Pediatric pharmacology (New York, N.Y.)最新文献

Using a flow-through system, the pulmonary excretion rate of carbon monoxide (VECO) was determined by gas chromatography and used as an index of bilirubin production in newborn rats treated with tin protoporphyrin. Hepatic and splenic heme oxygenase activities were determined spectrophotometrically. No significant differences in the VECO were found between experimental and control animals despite significant decreases in hepatic heme oxygenase activity (P less than .0005) and splenic heme oxygenase activity (P less than .025). These results suggest that 1) there is no simple relation between heme oxygenase activity and bilirubin production; 2) heme oxygenase is present in excess amounts in neonatal rats; and 3) the lowering of serum bilirubin levels caused by tin protoporphyrin cannot be attributed to decreased bilirubin production and may be owing instead to increased uptake, conjugation, or excretion of bilirubin, or decreased enterohepatic circulation of bilirubin.

Risk factors associated with the occurrence of adverse drug reactions were evaluated in 1,200 neonates in an intensive care setting. Three-hundred-and-twenty-six neonates (27.1%) developed at least one ADR, 153 of whom had moderate to severe (fatal or life threatening) ADR. Severe prematurity (less than 28 weeks) gestation and diseases of prematurity (eg, RDS, apnea, and necrotizing enterocolitis) as well as the use of mechanical ventilation and parenteral nutrition were associated with highly significant increase in ADR occurrence. Impairment of liver and renal function both predisposed neonates to develop ADR.

Blood levels of ACTH, FSH, and estriol were measured throughout the estrous cycle and estriol was determined at different stages during pregnancy in Charles River CD-1 mice treated with 10 mg/kg/day of methadone or vehicle (physiological saline). Animals received one dose in a constant volume (10 ml/kg) per day subcutaneously of either methadone or saline. Blood samples of nonpregnant mice were collected 1 hour after the first dose for acute effects and 1 hour after the last dose treatment for subchronic effects. The acute administration of methadone in nonpregnant mice produced an increase in ACTH level throughout the estrous cycle whereas subchronic treatment reduced ACTH level by 51%. Acute treatment did not alter the estriol or FSH levels whereas subchronic treatment significantly lowered estriol by 17% and FSH by 79%. Methadone injected beginning on day 1 of gestation and continued through day 15 did not produce any effect on maternal body weight or food consumption but resulted in an increase in resorption sites and decrease in implantation sites. The estriol levels in control pregnant mice were 19.8, 54.8, and 109.1 ng/ml on days 1, 10, and 15 of gestation, respectively. A significant reduction of 18.8% and 35.2% in estriol was associated with methadone treatment by days 10 and 15 of gestation, respectively. Methadone, by affecting several hormonal levels in both pregnant and nonpregnant CD-1 mice, may be responsible for some of the adverse effects on reproduction encountered in this species.

Neonatal hypoglycemia and hyperinsulinemia have been reported following maternal ritodrine administration, but no prospective controlled study of the neonatal metabolic and cardiovascular effects of maternal ritodrine is available. We conducted a double-blind prospective study in 35 patients with preterm labor and/or ruptured membranes. Patients in premature labor received ritodrine (max dose, 350 mcg/min) or a placebo intravenously for 12 hours, and then orally (20 mg every 4 hours) until labor ensued. Patients with ruptured membranes received only oral therapy. Only patients who were maintained on oral therapy for a minimum of 12 hours and who were within 6 hours of their last dose of oral therapy were included in the analysis. Glucose and insulin values in cord blood at 6 and 12 hours of age were not significantly different between the ritodrine and placebo groups. There were no hypoglycemic infants in the ritodrine group. Mean systolic and diastolic blood pressure, heart rate and blood volume were similar for ritodrine and control infants. Although premature infants are at high risk for hypoglycemia it appears from this study that chronic oral ritodrine therapy does not significantly affect neonatal glucose homeostasis.

The use of oral gentamicin in infantile diarrhea is recommended by some authors. However, no data are available concerning the gastrointestinal absorption of gentamicin in infants when the mucosa of the small intestine is damaged. In this study, plasma gentamicin concentrations were measured in 14 infants suffering from prolonged diarrhea and treated with oral gentamicin (mean dose: 17 mg/kg every 8 hr). Plasma gentamicin levels were determined serially following the oral dose. Although marked individual and erratic temporal variations existed, average plasma gentamicin concentrations were low and stable (0.31 +/- 0.12 micrograms/ml). A positive correlation was found between the duration of the diarrhea and plasma gentamicin concentrations (r = 0.59, P less than 0.05). It is theorized that the damage to the mucosa as it occurs in prolonged diarrhea allows the absorption of the polar gentamicin molecule.

Twenty-four children (2-15 years old) with acute lymphocytic leukemia (ALL) were treated intravenously with 1-Asparaginase (1-Asp) isolated from E coli at a dose of 3,000 U/kg body weight four times every third day as part of a standard chemotherapy protocol. Sera of patients were obtained prior to each infusion, immediately following each infusion, and at defined intervals (2, 4, 12, 24, 36, and 48 hours postinfusion) and assayed for 1-Asp enzymatic activity.1-Asp antigen, and anti-1-Asp antibodies. Results indicate that the in-vivo elimination half-life of 1-Asp activity in patients with no demonstrable specific antibody is approximately 5.5 hours. Half-life of enzymatic activity in patients with a moderately high level of specific antibodies (pre-infusion) was prolonged (approximately 7.0 hours) in comparison to the group with no specific antibodies. In patients with very high levels of specific antibodies several infusions could not be completed because of apparent anaphylactic reactions. In-vitro studies showed that experimental immune complexes made of 1-Asp and the IgG-fraction of a rabbit-anti-1-Asp antibody under conditions of antigen excess still exhibit enzymatic activity. On the basis of this observation we conclude that specific antibodies to 1-Asp in vitro and, most likely, in vivo do not inactivate the drug but may lead to either delayed elimination of enzyme activity or, in the presence of high levels of specific antibodies, anaphylactic reaction.

In three patients with neuroblastoma and high circulating levels of dopamine and dopa, we interfered pharmacologically with catecholamine biosynthesis either at the tyrosine hydroxylase or dopa decarboxylase step in an attempt to 1) improve the efficacy of antitumor therapy and 2) avoid the potential arrythmogenic interaction between elevated circulating catecholamines and an halogenated hydrocarbon anesthetic during surgery. Biochemical evidence indicated that inhibition of catecholamine biosynthesis had occurred but there was no associated significant change in clinical status or response to other therapy.

The pharmacokinetics of chlorpromazine in the newborn have not been reported. We studied the kinetics of removal of chlorpromazine from plasma in an infant whose mother was treated with high doses of chlorpromazine and lithium throughout the last trimester of pregnancy. The infant exhibited symptoms of severe neurologic depression that slowly abated over the first 9 days of life. The kinetics of plasma chlorpromazine removal were described with a two-compartment model, exhibiting a rapid half-life of 1.46 days and a slow half-life of 3.19 days. Both half-lives are considerably longer than the rapid and slow half-lives described in adults. Caution in exposing the fetus or newborn to chlorpromazine is warranted. Further information on the distribution and excretion of chlorpromazine by the newborn is needed.

Since 1966 the problem of evaluation of drugs for use in man has increasingly become the subject of both international and national consideration. It was generally felt, that there is a need for a special protection for children being the subjects of the clinical evaluation of drugs. A new impulse with regard to the protection of children was recently set by the Council for International Organizations of Medical Sciences. German legislation has included these international convictions and recommendations pertaining to the performance of clinical trials. Articles 40 and 41 of the German Drug Law of 1976 are an emanation of WHO principles as well as of the Declaration of Helsinki. These articles include special provisions for the protection of children as volunteers of clinical trials, because clinical trials in children are indispensable for research on diseases of children. It is laid down in the Law that children should never be subject of research that might equally well be carried out on adults. The willing cooperation and, as far as feasible, consent of the child and its custodians has to be sought. The German Law provides that trials in healthy children may take place only with regard to diagnostic and prophylactic drugs, not with regard to the therapeutics. Article 41 of the German Drug Law permits the clinical evaluation of drugs in ill children. Therapeutic drugs may, however, be tested in children only under the condition that the drug is determined to cure the special disease under which the child is suffering. Special aspects of the clinical evaluation of drugs in children, not contained in the law, need further discussion and clarification.