This study confirms that the currently recommended dose regimen (10-5-5 mg/kg) of IBU is associated with a high closure rate (80%) and few adverse effects in premature infants with a PMA of 27-29 weeks. The failure rate was much higher below 27 weeks. A higher dose regimen (20-10-10 mg/kg) might achieve a higher closure rate. However, tolerability and safety of this dose regimen should be assessed in a larger population before considering the use of these doses for ductus arteriosus closure.

1 Caffeine metabolism was studied in human liver microsomes from foetuses (n = 10), neonates (n = 10), infants (n = 9) and adults (n = 5). Caffeine and its metabolites, 1-3-7-trimethyluric acid, paraxanthine, theophylline and theobromine, were assayed by h.p.l.c. Methoxyresorufin-O-demethylase activity (MEROD) was determined and immunoquantifiable levels of CYP1A2 were measured.2 The formation of the dimethylxanthines by N-3, N-7 or N-i-demethylation was significantly less in foetuses, neonates and infants than in adults, as shown previously in vivo. The formation of 1-3-7-trimethyluric acid (C-8-hydroxylation) was not significantly different between age groups. The production of total dimethylxanthines, paraxanthine and theophylline increased significantly with age within the neonate-infant group over at least the 0-300 day range (rs = 0.739, 0.667, 0.682, respectively). These data differ from those reported in vivo which suggested that N-3 and N-7-demethylations matured at about 120 days. The difference in maturational profiles of each metabolic pathway suggests that the reactions depend on different isoenzymes. The delay in the maturation of N-1 compared with N-3 and N-7-demethylation is in agreement with previous in vivo data. 3 In the neonate-infant group, only N-3-demethylation correlated with both MEROD activity (rs = 0.681; P < 0.05) and CYP1A2 microsomal concentration (r, = 0.454; P = 0.05), suggesting that, as in adults, this reaction depends on CYP1A2. 4 In the foetal samples, the production of total dimethylxanthines, paraxanthine and theobromine decreased significantly (rs = -0.879, -0.767, -0.708, respectively) with increasing gestational age. Only CYP3A has previously been detected in human foetal liver; neither CYPlAl nor CYP1A2 were present, suggesting that the metabolic pathways of caffeine depend on CYP3A at this stage of development.

Diarrhea is only one of the many manifestations of intestinal parasites. Environmental influences are inescapable, regardless of an individual's state of health: in a highly endemic region, intestinal parasitic colonization is almost the rule. The clinical expression of the parasitoses, however, is largely determined by host defenses; and when they are weakened, parasitic diarrhea is frequent and severe. Protein-energy malnutrition is by far the most important cause of immune deficiency in developing countries. Diarrhea caused by Strongyloides or Giardia is common and severe in malnourished children, while well-nourished children remain healthy carriers. These parasites require specific treatment in the malnourished; and the well-nourished should have preventive treatment when they are to receive corticosteroids or immunosuppressive agents. Diarrhea caused by Cryptosporidium spp. may be severe in malnourished or immunodeficient children, and recovery is achieved only after renutrition or treatment of the immunodeficiency.

Context: Acyclovir is an antiviral currently used for prevention and treatment of herpes simplex virus (HSV) and varicella-zona virus (VZV) infections. This study aimed to characterize pharmacokinetics of acyclovir and its oral prodrug valacyclovir to optimize dosing in children. Method: Children receiving acyclovir or valacyclovir were included in this study. Pharmacokinetics (PK) were described using the non-linear mixed-effect modelling. Dosing simulations were used to obtain trough concentrations above 50% inhibitory concentration for HSV or VZV (0.56mg/L and 1.125mg/L respectively) and maximal peak concentrations below 25 mg/L. Results: A total of 79 children (212 concentration-time observations) were included, 50 were taking IV acyclovir, 22 oral and 7 both IV and oral, 57 for preventive and 22 for curative purposes. A one-compartment model with first-order elimination best described the data. An allometric model was used to describe body weight effect and estimated glomerular filtration rate (eGFR) was significantly associated with acyclovir elimination Conclusion: To obtain target maximal and trough concentrations, the more suitable initial acyclovir IV dose was 10 mg/kg/6h for children with normal renal function (eGFR ≤ 250 mL/min/1.73m2) and 15 to 20 mg/kg/6h for children with ARC. (eGFR > 250 mL/min/1.73m2) The 20 mg/kg/8h for acyclovir and valacyclovir produced effective concentrations in more than 75% of children, however a 15 mg/kg/6h, if possible, should be preferred. These doses should be prospectively confirmed and a therapeutic drug monitoring could be used to refine them individually.