Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

AZT susceptibility of sequential 12 HIV-1 isolates was investigated by culture method. These isolate were obtained from three patients who had received AZT for at least 12 months and switched to ddI after they appeared to deteriorate clinically. Cultures of isolate from a patient before therapy with AZT or ddI did not show cytopathic effect (CPE) in the presence of 0.1 microM or 1.0 microM AZT. Culture of 2 isolates from two patients treated with AZT more than 6 months before switched to ddI therapy showed CPE in the presence of AZT and HIV-1 p24 antigen was detected by ELISA in the supernatants. Culture of 6 of 7 isolates from three patients treated with ddI after long-term therapy with AZT also showed CPE in the presence of 1.0 microM AZT and HIV-1 p24 antigen was detected. These results demonstrated that AZT-resistant variant was still a dominant population in the isolate from patients after 11 to 13 months of discontinuing AZT therapy.
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PMID:[Investigation of AZT susceptibility of sequential HIV-1 isolates from patients treated with ddI after long-term therapy with AZT]. 808 46

In order to enhance the brain delivery of 2'-F-ara-ddI,2'-F-ara-ddP 6 was synthesized and its in vitro and in vivo bioconversion reaction studied. For the study, a new efficient synthetic method for 2'-F-ara-ddP 6 was developed from 5-benzoyl-1,2-O-isopropylidene-3-deoxyribose 1. For in vitro study 2'-F-ara-ddP was incubated in pH 2, mouse liver homogenate, and mouse serum at 37 degrees C. No degradation was observed in pH 2 and serum, while in liver homogenate 2'-F-ara-ddP was almost completely converted to 2'-F-ara-ddI within 20 min (t1/2 = 3.54 min). In order to determine the role of xanthine oxidase in the conversion of 2'-F-ara-ddP to 2'-F-ara-ddI, in vitro studies were conducted in phosphate buffer (pH 7.4) in the presence or absence of allopurinol, in which the half-lives of 2'-F-ara-ddP were 7.4 and 3.4 h, respectively, indicating the conversions were catalyzed by the xanthine oxidase. A similar experiment with aldehyde oxidase isolated from the human liver did not affect the biotransformation. The biotransformation was also detected in the brain homogenate, although the rate of conversion was low and incomplete. In order to assess the bioconversion in vivo, pharmacokinetic studies of 2'-F-ara-ddP and 2'-F-ara-ddI were conducted in mice. The maximum serum concentrations of 2'-F-ara-ddI administered itself and as 2'-F-ara-ddP reached 48.1 +/- 10.00 and 89.3 +/- 26.0 microM and were observed in 1 and 0.25 h, respectively. The data indicate that 2'-F-ara-ddI is absorbed at a slower rate than that of 2'-F-raa-ddP. The bioavailability of the prodrug after oral administration was 60.7%. The concentration of 2'-F-ara-ddI following oral administration of 2'-ara-ddI was close to the detection limits while 2'-F-ara-ddI was detected at significantly higher concentrations in the brain after oral administration of 2'-F-ara-ddP. From this study, we have administered the enhanced brain delivery of anti-HIV nucleoside utilizing an in vivo biotransformation system.
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PMID:Enhanced brain delivery of an anti-HIV nucleoside 2'-F-ara-ddI by xanthine oxidase mediated biotransformation. 814 33

Zidovudine (3'-azido-2',3'-dideoxythymidine) resistant isolates of human immunodeficiency virus type I (HIV-1) were previously demonstrated in zidovudine-treated AIDS patients. The genetic linkage of multiple mutations characteristic of zidovudine-resistance as well as dideoxyinosine-resistance were demonstrated by examining clones of viral reverse transcriptase after polymerase chain reaction (PCR) amplification of plasma culture DNA. The zidovudine-resistance mutations persisted in seven timepoints from four patients for 5 to 22 months despite cessation of zidovudine therapy (and while patients underwent ddI therapy). One patient's plasma virus isolate at 14 months possessed a genotype doubly resistant to ZDV and ddI. Virus recovered from four timepoints showed Intermediate to high levels of zidovudine-resistance. As these genotypes were mainly derived from plasma culture, the zidovudine resistant virus appears to persist and replicate well in vivo after cessation of zidovudine therapy.
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PMID:Long-term persistence of AZT-resistance mutations in the plasma HIV-1 of patients removed from AZT therapy. 815 87

At the end of 1992, according the World Health Organization, 611,589 AIDS cases had been reported, but the actual number of cases reached about two million. The actual number of HIV-infected people in the world, according to WHO, in 1992 ranged between 10 and 12 million. It is estimated that by the year 2000 there will be 30-40 million infected people and about 12-18 million AIDS cases. In the 1980's the increase was especially great in Sub-Saharan Africa, with about 6 million infected cases of whom 1/3 were pregnant women in big city maternity wards. In recent years the steep increase of cases in Africa led to its appellation as the AIDS continent. The percentage of infected people is put at 15-20% and it is steadily increasing. On the American continents by the end of 1992, a total of 313,083 cases were reported, of which 242,000 were in the US (970 per 1 million inhabitants). In Brazil there were 31,000, in Mexico 11,000, and in Canada 7000 cases. The highest figure was in the Bahamas: 4087 per 1 million inhabitants. In Asia only 2582 AIDS cases were reported at the end of 1992, because HIV still had not exploded on this continent. The latest data indicated an increase of the infection in Asia among IV drug users and prostitutes, so that seropositive persons were estimated at half a million. The highest number of clinical cases were in Thailand (909), Japan (508), and in Israel (192). In Europe there were 88,810 cases reported, of which 21,487 were in France. At the end of 1992 in Yugoslavia 268 cases were registered (25 per 1 million inhabitants). In Serbia there were 262 cases (in Belgrade 75% of them) and in Montenegro 3 cases. It is worrisome that about 2000 HIV-positive persons have been detected since 1985. AZT (azidothymidine, zidovudin) and ddI (dideoxyinosine) are the main drugs for treatment. Since an effective vaccine is still unavailable, the only means of halting the spread of HIV infection is warning and education, beginning with prepubescents, about first intercourse and IV drug use.
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PMID:[AIDS throughout the world and possibilities of preventing the spread of HIV infection]. 821 57

3'-azido-3'-deoxythymidine (zidovudine-AZT) was the first clinically approved reverse transcriptase inhibitor for the treatment of acquired immunodeficiency syndrome (AIDS) and recently, 2',3'-dideoxyinosine (didanosine-ddI) has also been approved in France. These nucleoside analogs have no intrinsic anti-HIV activity and must be metabolized to their respective 5'-triphosphates by means of kinases, nucleotidases, or other activating enzymes present naturally in cells. The presence and activity of the necessary intracellular enzymes for activation of nucleoside analogs is highly dependent on species, cell type, and cell cycle stage, illustrating the importance of cellular functions in the mechanism(s) of action or toxicity of nucleoside analogs. Although the apparent plasma elimination half-life of the parent drug varies between 1 and 2 hours, the active triphosphate derivatives have intracellular half-lives between 4 and 12 h with 2',3'-dideoxyadenosine-5'-triphosphate (ddATP), the active component of ddl being one of the most stable with an intracellular half-life of 8 to 12 hours which result in relatively infrequent dosing as compared to other classes of potential anti-HIV drugs under development. The multifactorial mechanism(s) of toxicity of this class of drugs likely explains the different spectrums of toxicity observed with the various nucleoside analogs, and demonstrates the uniqueness of each compound. Recently, AZT-resistant strains have been isolated from AZT-treated patients, probably reflecting a sequential acquisition of amino-acid mutations in the HIV-RT. Of importance, cross-resistance was demonstrated with other compounds with an 3'-azido group, but no cross-resistance was detected with either ddl of 2',3'-dideoxycytidine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[What is known about the cellular and molecular pharmacodynamics of nucleosides?]. 830 21

Dideoxyinosine (DDI) has been recently approved for the treatment of AIDS. In anticipation of its use in HIV-infected women during pregnancy, the transfer and metabolism of DDI by the perfused human placenta have been investigated. Transfer characteristics are those of simple diffusion: clearance is the same as that for L-glucose (transfer index of 0.98 +/- 0.09), it is equivalent in both directions across the placenta, and the transfer rate is proportional to the transplacental gradient over a very broad range (1 to 500 microM). Because of extensive placental metabolism, only about one-half of the cleared DDI (51 +/- 21%) is transferred intact to the fetal circulation. No dideoxyadenine triphosphate, the antiviral product of DDI, could be detected in the placenta following perfusion. Comparison of the pharmacological information on DDI and zidovudine (ZDV) indicates that treatment of HIV-infected women during pregnancy with DDI will expose the fetus to much less drug than if ZDV were used. DDI may therefore be less effective than ZDV in the treatment of the infected fetus. However, the uninfected fetus of an HIV-infected woman will gain by reduced exposure to a drug that is known to be toxic.
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PMID:Transfer and metabolism of dideoxyinosine by the perfused human placenta. 841 71

Twenty-one 6-alkoxypurine 2',3'-dideoxynucleosides were enzymatically synthesized with nucleoside phosphorylases purified from E. coli. Eighteen analogs exhibited anti-HIV-1 activity in MT4 cells. Two analogs, 6-(hexyloxy)-(17) and 6-(heptyloxy)-(18) purine 2',3'-dideoxynucleoside, were as potent as 2',3'-dideoxyinosine (ddI, didanosine, Videx). Although the antiviral activities of 17 and 18 were equivalent, 18 was more cytotoxic. Analogs containing less than four carbons in the 6-alkoxypurine substituent exhibited weak anti-HIV-1 activity. Analogs containing more than seven carbons in the 6-alkoxypurine substituent were too cytotoxic to be effectively evaluated for antiviral activity. Several 6-alkoxypurine 2',3'-dideoxynucleosides were evaluated for substrate activity with calf intestinal adenosine deaminase (ADA). Increasing the carbon chain length of the 6-alkoxypurine substituent decreased the rate of dealkoxylation. The best substrate in this series was 6-methoxypurine 2',3'-dideoxynucleaside (1); however, the rate of dealkoxylation of 100 microM 1 was 0.17% of the rate of deamination of 100 microM 2',3'-dideoxyadenosine. Compound 17, the most potent anti-HIV-1 analog, was not a substrate for ADA. EHNA (erthro-9-(2-hydroxy-3-nonyl)adenine), a potent inhibitor of ADA, had little effect on the antiviral activities of 17 and ddI. In contrast, coformycin, a potent inhibitor of both ADA and AMP deaminase, dramatically decreased the antiviral activity of 17, but not the antiviral activity of ddI. Thus, AMP deaminase appeared to be involved in the anabolism of 17. The pharmacokinetic profile of 17, the most promising analog in this series, was determined in the rat. At least seventeen metabolites of 17, including ddI, were detected in plasma samples. This analog also had poor oral bioavailability.
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PMID:Novel 6-alkoxypurine 2',3'-dideoxynucleosides as inhibitors of the cytopathic effect of the human immunodeficiency virus. 842 65

Zidovudine (ZDV) has antibacterial activity against many members of the family Enterobacteriaceae, including Salmonella species, and may be responsible for a decrease in the frequency of salmonellosis in persons infected with human immunodeficiency virus (HIV). Other nucleoside analogs, such as didanosine (2',3'-dideoxyinosine [ddI]) and zalcitabine (2',3'-dideoxycytidine [ddC]), which have undefined anti-salmonella activity, increasingly are being used in the treatment of HIV infection. To evaluate the anti-Salmonella activity of the antiviral agents ZDV, ddI, ddC, and acyclovir (ACV), we determined MICs for 39 nontyphoidal Salmonella blood isolates. ZDV (MIC for 50% of strains tested [MIC50], 0.5 microgram/ml; MIC range, 0.125 to 4 micrograms/ml) and ddI (MIC50, 8 micrograms/ml; MIC range, 2 to 125 micrograms/ml) had concentration-dependent activity. Anti-Salmonella activity was not observed for ddC or ACV. Nine Escherichia coli blood isolates were inhibited by ZDV (MIC50, 0.125 microgram/ml; MIC range, 0.031 to 1 microgram/ml) to a greater degree than they were by ddI (MIC50, 62.5 micrograms/ml; MIC range, 31 to > 62.5 micrograms/ml). Inoculum size affected susceptibility to ZDV and ddI for Salmonella and E. coli isolates. Resistance to ZDV or to ddI could be induced in vitro in Salmonella isolates, but cross-resistance was not observed. These results indicate that at concentrations achieved during the treatment of HIV infection, ZDV has activity against nontyphoidal salmonellae, although resistance can develop. ddI, ddC, and ACV at currently used dosages would not be expected to be effective in the prevention or treatment of Salmonella infections.
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PMID:In vitro activities of nucleoside analog antiviral agents against salmonellae. 843 Oct 5

2'-beta-Fluoro-2',3'-dideoxyadenosine (F-ddA), an acid-stable, purine dideoxynucleoside with in vitro anti-HIV activity, has been selected by the NCI as a clinical trial candidate. A recent report that high, single doses of F-ddA produce cardiotoxicity in rats prompted the present investigation whose objective was to quantitate this effect and establish a relationship between this toxicity and F-ddA plasma concentrations. Microscopic examination of cardiac tissues for degenerative lesions established the effects of F-ddA and ddA on three iv schedules [daily x 1(2.5-250 mg/kg); daily x 5(125, 250 mg/kg), and BID x 1 (250 mg/kg)] as well as one oral schedule [BID x 1 (500 mg/kg) using 8- to 12-week old female Sprague-Dawley rats. For both F-ddA and ddA, the group mean severity of the cardiac lesions was dose-dependent and proportional to the measured plasma concentrations of the undeaminated parent drugs. F-ddI and ddI, were essentially nontoxic in this study (iv, 250 mg/kg, daily x 1 and daily x 5), since plasma concentrations exceeding 2 mM produced only minimal cardiac lesions. The cardiomyopathy of F-ddA was minimal to mild for all iv doses except 250 mg/kg (daily x 1) and usually was greater than that of ddA at any given dose. This is a consequence of the fact that F-ddA is deaminated 20 times more slowly than ddA, resulting in higher plasma concentrations of F-ddA relative to ddA at any given time for any given dose. Neither F-ddA nor ddA was more cardiotoxic on a repeated iv schedule (daily x 5) than when administered only once, suggesting that rat cardiotoxicity is related Cmax rather than total exposure. In this most sensitive species, the formation of cardiac lesions above the background level is associated with i.v. F-ddA administration when the F-ddA plasma concentration approaches 300 microM, 30-50 times the anticipated therapeutic level in humans.
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PMID:Acute cardiotoxicity of the Anti-HIV dideoxynucleoside, F-ddA, in the rat. 852 11

Ribavirin has been reported to enhance the activity of ddI against HIV. We explored this enhancement of antiviral activity in Rauscher murine leukemia virus (RMuLV) models in vitro and in vivo. The significant finding in these studies was that combinations of the drugs exhibited virus titer reductions that were greater than would be expected if the drug interactions were simply additive. These effects were designated synergistic by the method of Prichard and Shipman (Prichard, M.N. and Shipman, C., Jr. (1990). A three-dimensional model to analyze drug-drug interaction, Antiviral Res. 14, 181-206). In addition to the antiviral synergy, we also observed some synergistic toxicity in the animal model.
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PMID:In vitro and in vivo enhancement of ddI activity against Rauscher murine leukemia virus by ribavirin. 854 Jul 52


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