Developmental pharmacology and therapeutics最新文献

We performed a randomized nonblinded, cross-over comparison of patient-controlled analgesia (PCA) with conventional intramuscular analgesia in 10 adolescents (13-18 years) undergoing spinal fusion for idiopathic scoliosis. PCA use afforded more effective pain control (p < 0.02) on a 10-point linear pain intensity scale than did intramuscular injections, while causing an equal amount of sedation and no side effects. PCA appears to be a promising technique for providing postoperative pain relief in this group of adolescents. Further studies are needed to define its role for other pediatric conditions.

Wilson's disease is an autosomal recessive disorder characterized by an accumulation of a toxic amount of copper in the body. Triethylene tetramine dihydrochloride (trientine, 2HCl) is a new chelating agent that may be effective in the removal of excess copper but long-term efficacy has not yet been investigated. Here we report the use of trientine over more than 8 years in 2 patients with Wilson's disease who could not tolerate D-penicillamine. We found no significant side effect, except a decreased serum iron concentration without clinical symptoms of anemia. In annual examinations at a steady state, the serum copper levels remained below 20 micrograms/100 ml. The 24-hour urinary copper excretion was less than that found using D-penicillamine, while the basal copper excretion, after 5 days abstinence from trientine, was maintained below 100 micrograms/day. Both hepatic and neurological manifestations except bulbar symptoms were recovered without any initial deterioration.

Marked changes in rates of drug metabolism occur during adolescence; however, biochemical events underlying alterations in drug metabolism in whole hepatocytes during this period of development are not well established. Accordingly, metabolism of 7-ethoxycoumarin, a model substrate for mixed-function oxidation, was studied in hepatocytes isolated from prepubescent and postpubescent male rats. Rates of 7-ethoxycoumarin O-deethylation increased 2.4-fold from 65 to 154 pmol/10(6) cells/min in intact hepatocytes during the narrow period of adolescence. In contrast, microsomal 7-ethoxycoumarin O-deethylase was the same in preparations from the two groups of animals. 7-Hydroxycoumarin glucuronide production in hepatocytes increased 2-fold and sulfate formation increased 16-fold across puberty. The results indicate that increases in drug metabolism, particularly sulfate conjugation, are mediated by biochemical events in addition to increases in total amounts and specific activities of hepatic drug-metabolizing enzymes.

The disposition kinetics of cyclosporin A in the neonates as well as age-related differences in lymphocyte responses to cyclosporin A are unknown. A single intravenous infusion of cyclosporin A was given to neonatal (2.5 or 5 mg/kg) and mature pigs (10 mg/kg) and blood cyclosporin A levels were measured by RIA. The neonates had longer elimination half-life and lower drug clearance than mature animals. Suppression in lymphocyte proliferation was only observed in mixed lymphocyte reaction and phytohemagglutinin-stimulated cultures of the 2-hour samples from neonates receiving 5 mg/kg. We conclude that neonatal pig exhibit different cyclosporin A pharmacokinetics and show higher sensitivity to cyclosporin A than mature animals.

The present study examines the effect of butylated hydroxyanisole (BHA) exposure through mother's milk on some of the hepatic xenobiotic metabolizing enzymes in the F1 offspring. Lactating Swiss albino mice received either a 0.5 or 1% BHA diet during the lactation period. The acid-soluble sulfhydryl content and activities of glutathione S-transferase and glutathione reductase increased significantly (p < 0.01) whereas the activity of glutathione peroxidase decreased significantly (p < 0.01) in the liver of pups exposed to BHA via milk. The hepatic content of cytochrome b5 increased (p < 0.01) while that of cytochrome P-450 decreased (p < 0.01) in the pups of dams which received a 1% BHA diet during lactation.

Atrial natriuretic peptide (ANP) is a hormone involved in fluid and blood pressure homeostasis. We studied the effects of left-to-right shunting through a patent ductus arteriosus on blood pressure changes and plasma ANP concentrations in newborn piglets. In five experimental piglets, the ductus arteriosus was bathed with PGE1 and infiltrated with formalin to maintain its patency. In four age-matched control piglets, the ductus arteriosus was ligated. Plasma ANP concentrations and blood pressure determinations were obtained prior to (base-line) and 25 +/- 1 h (day 1), and 48 +/- 1 h (day 2) after surgery. Radionuclide-microsphere determinations of left-to-right patent ductus arteriosus shunts were performed on days 1 and 2 in the 5 piglets with a patent ductus arteriosus. Plasma ANP concentrations were significantly elevated in the left atrium on day 1 and the right atrium on day 2 in the PDA piglets. No correlation was demonstrated between plasma ANP concentrations and right or left atrial pressures. We conclude that left and right plasma atrial ANP concentrations are significantly elevated in newborn piglets with left-to-right patent ductus arteriosus shunts.