro-cilostazol (OPC-13015) by cytochrome P450 (CYP) 3A4 and to monohydroxy-cilostazol (OPC-13213) via CYP2C19. A radiolabeled dose of cilostazol in healthy volunteers showed that urine (73.8%) and feces (21.7%) were the major routes of excretion. Cilostazol had an elimination half-life of 10.5 hours in patients with intermittent claudication.

The pharmacokinetic profiles of cilostazol and its two main metabolites (OPC-13015 and OPC-13213) after the administration of cilostazol 100mg twice daily over a 7-day period to healthy middle-aged and elderly men and women (aged 50–80 years) were not significantly affected by age or gender.

Mild to moderate renal impairment did not affect the pharmacokinetics of multiple doses of cilostazol (50mg twice daily for 6 days). However, severe renal impairment alters plasma concentrations and the protein binding of cilostazol and its metabolites, and the drug is contraindicated in these patients in Europe. Mild or moderate hepatic impairment had no appreciable effect on the pharmacokinetic properties of a single dose of cilostazol 100mg or its metabolites, while the effects of severe hepatic impairment on cilostazol pharmacokinetics have not been evaluated.

Coadministration of cilostazol with moderate inhibitors of CYP3A4 led to significantly increased cilostazol Cmax values (by 47% with erythromycin) or exposure (by 53% with diltiazem). Coadministration of cilostazol with an inhibitor of CYP2C19, omeprazole, resulted in a significant increase in the systemic exposure of cilostazol (26%).

Cilostazol does not appear to inhibit CYP3A4, as there were no changes in the pharmacokinetics of a single dose of lovastatin 80mg or its metabolites when coadministered with cilostazol at steady state (lovastatin is primarily metabolised by CYP3A4.

There were no clinically significant interactions after coadministration of cilostazol 100mg twice daily and aspirin 325 mg/day and cilostazol 100mg twice daily and a single dose of warfarin 25mg as measured by the prothrombin time, activated partial thromboplastin time and bleeding time or platelet aggregation.

Therapeutic Efficacy

Results from eight well designed 12- to 24-week clinical trials involving more than 2000 patients with intermittent claudication have shown that treatment with cilostazol 100mg twice daily is generally associated with significant improvements in maximum walking distance (MWD) and pain-free walking distance (PFWD) at study end compared with placebo (p < 0.05). The efficacy of cilostazol was seen as early as 4 weeks after initiation of therapy.

The efficacy of cilostazol 50mg twice daily has been studied in two clinical trials. One trial, found that cilostazol 50mg twice daily resulted in significantly greater improvements in MWD (p < 0.001) and PFWD (p < 0.001) compared with placebo. However, the other trial found no significant difference in the improvements in MWD seen with cilostazol 50mg twice daily and placebo.

Cilostazol 100mg twice daily (n = 205 intent-to-treat [ITT] analysis) was significantly more effective in increasing the MWD (p < 0.0002) and PFWD (p < 0.02) than pentoxifylline 400mg three times daily (n = 212 ITT analysis) after 24 weeks of treatment in a large clinical trial in patients with moderate to severe intermittent claudication. There was no significant difference between pentoxifylline and placebo with regards to changes in walking distance during the trial.

Evidence suggests that patients with intermittent claudication perceive their functional status and quality of life to be significantly improved with cilostazol compared with placebo. Patient perceptions of functional status or quality of life were similar for those receiving cilostazol 100mg twice daily or pentoxifylline 400mg three times daily. However, significantly more patients treated with cilostazol assessed their response to treatment as successful relative to baseline compared with those receiving pentoxifylline.

Treatment with cilostazol 100mg twice daily significantly increased the resting ankle brachial index (ABI) compared with placebo (p < 0.05); however, this was only a moderate improvement in terms of clinical significance. There was no significant difference for the change in ABI between the cilostazol or pentoxifylline treatment groups.

Withdrawal of treatment was studied in a subgroup of patients (n = 45) who participated in the large comparative study with pentoxifylline. The results of this small study suggest that withdrawal of cilostazol resulted in a significant loss of walking distance in patients with intermittent claudication by 2 weeks (p = 0.001). Conversely, the withdrawal of pentoxifylline did not significantly affect walking distances.

Tolerability

Cilostazol was generally well tolerated in clinical trials. Pooled tolerability data from placebo-controlled clinical trials indicated headache, diarrhea, abnormal stools, pain, infection, pharyngitis, rhinitis, peripheral edema and nausea were the most common adverse events, occurring in 5% or more of cilostazol recipients (n = 1301). Adverse events were generally mild to moderate in intensity, transient or resolved after symptomatic treatment and rarely required treatment withdrawal.

Adverse events reported more often with cilostazol than with pentoxifylline were headache, diarrhea, abnormal stools and palpitations. However, a similar percentage of patients receiving cilostazol and pentoxifylline withdrew from the large clinical trial because of adverse events (16% vs 19%).

The rate of serious adverse events (myocardial infarction, chest pain or angina pectoris) was low and similar between the three treatment groups (cilostazol, pentoxifylline and placebo).

Pharmacoeconomic Considerations

Data from a single study presented as an abstract and poster suggest that although cilostazol has a higher acquisition cost than both pentoxifylline and placebo the incremental cost per quality-adjusted life-year is reasonable compared with pentoxifylline and placebo. No studies assessing the cost effectiveness of cilostazol have been reported.

Dosage and Administration

Cilostazol is indicated for the reduction of symptoms of intermittent claudication in the US and for the improvement of MWD and PFWD in patients with intermittent claudication in Europe.

The recommended dosage of cilostazol for intermittent claudication is 100mg twice daily administered orally half an hour before, or 2 hours after, meals. No dosage adjustments are recommended for the elderly. In Europe, no dosage adjustments are recommended for patients with mild hepatic impairment or those with mild to moderate renal dysfunction (creatinine clearance [CLCR] of >1.5 L/h [>25 mL/min]).

Cilostazol is contraindicated in patients with congestive heart failure of any severity due to theoretical concerns related to its mechanism of action and classification as a PDE-III inhibitor. Caution is recommended when using cilostazol in patients with coronary heart disease as the long-term effects of cilostazol in these patients are unknown. The effects of cilostazol in patients with moderate or severe hepatic impairment and in nursing or pregnant women have not been extensively studied; however, in Europe cilostazol is contraindicated in these patients. In Europe, cilostazol is also contraindicated in patients with severe renal impairment (CLCR <-1.5 L/h [<-25 mL/min]), patients with any known predisposition to bleeding, those with a history of ventricular tachycardia, ventricular fibrillation or multifocal ventricular ectopics or patients with a prolongation of the corrected QT interval. In the US, caution is recommended when cilostazol is to be coadministered with inhibitors of CYP3A4 or CYP2C19 and a lower dosage of 50mg twice daily should be considered; however, in Europe cilostazol is contraindicated in patients receiving these drugs.

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Notes

  1. Use of tradename is for product identification purposes only and does not imply endorsement.

References

  1. Crouse III JR. Allan MC, Elara MB. Clinical manifestation of atherosclerotic peripheral arterial disease and the role of cilostazol in treatment of intermittent claudication. J Clin Pharmacol 2002; 42: 1291–8

    Article  CAS  Google Scholar 

  2. Olin JW. Management of patients with intermittent claudication. Int J Clin Pract 2002; 56(9): 687–93

    PubMed  CAS  Google Scholar 

  3. Fernandez Jr BB. A rational approach to diagnosis and treatment of intermittent claudication. Am J Med Sci 2002 May; 323(5): 244–51

    PubMed  Article  Google Scholar 

  4. Donnelly R. Assessment and management of intermittent claudication: importance of secondary prevention. Int J Clin Pract 2001 Apr; Suppl. 119: 2–9

    Google Scholar 

  5. TransAtlantic Inter-Society Consensus (TASC) Working Group. Management of peripheral arterial disease (PAD). J Vasc Surg 2000 Jan; 31(1 Suppl. l):S1–289

    Article  Google Scholar 

  6. Criqui M.H., Fronek A, Barrett-Connor E, et al. The prevalence of peripheral arterial disease in a defined population. Circulation 1985; 71: 510–5

    PubMed  Article  CAS  Google Scholar 

  7. Scottish Intercollegiate Guidelines Network. Drag therapy for peripheral vascular disease: a national clinical guideline [online]. Available from URL: www.sign.ac.uk/pdf/sign27.pdf [Accessed 2003 Mar 13]

  8. Okuda Y, Kirnura Y, Yamashita K. Cilostazol. Cardiovasc Drag Rev 1993; 11(4): 451–65

    Article  CAS  Google Scholar 

  9. Liu Y, Shakur Y, Yoshitake M, et al. Cilostazol (Pletai®): a dual inhibitor of cyclic nucieotide phosphodiesterase type 3 and adenosine uptake. Cardiovasc Drag Rev 2001; 19(4): 369–86

    Article  CAS  Google Scholar 

  10. Reiliy MP, Mohler III ER. Cilostazol: treatment of intermittent claudication. Ann Pharmacother 2001 Jan; 35(1): 48–56

    Article  Google Scholar 

  11. Saniabadi AR, Urnemura K, Shirnoyama M, et al. Aggregation of human blood platelets by remnant like lipoprotein particles of piasma chylornicrons and very low density lipoproteins. Thrornb Haernost 1997 May; 77(5): 996–1001

    CAS  Google Scholar 

  12. Uehara S, Hirayama A. Effects of cilostazol on platelet function. Arzneimittelforsehung 1989 Dec; 39(12): 1531–4

    CAS  Google Scholar 

  13. Kariyazono H, Nakamura K, Shinkawa T, et al. Inhibition of platelet aggregation and the release of P-selectin from platelets by cilostazol. Thrornb Res 2001 Mar 15; 101(6):-445–53

    Article  CAS  Google Scholar 

  14. Kimura Y, Tani T, Kanbe T, et al. Effect of cilostazol on platelet aggregation and experimental thrombosis. Arzneimittelforschung 1985; 35(7a): 1144–9

    PubMed  CAS  Google Scholar 

  15. Tani T, Sakurai K, Kimura Y, et al. Pharmacological manipulation of tissue cyclic AMP by inhibitors: effects of phosphodiesterase inhibitors on the functions of platelets and vascular endothelial cells. Adv Second Messenger Phosphoprotein Res 1992; 25: 215–27

    PubMed  CAS  Google Scholar 

  16. Minami N, Suzuki Y, Yamamoto M, et al. Inhibition of shear stress-induced platelet aggregation by cilostazol, a specific inhibitor of cGMP-inhibited phosphodiesterase, in vitro and ex vivo. Life Sci 1997; 61(25): 383–9

    Article  Google Scholar 

  17. Tanemoto K, Kanaoka Y, Kuinose M. Assessment of antithrombotic agents using the platelet aggregation test. Curr Ther Res Clin Exp 2000 Nov; 61: 798–806

    Article  CAS  Google Scholar 

  18. Nakamura M. Effect of OPC 13013 on platelet aggregation and haemomeoiogy [in Japanese]. Yakuri To Chiryo 1993 Jun; 21: 1985–9

    Google Scholar 

  19. Ikeda Y, Kikuchi M, Murakami H, et al. Comparison of the inhibitory effects of cilostazol, acetylsalicylic acid and ticlopidine on plateiet functions ex vivo: randomized, double-blind cross-over study. Arzneimittelforschung 1987 May; 37(5): 563–6

    PubMed  CAS  Google Scholar 

  20. Yasunaga K, Mase K. Clinical effects of oral cilostazol on suppression of platelet function in patients with cerebrovascular disease. Arzneimittelforschung 1985; 35(7a): 1186–8

    PubMed  CAS  Google Scholar 

  21. Yasunaga K, Mase K. Antiaggregatory effect of oral cilostazol and recovery of platelet aggregability in patients with cerebrovascular disease. Arzneimitteiforschung 1985; 35(7a): 1189–92

    CAS  Google Scholar 

  22. 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 Nov 15: 96(4): 261–8

    PubMed  Article  CAS  Google Scholar 

  23. Shiraishi Y, Kanmura Y, Itoh T. Effect of cilostazol, a phosphodiesterase type III inhibitor, on histamine-induced increase in [Ca2+]j and force in middle cerebral artery of the rabbit. Br J Pharmacol 1998 Mar; 123(5): 869–78

    PubMed  Article  CAS  Google Scholar 

  24. Tanaka T, Ishikawa T, Hagiwara M. et al. Effects of cilostazol, a selective cAMP phosphodiesterase inhibitor on the contraction of vascular smooth muscle. Pharmacology 1988; 36: 313–20

    PubMed  Article  CAS  Google Scholar 

  25. Kawamura K, Watanabe K, Kirmura Y. Effect of cilostazoi, a new antithrombotic drug, on cerebral circulation. Arzneimittelforschung 1985; 35(7a): 1149–54

    PubMed  CAS  Google Scholar 

  26. Shintani S, Watanabe K, Kawamura K, et al. General pharmacological properties of cilostazol, a new antithrombotic drag. Part II: Effect on the peripheral organs. Arznei mittelforschung 1985; 35(7a): 1163–72

    CAS  Google Scholar 

  27. Takahashi S, Oida K, Fujiwar a R, et al. Effect of cilostazoi, a cyclic AMP phosphodiesterase inhibitor, on the proliferation of rat aortic smooth muscle cells in culture. J Cardiovasc Pharmacol 1992; 20: 900–6

    PubMed  Article  CAS  Google Scholar 

  28. Hayashi S, Morishita R, Matsushita H, et al. Cyclic AMP inhibited proliferation of human aortic vascular smooth muscie cells, accompanied by induction of p53 and p21. Hypertension 2000 Jan; 35(Pt 2): 237–43

    PubMed  Article  CAS  Google Scholar 

  29. Eiam MB, Heckman J, Crouse JR, et al. Effect of the novel antiplatelet agent cilostazol on plasma lipoproteins in patients with intermittent claudication. Arterioscler Thromb Vasc Biol 1998 Dec; 18(12): 1942–7

    Article  Google Scholar 

  30. Lee T-M, Su S-F, Hwang J-J, et al. Differential lipogenic effects of cilostazol and pentoxifylline in patients with intermittent claudication: potential role for interleukin-6. Atherosclerosis 2001 Oct; 158(2): 471–6

    PubMed  Article  CAS  Google Scholar 

  31. Liu Y, Fong M, Cone I, et al. [nhibition of adenosine uptake and augmentation of ischemia-induced increase of interstitial adenosine by cilostazoi, an agent to treat intermittent claudication. J Cardiovasc Pharmacol 2000 Sep; 36(3): 351–60

    PubMed  Article  CAS  Google Scholar 

  32. Wang S, Cone J, Fong M, et al. Interplay between inhibition of adenosine uptake and phosphodiesterase type 3 on cardiac function by cilostazoi, an agent to treat intermittent claudication. J Cardiovasc Pharmacol 2001 Nov; 38(5): 775–83

    PubMed  Article  CAS  Google Scholar 

  33. Sun B, Le SN, Lin S, et al. New mechanism of action for cilostazoi: interplay between adenosine and cilostazol in inhibiting platelet activation. J Cardiovasc Pharmacol 2002 Oct; 40(4): 577–85

    PubMed  Article  CAS  Google Scholar 

  34. Tamai Y, Takami H, Nakahata R, et al. Comparison of the effects of acetylsalicylic acid, ticlopidine and cilostazol on primary hemostasis using a quantitative bleeding time test apparatus. Haemostasis 1999; 29(5): 269–76

    PubMed  CAS  Google Scholar 

  35. Igawa T, Tani T, Chijiwa T, et al. Potentiation of anti-platelet aggregating activity of cilostazol with vascular endothelial cells. Thromb Res 1990 Feb 15; 57(4): 617–23

    PubMed  Article  CAS  Google Scholar 

  36. Ozeki Y, Matsumoto Y, Kimura Y. Effects of various anti-platelet agents on platelet-derived microparticle production [abstract]. 17th Congress of the International Society on Thrombosis and Haemostasis; 1999 Aug 14; Washington, DC

  37. Yasuda K, Sakuma M, Tanabe T. Hemodynamic effect of cilostazol on increasing peripheral blood flow in arteriosclerosis obliterans. Arzneimittelforschung 1985; 35(7a): 1198–200

    PubMed  CAS  Google Scholar 

  38. Ohashi S, Iwatani M, Hyakuna Y, et al. Thermographic evaluation of the hemodynamic effect of the antithrombotic drug cilostazol in peripheral arterial occlusion. Arzneimittelforschung 1985; 35(7a): 1203–8

    PubMed  CAS  Google Scholar 

  39. Ikeda Y. Antiplatelet therapy using cilostazoi, a specific PDE3 inhibitor. Thromb Haemost 1999 Aug; 82(2): 435–8

    PubMed  CAS  Google Scholar 

  40. Rybalkin SD, Bornfeldt KE. Cyclic nucieotide phosphodiesterases and human arterial smooth muscle celi proliferation. Thromb Haemost 1999; 82(2): 424–34

    PubMed  CAS  Google Scholar 

  41. Ikeda U, Ikeda M, Kano S, et al. Effect of cilostazoi, a cAMP phosphodiesterase inhibitor, on nitric oxide production by vascular smooth muscle cells. Eur J Pharmacol 1996 Oct 24; 314(1–2): 197–202

    PubMed  Article  CAS  Google Scholar 

  42. Nakamura T, Houchi H, Minarni A, et al. Endothelium-dependent relaxation by cilostazoi, a phosphodiesterase III inhibitor, on rat thoracic aorta. Life Sci 2001 Aug 31; 69(15): 1709–15

    PubMed  Article  CAS  Google Scholar 

  43. Mizutani M, Okuda Y, Yamashita K. Effect of cilostazol on the production of platelet-derived growth factor in cultured human vascular endothelial cells. Biochem Mol Med 1996 Apr; 57(2): 156–8

    PubMed  Article  CAS  Google Scholar 

  44. Lee T-M, Su S-F. Tsai C-H, et al. Differential effects of cilostazol and pentoxifyiline on vascular endothelial growth factor in patients with intermittent ciaudication. Clin Sci (Lond) 2001 Sep; 101(3): 305–11

    Article  CAS  Google Scholar 

  45. Nishio Y, Kashiwagi A, Takahara N, et al. Cilostazol, a cAMP phosphodiesterase inhibitor, attenuates the production of monocyte chemoattractant protein-1 in response to tumor necrosis factor-α in vascular endothelial cells. Horm Metab Res 1997 Oct; 29(10): 491–5

    PubMed  Article  CAS  Google Scholar 

  46. Aoki M, Morishita R, Hayashi S, et al. Inhibition of neointimal formation after balioon injury by ciostazoi, accompanied by improvement of endothelial dysfunction and induction of hepatocyte growth factor in rat diabetes model. Diabetologia 2001; 44: 1034–42

    PubMed  Article  CAS  Google Scholar 

  47. Bramer SL, Forbes WP, Mallikaarjun S. Cilostazol pharmacokinetics after single and multiple oral doses in healthy males and patients with intermittent claudication resulting from peripheral arterial disease. Clin Pharmacokinet 1999; 37 Suppl. 2: 1–11

    PubMed  Article  CAS  Google Scholar 

  48. Woo SK, Kang WK, Kwon K. Pharmacokinetic and pharmacodynamic modeling of the antiplatelet and cardiovascular effects of cilostazol in healthy humans. Clin Pharmacol Ther 2002 Apr; 71(4): 246–52

    PubMed  Article  CAS  Google Scholar 

  49. Akiyama H, Kudo S, Shimizu T. The absorption, distribution and excretion of a new antithrombotic and vasodilating agent, cilostazoi, in rat, rabbit, dog and man. Arzueimittelforschung 1985; 35(7a): 1124–32

    CAS  Google Scholar 

  50. Niki T, Mori H. Phase I study of cllostazol: safety evaluation at increasing singledoses in healthy volunteers. Arzneimittelforschung 1985; 35(7a): 1173–85

    PubMed  CAS  Google Scholar 

  51. Akiyama H, Kudo S, Shimizu T. The metabolism of a new antifhrombotic and vasodilating agent, cilostazol, in rat, dog and man. Arzneimittelforschung 1985; 35(7a): 1133–40

    PubMed  CAS  Google Scholar 

  52. Suri A, Forbes WP, Bramer SL. Pharmacokinetics of multipie-dose oral cilostazol in middle-age and elderly men and women. J Clin Pharmacol 1998 Feb; 38(2): 144–50

    PubMed  CAS  Google Scholar 

  53. Mallikaarjun S, Forbes WP, Bramer SL. Effect of renal impairment on the pharmacokinetic s of cilostazol and its metabolites. Clin Pharmacokinet 1999; 37 Suppl. 2: 33–40

    PubMed  Article  CAS  Google Scholar 

  54. Bramer SL, Forbes WP. Effect of hepatic impairment on the pharmaco kinetics of a single dose of cilostazol. Clin Pharmacokinet 1999; 37 Suppi. 2: 25–32

    PubMed  Article  CAS  Google Scholar 

  55. Bramer SL, Forbes WP. Relative bioavail ability and effects of a high fat rneal on singie dose cilostazol pharmacokinetics. Clin Pharmacokinet 1999; 37 Suppl. 2: 13–23

    PubMed  Article  CAS  Google Scholar 

  56. Abbas R, Chow CP, Browder NJ, et al. In vitro metabolism and interaction of cilostazoi with human hepatic cytochrome P450 isoforms. Hum Exp Toxicol 2000 Mar; 19(3): 178–84

    PubMed  Article  CAS  Google Scholar 

  57. Braner SL, Tata PNV, Mallikaarjun S, et al. Disposition of 14C-cilostazoi after singie dose administration to healthy human subjects [abstract no. 3452]. Pharrn Res 1997 Nov; 14 (11 Suppl. 1): S612

    Google Scholar 

  58. Suri A, Forbes WP, Bramer SL. Effects of CYP3A inhibition on the metabolism of cilostazol. Clin Pharmacokinet 1999; 37 Suppl. 2: 61–8

    PubMed  Article  CAS  Google Scholar 

  59. Suri A, Bramer SL. Effect of omeprazole on the metabolism of cilostazoi. Clin Pharmacokinet 1999; 37 Suppl. 2: 53–9

    PubMed  Article  CAS  Google Scholar 

  60. Otsuka Pharmaceuticals. Summary of product characteristics: Pletal. 2001 Dec.

  61. Bramer SL, Suri A. Inhibition of CYP2D6 by quinikline and its effects on the metabolism of cilostazol. Clin Pharmacokinet 1999; 37 Suppl. 2: 41–51

    PubMed  Article  CAS  Google Scholar 

  62. Gibiansky E, Malllkaarjun S, Bramer SL. Nonparametric population pharmacokinetics of cilostazol [abstract no. 3150]. Pharm Res 1997 Nov; 14 (11Suppl. 1): S515–6

    Google Scholar 

  63. Otsuka Pharmaceuticals. Pletal: Prescribing Information [online]. Available from URL: www. pletal.com.pro/0_7. asp [Accessed 2003 Mar 13]

  64. Bramer SL, Brisson J. Corey AE, et al. Effect of multiple cilostazol doses on singie dose lovastatin pharmacokinetics in healthy volunteers. Clin Pharmacokinet 1999; 37 Suppl. 2: 69–77

    PubMed  Article  CAS  Google Scholar 

  65. Mailikaarjun S, Bramer SL. Effect of cilostazol on the pharmacokinetics and pharmacodynamics of warfarin. Clin Pharmacoldnet 1999; 37 Suppl. 2: 79–86

    Article  Google Scholar 

  66. Mailikaarjun S, Forbes WP, Bramer SL. Interaction potential and tolerability of the coadministration of cilostazol and aspirin. Clin Pharmacokinet 1999; 37 Suppl. 2: 87–93

    Article  Google Scholar 

  67. European Agency for the Evaluation of Medicinal Products. Note for guidance on clinical investigation of medicinal products for the treatment of peripheral arterial occlusive disease [online]. Available from URL: www.emea.eu.int/ pdfs/human/ewp/071498en.pdf [Accessed 2003 Mar 13]

  68. Hiatt WR, Hirsch AT, Regensteiner JG, et al. Clinical trials for claudication: assessment of exercise performance, functional status, and clinical end points. Circulation 1995; 92: 614–21

    PubMed  Article  CAS  Google Scholar 

  69. Strandness Jr DE, Dalman RL, Panian S, et al. Effect of cilostazol in patients with intermittent claudication: a randomized, double-blind, placebo-controlled study. Vasc Endovascular Surg 2002; 36(2): 83–91

    PubMed  Article  Google Scholar 

  70. Dawson DL, Cutler BS, Hiatt WR, et al. A comparison of cilostazol and pentoxifylline for treating intermittent claudication. Am J Med 2000 Nov; 109(7): 523–30

    PubMed  Article  CAS  Google Scholar 

  71. Beebe HG, Dawson DL, Cutler BS, et al. A new pharmacological treatment for intermittent claudication: results of a randomized, multicenter trial. Arch Intern Med 1999 Sep 27; 159(17): 2041–50

    PubMed  Article  CAS  Google Scholar 

  72. Dawson DL, Cutler BS, Meissner MH, et al. Cilostazol has bénéficiai effects in treatment of intermittent claudication: resuits from a multicenter, randomized, prospective, doubie-blind triai. Circulation 1998 Aug 18; 98(7): 678–86

    PubMed  Article  CAS  Google Scholar 

  73. 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 Vasc Surg 1998 Feb; 27(2): 267–74

    PubMed  Article  CAS  Google Scholar 

  74. Thompson PD, Zimet R, Forbes WP, et al. Meta-analysis of results from eight randomized, placebo-controiled trials on the effect of cilostazol on patients with intermittent claudication. Am J Cardiol 2002; 90: 1314–9

    PubMed  Article  CAS  Google Scholar 

  75. Dawson DL, DeMaioribus CA, Hagino RT, et al. The effect of withdrawal of drugs treating intermittent claudication. Am J Surg 1999 Aug; 178(2): 141–6

    PubMed  Article  CAS  Google Scholar 

  76. Sacks D, Bakai CB, Beatty PT, et al. Position statement on the use of the ankiebrachiai index in the evaluation of patients with peripheral vascular disease: a consensus statement developed by the standards division of the Society of Cardiovascular & Interventional Radiology. J Vasc Interv Radiol 2002; 13: 353

    PubMed  Article  Google Scholar 

  77. Otsuka Pharmaceuticals. Product Monograph: Pietai [online]. Available from URL: www.pletai.com/pro/toc.asp [Accessed 2003 Mar 13]

  78. Rendell M, Cariski AT, Hittel N, et al. Cilostazol treatment of claudication in diabetic patients. Curr Med Res Opin 2002; 18(8): 479–87

    PubMed  Article  CAS  Google Scholar 

  79. Mohler III ER, Beebe HG, Salles-Cuhna S, et al. Effects of cilostazol on resting ankle pressures and exercise-induced ischemia in patients with intermittent claudication. Vasc Med 2001; 6(3): 151–6

    PubMed  Article  Google Scholar 

  80. Regensteiner JG, Ware Jr JE, McCarthy WJ, et al. Effect of cilostazoi on treadmill walking, community-based walking ability, and health-related quality of life in patients with intermittent claudication due to peripheral arterial disease: metaanalysis of six randomized controlled trials. J Arn Geriatr Soc 2002 Dec; 50(12): 1939–46

    Article  Google Scholar 

  81. Pratt CM. Analysis of the cilostazol safety database. Am J Cardiol 2001 Jun 28; 87 (12 Suppl. 1): 28D–33D

    PubMed  Article  CAS  Google Scholar 

  82. Gamssari F, Mahmood H. Ho JS, et al. Rapid ventricular tachycardias associated with cilostazol use [letter]. Tex Heart Inst J 2002; 29: 140–2

    PubMed  Google Scholar 

  83. McGhan WF. Cost-utility analysis of drug therapy options for intermittent claudication [abstract no. PCV7]. Value Health 2001 Mar; 4: 97–98 plus poster presented at the 6th Annual Meeting of the International Society for Pharmaeoeconomics and Outcomes Research; 2001 May 20-23; Arlington, VA.

    Article  Google Scholar 

  84. Dawson DL. Comparative effects of cilostazol and other therapies for intermittent claudication. Am J Cardiol 2001 Jun 28; 87 (12 Suppl. 1): 19D–27D

    PubMed  Article  CAS  Google Scholar 

  85. Ernst E. Pentoxifyiline for intermittent claudication: a critical review. Angiology 1994 May; 45(5): 339–45

    PubMed  Article  CAS  Google Scholar 

  86. Girolami B, Bernardi E, Prins MH, et al. Treatment of intermittent claudication with physical training, smoking cessation, pentoxifylline, or natronyl: a metaanalysis. Arch Intern Med 1999; 159: 337–45

    PubMed  Article  CAS  Google Scholar 

  87. Hood SC, Moher D, Barber GG. Management of intermittent claudication with pentoxifylline: meta-anaiysis of randomized, controlled triais. Can Med Assn J 1996; 155: 1053–9

    CAS  Google Scholar 

  88. Weitz JL Byrne J, Clagett P, et al. Diagnosis and treatment of chronic arterial insufficiency of the lower extremities: a critical review. Circulation 1996; 94: 3026–49

    PubMed  Article  CAS  Google Scholar 

  89. Jackson MR, Ciagett GP. Antithrombotic therapy in peripheral arterial occlusive disease. Chest 1998; 114: 666S–82S

    PubMed  Article  CAS  Google Scholar 

  90. Barradell LB, Brogden RN. Oral naftidrofuryi: a review of its pharmacology and therapeutic use in the management of peripheral occlusive arteriai disease. Drugs Aging 1996; 8: 299–322

    PubMed  Article  CAS  Google Scholar 

  91. Hiatt WR. New medical treatment options in intermittent ciaudication: the US experience. Int J Clin Pract 2001 Apr; Suppl. 119: 20–7

    CAS  Google Scholar 

  92. Spengel F, Cliément D, Boccalon H, et al. Findings of the naftidrofuryi in quality of life (NIQOL) European study program. Int. Angiol. 2002 Mar; 21(1): 20–7

    PubMed  CAS  Google Scholar 

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  1. Adis International Inc., 860 Town Center Drive, Langhorne, Pennsylvania, 19047, USA

    Therese M. Chapman & Karen L. Goa

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  1. Therese M. Chapman
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  2. Karen L. Goa
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Correspondence to Therese M. Chapman.

Additional information

Various sections of the manuscript reviewed by: H. Boccalon, Service de Médecine Vasculaire, Centre Hospitalier Universitaire de Rangueil, Toulouse, France; R. Donnelly, Division of Vascular Medicine, University of Nottingham, Nottingham, England; E.D. Reis, Department of Surgery, Mount Sinai School of Medicine, New York, New York, USA; V. Riambau, Institute of Cardiovascular Diseases, University of Barcelona, Barcelona, Spain; H. Rieger, Klinik F. Gefaesskrankheiten, Engelskirchen, Germany.

Data Selection

Sources: Medical literature published in any language since 1980 on cilostazol, identified using Medline and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: Medline search terms were (‘cilostazol’ or ‘OPC-13013’) and ‘intermittent claudication’. EMBASE search terms were ‘cilostazol’ and ‘intermittent claudication’. AdisBase search terms were (‘cilostazol’ or ‘OPC 13013’) and ‘intermittent-claudication’. Searches were last updated 13 March 2003.

Selection: Studies in patients with intermittent claudication who received cilostazol. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Cilostazol, intermittent claudication, pharmacodynamics, pharmacokinetics, therapeutic use.

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Chapman, T.M., Goa, K.L. Cilostazol. Am J Cardiovasc Drugs 3, 117–138 (2003). https://doi.org/10.2165/00129784-200303020-00006

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Keywords

  • Peripheral Arterial Disease
  • Hepatic Impairment
  • Pentoxifylline
  • Cilostazol
  • Severe Renal Impairment