Clinical safety profile of sotalol in patients with arrhythmias.

Key safety parameters of sotalol were examined in 1,288 patients entered into recent controlled trials of ventricular (85% of patients) or supraventricular arrhythmias (15%). Most patients were middle-aged male Caucasians with significant heart disease. The most serious adverse event was proarrhythmia, occurring in 56 patients (4.3%). Of these, 27 had hemodynamic compromise due to malignant ventricular arrhythmias. Most had a history of sustained ventricular tachycardia, myocardial infarction, congestive heart failure (CHF) or cardiomyopathy, or a combination of these. The other 29 had nonsevere events; 38% continued taking sotalol. Proarrhythmia was manifested by torsades de pointes in 24 of the 56 patients. No universal causal relation was found with commonly associated factors such as bradycardia, hypokalemia and long QT interval. The mean QT and QTc at baseline within 1 week of a severe proarrhythmic event were greater than those of patients not having proarrhythmia. Nineteen patients (1%) discontinued therapy with sotalol because of drug-related CHF. Predisposing conditions included low initial baseline ejection fraction, history of CHF, cardiomyopathy or cardiomegaly, or both, male gender and age greater than 65 years. Heart failure usually occurred within 7 to 30 days of initiating therapy. The most common reason for premature discontinuation of the drug in patients treated for sustained ventricular tachycardia was ineffectiveness (39%), whereas adverse effects were the most common reasons among patients treated for complex ventricular ectopy (21%). Dyspnea and bradycardia were the most common cardiovascular effects, and fatigue, dizziness and asthenia the most common noncardiac, adverse effects. Although frequently reported, these adverse effects resulted in discontinuation of only 1 to 4% of the patients at risk.(ABSTRACT TRUNCATED AT 250 WORDS)

Safety considerations and dosing guidelines for encainide in supraventricular arrhythmias.

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.

Safety of encainide for the treatment of ventricular arrhythmias.

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)

Caffeine ingestion during pregnancy: in utero exposure and possible effects.

The vast majority of fetuses are exposed to one or more of the methylxanthines, primarily caffeine, often at frequent intervals, during gestation. Caffeine has a multitude of pharmacologic actions and its effects must be determined on the fetus and newborn in the immediate future for suggestive evidence links caffeine with such fetal and newborn pathology as pre- and postmaturity and intrauterine growth retardation. Since both caffeine and theophylline have markedly prolonged and variable half-lives especially in the premature infant, the possibility of prolonged effects from these drugs cannot be dismissed.

Studies of caffeine and theophylline in the neonate.

About 50% of 327 umbilical cord sera from infants born at the Medical Center Hospital of Vermont contained 1.0 microgram/ml or more of caffeine; about 25% contained equivalent concentrations of theophylline. Cord concentrations of caffeine greater than 3.0 micrograms/ml were associated with a significantly increased incidence of birthweights greater than 4 kg and a decrease in the incidence of 1-minute Apgar scores of less than seven. Cord blood caffeine concentrations of 69 infants born in Marburg, West Germany had a mean of 1.6 micrograms/ml, with 64% greater than 1 microgram/ml. Caffeine accumulated in the serum of infants treated with aminophylline for apnea of prematurity, apparently from methylation of theophylline.

Monitoring of serum theophylline concentrations.

When properly performed, analysis of serum theophylline concentrations can yield important data for management, whether one is dealing with premature babies being treated for apnea or older children being treated for asthma. Serum levels are not fault-free and must be interpreted in concert with historical and clinical observations. One day we will monitor serum levels of theophylline and a number of other drugs as frequently and as accurately as we currently monitor serum electrolytes.

Hepatic drug metabolizing enzyme activity and tumorigenesis in mice following perinatal exposure to benzo(a)pyrene.

It is known that in utero exposure to polycyclic aromatic hydrocarbon carcinogens (PAH) results in a high incidence of pulmonary and other tumors in the offspring, usually after a long latency period. The present study tested the hypothesis that perinatal exposure to benzo(a)pyrene (BP) produces alterations in microsomal mixed-function oxidase (MFO) activity that modify the response to postnatal challenge with a PAH in such a way as to render the offspring to be more susceptible to tumorigenesis, and to determine whether the gestational age at which BP exposure occurred was a determinant of the proposed alterations. Swiss mice were treated with BP on day 3, 8, 10, 12, 14, or 18 of gestation. Subgroups from each gestational-age treatment group and appropriate controls were studied for enzyme activity or were challenged with 3-methylcholanthrene (3-MC) when three months old. Female offspring of BP-treated mice had significantly elevated hepatic microsomal aminopyrine demethylase activity; cytochrome P-450 concentrations were significantly lower in male offspring. The most striking finding was the increased susceptibility to tumorigenesis of female offspring. Latency for local tumors was decreased by two weeks; tumors were more frequent and grew more rapidly. Significantly more female offspring had both local and pulmonary lesions, and the total number of pulmonary adenomas was also significantly higher. Further studies are required to determine if the developmental alterations in hepatic (MFO) activity resulting from perinatal exposure to PAH relate in a causative way to the enhanced susceptibility of female offspring to tumorigenesis.

Influence of concurrent testosterone on the effects of methadone on male rats and their progeny.

This study was conducted to test the hypothesis that the adverse effects on progeny that result from administering methadone to male rats are mediated by a decrease in serum testosterone. Male rats were treated with methadone HCl, 10 mg/kg/day for 4 days while an equal number received the same dose plus testosterone propionate, 2.5 mg/kg/day. Neonatal mortality was significantly lower among the progeny of sires which had received the testosterone, 22/132 vs. 33/101, x2 = 8.13, p less than 0.01. The mean body weight at weaning of the progeny of sires treated with methadone plus testosterone was about 4 g lower (p less than 0.01) than that of the progeny of sires which had received methadone only; one-half of this variability was attributable to the greater number of survivors in the former group. Testosterone administered concurrently with methadone to sires resulted in significant reductions in the weights of their testes and adrenals, but increased weights of their seminal vesicles. It was concluded that administration of testosterone concurrent with methadone by preventing dysfunction and/or atrophy of the accessory sex organs of the sire, may have been responsible for the improved neonatal survival of their offspring.

Effects of methylxanthines on the fetus.

The role of caffeine and other methylxanthines in prematurity, intrauterine growth retardation, and the respiratory distress syndrome is currently under investigation. Their pharmacokinetics are discussed together with their newly discovered beneficial role as possible inhibitors of premature labor and accelerators of fetal lung maturation.