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Biomedical subjects

G B Elion

Publications and source records attributed to G B Elion.

At least 19 recordsLinked to original sources
PubMed1979

Metabolism of pyrazolo(3,4-d)pyrimidines in Leishmania braziliensis and Leishmania donovani. Allopurinol, oxipurinol, and 4-aminopyrazolo(3,4-d)pyrimidine.

Leishmania donovani and Leishmania braziliensis grown in culture formed millimolar concentrations of allopurinol ribonucleoside 5'-monophosphate from [6-14C]allopurinol. In addition, allopurinol 1-ribonucleoside, oxipurinol riboside 5'-monophosphate, and three new metabolites of allopurinol, namely, 4-aminopyrazolo(3,4-d)pyrimidine ribonucleoside 5'-monophosphate and the corresponding di- and triphosphates (1-ribosyl 4-aminopyrazolo(3,4-d)pyrimidine 5'-diphosphate and 1-ribosyl 4-aminopyrazolo(3,4-d)pyrimidine 5'-triphosphate) were identified in the parasitic cells. They were formed via a unique amination reaction from 1-ribosyl allopurinol 5'-phosphate, analogous to the conversion of IMP to AMP. [6-14C]Allopurinol was incorporated into RNA of L. donovani in the form of 4-aminopyrazolo(3,4-d)pyrimidine. Adenine reversed the growth inhibition of allopurinol and prevented its metabolism to all of the ribonucleotide metabolites. L. donovani was 2- to 4-fold more active in its metabolism of allopurinol to ribonucleotides than L. braziliensis. 4-Aminopyrazolo(3,4-d)pyrimidine inhibited cell growth and resulted in high intracellular levels of 1-ribosyl allopurinol 5'-phosphate and smaller amounts of the 4-aminopyrazolo(3,4-d)pyrimidine ribonucleotides. The metabolism of allopurinol to 4-aminopyrazolo(3,4-d)pyrimidine ribonucleotides and its resultant cytotoxicity occurs in these parasitic protozoans, but not in mammalian cells.

Adenine↗
PubMed1979

Acyclovir kinetics after intravenous infusion.

The disposition and safety of the antiviral drug acyclovir were studied in 14 subjects with advanced malignancies. Acyclovir was administered by a 1-hr intravenous infusion at doses of 0.5, 1.0, 2.5, and 5.0 mg/kg. At the end of infusion, mean peak plasma levels (+/- SEM), determined by radioimmunoassay, were 6.4 +/- 0.7, 12.1 +/- 2.3, 14.9 +/- 2.7, and 33.7 +/- 7.1 microM. The plasma concentration-time profiles could be described by a biexponential equation. The half-life of acyclovir in the slow disposition phase ranged from 2.2 to 5 hr and the drug was detected in the plasma for at least 18 hr after infusion. The total body clearance ranged from 117 to 396 ml/min/1.73 m2. A proportionality between area under the curve and dose suggests that acyclovir exhibits dose-independent kinetics in the dose range studied. There was wide variation in cumulative urinary excretion of unchanged drug, ranging from 30 to 69% of the dose. From renal clearances of acyclovir, which were higher than creatinine clearances, it appears that both glomerular filtration and tubular secretion contribute to its renal excretion. Analysis of the urine by reverse-phase high-performance liquid chromatography revealed the presence of the metabolite 9-carboxymethoxymethylguanine. There was no indication of toxicity either clinically or from laboratory findings in any of the study subjects. This study demonstrates that in addition to selectivity and low toxicity, the kinetic profile and metabolic disposition of acyclovir make it an attractive candidate for therapy in a variety of herpes infections.

Aged↗
PubMed1979

Comparative metabolism of a new antileishmanial agent, allopurinol riboside, in the parasite and the host cell.

HPP-Rib is a potent antileishmanial agent, which has been useful in defining new and unusual purine metabolizing pathways in leishmaniae, in comparison with those in the host. The ribosyl linkage both in the parasite and in the host is resistant to cleavage. In the parasite there is a selective and marked conversion of HPP-Rib to HPP-Rib-5'-P and 4-APP ribonucleotides as well as incorporation into RNA, which does not occur in the host. These findings with HPP-Rib suggest a new chemotherapeutic approach which may be exploited in the treatment of leishmaniasis.

Allopurinol↗
PubMed1979

Effect of acycloguanosine treatment of acute and latent herpes simplex infections in mice.

Systemic treatment of mice with the nucleoside analog 9-(2-hydroxyethoxymethyl)guanine (acycloguanosine [aciclovir]) was found to be highly effective against acute type 1 herpes simplex virus infection of the pinna. The drug ablated clinical signs and reduced virus replication both in tissue local to the inoculation site and within the nervous system. Provided that moderate-sized virus inocula were used, acycloguanosine treatment reduced or prevented the establishment of a latent infection in the dorsal root ganglia relating to the sensory nerve supply of the ear. However, although it aborted artificially produced infections in dorsal root ganglia, acycloguanosine was found not to be effective against the latent infection once established. This finding strongly indicated that latent herpes simplex virus in mice can exist in a nonreplicating form.

Animals↗
PubMed1979

Inhibition of herpes simplex virus-induced DNA polymerase activity and viral DNA replication by 9-(2-hydroxyethoxymethyl)guanine and its triphosphate.

The effect of the nucleoside analog 9-(2-hydroxyethoxymethyl)guanine (acycloguanosine) on herpes simplex virus type 1 DNA synthesis was examined. Acycloguanosine inhibited herpesvirus DNA synthesis in virus-infected cells. The synthesis of host cell DNA was only partially inhibited in actively growing cells at acycloguanosine concentrations several hundred-fold greater than the 50% effective dose for herpes simplex virus type 1. Studies using partially purified enzymes revealed that the triphosphate of this compound inhibited the virus-induced DNA polymerases (DNA nucleotidyltransferases) to a greater degree than the DNA polymerase of the host cell, that the inhibition was dependent upon the base composition of the template, and that the triphosphate was a better substrate for the virus-induced polymerases than for the alpha cellular DNA polymerases.

Animals↗
PubMed1977

Selectivity of action of an antiherpetic agent, 9-(2-hydroxyethoxymethyl) guanine.

A guanine derivative with an acyclic side chain, 2-hydroxyethoxymethyl, at position 9 has potent antiviral activity [dose for 50% inhibition (ED(50)) = 0.1 muM] against herpes simplex virus type 1. This acyclic nucleoside analog, termed acycloguanosine, is converted to a monophosphate by a virus-specified pyrimidine deoxynucleoside (thymidine) kinase and is subsequently converted to acycloguanosine di- and triphosphates. In the uninfected host cell (Vero) these phosphorylations of acycloguanosine occur to a very limited extent. Acycloguanosine triphosphate inhibits herpes simplex virus DNA polymerase (DNA nucleotidyltransferase) 10-30 times more effectively than cellular (HeLa S3) DNA polymerase. These factors contribute to the drug's selectivity; inhibition of growth of the host cell requires a 3000-fold greater concentration of drug than does the inhibition of viral multiplication. There is, moreover, the strong possibility of chain termination of the viral DNA by incorporation of acycloguanosine. The identity of the kinase that phosphorylates acycloguanosine was determined after separation of the cellular and virus-specified thymidine kinase activities by affinity chromatography, by reversal studies with thymidine, and by the lack of monophosphate formation in a temperature-sensitive, thymidine kinase-deficient mutant of the KOS strain of herpes simplex virus type 1 (tsA1).

Antiviral Agents↗
PubMed1976

2-Fluoroadenosine 3':5'-monophosphate. A metabolite of 2-fluoroadenosine in mouse cytotoxic lymphocytes.

2-Fluoroadenosine (F-Ado) is a potent inhibitor of lymphocyte-mediated cytolysis studied in vitro. The inhibition of cytolysis by F-Ado was potentiated markedly by an inhibiotr (Ro 20-1724) of adenosine 3':5'-monophosphate (cAMP) phosphodiesterase and, unlike the inhibition caused by adenosine, was irreversible when the cytotoxic lymphocytes were incubated with F-Ado and were then washed free of exogenous nucleoside. Incubation of cytotoxic lymphocytes with F-Ado resulted in the rapid, dose-dependent formation of 2-fluoroadenosine 5'-triphosphate (F-ATP); the build-up of F-ATP within these cells was accompanied by a reciprocal depletion of ATP. Once formed intracellularly, the F-ATP was not diminished during a subsequent 30-min incubation of the cells in F-Ado-free medium. 2-Fluoroadenosine 3':5'-monophosphate (F-cAMP), a novel compound, was synthesized chemically. This cAMP analogue was found to be highly cross-reactive in a radioimmunoassay specific for cAMP and to be equipotent to cAMP in its ability to activate a crude preparation of protein kinase derived from rat brain. A column chromatographic procedure was devised whereby F-cAMP and cAMP could be purified simultaneously from tissue extracts. Treatment of cytotoxic lymphocytes with F-Ado resulted in the formation of presumptive F-cAMP in amounts greater than that of cAMP, as determined by the concentration of F-Ado added to the medium and was not observed when the lymphocytes were incubated with either adenosine or 2-chloroadenosine, two agents which caused large increases in cAMP. The simultaneous presence of Ro 20-1724 enhances greatly the formation of F-cAMP from F-Ado without affecting the pool size of F-ATP. Removal of exogenous F-Ado from cells previously incubated with this drug and subsequent incubation of these cells in drug-free medium did not result in a substantial reduction in intracellular F-Ado (via prior incubation with F-Ado); 2'-deoxyadenosine was also effective in this capacity, while 9-beta-D-arabinofulanosyladenine was without effect. The level of cAMP was elevated transiently, in a dose-dependent manner, by F-Ado, and returned to control value after removal of exogenous F-Ado from the cells. Ro 20-1724 enhanced greatly this transient elevation of cAMP caused by F-Ado.

Adenosine↗
PubMed1976

Deoxycytidine kinase from calf thymus. Substrate and inhibitor specificity.

Kinetic constants were determined for 34 nucleoside substrates of deoxycytidine kinase (EC 2.7.1.74) from calf thymus. Substrate efficiency was assessed by the ratio of Vmax to Km. Inhibition constants were determined for 61 nonsubstrate nucleosides or nucleoside analogues. The enzyme was relatively specific for the pentose moiety of nucleoside substrates. beta-D-2'-Deoxyribonucleosides were more efficient substrates than the corresponding beta-D-arabinonucleosides. Unexpectedly, the L isomer of the beta-arabinonucleoside of cytosine was a more efficient substrate than was the D isomer. beta-Cytidine and beta-5-azacytidine were the only beta-D-ribonucleosides studied that had detectable substrate activity. alpha-Cytidine was an inhibitor but not a substrate. Nucleosides containing a variety of sugar moieties other than those mentioned above did not have detectable substrate activity. The enzyme was relatively nonspecific for the base moiety of nucleoside substrates. 2'-Deoxyribonucleosides of a variety of pyrimidines, purines, and other heterocycles were substrates. Cytosine was the most preferred pyrimidine moiety. 5-Substitution, except with fluorine, decreased substrate efficiency with nucleosides of cytosine or uracil. 2-Fluoradenine was the most preferred purine moiety. The effects of various purine ring substituents were interdependent. Nucleosides containing bulky, hydrophobic substituents on either the base or the pentose moiety had no substrate activity but were relatively potent competitive inhibitors. This suggested the presence of a hydrophobic region on the surface of the enzyme near the active site.

Adenine↗