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PubMed1984

Torsade de pointes induced by N-acetylprocainamide.

N-Acetylprocainamide (NAPA), a class III antiarrhythmic drug, caused torsade de pointes in a 72 year old woman who had this arrhythmia on two previous occasions while being treated with quinidine and disopyramide. Initial evaluation with an intravenous infusion of NAPA indicated a favorable antiarrhythmic response. The QTC interval was prolonged, but the 2.4 ms/microgram per ml incremental QTC interval lengthening caused by NAPA was not greater than usual. During subsequent oral therapy with NAPA, torsade de pointes developed at plasma levels of this drug that appeared to be well tolerated during the initial evaluation.

Acecainide↗
PubMed1985

Prevention of sudden death after repair of tetralogy of Fallot: treatment of ventricular arrhythmias.

The majority of sudden deaths after repair of tetralogy of Fallot have been presumed to be due to ventricular arrhythmia; however, it remains to be demonstrated that antiarrhythmic medication reduces the incidence of sudden death. Since 1978, ventricular arrhythmias have been treated aggressively; these include any ventricular arrhythmia on routine electrocardiogram and more than 10 uniform premature ventricular complexes per hour on 24 hour electrocardiogram. A review was undertaken of 488 patients followed up for more than 1 month after repair of tetralogy of Fallot (mean follow-up time 6.1 years); 13.5% had ventricular arrhythmia on routine electrocardiogram. Ventricular arrhythmia appeared from 2 months to 21 years postoperatively (mean 7.3 years). Ventricular arrhythmias were significantly (p less than 0.01) related to: longer follow-up duration, older age at follow-up, older age at operation and higher postoperative right ventricular systolic and end-diastolic pressures. Ventricular arrhythmia on routine electrocardiogram occurred in 100% of those who later died suddenly compared with 12% of those who did not die (p less than 0.01). Treatment for ventricular arrhythmia was given to 46 patients and considered "successful" if there were fewer than 10 uniform premature ventricular complexes per hour on 24 hour electrocardiogram. A successful drug was found in 44 of the 46: 30 of 34 given phenytoin, 6 of 9 given propranolol, 1 of 7 given quinidine, 1 of 2 given disopyramide, 8 of 9 given mexiletine and 4 of 5 given amiodarone.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed2001

Comparative safety of the different macrolides.

The macrolides are generally well tolerated when used for the treatment of acute infections. Even when given long term for prophylaxis, there are few discontinuations due to side-effects. There are isolated reports of QT(c) prolongation in patients treated with erythromycin and other 14-membered-ring macrolides. Since the 14-membered-ring macrolides are metabolized by P450 isoenzymes, there is the potential for interaction with other therapeutic agents also metabolized in this way. Pharmacokinetic studies have demonstrated interactions between either erythromycin or clarithromycin and cyclosporin, cisapride, pimozide, disopyramide, astemizole, carbamazepine, midazolam, digoxin, hydroxymethylglutaryl-coenzyme A reductase inhibitors (i.e. 'statins') and warfarin. In patients receiving such concurrent therapy, azithromycin may be superior to erythromycin and clarithromycin.

Anti-Bacterial Agents↗
PubMed2001

Evaluation and treatment of pediatric patients with neurocardiogenic syncope.

Neurocardiogenic syncope is the most common form of syncope in children. The most widely accepted mechanism of its etiology is a vigorous contraction of the heart due to relative hypovolemia leading to stimulation of C-fibers and sympathetic withdrawal. Episodes usually occur with an upright position and are preceded by a typical prodrome. A classic history is paramount to the diagnosis. Tilt testing aids in the diagnosis in certain cases. The cornerstone of therapy is maintaining adequate hydration and avoiding situations that may lead to harm with syncopal events. Beta blockers, fludrocortisone, alpha adrenergic agents and disopyramide are commonly used to prevent syncope. Seratonin reuptake inhibitors, pacing with rate drop algorithms and tilt training are relatively new in the armamentarium of therapy.

Journal Article↗
PubMed1992

Synthesis and biological action of the aminotetrahydroisoquinocarbazoles and related compounds: a new class of compounds with antiarrhythmic activity.

A series of 12-aminotetrahydroisoquinocarbazoles and related compounds were synthesized using an intramolecular Diels-Alder reaction and screened for antiarrhythmic activity in chloroform-induced ventricular arrhythmias in mice. Several compounds showed more potent activity than disopyramide. There was some correlation between substituents on aromatic ring and angular position, and antiarrhythmic activity. An amino group or some functional groups containing an amino group on C-12 seemed to be essential to exhibit the activity. Ring size also influenced the activity. The compound (+)-10 (RS-2135) had the most favorable combination of antiarrhythmic activity and toxicity and was selected for further evaluation.

Action Potentials↗
PubMed1991

Spatial requirements of the Na channel binding site for class I antiarrhythmics as derived from the crystal structures of 4-substituted 2,6-bis(1-pyrrolidinylmethyl)phenols.

The molecular structures of four class I antiarrhythmic agents containing a bis(1-pyrrolidinylmethyl)phenol framework were determined by X-ray diffraction methods and their conformations were analyzed by molecular mechanics. Each structure has an intramolecular hydrogen bond between the phenol OH group and one pyrrolidine N atom; this bond determines the orientation of the pyrrolidine ring. Only two distinct orientations are observed for the other pyrrolidine ring; the combination of the pyrrolidine ring positions produces molecular conformers that either have the two N atoms on the same side of the phenol ring plane or have the N atoms nearly coplanar with the phenol ring. Crystallographic conformations of benzamides as well as those calculated with molecular mechanics find a preferred conformation that has the three planar regions tilted by ca. 30 degrees with respect to one another. The combined restrictions of the hydrogen bond, the conformational preferences for the bis(pyrrolidinylmethyl)phenol moiety, and a consistent conformation for the central benzamide portion provide a suggestion of the active shape of class Ic antiarrhythmic drugs. The distance between two potential recognition groups--a phenyl ring (lipophilic group) separated by 3.8 A from an oxygen atom and a secondary or tertiary amine--is found to be unique for class Ic antiarrhythmics as compared to other class I antiarrhythmics, such as lidocaine, quinidine, procainamide, and disopyramide, and suggests a correlation between the molecular structures and the activity of class I antiarrhythmics.

Anti-Arrhythmia Agents↗
PubMed1981

Synthesis and antiarrhythmic activity of new benzofuran derivatives.

Various 5-aminobenzofuran derivatives were prepared from khellin and screened intravenously in the dog for their potential antiarrhythmic activity against ouabain-induced ventricular arrhythmia and in the Harris test. From systematic structural variations it was found that two methoxy groups in positions 4 and 7 on the benzofuran ring, a tertiary aminoethoxy side chain in position 6, and a N-methylurea group in position 5 led to the most active compounds. These were then tested orally in the Harris test in the dog. The two long-acting derivatives N-[4,7-dimethoxy-6-(2-pyrrolidinoethoxy)-5-benzofuranyl]-N'-methylurea (8j) and N-[4,7-dimethoxy-6-(2-piperidinoethoxy)-5-benzofuranyl]-N'-methylurea (8m) showed advantages when compared to quinidine and disopyramide and have been selected for further studies.

Animals↗
PubMed1980

Synthesis and antiarrhythmic activity of alpha, alpha-bis[(dialkylamino)alkyl]phenylacetamides.

The synthesis and biological evaluation of a series of alpha, alpha-bis[(dialkylamino)alkyl]phenylacetamides, 2, are presented. These compounds are structurally related to the antiarrhythmic agent disopyramide (1) and in many cases were found to possess greater antiarrhythmic activity in coronary ligated dogs. Within this series of compounds, a separation of the antiarrhythmic properties from the unwanted cardiac depressant side effects observed with the parent compound, 7, was also often attained. A discussion of the structure-activity relationships within the series is presented; this work has culminated in the identidiction of compound 35 (disobutamide) as a candidate for clinical evaluation as an antiarrhythmic agent in man.

Acetamides↗
PubMed1984

Synthesis and antiarrhythmic activity of new 1-[1-[2-[3-(alkylamino)-2-hydroxypropoxy]phenyl]vinyl]-1 H-imidazoles and related compounds.

Various 1-[1-[2-[3-(alkylamino)-2-hydroxypropoxy]phenyl]vinyl]-1 H-azoles were synthesized and investigated for beta-adrenoceptor-blocking and antiarrhythmic activities. Although no compounds showed more potent beta-blocking effects than propranolol in the isolated guinea pig right atria, many compounds exhibited significant antiarrhythmic effects against aconitine or ischemic arrhythmia in mice or dogs. 1-[2,5-Dichloro-6-[1-(1H-imidazol-1-yl)-ethenyl] phenoxy]-3-[(1-methylethyl)amino]-2-propanol hydrochloride (48) (711389-S) was selected as a candidate for clinical evaluation in man, since its antiarrhythmic effects were superior to those of quinidine, disopyramide, or propranolol. Asymmetric synthesis of (R)-(+)- and (S)-(-)-48 is described, and it is proven that there is no stereospecificity in the antiarrhythmic effect of 48.

Adrenergic beta-Antagonists↗
PubMed1999

Preliminary observations on the use of midodrine hydrochloride in the treatment of refractory neurocardiogenic syncope.

Recurrent episodes of neurocardiogenic syncope that occur without warning are a common cause of recurrent syncope that can be identified during head upright tilt table testing. While the use of beta blockers, theophyllines, fludrocortisone, disopyramide, and serotonin reuptake inhibitors can be useful in the prevention of episodes, some patients are either unresponsive to or poorly tolerant of these agents. We investigated the use of the peripheral alpha stimulating agent midodrine in preventing both tilt-induced and spontaneous neurocardiogenic syncope. Twenty-five patients (16 women, 9 men, mean age 30 +/- 23 years) with severe recurrent syncope and a positive head upright tilt table study (refractory to or intolerant of standard therapies) were placed on midodrine 5-10 mg orally three times per day, (two patients required 15 mg/day). Of these, twelve became asymptomatic and five had a marked reduction in symptoms. We conclude that midodrine may be an effective therapy in patients with recurrent neurocardiogenic syncope refractory to other forms of therapy.

Administration, Oral↗
PubMed2001

Distinct characteristics of organic cation transporters, OCT1 and OCT2, in the basolateral membrane of renal tubules.

PURPOSE: This study was performed to determine the detailed mRNA distribution of organic cation transporters, rOCT1 and rOCT2, along the rat nephron and to distinguish the substrate affinities of these transporters. METHODS: The distributions of rOCT1 and rOCT2 mRNA were determined by reverse transcriptase polymerase chain reaction analysis of microdissected nephron segments. Using MDCK cells transfected with rOCT1 or rOCT2 cDNA, the inhibitory effects of various compounds on the uptake of [14C]tetraethylammonium were assessed. RESULTS: rOCT1 mRNA was detected primarily in the superficial and juxtamedullary proximal convoluted tubules, whereas rOCT2 mRNA was detected widely in the superficial and juxtamedullary proximal straight and convoluted tubules, medullary thick ascending limbs, distal convoluted tubule, and cortical collecting duct. The IC50 values for cationic drugs and endogenous cations on [14C]tetraethylammonium uptake across the basolateral membranes in the transfectants indicated that rOCT1 and rOCT2 had similar inhibitor specificity for many compounds but showed moderate differences in the specificity for several compounds, such as 1-methyl-4-phenylpyridinium, dopamine, disopyramide, and chlorpheniramine. CONCLUSIONS: rOCT1 and rOCT2 possess similar but not identical multispecificities for various compounds with distinct distributions along the nephron, indicating that the two transporters share physiologic and pharmacologic roles in the renal handling of cationic compounds.

Animals↗
PubMed1995

Protective effects of antiarrhythmic agents against anoxic injury in CNS white matter.

Irreversible anoxic injury is dependent on extracellular Ca2+ in mammalian CNS white matter, with a large portion of the pathologic Ca2+ influx occurring through reverse Na(+)-Ca2+ exchange, stimulated by increased intracellular [Na+]. This Na+ leak likely occurs via incompletely inactivated voltage-gated Na+ channels. This study reports that clinically used antiarrhythmic compounds, likely by virtue of their Na+ channel-blocking properties, significantly protect CNS white matter from anoxia at concentrations that cause little suppression of the preanoxic response. Rat optic nerves were pretreated with various agents for 60 min, then subjected to 60 min of anoxia in vitro. Functional recovery was measured electrophysiologically as the area under the compound action potential (CAP). Without drug, the CAP areas recovered to a mean of 32 +/- 12% of control after 1 h of reoxygenation. Recoveries using prajmaline 10 microM were 82 +/- 15% (p < 0.0001), and using tocainide 1 mM, 78 +/- 8% (p < 0.0001), with little suppression (< or = 10%) of the preanoxic response. Ajmaline (10-100 microM), disopyramide (10-300 microM) and bupivacaine (10-100 microM) were somewhat less effective, whereas verapamil produced 52 +/- 11% recovery before reduction of the preanoxic CAP was observed at 30 microM. Procainamide (100-300 microM) was ineffective. These results suggest that Na+ channel blockers, including commonly used antiarrhythmic agents, may be effective in protecting central white matter, which is a target for anoxic/ischemic injury in diseases such as stroke and spinal cord injury.

Action Potentials↗
PubMed1997

Reports of hypoglycaemia associated with the use of ACE inhibitors and other drugs: a case/non-case study in the French pharmacovigilance system database.

AIMS: To test the existence of an association between reports of hypoglycaemia and angiotensin converting enzyme inhibitors, in a spontaneous reports database. METHODS: The French Pharmacovigilance database was examined for an association between adverse drug reaction reports mentioning hypoglycaemia, and angiotensin converting enzyme inhibitors (ACEI) using the case/non-case methodology, with reports of hypoglycaemia as cases and all other reports as comparators. The association between ACEI or other chosen drugs and hypoglycaemia was also tested in the subgroups of patients taking or not antidiabetic agents (ADA). RESULTS: 428 of 93,338 reports mentioned hypoglycaemia (202/2227 with ADA (OR 40, 95% CI 33-48)). 46/5717 reports mentioned ACEI (OR 1.8 (1.25-2.54)). Other study drugs associated with hypoglycaemia were cibenzoline (OR 80 (57-112)), disopyramide (OR 32 (22-46)), nifedipine (OR 2.16 (1.32-3.51)), diltiazem (OR 1.76 (1.01-3.06)) nitrates (nitroglycerin, molsidomine) (OR 1.91 (1.16-3.16)) and frusemide (OR 1.89 (1.31-1.76)), but not nicardipine, amlodipine, felodipine or nitrendipine, diazepam, atenolol or combination thiazide diuretics. However, ACEI and other drugs were associated with ADA, so that in the subgroups of patients taking or not ADA, the association of ACEI with hypoglycaemia disappeared (OR 0.9 (0.5-1.4) and 1.2 (0.7-2.2), respectively). The same was found for other drugs except cibenzoline. CONCLUSION: The association between reporting of hypoglycaemia and ACE inhibitors was related to concomitant use of antidiabetic agents. This was true also for other drugs used in arterial disease or renal failure, such as calcium channel blockers, nitrates, and frusemide.

Adverse Drug Reaction Reporting Systems↗
PubMed1998

Inhibitory effects of antiarrhythmic drugs on phenacetin O-deethylation catalysed by human CYP1A2.

AIMS: The aim of the study was to clarify whether the pharmacokinetic interaction between theophylline and mexiletine is mediated by inhibition of CYP1A2 and to assess the possible interaction potential of other antiarrhythmic drugs with drugs metabolized by CYP1A2. METHODS: The inhibitory effects of mexiletine and 10 antiarrhythmic drugs on phenacetin O-deethylation, a marker reaction of CYP1A2, were studied using human liver microsomes and cDNA-expressed CYP1A2. RESULTS: Propafenone and mexiletine inhibited phenacetin O-deethylation with IC50 values of 29 and 37 microM, respectively. Disopyramide, procainamide and pilsicainide produced negligible inhibition of phenacetin O-deethylation (IC50 >1 mM). Amiodarone, bepridil, aprindine, lignocaine, flecainide and quinidine inhibited phenacetin O-deethylation in a concentration-dependent manner, although the inhibitory effects were relatively weak with IC50 values ranging from 86 to 704 microM. Propafenone and mexiletine selectively abolished the high-affinity component of phenacetin O-deethylation in human liver microsomes. In addition, propafenone and mexiletine inhibited phenacetin O-deethylation catalysed by cDNA-expressed CYP1A2. CONCLUSIONS: These data suggest that, among the antiarrhythmic drugs studied, propafenone and mexiletine are relatively potent inhibitors of CYP1A2, which may cause a drug-drug interaction with drugs metabolized by CYP1A2.

Anti-Arrhythmia Agents↗
PubMed2002

What is the minimal pacing rate that prevents torsades de pointes? Insights from patients with permanent pacemakers.

In the acquired long QT syndrome, torsades de pointes (TP) is invariably preceded by pauses or bradycardia. Thus, it has been proposed that out-of-hospital initiation of drugs that prolong repolarization should be safe in patients with permanent pacemakers. However, a minimal protective pacing rate has not been identified. The authors reviewed published reports of acquired TP in patients with permanent pacing. Those providing documentation of tachycardia onset and pacemaker programming were included in the analysis. Events occurring < or = 1 month after AV nodal ablation were excluded. Eighteen cases were identified (age 74 +/- 5; 10 women). QT prolonging drugs were present in 15 patients (quinidine 5, sotalol 3, disopyramide 3, amytriptiline, chloroquine, cisapride + haloperidol, and monopride + flecainide 1 each). Hypokalemia was present in eight patients. At the time of TP, the programmed lower rate was 63 +/- 13 beats/min. However, the effective pacing rate was lower (55 +/- 11 beats/min) due to invocation of pause-promoting features (hysteresis [4 patients]; + PVARP extension on PVC [1 patient]) or ventricular oversensing (2 patients). No patient developed TP with an effective pacing rate > 70 beats/min. TP is possible in the presence of a functional permanent pacemaker. Programmed lower rates < or = 70 beats/min are not protective. At programmed lower rates > 70 beats/min, TP may occur only when facilitated by programmable pause-promoting features or oversensing. It remains to be seen if rate smoothing algorithms can prevent TP when the baseline rate is programmed < or = 70 beats/min.

Aged↗
PubMed2003

Randomized clinical trials of neurally mediated syncope.

Evidence for therapy of neurally mediated syncope is generally weak. Many drugs have been used for the treatment of vasovagal syncope (beta-blockers, disopyramide, scopolamine, clonidine, theophylline, fludrocortisone, ephedrine, dihydroergotamine, etilefrine, midodrine, clonidine, serotonin reuptake inhibitors, enalapril). In general, although the results have been satisfactory in uncontrolled trials or short-term controlled trials, the majority of long-term placebo-controlled prospective trials have not been able to show a benefit of the active drug over placebo. Only two well-designed double-blind placebo-controlled randomized trials have been performed-one for etilefrine and the other for atenolol-and both were unable to show a superiority of the active drug versus placebo. Four randomized clinical trials of pacing therapy-three positive and one negative-have been performed in patients affected by vasovagal syncope. The relationship between carotid sinus hypersensitivity and spontaneous, otherwise unexplained, syncope has been demonstrated. Cardiac pacing appears to be beneficial in carotid sinus syndrome; its efficacy has been demonstrated by two randomized controlled trials and confirmed by several pre-post comparative studies, one controlled trial, and one prospective observational study. There is evidence and general agreement that cardiac pacing is useful in patients with cardioinhibitory or mixed carotid sinus syndrome. Usefulness of the treatment is less well established and divergence of opinion exists with regard to cardiac pacing in patients with cardioinhibitory vasovagal syncope. The evidence fails to support the efficacy of beta-blocking drugs. As yet there are insufficient data to support the use of any other pharmacologic therapy for vasovagal syncope.

Adrenergic alpha-Antagonists↗
PubMed2004

Repolarization abnormality in idiopathic ventricular fibrillation: assessment using 24-hour QT-RR and QaT-RR relationships.

INTRODUCTION: We evaluated the characteristics of QT-RR and QaT (apex of T wave)-RR relationships in patients with idiopathic ventricular fibrillation (IVF) compared with control subjects. We hypothesized that IVF patients have unique repolarization dynamics related to a reduced fast Na current and a prominent transient outward current. METHODS AND RESULTS: The study group consisted of 9 men (age 47 +/- 10 years) with IVF (6 with Brugada type and 3 with non-Brugada type) who had experienced nocturnal episodes of VF. The control group consisted of 28 healthy age-matched men (age 44 +/- 12 years). The relationships between QT and RR intervals and between QaT and RR intervals were analyzed from 24-hour Holter ECG data using an automatic measurement system. Both QT and QaT at RR intervals of 0.6, 1.0, and 1.2 seconds were determined from QT-RR and QaT-RR linear regression lines. Both QT-RR and QaT-RR slopes were lower in the IVF group than in the control group (QT-RR: 0.092 +/- 0.023 vs 0.137 +/- 0.031, P < 0.001; QaT-RR: 0.109 +/- 0.025 vs 0.153 +/- 0.028, P < 0.001). QT at an RR interval of 0.6 second did not differ between two groups, but QT at RR intervals of either 1.0 or 1.2 seconds was significantly shorter in the IVF group than in the control group (RR 1.0 s: 0.384 +/- 0.018 vs 0.399 +/- 0.017, P < 0.05; RR 1.2 s: 0.402 +/- 0.019 vs 0.426 +/- 0.020, P < 0.01). QaT at RR intervals of either 1.0 or 1.2 seconds also was shorter in the IVF group (RR 1.0 s: 0.289 +/- 0.022 vs 0.312 +/- 0.021, P < 0.01; RR 1.2 s: 0.311 +/- 0.024 vs 0.343 +/- 0.024, P < 0.01). In four patients, oral administration of disopyramide (300 mg/day) was effective in suppressing VF episodes and increased slopes of QT-RR and QaT-RR relationships. CONCLUSION: IVF patients had lower slopes of QT-RR and QaT-RR regression lines and impaired prolongation of QT and QaT at longer RR intervals compared with control subjects. These unique repolarization dynamics may be related to the frequent occurrence of VF episodes at night.

Adult↗
PubMed2004

Myocardial bundles with slow conduction properties are present on the left interventricular septal surface of normal human hearts.

INTRODUCTION: The aim of this study was to examine the electrophysiologic characteristics of the normal left interventricular septum (LIVS). METHODS AND RESULTS: We explored the LIVS in search of endocardial potentials following ventricular electrograms during sinus rhythm in 28 patients without structural heart disease. In all patients, low-frequency (mean amplitude: 0.81 +/- 0.33 mV) systolic potentials (LA1) were detected in a basal-to-apical activation sequence (earliest to latest QRS-LA1 interval: 93.3 +/- 10.8 ms to 127.1 +/- 16.6 ms). Programmed stimulation demonstrated decremental conduction properties, and the effective refractory period of the tissue between the ventricular electrogram and LA1 at baseline (376.7 +/- 48.8 ms) was significantly prolonged by disopyramide (421.3 +/- 54.1 ms, P < 0.05 vs baseline). In 21 patients (75%), diastolic potentials (LA2) morphologically similar to LA1 (mean amplitude: 0.52 +/- 0.17 mV) were detected in an apical-to-basal activation sequence (earliest to latest QRS-LA2 interval: 368.9 +/- 32.4 ms to 440.7 +/- 45.8 ms). Para-Hisian pacing with capture of the His bundle showed shorter S-LA1 and S-LA2 intervals compared to the beats without His-bundle capture but with ventricular capture (156.3 +/- 11.2 ms vs 183.2 +/- 12.3 ms, and 385.7 +/- 21.6 ms vs 397.4 +/- 23.4 ms, respectively, P < 0.0001). At the same rate, the LA1-LA2 interval was significantly shorter during right ventricular apical than atrial overdrive pacing (220.4 +/- 23.1 ms vs 261.4 +/- 30.7 ms, P < 0.0001). CONCLUSION: Unique myocardial bundles with slow conduction properties and various electrical connections with the specialized conduction system may exist in the LIVS of normal human hearts.

Adult↗