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Background: Vismodegib is an oral inhibitor of the Hedgehog pathway approved by the US Food and Drug Administration. It is the first systemic treatment for patients with locally advanced or metastatic basal cell carcinoma that is not amenable to surgery and radiation. This is the first drug to use the Hedgehog pathway to inhibit the proliferation of tumors and is also implicated in the development of other cancers such as medulloblastoma., Objective: The goal of this review was to summarize the development, pharmacology, efficacy, and safety of vismodegib., Methods: Relevant English-language literature was identified and then evaluated based on results from database searches of MEDLINE and EMBASE from 1975 to June 19, 2012. The terms searched included, but were not limited to, vismodegib, Erivedge, GDC-0449, basal cell carcinoma, and 2-chloro-N-[4-chloro-3-(pyridin-2-yl)phenyl]-4-(methylsulfonyl)benzamide. Additional literature was identified by assessing the reference lists of previously identified articles and through abstracts presented by the American Society of Clinical Oncology., Results: A total of 70 full text citations were identified although two national conference proceedings were then excluded. An additional 10 published abstracts were also identified. A Phase II, nonrandomized, multicenter, international study demonstrated a 30.3% objective response rate in metastatic basal cell carcinoma and a 42.9% objective response rate in locally advanced basal cell carcinoma. The adverse effect profile for vismodegib is similar to other identified Hedgehog pathway inhibitors; muscle cramps (71.7%), alopecia (63.8%), and dysgeusia (55.1%) were the most common adverse effects seen in trials. A Phase II, randomized, placebo-controlled trial in Gorlin syndrome patients with basal cell carcinoma concluded that vismodegib was significantly better than placebo at reducing new basal cell carcinoma lesions (P < 0.001) and at decreasing the sum of the longest diameter of existing lesions (P = 0.003)., Conclusions: For patients with unresectable basal cell carcinoma or where resection would be cosmetically disadvantageous, vismodegib is an effective therapy with good response rates. At this time, the data are too limited to determine overall survival. The Hedgehog pathway is a newly identified area in which mutations or dysregulation can occur, leading to the development and progression of tumors. Studies continue to look at other cancers with involvement of the Hedgehog pathway., (Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.)

Background: Bicalutamide is an oral nonsteroidal antiandrogenic drug used in the treatment of prostate cancer. A new generic 50-mg tablet formulation of bicalutamide has recently been developed., Objective: This study evaluated the relative bioavailability and tolerability of the new generic formulation of bicalutamide 50-mg tablets (test) and the currently marketed formulation (reference) in healthy Korean male subjects. The study was conducted to meet Korean regulatory requirements for authorization to market the generic formulation., Methods: This was a randomized-sequence, open-label study in which healthy Korean male subjects (aged 20-55 years) received single doses of the test and reference formulations in a 2-period crossover fashion, with a 6-week washout period between doses. Blood samples for the determination of plasma bicalutamide concentrations were obtained at regular intervals over 672 hours after dose administration. Pharmacokinetic parameters were determined using noncompartmental methods. Relative bioavailability was evaluated by comparing the log-transformed C(max) and AUC(0-672) of the 2 formulations; Korean regulatory requirements for the assumption of bioequivalence were met if the 90% CIs fell within the range of 0.80 to 1.25. Tolerability was assessed based on physical examinations, vital signs, clinical laboratory tests, electrocardiograms (ECGs), and adverse events (AEs) (spontaneously reported or observed by investigators)., Results: Of 47 volunteers screened for inclusion, 38 were enrolled and 32 completed the study (mean [SD] age, 24.9 [3.7] years; mean height, 173.8 [6.2] cm; mean weight, 66.1 [7.1] kg). Median T(max) was 24 hours for both formulations. The C(max) of the test and reference formulations was 1176.2 (191.6) and 1118.9 (209.5) μg/L, respectively. The corresponding values for AUC(0-672) were 277,503 (66,865) and 271,961 (75,597) μg · h/L. The 90% CIs for the geometric mean ratios of log-transformed C(max) and AUC(0-672) were 1.00 to 1.11 and 0.99 to 1.07, respectively. Thirty-three AEs were reported, including 17 events in 9 subjects who received the test formulation and 16 events in 12 subjects who received the reference formulation. All AEs were mild, and no subjects discontinued the study because of AEs., Conclusions: In this single-dose study in healthy Korean male subjects, the pharmacokinetic parameters of the new generic formulation of bicalutamide 50-mg tablets did not differ significantly from those of the reference formulation. The new generic formulation met Korean regulatory criteria for the assumption of bioequivalence to the currently marketed formulation. Both formulations were well tolerated. Korea Food and Drug Administration registration number: PSPD 3057., (Copyright © 2010 Elsevier HS Journals, Inc. All rights reserved.)

Background: Bicalutamide is an oral nonsteroidal antiandrogen drug used during hormone ablation therapy for prostate cancer. A new generic formulation of bicalutamide has been developed., Objectives: This study was conducted to meet Korean and US regulatory requirements for the marketing of the generic 50-mg tablet formulation of bicalutamide. To this end, the pharmacokinetic properties of the new (test) formulation were compared with those of the currently marketed (reference) formulation. Tolerability was also evaluated., Methods: An open-label, randomized-sequence, single-dose, 2-period crossover study was conducted in healthy Korean male volunteers. Subjects received either the test or reference formulation of bicalutamide 50-mg tablets in the first period and crossed over to the alternative formulation in the second period. Serial blood samples for pharmacokinetic analysis were taken over 672 hours after dosing. Plasma concentrations of bicalutamide were measured by HPLC-MS/MS. Pharmacokinetic parameters, including AUC(0-672h), were determined by noncompartmental analysis. Log-transformed C(max) and AUC(0-672h) for the 2 formulations were compared. Tolerability was monitored based on laboratory tests, ECGs, vital signs, and physical examinations., Results: Of the 34 subjects initially enrolled, 33 completed the study. The mean (SD) age, height, and weight of participants were 25.8 (4.1) years, 173.6 (5.7) cm, and 68.9 (7.8) kg, respectively. The median T(max) was 36.0 hours for both formulations. The mean (SD) t(1/2), C(max), and AUC(0-672h) for the reference formulation were 135.4 (28.6) hours, 933.2 (169.2) microg/L, and 215,680.1 (48,753.4) microg x h/L, respectively. Corresponding values for the test formulation were 134.3 (30.7) hours, 946.7 (179.9) microg/L, and 221,708.8 (54,935.1) microg x h/L. The 90% CIs for the mean ratios (test/reference) of log-transformed C(max) and AUC(0-672h) were 0.97 to 1.06 and 0.98 to 1.07, respectively. Twelve adverse events were reported for each formulation, none of which were considered drug related in the test-formulation group and 4 of which were considered drug related in the reference-formulation group (3 cases of headache, 1 case of erythematous rash)., Conclusions: In this single-dose study in healthy Korean male subjects, the new formulation of bicalutamide 50-mg tablets met Korean and US regulatory criteria for assumption of bioequivalence with the currently marketed formulation. Both formulations were generally well tolerated, with no clinically relevant safety concerns., (Copyright 2009 Excerpta Medica Inc. All rights reserved.)

In a recent clinical trial, the class Ic antiarrhythmic drugs encainide and flecainide were found to be associated with an increased mortality risk in patients with new myocardial infarction and ventricular arrhythmias. The purpose of this study was to assess whether an increased mortality risk also accompanied the use of these drugs to treat patients with supraventricular arrhythmias. Data were obtained from the respective pharmaceutical sponsors on the mortality observed with each drug in United States and foreign protocols enrolling patients with supraventricular arrhythmias. Mortality in the encainide population (343 patients) and the flecainide population (236 patients) was compared with that in a research arrhythmia clinic, the Duke population (154 patients). Nine deaths occurred in the combined encainide-flecainide population and 10 deaths occurred in the Duke population; the follow-up periods averaged 488 days and 1,285 days, respectively. The 6-year survival functions of these 2 populations, estimated by the Kaplan-Meier technique, did not differ significantly (p = 0.62). The hazard ratio for the combined encainide-flecainide population relative to the Duke population was estimated to be 0.6 with a 95% confidence interval of 0.2, 1.7. These descriptive comparisons did not demonstrate any excess mortality when flecainide and encainide were used in patients with supraventricular arrhythmias.

Moricizine was studied in 908 patients with ventricular arrhythmias. A proarrhythmia occurred in 29 (3.2%). When the severity of the proarrhythmia and the type of presenting ventricular arrhythmia were correlated, no proarrhythmic events occurred in patients who presented with benign ventricular arrhythmias. Four deaths were attributed to the proarrhythmic effects of moricizine. Of these, 3 occurred in patients presenting with lethal ventricular arrhythmias. A total of 15 serious proarrhythmic events occurred, all of which resolved without lethal consequence. The overall proarrhythmia incidence in the lethal and potentially lethal ventricular arrhythmia categories was not different (3.2 vs 3.7%, respectively). Thus, a proarrhythmia occurred in patients with more advanced structural heart disease, and occurred almost exclusively in patients who presented with potentially lethal or lethal ventricular arrhythmia. There was no relation between the dose of moricizine and the incidence of proarrhythmic events. Of the 29 proarrhythmic events, 26 occurred within 7 days (90%) of the initiation of moricizine therapy. Thus, moricizine appears to have a low proarrhythmic potential in the populations tested, including patients presenting with lethal ventricular arrhythmias. The implications of the Cardiac Arrhythmia Suppression Trial on such a data base analysis are discussed.

The Cardiac Arrhythmia Suppression Trial (CAST) is a randomized, placebo-controlled, double-blind, multicenter clinical trial involving 27 centers and more than 100 hospitals in North America and Europe to test the 1-tailed hypothesis that suppression of ventricular arrhythmias in patients with left ventricular dysfunction after myocardial infarction will reduce arrhythmic death. Since April 18, 1989, the CAST is enrolling patients aged less than 80 years with greater than or equal to 6 ventricular premature complexes and left ventricular ejection fraction less than or equal to 40%. Sustained ventricular tachycardia, class IV congestive heart failure or class IV angina pectoris are exclusion criteria. During a prerandomization period, antiarrhythmic drugs are titrated to suppress ventricular arrhythmias. If greater than or equal to 80% suppression is achieved during open-label titration, patients are randomized to the effective dose or to a matched placebo. If only partial suppression (1 to 79%) is achieved, patients are eligible for a substudy that randomizes them to the best dose found during open-label titration or to placebo. The only patients not randomized to treatment are those with increased arrhythmias or drug intolerance during titration. On April 18, 1989, encainide and flecainide were removed from the CAST because these drugs increased the death rate 2.5-fold. There were no imbalances in baseline risk variables between the encainide/flecainide group and the placebo group that might explain the adverse treatment effect. There was remarkable uniformity of the adverse effect across all subgroups. There were no subgroups that benefited from treatment; all were either harmed or not evaluable.(ABSTRACT TRUNCATED AT 250 WORDS)

Encainide is a class IC agent possessing a broad spectrum of antiarrhythmic actions in a variety of animal models. It increases the ventricular fibrillation threshold of the perfused rabbit heart and in situ dog myocardium. Encainide suppresses atrial fibrillation resulting from topical application of aconitine in the anesthetized dog and ventricular fibrillation induced by chloroform asphyxiation in the mouse. In these latter 2 models, encainide is approximately 7 to 11 and 16 to 18 times more potent, respectively, on a milligram basis than quinidine. In anesthetized dogs encainide converts ouabain-induced tachyarrhythmias to normal sinus rhythm at a mean intravenous dose of 0.67 mg/kg. Single doses of 0.5 mg/kg intravenously or 1 mg/kg orally significantly reduced ventricular ectopy in conscious dogs 18 to 22 hours after 2-stage ligation of the left coronary artery. At doses and plasma concentrations exceeding efficacious therapeutic levels, encainide has no major negative inotropic effects and does not compromise cardiac function or hemodynamics. It is devoid of peripheral autonomic or mediator-evoked responses and, in particular, lacks anticholinergic actions. Encainide is rapidly absorbed by all routes of administration and extensively metabolized by the liver. The major metabolites, O-demethyl encainide and 3-methoxy-O-demethyl encainide, have been shown to have quantitatively different, but qualitatively similar, profiles of pharmacodynamic effects. Subacute and chronic administration of encainide at doses representing 11 times an effective oral human dose have produced no distinct or consistent toxicologic findings. Carcinogenicity and mutagenicity studies were negative.(ABSTRACT TRUNCATED AT 250 WORDS)

Fifteen children, aged 5 days to 19 years (mean 4.7 years), with medically refractory supraventricular tachycardia were given oral encainide. In 10 of 15 children with "incessant" tachycardia (greater than 10% of the day), encainide alone controlled supraventricular tachycardia in 5 children; in combination with other antiarrhythmic agents, it partially controlled supraventricular tachycardia in 4 and was ineffective in 1. In 5 children with accessory atrioventricular connections, encainide eliminated supraventricular tachycardia in 3 and was ineffective in 2. Therapeutic encainide dosages ranged from 60 to 120 mg/m2/day (mean 90) (2.0 to 5.7 mg/kg/day). Encainide caused prolongation of the PR interval by 35%, RP interval by 17%, QRS interval by 44% and corrected QT interval by 10%. In 5 children with depressed left ventricular function administration of encainide, by controlling the arrhythmia, increased echocardiographic left ventricular shortening fraction from a mean of 24% to a mean of 36%. Three patients developed excessive QRS aberrancy, which was associated with wide QRS tachycardia in 2. No adverse reactions were noted in the absence of QRS aberration. Side effects were minor and noted in only 1 of 9 patients continuing to take the drug in 9 months of follow-up. Encainide was effective, or partially effective, in the control of resistant or incessant supraventricular tachycardia in 80% of children treated. Encainide allowed rapid resolution of arrhythmia-induced cardiomyopathy by controlling chronic supraventricular tachycardia.

To establish long-term efficacy and the relation between drug plasma concentration and antiarrhythmic response, 12 patients with encainide-responsive frequent complex ventricular ectopic activity underwent 1 year of therapy with encainide. Twenty-four hour ambulatory electrocardiograms were obtained at baseline and every 2 months. Drug withdrawal with concomitant plasma sampling and electrocardiographic monitoring was performed at 6 and 12 months. Average group premature ventricular contraction (PVC) suppression during the year was 97 to 99%, with nearly total suppression of pairs and salvos. The most common adverse effects were transient visual disturbances and dizziness or lightheadedness. During a dose interval (6 to 12 hours) the concentration of encainide metabolites exceeded that of encainide by several-fold. The median time of arrhythmia return after drug withdrawal was 12 to 14 hours. At the time of arrhythmia return encainide was generally no longer detectable but the average concentration of O-demethylencainide and 3 methoxy-O-demethylencainide was 72 +/- 49 and 172 +/- 74 ng/ml, respectively. It is concluded that encainide therapy is extremely effective for continuous long-term suppression of complex ventricular arrhythmias and its metabolites contribute significantly to its antiarrhythmic action during chronic oral therapy.

The Cardiac Arrhythmia Pilot Study (CAPS) was a randomized, double-blind trial of antiarrhythmic drugs (encainide, flecainide, moricizine, imipramine and placebo) in 502 patients with an ejection fraction greater than 0.20 and at least 10 ventricular premature complexes/hour, 6 to 60 days after acute myocardial infarction. Patients were followed for 1 year and the incidence of new or worsened congestive heart failure (CHF) was evaluated. Heart failure in the 1-year follow-up was gauged by the development (in order of increasing severity) of new symptoms (grade 1), the need for a change in therapy, including addition of digitalis, addition or increase of dose of diuretics or afterload reduction agents or discontinuation of beta-blocking agents (grade 2), or by hospitalization (grade 3). Sixty-one of 502 patients (12%) required hospitalization for CHF in the 1-year follow-up. One hundred five of 403 patients (26%) in the active treatment group and 18 of 99 patients (18%) in the placebo group (difference not significant) developed CHF requiring hospitalization or a change in therapy or both. Although patients with severely impaired ejection fraction were excluded, new or worsened CHF was common in follow-up during CAPS.

For treatment of chronic atrial and junctional ectopic tachycardia, standard antiarrhythmic therapy has been shown to be ineffective in most patients. Both the intravenous efficacy and the oral efficacy of 2 class IC antiarrhythmic drugs, encainide and flecainide, were studied in 16 patients with atrial ectopic tachycardia and in 3 patients with junctional ectopic tachycardia, using exercise testing, 24-hour long-term electrocardiography and programmed electrical stimulation. All patients had been previously treated unsuccessfully with several antiarrhythmic drugs. In 5 patients, tachycardia was persistent; in the remaining patients, it occurred intermittently for more than 12 hours/day. Intravenous encainide, in doses ranging from 0.3 to 2.0 mg/kg body weight, was given to 5 patients with atrial ectopic tachycardia, and it terminated atrial ectopic tachycardia in all patients. Intravenous flecainide was given to 9 patients, and it terminated atrial tachycardia in 4 and slowed the tachycardia rate in 2. It terminated junctional tachycardia in 2 patients and slowed tachycardia rate in 1. During a follow-up period of 10 +/- 5 months, oral encainide, in dosages between 150 and 225 mg/day, completely suppressed atrial ectopic activity in 4 patients. In the remaining patient, encainide reduced the number of tachycardia episodes markedly but had to be withdrawn because of intolerable side effects. During a 12 +/- 11-month (median 6) follow-up, oral flecainide at dosages between 200 and 300 mg/day, completely suppressed ectopic activity in 7 patients and improved symptoms in 5. Only 1 patient failed to respond to oral flecainide. The results of this study indicate that both encainide and flecainide are effective in the treatment of chronic ectopic atrial and junctional tachycardia.

Definitions of proarrhythmia, including clinical consequence, were applied to the flecainide and encainide data bases to determine risk factors for serious proarrhythmic events or deaths. Such outcomes with flecainide were far less common for patients with benign or potentially lethal ventricular arrhythmias compared to patients with predominantly lethal ventricular arrhythmias. No deaths from proarrhythmia during flecainide therapy occurred in patients without structural heart disease. Serious proarrhythmic events and deaths were more common in patients in whom therapy was initiated in hospital than in those in whom therapy was initiated out of hospital. When the flecainide dosage for patients with lethal ventricular arrhythmias was chosen using steady-state pharmacologic principles, the occurrence of all proarrhythmic events and deaths dropped from 26% and 13% to 10% and 0%, respectively. Structural heart disease, sustained ventricular tachycardia, inpatient initiation and large-dose escalation of class IC drugs are the primary risk factors for development of proarrhythmic events.

Thirty-six patients with a history of atrial fibrillation and Wolff-Parkinson-White syndrome were treated with oral encainide, 175 +/- 44 mg/day, after undergoing baseline drug-free electrophysiologic studies. The mean age was 38 +/- 15 years, with structural heart disease present in only 3 patients. Nine patients had only paroxysmal atrial fibrillation and 27 patients had both atrial fibrillation and atrioventricular reciprocating tachycardia (AVRT). Symptoms were present for a mean of 195 +/- 168 months and were treated with an average of 2.7 +/- 1.6 drugs before encainide. Anterograde block in the accessory pathway occurred in 12 of 30 patients (40%) and retrograde block accessory pathway occurred in 10 of 24 patients in whom comparison could be made. AVRT was initiated in 29 of 36 patients during the control study and could be initiated in 19 of 29 patients while receiving encainide. Drug efficacy was determined by the clinical response judged completely effective, partially effective or ineffective. During a mean follow-up of 30.1 +/- 25 months, 24 patients (67%) continued to take encainide. Encainide was completely effective in 14 of 24 patients and partially effective in another 7 patients. Noncardiac side effects were mild and generally resolved, and required discontinuance in only 1 patient. More frequent AVRT occurred in 2 patients, but was managed with dose reduction and the addition of a beta blocker. Three patients had ventricular tachycardia requiring discontinuance; however 2 of 3 patients had a history of ventricular tachycardia before receiving encainide. Encainide is an effective and safe agent for treating atrial fibrillation in patients with Wolff-Parkinson-White syndrome.

Twenty-three patients were treated for at least one month with encainide, a new antiarrhythmic drug. No patient was treated for hyperglycemia prior to encainide therapy. During encainide administration, five episodes of marked hyperglycemia (serum glucose level greater than or equal to 200 mg/dl) developed in four patients. (One patient received encainide twice.) The mean pretreatment glucose level was 190 +/- 69 mg/dl and rose to 397 +/- 163 mg/dl after one month of encainide therapy in patients in whom hyperglycemia developed (p less than 0.025). The glucose level was 111 +/- 27 mg/dl in nonhyperglycemic patients before encainide administration and 108 +/- 22 mg/dl after one month of encainide therapy (p = NS). There was no difference in age or encainide dosage between hyperglycemic and nonhyperglycemic patients. Treatment for hyperglycemia was given during four of the five encainide treatment periods in hyperglycemic patients. Encainide was discontinued in each of the five hyperglycemic episodes; therapeutic requirements for hyperglycemia markedly decreased. Hypoglycemic reactions to insulin occurred in two patients when encainide was stopped. Thus, encainide exacerbates hyperglycemia in some patients. These patients usually have mild hyperglycemia not requiring therapy before administration of encainide but may require insulin while receiving encainide. Treatment requirements for hyperglycemia decrease following withdrawal of encainide. The mechanism of this effect and the consequences of long-term encainide therapy on glucose metabolism are unknown.

The onset of antiarrhythmic action of encainide in patients with ventricular arrhythmias occurred within 3 hours after a single dose of 25 or 50 mg. No significant antiarrhythmic activity was noted after only 10 mg. After 14 days of daily dosing, both the 25- and 50-mg dose levels of encainide administered 3 times/day abolished or decreased ventricular arrhythmias in patients tested over a 24-hour period, whereas the 10-mg dose was ineffective. In 5 well-controlled studies involving 331 patients, encainide produced a dose-related decrease in the absolute number of ventricular arrhythmias as well as an increase in the percentage of responders (greater than 75% decrease in ventricular arrhythmias). Doses of 75 mg/day were required to obtain at least a 50% reduction in ventricular arrhythmias or 50% of patients responding or both. Three-times-a-day dosing was as effective as 4-times-a-day dosing. Further, doses greater than 200 mg/day gave little or no increase in incidence of efficacy. Important side effects were very low using doses of less than or equal to 150 mg/day and increased significantly at greater than or equal to 150 mg/day. It is recommended that encainide be initiated at 25 mg 3 times/day for 4 to 7 days, then carefully titrated upward, as needed, to 35 and 50 mg 3 times/day, respectively, every 4 to 7 days. If needed, 50 mg 4 times/day is an appropriate next dosage. Rapid dose escalation or doses greater than 200 mg are discouraged. Patients with severe life-threatening arrhythmias should receive encainide in a setting with cardiac monitoring and advanced life support systems.

A data base of 1,245 patients treated for ventricular arrhythmias, most of whom had serious cardiac disease, was reviewed. Only 2.9% of these patients had benign ventricular arrhythmias without structural heart disease. The overall incidence of proarrhythmia in this population was 9.2% (115/1,245), but was as frequent as 16% in patients with a history of cardiomyopathy. The proarrhythmic form was new sustained ventricular tachycardia in 22 patients (1.8%). Only 2 of 71 patients (2.8%) with primary arrhythmia had a proarrhythmic event. The incidence has decreased markedly over the past years as reduced doses and gradual titration have been used. There were 137 deaths in the data base of which 82 were sudden, all in patients with advanced (79) or moderately severe (3) cardiac disease. High initial doses, prior myocardial infarction and congestive heart failure (CHF) were positively associated with sudden cardiac death. There were no deaths among the 71 patients with benign arrhythmias. Death rates were related to the severity of the arrhythmia being treated. Comparisons with published survival curves indicated modest improvement; in no case was survival decreased. Invasive and noninvasive measures of left ventricular function indicated no adverse hemodynamic effects. There was only 1 case of new and 3 cases of worsened CHF probably related to encainide. Only 5 patients discontinued for CHF or related signs and symptoms. The most frequent drug-related noncardiac adverse reactions were dizziness (26%), abnormal or blurred vision (19%), QRS interval prolongation (5%), taste perversion (4%) and tremor (3%). In conclusion, the use of reduced doses and gradual titration of encainide has markedly decreased the incidence of proarrhythmia.(ABSTRACT TRUNCATED AT 250 WORDS)

The National Heart, Lung, and Blood Institute initiated the Cardiac Arrhythmia Pilot Study (CAPS) to evaluate the feasibility of suppressing ventricular arrhythmias after acute myocardial infarction. Ten centers enrolled 502 patients younger than 75 years of age with greater than or equal to 10 ventricular premature complexes (VPC) per hour in a 24-hour electrocardiographic recording and a left ventricular ejection fraction greater than 20%. Patients were enrolled 6 to 60 days after acute myocardial infarction and randomized to 1 of 5 treatment tracks with 2 drugs that included encainide, flecainide, imipramine, moricizine or placebo. During a double-blind drug and dose selection phase, investigators were permitted to change drug or dosage to achieve greater than or equal to 70% suppression in VPC frequency and greater than 90% suppression of runs of VPC with the exception of patients assigned to placebo, who continued receiving it. Patients were followed for a year after randomization. Patients in the 5 treatment arms were similar in age, sex, clinical characteristics, VPC frequency, left ventricular ejection fraction and concomitant drug treatment. As first drugs, encainide and flecainide had higher efficacy rates, 79% and 83%, respectively, than imipramine, 52%, moricizine, 66%, or placebo, 37%. Encainide and flecainide also had high efficacy rates, 68% and 69%, in patients who failed imipramine or moricizine. Encainide, flecainide and moricizine were well tolerated. These 3 drugs had intolerable adverse effect rates of 6% or less, i.e., similar to placebo. More than 70T of the patients who started the follow-up phase on encainide, flecainide or moricizine remained on these drugs to the end of the study.(ABSTRACT TRUNCATED AT 250 WORDS)

The electropharmacology of tocainide, an orally active congener of lidocaine, was evaluated in 10 patients with coronary artery disease. Electrophysiologic measurements including sinus nodal recovery time, sinoatrial conduction time, intraatrial conduction time, atrial, atrioventricular (A-V) nodal and ventricular refractory periods and intraventricular conduction time were obtained before and after intravenous infusion of tocainide. At blood levels shown to be effective against ventricular arrhythmias, tocainide produced no statistically significant changes in the electrophysiologic measurements, although occasional marked individual effects were observed. No side effects were observed during these studies. No adverse effects on A-V conduction were observed in patients with an intraventricular conduction disturbance or a prolonged control H-V interval. Thus, plasma tocainide concentrations effective in the therapy of ventricular arrhythmias exert no adverse effects on cardiac electrophysiologic properties in patients with coronary artery disease.

Forty-one children (26 weeks gestational age to 20 years) with drug-resistant supraventricular tachycardia were treated with oral encainide, and 29 were followed for 3 to 34 months (mean 15). Diagnoses obtained by electrocardiographic criteria (23 patients) or electrophysiologic testing (18 patients) included permanent junctional reciprocating tachycardia in 15 children, paroxysmal atrioventricular reciprocating tachycardias (AVRT) in 13, atrial ectopic tachycardia in 4, atrial flutter in 1, chaotic atrial tachycardia in 5 and junctional ectopic tachycardia in 3. Encainide was completely effective in 54% (22 of 41 study patients) and partially effective in an additional 24% (10 of 41 patients), when combined with propranolol or verapamil. Within 1 month, 13 (32%) discontinued encainide for inefficacy or intolerance. Encainide was most effective in the treatment of permanent junctional reciprocating tachycardia (60% effective) and AVRT (69% effective). It controlled only 40% of primary atrial tachycardias. Encainide was well tolerated on a long-term basis in patients not experiencing symptoms during initiation. In study infants younger than age 6 months, encainide was associated with excessive QRS aberrancy during initiation in 4 of 13 (31%), compared with 3 of 28 (11%) in older children. Ventricular proarrhythmia occurred in 2 children and 1 died suddenly. Mean effective encainide dose was 3.5 mg/kg/day or 86 mg/m2/day. In 4 children who had nonextensive metabolism of encainide, the drug was ineffective. Encainide is effective in the treatment of some resistant forms of permanent junctional reciprocating tachycardia and AVRT in otherwise healthy children. Children younger than age 6 months and those with either previous proarrhythmic events or severe cardiac dysfunction appear to have a high incidence of adverse effects.

The safety issues relevant to treatment with encainide in patients with supraventricular arrhythmia were reviewed based on 349 patients enrolled in clinical trials in the United States and Europe. Although 20% of patients had a history of congestive heart failure, cardiomegaly, or cardiomyopathy at entry, there was no case of new or worsened heart failure. There were 5 cases (1.4%) of proarrhythmia in adults, reflecting a worsening of the arrhythmia being treated or of a coexisting ventricular arrhythmia. The profile of drug-related adverse effects was comparable to that previously reported, causing discontinuance in 6% of patients. The effects most often seen were dizziness, visual disturbance, headache, nausea and vertigo. Only 1 patient had clinically significant abnormal laboratory values, possibly reflecting hepatocellular injury in conjunction with viral hepatitis. Most responders received a daily dose of 75 to 200 mg/day, generally given in 3 divided doses. Encainide has a very favorable safety profile for use in the treatment of supraventricular arrhythmias.

The effect of intravenous and oral encainide was studied in 12 patients with an accessory atrioventricular pathway (AP). Eight patients had Wolff-Parkinson-White syndrome and 4 had a concealed AP. Electrophysiologic studies were performed before and after intravenous encainide, 1.0 to 1.5 mg/kg, and 4 weeks after oral encainide, 75 to 200 mg/day. Mean follow-up was 19 +/- 6 months. During sinus rhythm, intravenous and oral encainide significantly prolonged the AH and HV intervals. In patients with Wolff-Parkinson-White syndrome, after intravenous encainide, anterograde conduction over the AP was blocked in 3 patients, and the anterograde effective refractory period (ERP) of the AP was markedly increased in 3. Five of these 6 patients had a control value of the anterograde AP ERP of less than 270 ms. Anterograde AP block was maintained in 2 patients after oral encainide therapy. Retrograde AP block or marked increase of retrograde AP ERP was seen in 4 of 9 patients after intravenous encainide and in 2 of 7 after oral therapy. Encainide either prevented induction of circus movement tachycardia (intravenous, 4 of 11 patients; oral, 2 of 7 patients) or significantly prolonged tachycardia cycle length (intravenous, 7 of 11 patients; oral, 5 of 7 patients). During long-term follow-up of 9 patients, 6 patients had no recurrences of tachyarrhythmia after individual adjustment of encainide dosage. One patient had worsening of supraventricular tachycardia after intravenous encainide therapy and 4 patients complained of visual blurring; in 1 patient it was so severe that it required withdrawal of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Aggravation of ventricular arrhythmia is a serious, potentially lethal, side effect that can occur with all antiarrhythmic agents. The purpose of this retrospective case-controlled study was to identify clinically useful parameters that would predict aggravation of arrhythmia. Patients in whom arrhythmia worsened while taking either quinidine, mexiletine or encainide were selected and matched to 2 similar patients who never developed this drug complication with any antiarrhythmic tested. A number of hemodynamic, electrophysiologic and pharmacologic parameters were compared. Only the presenting arrhythmia and a left ventricular ejection fraction less than 35% identified patients at risk for drug-induced aggravation of arrhythmia. Patients who presented with either sustained ventricular tachycardia or ventricular fibrillation were 3.4 times more likely to have arrhythmia aggravation compared with patients presenting with nonsustained ventricular tachycardia or ventricular premature beats. Patients with a left ventricular ejection fraction less than 35% were 2.2 times more likely to develop this drug complication compared with patients with an ejection fraction greater than 35%. There was no association between other clinical parameters, electrocardiographic intervals, ventricular arrhythmia density, drug dose or drug levels and aggravation of arrhythmia. In addition, drug aggravation to 1 drug did not predict its occurrence with another drug of the same class. Patients with a history of a sustained ventricular arrhythmia, especially when left ventricular dysfunction is present, are at high risk for the development of aggravation of arrhythmia.

The antiarrhythmic efficacy and tolerability of encainide and quinidine were compared in an open-design study in which 50 patients with recurrent supraventricular tachyarrhythmias received intravenous encainide in an initial phase and oral encainide and quinidine in a subsequent, randomized crossover phase. Oral encainide (75 to 200 mg/day), administered to 47 patients for an average of 4.7 months, was effective in 77%, and oral quinidine (1,200 mg/day), administered to 44 patients for an average of 3.2 months, was effective in 66% of the patients (difference not significant). When the duration of therapy at each crossover period was compared, the percentage of patients who continued to take encainide was consistently higher than the percentage who continued to take quinidine (p less than 0.01). Twenty-nine percent of the patients discontinued encainide treatment, 23% because of clinical inefficacy and 6% because of adverse effects. Fifty-nine percent of the patients discontinued quinidine treatment, 20% because of inefficacy and 39% because of adverse effects. Based on antiarrhythmic efficacy, encainide is at least as effective as quinidine in the treatment of patients with supraventricular tachyarrhythmias. However, because of encainide's much greater tolerability, it was distinctly superior in terms of clinical use. This study was an open-design, randomized crossover trial to compare the efficacy and tolerability of encainide with those of quinidine in the treatment of supraventricular tachyarrhythmias.

The antiarrhythmic effect of encainide was evaluated in 140 patients with documented symptomatic ventricular tachycardia or ventricular fibrillation refractory to conventional agents. In 102 patients with reproducible spontaneous arrhythmia, noninvasive methods, including ambulatory monitoring and exercise testing, were used to evaluate drug efficacy, while in the remaining 38 patients electrophysiologic testing was performed. Side effects necessitated drug discontinuation in 10 patients before noninvasive evaluation. Of the remaining 92 patients 44 (48%) responded to encainide. Of the 38 patients who underwent electrophysiologic study, 1 discontinued encainide because of side effects and in 4 patients the spontaneous occurrence of sustained ventricular tachycardia precluded repeat study. Of the remaining 33 patients, 10 (30%) were rendered noninducible with encainide. The drug was more effective in those with a left ventricular ejection fraction greater than 35% (p less than 0.03) and in those presenting with nonsustained ventricular tachycardia. Side effects were reported in 53 of 140 patients (38%) and were primarily nausea, vomiting, headaches and tremors. Aggravation of arrhythmia occurred in 4% of patients with a history of nonsustained arrhythmia and in 25% of those with a history of sustained ventricular tachycardia or ventricular fibrillation. Worsening of arrhythmia was not related to mean dose of drug, mean blood level or electrocardiographic changes; it was more likely to occur in patients with a markedly reduced left ventricular ejection fraction (average 32%) and in those with a history of sustained ventricular tachyarrhythmia (p less than 0.05). Long-term encainide therapy was continued in 48 patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Encainide, a newly released class IC antiarrhythmic agent, was studied in 193 patients with ventricular tachycardia (VT) and depressed left ventricular ejection fraction or important arrhythmia-related symptoms. Therapy was evaluated by 24-hour continuous Holter monitoring if patients had nonsustained VT or by electrophysiologic testing if they had sustained VT. Holter monitoring was used in 99 patients and electrophysiologic testing in 94 patients. At baseline the mean age, percent men, percent with coronary artery disease and mean ejection fraction in the 2 groups was 62 versus 58 years, 76 versus 72%, 62 versus 89%, and 27 versus 30%, respectively. In the Holter monitoring group, 71 of 99 (72%) responded with a significant reduction in VT (35% received 25 mg 3 times day, 47% received 35 mg 3 times a day, 14% received 50 mg 3 times a day and 4% received 50 mg 4 times a day). Adverse cardiac effects in these patients included a 7% incidence of serious proarrhythmic events that were probably related to encainide and a 2% incidence of sick sinus syndrome. In this group no patient developed congestive heart failure that was clearly attributed to encainide. Using electrophysiologic testing, 14 of 94 (15%) had sustained VT rendered noninducible, whereas 18 of 94 (19%) additional patients had partial electrophysiologic response defined as a more tolerable, slower VT. Overall, 32 of 94 (34%) were believed to be effectively treated in this group and were treated with encainide long-term. In the population evaluated by electrophysiologic testing, serious proarrhythmic events occurred in 15 of 94 (16%) and 3% had sinus pauses.(ABSTRACT TRUNCATED AT 250 WORDS)