Volume 5, Number 5: May 2002
Three cases of digital
ischemia successfully treated with cilostazol.
Pharmacokinetic
and pharmacodynamic modeling of the antiplatelet and
cardiovascular effects of cilostazol in healthy humans.
Effect of cilostazol in
patients with intermittent claudication: a randomized, double-blind, placebo-controlled
study.
A phosphodiesterase inhibitor, cilostazol, prevents the onset of silent brain infarction
in Japanese subjects with Type II diabetes.
| Three cases of digital
ischemia successfully treated with cilostazol. Reference: Vasc Med 2001;6(4):245-8. Three patients were evaluated for refractory digital ischemia. The first patient presented with chronic, post-traumatic, unremitting, cold, painful, right fourth and fifth fingers. The symptoms had failed to improve despite topical nitroglycerin and a calcium channel blocker. Baseline digital plethysmography documented impaired perfusion within the affected digits. Cilostazol (Pletal) was added to the medical regimen and at the 8-week follow-up the fourth and fifth fingers were warm with repeat plethysmography displaying normal perfusion. A second patient had CREST syndrome-associated painful bilateral index finger ulcerations that had evolved despite taking a calcium channel blocker. Consequently the patient was started on cilostazol and within 4 weeks the digital ulcerations and pain had resolved. The third patient with traumatic right fifth digital arterial thrombosis was seen for persistent pain and cyanosis in spite of undergoing thrombolysis and subsequent anticoagulation with vasodilator therapy. Digital plethysmography established fixed ischemia within the fifth finger; subsequently, cilostazol was prescribed. Four weeks later the digital pain and cyanosis had essentially resolved. A follow-up plethysmographic waveform documented restored perfusion. Although approved for the treatment of intermittent claudication, cilostazol was successfully utilized in the setting of severe digital ischemia.
METHODS: A single oral dose of 100 mg cilostazol was administered to 20 healthy volunteers. Serial blood sampling and pharmacodynamic measurements were performed up to 48 hours thereafter. The effects of cilostazol on platelet aggregation, blood pressure, and heart rate were measured during the same period. The plasma concentration of cilostazol was measured with a validated HPLC method that entailed ultraviolet detection. The time courses of plasma cilostazol concentration, platelet aggregation, and cardiovascular effects were analyzed by means of pharmacokinetic-pharmacodynamic modeling with the program ADAPT II. RESULTS: The plasma concentration-time course followed a 2-compartment model. Mean peak concentration was 775 ng/ml approximately 3.65 hours after administration of cilostazol. The maximal effect on platelet aggregation was a 31.14% reduction 6.05 hours after administration. No significant difference in systolic blood pressure was found. The maximal increase in heart rate was 13.49%, whereas the maximal decrease in diastolic blood pressure was 29.51%. Both peak effects were detected approximately 6 hours after administration of the drug. Platelet aggregation and cardiovascular effects (change in diastolic blood pressure and heart rate) were analyzed with the effect-link sigmoid maximal effect model. CONCLUSION: This pharmacokinetic-pharmacodynamic model successfully described the relation between plasma concentration of cilostazol and the antiplatelet and cardiovascular effects of the drug.
METHODS: A total of 89 subjects were allocated at
random to the cilostazol RESULTS: After the study period (3.2 +/- 0.5 years), carotid intima-media thickness (IMT) (means +/- SD) had increased ( p < 0.01) by 0.18 +/- 0.19 mm in the control group. In the cilostazol group, intima-media thickness showed almost no change (-0.00 +/- 0.16 mm). In the control group, 2 out of 46 subjects showed symptomatic brain infarctions and 10 out of 34 subjects without infarct-like region assessed by standard brain MRI examination showed silent brain infarctions after the observation period. On the other hand, no subjects in the cilostazol group showed silent brain infarction or strokes during the study period. Both at the beginning and end of the study period, the number of infarct-like regions positively correlated with IMT ( r = 0.335, p < 0.001 or r = 0.347, p < 0.001 respectively). The progression of infarct-like regions was directly related to the increase in IMT during the study period ( r = 0.299, p = 0.004). CONCLUSION/INTERPRETATION: These data demonstrated that cilostazol could prevent the onset of silent brain infarction in Japanese subjects with Type II (non-insulin-dependent) diabetes mellitus. Also, an increase in intima-media thickness of the carotid artery wall could be able to predict the onset of silent brain infarction |
