I.V. acetaminophen pharmacokinetics in neonates after multiple doses.

BACKGROUND: Pharmacokinetics of an i.v. prodrug of acetaminophen (propacetamol) in neonates after repeat dosing are reported, with scant data for i.v. acetaminophen formulation. METHODS: Neonates from an intensive care unit received 6-hourly prn i.v. acetaminophen dosed according to postmenstrual age (PMA): 28-32 weeks, 10 mg kg(-1); 32-36 weeks, 12.5 mg kg(-1); and > or =36 weeks, 15 mg kg(-1). A maximum of five blood samples for assay and liver function tests (LFTs) were collected. A one-compartment linear disposition model (zero-order input; first-order elimination) was used to describe time-concentration profiles using population modelling (NONMEM). RESULTS: Fifty neonates, median (range) PMA 38.6 (32-45) weeks, mean (SD) weight 2.9 (0.7) kg, received a mean of 15 doses over a median 4 days with 189 serum acetaminophen and 231 LFT measurements. Standardized population parameter estimates for a term neonate were clearance (CL) 5.24 (CV 30.5%) litre h(-1) 70 kg(-1) and volume of distribution (V) 76 (29.6%) litre 70 kg(-1). CL increased with PMA from 4.4 litre h(-1) 70 kg(-1) at 34 weeks to 6.3 litre h(-1) 70 kg(-1) at 46 weeks. The presence of unconjugated hyperbilirubinaemia was associated with reduced CL: 150 micromol litre(-1) associated with 40% CL reduction. Acetaminophen concentrations between 10 and 23 mg litre(-1) at steady state are predicted after 15 mg kg(-1) 6-hourly for a neonate of PMA 40 weeks. Hepatic enzyme analysis of daily samples changed significantly for one patient whose alanine aminotransferase concentration tripled. CONCLUSIONS: The parameter estimates are similar to those described for propacetamol. There was no evidence of hepatotoxicity. Unconjugated hyperbilirubinaemia impacts upon CL, dictating dose reduction.

Calcium ionophore-induced secretion from mast cells correlates with myosin light chain phosphorylation by protein kinase C.

Rat basophilic leukemia mast cells (RBL-2H3) secrete histamine when activated by Ag. This secretion correlates with increased phosphorylation of myosin light chain by protein kinase C (PKC). Calcium ionophores (A23187) also elicit secretion, which is enhanced by PMA. To analyze the roles of Ca2+ and PKC in the secretory process, A23187-induced myosin light chain phosphorylation was examined in the presence and absence of PMA. A23187-induced secretion correlated best with myosin light chain phosphorylation by PKC, not with phosphorylation by myosin light chain kinase (MLCK). A23187 induced the translocation to membranes of the alpha, beta, delta, and epsilon isozymes of PKC. PMA not only increased the phosphorylation of myosin light chains at PKC-specific sites (Ser1 and Ser2) but also at sites attributed to MLCK (Ser19 and Thr18-Ser19). A23187 plus PMA induced higher levels of secretion concomitantly with increased myosin light chain phosphorylation at the PKC-specific sites. However, there was little correlation between the translocation of specific PKC isozymes and the phosphorylation of myosin light chains by PKC. Activation induced a novel triphosphorylated form of myosin light chain with a higher level of phosphorylation at the diphosphorylated MLCK sites. Quantitation of A23187 plus PMA-induced myosin light chain phosphorylation revealed that phosphorylation at PKC sites increased from zero to 0.35 mol/mol, was little changed at the monophosphorylated MLCK site (0.30 mol/mol), and increased from zero to 0.06 mol/mol at the diphosphorylated MLCK sites. Therefore, Ca2+-induced secretion correlates best with myosin light chain phosphorylation by PKC, and diphosphorylation by MLCK is unlikely to contribute to secretion.

Cell free serum interleukin-2 receptor levels after heart transplantation.

The aim of this study was to predict episodes of rejection or infection in heart transplant recipients by monitoring serum interleukin-2 receptor (IL-2R) levels, rather than by endomyocardial biopsy. The shedding of IL-2R from activated lymphocytes results in increased serum interleukin-2 levels and is probably a result of immune activation occurring in both rejection and infection processes. As a group, heart transplant recipients who had no rejection of infection had significantly increased serum IL-2R levels compared with healthy controls. Patients who had moderate and severe rejection, and infection, had significantly increased serum IL-2R levels compared with levels in patients without rejection or infection. High serum IL-2R levels were seen mainly within the first 3 months after transplantation. Of 15 patients studied, nine had consistent increases in serum IL-2R levels with episodes of rejection or infection. Serum IL-2R levels did not correlate with serum cyclosporine levels. The monitoring of serum IL-2R levels was not a sensitive test of rejection because increases were not seen in all episodes of rejection; increases were seen, however, in all cases of infection. This test lacked specificity as serum IL-2R levels increased during episodes of both rejection and infection. In conclusion, the monitoring of serum IL-2R levels may be a useful way to routinely monitor or screen for possible rejection infection in heart transplant recipients, but this method should not replace endomyocardial biopsy for diagnosing rejection.