Developmental pharmacology and therapeutics最新文献

Twenty newly diagnosed growth hormone-deficient children (19 males) were randomized to receive methionyl growth hormone (0.3 mg/kg/week) in subcutaneous doses divided daily (n = 12) or 3 times per week (TIW). With the initial dose and at 4-6 weeks after beginning therapy, procollagen type III propeptide (PIIIP) concentrations were determined. Growth velocities were calculated before and at 1, 3, and 6 months after beginning the therapy. Pretreatment growth velocities were 3.66 +/- (SD) 1.45 and 3.79 +/- 0.55 cm/year for the daily and TIW groups, respectively. At 1, 3, and 6 months mean growth velocities increased to 17.2, 10.2, and 9.5 cm/year for the daily group and 9.8, 6.8, and 7.6 cm/year for the TIW group, with differences between groups significant (p < 0.05) at 1 and 3 months. PIIIP concentrations increased significantly (p < 0.05) over 1 month in both groups, from 11.3 to 18.8 ng/ml and from 10.0 to 12.0 ng/ml in the daily and TIW groups, respectively. In addition PIIIP concentrations were significantly higher (p < 0.05) in the daily group at 1 month. A significant correlation was found between PIIIP concentrations at 1 month and the growth velocity at 1 (r = 0.47), 3 (r = 0.60), and 6 (r = 0.67) months. Pretreatment growth velocity was weakly correlated with posttreatment growth velocity at both 1 (r = -0.45) and 3 (r = -0.42) months. We conclude that (1) growth hormone is more effective when administered daily, (2) pretreatment growth velocity and PIIIP plasma concentration at 1 month correlate with 1 month growth velocity, and (3) PIIIP at 1 month provides a good evaluation of 6 months' response to methionyl growth hormone therapy.

The single-dose pharmacokinetics of dexamethasone were studied in 7 extremely low birth weight infants of mean (+/- SD) gestational age 25.6 +/- 0.5 weeks suffering bronchopulmonary dysplasia. A mean peak dexamethasone concentration of 250.5 +/- 70.7 ng/ml was obtained following an intravenous bolus dose (0.369 +/- 0.04 mg/kg dexamethasone) of dexamethasone sodium phosphate. Dexamethasone was measured in plasma by HPLC. Mean clearance (0.143 +/- 0.028 litres/kg/h) was approximately half that reported previously in children and adults, while the half-life (9.26 +/- 3.34 h) was 2- to 3-fold longer than in these patients. The volume of distribution (1.9 +/- 0.483 litres/kg) was larger than reported in a previous study in adults, but was similar to that determined in pediatric and adult patients in another study.

Neonates, especially preterms, are known to have low glomerular filtration rates (GFR). This may result in elevated trough concentrations during multiple administration of aminoglycosides (AGs), potentially leading to nephro- and ototoxic reactions. The once-daily administration (q.d.) of AGs has been shown to be equally or better tolerated in adults and children than the conventional schedules (twice daily, b.i.d.; thrice daily, t.i.d.), while offering potential pharmacodynamic and nursing advantages. No data, however, are available for neonates. As a consequence, this pilot study was conducted in order to assess the tolerance of the once-a-day administration of amikacin in comparison with the twice daily dose regimen, in relation to the pharmacokinetics of the drug under these two schedules. 22 Male neonates (gestational age > or = 34 weeks; postnatal age < or = 2 days) were randomized to receive amikacin (AK) (15 mg/kg/day) q.d. (n = 10) or b.i.d. (n = 12) together with ampicillin (50 mg/kg/12 h). AK plasma levels were measured at days 1, 3, 5 and 7 of treatment just before the next dose (trough level) and 1 h after completion of infusion (peak level) and after 3 and 6 h only at day 1. Due to the small size of the samples, no difference in efficacy could be assessed and was not the aim per se. Glomerular dysfunction was assessed by creatinine clearance, and tubular injuries by the urinary excretion of proteins (retinol binding protein, beta 2-microglobulin, clara cell protein (P1) and microalbumin), enzymes (N-acetyl-beta-D-glucosaminidase, alkaline phosphatase, alanine aminopeptidase, and gamma-glutamyltransferase), and total phospholipids (TPL) in urine. Ototoxicity was assessed by brainstem auditory evoked potentials (BAEPs) at days 0, 3 and 9 of therapy. Eight healthy neonates served as controls. All patients showed a normal and similar increase of GFR during the first postnatal days. Proteinuria did not increase, but enzymuria and TPL increased significantly during the treatment in both AK groups without significant difference between groups. BAEPs at day 9 were not significantly different between treated and untreated patients. We conclude from this pilot study that, in the absence of more toxicity, the q.d. administration of AK in neonates of > or = 34 weeks of gestational age may be recommended over its bid schedule in view of its potential advantages.

In order to evaluate parental awareness of the law governing clinical trials in France (Loi Huriet), a study was performed by questionnaire between February and April 1991 in a maternity unit during the days following delivery. The response rate was 59%. 59% of the parents (319/541) were informed of the existence of the law by the media (75%) or their general practitioners (12%). Twenty-one percent (116/541) of the parents would accept the participation of their children in a clinical trial and 74% would refuse. The principal reasons for acceptance were: for the benefit of other children, contribution to medical progress and confidence in physicians. The reasons for refusal were: risk of side effects and unproven efficacy. Parents who would accept had more often received higher education (44%) than parents who would refuse (30%), the latter being less influenced by the explanations of physicians and less willing to accept that a physician should decide for them. Physicians should consider transmitting information directly to parents and indirectly via the media.

The effect of repeated doses of indomethacin on mean peak velocity (MPV) and time-averaged mean velocity in the middle cerebral artery was assessed in 10 ventilated neonates with a patent ductus arteriosus using colour/duplex Doppler technique prior to, and 10, 30, and 120 min after the first and the third dose. Velocities were significantly reduced up to 120 min after the first dose. The third dose resulted in a significant reduction in MPV at 10 and 30 min following treatment. This reduction was half of that observed after the first dose. Systemic blood pressure (BP) and heart rate did not change significantly after each separate dose. However, by the third dose, mean and diastolic BP were significantly increased from pretreatment levels. The attenuated response of cerebral blood flow (CBF) velocities to the third dose of indomethacin compared with the first dose is probably related to altered haemodynamics. Indomethacin should be used cautiously in infants with other conditions which are known to decrease CBF such as hypotension, hypocarbia and polycythaemia.

The P-450-associated O-dealkylase activity towards ethoxyresorufin (EROD) and pentoxyresorufin (PROD) was measured in liver microsomes from 1-day-, 1-week-, 4-week-, 6-week-old and adult goats in order to characterize the ontogeny of cytochrome P-450 in this species. The inhibition of these enzyme activities by monoclonal antibodies raised against 3-methyl-cholanthrene-induced (MAb 1-7-1) and phenobarbital-induced (MAb 2-66-3) rat hepatic cytochrome P-450 was used to measure the contribution of the MAb-defined, epitope-specific P-450 to the total activities during these ages of goat development. EROD activity was undetectable until the 1st week of life and increased more than 25-fold by 4 weeks of age. The inhibition of EROD by MAb 1-7-1 increased from 20% in 1-week-old to 70% in adult goats. PROD activity, however, was detectable in the 1-day-old and reached adult levels by 6 weeks of age. The maximal inhibition (40%) of PROD activity by MAb 2-66-3 was demonstrated in 1-day-old goats. The measurement of these enzyme activities and their inhibition by the monoclonal antibodies demonstrated major differences in the ontogeny of these P-450 isozymes in goats. On the other hand, adult goat lung lacked detectable PROD activity, while it expressed approximately one tenth of the EROD activity exhibited by the liver. Over 70% of this activity was inhibitable by MAb 1-7-1.

The chronic effects of short-term administration of a high salt diet to postweaning rats on blood pressure (BP) was studied. BP was significantly elevated following 4 weeks of treatment. After stopping the high salt diet, BP dropped to control levels but then progressively rose again to hypertensive levels. A significant increase in arterial medial thickness as well as an increase in contractile sensitivity and a decrease in relaxation responsiveness were observed in aortic smooth muscle. These data show that short-term administration of a high salt diet to normal postweaning rats results in a chronic elevation in BP accompanied by significant alterations in vascular structure and function.

Developmental exposure to cocaine can produce adverse neurobehavioral and cardiovascular effects. Few animal models of human neonatal exposure have been established. A pharmacokinetic study was therefore conducted to characterize the disposition of cocaine and a major metabolite benzoylecgonine (BE) using piglets as an animal model. Eight piglets (postnatal days 8-9) were instrumented with a jugular cannula for drug administration and blood sampling. One group of subjects (controls) received 6.0 mg/kg of cocaine-HCl (i.v.) and blood samples were drawn over 0-24 h. In another group (labetalol), 0.25 mg/kg labetalol-HCl was coadministered 15 min following cocaine dosing. Plasma levels of cocaine and BE were determined using GC-MS methods. Pharmacokinetics were evaluated by using a model-independent approach and compartmental modeling. For controls model-independent results were as follows: AUC = 148.9 +/- 9.0 mg/l x min, systemic clearance = 0.041 +/- 0.003 liters/min/kg, volume of distribution = 1.543 +/- 0.470 liters/kg, and t1/2 beta = 29.4 +/- 6.8 min. Cocaine followed two-compartment model kinetics with distribution and elimination half-lives of 0.3 +/- 0.1 and 58.0 +/- 18.0 min, respectively. Labetalol significantly decreased systemic clearance to 0.029 +/- 0.004 liters/min/kg. BE kinetics revealed a elimination half-life of 230.0 +/- 83.2 min. The results demonstrate a rapid distribution and metabolism of cocaine to BE followed by a prolonged elimination phase which is extended by labetalol treatment.

Developmental differences in adrenergic responsiveness may cause age-related changes in the cellular response to ischemia. Standard microelectrode techniques were used in isolated young and adult canine Purkinje fibers to determine the effect of simulated ischemia ([K+]o = 10 mM, pH 6.7, pO2 < 25 mm Hg) alone or with adrenergic stimulation on the rhythmic activity in spontaneously beating Purkinje fibers and on transmembrane potentials and delayed afterdepolarizations in paced Purkinje fibers (basic cycle length = 800-300 ms). The adrenergic agonists used were phenylephrine (5 x 10(-8) M) and isoproterenol (1 x 10(-6) M). For all automatic fibers studied, the control maximum diastolic potential in adults (-96 +/- 1 mV, n = 37) and in the young (-98 +/- 1 mV, n = 36) went to -62 +/- 1 mV during ischemia in both groups and returned to -96 +/- 2 mV with reperfusion. The incidence of rhythmic activity (expressed as percent) during ischemia alone was similar at both ages: adults, 22%; young, 25%. The incidence of ectopic activity with phenylephrine superfusion during ischemia for adults was 63%, an effect blocked by prazosin (1 x 10(-6) M) but not by propranolol (2 x 10(-7) M); the incidence for the young was 25%. Isoproterenol caused ectopic rhythms in 86% of young fibers and 17% of adult fibers (p < 0.05 young vs. adult). During reperfusion the return to control rhythm was slower in adults after ischemia alone or ischemia + alpha-adrenergic stimulation with phenylephrine. There were no age-related differences in the transmembrane potential response of paced fibers to ischemia or reperfusion, and there were no delayed afterdepolarizations with interruption of pacing at 800, 500, or 300 ms in either group. These data suggest that age-related differences in adrenergic responses alter the cellular response to an ischemic insult. To the extent that an ectopic beat may initiate an abnormal rhythm, these differences in sensitivity to adrenergic agonists may lead to developmental differences in arrhythmogenic potential during ischemia.