Thomas L. Wenger

Digoxin Immune Fab Therapy in the Management of Digitalis Intoxication: Safety and Efficacy Results of an Observational Surveillance Study

An observational surveillance study was conducted to monitor the safety and effectiveness of treatment with Digoxin Immune Fab (Ovine) (Digibind) in patients with digitalis intoxication. Before April 1986, a relatively limited number of patients received treatment with digoxin-specific Fab fragments through a multicenter clinical trial. Beginning with commercial availability in July 1986, this study sought additional, voluntarily reported clinical data pertaining to treatment through a 3 week follow-up. The study included 717 adults who received Digoxin Immune Fab (Ovine). Most patients were greater than or equal to 70 years old and developed toxicity during maintenance dosing with digoxin. Fifty percent of patients were reported to have a complete response to treatment, 24% a partial response and 12% no response. The response for 14% of patients was not reported or reported as uncertain. Six patients (0.8%, 95% confidence interval 0.3% to 1.8%) had an allergic reaction to digoxin-specific antibody fragments. Three of the six had a history of allergy to antibiotic drugs. Twenty patients (2.8%, 95% confidence interval 1.7% to 4.3%) developed recrudescent toxicity. Risk of recrudescent toxicity increased sixfold when less than 50% of the estimated dose of antibody was administered. A total of 215 patients experienced posttreatment adverse events. The events for 163 patients (76%) were judged to result from manifestations of underlying disease and thus considered unrelated to Fab treatment. Digoxin-specific antibody fragments were generally well tolerated and clinically effective in patients judged by treating physicians to have potentially life-threatening digitalis intoxication.

Hypersensitive Carotid Sinus Syndrome Manifested as Cough Syncope

We describe a patient with cough syncope who was found to have carotid sinus hypersensitivity with mixed cardioinhibitory and vasodepressor responses. Symptoms were ameliorated by denervation of the more hypersensitive carotid sinus. Spontaneous atypical Wenckebach cycles in this patient were caused by the combined hypersensitive cardioinhibitory and vasodepressor responses. This report stresses the importance of checking blood pressure as well as heart rate in all pa‐tients in whom carotid sinus syndrome is suspected.

Terfenadine alters action potentials in isolated canine Purkinje fibers more than acrivastine.

Summary Acrivastine and terfenadine are second-generation antihistamines with similar pharmacologic profiles and comparable clinical efficacies for allergic rhinitis. However, terfenadine therapy has been associated with cardiovascular side effects that include prolonged QT interval, torsades de pointes, and ventricular fibrillation (VF). We examined the adverse effects induced by terfenadine on evoked action potentials (APs) in isolated canine cardiac Purkinje fibers and determined whether acrivastine causes similar disturbances in this preparation. Terfenadine produced a statistically significant decrease in the maximal rate of increase in the AP (dV/dt) at 10-7 M, which corresponds to the highest plasma concentration observed clinically. The IC50 (mean

Experience with digoxin immune Fab (ovine) in patients with renal impairment

pM SEM) value for terfenadine-induced inhibition of dV/dt was 1.3

Effects of flecainide on occlusion and reperfusion arrhythmias in dogs.

pM 0.3 χ 10-6 M. The decrease in dV/dt caused by terfenadine became more pronounced with faster rates of stimulation. Acrivastine at a concentration of 10-5 M, a value 10 times higher than plasma concentrations observed in clinical studies, caused no significant changes in AP duration (APD) or dV/dt. The IC50 (mean

Procainamide delivery to ischemic canine myocardium following rapid intravenous administration.

pM SEM) value for the acrivastine-induced inhibition of dV/dt was estimated to be 8.0

Simultaneous determination of lidocaine and its metabolites in plasma and myocardium.

pM 3.7

Lidocaine and Its Metabolites in Canine Plasma and Myocardium

10-3 M. Terfenadine blocked the evoked AP at 3 χ 10-6 M, whereas no block was observed with acrivastine at 10-3M. The effective serum concentration of acrivastine is ~ 100 times higher than that of terfenadine. Because the IC50 value for inhibition of dV/dt for acrivastine is ~6,000 times greater than that for terfenadine, we estimate that acrivastine is ~60-fold less likely to cause disturbances in cardiac conduction than terfenadine.

Myocardial procainamide concentration in canine atria and ventricles.

Digibind is a purified antigen binding fragment (Fab) of immunoglobulin G antibodies raised to bind digoxin. Studies in animals suggest renal excretion accounts for a substantial portion of Fabs elimination. Thus it is expected that elimination of antidigoxin Fab fragments would be prolonged in patients with renal impairment; it remains unclear whether digoxin might be released with possible recurrence of toxicity. To shed light on this potential for recrudescent digitalis toxicity following release of bound digoxin, the author scrutinized the records of patients with impaired renal function who were treated with Digibind. Data are available from three sources: the original multicenter investigation of Digibind in 150 patients with life-threatening digoxin or digitoxin toxicity, a postmarketing surveillance study of 745 patients treated with Digibind, and all other reports in the literature or to Burroughs Wellcome Co of physician experience with any antidigoxin Fab. Sixty percent of patients in the multicenter trial and 80% of patients in the postmarketing surveillance trial had some degree of renal impairment. Patients with poor renal function had no evidence of decreased effectiveness or safety either in terms of percent of patients responding, onset of effect or evidence of recrudescence. From all sources the authors identified 28 patients treated with Fab who were functionally anephric. Twenty-seven of these patients had no evidence of recrudescent toxicity. One patient was reported to have complete resolution of digoxin-induced third-degree atrioventricular (AV) block, but AV block recurred 10 days after Fab treatment and persisted for 10 days thereafter. Although this case offers the only clinical evidence suggesting recrudescence can occur, there were no likely alternative explanations for the clinical findings.(ABSTRACT TRUNCATED AT 250 WORDS)