acyclovir and 2-6-diamino-9-(2-hydroxyethoxymethyl)purine

The following paper is intended to review those nucleoside analogs currently licensed for the treatment of herpetic diseases. Potentially efficacious congeners also will be considered. The mechanism of action, preclinical and clinical efficacy, and the problems associated with the use of each nucleoside analog will be described.

Topics: Acyclovir; Ganciclovir; Herpes Simplex; Humans; Purine Nucleosides; Pyrimidine Nucleosides

Acyclovir (Zovirax) is a highly specific antiherpes virus agent. Extensive investigations of the pharmacokinetics in man have shown it to have a useful half-life of about three hours and to be largely excreted unchanged in the urine. Crystaluria can be avoided provided the patient is well hydrated and attention is paid to the dosing instructions especially in patients with renal failure. In vitro ED50s (the drug concentration inhibiting virus replication by 50%) bear some general relevance to effective plasma levels in man. A new prodrug of acyclovir, 2-amino-9-[2-hydroxyethoxy methyl]-9H-purine (A515U), which is converted to acyclovir by xanthine oxidase is rapidly absorbed from the human gut and converted to acyclovir. This prodrug provides the opportunity to design regimes that are more convenient for the patient and may be more effective than acyclovir itself in the therapy of the less sensitive herpes viruses (e.g. Epstein-Barr virus and the Cytomegalovirus).

Topics: Absorption; Acyclovir; Administration, Oral; Adolescent; Adult; Child; Child, Preschool; Digestive System; Half-Life; Humans; Infant; Infant, Newborn; Kidney; Kinetics

The oral administration of BW 134U to Beagle dogs in a 1-month study was associated with lameness, footpad erosions, and nail loss. Groups of dogs received 60, 120, and 240 mg/kg/day. Compound-related effects were observed in the high dose group and only during the postdose period. Light microscopy revealed prominent cell maturation or radiomimetic defects in the stratum germinativum of the distal phalanges and footpads. The mechanism by which BW 134U produced these cell maturation defects is unknown. There were no signs of adverse effects in other keratin-producing or keratin-containing tissues.

Topics: Acyclovir; Animals; Antiviral Agents; Dogs; Dose-Response Relationship, Drug; Female; Foot Diseases; Hoof and Claw; Lameness, Animal; Male; Nucleosides

Adenosine deaminase (ADA) was partially purified from several sources using affinity chromatography. These enzymes have the capacity to catalyze the deamination of 2,6-diamino-9-(2-hydroxyethoxymethyl)purine (A134U) to form the antiviral agent acyclovir [9-(2-hydroxyethoxymethyl)guanine]. Their relative substrate efficiencies (Vmax/Km) with A134U (standardized to adenosine = 100) were: dog ADA, 0.092; human ADA, 0.015-0.029; rat ADA, 0.025; calf ADA, 0.016; and Escherichia coli ADA, 0.0003. In addition to having the lowest efficiency with A134U, the bacterial ADA was also distinguished by its lack of binding of the mammalian ADA inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine and by its weak binding to the 9-(p-aminobenzyl)adenine-agarose affinity column. Four minor metabolites of A134U and acyclovir have been reported to be produced in the rat. These compounds are oxidized on either the C-8 position of the ring or the terminal carbon of the side chain. Neither acyclovir nor any of these metabolites produced significant inhibition of calf intestine ADA. The oxidized metabolites containing an N-6 amino group were extremely slow substrates of this enzyme.

Topics: Acyclovir; Adenosine Deaminase; Animals; Dogs; Erythrocytes; Escherichia coli; Humans; Intestine, Small; Kinetics; Nucleoside Deaminases; Rats; Species Specificity; Spectrophotometry, Ultraviolet; Substrate Specificity

2,6-Diamino-9-(2-hydroxyethoxymethyl)purine (A134U), the 6-deoxy-6-amino analog of the antiviral agent acyclovir (ACV), was administered orally to dogs and rats. Plasma concentration-time profiles and urinary excretion of A134U and its deamination product, ACV, were determined. Mean peak plasma ACV concentrations achieved in the dog were 57, 156 and 285 microM after A134U doses of 20, 50 and 120 mg/kg, respectively, and increased in near proportion to the dose. The urinary recovery of ACV accounted for 60-92% of the two lower doses, but only 40-58% of the highest dose. In the rat, peak plasma ACV concentrations were 3.1 and 10.7 microM, respectively, after 20- and 50-mg/kg doses of A134U. After 5- and 20-mg/kg oral doses of [2-14C]A134U, the urinary recovery of ACV (20-27%) accounted for 59 to 76% of the absorbed dose. The remainder was excreted largely as unchanged A134U, with negligible (0.4-1.3%) biotransformation to inactive metabolites. Except for small decreases in absorption and increases in deamination, no change in the metabolism of A134U was observed after its repeated oral administration to rats. Oral dosing of dogs and rats with A134U resulted in peak plasma concentrations and total urinary recoveries of ACV greater than those observed after equivalent oral doses of ACV, suggesting that A134U might be an effective prodrug of ACV for use in the oral therapy of herpes simplex virus infections.

Topics: Acyclovir; Administration, Oral; Animals; Biotransformation; Chromatography, High Pressure Liquid; Dogs; Kinetics; Male; Radioimmunoassay; Rats; Time Factors

A direct radioimmunoassay for the detection of A134U in biological fluids and extracts has been developed. The entire assay, including scintillation counting, is performed using 12 X 55-mm centrifuge tubes and results in a sensitive, reliable, and relatively inexpensive procedure. The log-logit transformation is linear over a range of 1 to 30 pmol per sample. Intra-assay precision was found to be excellent with a coefficient of variation ranging from 4.1 to 14.5% for the standard curve with plasma and a coefficient of variation ranging from 4.0 to 17.8% for the standard curve with urine. Interassay precision and accuracy were also found to be good. With the antisera chosen for use, no cross-reactivity was found with acyclovir or its two known metabolites, while some cross-reactivity was seen with the corresponding two derivatives of A134U. Only very minor cross-reactivities were seen with a small number of other compounds out of a large number tested.

Topics: Acyclovir; Animals; Antiviral Agents; Cross Reactions; Dogs; Drug Stability; Humans; Rabbits; Radioimmunoassay; Rats