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CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.

9-R-[2-(Phosphonomethoxy)propyl]-adenine (tenofovir) is an acyclic nucleoside phosphonate with antiviral activity against human immunodeficiency virus type 1 (HIV-1) and hepatitis B virus (HBV). Tenofovir is not orally bioavailable but becomes orally active against HIV-1 infection as the disoproxil ester (tenofovir disoproxil fumarate [Viread]). We have developed an alternative strategy for promoting the oral availability of nucleoside phosphonate analogs which involves esterification with a lipid to form a lysolecithin mimic. This mimic can utilize natural lysolecithin uptake pathways in the gut, resulting in high oral availability. Since the mimic is not subject to cleavage in the plasma by nonspecific esterases, it remains intact in the circulation and facilitates uptake by target cells. Significant drops in apparent antiviral 50% effective concentrations (EC(50)s) of up to 3 logs have been observed in comparison with non-lipid-conjugated parent compounds in target cells. We have applied this technology to tenofovir with the goal of increasing oral availability, decreasing the apparent EC(50), and decreasing the potential for nephrotoxicity by reducing the exposure of the kidney to the free dianionic tenofovir. Here we report that, in vitro, the hexadecyloxypropyl ester of tenofovir, CMX157, is 267-fold more active than tenofovir against HIV-1 and 4.5-fold more active against HBV. CMX157 is orally available and has no apparent toxicity when given orally to rats for 7 days at doses of 10, 30, or 100 mg/kg/day. Consequently, CMX157 represents a second-generation tenofovir analog which may have an improved clinical profile.

A high-performance liquid chromatographic procedure for the determination of cocaine and selected metabolites (benzoylecgonine, norcocaine and benzoylnorecgonine) from human and canine serum has been developed. The analytes are extracted from 0.5-ml serum samples using strong cation-exchange and octadecylsilane solid-phase extraction columns. Chromatographic separation was accomplished on coupled cyanopropyl and silica columns using acetonitrile-6.25 mM phosphate buffer, pH 2.9 (80:20 v/v) as eluent and a flow-rate of 1.1 ml/min. Low-wavelength UV detection (228 nm, cadmium lamp) allowed detection of 1 ng/ml for each analyte. The assay was linear from 0 to 200 ng/ml (r2 = 0.997-0.999, n = 15 for each analyte) and showed good precision (relative standard deviation = 0.66-13.8%, n = 6) and accuracy (98-115% relative recovery).

We determined the intraoperative concentrations of cefmetazole and cefoxitin in serum and muscle from the wound of 30 patients who were undergoing cholecystectomies. The study employed an open-label design in which all patients randomly received cefoxitin sodium (30 mg/kg) or cefmetazole sodium (15 or 30 mg/kg) intravenously with the induction of anesthesia. Total serum and wound-muscle concentrations achieved with cefmetazole 30 mg/kg were significantly greater than those achieved with a similar dose of cefoxitin. Cefmetazole in a 15 mg/kg dose was comparable with cefoxitin 30 mg/kg in achieved concentrations. The elimination half-life for cefoxitin was much shorter than that for cefmetazole (41 min v. 64-68 min, respectively) and this relates to a shorter duration of action for the former. The choice of agent for surgical prophylaxis should incorporate factors relating to drug pharmacokinetic properties as well as microbiological factors.