Allongement du temps QT
Événements indésirables médicamenteux
Variantes ✨Pour une évaluation intensive des variantes par ordinateur, veuillez choisir l'abonnement standard payant.
Explications concernant les substances pour les patients
Nous n'avons pas de mise en garde supplémentaire concernant l'association de clomipramine et de astémizole. Veuillez également consulter les informations pertinentes des spécialistes.
Les changements d'exposition rapportés correspondent aux changements de la courbe concentration-temps plasmatique [ AUC ]. Nous n'avons détecté aucun changement dans l'exposition à la clomipramine. Nous ne pouvons actuellement pas estimer l'influence de la astémizole. Nous n'avons détecté aucun changement dans l'exposition à la astémizole. Nous ne pouvons actuellement pas estimer l'influence de la clomipramine.
Les paramètres pharmacocinétiques de la population moyenne sont utilisés comme point de départ pour calculer les changements individuels d'exposition dus aux interactions.
La clomipramine a une biodisponibilité orale moyenne [ F ] de 50%, c'est pourquoi les concentrations plasmatiques maximales [Cmax] ont tendance à changer avec une interaction. La liaison aux protéines [ Pb ] est 97% forte. Le métabolisme a lieu via CYP1A2, CYP2C19, CYP2D6 et CYP3A4, entre autres.
La astémizole a une faible biodisponibilité orale [ F ] de 3%, c'est pourquoi la concentration plasmatique maximale [Cmax] a tendance à changer fortement avec une interaction. La demi-vie terminale [ t12 ] est de 22 heures et des taux plasmatiques constants [ Css ] sont atteints après environ 88 heures. La liaison aux protéines [ Pb ] est 97% forte. Le métabolisme a lieu via CYP2D6 et CYP3A4, entre autres.
|Effets sérotoninergiques a||2||++||Ø|
Recommandations: Par mesure de précaution, les symptômes de surstimulation sérotoninergique doivent être pris en compte, en particulier après l'augmentation de la dose et à un niveau compris dans le spectre thérapeutique supérieure.
Note: La clomipramine module le système sérotoninergique de façon modérée. Le risque de syndrome sérotoninergique peut être classé comme faible avec ce médicament si la posologie est dans la fourchette habituelle. À notre connaissance, la astémizole n'augmente pas l'activité sérotoninergique.
|Kiesel & Durán b||3||+++||Ø|
Recommandation: Par mesure de précaution, une attention particulière doit être portée aux symptômes anticholinergiques, en particulier après augmentation de la dose et à de celles situées dans la marge thérapeutique supérieure.
Notation: La clomipramine augmente considérablement l'activité anticholinergique. À notre connaissance, la astémizole n'augmente pas l'activité anticholinergique.
Allongement du temps QT
Note: En association, la clomipramine et la astémizole peuvent potentiellement déclencher des arythmies ventriculaires de type torsades de pointes.
Effets indésirables généraux
|Effets secondaires||∑ fréquence||clo||ast|
|Mal de crâne||40.0 %||40.0||n.a.|
|Éjaculation anormale||24.0 %||24.0||n.a.|
|La nausée||21.0 %||21.0||n.a.|
Insomnie (18%): clomipramine
Myoclonie (7.5%): clomipramine
Crise d'épilepsie: clomipramine
Dyspepsie (17.5%): clomipramine
Perte d'appétit (17%): clomipramine
La diarrhée (10%): clomipramine
Rhinopharyngite (14%): clomipramine
Myalgie (13%): clomipramine
Vision floue (12.5%): clomipramine
Tachycardie (11%): clomipramine
Hypotension orthostatique (5%): clomipramine
Syncope (2%): clomipramine
Arrêt cardiaque: clomipramine
Gain de poids (11%): clomipramine
Nervosité (11%): clomipramine
Sur la base de vos réponses et des informations scientifiques, nous évaluons le risque individuel d'effets secondaires indésirables. Ces recommandations sont destinées à conseiller les professionnels et ne se substituent pas à la consultation d'un médecin. Dans la version d'essai (alpha), le risque de toutes les substances n'a pas encore été évalué de manière concluante.
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: The influence of the sparteine and the S-mephenytoin oxidation polymorphisms on the kinetics of clomipramine were investigated in 25 healthy volunteers: 10 extensive metabolizers of sparteine and mephenytoin (EMs/EMm), nine poor metabolizers of sparteine and extensive metabolizers of mephenytoin (PMs/EMm), five extensive metabolizers of sparteine and poor metabolizers of mephenytoin (EMs/PMm), and one poor metabolizer of sparteine and mephenytoin (PMs/PMm). A single oral dose of 100 mg clomipramine hydrochloride was given to each subject after an overnight fast. Serum and urine levels of clomipramine and its metabolites were monitored after 1, 2, 3, 4, 6, 8, 11, 14, 24, 36, 48, and 96 hours. Additional serum was monitored after 6, 9, 12, and 15 days in the poor metabolizers. 2-Hydroxyclomipramine was undetectable in most subjects before enzymatic hydrolysis of serum and urine. The total median clearance of clomipramine was 99 L.hr-1 (range, 68 to 210) in the EMs/EMm subjects, 56 L.hr-1 (range, 37 to 183) in the PMs/EMm subjects, 66 L.hr-1 (range, 37 to 89) in the EMs/PMm subjects, and 43 L.hr-1 in the PMs/PMm subject. It was significantly lower in PMs/EMm and EMs/PMm subjects compared with EMs/EMm subjects (p = 0.006 and 0.028, respectively; Mann-Whitney). In addition, the formation clearance of 2-hydroxyclomipramine and the hydroxylation indexes were significantly lower in PMs/EMm subjects, as was the demethylation index in EMs/PMm subjects compared with EMs/EMm subjects. Our data thus provide evidence that the 2- and 8-hydroxylation of clomipramine are catalyzed by CYP2D6 and that the N-demethylation is catalyzed in part by CYP2C.
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: Incidence of serotonin syndrome was determined by two different diagnostic criteria during clomipramine monotherapy. Incidence, determined by Sternbach's criteria, was 12.1% (8/66 patients), and that determined by the criteria of Dursun et al. was 3.0% (2/66 patients). The two patients who met the latter criteria also met the former criteria. The lower incidence with the latter was attributable to the fact that it does not include certain symptoms, such as tremors and diaphoresis, which are included in the former, and were seen in a relatively large number of patients; as well as the fact that the latter more strictly define certain symptoms. Both criteria have pros and cons. Sternbach's diagnostic criteria make it possible to diagnose serotonin syndrome in a wider range of patients, but they sometimes make it difficult to make it differential diagnosis in the presence of certain limited symptoms. In contrast, the criteria of Dursun et al. may make a more accurate diagnosis possible, though only in severe cases.
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: No Abstract available
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: No Abstract available
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: The QT interval measuring depolarisation and repolarisation has, when lengthened, been implicated as a risk factor for the development of torsades de pointes and sudden death, particularly in patients predisposed to these complications due to cardiovascular impairment. Since some of the medications used in psychiatry have been implicated, an extensive review of available literature was made of the major classes, including antipsychotics, antidepressants, lithium, anticonvulsants and benzodiazepines. Further, where no publications were found on a particular medication, the pharmaceutical firms responsible for these items were contacted concerning possibly unpublished data. Results of the survey indicate that there may be difficulty in one of three situations: immediate (in the first minutes to hours after oral or parenteral administration), short-term use of 4 - 12 weeks or long-term use of 6 months. Based on this approach, the greatest concern is directed at the immediate application of haloperidol, droperidol, pimozide and trazodone, the short-term use of thioridazine, pimozide, sertindole, nortriptyline, clomipramine, doxepin and the long-term use of clozapine, olanzapine and carbamazepine. It is of interest that a reduction in QTc is reported with aripiprazole. Among the antidepressants, the tertiary tricyclic antidepressants (imipramine, amitriptyline and doxepin) appear to have a more general impact, while the secondary tricyclic antidepressants (nortriptyline, desipramine) may impact more on children and the elderly. Among other antidepressants, the only reports of torsades de pointes appeared to occur with mirtazapine. It was also of interest to find data showing no effect or reductions in QTc produced by sertraline, citalopram, paroxetine and bupropion in multiple studies. Effects of medications on other heart parameters are also briefly reviewed. In particular, the safety of sertraline in post-MI patients and of bupropion in heart disease patients is highlighted. Little information was available on other classes of medications used in psychiatric disorders. What is available concerning lithium, the anticonvulsants and the benzodiazepines indicates little effect on the QTc, although there may be effects on other cardiovascular parameters.
Abstract: BACKGROUND: Several antipsychotic agents are known to prolong the QT interval in a dose dependent manner. Corrected QT interval (QTc) exceeding a threshold value of 450 ms may be associated with an increased risk of life threatening arrhythmias. Antipsychotic agents are often given in combination with other psychotropic drugs, such as antidepressants, that may also contribute to QT prolongation. This observational study compares the effects observed on QT interval between antipsychotic monotherapy and psychoactive polytherapy, which included an additional antidepressant or lithium treatment. METHOD: We examined two groups of hospitalized women with Schizophrenia, Bipolar Disorder and Schizoaffective Disorder in a naturalistic setting. Group 1 was composed of nineteen hospitalized women treated with antipsychotic monotherapy (either haloperidol, olanzapine, risperidone or clozapine) and Group 2 was composed of nineteen hospitalized women treated with an antipsychotic (either haloperidol, olanzapine, risperidone or quetiapine) with an additional antidepressant (citalopram, escitalopram, sertraline, paroxetine, fluvoxamine, mirtazapine, venlafaxine or clomipramine) or lithium. An Electrocardiogram (ECG) was carried out before the beginning of the treatment for both groups and at a second time after four days of therapy at full dosage, when blood was also drawn for determination of serum levels of the antipsychotic.Statistical analysis included repeated measures ANOVA, Fisher Exact Test and Indipendent T Test. RESULTS: Mean QTc intervals significantly increased in Group 2 (24 +/- 21 ms) however this was not the case in Group 1 (-1 +/- 30 ms) (Repeated measures ANOVA p < 0,01). Furthermore we found a significant difference in the number of patients who exceeded the threshold of borderline QTc interval value (450 ms) between the two groups, with seven patients in Group 2 (38%) compared to one patient in Group 1 (7%) (Fisher Exact Text, p < 0,05). CONCLUSIONS: No significant prolongation of the QT interval was found following monotherapy with an antipsychotic agent, while combination of these drugs with antidepressants caused a significant QT prolongation. Careful monitoring of the QT interval is suggested in patients taking a combined treatment of antipsychotic and antidepressant agents.
Abstract: OBJECTIVE: To assess the potential of anticholinergic drugs as a cause of non-degenerative mild cognitive impairment in elderly people. DESIGN: Longitudinal cohort study. SETTING: 63 randomly selected general practices in the Montpellier region of southern France. PARTICIPANTS: 372 people aged > 60 years without dementia at recruitment. MAIN OUTCOME MEASURES: Anticholinergic burden from drug use, cognitive examination, and neurological assessment. RESULTS: 9.2% of subjects continuously used anticholinergic drugs during the year before cognitive assessment. Compared with non-users, they had poorer performance on reaction time, attention, delayed non-verbal memory, narrative recall, visuospatial construction, and language tasks but not on tasks of reasoning, immediate and delayed recall of wordlists, and implicit memory. Eighty per cent of the continuous users were classified as having mild cognitive impairment compared with 35% of non-users, and anticholinergic drug use was a strong predictor of mild cognitive impairment (odds ratio 5.12, P = 0.001). No difference was found between users and non-users in risk of developing dementia at follow-up after eight years. CONCLUSIONS: Elderly people taking anticholinergic drugs had significant deficits in cognitive functioning and were highly likely to be classified as mildly cognitively impaired, although not at increased risk for dementia. Doctors should assess current use of anticholinergic drugs in elderly people with mild cognitive impairment before considering administration of acetylcholinesterase inhibitors.
Abstract: Anticholinergic Drug Scale (ADS) scores were previously associated with serum anticholinergic activity (SAA) in a pilot study. To replicate these results, the association between ADS scores and SAA was determined using simple linear regression in subjects from a study of delirium in 201 long-term care facility residents who were not included in the pilot study. Simple and multiple linear regression models were then used to determine whether the ADS could be modified to more effectively predict SAA in all 297 subjects. In the replication analysis, ADS scores were significantly associated with SAA (R2 = .0947, P < .0001). In the modification analysis, each model significantly predicted SAA, including ADS scores (R2 = .0741, P < .0001). The modifications examined did not appear useful in optimizing the ADS. This study replicated findings on the association of the ADS with SAA. Future work will determine whether the ADS is clinically useful for preventing anticholinergic adverse effects.
Abstract: BACKGROUND: Nonchemotherapy drug-induced agranulocytosis is a rare adverse reaction that is characterized by a decrease in peripheral neutrophil count to less than 0.5 x 10(9) cells/L due to immunologic or cytotoxic mechanisms. PURPOSE: To systematically review case reports of drugs that are definitely or probably related to agranulocytosis. DATA SOURCES: English-language and German-language reports in MEDLINE (1966 to 2006) or EMBASE (1989 to 2006) and in bibliographies of retrieved articles. STUDY SELECTION: Published case reports of patients with nonchemotherapy drug-induced agranulocytosis. DATA EXTRACTION: One reviewer abstracted details about cases and assessed causality between drug intake and agranulocytosis by using World Health Organization assessment criteria. DATA SYNTHESIS: Causality assessments of 980 reported cases of agranulocytosis were definite in 56 (6%), probable in 436 (44%), possible in 481 (49%), and unlikely in 7 (1%). A total of 125 drugs were definitely or probably related to agranulocytosis. Drugs for which more than 10 reports were available (carbimazole, clozapine, dapsone, dipyrone, methimazole, penicillin G, procainamide, propylthiouracil, rituximab, sulfasalazine, and ticlopidine) accounted for more than 50% of definite or probable reports. Proportions of fatal cases decreased between 1966 and 2006. More patients with a neutrophil count nadir less than 0.1 x 10(9) cells/L had fatal complications than did those with a neutrophil count nadir of 0.1 x 10(9) cells/L or greater (10% vs. 3%; P < 0.001). Patients treated with hematopoietic growth factors had a shorter median duration of neutropenia (8 days vs. 9 days; P = 0.015) and, among asymptomatic patients at diagnosis, had a lower proportion of infectious or fatal complications (14% vs. 29%; P = 0.030) than patients without such treatment. LIMITATIONS: Case reports cannot provide rates of drug-induced complications, sometimes incompletely assess or describe important details, and sometimes emphasize atypical features and outcomes. CONCLUSIONS: Many drugs can cause nonchemotherapy drug-induced agranulocytosis. Case fatality may be decreasing over time with the availability of better treatment.
Abstract: BACKGROUND: Anticholinergic drugs put elderly patients at a higher risk for falls, cognitive decline, and delirium as well as peripheral adverse reactions like dry mouth or constipation. Prescribers are often unaware of the drug-based anticholinergic burden (ACB) of their patients. This study aimed to develop an anticholinergic burden score for drugs licensed in Germany to be used by clinicians at prescribing level. METHODS: A systematic literature search in pubmed assessed previously published ACB tools. Quantitative grading scores were extracted, reduced to drugs available in Germany, and reevaluated by expert discussion. Drugs were scored as having no, weak, moderate, or strong anticholinergic effects. Further drugs were identified in clinical routine and included as well. RESULTS: The literature search identified 692 different drugs, with 548 drugs available in Germany. After exclusion of drugs due to no systemic effect or scoring of drug combinations (n = 67) and evaluation of 26 additional identified drugs in clinical routine, 504 drugs were scored. Of those, 356 drugs were categorised as having no, 104 drugs were scored as weak, 18 as moderate and 29 as having strong anticholinergic effects. CONCLUSIONS: The newly created ACB score for drugs authorized in Germany can be used in daily clinical practice to reduce potentially inappropriate medications for elderly patients. Further clinical studies investigating its effect on reducing anticholinergic side effects are necessary for validation.