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

Cardiac involvement in cystic fibrosis (CF) occurs commonly but may remain undetected by usual evaluation in its early stages when right ventricular dysfunction (RVD) may be treatable. To assess the role of vasodilator therapy for early RVD in CF, we performed a prospective study in 23 ambulatory CF patients with mild CF (clinical score m = 79 +/- 8, range 61 to 90). Echocardiography (echo) and radionuclide angiography (RA) were performed at rest and with exercise stress testing (EST) in all 23 to select patients with early RVD. Thirteen of twenty-three had RVD on echo or RA evidenced by increased RV dimensions (P less than 0.001) on echo and decreased RV ejection fraction (EF) on RA (P less than 0.01) but 30% of these patients were abnormal only with EST. All 13 with RVD underwent inpatient double-blinded randomization to receive placebo or hydralazine orally without changing other standard therapy. Nine of thirteen received hydralazine (2 mg/kg/day) for 3 days. With hydralazine no change from placebo was seen on any echo or RA measurement at rest or with EST other than left ventricular STI which fell (P less than 0.05). These data indicate: 1) EST with echo and RA detects RVD in CF earlier than resting studies, 2) patients with mild CF (clinical score less than 85) frequently have RVD on EST, and 3) hydralazine does not improve RVD in CF even very early in its development.

To determine if the pharmacodynamics of ethanol are altered in advanced pregnancy, 20-days pregnant Lewis rats and nonpregnant rats of the same age received an i.v. infusion of ethanol, 96 mg/min/kg, until they lost their righting reflex. The concentrations of ethanol at that time in adult and fetal serum, and in the cerebrospinal fluid (CSF) and brain of the adult animals were determined. Ethanol concentrations in the pregnant rats were only slightly (less than 10%) but statistically significantly lower than in nonpregnant controls. Brain/serum, CSF/serum, and CSF/brain concentration ratios of ethanol were essentially identical in pregnant and nonpregnant rats, indicating no apparent effect of pregnancy on the distribution kinetics of ethanol. The serum concentrations of ethanol in mothers and their fetuses were similar and significantly correlated. The results of this investigation show that the central nervous system depressant effect of ethanol is not appreciably altered by pregnancy.

The effect of indomethacin on carbohydrate metabolism was studied in six premature infants with significant patent ductus arteriosus (mean +/- S.D., birth weight 1,066 +/- 244 gm, gestational age 30 +/- 1.6 weeks). All infants were in a glucose steady state between 50 and 100 mg/dl over a 2-hour period before indomethacin administration. There was a significant fall in plasma glucose at 1, 6, 12, and 24 hours following intravenous indomethacin infusion. Since there was no significant change in insulin levels from the baseline, the mechanism of indomethacin-mediated lack of prostaglandin inhibition of insulin release was not substantiated. Based on this study, plasma glucose levels should be followed closely in the first 24 hours following intravenous indomethacin administration.

The pharmacokinetic parameters of MgSO4 were followed in the pregnant sheep model following intravenous dosages of MgSO4 comparable to those used in the therapy of the preeclamptic woman. Hemodynamic parameters, including maternal arterial pressure, central venous pressure, systemic vascular resistance, pulmonary artery pressure, heart rate, cardiac output, cardiac index, rate pressure product, stroke volume, stroke index, blood gases, fetal arterial pressure, heart rate, and blood gases, all remain stable during the infusion of MgSO4. Biochemical changes accompanying MgSO4 infusion in these doses were evaluated. It was found that the fetal serum levels of MgSO4 were approximately 70% of those in the mother. The MgSO4 was rapidly excreted into the maternal urine and 8.9% of the MgSO4 infused was cleared by 2 hr after the termination of the infusion. MgSO4 was also excreted by the fetus into amniotic fluid. It was found that a minimum dosage of 1 mg/kg/hr of magnesium was required to achieve a magnesium level in maternal serum at the lower limit of the therapeutic range of 4 mEq/L.

A case of fetal supraventricular tachycardia (SVT) diagnosed by fetal echocardiography at 31 weeks gestation and successfully converted in utero is reported. Administration of digoxin orally to the mother resulted in very brief periods of normal fetal cardiac rhythm. Intravenous administration of verapamil to the mother resulted in sustained conversion to normal fetal sinus rhythm. Maintenance therapy with oral digoxin and verapamil was given to the mother for the remainder of the pregnancy with no recurrence of the fetal arrhythmia.

Twenty-one cystic fibrosis patients under 3 years of age were enrolled in an open multicenter study to assess the feasibility of the study design and to compare selected pharmacologic features of cephalexin or dicloxacillin administered orally for 2 months. Patient tolerance and compliance were significantly less for dicloxacillin (p less than .01 and p less than .001, respectively). Superficial Candida infections were more common in the cephalexin group (p = 0.02), however increased stool frequency and nonspecific diaper rashes were more prevalent in patients receiving dicloxacillin (p less than .05). Staphylococcus aureus was isolated from respiratory secretions after 2 months from two dicloxacillin and no cephalexin patients. Areas under the curve and peak serum concentrations were higher for cephalexin (p less than .05 and p = .02), but antistaphylococcal activity in serum was higher for dicloxacillin (p less than .05) due to a lower mean MIC compared to cephalexin. Deep pharyngeal plus routine throat culture yielded more pathogens than either method alone. Express mail and central processing of respiratory specimens was efficient for most organisms, however there was some loss of Streptococcus pneumoniae and Haemophilus influenzae. Cephalexin was associated with better patient acceptance and compliance despite higher rates of superficial fungal infections as compared to dicloxacillin. Cephalexin, routine bacteriologic throat swabs processed locally or centrally, mail-in urine compliance assessment and a multicenter design are feasible components for a long-term prospective evaluation of antibiotic prophylaxis in patients with cystic fibrosis.

Diamide (dicarboxylic acid bis-(N,N-dimethylamide) has been shown in previous studies to block the uptake of the beta-amino acid taurine at its high affinity transport site in rat renal cortex slices. Diamide may act by increasing the efflux of taurine from the slice. Studies performed in rat slices again indicate enhanced efflux over 8-12 minutes. The time course of reduced glutathione (GSH) depletion from renal cortex is similar, indicating a potential interaction between GSH depletion and inhibition of taurine accumulation. Diamide further blocks the uptake of taurine by collagenase-isolated renal tubules in a dose-dependent fashion with greater inhibition at 20 minutes than at 5 minutes. The effect of 9 mM diamide on the Na+ -dependent accumulation of taurine (10 and 250 microM) by brush border membrane vesicles was examined, and the taurine uptake value both initially and at equilibrium was the same in the presence and absence of diamide. That the effect in tubules is greater at 20 minutes than at 5 minutes is consistent with the idea that diamide enhances efflux of taurine immediately after exposure of tubules to taurine, or that diamide influences some intracellular process, requiring a time interval before this action is observed. Isolation of the brush border surface and subsequent transport studies of taurine are not influenced by diamide. Thus, diamide inhibition of taurine uptake does not involve physiochemical alteration of the membrane surface where active amino acid transport occurs, despite the thiol-oxidizing properties of this agent. Further, these studies suggest that diamide either acts at the basolateral surface, rather than the brush border surface of rat renal cortex or requires the presence of an intact tubule, capable of metabolism, prior to its inhibitory action.

A case of parent-induced theophylline toxicity in a preterm infant is described. Despite a theophylline level of 97 mcg/ml no clinical seizure activity was apparent. Pharmacokinetic data suggested that use of oral activated charcoal may have enhanced drug clearance. Further study is necessary before such therapy can be routinely advocated. Additional clinical features are discussed, including avoidance of dosing errors through careful instruction of all caretakers prior to discharge.

In order to optimize gentamicin (G) therapy we studied G pharmacokinetics in 48 preterm infants (gest. age 31.6 +/- 3.4, range 25-37 wk; birth weight 1.5 +/- 0.5 kg, range 0.7-2.5 kg). They received IV G twice daily (5.2 +/- 0.6 mg/kg/day). After at least 2 days of treatment trough and peak levels were measured for 2 successive doses. Trough levels were significantly higher in infants less than 1 kg receiving 5 mg/kg/day than in other infants (1-2.5 kg) who received the same dose (3.1 +/- 1.0 vs. 2.3 +/- 0.5 micrograms/ml; p less than 0.01). Mean G t 1/2 was significantly longer in infants under 1 kg than in those weighing 1-2.5 kg (7.9 +/- 1.9 and 6.5 +/- 1.6 hr, respectively; p less than 0.01). These differences could be attributed to lower G clearance in infants less than 1 kg (31 +/- 6 vs. 39 +/- 8 ml/kg/hr; p less than 0.005). There was no difference in G distribution volume between less than 1 kg and 1-2.5 kg infants (0.35 +/- 0.07 and 0.38 +/- 0.13 L/kg, respectively). A correlation was found between clearance and t 1/2 for the total group (r = 0.57, p less than 0.01). No correlation was detected between BUN and clearance or between gestational age and clearance. Our data suggest that G dose in infants less than 1 kg should be reduced to 3.5-4 mg/kg/day in order to avoid excessive levels associated with nephrotoxicity.

The effect of tolazoline (1 X 10(-5) M) upon the norepinephrine concentration-response relationship is compared in pulmonary and femoral arterial rings from neonatal goats. As we have reported previously in neonatal lambs, the pulmonary vessels are more sensitive to norepinephrine (pED50 7.23 +/- 0.22 for the pulmonary vs. 6.49 +/- 0.42 for the femoral). However, there is no difference in the response to tolazoline of the two vessel types (pKB for tolazoline 5.77 +/- 0.23 in the pulmonary and 5.79 +/- 0.33 in the femoral).