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

Some of the difficulties inherent in studies of pulmonary vasoactivity are reviewed. We have outlined the various experimental approaches used to evaluate the effect of pharmacologic and other interventions on the pulmonary vascular bed, and have described the advantages and limitations of these techniques.

The pharmacokinetics of trimethoprim-sulphamethoxazole was examined in seven malnourished (marasmic) infants receiving cotrimoxazole (CMZ) for treatment of urinary tract infection. Comparisons were made with the SMZ level of ten nutritionally normal infants, hospitalized for first and second degree burns, receiving CMZ for treatment of bronchitis. CMZ was administered as an oral suspension (20 mg TMP and 100 mg SMZ, 5 ml), patients receiving 22 mg SMZ/kg body weight. Capillary blood samples, 0.05 ml were taken at prescribed intervals. Elimination half-life of SMZ in the marasmic infants was prolonged, 9.6 vs 4.9 hr, in their eutrophic counterparts. In addition, greater area under the curve (AUC), 573 vs 328 micrograms/ml/h, was noted in the malnourished group. This disparity may be due to differences in body fluid distribution between the two groups.

The pharmacokinetics and metabolism of trimethoprim (TMP) was studied in newborn, 1 and 8-week-old piglets after intravenous administration of 5 mg/kg. Kinetic parameters were calculated using a two-compartment open model. Steady-state volume of distribution increased from 0.78 L/kg at birth to 1.32 L/kg at 1 week, and 1.83 L/kg at 8 weeks due to changes in plasma protein binding and tissue accumulation. Elimination half-life decreased from 485 minutes at birth to 224 minutes at 1 week, and 120 minutes at 8 weeks leading to a rise in body clearance from 1.18 to 11.8 ml/min/kg during the same period. Urinary excretion data indicated that the increase in body clearance reflects maturational changes in both metabolic capacity and renal function. Metabolism was the main contributor to the elimination of TMP at all ages, although the major metabolic pathway, O-demethylation and subsequent conjugation, was only slightly developed at birth. The capacity to form conjugates with either glucuronic acid or sulphate appeared to be at least as high as the capacity for O-demethylation since more than 90% of the metabolites were excreted as conjugates in all groups.

We used chronically instrumented, unanesthetized lambs to study the circulatory response to tolazoline and prostacyclin. During normoxia, tolazoline given in ten incremental doses from .01 to 6 mg/kg increased heart rate beginning at 1.1 mg/kg, cardiac output, and PVR/SVR. Systemic vascular resistance (SVR) fell, and pulmonary vascular resistance (PVR) did not change. Tolazoline given during hypoxemia, when basal PVR and heart rate were increased, caused SVR to fall at both 3.3 and 6.6 mg/kg doses, while PVR fell only at 6.6 mg/kg. During hypoxemia, even .01 mg/kg of tolazoline caused tachycardia, but cardiac output rose insignificantly, due to high variability. Prostacyclin given during normoxia caused SVR to fall without change in PVR. A significantly greater fall in SVR occurred when 6.6 micrograms/kg of PGI2 was the first dose given than when the same dose was given later in an incremental titration. Thus, neither drug is a selective pulmonary vasodilator in unanesthetized lambs. Dosing protocol may be important in determining the overall circulatory response to a given drug dose.

The N-acetylation of the reduced metabolite of clonazepam 7-amino-clonazepam was studied in cytosolic preparation from human fetal and adult livers. The metabolite formed 7-acetamido-clonazepam was measured with high performance liquid chromatography. A bimodal distribution of the N-acetyltransferase activities was observed in cytosols from human adult livers. These activities were 117 +/- 11 and 27 +/- 16 pmoles X mg-1 X min-1 for rapid and slow acetylators, respectively. The data observed in the fetal specimens did not allow any conclusion about bimodality because of a low number of samples.

Adverse renal reaction during prolonged indomethacin therapy (1 week) was studied in 15 preterm infants with persistent ductus arteriosus (PDA), which was associated with an ineffective circulatory volume. Following the medication a decrease in diuresis and creatinine clearances together with an increase in urinary osmolality and body weight was observed. Determinations of selected vasoactive hormones, such as plasma renin activity (PRA), antidiuretic hormone (ADH), and renal and systemic prostaglandins, indicated a complex pathophysiological condition of renal hypoperfusion and antidiuretic excess. During the treatment with indomethacin an effective circulatory volume had been restored by closing the ductus, which was followed by hormonal normalization. Subsequently kidney function was recovering despite continued indomethacin therapy. Based on these observations, one may assume that prolonged indomethacin therapy for prevention of PDA relapses is probably of no further harm to kidney function once the ductus has been closed successfully.

Ovarian reduced glutathione concentration (microgram/mg wet ovarian weight) develops from levels of less than 0.2 microgram/mg in newborn Osborn Mendel rats to plateau at 0.7 microgram/mg between the ages of 3-7 weeks of age, finally reaching mature levels of approximately 1.0 microgram/mg between 7-8 weeks of age. Ovarian reduced glutathione concentration matures somewhat faster in Sprague Dawley rats, reaching mature levels of 1.0 microgram/mg between 4-6 weeks of age. The development of ovarian glutathione from immature (less than 0.2 microgram/mg) to mature levels (1.0 microgram/mg) was also observed over similar developmental time spans in DBA/2N and C57BL/6N mice. The sensitivity of primordial oocytes to destruction by cyclophosphamide in C57BL/6N mice was considerably different at 4 and 6 weeks of age. The ED50 for primordial oocyte destruction at 4 weeks of age in C57BL/6N mice was 140 mg/kg while at 6 weeks of age the ED50 was 260 mg/kg. The increase in ovarian reduced glutathione with age and the increasing resistance to primordial oocyte destruction over the same time period are consistent with the hypothesis that glutathione plays a major role in the modulation of primordial oocyte destruction.

The effect of phenobarbital (PB) treatment on erythrocyte glucose-6-phosphate dehydrogenase (G-6-PD) levels was studied in normal and G-6-PD-deficient human newborns. An increase of erythrocyte G-6-PD levels was observed in normal G-6-PD patients, while increase in the enzymatic activity was not observed in G-6-PD-deficient neonates.

In preterm infants, persistent ductus arteriosus (PDA) fails to close soon after birth and becomes symptomatic (sPDA) in about 40% of the infants, causing cardio-respiratory deterioration by a left-to-right shunt across the PDA. Aortic run-off of blood, predominantly occurring during ventricular diastole, causes an abnormal diastolic retrograde aortic blood flow. This aortic reverse flow can be assessed semi-quantitatively in a noninvasive way, using continuous-wave Doppler-ultrasonography. An increased ratio (R/F ratio) of the abnormal retrograde aortic blood flow (R) related to the normal forward flow (F) in the aorta indicates presence of sPDA in preterm infants. The R/F ratio was assessed in 30 premature infants, including 13 cases without sPDA, and 17 infants with sPDA--in 12 of them before and after surgical ligation of PDA, in five concomitantly to pharmacological closure of PDA by the application of indomethacin. The R/F ratio was low in all infants without sPDA and in infants following surgical ligation of PDA. On the other hand, a high R/F ratio was found in all patients with sPDA before specific treatment. During indomethacin-induced closure of PDA the R/F ratio decreased continuously, whereas it remained high in infants with sPDA not responding to indomethacin treatment.

Epoxide formation from drugs, chemicals, food additives and environmental pollutants is catalyzed by cytochrome P-450 dependent monooxygenase(s). Epoxides are converted to glycols or dihydrodiols by epoxide hydrolase (EH). These enzymes are known to be present in the microsomes of different mammalian tissues and in the hepatic nuclei from rats and humans. The balance between the epoxide forming (AHH) and metabolizing (EH) enzyme activities may provide information about the "epoxide exposure" of a tissue. We thus investigated AHH and EH in the nuclear and microsomal fractions from six livers, four kidneys, four lungs, and two adrenals from human fetuses (gestational age between 15 and 24 weeks). Tissues were obtained at legal abortion for sociomedical reasons. AHH activity was measured according to van Cantfort et al (Biochem Biophys Res Commun 79: 505, 1977) using beno (a)pyrene as substrate. EH was measured as described by Jerina et al (Mol Pharmacol 13:342, 1977) using both styrene oxide (SO) and benzo(a)pyrene-4,5-oxide (BPO) as substrate. The nuclear fraction was isolated by a multistep procedure including centrifugation in high density sucrose ( Pacifici et al, unpublished). The hepatic AHH activity (pmole/min/mg; mean +/- SEM) was 11.5 +/- 2.2 in the nuclear fraction and 34.7 +/- 1.7 in the microsomes. In adrenals it was 6.0 (nuclei) and 4.4 (microsomes). The nuclear fraction from kidneys and lungs did not catalyze this reaction at a measurable rate, whereas microsomal AHH activity was 1.3 +/- 0.3 and 5.3 +/- 1.1, respectively, in these tissues.(ABSTRACT TRUNCATED AT 250 WORDS)