Pharmacokinetics and analgesic effects of intravenous propacetamol vs rectal paracetamol in children after major craniofacial surgery.

BACKGROUND: The pharmacokinetics and analgesic effects of intravenous and rectal paracetamol were compared in nonventilated infants after craniofacial surgery in a double-blind placebo controlled study. METHODS: During surgery all infants (6 months-2 years) received a rectal loading dose of 40 mg.kg(-1) paracetamol 2 h before anticipated extubation. On admittance to the pediatric surgical ICU, the children were randomized to receive either a 15 min intravenous infusion of 40 mg.kg(-1) propacetamol, a prodrug of paracetamol, or 20 mg.kg(-1) paracetamol rectally every 6 h. A population pharmacokinetic analysis of the paracetamol plasma concentration time-profiles was undertaken using nonlinear mixed effects models. The visual analogue scale (VAS) (score 0-10 cm) and COMFORT Behavior scale (score 6-30) were used to monitor analgesia in the 24-h period following surgery. RESULTS: Twelve infants received intravenous propacetamol and 14 paracetamol suppositories. Paracetamol pharmacokinetics were described according to a two-compartmental model with linear disposition. Pharmacokinetic parameters were standardized to a 70 kg person using allometric '1/4 power' models. Parameter estimates were: absorption half-life from the rectum 4.6 h, propacetamol hydrolysis half-life 0.028 h, clearance 12 l.h(-1).70 kg(-1), intercompartmental clearance 116 l.h(-1).70 kg(-1), central and peripheral volume of distribution 7.9 and 44 l.70 kg(-1), respectively. During the 24-h study period 22 infants exhibited VAS scores <4 cm, which was considered a cutoff point. On single occasions four patients, two in each group, exhibited a VAS score >/=4 cm. Nine patients in the rectal treatment group and three patients in the intravenous treatment group received midazolam for COMFORT-B scores exceeding 17 (P < 0.05). CONCLUSIONS: Intravenous propacetamol proved to be more effective than rectal paracetamol in infants after craniofacial surgery. Midazolam was more frequently administered to patients receiving paracetamol suppositories, indicating that these children experienced more distress, possibly caused by pain.

Divalent cation transport and susceptibility to infectious and autoimmune disease: continuation of the Ity/Lsh/Bcg/Nramp1/Slc11a1 gene story.

Solute carrier family 11 member a1 (Slc11a1), formerly known as Nramp1/Ity/Lsh/Bcg, is a proton/divalent cation antiporter that regulates susceptibility to infectious and autoimmune disease. Here we review recent studies on (1) the role of Slc11a1 in iron metabolism and iron recycling in macrophages; (2) the use of mouse breeding and introgression of knockouts onto Slc11a1 congenic backgrounds for genes encoding the multiple pleiotropic functions associated with Slc11a1; and (3) associations/linkages of SLC11A1 with human disease and how these relate to functional promoter region polymorphisms.

Solute carrier 11a1 (Slc11a1; formerly Nramp1) regulates metabolism and release of iron acquired by phagocytic, but not transferrin-receptor-mediated, iron uptake.

Solute carrier 11a1 (Slc11a1; formerly Nramp1; where Nramp stands for natural-resistance-associated macrophage protein) is a proton/bivalent cation antiporter that localizes to late endosomes/lysosomes and controls resistance to pathogens. In the present study the role of Slc11a1 in iron turnover is examined in macrophages transfected with Slc11a1(Gly169) (wild-type) or Slc11a1(Asp169) (mutant=functional null) alleles. Following direct acquisition of transferrin (Tf)-bound iron via the Tf receptor, iron uptake and release was equivalent in wild-type and mutant macrophages and was not influenced by interferon-gamma/lipopolysaccharide activation. Following phagocytosis of [(59)Fe]Tf-anti-Tf immune complexes, iron uptake was equivalent and up-regulated similarly with activation, but intracellular distribution was markedly different. In wild-type macrophages most iron was in the soluble (60%) rather than insoluble (12%) fraction, with 28% ferritin (Ft)-bound. With activation, the soluble component increased to 82% at the expense of Ft-bound iron (<5%). In mutant macrophages, 40-50% of iron was in insoluble form, 50-60% was soluble and <5% was Ft-bound. Western-blot analysis confirmed failure of mutant macrophages to degrade complexes 24 h after phagocytic uptake. Confocal microscopy showed that complexes were within lysosome-associated membrane protein 1-positive vesicles in wild-type and mutant macrophages at 30 min and 24 h, implying failure in the degradative process in mature phagosomes in mutant macrophages. NO-mediated iron release was 2.4-fold higher in activated wild-type macrophages compared with mutant macrophages. Overall, our data suggest that iron acquired by phagocytosis and degradation is retained within the phagosomal compartment in wild-type macrophages, and that NO triggers iron release by direct secretion of phagosomal contents rather than via the cytoplasm.