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 most attractive "adrenergic theory" has proposed that in asthmatic patients the bronchial hyperreactivity might be caused by a decreased beta-receptor and an increased alpha-receptor responsiveness. Based upon the assumption that an abnormality of adrenergic receptors might be a general phenomenon, we have performed receptor-binding studies on lymphocytes and thrombocytes from asthmatic children who had and had not undergone treatment with beta-receptor agonists and/or glucocorticoids. Iodo-cyano-pindolol and tritium-labeled yohimbine were used as beta- and alpha-receptor ligands. The following results have been obtained: 1) The number and affinity of alpha- and beta-adrenoceptors on thrombocytes and lymphocytes showed no significant differences in asthmatic children and their age-matched controls. 2) In vivo treatment of asthmatic children with beta-receptor agonists immediately reduced the number of beta-receptors ("down regulation"). A reversal of the number of beta-receptors occurred within 1 day after cessation of the therapy. Although it appeared that some asthmatics with severe asthma have a reduced number of beta-receptors, in vivo treatment with beta-receptor agonists thus might mimic a beta-receptor blockade. 3) High-dose treatment with glucocorticoids increased the number of beta-receptors but left the alpha-receptors unaffected.

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.

Six lamb fetuses at 63-101 days gestation had thyroidectomy (Thx) and were investigated at term for weights, radiologic study, serum thyroxine (T4), and thyroid-stimulating hormone concentrations (TSH), electron-microscopic lung examination, acid base, blood flow, EEG, and brain metabolism. Compared to age-matched controls, body weight was significantly reduced (P less than .025). Brain and lung weights were reduced but not significantly. Brain weight as a percent of body weight was significantly increased in Thx fetuses (Thx = 1.85% +/- 0.18; control = 1.41% +/- 0.08; P less than .025). Hemoglobin was reduced (P less than .025), as was O2 content (P less than .005) and cerebral blood flow (P less than .05). Fetal T4 was low (Thx = 4.1 +/- 1.7 microgram %, control = 9.4 +/- 1.3 microgram %); (P less than .05). Fetal Thx cortisol, calcium, phosphate, glucose, lactate, pH, pO2, pCO2, O2 saturation, heart rate, and blood pressure remained unchanged. Thx-fetal brain O2 consumption and glucose consumption, as well as lactate production, were unchanged. EEG showed no consistent pattern of change regarding maturity, but did show immaturity with the two lowest T4 levels. Bone microradiographs showed growth and maturity retardation, specifically delayed epiphyseal closure, endochrondral ossification, and lack of secondary ossification centers in Thx fetuses. Electron-microscopic examination of lung showed Thx fetuses had fewer lamellar bodies in type II cells, fewer type II cells, and more glycogen granules. Thx causes fetal reduction of T4 and anemia, delays lung maturation and bone growth and maturation.(ABSTRACT TRUNCATED AT 250 WORDS)