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

Guanabenz, a centrally acting antihypertensive agent that acts through stimulation of central alpha-adrenergic receptors, appears to produce neither sodium retention nor clinically significant renal, cardiac, hepatic, or metabolic abnormalities. This 2-month open, uncontrolled dose-finding and short-term safety and efficacy trial was conducted in 11 male outpatients (12 to 21 years old) to establish the potential use of guanabenz in treating children with hypertension. Doses of 3 to 12 mg/day (0.07 to 0.17 mg/kg/day) given twice daily effectively lowered blood pressure in all patients. Mean supine blood pressure was significantly (P less than 0.05) reduced from 135/91/81 mmHg (phase I/IV/V) at baseline to 124/80/66 mmHg after approximately 2 months of treatment. Mean supine pulse rate also was significantly (P less than 0.05) reduced (10 beats/minute), while standing pulse rate and body weight were unaffected by guanabenz therapy. Adverse effects, the most common being headache, dry mouth, and drowsiness, were generally mild and did not interfere with continued therapy. No abnormal findings were noted in laboratory test results or physical examinations. These preliminary results suggest that guanabenz is safe and effective for the treatment of childhood hypertension.

The effects of digoxin on pulmonary vascular resistance (PVR) were evaluated in normoxic (N) and hypoxic (H) newborn lambs with normal and elevated PVR, respectively. Lambs were anesthetized and instrumented to enable continuous measurement of mean pulmonary arterial pressure (PPA), mean left atrial pressure (PLA), mean pulmonary blood flow (Qp), and mean aortic pressure (PAO). Digoxin (10-20 micrograms/kg) was injected via central venous catheters in 11 N lambs and 4 H lambs. Under N conditions, baseline PVR was equal to 0.12 mm Hg/ml/min/kg, PPA was 33 mm Hg, PLA was 6 mm Hg, Qp was 235 ml/min/kg, and PAO was 69 mm Hg. Following digoxin, mean PVR increased by 24% (P less than 0.001) and PPA increased by 23% (P less than 0.001) for an average duration of 199 sec while QP increased by 5% (P less than 0.02) and PLA was constant suggesting a direct vasoconstrictive effect. Under H conditions, baseline PVR was equal to 0.26 mm Hg/ml/min/kg, PPA was 58 mm Hg, PLA was 4 mm Hg, Qp was 208 ml/min/kg, and PAo was 65 mm Hg. Following digoxin, mean PVR, Qp, PLA, and PAo did not change appreciably although PPA had a uniform increase of 5% (P less than 0.001). The blunted response may suggest that either the pulmonary vascular bed was maximally constricted or that digoxin and hypoxia share a common mechanism. In conclusion, digoxin has a direct pulmonary vasoconstrictor action in newborn lambs. Because of its short duration, this action probably should not alter the clinical use of this drug in newborn humans.

Fractional sodium excretion (FENa) was measured in 25 neonates during and after treatment with tobramycin. Mean birthweight of infants was 1.83 kg and mean gestational age was 34.3 weeks. Tobramycin therapy was initiated within 48 hours of birth and levels were maintained within the therapeutic range. Mean FENa values were persistently elevated during treatment and decreased to the normal range within 2 days of stopping antibiotics. Blood urea and creatinine concentrations were normal throughout the period of study. Exposure to the aminoglycoside appears to delay the previously described postnatal decline in FENa, most likely reflecting subtle renal tubular dysfunction.

Benzodiazepine receptors appear to be pharmacologically important as the modulator of anxiolytic, anticonvulsant, and muscle relaxant activities in the central nervous system. The acute effects of valproic acid (VPA), diazepam (DZ), phenobarbital (PB), and phenytoin (PHT) on benzodiazepine receptor binding as measured by 3H-flunitrazepam were studied in Sprague Dawley (S/D) rat cerebral cortices. The acute effects of seizures were also studied in both S/D rats and audiogenic seizure rats. In the VPA (100 mg/kg, IP) treated rats, there was a 11% increase in benzodiazepine receptor density (Bmax). This effect appear to be dose dependent as higher doses of VPA (200-500 mg/kg) resulted in more increase in Bmax. No significant change occurred in Kd after acute VPA treatment. However, acute PB (100 mg/kg), PHT (100-200 mg/kg), or DZ (50 mg/kg) did not produce any changes in Bmax or dissociation constants (Kd). In S/D rats, significant increases in Bmax were observed 30 minutes after seizures induced by electroshock or pentylenetetrazol (50 mg/kg) IP injection. However, audiogenic seizure rats had higher Bmax prior to the induction of seizures when compared to normal S/D rats, and no changes in Bmax occurred after seizures in audiogenic seizure rats. No changes in Kd were seen in either S/D rats or audiogenic seizure rats before and after seizures. These data suggest that an increase in benzodiazepine receptor density might correlate with the mechanism of anticonvulsant action of VPA, and that a possible disorder of the GABA/benzodiazepine receptor complex may be involved in the seizure susceptibility in audiogenic seizure rats.

Single-dose intravenous phenytoin (9.4-21.3 mg/kg) effectively eradicated seizures within 3 minutes in 12 out of 13 patients in status epilepticus. Eleven additional patients were treated prophylactically. No adverse effects were observed and neurological status was unaltered in all 24 cases. Phenytoin volume of distribution was found to decline significantly with age from 1.6 L/kg at 1 year to 0.6 at 10 years (P less than 0.01). Estimates of Vmax, the maximal rate of phenytoin metabolism, were obtainable in 8/24 patients and were in the expected range (10.6 +/- 4.2 mg/kg/day) for their age (6.6 +/- 2.8 years). Therapeutic serum concentrations (initial post distribution values 17.9 +/- 9.0 micrograms/ml) were maintained for more than 10 hours in 15/24 patients. Single-dose intravenous phenytoin is both effective and safe in the treatment and prevention of epileptic seizures in pediatric patients.

Selected parameters of renal function were studied in premature infants with a significant patent ductus arteriosus who were treated with intravenous indomethacin according to a specific protocol. Urine volume, glomerular filtration rate, urine sodium, and the fractional excretion of sodium were analyzed in 17; osmolar, sodium, and free water clearances in 8; and indomethacin pharmacokinetics in 7 premature infants. All renal function parameters analyzed decreased during indomethacin therapy: urine volume and glomerular filtration rate returned to normal, while urine sodium, fractional excretion of sodium, and the osmolar, sodium, and free water clearances remained low 24 hours after cessation of therapy. The water retention, shown by the reduced free water clearance, had no apparent deleterious effects, probably because of the infants' low fluid intake. Indomethacin pharmacokinetic parameters (clearance, area under the curve) may account in part for the variability of the fractional excretion of sodium, glomerular filtration, and urine flow rate.

Ventilator care in premature infants with hyaline membrane disease (HMD) may be complicated by episodes of irritability and "fighting" the respirator, resulting in significant hypoxemia. Neuromuscular blockade with pharmacologic agents such as pancuronium bromide is frequently used to manage this problem [Crone and Favorito, 1980]. This therapy results in the loss of important clinical signs, such as alterations in muscle tone and spontaneous movements, which are important in monitoring the critically ill newborn. As a result of these considerations, we occasionally have utilized the sedative-hypnotic effects of chloral hydrate to achieve adequate ventilation and oxygenation in these infants. We report, however, a case of a preterm infant who developed severe chloral hydrate toxicity after its administration as an adjunct to the treatment of HMD.

We studied the disposition of two 100 mg/kg doses of cefoperazone given intravenously 12 hr apart in ten newborn infants. Peak levels were a mean 352 +/- SD 75 and 371 +/- 68 micrograms/ml immediately after the first and second dose, respectively, with corresponding troughs of 60 +/- 10 and 76 +/- 28 mcg/ml 12 hr later. Mean half-life was 6.5 +/- 0.9 hr and decreased with increasing gestational age and birthweight. Steady-state volume of distribution averaged 410 +/- 40 ml/kg and total clearance 0.78 +/- 0.13 ml/min X kg and neither varied with gestational age nor birthweight. No untoward physical or laboratory effects were noted. Additional studies including postnatal age effects on kinetics, efficacy, and cerebrospinal fluid penetrance are necessary prior to widespread use of this potentially valuable antibiotic in newborn infants.

Protein in vitamin K absence (PIVKA) is the prothrombin precursor found in plasma when carboxylation to prothrombin is impaired. We report on two cases in which mother-infant PIVKA concentrations were measured at birth after chronic anticonvulsant therapy during pregnancy. Maternal values were 2.4 and 4%, and infant values 20.0 and 18% in cases 1 and 2, respectively. This demonstrates that, despite the normal coagulation profiles previously described, mothers on chronic anticonvulsant therapy may have a subclinical carboxylation defect, while their infants are at risk for hemorrhagic disease. Estimation of maternal PIVKA levels may be of value for predicting risk of hemorrhage in the neonate.

It is clear that the products of arachidonate metabolism (prostaglandins, leukotrienes, thromboxanes, etc) are involved in both normal and pathophysiologic pulmonary vascular responses. However, the precise roles of these compounds in the various pulmonary vasoregulatory processes remain unclear. This paper reviews the synthetic pathways for these compounds and summarizes the current state of knowledge regarding their involvement in the perinatal pulmonary circulation. Data regarding endogenous compounds as well as the effects of exogenously administered agents are presented.