This phase I double-masked, randomized, placebo-controlled study evaluated the safety of single intravenous or subcutaneous doses of recombinant human nerve growth factor (rhNGF) in healthy human volunteers at doses ranging from 0.03 to 1 micrograms/kg. No life-threatening adverse events were seen at any dose. At doses above 0.1 microgram/kg, subjects reported mild to moderate muscle pain, primarily in the bulbar and truncal musculature. The duration and severity of these myalgias varied in a dose-dependent manner, and women appeared to be more susceptible than men. Intravenous rhNGF produced earlier and more pronounced systemic effects than did identical subcutaneous doses. Subjects receiving subcutaneous rhNGF noted hyperalgesia at the injection site, a local effect persisting up to 7 weeks, that also varied in a dose-dependent manner. Antibodies to NGF were not detected in any subject. These results indicate that systemically administered rhNGF exerts a characteristic and reproducible biological effect in healthy subjects at very low doses and in a dose-dependent manner.

The pharmacokinetics of cidofovir (HPMPC; (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine) were examined at five dose levels in three phase I/II studies in a total of 42 human immunodeficiency virus-infected patients (with or without asymptomatic cytomegalovirus infection). Levels of cidofovir in serum following intravenous infusion were dose proportional over the dose range of 1.0 to 10.0 mg/kg of body weight and declined biexponentially with an overall mean ؎ standard deviation terminal half-life of 2.6 ؎ 1.2 h (n ‫؍‬ 25). Approximately 90% of the intravenous dose was recovered unchanged in the urine in 24 h. The overall mean ؎ standard deviation total clearance of the drug from serum (148 ؎ 25 ml/h/kg; n ‫؍‬ 25) approximated renal clearance (129 ؎ 42 ml/h/kg; n ‫؍‬ 25), which was significantly higher (P < 0.001) than the baseline creatinine clearance in the same patients (83 ؎ 21 ml/h/kg; n ‫؍‬ 12). These data indicate that active tubular secretion played a significant role in the clearance of cidofovir. The steady-state volume of distribution of cidofovir was approximately 500 ml/kg, suggesting that the drug was distributed in total body water. Repeated dosing with cidofovir at 3.0 and 10.0 mg/kg/week did not alter the pharmacokinetics of the drug. Concomitant administration of intravenous cidofovir and oral probenecid to hydrated patients had no significant effect on the pharmacokinetics of cidofovir at a 3.0-mg/kg dose. At higher cidofovir doses, probenecid appeared to block tubular secretion of cidofovir and reduce its renal clearance to a level approaching glomerular filtration.Cidofovir (HPMPC; (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine) is an acyclic nucleotide analog with potent activity against a broad spectrum of herpesviruses, including cytomegalovirus (CMV). The in vivo and in vitro antiviral activities of cidofovir have been reviewed (1). Unlike ganciclovir and other nucleoside analogs currently used for clinical therapy of human herpesvirus infections, cidofovir does not depend on phosphorylation by viral nucleoside kinases to exert its antiviral effect (2). Instead, the drug is phosphorylated to its active form by cellular enzymes. In vitro studies have suggested that the resulting active metabolites are cleared slowly from the intracellular space (2).Preclinical pharmacokinetic studies with radiolabelled cidofovir in rats and mice (10) and in rabbits and monkeys (3) have demonstrated that the majority of the drug is distributed to the kidneys and is excreted in the urine within 24 h of intravenous administration. In monkeys, a fraction of the radioactive dose (approximately 10%) was excreted in a slow elimination phase, with a terminal elimination half-life of 24 to 35 h. This slower excretion phase may reflect the long intracellular half-life of the phosphorylated metabolites of cidofovir (2). In both monkeys and rabbits, approximately 98% of the excreted radioactive dose was present in the urine as unchanged drug. The oral bioavailability of the drug was estimated to be 3% i...

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