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Mechanism of Action
The mechanism of the effects of Pletal (cilostazol) on the symptoms of intermittent claudication is not fully understood. Pletal (cilostazol) and several of its metabolites are cyclic AMP (cAMP) phosphodiesterase III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in cAMP in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.
Pletal (cilostazol) reversibly inhibits platelet aggregation induced by a variety of stimuli, including thrombin, ADP, collagen, arachidonic acid, epinephrine, and shear stress. Effects on circulating plasma lipids have been examined in patients taking Pletal (cilostazol) . After 12 weeks, as compared to placebo, Pletal (cilostazol) 100 mg b.i.d. produced a reduction in triglycerides of 29.3 mg/dL (15%) and an increase in HDL-cholesterol of 4.0 mg/dL (≡ 10%).
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, carotid or superior mesenteric arteries. Renal arteries were not responsive to the effects of cilostazol.
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with Holter monitors, numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained ventricular tachycardia events than did placebo-treated patients; the increases were not dose-related.
Pletal (cilostazol) is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of Pletal (cilostazol) . Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).
The mean ± SEM plasma concentration-time profile at steady state after multiple dosing of Pletal (cilostazol) 100 mg b.i.d. is shown below:
Plasma Protein and Erythrocyte Binding
Cilostazol is 95 - 98% protein bound, predominantly to albumin. The mean percent binding for 3,4-dehydro-cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.
Metabolism and Excretion
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are CYP3A4 and, to a lesser extent, CYP2C19. The enzyme responsible for metabolism of 3,4-dehydro-cilostazol, the most active of the metabolites, is unknown.
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.
Age and Gender
The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50-to-80-year-old age range.
Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.
The pharmacokinetics of cilostazol and its metabolites were similar in subjects with mild hepatic disease as compared to healthy subjects.
Patients with moderate or severe hepatic impairment have not been studied.
The total pharmacologic activity of cilostazol and its metabolites was similar in subjects with mild to moderate renal impairment and in normal subjects. Severe renal impairment increases metabolite levels and alters protein binding of the parent and metabolites. The expected pharmacologic activity, however, based on plasma concentrations and relative PDE III inhibiting potency of parent drug and metabolites, appeared little changed. Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95 - 98%).
Pharmacokinetic and Pharmacodynamic Drug-Drug Interactions
Cilostazol could have pharmacodynamic interactions with other inhibitors of platelet function and pharmacokinetic interactions because of effects of other drugs on its metabolism by CYP3A4 or CYP2C19. A reduced dose of Pletal (cilostazol) should be considered when taken concomitantly with CYP3A4 or CYP2C19 inhibitors. Cilostazol does not appear to inhibit CYP3A4 (see Pharmacokinetic and Pharmacodynamic Drug-Drug Interactions, Lovastatin).
Short-term ( ≤ 4 days) coadministration of aspirin with Pletal (cilostazol) increased the inhibition of ADP-induced ex vivo platelet aggregation by 22% - 37% when compared to either aspirin or Pletal (cilostazol) alone. Short-term ( ≤ 4 days) coadministration of aspirin with Pletal (cilostazol) increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to Pletal (cilostazol) alone and by 48% compared to aspirin alone. However, short-term coadministration of aspirin with Pletal (cilostazol) had no clinically significant impact on PT, aPTT, or bleeding time compared to aspirin alone. Effects of long-term coadministration in the general population are unknown. In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was coadministered with cilostazol to 201 patients. The most frequent doses and mean durations of aspirin therapy were 75-81 mg daily for 137 days (107 patients) and 325 mg daily for 54 days (85 patients). There was no apparent increase in incidence of hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.
The cytochrome P-450 isoenzymes involved in the metabolism of R-warfarin are CYP3A4, CYP1A2, and CYP2C19, and in the metabolism of S-warfarin, CYP2C9. Cilostazol did not inhibit either the metabolism or the pharmacologic effects (PT, aPTT, bleeding time, or platelet aggregation) of R- and S-warfarin after a single 25-mg dose of warfarin. The effect of concomitant multiple dosing of warfarin and Pletal (cilostazol) on the pharmacokinetics and pharmacodynamics of both drugs is unknown.
Multiple doses of clopidogrel do not significantly increase steady state plasma concentrations of cilostazol.
Inhibitors of CYP3A4
Strong Inhibitors of CYP3A4: A priming dose of ketoconazole 400 mg (a strong inhibitor of CYP3A4), was given one day prior to coadministration of single doses of ketoconazole 400 mg and cilostazol 100 mg. This regimen increased cilostazol Cmax by 94% and AUC by 117%. Other strong inhibitors of CYP3A4, such as itraconazole, fluconazole, miconazole, fluvoxamine, fluoxetine, nefazodone, and sertraline, would be expected to have a similar effect (see DOSAGE AND ADMINISTRATION).
Moderate Inhibitors of CYP3A4
- Erythromycin and other macrolide antibiotics: Erythromycin is a moderately strong inhibitor of CYP3A4. Coadministration of erythromycin 500 mg q 8h with a single dose of cilostazol 100 mg increased cilostazol Cmax by 47% and AUC by 73%. Inhibition of cilostazol metabolism by erythromycin increased the AUC of 4´-trans-hydroxy-cilostazol by 141%. Other macrolide antibiotics (e.g., clarithromycin), but not all (e.g., azithromycin), would be expected to have a similar effect (see DOSAGE AND ADMINISTRATION).
- Diltiazem: Diltiazem 180 mg decreased the clearance of cilostazol by ~30%. Cilostazol Cmax increased ~30% and AUC increased ~40% (see DOSAGE AND ADMINISTRATION).
- Grapefruit Juice: Grapefruit juice increased the Cmax of cilostazol by ~50%, but had no effect on AUC.
INHIBITORS OF CYP2C19
Omeprazole: Coadministration of omeprazole did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%, probably the result of omeprazole's potent inhibition of CYP2C19 (see DOSAGE AND ADMINISTRATION).
Concomitant administration of quinidine with a single dose of cilostazol 100 mg did not alter cilostazol pharmacokinetics.
The concomitant administration of lovastatin with cilostazol decreases cilostazol Css, max and AUCτ by 15%. There is also a decrease, although nonsignificant, in cilostazol metabolite concentrations. Coadministration of cilostazol with lovastatin increases lovastatin and β-hydroxi lovastatin AUC approximately 70%. This is most likely clinically insignificant.
The ability of Pletal (cilostazol) to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks' duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998), and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.
Compared to patients treated with placebo, patients treated with Pletal (cilostazol) 50 or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of Pletal (cilostazol) on walking distance was seen as early as the first on-therapy observation point of two or four weeks.
The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.
Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with Pletal (cilostazol) 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.
The corresponding changes in the placebo group were -10% to 41%.
The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either Pletal (cilostazol) 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age, and concomitant use of beta blockers or calcium channel blockers. Pletal (cilostazol) has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers, or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.
A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8 to 8.4 %) on cilostazol and 6.8% (95% CI of 1.9 to 11.5 %) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.
Last reviewed on RxList: 12/19/2007
This monograph has been modified to include the generic and brand name in many instances.
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