Time-to-Onset Analysis of Drug-Induced Long QT Syndrome Based on a Spontaneous Reporting System for Adverse Drug Events.

Long QT syndrome (LQTS) is a disorder of the heart's electrical activity that infrequently causes severe ventricular arrhythmias such as a type of ventricular tachycardia called torsade de pointes (TdP) and ventricular fibrillation, which can be fatal. There have been no previous reports on the time-to-onset for LQTS based on data from spontaneous reporting systems. The aim of this study was to assess the time-to-onset of LQTS according to drug treatment. We analyzed the association between 113 drugs in 37 therapeutic categories and LQTS including TdP using data obtained from the Japanese Adverse Drug Event Report database. For signal detection, we used the reporting odds ratio (ROR). Furthermore, we analyzed the time-to-onset data and assessed the hazard type using the Weibull shape parameter. The RORs (95% confidence interval) for bepridil, amiodarone, pilsicainide, nilotinib, disopyramide, arsenic trioxide, clarithromycin, cibenzoline, donepezil, famotidine, sulpiride, and nifekalant were 174.4 (148.6-204.6), 17.3 (14.7-20.4), 52.0 (43.4-62.4), 13.9 (11.5-16.7), 69.3 (55.3-86.8), 54.2 (43.2-68.0), 4.7 (3.8-5.8), 19.9 (15.9-25.0), 8.1 (6.5-10.1), 3.2 (2.5-4.1), 7.1 (5.5-9.2), and 254.8 (168.5-385.4), respectively. The medians and quartiles of time-to-onset for aprindine (oral) and bepridil were 20.0 (11.0-35.8) and 18.0 (6.0-43.0) days, respectively. The lower 95% confidence interval of the shape parameter ß of bepridil was over 1 and the hazard was considered to increase over time.Our study indicated that the pattern of LQTS onset might differ among drugs. Based on these results, careful long-term observation is recommended, especially for specific drugs such as bepridil and aprindine. This information may be useful for the prevention of sudden death following LQTS and for efficient therapeutic planning.

Relationship between serum aprindine concentration and neurologic side effects in Japanese.

The aim of this study was to evaluate the relationship between the neurologic side effects associated with serum aprindine concentrations and the safety range of aprindine for the prevention of neurologic side effects in 142 Japanese inpatients. Serum aprindine concentrations were determined by high-performance liquid chromatography. A poor positive correlation was observed between dose and serum aprindine concentration (r(2)=0.0419, p=0.0114), and between age and ratio of serum aprindine concentration to the dose per body weight of aprindine (r(2)=0.0159, p=0.121). When aprindine concentration was <1 microg/ml, almost no patients showed neurologic side effects associated with aprindine. On the other hand, about 50% of the patients showed neurologic side effects when aprindine concentrations were >1 microg/ml. Here, the side effects associated with aprindine such as dizziness or intention tremors were observed in 15 patients, which later disappeared after discontinuance of aprindine therapy or a decrease in the dose. In conclusion, serum aprindine concentration should be maintained under approximately 1 microg/ml in Japanese patients to prevent neurologic side effects.

Prediction of catalepsies induced by amiodarone, aprindine and procaine: similarity in conformation of diethylaminoethyl side chain.

Recently, clinical cases of parkinsonism due to antiarrhythmics drugs amiodarone and aprindine and a local anesthetic drug procaine have been reported. We performed both in vivo and in vitro experiments to quantitatively predict the intensity of catalepsy by these drugs and haloperidol in mice. Haloperidol showed the most potent relative intensity of catalepsy, followed by aprindine, metoclopramide, tiapride, amiodarone and procaine, in that order. In vivo dopamine D1 and D2 receptor occupancies of the six drugs to the striatum were observed. In vitro binding affinity (Ki) of these drugs to the D1 and D2 receptors in the striatum synaptic membrane was within the range of 60 nM to 706 microM, 0.5 nM to 75 microM and 860 nM to 115 microM, respectively. A good correlation between the relative intensity of drug-induced catalepsy and the Ki values for the dopamine D1 and D2 receptors was obtained (r =.911 and r =.896, respectively; P <.05). The partial tertiary structure of the tested drugs was well superimposed on that of haloperidol. In conclusion, these drug-induced catalepsies were due to the blockade of the D1 and D2 receptors, which was related to the analogous tertiary structures (diethylaminoethyl side chain).

Aprindine-induced hepatic granulomata.

Aprindine is a very effective antiarrhythmic agent with a narrow therapeutic ratio. We report a patient who suffered from granulomatous hepatitis probably due to the administration of aprindine. Evidence of hepatitis appeared within 6 weeks of initiating aprindine therapy and resolved rapidly when the drug was withdrawn. Six months later, fibrosis but no granulomata were found in the expanded portal tracts. Our observations suggest that granulomatous hepatitis can occur during aprindine therapy.

Agranulocytosis associated with aprindine and other antiarrhythmic drugs: an epidemiological approach.

The risk of agranulocytosis associated with anti-arrhythmic drugs has been assessed by studying previous drug exposure of all cases collected through a multicentre surveillance network in a defined geographical area during the period 1980-1988. One hundred and eighty-one patients with agranulocytosis (less than 500 granulocytes mm-3 at least in two different blood counts) were interviewed with a structured questionnaire. Eight cases attributable to anti-arrhythmic drugs were identified, all of them related to aprindine. Data on the consumption of several anti-arrhythmic drugs were identified, all of them related to aprindine. Data on the consumption of several anti-arrhythmic drugs (amiodarone, aprindine, quinidine, propafenone) were obtained in order to estimate the risk of agranulocytosis related with the previous use of these drugs. A relevant risk was identified only for aprindine, of the order of two cases per 1000 patient-years. Our data suggest that the risk of agranulocytosis associated with aprindine is lower than previously found.

[A case of aprindine-induced pneumonitis].

A 73-year-old man had been treated with Aprindine because of paroxysmal atrial fibrillation. On July 13, 1987, five months after the commencement of aprindine administration, he developed dyspnea and low grade fever. His chest X-ray revealed multiple infiltrative shadows in both lung fields. He was treated by various antibiotics, but the infiltrative shadows increased. BALF showed increased percentage of lymphocytes and a decrease in the OKT4/T8 ratio, and the histological findings of TBLB carried out on August 6, 1987, showed alveolitis with Masson bodies. The lymphocyte stimulation test by drugs was positive only for aprindine. After cessation of Aprindine administration, his complaints and laboratory data improved, but his abnormal shadow on chest X-ray did not diminish completely. Open lung biopsy was performed for differential diagnosis of BOOP, on Sep. 14, 1987. The histopathology of specimens of the lung was compatible with drug-induced pneumonitis. The administration of 30 mg of prednisolone was started on Oct. 14, 1987, and the dosage was decreased gradually. The abnormal shadow on chest X-ray improved. To our knowledge, there has been no reported case of Aprindine-induced pneumonitis, and this could be the first report.

[Drug-induced major anomalies of ventricular repolarization masked by a left branch block]. / Anomalies majeures de la repolarisation ventriculaire d'origine médicamenteuse masquées par un bloc de branche gauche.

The presence of a left bundle branch block (LBBB) may hamper the electrocardiographic diagnosis of diseases that involve the QRS complexes. That it may conceal, or even completely erase, major abnormalities of ventricular repolarization induced by certain drugs is not so well known. In this paper, two highly demonstrative examples of such abnormalities observed with bepridil (case 1) or with the amiodarone-aprindine combination (case 2) are reported. In both cases, the intermittent character of the LBBB revealed the phenomenon which deserves to be known as it is not without practical consequences: in patients under treatments likely to modify repolarization and induce severe dysrhythmias (notably torsades de pointes) the presence of a LBBB indicates that the QT and/or QU intervals must be very carefully measured. In case of phase 3 LBBB compression of the carotid sinus or intravenous ATP injection helps the diagnosis since in the presence of even moderately prolonged ventricular cycles such manoeuvres create a refinement of QRS complexes which then demonstrate the major alteration of the underlying repolarization.

Drug-induced torsade de pointes.

Three patients who developed torsade de pointes associated with antiarrhythmic or psychotropic drugs are described, and the electrocardiographic characteristics, clinical presentation, predisposing factors, and management of this form of ventricular tachycardia are reviewed. The first patient was a 56-year-old schizophrenic man receiving thioridazine hydrochloride, trifluoperazine hydrochloride, and benztropine mesylate who was admitted to a hospital after a syncopal episode. Subsequently, the patient experienced several episodes of ventricular tachycardia combined with multifocal premature ventricular contractions (PVCs) and torsade de pointes; the arrhythmias were attributed to antipsychotic therapy. The second patient was a 69-year-old man who experienced ventricular tachycardia that progressed to ventricular fibrillation 41 days after surgery. Quinidine sulfate probably induced the ventricular tachycardia, which was identified as torsade de pointes. The third patient was a 71-year-old man admitted to the hospital for treatment of refractory ventricular arrhythmias. Previous drug therapy with quinidine sulfate and procainamide hydrochloride had been associated with torsade de pointes. Despite unsuccessful treatment of ventricular ectopy, the patient was discharged on maintenance therapy with pindolol, topical nitrates, and phenytoin. No additional episodes of torsade de pointes have been observed. Torsade de pointes is characterized by polymorphous electrocardiographic appearance and delayed repolarization (prolonged QT interval). It may occur in association with a number of disease states and also as a complication of treatment with therapeutic doses of drugs that affect repolarization (quinidine, disopyramide, procainamide, and phenothiazines). Clinical outcomes range from asymptomatic, self-terminating arrhythmias to ventricular fibrillation resulting in cardiac arrest. The definitive emergency therapy for torsade de pointes is overdrive pacing; cautious isoproterenol administration can also be used. Lidocaine and bretylium are often ineffective in treating this form of ventricular tachycardia. Potassium and magnesium repletion appear to be essential in abolishing drug-induced torsade de pointes. Drug-induced torsade de pointes is best prevented by avoiding agents known to induce arrhythmias in patients with a pre-existing prolonged QT interval. Periodic serum electrolyte assessment is warranted, and new drugs that prolong the QT interval should be considered potential causative agents of torsade de pointes.

Torsade des pointes and aprindine.

Aprindine was given orally to an 88-year-old patient with atrial fibrillation and ventricular premature depolarizations. The premature beats disappeared and sinus rhythm was restored on the third day of treatment. While on aprindine the QT interval was prolonged and the U wave became very prominent. The aprindine was stopped but 36 hr following the last oral dose, ventricular arrhythmia appeared with the characters of torsade des pointes. Three such episodes occurred within 24 hr. It is suggested that aprindine both eliminated the premature depolarizations and rendered the myocardium vulnerable by prolonging the QT interval. On discontinuing the medicament the premature beats reappeared while the myocardium was still vulnerable, so that torsade des pointes resulted.

Antiarrhythmic drug therapy. Recent advances and current status.

A number of conventional and newer antiarrhythmic agents are available for the treatment and prophylaxis of ventricular tachycardia and sudden death. Using a multifaceted approach of programmed electrical stimulation studies, drug level determinations, exercise tolerance testing, and 24-hour ambulatory electrocardiographic monitoring, the physician can identify those patients who require therapy and then predict the likelihood of efficacy with each antiarrhythmic agent. This approach affords evaluation of both aspects of the sudden death equation-ectopy frequency (triggering mechanism) and vulnerability to development of sustained ventricular tachycardia (substrate). After institution of therapy, careful follow-up is necessary to document sustained drug efficacy and detect side effects. Serious adverse reactions necessitate a change in antiarrhythmic therapy, as opposed to lowering drug dosage to an ineffective level. The unacceptably high incidence of sudden death due to electrical instability can be reversed only by a rigorous and dedicated long-term approach to the management of serious ventricular arrhythmias.

Aggravation of ventricular arrhythmia. A drug-induced complication.

Each antiarrhythmic agent can cause side effects, but most of these are easily recognised by the patient or physician. However, one potentially serious side effect common to all of these drugs is aggravation of ventricular arrhythmia. Often this is without symptoms and goes unrecognised by the patient. It occurs in 11 to 16% of drug tests depending upon the method of drug evaluation employed. There are no ECG changes which predict its occurrence and blood concentrations of drug are usually within a therapeutic range. There are no clinical patient features which are associated with this toxic reaction and it does not correlate with the presence or extent of underlying heart disease, the nature of the presenting arrhythmia or the known electrophysiological properties of the antiarrhythmic drug. Careful evaluation of these drugs is therefore essential.

Mechanism of aprindine induced agranulocytosis: direct toxicity on CFU-C and CFU-GEMM.

The in vitro bone marrow growth of 2 patients with aprindine-induced agranulocytosis was studied. Granulocyte-macrophage committed stem cell (CFU-C) growth is inhibited by aprindine in a dose dependent manner. 50% inhibition of CFU-colony growth (TD50) was seen at 5.1 and 3.4 micrograms aprindine/ml medium respectively. The TD50 of control marrow CFU-C was 3.2 micrograms/ml. 100% inhibition was seen at 16 micrograms aprindine/ml, both in patients and controls. Pluripotential stem cell growth (CFU-GEMM) in control marrow was equally inhibited in a dose dependent manner by aprindine, though to a lesser extent (TD50: 9.1 micrograms/ml) and with relative sparing of pure megakaryocyte and erythroid colonies. Co-culturing of patients marrows with their respective acute phase serum did not inhibit CFU-C growth.