We report two infants with cystic fibrosis (CF), presenting with meconium ileus and meconium plug, who had no clinical or biochemical evidence of pancreatic insufficiency during infancy. They underwent pancreatic secretory function testing at 11 and 9 months of age, respectively. Both patients had sufficient lipase and colipase secretion to maintain normal digestion of fat, confirming that meconium disease in CF does not necessarily imply pancreatic insufficiency and the need for enzyme supplementation in infancy. Nonetheless, we documented markedly reduced enzyme secretion in both patients, implying a potential role for the pancreas in the pathogenesis of meconium disease, even when clinical pancreatic insufficiency is absent. In addition, our patient with meconium ileus had a severely limited fluid secretory capacity (10.3% of mean normal values). In contrast, the patient with the milder presentation of meconium plug had a far greater ability to secrete fluid (75% of mean normal), but had poorer pancreatic proteolytic activity. We suggest that impaired fluid secretion may be a very significant factor in the pathogenesis of meconium ileus, and we speculate that an inability to maintain sufficient intraluminal fluid relative to the degree of pancreatic proteolytic deficiency may more adequately explain the risk of occurrence and the severity of intestinal obstruction in CF than either factor alone.

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Pharmacokinetics of a series of 6-chloro-2,3,4,5-tetrahydro-3-substituted-1H- 3-benzazepines in rats. Determination of quantitative structure-pharmacokinetic relationships.

To aid in the effort to discover novel agents for the treatment of cardiovascular disease, the relationships between pharmacokinetic parameters in the rat and lipophilicity and basicity were studied for a series of 6-chloro-2,3,4,5-tetrahydro-3-substituted-1H-3-benzazepines. Eight compounds, ranging in lipophilicity from log P = 1.64 to 3.50 and basicity from pKa = 6.75 to 9.36, were studied. The compounds were administered iv to rats, and the pharmacokinetic parameters were calculated from the plasma concentration-time curves. Plasma protein binding was determined in vitro using equilibrium dialysis to allow calculation of steady state volume of distribution of unbound drug, Vss,u; and tissue binding. Stepwise regression analysis with each pharmacokinetic parameter as the dependent variable and log P and pKa as the independent variables was performed. In no case was there a significant relationship between a pharmacokinetic parameter and both of the independent variables. Statistically significant linear relationships were found between pKa and Vss and t 1/2z. Lipophilicity was found to correlate with the free fraction in plasma and the free fraction in tissues. The clearance parameters did not correlate with either of the physicochemical parameters. The pharmacokinetics of the one secondary amine in the series were clearly different from those of any of the tertiary amines. The clearance of the secondary amine was lower and the volume of distribution higher than any of the tertiary amines. These results demonstrate that alteration of the lipophilicity of 3-substituted benzazepines does not alter their pharmacokinetics in a predictable fashion but that the pharmacokinetics of secondary amines may be substantially different than tertiary amines.

Animals↗

PubMedDate not supplied

Home i.v. therapy. A hospital-based program.

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