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

In vitro challenge of peripheral white blood cells (WBC) from 15 food sensitive individuals and 16 asymptomatic controls was studied in allergic autocytotoxicity (ACT) assay using extracts of cow's milk, corn, and wheat. The observed disintegration of the WBC in the direct and antibody-dependent ACT was inhibited by ketotifen in a linear, dose-dependent manner. Therefore, our data demonstrate that the ACT response is associated with anaphylactic injury which is prevented by pretreatment with ketotifen, in vitro.

Prepuberal female mice were treated with estradiol benzoate (EB), testosterone (T), or phenobarbital (PB), or were untreated. At 8 days after treatment treated mice had lower uterine weights than did untreated mice. Mice treated with EB and PB also had higher levels of hepatic cytochrome P450 at this time. The uteri of mice treated with EB, T, or PB were capable of responding to exogenous EB 8 days following the treatment with an increase in weight. In a second experiment mice were treated with a range of doses of EB, T, or PB,. At the lower doses there was an inverse association of uterine weight and cytochrome P450 levels. At higher doses there was no apparent association. These data indicate that uterine weight may be influenced in part by prior treatment that also affects the level of liver enzymes.

Meperidine hydrochloride (MHCl) is one of the most widely used analgesics today. Its effect upon maternal and fetal sheep hemodynamics and acid base were investigated in 13 experiments following maternal IV administration of 100 mg (approximately 2 mg/kg) of the drug. Blood samples were taken at baseline and at 7.5, 15, 30, 45, 60, 75, 90, and 120 minutes postinfusion. Significant changes were an increase in maternal pH at 45 minutes, P less than 0.01 and 120 minutes, P less than .01 accompanied by a decrease in pCO2 at 45 minutes, P less than .01. No changes in maternal pO2, O2 saturation (O2%), base excess (BE), hemoglobin (Hb), heart rate (HR), blood pressure (BP), and uterine blood flow (ut. BF) were noted. Fetal PH, pO2, pCO2, O2%, bicarbonate, BE, Hb, HR, and BP remained unchanged. It is suggested that MHCl causes transient maternal respiratory alkalosis without any significant changes in uterine blood flow. With the dose used in this study, no adverse effect was observed in the fetus. Therefore, based upon this study, MHCl seems to be tolerated well by both ewe and her fetus.

Cord blood lymphocytes were isolated from 40 normal newborns. The initial 20 samples were used to determine the dose-response curve of bovine thymic extract (Thymostimulin) by the measurement of active T cells. Results showed that the active T cells increased significantly when the Thymostimulin concentration was increased to 50 ng/ml and 100 ng/ml. The remaining 20 samples were divided into three portions and preincubated either with 50 ng and 100 ng of Thymostimulin or without Thymostimulin. The total T cells, active T cells, B cells, T-cell subsets, and lymphoproliferative responses to phytohemagglutinin, concanavalin A, and pokeweed mitogen were determined. The results showed that the active T cells, total T cells, B cells, OKT4 cells, and OKT8 cells were significantly increased after Thymostimulin treatment. The lymphoproliferative responses were also significantly increased. These data strongly support our conclusion that Thymostimulin has a marked stimulating effect on human lymphocyte proliferation and differentiation.

In vivo phenytoin (PHT) and its metabolites are present in the fetal plasma. In order to determine the transfer kinetics and biotransformation characteristics for phenytoin in the human placenta, a dual recirculating perfused human placental lobule preparation was utilized. A single bolus of 14C-PHT with or without tritiated water (3H2O) was injected into the maternal reservoir. Peak concentrations of 3H2O and PHT appeared simultaneously in the maternal artery at 4 minutes and in the maternal vein at 9 minutes, whereas the peak concentrations of 14C-PHT and 3H2O in the fetal vein were at 9 and 7 minutes, respectively. After 4 hours of perfusion, the total phenytoin concentration in the fetal perfusate was only 73% of the maternal perfusate level. Protein-bound PHT was 37 +/- 8% and 7 +/- 3% of the total phenytoin in the maternal and fetal perfusate. The concentrations of free phenytoin in the maternal and fetal compartments were identical by 60 minutes and were maintained for the remainder of the experiment. The concentration of total PHT in perfused placenta was more than 3.5 times greater than the total maternal perfusate levels. In the placenta, PHT concentration was highest in the cytosolic fraction, and 57% of the placental PHT was in the free form. There was no evidence of parahydroxylation, oxidation, or conjugation of PHT. Phenytoin was also concentrated in nonperfused placental tissue. Thus the transfer of PHT by the human placenta is rapid and dependent upon protein binding and flow in both maternal and fetal circulations. Even though the human placenta does concentrate PHT, it does not metabolize PHT under these conditions.

Phenytoin is one of the most commonly used anticonvulsants in pregnant epileptic women. Unrelatedly, the drug is also an inducer of hepatic drug metabolizing enzymes. We report here that maternal treatment with therapeutic-like doses for the rat of phenytoin produces significant elevations in the Michaelis constants and maximal velocities of hepatic aminopyrine N-demethylase in the dams' 8-day-old offspring. Although the drug apparently had little, if any, adverse effects on the course of pregnancy or neonatal development, it appears that the maternally administered phenytoin was transferred to the perinates where it induced hepatic drug metabolizing enzymes.

Digoxin tissue concentrations and elimination kinetics were determined to explore possible explanations of the age-related changes in response to digoxin in the rat. Digoxin concentrations were measured in brain, myocardium, and plasma of newborn and adult rats at serial time intervals after nontoxic doses and at the time of death after toxiequivalent doses. After SC administration of a nonlethal dose of 500 micrograms/kg digoxin, brain, myocardium and plasma concentrations and areas under the curve of digoxin concentrations vs time were considerably greater (P less than 0.01) in the newborn than in the adult rats. Following toxiequivalent doses of digoxin (2.5X LD50), digoxin concentrations were several fold greater in the myocardium and plasma of adult rats than in newborn specimens; in contrast, despite the 30-fold smaller digoxin dose per kilogram body weight given to 1-day-old rats, mean digoxin concentration was 2.9 times greater in their brain than in adult brain. These findings suggest that changes in tissue distribution and in the disposition of digoxin play a role in the greater sensitivity of newborn rats to digitoxicity and in the distinct digitoxic arrhythmic effects observed in the newborn as compared to the adult rat.

Vancomycin pharmacokinetics were studied in nine premature infants. Infants weighing less than 1,000 gm had significantly larger volumes of drug distribution and consequently longer drug half-lives than larger premature infants, regardless of postconceptual or actual age. These differences alter the vancomycin dosing recommendations in these two groups of premature infants. We recommend initial dosage regimens consisting of a loading dose of vancomycin of 25 mg/kg followed by doses of 15 mg/kg every 12 hours for infants with weights less than 1,000 gm. Infants weighing over 1,000 gm should receive 10 mg/kg every 12 hours, with a loading dose of 12.5 mg/kg. Serum vancomycin concentration should be monitored, however, for final optimization of therapy.

We studied the effects of nifedipine, a calcium-channel blocker, in two acutely instrumented groups of newborn lambs during normoxic and hypoxic conditions. Nifedipine at 10 or more micrograms/kg reduced systemic, but not pulmonary artery pressure and resistance in normoxic lambs. When acute hypoxia was produced in these animals, 50 or more micrograms/kg reduced, but did not prevent, the expected rise in pulmonary pressure and resistance. When infused into already hypoxic lambs, nifedipine in doses of 50 micrograms/kg or more reduced both systemic and pulmonary pressures and resistances equally. Thus, nifedipine is a nonspecific vasodilator in newborn lambs.

Gentamicin serum levels were measured and elimination half-life was calculated in a group of neonates with postconceptual ages ranging between 25-42 weeks. Infants were receiving intravenous gentamicin (2.5 mg/Kg/dose) at various dosage intervals and t 1/2e was calculated using a one-compartment open model. Evidence of gentamicin accumulation was present in 82% of infants 34 weeks. T 1/2e was 8.8 +/- .7 hours in infants 30 weeks, 7.8 +/- 1.1 hour in infants between 30-34 weeks and 6.2 +/- .5 in infants greater than 34 weeks. The results of the study suggest that gentamicin elimination is related to postconceptual age and that infants treated with recommended dosage regimens may have possible gentamicin tissue accumulation and nephrotoxicity. Therefore, the dosage interval may have to be lengthened to 18 hours in infants less than 34 weeks with close gentamicin plasma level monitoring.