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)

A total of 62 patients with HIV-related conditions were examined for clinical and mycological oral findings. Cultures from 51 patients were positive for yeasts and included 49 Candida albicans and 8 non-albicans isolates. Of patients with positive culture, 35% had pseudomembranous thrush. In vitro susceptibility testing of 49 C. albicans isolates revealed that the minimal inhibitory concentration for 50% of the strains (MIC50) was 2.0 mg/l for fluconazole, and the MIC50 was < or = 0.125 mg/l for both ketoconazole and itraconazole. Fluconazole resistance (MIC > or = 32.0 mg/l) was found for 14% of the C. albicans isolates tested. Two C. albicans isolates showed cross-resistance to ketoconazole and itraconazole. Associations between reduced susceptibility to fluconazole and low CD4+ cell counts, the length of time since the first AIDS-defining illness and the interval from the first fluconazole treatment, indirectly reflecting the total fluconazole exposure, were observed.
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PMID:Oral Candida albicans isolates with reduced susceptibility to fluconazole in Swedish HIV-infected patients. 865 76

1. The population pharmacokinetics of fluconazole have been investigated in 113 male subjects with HIV infection and AIDS. Plasma concentration-time data (between 1 and 17 observations per dose) were collected from individuals as part of a pharmacokinetic investigation (13 subjects) or during routine fluconazole therapy (100 subjects) for the treatment or prophylaxis of fungal infection. 2. A one-compartment pharmacokinetic model was used to describe the disposition of fluconazole after oral and intravenous infusion doses. Population pharmacokinetic parameters were generated using the NONMEM and P-PHARM computer programs. 3. The population estimates (calculated using NONMEM) of fluconazole clearance and volume of distribution were 0.78 l h-1 and 47.61, respectively. The intersubject variability for these parameters was 41% and 8%, respectively. The model-dependent estimate of the extent of absorption was 0.99 with an intersubject variability of 6%. Mean population estimates generated by NONMEM and P-PHARM were in close agreement. 4. Examination of the relationship between patient covariates and pharmacokinetic parameters indicated that intersubject variability in fluconazole clearance could in part be explained by the severity of disease (as indicated by CD4 + T-lymphocyte count) and renal function (indicated by estimated creatinine clearance). Other pharmacokinetic parameters were unaffected by these covariates. 5. Fluconazole clearance (estimated using NONMEM) in subjects with a CD4 + T-lymphocyte count less than and greater than 200 cells mm3 was 0.73 l h-1 (95% CI; 0.64-0.82 l h-1) and 0.99 l h-1 (95% CI; 0.86-1.12 l h-1), respectively. The regression model for fluconazole clearance that accounted for changes in renal function and disease severity was CL (l h-1) = 0.25 (33%) + 0.0057 (32%) x CLcr (in ml min-1) + 0.00068 (10%) x CD4 cell count (in cells mm-3) where intersubject variability (expressed as %CV) is shown in brackets. 6. Based on pharmacokinetic considerations a reduction in the dose of fluconazole would appear to be warranted in people with HIV infection who are seriously ill or who have compromised renal function. However, the emergence of resistance to fluconazole must also be considered when thinking of dosage adjustments.
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PMID:Pharmacokinetics of fluconazole in people with HIV infection: a population analysis. 873 Sep 74

Fluconazole-resistant Candida species are an emerging problem. In this report, the in vitro activity of C. zeylanicum against fluconazole-resistant and-susceptible Candida isolates is described. The MICs of the bark of C. zeylanicum ranged from < 0.05-30 mg/ml, and were slightly better than commercially available cinnamon powder. Trans-cinnamaldehyde and O-methoxycinnamaldehyde had MICs of 0.03-0.5 mg/ml. The MICs of selected cinnamon candies and gums generally ranged from 25-100 mg/ml. Five patients with HIV infection and oral candidiasis received a commercially available cinnamon preparation for one week. There of the five patients had improvement of their oral candidiasis. Clinical trials will be necessary to determine the usefulness of cinnamon for the treatment of mucosal candidiasis.
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PMID:In vitro activity of Cinnamomum zeylanicum against azole resistant and sensitive Candida species and a pilot study of cinnamon for oral candidiasis. 887 67

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

The bis triazole agent fluconazole is used widely in the treatment of superficial and deep mycoses. A single oral dose of fluconazole 150 mg gives a mean long term clinical cure rate of 84 +/- 5% and is considered a valuable alternative to other topical antifungal drugs for vaginal candidiasis. A clinical cure rate of 90.4% for oropharyngeal candidiasis was obtained with 100mg daily for a minimum of 14 days; however, as for the other azoles the rate of relapse was large (40%) in immunocompromised patients. A daily dose of 100mg for at last 3 weeks gave satisfying outcomes for oesophageal candidiasis. Most patients (71 to 86%) with signs and symptoms of urinary tract candidiasis show beneficial clinical results when given oral fluconazole 50mg for several weeks. Fluconazole 50 to 150 mg given for weeks or months results in over 90% clinical cure or improvement for cutaneous mycosis including tinea, pityriasis, cryptococcosis and candidiasis. Prolonged (6 to 12 months) fluconazole 150 mg once a week is needed to treat onychomycosis successfully. Higher oral doses (200 to 400 mg daily) for long periods are generally used to treat deep mycoses such as meningitis, ophthalmitis, pneumonia, hepatosplenic mycosis and endocarditis. Fluconazole is effective for treating the fungal peritonitis which can complicate continuous ambulatory peritoneal dialysis (CAPD). A regimen of 50 mg intraperitoneally or 100 mg orally was used in these patients with impaired renal function. The dosage schedules used to treat disseminated fungal infections due to systemic mycoses with different or multiple foci of infections vary widely, with doses of 50 to 400 mg given orally or intravenously for between 1 week and several months. The most recent clinical reports have investigated the use of prophylaxis with fluconazole 100 to 400 mg daily, in immunocompromised patients. Fluconazole is found in body fluids such as vaginal secretions, breast milk, saliva, sputum and cerebrospinal fluid at concentrations comparable with those determined in blood after single or multiple doses. There is an excellent linear plasma concentration-dose relationship, but the mycological and clinical responses do not appear to be well correlated with the dose. A total maximum daily dose of 1600 mg is recommended to avoid neurological toxicity. Data from pharmacokinetic studies conducted in patients, mainly those with AIDS, and using a 1-compartment model give very constant parameters similar to those obtained in healthy individuals. Bioavailability, measured in HIV-positive patients and those with AIDS, exceeded 93% for tablets, suspension and suppositories. The time to reach peak plasma concentrations (tmax) was 2.4 to 3.7 hours. The peak plasma drug concentration (Cmax) obtained after a 100 mg oral dose was 2 mg/L. Areas under the concentration-time curve (AUC) obtained in different studies all correlate well with the dose (r = 0.926). The AUC determined after 200 and 25 mg suppositories were similarly well correlated. Hypochlorhydria does not affect the absorption of fluconazole, neither does food intake, race (Japanese or Caucasian) or gastrointestinal resection. Binding to plasma protein is low (11.14%) and is increased to 23% in cancer patients. Fluconazole is rapidly distributed to the tissue, where it accumulates. Tissues fall into 1 of 4 groups of increasing drug concentration: blood, bone and brain have the lowest concentrations, and spleen has the highest. The volume of distribution (Vd) remains stable at 46.3 +/- 7.9L and is considered to be an 'invariant' parameter across species. Fluconazole is poorly metabolised and is mainly eliminated unchanged in the urine. The percentage of the dose recovered in the urine in 48 hours is close to 60%. Concentrations in the urine are high and the half-life (t1/2) is long (37.2 +/- 5.5h) in patients, mainly those with AIDS, which is not significantly different from the t1/2 (31.4 +/- 4.7 hours) in healthy individuals. (ABSTRACT TRUN
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PMID:Clinical pharmacokinetics of fluconazole in superficial and systemic mycoses. 925 Apr 23

Fluconazole, an inhibitor of certain human cytochrome P-450 isozymes, is used for the prevention and treatment of a broad range of fungal infections that predominantly affect immunocompromised individuals. This study evaluated the influence of fluconazole on the steady-state pharmacokinetics of delavirdine, a nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase, in 13 HIV-1-infected patients with CD4 counts ranging from 186 to 480/mm3. Both the control group (n = 5) and the fluconazole group (n = 8) received 300 mg of delavirdine mesylate every 8 h for 30 days; subjects in the fluconazole group took a 400-mg, once-daily dose of fluconazole on study days 16 to 30. Harvested plasma from serial blood samples collected on days 15, 16, and 30 were assayed for concentrations of delavirdine and its N-desalkyl metabolite by a reversed-phase high-pressure liquid chromatography (HPLC) method. Blood samples obtained on days 16 and 30 were also assayed for fluconazole by HPLC. Delavirdine mesylate alone and in combination with fluconazole was well tolerated. There were no significant differences (P > 0.16) in delavirdine pharmacokinetic parameters between treatment groups on day 15 or day 30. After coadministration of fluconazole and delavirdine mesylate for 2 weeks (day 30), no significant differences (P > 0.058) were observed in any delavirdine pharmacokinetic parameters relative to those after receiving delavirdine mesylate alone (day 15) after in the fluconazole group. Fluconazole pharmacokinetic parameters were similar to those previously reported for healthy volunteers and HIV-positive patients. On the basis of these findings, fluconazole and delavirdine mesylate may be taken concurrently without adjustment of the dose of either drug.
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PMID:Effect of fluconazole on the steady-state pharmacokinetics of delavirdine in human immunodeficiency virus-positive patients. 930 80

Fluconazole dosages greater than 800 mg day-1 have been reported in about 900 patients treated for candidemia, oropharyngeal candidiasis and cryptococcal meningitis in HIV-infected patients, and for initial therapy of endemic mycoses. In patients with life-threatening infections caused by Candida spp., Cryptococcus neoformans and Coccidioides immitis, results of a limited number of dose-finding trials with non-neutropenic and HIV-infected patients show dose-dependent responses. These study results indicate that higher daily doses of fluconazole than are currently approved for these indications are well tolerated and tend to provide better clinical efficacy in selected patient populations. An excellent safety profile of dosages up to 2000 mg day-1 and linear predictable pharmacokinetics up to 1600 mg day-1 appear to justify further clinical investigations to better determine the optimum dosage and duration of treatment.
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PMID:High-dose therapy with fluconazole > or = 800 mg day-1. 947 9

We reviewed the records of 15 Human Immunodeficiency Virus (HIV) infected patients with pulmonary cryptococcosis (PC). PC was the first AIDS-defining manifestation in nine patients. HIV infection was identified simultaneously with the onset of PC in 4 patients. The CD4+ lymphocyte count was low in all cases (median, 24/m3). Chest radiography showed interstitial infiltrates in 13 instances, associated with pleural effusion in 5 cases and hilar adenopathy in 2 cases. In one case, chest-X-ray showed isolated pleural effusion and was normal in one patient. For 11 of 12 patients, bronchoalveolar lavage fluid culture was positive for Cryptococcus neoformans. Seven of 15 patients had evidence of extrapulmonary cryptococcal disease with positive cerebrospinal fluid culture. Serum cryptococcal antigen was detected in all 15 patients. Concomitant lung infection with Pneumocystis carinii was diagnosed in 4 patients. First-line regimen was fluconazole in 10 patients and amphotericin B in 4 patients. Fluconazole has been prescribed in 7 patients as a permanent suppressive therapy and should be continued indefinitely.
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PMID:[Pulmonary cryptococcosis during HIV infection. 15 cases]. 948 Apr 80

The purpose of this study was to examine the effect of preceding fluconazole treatment on the oral mycologic flora and on the sensitivity of oral Candida albicans isolates to fluconazole. Saline oral rinses were collected from 89 HIV-positive patients, of whom 48 had been exposed to fluconazole and 41 were fluconazole-naive. The rinses were cultured on Sabouraud's and Pagano Levin agars, and yeasts were identified by standard methods. Fluconazole sensitivity of C. albicans isolates was measured by disk diffusion assay. C. albicans was isolated from 69% of patients who had received fluconazole and from 93% of the patients who were fluconazole-naive (p < 0.05). Nine other species of yeasts were also isolated, most commonly C. glabrata. Five patients previously exposed to fluconazole harbored fluconazole-resistant C. albicans, whereas no resistance was detected among the patients who were fluconazole-naive (p < 0.01). Sixteen of the patients who were fluconazole-exposed carried yeasts other than C. albicans, compared with only five patients in the fluconazole-naive group (p < 0.01). All of the fluconazole-resistant strains were isolated from patients with low CD4 counts (less than 100 cells/ml) and after lengthy fluconazole exposures. Nevertheless, patients in Charlotte, N.C., who had a greater mean fluconazole exposure time (10.25 +/- 1.41 months) than patients in Glasgow, UK, (0.65 +/- 0.18 months; p < 0.005), did not develop significantly more in vitro resistance or species diversity. This study indicates that long-term fluconazole treatment can have significant effects on the yeast flora of the mouth, particularly in a patient with a CD4 count of less than 100 cells/ml.
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PMID:Fluconazole-resistant Candida species in the oral flora of fluconazole-exposed HIV-positive patients. 961 74

Zidovudine (3'-azido-3'-deoxythymidine [AZT]), an antiviral nucleoside analog effective in the treatment of human immunodeficiency virus infection, is primarily metabolized to an inactive glucuronide form, GAZT, via uridine-5'-diphospho-glucuronosyltransferase (UGT) enzymes. UGT enzymes exist as different isoforms, each exhibiting substrate specificity. Published clinical studies have shown that atovaquone, fluconazole, methadone, and valproic acid decreased GAZT formation, presumably due to UGT inhibition. The effect of these drugs on AZT glucuronidation was assessed in vitro by using human hepatic microsomes to begin understanding in vitro-in vivo correlations for UGT metabolism. The concentrations of each drug studied were equal to those reported with the usual clinical doses and at concentrations at least 10 times higher than would be expected with these doses. High-performance liquid chromatography was used to assess the respective metabolism and formation of AZT and GAZT. All four drugs exhibited concentration-dependent inhibition of AZT glucuronidation. The respective concentrations of atovaquone and methadone which caused 50% inhibition of GAZT were > 100 and 8 micrograms/ml, well above their usual clinical concentrations. Fluconazole and valproic acid exhibited 50% inhibition of GAZT at 50 and 100 micrograms/ml, which are within the clinical ranges of 10 to 100 and 50 to 100 micrograms/ml, respectively. These data suggest that inhibition of AZT glucuronidation may be more clinically significant with concomitant fluconazole and valproic acid. Factors such as inter- and intraindividual pharmacokinetic variability and changes in AZT intracellular concentrations should be considered as other mechanisms responsible for changes in AZT pharmacokinetics with concomitant therapies.
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PMID:Glucuronidation of 3'-azido-3'-deoxythymidine (zidovudine) by human liver microsomes: relevance to clinical pharmacokinetic interactions with atovaquone, fluconazole, methadone, and valproic acid. 966 Sep 89


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