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

Following local anesthetic use, maternal and umbilical serum levels of lidocaine were determined at delivery by means of a gas-chromatography-mass-spectrometry technique in 13 cases. In six cases, where delivery was performed by cesarean section, lidocaine was used for epidural analgesia. The dose given averaged 4.0 +/- 1.7 mg/kg, and the time between analgesia and delivery was 22.0 +/- 4.5 minutes. The mean umbilical serum level of lidocaine was 1.19 +/- 0.79 micrograms/ml and that of the maternal serum was 2.18 +/- 1.25 micrograms/ml. The fetal to maternal ratio was 0.52 +/- 0.18. Lidocaine levels of neonatal plasma were followed at 3, 6, 12, and 24 hours after delivery, and the mean half-life was found to be 6.7 +/- 1.3 hours. In the other seven cases, lidocaine was given in normal vaginal delivery for pudendal nerve block, and the dose was as small as 0.79 +/- 0.06 mg/kg. The mean umbilical and maternal serum concentrations of lidocaine were 0.064 +/- 0.039 micrograms/ml and 0.143 +/- 0.071 micrograms/ml, respectively, and the ratio was 0.45 +/- 0.16. Lidocaine given to the mothers crossed to the fetuses readily and resulted in neonatal plasma levels that were half those of the mothers'. The elimination of lidocaine from the newborn after birth was prolonged so that it might prevent the adaptation of the infant to postnatal circumstances. Viewed from the standpoint of infant care, anesthetics at delivery should be given to the mother only when the benefit obtained by their use outweighs any possible disadvantages.

We recently encountered a male newborn with ambiguous genitalia who had been exposed to the anticonvulsant phenytoin in utero. In an attempt to investigate a possible teratogenic connection between phenytoin exposure and genital anomalies, the effect of phenytoin on the conversion of testosterone to dihydrotestosterone by human skin slices was studied. Neonatal foreskins obtained at circumcision were incubated for two hours with testosterone-4-14C and various concentrations of phenytoin. The incubation mixture was then assayed for testosterone, dihydrotestosterone, androstanedione, androstenedione, androstanediol, and androsterone using thin-layer chromatography and liquid scintillation spectrometry. The amounts of testosterone metabolites formed with phenytoin added were compared to values obtained under control conditions without phenytoin. There was a significant decrease in the amounts of 5 alpha reduced metabolites formed with increasing amounts of phenytoin added. Implications for male phenotypic sexual differentiation of the fetus exposed to phenytoin in utero are discussed.

Two groups of pregnant Wistar rats were constituted, one treated with Furosemide IP and one with saline. The drug was given on days 7-11 and 14-18 of the pregnancy. Litters from the two groups were not different in number of pups, body weight, and/or kidney weight, but exposed in-utero neonates, studied shortly after birth, exhibited a significant lower number of differentiated glomeruli than those of the control group. As well as the difficulty of explaining this phenomenon, this condition raises the problem of a possible compensation by the postnatal nephrogenesis, which is important in the rat, and leads to the question of what will be the total amount of nephrons for the adult life in species with or without complete in utero nephrogenesis.

Tolazoline has often been administered experimentally to lambs without consideration of its pharmacokinetics. We have used a chemically specific assay to determine tolazoline pharmacokinetic parameters in lambs after pulse and infusion doses: alpha = 0.184 +/- 0.046 (min-1), beta = 0.010 (pulse) and 0.0098 (infusion) +/- 0.0010 (min-1), Vdarea = 2534 +/- 688 ml/kg (pulse), and Vdss = 2890 +/- 342 ml/kg (infusion). The following doses can be used to reach steady-state plasma tolazoline concentrations: loading dose (microgram/kg) = 2890 X desired concentration (microgram/ml); infusion rate (microgram/kg X min) = 2890 (.010) X desired concentration (microgram/ml). These doses were used to produce 68 steady-state concentrations from 0.25 to 10.0 micrograms/ml. Clearances at steady state averaged 166 ml/min or 27.1 ml/min X kg at 2-17 days but increased markedly by 4 weeks of age. Using these doses, tolazoline-receptor interactions can be studied at constant plasma concentrations that approximate constant receptor concentrations.

Acute toxicity from ingestion of isoniazid (INH) is manifested by coma and seizures unresponsive to conventional therapy. Though small doses of pyridoxine can reverse the seizure activity of acute isoniazid toxicity, large doses of pyridoxine (B6) are needed to completely reverse the symptoms. A case report is presented demonstrating the need for large doses of pyridoxine to reverse the symptoms of isoniazid intoxication and the literature of isoniazid toxicity in the pediatric age group is reviewed.

It has been well documented that the lungs are able to remove or metabolize several vasoactive substances passing through the pulmonary circulation. One such function, the conversion of angiotensin I to angiotensin II and hydrolysis of bradykinin to inactive peptide fragments is performed by angiotensin-converting enzyme (ACE). Although a precise role of these functions for systemic vasoregulation has not been defined, measurement of pulmonary metabolic capacity has the potential for providing substantial information about the integrity and physiology of the pulmonary microcirculation. Studies are described using 3H-benzoyl-phenylalanyl-alanyl-proline (a synthetic substrate for pulmonary ACE) in developing conscious lambs and older sheep. Outflow curves from indicator dilution measurements contain information regarding apparent kinetics of ACE activity. Using a nonlinear model for saturable pulmonary metabolic functions, the derived data demonstrate a) a marked increase in Vmax, the apparent maximal velocity of ACE, with age; and b) no significant change with age in apparent Km, the concentration at which the velocity of ACE is one-half Vmax. This approach has the potential for providing a biochemical tool for examining postnatal growth of the pulmonary microcirculation as well as functional integrity of the pulmonary endothelium during a variety of conditions.

Tolazoline was infused intravenously (2 mg/kg over 2 minutes) in awake neonatal and mature calves. In normoxic pulmonary normotensive neonatal calves, tolazoline induced minimal hemodynamic changes, except for an immediate bradycardia. Tolazoline caused increases in systemic arterial pressure and vascular resistance and a bradycardia in normoxic normotensive mature calves. Calves were also made hypoxic, by breathing 12% O2 by facemask, in order to produce pulmonary hypertension. In hypoxic pulmonary hypertensive neonatal calves, tolazoline induced transient pulmonary vasodilation, a reduction in systemic arterial pressure, and marked bradycardia. Similarly, tolazoline caused reductions in pulmonary and systemic arterial pressure and bradycardia in hypoxic pulmonary hypertensive mature calves. Pentobarbital anesthesia in neonatal calves induced marked hemodynamic changes but did not alter the cardiovascular responses to tolazoline. A significant correlation was found between the baseline pulmonary arterial pressure and the magnitude of the pulmonary depressor response to tolazoline when all interventions were evaluated. Thus, tolazoline induced transient pulmonary vasodilation in pulmonary hypertensive calves but simultaneously caused profound transient bradycardia, particularly in neonatal calves.

Oocyte and follicle destruction produced by cyclophosphamide was investigated in Sprague-Dawley (SD) rats, and inbred C57BL/6N (B6) and DBA/2N (D2) mice. Primordial oocytes were the most sensitive to destruction after intraperitoneal treatment with cyclophosphamide. A delayed decrease in the number of medium-sized follicles occurred between 1 and 2 weeks after treatment. No reduction in the number of large follicles was observed over the 3-week period of this experiment. Primordial oocyte destruction produced by cyclophosphamide occurred in a time-, dose-, strain-, and species-dependent fashion. The threshold for primordial oocyte/follicle destruction in B6 and D2 mice, and SD rats was less than 10, 40, and greater than 500 mg/kg, respectively. ED50S for primordial oocyte/follicle destruction were 49 and 137 mg/kg in B6 and D2 mice, respectively. The ED50 for oocyte destruction was greater than 500 mg/kg in SD rats. Primordial oocyte destruction occurred rapidly and was completed between 48 and 72 hours after treatment with cyclophosphamide in both murine strains. Oocyte destruction and premature ovarian failure is a significant side effect in women treated with alkylating agents. The rodent ovotoxicity model used in these experiments may be useful in elucidating mechanisms of ovotoxicity and evaluating treatment protocols designed to protect the ovary.

Plasma concentrations of imipramine and three of its metabolites were determined in children 6 to 15 years of age who received imipramine for treatment of nocturnal enuresis. In 14 patients with reliable data the reduction in wet nights after beginning drug therapy had no apparent relationship to either imipramine concentration alone or imipramine combined with its metabolites. This finding may be related to the relatively low drug concentrations in this group of patients, a high placebo response rate, or noncompliance with the prescribed dosage regimen. Determining plasma imipramine concentrations during treatment for enuresis has questionable value as an aid to improve clinical response. This practice may occasionally be justified when avoidance of toxicity is a major concern.