Pharmacodynamics and safety of pantoprazole in neonates, preterm infants, and infants aged 1 through 11 months with a clinical diagnosis of gastroesophageal reflux disease.

BACKGROUND: Limited data on proton pump inhibitors in infants led regulatory agencies to request sponsors to conduct pediatric studies. AIM: To determine the pharmacodynamic response to pantoprazole in infants with GERD to aid the dose selection for an efficacy study. METHODS: In two open-label studies, neonates and preterm infants (study 1, ~1.2 mg/kg [high dose]) and infants 1 through 11 months (study 2, ~0.6 [low dose] or ~1.2 mg/kg [high dose]) received once-daily pantoprazole. Twenty-four-hour dual-electrode pH-metry parameters were compared between predose and steady state (≥5 days) (two-sided paired t test). Treatment was administered for ≤6 weeks. RESULTS: In studies 1 and 2, 21 and 24 patients, respectively, were enrolled for pharmacodynamic evaluation. The high dose provided similar responses in the two studies and improved these parameters significantly: mean gastric pH and percent time gastric pH > 4 increased (p < 0.05 both studies), normalized area under the curve (AUC) of gastric H(+) activity decreased (p < 0.05 study 2), and normalized AUC of esophageal H(+) activity decreased (p < 0.05 both studies). The AUC of esophageal pH < 4 decreased. Normalized AUC of esophageal H(+) activity decreased (p < 0.05 both studies), indicating refluxate pH increased, although this was not reflected in any change in mean esophageal pH or reflux index. The normalized AUC of esophageal H(+) activity was a more sensitive measure of changes in esophageal pH. CONCLUSIONS: In neonates, preterm infants, and infants aged 1 through 11 months, pantoprazole (high dose) improved pH-metry parameters after ≥5 consecutive daily doses, and was generally well tolerated for ≤6 weeks.

Role of intestinal transporters in neonatal nutrition: carbohydrates, proteins, lipids, minerals, and vitamins.

To support rapid growth and a high metabolic rate, infants require enormous amounts of nutrients. The small intestine must have the complete array of transporters that absorb the nutrients released from digested food. Failure of intestinal transporters to function properly often presents symptoms as "failure to thrive" because nutrients are not absorbed and as diarrhea because unabsorbed nutrients upset luminal osmolality or become substrates of intestinal bacteria. We enumerate the nutrients that constitute human milk and various infant milk formulas, explain their importance in neonatal nutrition, then describe for each nutrient the transporter(s) that absorbs it from the intestinal lumen into the enterocyte cytosol and from the cytosol to the portal blood. More than 100 membrane and cytosolic transporters are now thought to facilitate absorption of minerals and vitamins as well as products of digestion of the macronutrients carbohydrates, proteins, and lipids. We highlight research areas that should yield information needed to better understand the important role of these transporters during normal development.

Ontogenetic development of rat intestinal bile acid transport requires thyroxine but not corticosterone.

Absorption of bile acids by the distal ileum is an essential component of the enterohepatic circulation. In neonatal rats, the appearance of the apical sodium-dependent bile acid transporter (ASBT) at 17 d of age coincides with increases in serum corticosterone and thyroxine. We tested the hypothesis that these hormones modulate ASBT expression during ileal development. Taurocholate uptake into the isolated ileum of normal 20-d-old pups exhibited saturable (K(m) = 0.52 mM, J(max) = 0.34 pmol mg/min) and nonsaturable (K(diff) = 0.015 min(-1)) components and was two to five times greater than uptake in the proximal intestine. Hypothyroid or euthyroid pups received daily thyroxine injections starting at 6 d of age. At 12 d of age, serum concentrations of thyroxine, ileal abundance of ASBT mRNA, and ileal rates of taurocholate uptake were low in hypothyroid pups that received an injection of vehicle (HT-) or thyroxine (HT+) and in euthyroid pups that received an injection of vehicle (ET-) or thyroxine (ET+). At 20 and 26 d, ileal ASBT mRNA abundance and taurocholate uptake rate remained low in HT- pups but increased dramatically in ET- and ET+ pups, paralleling the increase in serum thyroxine. Restoration of normal plasma thyroxine in HT- pups by thyroxine injections (HT+) restored normal ASBT development. Sodium-glucose co-transporter activity and mRNA expression were independent of serum thyroxine levels. Corticosterone levels were significantly lower in pups that were adrenalectomized at 10 d of age. ASBT mRNA abundance and taurocholate uptake rate increased markedly with age but were the same in adrenalectomized, sham-operated, and nonoperated pups. Hence, endogenous thyroxine but not corticosterone regulates the developmentally timed appearance of ASBT.