Prophylactic ganciclovir, started before transplant and continued after recovery of the post-transplant neutrophil count, reduces the incidence and severity of CMV infection in CMV-sero-positive bone marrow transplant recipients but is frequently associated with neutropenia.

The pharmacokinetics and bioavailability of adefovir [9-[2-(phosphonomethoxy)ethyl]adenine] were examined at two dose levels in three phase I/II studies in 28 human immunodeficiency type 1-infected patients. The concentrations of adefovir in serum following the intravenous infusion of 1.0 or 3.0 mg/kg of body weight were dose proportional and declined biexponentially, with an overall mean ؎ standard deviation terminal half-life of 1.6 ؎ 0.5 h (n ‫؍‬ 28). Approximately 90% of the intravenous dose was recovered unchanged in the urine in 12 h, and more than 98% was recovered by 24 h postdosing. The overall mean ؎ standard deviation total serum clearance of the drug (223 ؎ 53 ml/h/kg; n ‫؍‬ 25) approximated the renal clearance (205 ؎ 78 ml/h/kg; n ‫؍‬ 20), which was significantly higher (P < 0.01) than the baseline creatinine clearance in the same patients (88 ؎ 18 ml/h/kg; n ‫؍‬ 25). Since adefovir is essentially completely unbound in plasma or serum, these data indicate that active tubular secretion accounted for approximately 60% of the clearance of adefovir. The steady-state volume of distribution of adefovir (418 ؎ 76 ml/kg; n ‫؍‬ 28) suggests that the drug was distributed in total body water. Repeated daily dosing with adefovir at 1.0 mg/kg/day (n ‫؍‬ 8) and 3.0 mg/kg/day (n ‫؍‬ 4) for 22 days did not significantly alter the pharmacokinetics of the drug; there was no evidence of accumulation. The oral bioavailability of adefovir at a 3.0-mg/kg dose was <12% (n ‫؍‬ 5) on the basis of the concentrations in serum or 16.4% ؎ 16.0% on the basis of urinary recovery. The subcutaneous bioavailability of adefovir at a 3.0-mg/kg dose was 102% ؎ 8.3% (n ‫؍‬ 5) on the basis of concentrations in serum or 84.8% ؎ 28.5% on the basis of urinary recovery. These data are consistent with preclinical observations in various species.

A randomized, double-blind, placebo-controlled, dose-escalation study of adefovir dipivoxil, an oral prodrug of adefovir, was conducted in 36 human immunodeficiency virus (HIV)-infected subjects to evaluate its anti-HIV activity, safety, and pharmacokinetics. Subjects received placebo or one of three dosages of adefovir dipivoxil daily for 14 days. Median decreases in serum p24 antigen of 31% (P = .02), 25% (P = .31), and 30% (P = .01) occurred in each drug-treated group, respectively, compared with an increase of 17% in the placebo group. Median decreases in serum HIV RNA of 0.4-0.6 log10 copies/mL occurred in the drug-treated groups (P = .03), compared with no change in the placebo group. Gastrointestinal complaints and reversible liver transaminase elevations were the most frequently noted adverse events. Decreases in serum free carnitine occurred in each drug-treated group during treatment. After 14 days of dosing, adefovir dipivoxil demonstrated anti-HIV activity and was best tolerated at the lowest dosage studied, 125 mg daily.

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Pretreatment with ketamine attenuates endotoxin-induced leukocyte adherence by a shear rate-independent mechanism, suggesting reduced expression of adhesion molecules. These results indicate that ketamine exerts an anti-inflammatory effect, which might be beneficial in septic patients.