Developmental pharmacology and therapeutics最新文献

Fourteen renal transplant and one heart transplant mothers receiving cyclosporin (mean dosage: 273 +/- 19 mg/day) underwent a Caesarean section at a mean gestational age of 34.1 +/- 1.9 weeks. Circulating cyclosporin was assayed by HPLC. The mean blood levels in the mothers before the Caesarean section were 210 +/- 16 ng/ml, in cord blood 62 +/- 16 ng/ml (14 infants) and in the peripheral blood within 6 h of birth 31 +/- 12 ng/ml (15 infants); there was no correlation between maternal and cord levels, nor between peripheral blood levels at 2 h and cord blood levels. Cyclosporin levels were undetectable at day 3 in 12 infants, but low levels were found in 1 infant up to day 12. There was no toxic effect on the fetus or neonate.

This study retrospectively characterized population-based pharmacokinetic parameters for gentamicin in neonates and young infants, and evaluated the predictive performance of these parameters in a Bayesian forecasting program. Population parameter estimates were determined from the serum concentration-time data of 19 neonates and infants using a one-compartment open infusion model and nonlinear least-squares regression analysis. Univariate and multiple stepwise linear regression analyses were used to determine significant relationships between demographic characteristics and gentamicin pharmacokinetic parameters. Creatinine clearance and postnatal age were the most significant predictors of weight-standardized gentamicin clearance (model r2 = 0.86). The relationships between patient characteristics and population-based parameters were incorporated into the one-compartment Bayesian forecasting model. A second group of 17 neonates and infants receiving 35 courses of gentamicin therapy were used to evaluate the predictive performance of the population-based parameters and a Bayesian forecasting model. The population parameters provided accurate prediction of steady state gentamicin concentrations throughout multiple courses of therapy within the same patient. Bayesian forecasting further minimized the mean prediction error (bias) once a set of steady state peak and trough serum gentamicin concentrations became available (peak concentrations: -0.062 vs. -0.273 mg/l; trough concentrations: -0.006 vs. -0.161 mg/l). The mean absolute error (accuracy) was similar for the two sets of parameters. The observed accuracy of both the population parameters and Bayesian forecasting suggests that monitoring of serum gentamicin concentrations can be kept to minimum in neonates and infants.

Antral hyperplasia (AH) induced by prostaglandins (PG) has been described by us recently in 5 infants with cyanotic heart disease receiving the drug. The purpose of the present study was to analyze 14 infants diagnosed as having AH either sonographically or pathologically in an attempt to characterize the dose-response characteristics of this adverse drug reaction, its clinical course and its optimal management. Infants with AH exhibiting large gastric aspirates have received a significantly lower cumulative dose (1,633 +/- 1,266 micrograms/kg) than those presented also with a palpable mass (3,458 +/- 1,703 micrograms/kg), (p < 0.01). While in general there is a dose-related clinical toxicity, variability in the location of the hyperplasia can explain cases of no apparent obstruction despite large cumulative doses of PG. In asymptomatic cases the antral hyperplasia, although visualized, it did not result in gastric outlet obstruction. In all cases followed by us to date, discontinuation of the PG has resulted in resolution of the clinical and sonographic findings. Nasojejunal tube was successfully attempted in several cases, preventing surgery in these very-high-risk infants.

The development of the motor component of the embryonic and fetal central nervous system can be studied by observation of fetal movements, using real-time ultrasound. In this paper data on emergence and development of fetal movement patterns and behavioural states are reviewed in the light of the normal development of the nervous system, identification of disturbances in normal development and testing behavioural teratogenicity in the human.

Prenatal exposure to benzodiazepines (BDZ) can cause behavioral dysfunctions both in humans and in experimental animals. In addition, prolonged impairment of cellular immune functions is found in rats after low dose BDZ exposure (e.g., diazepam 1.25 mg/kg/day) during part of fetal life [gestational days (GD) 14-20]. Analysis of diazepam and its metabolites in maternal and fetal tissues revealed that in this rat model the drug is no longer present at birth, which excludes direct effects of diazepam during the postnatal period. The main target of BDZ in brain, the GABAA receptor complex, is structurally and functionally heterogeneous. Besides alpha- and beta-subunits, gamma 2- or gamma 3-subunit should be coexpressed for a fully functional BDZ response. Signals of mRNAs encoding for alpha 1, beta 2 and gamma 2 are detected in fetal rat spinal cord and lower brainstem by GD 14 and reach telencephalic regions in later fetal life, reminiscent of BDZ receptor ontogeny. Regional subunit distribution differs from the adult brain, one interesting feature being a preponderance of gamma 2 mRNA throughout fetal life. Since subunit composition influences the sensitivity to BDZ, these data suggest that prenatal effects of BDZ depend upon regional subunit compositions present at different developmental stages. The delayed depression of cellular immune responses in prenatally BDZ-exposed rat offspring during the first 2 postnatal months is accompanied by various changes in immune cell biology. Binding characteristics of the peripheral (omega 3) type BDZ receptor are altered until adulthood (8 weeks). Membranes of spleen cell preparations containing mainly lymphocytes exhibit a decrease of affinity for the peripheral ligand [3H]PK11195, splenic macrophage preparations a decrease of maximal binding capacity. Various defects in cytokine production by macrophages and T lymphocytes were observed: Mitogen-stimulated release of macrophage-derived tumor necrosis factor-alpha (TNF-alpha) and of the T cell-derived interleukin-2 (IL-2) was drastically reduced at 2 and 4 weeks of life and recovered in young adulthood, exhibiting the same time course of depression as lymphocyte proliferation in response to immune stimuli. Interleukin-6 (IL-6) release remained diminished until adulthood. In female offspring, additional alterations were found in splenic noradrenaline turnover after immune stimulation. The mechanisms underlying the breakdown of the cytokine network in prenatally diazepam-exposed offspring, and the long-term consequences are as yet unknown.

Pregnant rats received propranolol (5 or 10 mg/kg/day) from day 10 of gestation; controls were untreated. Lung wet:dry weight ratios were increased in treated fetuses delivered by hysterotomy at day 21; no difference was seen at birth after vaginal delivery. On subsequent days, treated pups exhibited higher wet:dry weight ratios, implying impaired postnatal lung water clearance. Surfactant pools were decreased proportionately at both doses. Ongoing surfactant synthesis was unaffected at either dose. Baseline secretion was reduced for those exposed to 10 mg/kg/day. Secretory response to beta-agonist stimulation was impaired in both treatment groups. Chronic beta-blockade alters fetal lung water clearance, surfactant stores, and secretory response to beta-agonists.

We have determined the magnitude and sites of action of pentoxifylline (PTX), a methylxanthine derivative, in the adult and 3- to 4-week old ferret pulmonary circulation. Lungs of 8 ferrets, four 3- to 4-week-old and 4 adult, were isolated and perfused with blood. During perfusion, blood flow was kept constant, as were airway and left atrial pressures (6 and 8 cm H2O respectively, zone 3 conditions). In all lungs, pulmonary artery pressure was measured continuously and the circulation was partitioned into arteries, microvessels and veins, by measurement of pressures in 20-50 microns diameter subpleural arterioles and venules using the micropipette-servonulling method. Pressures were obtained in each lung during baseline, after vasoconstriction with hypoxia, and again after the infusion of PTX, 20 mg/kg, during hypoxia. We found that with hypoxia, total vascular resistance increased by approximately 90% in both adult and neonatal lungs; arterial and venous resistances increased by 100-180% in both age groups, with little change in microvascular resistance. PTX resulted in a significant decrease in total vascular resistance, due to a decrease in resistance in both arteries and veins. The decrease in resistance with PTX was greater in adult lungs (of the increase in resistance induced by hypoxia, 80% was eliminated by PTX) than in 3- to 4-week old lungs (51% elimination of tone induced by hypoxia). This difference was mainly due to a smaller reduction in arterial resistance with PTX in 3- to 4-week-old lungs. We conclude that PTX is a powerful pulmonary vasodilator in ferrets and that its effectiveness as a vasodilator depends on the age of the animal, the older animal showing greater responsiveness.

Placental transport of dioxins and furans from mother to fetus takes place. It is probably related to the fatty acid transport. Between 10 and 20% of fatty acids in a full-term baby are of maternal origin. In adipose tissue of children that died in the early neonatal period concentrations of +/- 25% were found of three dioxin and furan congeners 12378 P5CDD, 123678 H6CDD, and 23478 P5CDF in relation to a mean concentration of these congeners in the fat of 14 breastmilk samples. Data of concentrations are given as measured in liver and adipose tissue. In the placenta of a Dutch woman an accumulation of dioxins and furans is found in relation to blood. Animal studies support the hypothesis that polychlorobifenyls play a role in the cause of the late hemorrhagic disease in the newborn, in particular the 2, 4, 5, 2, 4, 5-hexachlorobifenyl that is present in relatively high concentrations in breastmilk.

We examined the effect of the alpha 1-adrenergic antagonist prazosin on blood pressure, left ventricular output and blood flow redistribution during normoxemia and mild hypoxemia in the chronically instrumented, unanesthetized newborn piglet employing the radiolabeled microsphere technique. Prior to prazosin, hypoxemia caused increases in aortic pressure and blood flows to the brain, myocardium and diaphragm, accomplished by small, statistically insignificant decreases in flows to the carcass and viscera without an increase in cardiac index. Prazosin treatment during normoxemia caused a fall in blood pressure and resulted in greater blood flows of left ventricular origin to the carcass, myocardium and lung. Hypoxemia after prazosin administration increased not only aortic pressure and blood flows to the brain, myocardium and diaphragm, but also, unlike the situation before drug treatment, cardiac index. Thus, in the newborn piglet, the maintenance of critical organ oxygen delivery during hypoxemia is not blocked by prazosin, but is accomplished by an increase in cardiac index rather than simply by redistribution of blood flow.