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Biomedical subjects

G B Elion

Publications and source records attributed to G B Elion.

At least 73 records · Page 4Linked to original sources
PubMed1982

Antileishmanial action of 4-thiopyrazolo (3.4-d) pyrimidine and its ribonucleoside. Biological effects and metabolism.

Thiopurinol [4-thiopyrazolo(3.4-dyprimidine, TPP] and its ribonucleoside (TPPR) were effective in vitro against the intracellular and extracellular forms of L. braziliensis and L. mexicana. They also inhibited the transformation of the amastigote of L. donovani to the promastigote. These thio-analogues had about the same activity as allopurinol [4-hydroxypyrazolo(3.4-d)pyrimidine, HPP] and its ribonucleoside (HPPR). the thiopyrazolopyrimidines were converted primarily to the ribonucleoside-5' -phosphate (TPPR-MP) and to an unidentified metabolite, but not to any of the adenine ribonucleoside analogues previously shown to be formed from allopurinol and its ribonucleoside. There was an antagonism between the growth-inhibitory effects of allopurinol and thiopurinol. This is consistent with the findings that the intracellular concentrations of TPP and TPPR-MP are sufficient to inhibit the conversion of allopurinol to allopurinol ribonucleotide (HPPR-MP) by the hypoxanthine-guanine phosphoribosyltransferase by 30 per cent and the amination of HPPR-MP by adenylosuccinate synthetase by 50 per cent respectively. Consequently, the incorporation of the aminated product (aminopyrazolopyrimidine) into RNA was substantially decreased. The difference in metabolism between the thio- and hydroxypyrazolopyrimidines suggests a difference in their mechanisms of action against the pathogenic leishmania.

Allopurinol↗
PubMed1982

Pyrazolo[3,4-d]pyrimidine ribonucleosides as anticoccidials. 1. Synthesis and activity of some nucleosides of purines and 4-(alkylthio)pyrazolo[3,4-d]pyrimidines.

The finding that 6-(methylthio)-9-beta-D-ribofuranosyl-9H-purine (6) was more toxic to the avian coccidium, Eimeria tenella, than to embryonic chick liver host cells in vitro prompted the synthesis and testing of analogues of this compound. It was revealed that the beta-D-ribofuranosyl moiety was an important structural feature and that several types of 2-substituents in the purine ring decreased efficacy, as did 3-deaza and 8-aza ring modifications of 6. In contrast, the pyrazolo[3,4-d]pyrimidine analogue of 6 (24) was an order of magnitude more active. Moreover, this analogue was 24-fold less toxic to the host cells than was 6. A series of 4-(alkylthio)-1-beta-D-ribofuranosyl-1H-pyrazolo[3,4-d]pyrimidines was prepared from 4-mercapto-1-beta-D-ribofuranosyl-1H-pyrazolo[3,4-d]pyrimidine (23) and various alkyl halides. The most effective compound in this series in vivo, 4-(ethylthio)-1-beta-D-ribofuranosyl-1H-pyrazolo[3,4-d]pyrimidine (25), cleared chicks of the parasite at 50 ppm in the diet and was much less toxic than was 24.

Animals↗
PubMed1982

Pyrazolo[3,4-d]pyrimidine ribonucleosides as anticoccidials. 2. Synthesis and activity of some nucleosides of 4-(alkylamino)-1H-pyrazolo[3, 4-d]pyrimidines.

A series of 4-(alkylamino)-1-beta-D-ribofuranosyl-1H-pyrazolo[3, 4-d]pyrimidines was synthesized by enzymatic and chemical methods. On the basis of the previous finding that 4-(alkylthio)-1-beta-D-ribofuranosyl-1H-pyrazolo[3,4-d]pyrimidines were effective anticoccidial agents, this series was examined for efficacy against Eimera tenella in chicks. The most active anticoccidial agent in the present study was the 4-cyclopentylamino derivative (8), which cleared chicks of the parasite at 200 ppm in the diet. Some members of this series were toxic to embryonic chick liver cells, mouse cells, and human cells in vitro. The 4-diethylamino derivative (16), which was not toxic in vitro, appeared to be toxic in chicks.

Animals↗
PubMed1982

Uptake, distribution, and anabolism of acyclovir in herpes simplex virus-infected mice.

The uptake, distribution, and anabolism of the nucleoside analog 9-(2-hydroxyethoxymethyl) guanine (acyclovir) were compared in herpes simplex virus-infected and uninfected mice. Analyses of tissue distribution and the concentration of acyclovir after either a single dose or multiple doses failed to reveal significant differences between drug levels in infected and uninfected animals. Extracts of tissues from [8-14C] acyclovir-treated animals were examined by high-performance liquid chromatography to detect the presence of any phosphorylated forms of the drug. The sensitivity of this method did not allow a reproducible demonstration of acyclovir anabolism in herpes simplex virus-infected tissues owing to the low numbers of infected cells per organ.

Acyclovir↗
PubMed1982

Immunosuppressive effects of the S-adenosylhomocysteine hydrolase inhibitor, 3-deazaadenosine.

Immunosuppressive effects of 3-deazaadenosine (3-DAA), an inhibitor of S-adenosylhomocysteine hydrolase, were tested in vivo in immune assays against sheep red blood cells (SRBC), involving serum titrations for hemagglutinins and hemolysins, cellular cytotoxicity tests and the direct plaque-forming cell assay. At daily doses up to 100 mg/kg, the compound was suppressive when injected before antigen and the effect appeared to be dose-dependent (ED50 = 52.6 +/- 4.9 mg/kg). When doses of 25 mg/kg of 3-DAA were given before antigen, co-injections of 250 mg/kg of L-homocysteine (L-HC) potentiated the suppressive effect, although L-HC alone was inactive. Daily administration of 100 mg/kg of 3-DAA or 250 mg/kg of L-HC alone was not suppressive when given after the antigen; however, in combination they were able to induce suppression. The possible biochemical mechanisms of the suppression, particularly those involving the inhibition of S-adenosylmethionine-dependent methylation reactions, are discussed.

Adenosylhomocysteinase↗
PubMed1982

Differential interference by azathioprine and 6-mercaptopurine with antibody-mediated immunoregulation: synergism of azathioprine and antibody in the control of an immune response.

Comparative studies on the effects of immunosuppressive agents azathioprine (AZ) and 6-mercaptopurine (6-MP) in antibody-mediated immunoregulation are reported. To determine the degree of interference of these agents with the generation of antibody molecules controlling an anti-SRBC response, the donors of mouse anti-SRBC sera were given daily doses of the drugs. Primary antisera from AZ-treated donors were not significantly inhibited by daily doses of 180, 270, and 360 mumol/kg in their ability to suppress the direct PFC response; on the other hand 6-MP was inhibitory at the two higher equimolar dose levels. When the antisera were used in the antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (AD phi) assays, similar differential effects of the two agents were found. Multiple doses of AZ and 6-MP given to the donors of ADCC effector cells enhanced the capacity of these cells to lyse antibody-sensitized SRBC target cells. The enhancement of ADCC with 6-MP was less manifest than that with AZ. When injected before the antigen, AZ acted synergistically with the antibody in the control of the direct PFC response. Possible mechanisms by which AZ can interact with antibody-mediated immune regulation are discussed.

Animals↗
PubMed1981

Inhibition of purified human and herpes simplex virus-induced DNA polymerases by 9-(2-hydroxyethoxymethyl)guanine triphosphate. Effects on primer-template function.

The inhibition of highly purified herpes simplex virus (HSV)-induced and host cell DNA polymerases by the triphosphate form of 9-(2-hydroxyethoxymethyl)guanine (acyclovir; acycloguanosine) was examined. Acyclovir triphosphate (acyclo-GTP) competitively inhibited the incorporation of dGMP into DNA, catalyzed by HSV DNA polymerase; apparent Km and Ki values of dGTP and acyclo-GTP were 0.15 microM and 0.003 microM, respectively. HeLa DNA polymerase alpha was also competitively inhibited; Km and Ki values of dGTP and acyclo-GTP were 1.2 microM and 0.18 microM, respectively. In contrast, HeLa DNA polymerase beta was insensitive to the analogue. The "limited" DNA synthesis observed when dGTP was omitted from HSV or alpha DNA polymerase reactions was inhibited by acyclo-GTP in a concentration-dependent manner. Prior incubation of activated DNA, acyclo-GTP, and DNA polymerase (alpha or HSV resulted in a marked decrease in the utilization of the primer-template in subsequent DNA polymerase reactions. This decreased ability of preincubated primer-templates to support DNA synthesis was dependent on acyclo-GTP, enzyme concentration, and the time of prior incubation. Acyclo-GMP-terminated DNA was found to inhibit HSV DNA polymerase-catalyzed DNA synthesis. Kinetic experiments with variable concentrations of activated DNA and fixed concentrations of acyclo-GMP-terminated DNA revealed a noncompetitive inhibition of HSV-1 DNA polymerase. The apparent Km of 3'-hydroxyl termini was 1.1 X 10(-7) M, the Kii and Kis of acyclo-GMP termini in activated DNA were 8.8 X 10(-8) M and 2.1 X 10(-9) M, respectively. Finally, 14C-labeled acyclo-GMP residues incorporated into activated DNA by HSV-1 DNA polymerase could not be excised by the polymerase-associated 3',5'-exonuclease activity.

Acyclovir↗
PubMed1981

Metabolism of acyclovir in virus-infected and uninfected cells.

The metabolism of acyclovir to its mono-, di-, and triphosphate derivatives was examined in uninfected and virus-infected cells. The level of phosphorylation of acyclovir was dependent upon virus type, cell line, exogenous drug concentration, and exposure time. Acyclovir phosphorylation was inhibited by exogenously added nucleosides. The order of inhibition was deoxythymidine greater than deoxycytidine greater than guanosine greater than or equal to deoxyguanosine. Acyclovir triphosphate persisted in infected cells after removal of the drug from the medium. The initial half-life of the triphosphate was 1.2 h in the absence of the drug in the medium, but triphosphate levels reached a plateau after 6 h. The presence of low concentrations of the drug in the medium resulted in a longer persistence of the intracellular triphosphate and a higher plateau level.

Acyclovir↗
PubMed1981

Phosphorylation of acyclovir [9-(2-hydroxyethoxymethyl)guanine] in Epstein-Barr virus-infected lymphoblastoid cell lines.

The extent of phosphorylation of 9-(2-hydroxyethoxymethyl)guanine (acyclovir [ACV]) in fresh peripheral leukocytes, in Epstein-Barr virus (EBV)-infected lymphoblastoid cell lines, and in herpes simplex virus type 1-infected lymphoblastoid (P3HR-1) and monkey kidney (Vero) cells was determined by high-pressure liquid chromatography, Mono-, di-, and triphosphorylated derivatives of [8-14C]ACV were detected at low levels at various times after superinfection of Raji cells with EBV. The extent of phosphorylation appeared to be related to the concentration of ACV in the medium. Small amounts of ACV mono-, di-, and triphosphates were formed in fresh peripheral leukocyte preparations from EBV- seropositive and -seronegative donors. Comparable ACV monophosphate levels were detected in EBV-negative BJAB and the EBV-positive BJAB/GC cell lines; however, no di- or triphosphate derivatives were detected. Comparable ACV-monophosphate levels were detected in both P3HR-1 and HSV-infected P3HR-1 cell lines; however, larger amounts of ACV di- and triphosphorylated derivatives were detected in the HSV-infected P3HR-1 cells. ACV was converted to the triphosphate to a greater extent in HSV-infected Vero cells than in mock-infected Vero cells or in HSV-infected P3HR-1 cells. ACV or its phosphorylated derivatives were converted to guanine nucleotides to a greater extent in lymphoblastoid cells than in fibroblasts (Vero). In conclusion, neither the productive replication of EBV nor the presence of latent viral DNA is required for ACV monophosphate formation in B lymphoblastoid cells. ACV triphosphate, however, was detected only in cells infected productively with EBV.

Acyclovir↗
PubMed1981

Differential inhibition by azathioprine and 6-mercaptopurine of specific suppressor T cell generation in mice.

Doses of 100 mg/kg/day and 55 mg/kg/day of azathioprine (AZ) and 6-mercaptopurine (6-MP), respectively, significantly suppressed anti sheep red blood cell (SRBC) responses in CBA mice, assayed by the complement-dependent cellular cytotoxicity (CDCC) test and by serum titration. Four injections of similar doses of the agents were given to donors of carrier-specific suppressor T cells, generated by two immunizations with SRBC, and transferred to syngeneic recipients sensitized with the TNP hapten on SRBC carrier. Anti-TNP response of the recipients was assayed by the CDCC, using TNP-coated EL4 target cells. Whereas 6-MP, given after or before the second immunization of the donors with carrier SRBC, caused abrogation of suppressor cell activity, equimolar doses of AZ were less inhibitory to suppressor cell generation.

Animals↗
PubMed1981

The disposition of acyclovir in different species.

The absorption, distribution and biotransformation of the antiviral drug acyclovir were investigated in several species. Its oral administration resulted in better absorption and higher plasma levels in the dog and mouse than in the rat and rhesus monkey. Although more total drug was absorbed, the fraction of the oral dose of acyclovir absorbed declined with increasing doses of drug. When 14C-labeled acyclovir was given s.c. to mice and rats it was distributed into all the tissues examined, including the brain. In the dog, the drug was present in the cerebrospinal fluid, the aqueous humor and saliva after an oral dose. Binding of acyclovir to plasma proteins was less than 35%. In metabolism studies with radioactive acyclovir, high-performance liquid chromatography showed that 94 and 95% of the urinary radioactivity in mice and rats was unchanged acyclovir. Minor urinary metabolites were identified as 9-carboxymethoxymethylguanine and 8-hydroxy-9-(2-hydroxy-ethoxymethyl)guanine. There was no enhanced metabolism of the drug after its repeated daily administration to mice or dogs.

Acyclovir↗
PubMed1981

Pharmacokinetics and bioavailability of acyclovir in the dog.

Acyclovir [9-(2-hydroxyethoxymethyl)guanine, ZoviraxTM] is a selective antiviral agent with indications for the treatment of the herpes virus group of injections. In a cross-over design study, three male beagle dogs were given acyclovir i.v. and p.o. (capsule) at 5, 20 and 50 mg/kg doses. Additionally, dogs received acyclovir by gavage at these three doses. After i.v. injection, the acyclovir plasma concentration-time profile, determined by radioimmunoassay, exhibited a biexponential decay with a terminal t1/2 of 2.2 to 3.6 hr. Plasma clearance (3.48-5.83 ml/min/kg) approximated the normal glomerular filtration rate in dogs and the Vd beta (0.97-1.17 liters/kg) indicated distribution of the drug into tissues. Similar kinetic findings were obtained after i.v. administration of [8-14C]acyclovir to dogs. The radioactivity recovered in the urine was 95% of the dose and 92% of the urinary 14C was identified as acyclovir. The remainder of 14C corresponded to minor urinary metabolites. The plasma acyclovir concentration-time curves generated from oral (capsule and gavage) data were fit to a one-compartment open pharmacokinetic model. The half-life and Vd parameters were similar to those calculated for the i.v. route. Peak plasma drug concentrations were reached within 2 hr of dosing. Good oral bioavailability (91 and 80%) was observed after the administration of a capsule at the lower doses (5 and 20 mg/kg, respectively) but bioavailability declined (52%) at the 50 mg/kg dose, indicating the possibility that the gastrointestinal absorption of acyclovir is a saturable process.

Acyclovir↗
PubMed1980

Adenosine analogues as substrates and inhibitors of S-adenosylhomocysteine hydrolase in intact lymphocytes.

A number of adenosine analogues have been examined for their ability to interact with S-adenosyl-L-homocysteine (SAH) hydrolase in intact mouse lymphocytes. In the presence of erythro-9-(2-hydroxy-3-nonyl)adenine, 3-deazaadenosine, 8-azaadenosine, formycin A, 2-aminoadenosine, 2-fluoroadenosine, N6-methyladenosine, N6-hydroxyadenosine, purine ribonucleoside and inosine were each metabilized to radioactive analogues of SAH when cells were labeled with either L-[2-3H]methionine or L-[35S]homocysteine. Tubercidin was shown to undergo metabolism both to S-[3H]tubercidinyl-L-methionine and to S-[3H]tubercidinyl-L-homocysteine in cells labeled with [2-3H]methionine. 9-beta-D-Arabinofuranosyladenine and 2'-deoxyadenosine caused marked elevations of [3H]SAH in cells preloaded with [2-3H]methionine but were not themselves metabolized detectably to SAH analogues. Adenine and 5'-deoxyadenosine also caused substantial elevations of [3H]SAH under these same conditions. Some of the adenosine analogues shown to be metabolized to SAH analogues also caused an elevation of SAH in the lymphocytes. These results indicate the potential of adenosine analogues to interfere with cellular methylation reactions due either to their inhibition of SAH hydrolase or to their metabolism, via this enzyme, to SAH analogues.

Adenosine↗