QT time prolongation
Adverse drug events
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Explanations of the substances for patients
We have no additional warnings for the combination of astemizole and cilostazol. Please also consult the relevant specialist information.
The reported changes in exposure correspond to the changes in the plasma concentration-time curve [ AUC ]. We did not detect any change in exposure to astemizole. We currently cannot estimate the influence of cilostazol. We did not detect any change in exposure to cilostazol. We currently cannot estimate the influence of astemizole.
The pharmacokinetic parameters of the average population are used as the starting point for calculating the individual changes in exposure due to the interactions.
Astemizole has a low oral bioavailability [ F ] of 3%, which is why the maximum plasma level [Cmax] tends to change strongly with an interaction. The terminal half-life [ t12 ] is 22 hours and constant plasma levels [ Css ] are reached after approximately 88 hours. The protein binding [ Pb ] is 97% strong. The metabolism takes place via CYP2D6 and CYP3A4, among others.
The bioavailability of cilostazol is unknown. The terminal half-life [ t12 ] is 11 hours and constant plasma levels [ Css ] are reached after approximately 44 hours. The protein binding [ Pb ] is 96.5% strong. The metabolism takes place via CYP2C19 and CYP3A4, among others.
|Serotonergic Effects a||0||Ø||Ø|
Rating: According to our knowledge, neither astemizole nor cilostazol increase serotonergic activity.
|Kiesel & Durán b||0||Ø||Ø|
Rating: According to our knowledge, neither astemizole nor cilostazol increase anticholinergic activity.
QT time prolongation
Rating: In combination, astemizole and cilostazol can potentially trigger ventricular arrhythmias of the torsades de pointes type.
General adverse effects
|Side effects||∑ frequency||ast||cil|
|Peripheral edema||8.0 %||n.a.||8.0|
|Abdominal pain||4.5 %||n.a.||4.5|
Based on your answers and scientific information, we assess the individual risk of undesirable side effects. These recommendations are intended to advise professionals and are not a substitute for consultation with a doctor. In the restricted test version (alpha), the risk of all substances has not yet been conclusively assessed.
Abstract: Astemizole is a long-acting, highly selective histamine1-receptor antagonist with minimal central and anticholinergic effects. Comparison studies have shown astemizole to be equal or superior to currently available antihistamines, beclomethasone nasal spray, and cromolyn sodium in relieving allergic symptoms of seasonal and perennial allergic rhinitis. Other uses include treatment of allergic conjunctivitis and chronic urticaria. Astemizole is not as effective for treatment of acute allergic symptoms because of its delayed onset of action. Astemizole and its active metabolite, desmethylastemizole, have long elimination half-lives permitting once-daily dosing. The incidence of sedation is lower than with conventional antihistamines, but increased appetite and weight gain do occur. Astemizole should be useful for both maintenance and prophylactic therapy in patients with chronic allergic conditions who cannot tolerate the sedative or anticholinergic effects of conventional antihistamines.
Abstract: Astemizole is an H1-histamine receptor antagonist with a long duration of action permitting once daily administration. Its efficacy in seasonal and perennial allergic rhinitis has been convincingly demonstrated, and several comparative studies suggest that astemizole is at least as effective as some other H1-histamine receptor antagonists. A few smaller studies have shown beneficial effects on the symptoms of allergic conjunctivitis and chronic urticaria (but not atopic dermatitis). While astemizole appears to share with other H1-histamine receptor antagonists a tendency to increase appetite and cause weight gain after prolonged use, it offers the important advantage of an absence of significant central nervous system depression or anticholinergic effects with usual doses. Thus, astemizole offers a worthwhile improvement in side effect profile over 'traditional' H1-histamine receptor antagonists, especially in patients bothered by the sedative effects of these drugs.
Abstract: An overdose of astemizole predisposes the myocardium to ventricular dysrhythmias, including torsades de pointes. Herein we describe a case of astemizole-induced torsades de pointes ventricular tachycardia and also review previous case reports in the literature. All the patients were young, and dysrhythmias developed only in those with corrected QT intervals greater than 500 ms. Although several mechanisms have been postulated, no clear explanation has been provided for why astemizole promotes myocardial dysrhythmias. Treatment of astemizole-induced torsades de pointes includes discontinuing use of astemizole, intravenous administration of magnesium sulfate and isoproterenol, temporary cardiac pacing, and, when necessary, direct current cardioversion. A cardiac cause of syncope or convulsions must not be overlooked, especially in patients taking H1 antagonists because they often have these symptoms before hospitalization or detection of torsades de pointes (or both).
Abstract: No Abstract available
Abstract: A 26 year-old woman was admitted to the hospital two hours after astemizole overdose. Electrocardiograph showed a prolonged QT interval. Torsade de pointes occurred 13 h after ingestion. Plasma levels of astemizole plus hydroxylated metabolites showed an apparent plasma half-life of 17 h. The possible occurrence of torsade de pointes in astemizole overdose, and the long elimination time of astemizole and hydroxylated metabolites, makes it necessary to maintain ECG monitoring until QT interval has returned to normal.
Abstract: AIMS: The aim of this study was to investigate the influence of chronic itraconazole treatment on the pharmacokinetics and cardiovascular effects of single dose astemizole in healthy subjects was studied. METHODS: Twelve male volunteers were taking orally 200 mg twice daily itraconazole or placebo for 14 days with a washout period of 4 weeks in between. Approximately 2 h after the morning dose of itraconazole or placebo on day 11, 10 mg astemizole was orally administered. The plasma concentrations of astemizole and desmethylastemizole were measured by radioimmunoassay up to 504 h after administration; electrocardiograms with analysis of the QTc interval were recorded up to 24 h post administration. RESULTS: Itraconazole treatment did not significantly change the peak concentration of astemizole (0.74 vs 0.81 ng ml-1) but it increased the area under the curve from 0 to 24 h (5.46 to 9.95 ng ml-1 h) and from 0 to infinity (17.4 to 48.2 ng ml-1 h), and the elimination half-life (2.1 to 3.6 days). The systemic bioavailability of desmethylastemizole was also increased. The QTc interval did not increase after astemizole administration and there was no difference in the QTc intervals between the itraconazole and placebo session. CONCLUSIONS: Chronic administration of itraconazole influences the metabolism of single dose astemizole in normal volunteers without changes of cardiac repolarization during the first 24 h after astemizole administration. However, the reduction in astemizole clearance under concomitant administration of itraconazole may result in a marked increase in astemizole plasma concentrations and QTc alterations during chronic combined intake of astemizole with itraconazole.
Abstract: Second-generation histamine H1 receptor antagonists (antihistamines) have been developed to reduce or eliminate the sedation and anticholinergic adverse effects that occur with older H1 receptor antagonists. This article evaluates second-generation antihistamines, including acrivastine, astemizole, azelastine, cetirizine, ebastine, fexofenadine, ketotifen, loratadine, mizolastine and terfenadine, for significant features that affect choice. In addition to their primary mechanism of antagonising histamine at the H1 receptor, these agents may act on other mediators of the allergic reaction. However, the clinical significance of activity beyond that mediated by histamine H1 receptor antagonism has yet to be demonstrated. Most of the agents reviewed are metabolised by the liver to active metabolites that play a significant role in their effect. Conditions that result in accumulation of astemizole, ebastine and terfenadine may prolong the QT interval and result in torsade de pointes. The remaining agents reviewed do not appear to have this risk. For allergic rhinitis, all agents are effective and the choice should be based on other factors. For urticaria, cetirizine and mizolastine demonstrate superior suppression of wheal and flare at the dosages recommended by the manufacturer. For atopic dermatitis, as adjunctive therapy to reduce pruritus, cetirizine, ketotifen and loratadine demonstrate efficacy. Although current evidence does not suggest a primary role for these agents in the management of asthma, it does support their use for asthmatic patients when there is coexisting allergic rhinitis, dermatitis or urticaria.
Abstract: OBJECTIVE: To study the pharmacokinetics of cilostazol following single oral administration of 50 to 200 mg in healthy young males, and after repeated oral administration of 100 mg every 12 hours to patients with peripheral arterial disease (PAD). DESIGN: The healthy male single dose study was a single-centre, randomised sequence, open-label, incomplete block, 3-period, 4-treatment, crossover design. The patient study was a single-centre, multiple dose, open-label study. STUDY PARTICIPANTS: 20 healthy nonsmoking male volunteers were enrolled and successfully completed the single dose study. 26 patients (21 males, 5 females) with intermittent claudication resulting from PAD were enrolled and completed the single/multiple dose study. MAIN OUTCOME MEASURES: Noncompartmental pharmacokinetic parameters, the area under the plasma concentration-time curve from zero to the time of last measurable plasma concentration, and maximum plasma concentration. RESULTS: Peak plasma concentrations of cilostazol occurred about 3 hours after drug administration and then declined biexponentially with concentrations detectable (> 20 micrograms/L) in the plasma for at least 36 hours postdose. The apparent elimination half-life of cilostazol (approximately 11 hours) was similar after a single dose or after multiple doses, with steady state being reached within 4 days. Cilostazol accumulated 1.7-fold following multiple dose administration. The apparent volume of distribution (Vz/F; 2.76 L/kg) suggested extensive distribution of cilostazol in the tissues. The oral clearance of cilostazol (CL/F; 0.18 L/h/kg) was much lower than liver blood flow, indicating a low extraction ratio drug, and hence low probability of a significant first-pass effect. None of the administered doses were recovered in the urine as unchanged cilostazol, suggesting that metabolism, rather than urinary excretion, is the major elimination route. Following single oral doses of 50 to 200 mg, the plasma concentrations of cilostazol and its metabolites increased less than proportionally to the dose. The pharmacokinetics of cilostazol in normal healthy volunteers are predictive of those in patients with PAD. Single oral doses of 50 to 200 mg cilostazol as well as 100 mg cilostazol every 12 hours were well tolerated. CONCLUSION: The plasma concentration of cilostazol and its metabolites increased less than proportionally with increasing doses. The relatively low plasma clearance and high volume of distribution of cilostazol suggest a low first-pass effect and extensive distribution. The pharmacokinetics of cilostazol in normal volunteers is predictive of that in patients with PAD. Cilostazol was well tolerated in healthy volunteers and patients with intermittent claudication resulting from PAD.
Abstract: OBJECTIVE: In vitro results are inconclusive as to whether cilostazol is metabolised by cytochrome P450 isoenzyme 2D6 (CYP2D6). The goals of this study were (1) to assure the dose of quinidine and timing relative to cilostazol used in this study were adequate to cause inhibition of CYP2D6, (2) to evaluate carryover effects of quinidine administration, and (3) to evaluate the effect of CYP2D6 deficiency and administration of quinidine (a CYP2D6 inhibitor) on the pharmacokinetics of a single 100 mg oral dose of cilostazol. DESIGN: This study was conducted as a single-centre, open-label, randomised sequence, 2-period, crossover pharmacokinetic trial. Water alone (treatment without quinidine) or two 200 mg oral doses of quinidine sulfate with water were administered 25 hours and 1 hour prior to a single 100 mg dose of cilostazol in period 1. Study participants were crossed over to opposite treatment in period 2. Metoprolol 25 mg, used as a positive control, was administered 1 hour after quinidine sulfate with water or using water alone to assess the magnitude of CYP2D6 inhibition by quinidine. STUDY PARTICIPANTS: 22 healthy nonsmoking Caucasian (14 male and 8 female) volunteers participated in the study. MAIN OUTCOME MEASURES: Serial blood and urine samples were collected at predose and after cilostazol administration to characterise cilostazol and its metabolite pharmacokinetics. Additional plasma samples were taken to assess the pharmacokinetics of quinidine. Urine samples were collected to measure metoprolol and hydroxymetoprolol. RESULTS: Administration of metoprolol with quinidine caused a significant (p < 0.001) decrease in the urinary 4-hydroxymetoprolol/metoprolol ratio compared with administration of metoprolol alone (42-fold decrease, 0.065 vs 2.707). Hence, quinidine effectively converted extensive metabolisers of CYP2D6 to poor metabolisers of CYP2D6. The 21-day washout period was adequate to have complete recovery from quinidine inhibition of CYP2D6. The analysis of variance demonstrated that the mean maximum plasma concentration (Cmax) for cilostazol, both adjusted and unadjusted for the free fraction, was higher in the control group than in the quinidine group (p = 0.023). However, the time to Cmax (p = 0.669), the area under the plasma concentration-time curve from time zero to infinity (AUC infinity; p = 0.133), and the apparent oral clearance (p = 0.135) were unchanged. The geometric mean ratios (90% confidence interval) comparing with quinidine (test) and without quinidine (reference) coadministration for Cmax and AUC infinity are 0.86 (0.77, 0.95) and 0.92 (0.84, 1.00), respectively. Similar patterns were observed for OPC-13015 and OPC-13213 with regard to Cmax, area under the plasma concentration-time curve from time zero to the last measurable concentration at time t, and AUC infinity (where determinable). The slight decrease in the systemic availability of cilostazol and its metabolites was thought to be a result of the increased gastrointestinal motility secondary to quinidine. CONCLUSIONS: Administration of quinidine sulfate 200 mg profoundly inhibited CYP2D6-mediated metabolism. The effects of quinidine inhibition of CYP2D6 metabolism were completely reversible during the 21-day washout period. Coadministration of quinidine with cilostazol had no substantial effect on cilostazol or its metabolites (OPC-13015 and OPC-13213). Hence, CYP2D6 does not have a significant contribution in the metabolic elimination of cilostazol.
Abstract: AIMS: The aims of the present study were to investigate the metabolism of astemizole in human liver microsomes, to assess possible pharmacokinetic drug-interactions with astemizole and to compare its metabolism with terfenadine, a typical H1 receptor antagonist known to be metabolized predominantly by CYP3A4. METHODS: Astemizole or terfenadine were incubated with human liver microsomes or recombinant cytochromes P450 in the absence or presence of chemical inhibitors and antibodies. RESULTS: Troleandomycin, a CYP3A4 inhibitor, markedly reduced the oxidation of terfenadine (26% of controls) in human liver microsomes, but showed only a marginal inhibition on the oxidation of astemizole (81% of controls). Three metabolites of astemizole were detected in a liver microsomal system, i.e. desmethylastemizole (DES-AST), 6-hydroxyastemizole (6OH-AST) and norastemizole (NOR-AST) at the ratio of 7.4 : 2.8 : 1. Experiments with recombinant P450s and antibodies indicate a negligible role for CYP3A4 on the main metabolic route of astemizole, i.e. formation of DES-AST, although CYP3A4 may mediate the relatively minor metabolic routes to 6OH-AST and NOR-AST. Recombinant CYP2D6 catalysed the formation of 6OH-AST and DES-AST. Studies with human liver microsomes, however, suggest a major role for a mono P450 in DES-AST formation. CONCLUSIONS: In contrast to terfenadine, a minor role for CYP3A4 and involvement of multiple P450 isozymes are suggested in the metabolism of astemizole. These differences in P450 isozymes involved in the metabolism of astemizole and terfenadine may associate with distinct pharmacokinetic influences observed with coadministration of drugs metabolized by CYP3A4.
Abstract: Seven forms of congenital long QT syndrome (LQTS) caused by mutations in ion channel genes have been identified. Genotype-phenotype correlation in clinical and experimental studies involving arterially-perfused canine left ventricular wedges suggest that beta-blockers are protective in LQT1, less so in LQT2, but not protective in LQT3. A class IB sodium channel blocker, mexiletine, is most effective in abbreviating QT interval in LQT3, but effectively reduces transmural dispersion of repolarization (TDR) and prevents the development of Torsade de Pointes (TdP) in all 3 models, suggesting its potential as an adjunctive therapy in LQT1 and LQT2. High concentrations of intravenous nicorandil, a potassium channel opener, have been shown to be capable of decreasing QT and TDR, and preventing TdP in LQT1 and LQT2 but not in LQT3. The calcium channel blocker, verapamil, has also been suggested as adjunctive therapy for LQT1, LQT2 and possibly LQT3. Experimental data using right ventricular wedge preparations suggest that a prominent transient outward current (I(to))-mediated action potential (AP) notch and a loss of AP dome in epicardium, but not in endocardium, give rise to a transmural voltage gradient, resulting in ST segment elevation and the induction of ventricular fibrillation (VF), characteristics of the Brugada syndrome. Since the maintenance of the AP dome is determined by the balance of currents active at the end of phase 1 of the AP, any intervention that reduces the outward current or boosts inward current at the end of phase 1 may normalize the ST segment elevation and suppress VF. Such interventions are candidates for pharmacological therapy of the Brugada syndrome. The infusion of isoproterenol, a beta-adrenergic stimulant, strongly augments L-type calcium current (I(Ca-L)), and is the first choice for suppressing electrical storms associated with Brugada syndrome. Quinidine, by virtue of its actions to block I(to), has been proposed as adjunctive therapy, with an implantable cardioverter defibrillator as backup. Oral denopamine, atropine or cilostazol all increase ICa-L, and for this reason may be effective in reducing episodes of VF.
Abstract: This 24-year-old woman had incessant polymorphic ventricular tachycardia (PVT) during week 24 of her pregnancy and received over 200 implantable cardioverter-defibrillator discharges. She failed to respond to quinidine, magnesium, isoproterenol, amiodarone, esmolol, and cilostazol during her PVT storm, although her dramatic response to verapamil was consistent with the diagnosis of short-coupled variant of torsades de pointes. The case illustrated the utility of extracorporeal membrane oxygenation during refractory PVT, while attempting diagnostic and therapeutic pharmacologic maneuvers.
Abstract: BACKGROUND: This study evaluated the effects of atypical antipsychotic drugs and selective serotonin reuptake inhibitors (SSRIs) on the corrected QT (QTc) interval using a large database obtained from clinical settings. Additionally, the effects of factors including age on QTc intervals were estimated. METHODS: Using an open-access QT database (ECG-ViEW), QTc-lengthening effects of 14 selected atypical antipsychotics and SSRIs were compared to those of a positive control drug, cilostazol, and a negative control drug, diazepam. We also evaluated effects of age, sexgender, and select electrolyte levels on observed QTc intervals. RESULTS: The frequency of QTc prolongation with the pooled data of the 14 study drugs was lower than that with cilostazol (age-adjusted odds ratio (OR) = 0.43, 95% confidence interval (CI) = 0.27-0.69), but no significant difference was found relative to when compared with that with diazepam (age-adjusted OR = 0.89, 95% CI = 0.55-1.47). Furthermore, administration of the 14 study drugs significantly increased the QTc interval by 2.89 ms after each 10-year age increment (p-value < 0.0001). CONCLUSIONS: This study suggests that atypical antipsychotic drugs and SSRIs are less likely to be associated with QTc prolongation in clinical settings. In addition, age showed a significant association with the QTc interval. Further studies with well-characterized cohorts are warranted.
Abstract: PURPOSE: CYP3A4, CYP2C19, and CYP3A5 are primarily involved in the metabolism of cilostazol. We investigated the effects of CYP2C19 and CYP3A5 genetic polymorphisms on the pharmacokinetics of cilostazol and its two active metabolites. METHODS: Thirty-three healthy Korean volunteers were administered a single 100-mg oral dose of cilostazol. The concentrations of cilostazol and its active metabolites (OPC-13015 and OPC-13213) in the plasma were determined by HPLC-MS/MS. RESULTS: Although the pharmacokinetic parameters for cilostazol were similar in different CYP2C19 and CYP3A5 genotypes, CYP2C19PM subjects showed significantly higher AUC,for OPC-13015 and lower for OPC-13213 compared to those in CYP2C19EM subjects (P < 0.01 and P < 0.001, respectively). Pharmacokinetic differences in OPC-13015 between CYP3A5 non-expressors and expressors were significant only within CYP2C19PM subjects. The amount of cilostazol potency-adjusted total active moiety was the greatest in subjects with CYP2C19PM-CYP3A5 non-expressor genotype. CONCLUSION: These results suggest that CYP2C19 and CYP3A5 genetic polymorphisms affect the plasma exposure of cilostazol total active moiety. CYP2C19 plays a crucial role in the biotransformation of cilostazol.