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

We report the development of severe hepatotoxicity in a patient on zidovudine therapy who received 3.3 g of acetaminophen in less than 36 hours. Three days later, the patient's serum aspartate aminotransferase level was 5,724 U/L, alanine aminotransferase was 3,124 U/L, lactate dehydrogenase was 12,675 U/L, alkaline phosphatase was 84 U/L, and total bilirubin was 20 mumol/L. These values substantially improved over the ensuing 4 days. Serologic results for hepatitis B, hepatitis A, and cytomegalovirus were all negative. The pattern and time sequence of transaminase elevation in this patient are consistent with acute acetaminophen hepatotoxicity, especially since zidovudine-induced hepatotoxicity is described as producing cholestasis rather than acute hepatitis. We hypothesize that our patient's susceptibility to acetaminophen-dependent hepatotoxicity may have been augmented by competitive utilization of glucuronidation by other drugs such as zidovudine and/or trimethoprim-sulfamethoxazole with subsequent increased cytochrome P450-dependent metabolism of acetaminophen. Additionally, due to malnutrition and/or to human immunodeficiency virus infection per se, our patient may have had decreased hepatic reserves of glutathione with which to conjugate the toxic acetaminophen product of the P450 system. Although severe acetaminophen-associated hepatotoxicity has not previously been reported in patients receiving zidovudine, we suggest that clinicians be aware of this potential interaction and counsel malnourished patients, especially those with concomitant hepatic disease, to exercise caution when taking both these medications.
 ...
PMID:Severe hepatotoxicity in a patient receiving both acetaminophen and zidovudine. 836 34

Diethyldithiocarbamate (Ditiocarb) is a drug with diverse biological activities suggesting that it may have multiple, clinical uses. Thus, it is an inhibitor of such enzymes as cytochrome P450, it is a chelating agent for nickel and cadmium, it is a free-radical scavenger and finally, it is an immunomodulator. As such, it can restore the immune responses of immunosuppressed mice. In the murine retrovirus-induced immunodeficiency disease (LP-BM5 in C57 black 10 mice), it can prevent the development of disease when given from the day of virus inoculation until 2 weeks after virus inoculation. In addition, it can reverse disease manifestations including lymphadenopathy when started as late as 10 weeks after virus inoculation. Associated with these effects is a reduction in mortality from 100 percent to between 0 and 10 percent. When drug is stopped however, disease progression resumes. In man, Ditiocarb has been used in a series of open, non-randomized as well as randomized prospectively-controlled clinical trials in patients with HIV infection. Three randomized placebo-controlled studies have been conducted. In the largest of these, involving 389 patients, Ditiocarb was shown to be safe, non-toxic and effective. Thus, there was a 62 percent reduction in new opportunistic infections (OI) in all of the treated patients, a 50 percent reduction in ARC patients and an 82 percent reduction in AIDS patients. When new and recurrent OI and other events indicating progression were taken together, there were 17 events in 193 treated patients and 42 events in 196 placebo control patients. Statistically significant reductions in these events were seen in ARC patients, AIDS patients and all patients.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Biological activity of diethyldithiocarbamate (Ditiocarb, Imuthiol) in an animal model of retrovirus-induced immunodeficiency disease and in clinical trials in patients with HIV infection. The Ditiocarb Study Group. 217 28

Standard short-course regimens for tuberculosis are used worldwide with very few problems. Unfortunately, the emergence of multiple drug-resistant tuberculosis in many parts of the world is leading to a diversification of drug regimens and to the use of drugs that are more toxic per se and more likely to interact with others. In addition, the treatment of HIV/AIDS patients with tuberculosis or disease due to Mycobacterium avium-intracellulare complex (MAC) infection with new drugs and multidrug regimens has added to the problem of drug interactions, especially as such patients may often be receiving concomitant treatment for a range of bacterial, fungal and viral infections. In general, there are very few clinically significant interactions between the first-line antituberculosis drugs themselves, although problems of bioavailability, notably of rifampicin (rifampin), have been encountered in the manufacture of combination tablets. Of the first-line drugs used to treat tuberculosis, i.e. rifampicin, isoniazid and pyrazinamide, rifampicin is particularly likely to cause clinically significant drug interactions as it is a potent inducer of the cytochrome P450 enzyme group, which is involved in the metabolism of many drugs, in particular oral contraceptives, corticosteroids, oral anticoagulants and cyclosproin. The use of quinolones to treat multiple drug-resistant tuberculosis and AIDS-related MAC disease raises further problems of drug interactions as, in contrast to rifampicin, these drugs inhibit some cytochrome isoenzymes, leading to reduced metabolism of certain drugs.
 ...
PMID:Clinically significant drug interactions with antituberculosis agents. 784 44

Intolerance to sulfonamides is very frequent in HIV-infected subjects and 10 times more common than in the general population. There are 2 types of intolerance to sulfonamides: early reactions with urticaria or angioedema, which are IgE-dependent, and late reactions with febrile rash, which occur between the 6th and 12th days of treatment and represent the vast majority of allergic manifestations in HIV-infected subjects. Clinically, these reactions resemble serum sickness, but all physiopathological hypotheses point to toxic process. The degradation of sulfonamides has two different pathways: the N-acetylation pathway which is genetically determined and saturable, and the cytochrome P450 pathway which produces toxic hydroxylamine metabolites "detoxified" by glutathione. In HIV-infected subjects detoxication is thought to be incomplete due to an acquired deficiency of glutathione and probably increased in the presence of a slow acetylation profile.
 ...
PMID:[Intolerance to sulfonamides in HIV infected subjects. Toxic and allergic origin]. 824 69

Ten years ago, the term "oxidative stress" (sigma -O2) was created to define oxidative damage inflicted to the organism. This definition brings together processes involving reactive oxygen species production and action such as free radical production during univalent reduction of oxygen within mitochondria, activation of NADPH-dependent oxidase system on the membrane surface of neutrophils, flavoprotein-catalyzed redox cycling of xenobiotics and exposure to chemical and physical agents in the environment. Since the discovery of the nitric oxide biosynthetic pathway, the deleterious effects of uncontrolled nitric oxide generation are generally classified as oxidative stress. Indeed, products of the reaction of NO and superoxide lead to oxidants such as peroxinitrite, nitrogen dioxide and hydroxyl radical, which are involved in mechanisms of cell-mediated immune reactions and defence of the intracellular environment against microbiol invasion. However NO can also regulate many biological reactions and signal transduction pathways that lead to a variety of physiological responses such as blood pressure, neurotransmission, platelet aggregation, endothelin generation or smooth muscle cell proliferation. Then the uncontrolled NO production can lead to a variety of physiological and pathophysiological responses similar to a Nitric Oxide Stress: activation of guanylate cyclase and production of cGMP: overstimulation of the inducible L-arginine to L-citrulline and NO pathway by bactericidal endotoxins and cytokines has been shown to promote undesired increases in vasodilatation, which may account for hypotension in septic shock and cytokine therapy. stimulation of auto-ADP-ribosylation and modification of SH-groups of glyceraldehyde-3-phosphate dehydrogenase in a cGMP-independent mechanism: by this way, NO in excess can strongly inhibits this important glycolytic enzyme and reduce the cellular energy production. inhibition of ribonucleotide reductase: extensive inhibition of this key enzyme in DNA synthesis in the presence of large amounts of NO could lead to important antiproliferative effects; inhibition of cytochrome P450-dependent metabolism: in Kupffer cells and hepatocytes, LPS-induced overproduction of NO has been shown to inhibit cytochrome P450-dependent metabolism and to mediate the suppression of hepatic metabolism. Moreover, NO synthetized in the peripheral nervous system is known to mediate nonadrenergic noncholinergic (NANC) neurotransmission. Overstimulation of NO synthases might therefore contribute to pathophysiological states such as: gastrointestinal motility, reflux oesophagitis, asthma, adult respiratory distress syndrome (ARDS) and chronic pulmonary artery hypertension. To these NO-mediated biological functions, one could add the biological effects of NO-derivatives such as N-nitrosocompounds, which act as carcinogenic agents, or C-nitrosocompound which were recently used as "zinc-ejecting" agents to inhibit HIV-1 infectivity of human T-lymphocytes.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:[Does nitric oxide stress exist?]. 852 Oct 87

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.
 ...
PMID:Metabolism of Zidovudine. 869 Feb 33

L-754,394, a furanopyridine derivative, is an experimental anti-HIV agent which has been shown to be an unusually potent and selective inhibitor of cytochrome P450 3A enzymes in a number of mammalian species. In the present studies, L-754,394 was demonstrated to undergo NADPH-dependent metabolic activation in hepatic microsomal preparations from rats, dogs, rhesus monkeys, and humans to electrophilic intermediates which became bound covalently to cellular proteins. The extent of binding was species-dependent, the highest levels being observed with liver microsomes from rhesus monkeys. Inclusion in incubation media of the nucleophilic trapping agents glutathione, cysteine, or methoxyamine led to a modest (15-25%) decrease in the covalent binding, while trichloropropylene oxide, an inhibitor of epoxide hydrolase, had no effect. When L-754,394 was incubated with monkey liver microsomes, the corresponding dihydrofurandiol was identified as a metabolite by liquid chromatography-tandem mass spectrometry. In contrast, when incubations were carried out in the presence of methoxyamine, the O-methyloxime derivative of the ring-opened dihydrodiol tautomer was formed, while inclusion of glutathione or N-acetylcysteine led to the formation of S-linked conjugates of a putative furan epoxide. Collectively, these results are taken to indicate that L-754,394 undergoes cytochrome P450-dependent oxidation of the fused furan ring system, leading to the formation of chemically-reactive intermediates. One or more of these electrophilic species may be responsible for the autocatalytic destruction of cytochrome P450 enzymes which accompanies L-754,394 metabolism in vitro and in vivo.
 ...
PMID:In vitro studies on the metabolic activation of the furanopyridine L-754,394, a highly potent and selective mechanism-based inhibitor of cytochrome P450 3A4. 887 Sep 89

1. Cytochrome P450-mediated bioactivation of sulphamethoxazole to a hydroxylamine has been implicated in the hypersensitivity reactions associated with co-trimoxazole administration. Inhibiting the formation of the hydroxylamine may be one method of preventing the high frequency of toxicity which is observed in HIV-infected patients. Therefore, in this study, we have investigated the ability of fluconazole and ketoconazole, known cytochrome P450 inhibitors, to inhibit the formation of sulphamethoxazole hydroxylamine. 2. Ten healthy male volunteers were given co-trimoxazole (800 mg sulphamethoxazole and 160 mg trimethoprim) alone or 1 h after either fluconazole (150 mg) or ketoconazole (200 mg) in a randomized fashion with a washout period of at least 1 week between each phase. Urine was collected for 24 h, and sulphamethoxazole and its metabolites were quantified by electrospray LC-MS. 3. Ketoconazole had no effect on the urinary recovery of sulphamethoxazole or any of its metabolites. In contrast, fluconazole significantly (P < 0.001) inhibited the formation of sulphamethoxazole hydroxylamine by 50.0 +/- 15.1%. Fluconazole also inhibited the oxidation of sulphamethoxazole to the 5-methylhydroxy and 5-methylhydroxy acetate metabolites by 69.9 +/- 15.8% and 64.0 +/- 12.0%, respectively, but had no effect on the amount of sulphamethoxazole, N4-acetyl sulphamethoxazole, or sulphamethoxazole N1-glucuronide excreted in urine. 4. The potential clinical benefit of using fluconazole to prevent hypersensitivity to co-trimoxazole in patients with AIDS needs to be assessed in a prospective study using both metabolite formation and the clinical occurrence of adverse reactions as end-points.
 ...
PMID:The effect of fluconazole and ketoconazole on the metabolism of sulphamethoxazole. 887 26

Saquinavir is a HIV protease inhibitor used in the treatment of patients with acquired immunodeficiency syndrome, but its use is limited by low oral bioavailability. The potential of human intestinal tissue to metabolize saquinavir was assessed in 17 different human small-intestinal microsomal preparations. Saquinavir was metabolized by human small-intestinal microsomes to numerous mono- and dihydroxylated species with K(M) values of 0.3-0.5 microM. The major metabolites M-2 and M-7 were single hydroxylations on the octahydro-2-(1H)-isoquinolinyl and (1,1-dimethylethyl)amino groups, respectively. Ketoconazole and troleandomycin, selective inhibitors of cytochrome P4503A4 (CYP3A4), were potent inhibitors for all oxidative metabolites of saquinavir. The cytochrome P450-selective inhibitors furafylline, fluvoxamine, sulfaphenazole, mephenytoin, quinidine, and chlorzoxazone had little inhibitory effect. All saquinavir metabolites were highly correlated with testosterone 6beta-hydroxylation and with each other. Human hepatic microsomes and recombinant CYP3A4 oxidized saquinavir to the same metabolic profile observed with human small-intestinal microsomes. Indinavir, a potent HIV protease inhibitor and a substrate for human hepatic CYP3A4, was a comparatively poor substrate for human intestinal microsomes and inhibited the oxidative metabolism of saquinavir to all metabolites with a Ki of 0.2 microM. In addition, saquinavir inhibited the human, small-intestinal, microsomal CYP3A4-dependent detoxication pathway of terfenadine to its alcohol metabolite with a Ki value of 0.7 microM. These data indicate that saquinavir is metabolized by human intestinal CYP3A4, that this metabolism may contribute to its poor oral bioavailability, and that combination therapy with indinavir or other protease inhibitors may attenuate its low relative bioavailability.
 ...
PMID:Selective biotransformation of the human immunodeficiency virus protease inhibitor saquinavir by human small-intestinal cytochrome P4503A4: potential contribution to high first-pass metabolism. 902 57

Coadministration with the human immunodeficiency virus (HIV) protease inhibitor ritonavir was investigated as a method for enhancing the levels of other peptidomimetic HIV protease inhibitors in plasma. In rat and human liver microsomes, ritonavir potently inhibited the cytochrome P450 (CYP)-mediated metabolism of saquinavir, indinavir, nelfinavir, and VX-478. The structural features of ritonavir responsible for CYP binding and inhibition were examined. Coadministration of other protease inhibitors with ritonavir in rats and dogs produced elevated and sustained plasma drug levels 8 to 12 h after a single dose. Drug exposure in rats was elevated by 8- to 46-fold. A > 50-fold enhancement of the concentrations of saquinavir in plasma was observed in humans following a single codose of ritonavir (600 mg) and saquinavir (200 mg). These results indicate that ritonavir can favorably alter the pharmacokinetic profiles of other protease inhibitors. Combination regimens of ritonavir and other protease inhibitors may thus play a role in the treatment of HIV infection. Because of potentially substantial drug level increases, however, such combinations require further investigation to establish safe regimens for clinical use.
 ...
PMID:Pharmacokinetic enhancement of inhibitors of the human immunodeficiency virus protease by coadministration with ritonavir. 905 9


1 2 3 4 5 6 7 8 9 10 Next >>