Lester F. Soyka

Postmortem tissue digoxin concentrations in infants and children.

The concentrations of digoxin in tissues of premature infants, full-term infants and older children obtained at autopsy were determined by a radioimmunoassay procedure. Infants were found to have much higher concentrations in the right and left ventricle (about 190 ng/g) than older children (about 70 ng/g) and adults as reported in the literature. Renal concentrations were lower in the premature group which may be related to their limited excretory capacity for digoxin. The relatively high myocardial concentrations of digoxin found in this study suggest that the usually recommended doses for infants may be excessive.

Further studies on the inhibition of drug metabolism by pregnanolone and related steroids.

Abstract Because of our previous findings that pregnanolone and related metabolites of progesterone inhibit drug demethylation and hydroxylation reactions in vitro , a variety of other steroids and naturally occurring substances were tested for inhibition of the O -demethylation of p -nitroanisole by 9000 g hepatic supernatants from adult male rats. Of some 58 steroids tested, none was more potent than pregnanolone. Other potent inhibitors, with the exception of norethindrome, had a similar structure (C 21 ) with hydroxyl or keto groups at C 3 and C 20 . Inhibitory activity was not related to the endocrine activity of the steroid. Inhibition by a group of 11 steroids was generally greater with 9000 g supernatants from female rats, and was uniformly increased with supernatants from pregnant rats. By 10 days after delivery, inhibition returned to levels equivalent to those found with supernatants from virgin females. Cholesterol and related compounds, fatty acids and esters, ceramides, gangliosides, phosphatidyl inositol and other natural fatty acid conjugates and a variety of indoles and lipids had no inhibitory activity. Pregnanolone administration increased the duration of hexobarbital- and of barbital-induced sleep in rats, apparently due to an additive sedative effect. However, microsomes prepared from these animals exhibited lesser rates of demethylation, with kinetics compatible with uncompetitive inhibition. These results indicate that progesterone, its metabolites and structurally similar steroids are potent inhibitors of microsomal drug metabolism. Such inhibition may be responsible in part for the low rates of drug metabolism seen in the female, during pregnancy, and in the neonate.

Digoxin intoxication in infants and children: Correlation with serum levels

A study was made of serum digoxin levels, as determined by radioimmunoassay, in twelve infants and four children with digitalis toxicity. Serum digoxin concentrations were significantly higher during digitalization than during maintenance therapy, but levels during digitalization did not differ between toxic and nontoxic infants. During maintenance therapy, however, the mean levels in intoxicated infants (3.6 ng. per milliliter and children (2.9 ng. per milliliter) were significantly higher than those of nontoxic patients (1.7 and 1.1 ng. per milliliter, respectively). It was concluded that when properly obtained and interpreted, determination of the serum digoxin concentration is a useful procedure for corroborating the diagnosis of digitalis toxicity in pediatric patients, as it is in adults.

Serum, Atrial, and Urinary Digoxin Levels During Cardiopulmonary Bypass in Children

Serum, urine, and tissue samples were collected from 42 children undergoing open-heart surgery and analyzed for digoxin by radioimmunoassay. Of these, 24 had been digitalized prophylactically (RECENT) and 18 had been receiving maintenance therapy (MAINT) for one month or longer. Twenty-five percent of the RECENT patients exhibited arrhythmias during the postoperative period as compared to none in the MAINT group. Serum digoxin levels were equivalent in the two groups throughout the study. Although no change in tissue digoxin concentrations occurred during bypass, right atrial appendage concentrations were significantly higher in the RECENT group (109 vs 62 ng/g; P < 0.001). This high atrial digoxin concentration presumably resulted from the large doses used for initial digitalization, and concomitant with postoperative hypokalemia and myocardial metabolic changes secondary to perfusion, may have been responsible for the high incidence of arrhythmias in the RECENT group. Both digoxin and creatinine excretion were depressed following bypass. The amount of biotransformation of digoxin was 2-59.

Toxicity and Tissue Distribution of Aminophylline in Neonatal and Adult Mice and Rats

Summary: The LD50 of aminophylline in adult mice differed from young mice and rats of both ages, in which the values were remarkably similar (Table 1). With the exception of fat, which had lower concentrations in all groups, tissue concentrations after a 4 mg/kg rectal dose of aminophylline in the 10-day-old animals ranged from 10–20 μg/g as compared to 4–10 μg/g in the adults (Table 2). To evaluate preferential distribution, an analysis of tissue to blood concentration ratios was made. All ratios approximated 1.0 except fat which had a ratio of 0.1–0.6. The neonates of each species had significantly higher tissue to blood ratios for brain, heart, small intestine, skeletal muscle, and fat (P < 0.05). Brain to plasma and brain to blood ratios were very similar ranging from 0.4–1.3 in adults versus 0.8–1.7 in neonates. Consideration of the time course indicated a trend toward unit, with the overall ratio in both groups being 1.15 at 2 hr. However, at all earlier time periods the ratios were clearly higher in neonates. Administration of aminophylline intraperitoneally to produce serum concentrations of tneophylline far in excess of the 10–20 μg/ml considered to be safe and effective in clinical use did not decrease bilirubin levels in young or old Gunn rats (Fig. 1).Speculation: The similarities of LD50 and tissue distribution between neonatal and adult rodents suggests that studies of metabolism may prove to be most important in explaining differences in serum elimination times noted in prematures treated with aminophylline.

Differential inhibition of drug metabolism by hepatic microsomal lipids of neonatal and adult rats

Summary When hepatic microsomes from adult male rats were incubated with microsomal lipids (ML) extracted from the microsomes of neonatal rats, ethylmorphine N-demethylase activity was inhibited by 55%, while aniline hydroxylase activity was not. ML produced a type I spectral change in microsomes of adult rats as did ethylmorphine. The inhibitory component of ML resided in the phospholipid fraction and was destroyed by exposure to O2. ML from adult male rats contained 20% unsaturated fatty acids and were only one-half as potent as those from neonates (38% unsaturated). These results suggest that phospholipid(s) containing unsaturated fatty acids inhibit the metabolism of type I drugs by combining with their binding site, and may be responsible, at least in part, for the low activity of drug metabolism in the neonate.

DECREASED HYPOXIC, HYPEROXIC AND BRADYCARDIC EPISODES AS RESPONSES OF NEONATES TO THEOPHYLLINE

Transcutaneous PO2 (tcPO2) is a new approach to the evaluation of drug effects. We investigated the effect of theophylline on 4 prematures (1130-1720 g) with apnea. TcPO2, heart rate (beat-to-beat) and thoracic impedance were continuously monitored during each of three 4-hour study periods; 12 hr before T, 12 hr after initiation of T2, (administered as aminophylline, 8 mg/kg per rectum q 12 hr × 2, 4 mg/kg q 12 hr × 1-4 d) and 24-58 hr after discontinuing. Plasma levels were measured by a radio-immunoassay developed in our lab. Polygraphic recordings were analyzed without knowledge of treatment.In each case during T, cardiorespiratory patterns were altered, with more regular respirations, apneic spells were reduced, PO2 was stabilized resulting in less hypoxia and hyperoxia and the number of bradycardic episodes decreased. These beneficial effects reverted upon cessation of short-term therapy.

Biliary excretion and enterohepatic circulation of pregnanolone in the rat

Abstract Studies were made of the metabolism and biliary excretion of pregnanolone, a metabolite of progesterone exhibiting a variety of pharmacologie activities, in rats bearing venous and biliary catheters. Pregnanolone glucuronide appeared rapidly and in large amounts in the bile, with a concentration gradient in the order of 400 relative to serum. The relative concentration of various metabolites in the bile remained constant over a 5-day period. An enterohepatic cycle was established by finding peaks in the serum concentration of pregnanolone after intragastric administration of bile collected from pregnanolone-pretreated rats, containing pregnanolone and pregnanolone glucuronide. It appeared that hydroxylation of pregnanolone at C6 and 17 and reduction of C20 occurred during its passage through the intestine.

LETHAL AND SUBLETHAL EFFECTS ON THE PROGENY OF MALE RATS TREATED WITH METHADONE

Fourteen male rats were treated with methadone HCl (METH) 10 mg/kg s.c. per day (or 12 days. Fifteen control males received saline injections for four days. Each male was caged with four drug-naive females each night. METH males lost weight over the treatment period and mated less frequently. At autopsy, their seminal vesicle weight was decreased, even when corrected for body weight. Progeny of METH males (507 pups) were of lower average birth weight than controls (276). Prior copulation had a differential effect, resulting in slightly heavier control pups but significantly decreased birth weights in the METH group. Neonatal mortality of the METH progeny was 18.2%, compared to 9.5% of the controls (P < .01). Mortality was related in a complex fashion to number of drug exposures and previous sexual experience of the sire. Male offspring were particularly affected. Ponderal growth of survivors from litters with high neonatal death rates was diminished, with females being significantly lighter at 75 and 132 days of age. Open field defecation scores were significantly different at two but not at four months of age. No differences in acquisition of a conditioned avoidance response were noted. These results together with previous data from our laboratory establish for the first time lethal and sublethal effects on the progeny of a drug-treated sire.

A comparison in man of the autonomic and behavioral effects of N-allylnoratropine with atropine

Summary1.A derivative of atropine, N-allylnoratropine (naltropine), was administered in doses 1.25, 2.5 and 5.0 mg in 41 trials to 23 medical student volunteers.2.Autonomic effects were bradycardia, slight drop in systolic blood pressure, and moderate decrease in saliva production.3.Pronounced behavioral and subjective effects were produced by 2.5 and 5.0 mg. These were quantified by the decreased score obtained on the friendly, energetic, and clear thinking sections of the Clyde Mood Scale.4.Naltropine produced central effects at a dose level where autonomic effects were minimal, in sharp contrast to atropine where marked peripheral effects obtained with very small doses, and no behavioral effects occurred with the highest dose employed (1.25 mg).