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)

Eleven medications used in the treatment of the human immunodeficiency virus or subsequent opportunistic infections were tested to determine their toxicity to the growth of the CEM line of transformed CD4+ T-cells. A selectivity ratio (IC50/EC50) for each agent against its target pathogen was calculated as an in vitro indication of the therapeutic value of that agent. Among the anti-HIV agents tested in this study, 2',3'-dideoxyinosine (ddI) had the highest in vitro selectivity ratio, 2.5 times higher than that of 3'-azido-3'-deoxythymidine (AZT). Dapsone had the highest selectivity ratio of the four agents used in the treatment of Pneumocystis carinii pneumonia that were tested. Ketoconazole had a very low selectivity ratio for Candida spp. due to its very high toxicity to CD4+T-cells.
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PMID:The selective toxicity of medications used in the treatment of AIDS on the CEM human leukemic CD4+ T-cell line. 168 33

Fungal infections figures large in HIV-infected patients. Candida infections of the mucous membranes belong to the main manifestations of immunodeficiency in HIV infection. For therapy and prophylaxis of oropharyngeal candidosis mainly systemically acting azoles as ketoconazole, fluconazole and itraconazole are applied; antimycotics to be administered topically regularly fail to act in patients with progressing disease. Ketoconazole tablets were used with good success in previous years of the AIDS epidemics. Application of ketoconazole in liquid formulation led to a significant increase in efficacy. Subsequently fluconazole proved to be a triazole with evidently better pharmacological properties leading to good clinical efficacy. Presently it represents the drug of first choice in acute and maintenance therapy of recurrent oropharyngeal and oesopharyngeal candidosis. In the case of therapy failure with fluconazole the administration of itraconazole in liquid cyclodextrine formulation can replace or at least delay the administration of amphotericin B plus flucytosine, a therapy rich in toxic side effects. The standard therapy of disseminated cryptococcosis--particularly of cerebral manifestation--is still the administration of amphotericin B combined with flucytosine. Alternative drugs are represented by fluconazole and itraconazole. However, an azole monotherapy seems to be legitimate only in primary cryptococcosis of the lungs or in early stages of secondary extrapulmonary infection. Cryptococcal meningitis requires an intense initial therapy. New therapy strategies were developed combining azoles with standard antimycotic drugs. The value of amphotericin B in liposomal or lipid complex formulations is still undetermined due to the up to now low number of AIDS patients treated.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Therapy of candidiasis and cryptococcosis in AIDS]. 760 45

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.
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PMID:The effect of fluconazole and ketoconazole on the metabolism of sulphamethoxazole. 887 26

Eighty-five consecutively seen HIV-positive persons with oral candidiasis were evaluated for clinical characteristics, staging of HIV disease, quantitation of candidal colony formation, and response to systemic antifungal treatment with Nizoral (ketoconazole). Fifty-five had CD4 counts less than 200. There was an inconsistent association between clinical signs, patient symptoms, CD4 counts, and candidal colony-forming units. However, there was a trend toward higher colony-forming unit counts (> 500) in patients with lower CD4 cells (< 200). Sixty-five patients had a complete clinical response to the ketoconazole treatment (200 mg daily for 7 days), even though 81% of posttreatment cultures remained positive. Nonsmokers were more likely to respond to antifungal treatment when compared with smokers, and there was a slight tendency for complete responses when colony-forming unit counts were low. The most common lesion presentation was a combination of the white (pseudomembranous) and red (erythematous) forms. Forty-nine percent had complaints of pain. The variable responses indicated the importance of flexible dose-time and drug considerations in antifungal management. Candida albicans was the predominant species.
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PMID:Clinical characteristics and management responses in 85 HIV-infected patients with oral candidiasis. 889 77

Tinea capitis in men, even if infected with HIV, is infrequent. Microsporum species nail infections are extremely rare. In most cases Microsporum canis infection is usually easy to treat with antifungal agents. We describe two HIV-infected men with an unusual M. canis infection. Both patients had tinea capitis, presenting as alopecia in one and scaling of the scalp in the other. One patient also had tinea unguium caused by M. canis. Ketoconazole was ineffective in both patients; terbinafine was tried in one patient without benefit; itraconazole was effective in both, but treatment took many months and only one patient was cured.
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PMID:Unusual Microsporum canis infections in adult HIV patients. 891 91

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.
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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

Amprenavir (141W94, VX-478, KVX-478) is metabolized primarily by CYP3A4 (cytochrome P450 3A4) in recombinant systems and human liver microsomes (HLM). The effects of ketoconazole, terfenadine, astemizole, rifampicin, methadone, and rifabutin upon amprenavir metabolism were examined in vitro using HLM. Ketoconazole, terfenadine, and astemizole were observed to inhibit amprenavir depletion, consistent with their known specificity for CYP3A4. The HIV protease inhibitors, indinavir, saquinavir, ritonavir, and nelfinavir, were included in incubations containing amprenavir to examine the interactions of HIV protease inhibitors in vitro. The order of amprenavir metabolism inhibition in human liver microsomes was observed to be: ritonavir > indinavir > nelfinavir > saquinavir. The Ki value for amprenavir-mediated inhibition of testosterone hydroxylation in human liver microsomes was found to be approximately 0.5 microM. Studies suggest that amprenavir inhibits CYP3A4 to a greater extent than saquinavir, and to a much lesser extent than ritonavir. Amprenavir, nelfinavir, and indinavir appear to inhibit CYP3A4 to a moderate extent, suggesting a selected number of coadministration restrictions.
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PMID:Metabolism of amprenavir in liver microsomes: role of CYP3A4 inhibition for drug interactions. 964 46

Endemic mycoses remain a major public health problem in several countries and they are becoming increasingly frequent with the spread of HIV infection. Amphotericin B remains the drug of choice during the acute stage of life-threatening endemic mycoses occurring in both immunocompetent and immunocompromised hosts. Ketoconazole is effective in non-AIDS patients with non-life-threatening histoplasmosis, blastomycosis, or paracoccidioidomycosis. Itraconazole is the treatment of choice for non-life-threatening Histoplasma capsulatum or Blastomyces dermatitidis infections occurring in immunocompetent individuals and is the most efficient secondary prophylaxis of histoplasmosis in AIDS patients. Itraconazole is also effective in lymphocutaneous and visceral sporotrichosis, in paracoccidioidomycosis, for Penicillum marneffei infection, and is an alternative to amphotericin B for Histoplasma duboisii infection. Coccidioidomycosis may be effectively treated with prolonged and sometimes life-long itraconazole or fluconazole therapy. Fluconazole has relatively poor efficacy against histoplasmosis, blastomycosis and sporotrichosis. New antifungal agents have been tested in vitro or in animal models and may soon be evaluated in clinical trials.
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PMID:Endemic mycoses: a treatment update. 1022 86

We performed a cross-sectional study to analyze patterns of azole susceptibility of oral isolates in the highly active antiretroviral therapy (HAART) era and compared current data with those obtained for isolates from 1994. We further identified patients with relapsing oral pharyngeal candidiasis (OPC) who had been included in a similar study in 1994. For these subjects, we compared the susceptibility pattern for the OPC isolates, and if a modification of azole resistance was observed, we analyzed the genotypic pattern for the 1994 and 2000 isolates to determine whether the dominant strain was closely related. We included 69 consecutive HIV-infected subjects with 137 episodes of OPC who were admitted to our ward from January to June 2000. Ninety-two strains (67%) and 21 non- strains (15%) were isolated. We identified 24 episodes of OPC caused by two different species. Compared with the pre-HAART era, the fluconazole resistance of isolates significantly decreased from 45% to 10% (p <.001). Itraconazole resistance decreased from 37% to 7% (p <.001). Ketoconazole resistance (3% in 1994) was not detected more. Nine patients whose isolate was susceptible to all azole drugs had a previous isolate resistant to all azole drugs. We observed that these isolates exhibited different fingerprint profiles. Our findings demonstrate that most cases of HIV-associated OPC observed in the HAART era are caused by azole-susceptible strains. The reversion of an isolate from azole resistant to azole susceptible is related to strain replacement.
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PMID:Azole susceptibility patterns and genetic relationship among oral Candida strains isolated in the era of highly active antiretroviral therapy. 1235 48

Vicriviroc (SCH 417690), a CCR5 receptor antagonist, is currently under investigation for the treatment of human immunodeficiency virus infection. The objective of this study was to identify human liver cytochrome P450 enzyme(s) responsible for the metabolism of vicriviroc. Human liver microsomes metabolized vicriviroc via N-oxidation (M2/M3), O-demethylation (M15), N,N-dealkylation (M16), N-dealkylation (M41), and oxidation to a carboxylic acid metabolite (M35b/M37a). Recombinant human CYP3A4 catalyzed the formation of all these metabolites, whereas CYP3A5 catalyzed the formation of M2/M3 and M41. CYP2C9 only catalyzed the formation of M15. There was a high correlation between the rates of formation of M2/M3, M15, and M41, which was determined using 10 human liver microsomal samples and testosterone 6beta-hydroxylation catalyzed by CYP3A4/5 (r > or = 0.91). Ketoconazole and azamulin (inhibitors of CYP3A4) were potent inhibitors of the formation of M2/M3, M15, M41, and M35b/M37a from human liver microsomes. A CYP3A4/5-specific monoclonal antibody (1 microg/microg of protein) inhibited the formation of all metabolites from human liver microsomes by 86 to 100%. The results of this study suggest that formation of the major vicriviroc metabolites in human liver microsomes is primarily mediated via CYP3A4. CYP2C9 and CYP3A5 most likely play a minor role in the biotransformation of this compound. These enzymology data will provide guidance to design clinical studies to address any potential drug-drug interactions.
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PMID:Identification of human liver cytochrome P450 enzymes involved in biotransformation of vicriviroc, a CCR5 receptor antagonist. 1782 38


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