Crossover comparison of cibenzoline and quinidine in ambulatory patients with chronic ventricular arrhythmias

This study was designed to compare the efficacy and safety of cibenzoline and quinidine in ambulatory patients with ventricular arrhythmias. Following washout of previous antiarrhythmic treatment, a 48-h ambulatory electrocardiographic (ECG) recording was obtained. Twenty-seven patients were screened, of whom 20 met the entry criteria of greater than or equal to 30 ventricular premature beats (VPBs)/h. Cibenzoline was started at 130 mg every 12 h and was increased to 160 mg every 12 h if necessary. Quinidine was started at 300 mg every 6 h and was increased to 400 mg every 6 h if necessary. Treatment was assessed by 24-h ambulatory ECG recording. Efficacy was defined as greater than 75% reduction in single VPBs, greater than 90% reduction in paired VPBs, and total abolition of ventricular tachycardia events. A 7-day washout with repeat 24-h ambulatory ECG recording to document return of ventricular arrhythmias was required prior to crossover. Efficacy was documented in 9 of 20 (45%) patients receiving cibenzoline and in 9 of 20 (45%) patients receiving quinidine. Response to cibenzoline 130 mg every 12 h was documented in 8 of 20 (40%) patients and in 1 of 11 (9%) patients receiving cibenzoline 160 mg every 12 h. Response to quinidine 300 mg every 6 h was documented in 8 of 20 (40%) patients and in 2 of 6 (33%) patients receiving 400 mg every 6 h. Dose-limiting side effects occurred in 1 of 20 (5%) patients receiving cibenzoline and in 7 of 20 (35%) patients receiving quinidine. Cibenzoline and quinidine are equal in efficacy, but cibenzoline is significantly better tolerated.     

Initial and long-term outpatient experience with pirmenol for control of ventricular arrhythmias

Summary Pirmenol, a new class IA antiarrhythmic agent, has shown promise in short-term trials, but long-term efficacy has not been documented. We thus evaluated 11 patients with frequent (60/h) premature ventricular complexes (PVC) given oral pirmenol for 25–727 days. Ten of 11 patients entering the long-term open trial had shown 70% (mean 83%) PVC suppression during in-hospital pirmenol dose ranging. Long-term pirmenol was given in divided doses of 100–600 mg/day. Mean PVC frequency during baseline was 13,078/24h (range, 3,218–32,718); couplets averaged 481/24h (1–2,829) and runs 45/24h (0–334). Ambulatory monitoring was performed at 1, 3, 6, and 12 months, then semiannually. Mean absolute PVC suppression at 1 month averaged 75% (p0.02). Median individual percentage PVC suppression was 94%. During the first 3 months, 8 patients (73%) continued to show a favorable response (70% suppression), and 3 had arrhythmia recurrence and were dropped. One responder was withdrawn after the onset of paroxysmal atrial fibrillation, and another early responder was withdrawn after 3 months because of arrhythmia relapse. Six patients have been treated for over 1 year, with 99% mean PVC suppression. Mean couplet and run frequencies at 1 month decreased by means of 76% (p0.05) and 92% (p=0.001) respectively. At 1 year, couplets were suppressed 99.8% and runs by 99.7% in the 6 patients remaining on pirmenol. Mean QT interval increased slightly (7.1%,p<0.05); mean PR and QRS intervals were unchanged. Plasma pirmenol concentrations averaged 1.49 µg/ml at clinic evaluations, 1.72 µg/ml in responders vs 1.08 µg/ml in nonresponders. Inade-quate plasma drug concentrations may be one cause for arrhythmia recurrence. Adverse effects were minimal. Thus, oral pirmenol is a safe and effective agent for long-term outpatient management of complex ventricular arrhythmias in selected patients.At the time this trial was conducted, Dr. Hampton was the American Society of Hospital Pharmacists postdoctoral fellow in cardiovascular pharmacotherapeutics     

Pirmenol in the long-term treatment of chronic ventricular arrhythmias: a placebo-controlled study

Pirmenol, a new class I antiarrhythmic drug, was given for the treatment of frequent premature ventricular complexes (PVCs) over a 6-month period. Ten patients who had their arrhythmia effectively suppressed by pirmenol in a dose-ranging study were treated with the lowest effective doses in an open investigation. The mean daily doses were 315 mg at the beginning and 340 mg at the end of 6 months. The mean reduction in the frequency of PVC/h remained between 85.5 and 88.6% during 24-h ambulatory electrocardiogram recordings at 1, 3, 5, and 6 months of therapy. With adjustment of the dosage, the predetermined efficacy criteria were fulfilled by eight to 10 patients at each of the four assessments. The PVC/h or repetitive PVC/h frequencies of the patient group did not decline spontaneously within 6 months of treatment, as shown in a placebo control phase. No aggravation of arrhythmias was observed. Side effects in two patients did not prevent prolonged use.     

Anesthetized rabbit as a model for ischemia- and reperfusion-induced arrhythmias: Effects of quinidine and bretylium

Experiments were performed to assess the feasibility of using anesthetizes rabbits for the study of ischemia- and reperfusion-induced arrhythmias. Initial studies indicated that occulusion of the left anterior descending coronary artery produced ectopic activity in only one out of eight rabbits. All rabbits subject to occlusion of the left circumflex artery below where it emerges from under the left atrial appendage had ECG changes (ST-segment elevation, Lead II), 80% had arrhythmias, and 50% died in ventricular fibrillation during the first 20 min of coronary artery occulusion. Subsequent reperfusion in the survivors produced further arrhythmias in the majority of rabbits, and one fibrillated. Although a high incidence of ectopic activity was also observed in rabbits subject to occlusion of the left circumflex artery close to its origin, or both the left anterior descending and circumflex arteries, this was accompanied by marked reductions in arterial blood pressure. Thus, occlusion of the left circumflex artery at the lower site was chosen for all further studies. Quinidine hydrochloride 10 mg kg⁻¹ (n = 1) or bretylium tosylate 20 mg kg⁻¹ (n = 10) administered 15 min prior to coronary artery occlusion reduced the incidence of ischemia-induced ventricular fibrillation to 10% compared with 60% in controls (n = 15). Although bretylium reduced arterial blood pressure and heart rate, neither drug altered the hemodynamic consequences of coronary artery occulusion (e.g., increased left ventricular end diastolic pressure). Bretylium at doses of 5 and 20 mg kg⁻¹, but not quinidine, reduced the ST-segment elevation that developed during the ischemic period. The ability to detect the antifibrillatory activity of quinidine and bretylium suggests that the anesthetized rabbit may provide a useful alternative or additional model for the study of arrhythmias induced by acute myocardial ischemia.     

Changes in lignocaine disposition during long-term infusion in patients with acute ventricular arrhythmias

Lignocaine disposition was studied in 30 patients with acute ventricular arrhythmias. Serum concentrations of lignocaine, its metabolites Monoethylglycine xylidide (MEGX) and glycine xylidide (GX), and alpha 1-acid glycoprotein (AAG) were analyzed during and after a 48-h lignocaine infusion. AAG concentrations tended to rise in patients with acute myocardial infarction (AMI), leading to binding of the drug in plasma. Lignocaine clearance was estimated at various times during the infusion using a Bayesian parameter estimation program and was found to decline over the course of the infusion. There was a significant reduction in clearance based on estimates obtained at the end of the infusion compared with estimates obtained during the first 0-5 h. Clearance was reduced both in patients who had an AMI and those who did not. Multiple linear regression analysis of the clearance data revealed that these changes could be described by a linear function of time and AAG concentration. These findings suggest that other factors in addition to protein binding changes may influence lignocaine disposition during long-term infusion.     

Prophylaxis against ventricular arrhythmias in suspected acute myocardial infarction: a comparison of tocainide and disopyramide.

Five hundred and seventy one patients admitted to a coronary care unit with suspected acute myocardial infarction were considered for entry into a double-blind study. Two hundred and eighty-three patients were excluded, mainly because of recent treatment with beta-adrenoceptor blocking agents, life threatening arrhythmias requiring specific treatment and left ventricular failure presenting with hypotension or pulmonary oedema. Two hundred and eighty-eight entered the trial of whom 202 were subsequently confirmed to have had myocardial infarction. The effects of tocainide and disopyramide on ventricular arrhythmias were compared with placebo over the first 48 h period. The three treatments were given by a combination of intravenous infusion and oral administration. The doses used were tocainide 500 mg intravenously over 30 min plus 2800 mg orally over 48 h and disopyramide 150 mg intravenously over 30 min plus 1050 mg orally over 48 h. As judged by counts of ventricular premature beats, tocainide and disopyramide exerted a similar and significant antiarrhythmic effect. The median number of ventricular premature beats over the first 24 h of treatment was 58 on placebo compared with 30 on tocainide (P less than 0.05) and 19 on disopyramide (P less than 0.05). The corresponding figures for the second 24 h were 9, 6 and 2, respectively. There were eight deaths and three episodes of ventricular fibrillation with no significant differences between the three treatment groups. Sustained ventricular tachycardia was observed in one patient in the tocainide group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Infliximab in severe ulcerative colitis: short-term results of different infusion regimens and long-term follow-up

BACKGROUND: Severe ulcerative colitis is a life-threatening disorder, despite i.v. glucocorticoids treatment. Infliximab has been proposed as a safe rescue therapy. AIM: To evaluate short- and long-term effectiveness and safety of infliximab in severe refractory ulcerative colitis. METHODS: Eighty-three patients with severe ulcerative colitis (i.v. glucocorticoids treatment-refractory) were treated with infliximab in 10 Italian Gastroenterology Units. Patients underwent one or more infusions according to the choice of treating physicians. Short-term outcome was colectomy/death 2 months after the first infusion. Long-term outcome was survival free from colectomy. Safety data were recorded. RESULTS: Twelve patients (15%) underwent colectomy within 2 months. One died of Legionella pneumophila infection 12 days after infliximab. Early colectomy rates were higher in patients receiving one infusion (9/26), compared with those receiving two/more infusions (3/57, P = 0.001, OR = 9.53). Seventy patients who survived colectomy and did not experience any fatal complications were followed-up for a median time of 23 months; 58 patients avoided colectomy during the follow-up. Forty-two patients were maintained on immunosuppressive drugs. No clinical features were associated with outcomes. CONCLUSIONS: Infliximab is an effective and relatively safe therapy to avoid colectomy and maintain long-term remission for patients with severe refractory ulcerative colitis. In the short term, two or more infusions seem to be more effective than one single infusion.     

Effect of chronic diuretics on epinephrine-induced ventricular arrhythmias: a comparison of hydrochlorothiazide and amiloride in the rat

The purpose of this study was to determine if chronic administration of the diuretics hydrochlorothiazide and amiloride alters the response to catecholamine-induced ventricular arrhythmias. The protocol consisted of four groups of Wistar rats. Group I, or control group, received daily subcutaneous injections of saline; group II received hydrochlorothiazide, 100 mg/kg/day s.c.; group III received amiloride, 0.5 or 1.0 mg/kg/day s.c.; and group IV received amiloride, 0.5 mg/kg/day, plus hydrochlorothiazide, 100 mg/kg/day. The treatment period lasted 18 days. After completion of the treatment period, under pentobarbital anesthesia, epinephrine was infused and the electrocardiogram and blood pressure recorded. Hydrochlorothiazide produced a significant (p less than 0.05) leftward shift in the dose-response relationship, that is, a smaller epinephrine concentration produced earlier onset of ventricular arrhythmias and mortality from fatal ventricular arrhythmias. Amiloride, at the higher dose, significantly (p less than 0.05) shifted to the right the dose-response relationship between epinephrine and occurrence of arrhythmias--i.e., a larger epinephrine dose was necessary to produce the same amount of arrhythmias. There were no significant differences in heart rate or blood pressure responses to epinephrine among the four groups. Serum and myocardial electrolytes were measured in a separate group of rats that did not receive epinephrine. There were no significant differences among groups for myocardial electrolytes. After hydrochlorothiazide administration, serum calcium and magnesium were decreased and bicarbonate was increased compared with the control group. In the amiloride group, only serum sodium was significantly changed, being slightly increased. This suggests that serum electrolyte levels may account for the effects of hydrochlorothiazide but do not account for the effect of amiloride.     

Lithium and memory: a long-term follow-up study

This study examined the effects of long-term lithium therapy on memory functions in 18 patients suffering from bipolar affective disorder. Patients were retested on the Wechsler Memory Scale, Benton Visual Retention Test, and Zung Self-Rating Depression Scale 6 years after initial testing. Mean memory test scores remained remarkably stable over the 6-year interval with only one of the 10 memory subtests showing a statistically, but not clinically, significant decrease. The sample was split at the median duration of lithium therapy into a long- and shorter term group (with means of 12.9 and 5.2 years, respectively). There were no significant differences between these groups on any of the memory tests when controlled for age and initial memory scores. Negative correlations between several memory test scores and the duration of lithium treatment could in part be explained by the effects of age. Patients' subjective complaints of impaired memory functioning, rated on a visual analogue scale, correlated with the level of depression at the second testing as well as with three memory test scores measuring immediate and short-term visual recall. The results are discussed in view of the demographic and clinical characteristics of the sample and are compared with previous research findings.     

Stereoselective genetically-determined interaction between chronic flecainide and quinidine in patients with arrhythmias.

1. Recent reports have indicated a role for the P450IID6 polymorphism in the stereoselective disposition of single doses of the antiarrhythmic flecainide. 2. In this study, we evaluated the effects of adding low dose quinidine, a potent inhibitor of P450IID6, to chronic flecainide therapy in patients with arrhythmias. 3. In five extensive metabolizer patients, quinidine significantly reduced the clearance of R-(-)-flecainide, from 395 +/- 121 (s.d.) to 335 +/- 88 ml min-1. This change was attributable to a decrease in metabolic clearance, was accompanied by decreased formation of the two major metabolites of flecainide and was not observed in a poor metabolizer subject. The renal clearance of R-(-)-flecainide rose significantly. 4. Quinidine did not alter the clearance of S-(+)-flecainide. 5. The pharmacologic effects of flecainide therapy (QRS widening, % arrhythmia suppression) were slightly, but not significantly, increased. 6. In extensive metabolizer patients receiving chronic flecainide, increased plasma concentrations will develop if P450IID6 is inhibited.     

Efficacy and tolerance of tocainide during acute and long-term treatment of chronic ventricular arrhythmias

Summary The acute efficacy of tocainide and procainamide was studied in 10 patients with chronic, reproducible ventricular arrhythmia. The drugs were administered in random order, by intravenous infusion, during repeated standardized, submaximal exercise tests. The proposed peak therapeutic plasma concentrations of both drugs were achieved. Both agents had an equal and statistically significant anti-arrhythmic effect; thus, a reduction in ventricular ectopic beat frequency by 70% or more was seen 9 patients after procainamide, and in 7 patients after tocainide. A fall in blood pressure was seen in two patients after procainamide and in one patient after tocainide. No other adverse reaction was observed. The long-term efficacy of tocainide was studied in 19 patients with chronic ventricular arrhythmias. All patients were monitored by 6–8-h electrocardiographic recordings, and 9 of them also during exercise tests. Tocainide 400 mg every 8 h resulted in a mean peak plasma tocainide concentration of 31.6 µmol/l, and caused suppression of ventricular extrasystolic beats by 70% or more in 11 patients. Adverse reactions to tocainide were seen in 14 patients. Gastro-intestinal and central nervous system side effects were most common, which often disappeared after a reduction in dose. In 5 patients adverse effects were more serious (one patient had syncope and 4 patients had skin rashes) and withdrawal of tocainide was required. Eight patients were treated with tocainide for more than 6 months, of whom 7 were restudied after withdrawal of tocainide; arrhythmias reappeared in 5.The studies demonstrate that tocainide is an effective antiarrhythmic drug in selected patients, but the high frequency of adverse effects may limit its long-term use.     

Short-term variability in QT interval and ventricular arrhythmias induced by dofetilide are dependent on high-frequency autonomic oscillations

Background and Purpose

The present study was undertaken to investigate an effect of dofetilide, a potent arrhythmic blocker of the voltage-gated K⁺ channel, hERG, on cardiac autonomic control. Combined with effects on ardiomyocytes, these properties could influence its arrhythmic potency.

Experimental Approach

The short-term variability of beat-to-beat QT interval (STV_QT), induced by dofetilide is a strong surrogate of Torsades de pointes liability. Involvement of autonomic modulation in STV_QT was investigated in healthy cynomolgus monkeys and beagle dogs by power spectral analysis under conditions of autonomic blockade with hexamethonium.

Key Results

Increase in STV_QT induced by dofetilide in monkeys and dogs was closely associated with an enhancement of endogenous heart rate and QT interval high-frequency (HF) oscillations. These effects were fully suppressed under conditions of autonomic blockade with hexamethonium. Ventricular arrhythmias, including Torsades de pointes in monkeys, were prevented in both species when HF oscillations were suppressed by autonomic blockade. Similar enhancements of heart rate HF oscillations were found in dogs with other hERG blockers described as causing Torsades de pointes in humans.

Conclusions and Implications

These results demonstrate for the first time that beat-to-beat ventricular repolarization variability and ventricular arrhythmias induced by dofetilide are dependent on endogenous HF autonomic oscillations in heart rate. When combined with evidence of hERG-blocking properties, enhancement of endogenous HF oscillations in heart rate could constitute an earlier and more sensitive biomarker than STV_QT for Torsades de pointes liability, applicable to preclinical regulatory studies conducted in healthy animals.     

Treatment of hypertensive out-patients with a sustained-release dosage form of clonidine: A comparison with standard tablet therapy and long-term follow-up Study

Summary

A 12-week crossover study was carried out in 24 patients with chronic hypertension to compare the effect of clonidine given in a sustained-release form with that of a standard tablet. A long-term study (48 weeks) was performed immediately afterwards in the same patients to determine the effectiveness and acceptability of the sustained-release form in maintenance therapy. Using approximately the same dose of clonidine (300 or 450 μgldayfor the standard tablet, 250 or 500 μg/day for the sustained-release form), no significant difference in hypotensive effect was found between the two forms of administration. The sustained-release form, however, was preferred by all patients because of lesser side-effects. During the long-term follow-up, the hypotensive effect was fully maintained in all patients. Side-effects which occasionally occurred at the start of the study, in particular dry mouth and a slight sensation of dizziness, subsided in the course of therapy. Laboratory investigations and clinical findings gave no indication of any chronic toxic changes.     

Delirium tremens: a prospective long-term follow-up study

A follow-up by health insurance records of 716 male hospital-treated alcoholics revealed a tendency to a more favorable long-term adjustment in patients with delirium tremens at first admission compared with others. Standardized ratings at first admission indicated that the delirium patients had lower frequencies of depressive symptomatology, personality disturbance and social complications. Slight cerebral impairment at first admission was more frequent in the delirium patients, perhaps indicating a more severe abuse. In a subsample of 105 personally followed-up patients it was found that subjects with delirium later during the course of their illness were characterized by a lower level of social stability at first admission, compared with those with an initial delirium or with no history of delirium tremens. Contrary to initial delirium, later delirium was related to an unfavorable course. Six subjects with a history of delirium tremens were found to have taken up social drinking. Patterns and processes of improvement were found to be related more to background characteristics in terms of personality disturbance and social stability than to the severity of withdrawal symptoms.     

Evaluation of a rapid ultrafiltration technique for determination of quinidine protein binding and comparison with equilibrium dialysis

The free level ultrafiltration (UF) assay by the enzyme multiplied immunoassay technique (EMIT) for determination of unbound quinidine concentration in serum (Qf) was evaluated in 50 samples obtained from cardiac patients treated with quinidine for ventricular arrhythmias. Equilibrium dialysis (ED) at 37 degrees C and high performance liquid chromatography (HPLC) served as standard methods for comparison. A good agreement was found between EMIT and HPLC at the low range of free quinidine concentration (0.1-0.7 mg/L) observed in our patients (r = 0.959). Although the correlation between UF and ED was high (r = 0.972), Qf was systematically underestimated by UF. This bias was due to the fact that UF was performed according to the recommendations of the manufacturer at 25 degrees C. No systematic differences were found when 20 additional samples were assayed by the two methods at the same temperature (25 degrees C; r = 0.992). The quinidine binding ratio showed a correlation with the serum concentration of alpha 1-acid-glycoprotein (r = 0.61). The metabolites 3(S)-hydroxyquinidine and quinidine-N-oxide did not influence the protein binding of the parent drug. The importance of adjusting the serum pH to physiological values before measurement of Qf was confirmed in this study. Our results show that, if performed under the same conditions, ED and UF yield practically identical values. Because of easy handling, the EMIT Free Level System II should be applicable under clinical conditions.     

索他洛尔治疗慢性室性和室上性心律失常44例

目的;观察索他洛尔（Ｓｏ）治疗难治性慢性室性早搏（ＶＰＣ）和症状性阵发性心房颤动（ＰＡＦ）的疗效,作用特点和不良反应。方法：２８例慢性ＶＰＣ患者和１６例ＰＡＦ患者接受Ｓｏ治疗,起始剂量１２０￣１６０ｍｇ／ｄ,无效则递增,最大剂量３２０ｍｇ／ｄ。