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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mechanisms of the effects of the dTTP analogues 3'-azido-3'-deoxythymidine 5'-triphosphate (AZTTP) and 3'-amino-3'-deoxythymidine 5'-triphosphate (NH2 TTP) upon the HIV-1 reverse transcriptase (RT) are discussed. These compounds block the RT in vitro and do so by different kinetic mechanisms. Infidelity of replication is a hallmark of the HIV-1 RT, and replication errors by the enzyme on RNA and DNA templates are discussed. The enzyme's infidelity has ramifications for inhibition: On the one hand, the propensity to produce mutations enhances the ability of the virus to escape inhibitors whereas on the other hand, the infidelity of the reverse transcriptase may allow the development of imaginative inhibitor strategies.
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PMID:Inhibitors of HIV-1 reverse transcriptase and fidelity of in vitro DNA replication. 128 1

5'-O-Phosphonomethylation of different pyrimidine 2',3'-dideoxynucleosides was accomplished by reaction of the latter with diethyl [(p-toylsulfonyl)oxy]methanephosphonate (1) in the presence of sodium hydride. The base-phosphonomethylated (15-19) and sugar-phosphonomethylated (8-12) derivatives could be readily distinguished by 1H and 13C NMR and MS analysis. Protection of the uracil or thymine residue with a N3-benzoyl group failed to prevent base modification. However, O4-methyl-protected 2',3'-dideoxyuridine readily afforded the 5'-O-phosphonomethylated derivative 12, which was converted to both the 2',3'-didoxyuridine analogue 27 and the 2',3'-dideoxycytidine counterpart 29. The 5'-O-phosphonomethyl derivatives of 3'-deoxythymidine (23), 2',3'-dideoxyuridine, (27), 2',3'-dideoxycytidine (29), 3'-O-methylthymidine (26), and 3'-amino-3'-deoxythymidine (28) did not show an appreciable anti-HIV activity in MT-4 cells. In contrast, the 5'-O-phosphonomethyl derivatives of 3'-deoxy-3'-fluorothymidine (24) and 3'-azido-3'-deoxythymidine (25) inhibited HIV-1 cytopathogenicity by 50% at a concentration of approximately 1 microM.
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PMID:5'-O-phosphonomethyl-2',3'-dideoxynucleosides: synthesis and anti-HIV activity. 169 45

The recent finding that 3'-amino-3'-deoxythymidine 5'-triphosphate is a noncompetitive inhibitor of the HIV-1 reverse transcriptase (Kedar, P.S.; et al. Biochemistry 1990, 29, 3603-3611), prompted an investigation of the conformation of 3'-amino-3'-deoxythymidine. An X-ray diffraction study has revealed that the glycosidic torsion angle of the nucleoside is in the less common syn region and this solid-state geometry is stabilized by a three-dimensional network of self-associated hydrogen-bonded molecules. On the other hand, the aqueous solution conformation, as determined by 1H NMR, places the glycosidic torsion angle in the more usual anti region with the sugar in an equilibrium between C3'-endo and C2'-endo puckering. The energy barrier between the solid-state and solution conformation is relatively low as was demonstrated by the MM2 calculations.
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PMID:Solid-state and solution conformation of 3'-amino-3'-deoxythymidine, precursor to a noncompetitive inhibitor of HIV-1 reverse transcriptase. 171 58

Treatment of 3'-amino-3'-deoxythymidine (1) with carboxylic acid anhydrides afforded the corresponding acylamino derivatives 2a-f. Reaction of 1 with a variety of isothiocyanates led to the corresponding thioureido derivatives 3a-i. Also, conversion of 1 into 3'-carbylamino-3'-deoxythymidine (7) is reported. The compounds 2, 3, and 8 were evaluated for their anti-HIV activity in MT-4 cells, but did not show sufficient efficacy.
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PMID:Synthesis of N-substituted 3'-amino-3'-deoxythymidines and their biological evaluation against HIV. 209 99

3'-Azido-3'-deoxythymidine (AZT), the main antiretroviral drug used against Human Immunodeficiency Virus, was approved by the Food and Drug Administration in 1987 with only little knowledge concerning its metabolism. The aim of our study was to evaluate the interspecies variability of AZT metabolism in primary cultures of hepatocytes, freshly isolated from rats, dogs, monkeys, and humans. Cultures were exposed to 10 or 100 microM [3H]AZT. Extracellular and intracellular compartments were analyzed using a HPLC method. Intracellular and extracellular metabolic patterns were qualitatively similar, but very low amounts of AZT and metabolites were detected within hepatocytes. In all species, the 3'-azido-3'-deoxy-5'-O-beta-D-glucopyranuronosylthymidine (GAZT) was identified as the major metabolite of AZT. In addition to this glucuronide, two minor peaks were detected: one coeluting with 3'-amino-3'-deoxythymidine(AMT); and the other with a retention time corresponding, on the basis of the publications in this field, to 3'-amino-3'-deoxythymidine glucuronide. However, further investigation allowed this compound to be characterized as tritiated water, possibly representing a catabolic endproduct of AZT. Although glucuronidation was the main metabolic pathway in the four species studied, AZT biotransformation rate was much lower in rat and dog hepatocytes than in monkey and human ones. Finally, an excellent correlation was obtained between in vivo and in vitro metabolic data.
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PMID:Comparative metabolism of 3'-azido-3'-deoxythymidine in cultured hepatocytes from rats, dogs, monkeys, and humans. 762 94

The effects of indomethacin and naproxen on zidovudine (ZDV) pharmacokinetics were studied in six patients with the acquired immunodeficiency syndrome (AIDS), AIDS related complex (ARC) or asymptomatic HIV disease using a placebo-controlled crossover design. Indomethacin 25 mg twice daily or naproxen 250 mg twice daily did not alter ZDV pharmacokinetics compared with placebo. The mean AUC value for the glucuronidated metabolite, GZDV, was reduced from 26.6 +/- 11.7 mumol l-1 h in the presence of placebo to 20.9 +/- 8.3 mumol l-1 h (95% C.I. of the difference 1.39-9.98; P < 0.05) following treatment with naproxen 250 mg twice daily for 3 days. The small decrease in plasma GZDV in the naproxen phase reflects an increase in clearance of ZDV to other metabolites and/or a decrease in the formation clearance to GZDV and/or an increase in the clearance of GZDV. A decrease in formation clearance to GZDV would be consistent with the results of in vitro studies reported previously. No significant increase in ZDV concentration in the presence of naproxen may reflect a lower sensitivity of parent drug measurements to selective inhibition of parallel pathways of metabolism. The clinical significance of these findings is unknown but toxicity may be increased if a decreased formation of GZDV is accompanied by shunting of metabolism to 3'-amino-3'-deoxythymidine which is alleged to be cytotoxic.
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PMID:The effects of indomethacin and naproxen on zidovudine pharmacokinetics. 837 16

1. The anti-HIV drug zidovudine (3'-azido-2',3'-dideoxythymidine; ZDV) has three important pathways of metabolism. ZDV is a prodrug and must be phosphorylated in lymphocytes in order to exert its antiviral action. However, in quantitative terms this is a minor pathway probably accounting for less than 1% of the overall metabolic profile. The predominant pathway of metabolism is glucuronidation to GZDV and the metabolite is renally excreted. A further metabolite, derived by reduction of the azido moiety is 3'-amino-3'-deoxythymidine (AMT). 2. Zidovudine glucuronidation has been characterised in human liver microsomes. A number of drugs (e.g., naproxen, indomethacin and probenecid) have been shown to inhibit the in vitro conjugation of ZDV. Some of these drugs have also been co-administered with ZDV in HIV-positive patients. Significant pharmacokinetic interactions have been demonstrated with probenecid, naproxen and fluconazole. 3. 3'-amino-3'-deoxythymidine formation is probably mediated by both cytochrome P450 isozymes and NADPH-cytochrome P450 reductase. Peak plasma concentrations of AMT are approximately 10-15% of ZDV in patients. This is a potentially important metabolite because of its alleged cytotoxicity. 4. Measurement of intracellular ZDV phosphates in patients provides the key to our understanding of both the efficacy and toxicity of ZDV. Important recent work has demonstrated that as patients deteriorate (i.e., CD4 counts decrease below 100 x 10(6)/L), there is a corresponding increase in intracellular ZDV-monophosphate. This could have toxicological implications.
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PMID:Metabolism of Zidovudine. 869 Feb 33

The plasma pharmacokinetics of zidovudine (ZDV, 3'-azido-3'-deoxythymidine) and its toxic catabolite 3'-amino-3'-deoxythymidine (AMT) was investigated in six HIV-infected patients receiving 100 or 500 mg of ZDV by oral administration. Zidovudine plasma pharmacokinetic parameters were in good agreement with previously reported data with a total plasma clearance (Cl) of 2.33 and 2.49 liters/hr/kg and an apparent elimination t1/2 of 1.14 and 1.20 hr at 100- and 500-mg doses, respectively. 3'-Amino-3'-deoxythymidine was detectable in the plasma of all patients, with maximum plasma levels (Cmax) being reached within 2 hr post-dosing. No dose relationship in the formation of AMT expressed as the area under the plasma level-time curve (AUC) was established within the studied dose range of ZDV. The AUCAMT was 145.4 and 92.4 ng/ml.hr after administration of 100 and 500 mg of ZDV, respectively. These results reflect an unexpectedly large interindividual variation in the formation of AMT. The lack of linearity in AMT pharmacokinetics prevents the prediction of its plasma levels based only on the administered oral dose of ZDV.
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PMID:Comparative pharmacokinetics of zidovudine and its toxic catabolite 3'-amino-3'-deoxythymidine in HIV-infected patients. 883 1

Human placental tissue and human trophoblast cells (JAr) were examined after exposure to the anti-HIV nucleoside analog AZT (Zidovudine) for the presence of 3'-amino-3'-deoxythymidine (AMT), a toxic catabolite. Placental cells were exposed to 7.6 mM AZT for 48 hr, and placental lobular tissue was perfused with 3.8 mM AZT for 14 hr. Cell homogenates were prepared, and supernatants were subjected to HPLC analysis. Despite large cellular concentrations of AZT, AMT was not detected in any of the samples analyzed. Exposure of JAr cells to this concentration of AZT produces a 72% inhibition of cell proliferation when compared with unexposed controls. Based upon the results of the current study, AMT was not formed by placental cells exposed to AZT and, thus, not a mechanism for toxicity after in vitro exposure to AZT.
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PMID:Human placenta does not Reduce AZT (zidovudine) to 3'-amino-3'-deoxythymidine. 920 59

The penetration of 3'-amino-3'-deoxythymidine (AMT) into the cerebrospinal fluid (CSF) of HIV-1-infected patients has been investigated. In 23 patients who used zidovudine (ZDV) chronically, CSF and plasma samples were assayed for AMT and ZDV. The influences of time between ZDV oral administration and lumbar puncture, of ZDV dose, and of the medical indication for lumbar puncture based on the concentration of AMT in CSF and on the CSF-plasma concentration ratio were investigated. AMT can be detected in the CSF after oral administration of ZDV; concentrations of AMT in CSF ranged from 0.75 to 4.8 ng/ml (median, 1.7 ng/ml). The median CSF-plasma concentration ratio was 1, and equaled that for ZDV. CSF and plasma concentrations of AMT were approximately threefold higher in patients with cerebral toxoplasmosis; the CSF-plasma concentration ratio remained equal to unity in these cases. This phenomenon might be caused by a pharmacokinetic interaction between AMT and pyrimethamine, sulfadiazine, folinic acid, or a combination of these. The clinical relevance of AMT, especially the possibility of decreased efficacy of ZDV, throughout the body and in the central nervous system, and the involvement of this metabolite in ZDV-induced myelosuppression, remains to be established.
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PMID:Penetration of 3'-amino-3'-deoxythymidine, a cytotoxic metabolite of zidovudine, into the cerebrospinal fluid of HIV-1-infected patients. 924 Nov 12


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