Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: ZK856 .18
48,410 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Baseline and posttreatment human immunodeficiency virus type 1 (HIV-1) isolates from 38 symptomatic, zidovudine-experienced HIV-1-infected children enrolled in a prospective trial of zalcitabine (dideoxycytidine) monotherapy (Pediatric AIDS Clinical Trials Group 138) were studied for the presence of syncytium-inducing (SI) phenotype and zalcitabine resistance. Twenty of the isolates were SI and 18 were non-SI (NSI) at baseline. After >44 weeks of zalcitabine treatment, the SI and NSI phenotypes were maintained in 16 and 17 patients, respectively. One patient had an NSI-to-SI phenotypic switch, while SI-to-NSI reversion occurred in 4 children (20%). Isolates from 30 of these patients were analyzed by in vitro drug susceptibility assay: Mean IC50 values were 0.14 microM at baseline and 0.18 microM following zalcitabine treatment. Only 1 child (3%) developed zalcitabine resistance. Knowledge of the low incidence of zalcitabine resistance and the switch from SI to NSI phenotype in some children may prove useful when selecting antiretroviral drugs to be used in combination.
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PMID:Human immunodeficiency virus type 1 phenotypes in children with advanced disease treated with long-term zalcitabine. 949 33

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

The actual prevalence of visceral leishmaniasis among human immunodeficiency type 1 (HIV-1)-infected patients in the Mediterranean basin remains unknown. There is also controversy about the risk factors for Leishmania infantum and HIV-1 coinfection. To appraise the prevalence of visceral leishmaniasis in patients infected with HIV-1 in southern Spain and to identify factors associated with this disease, 291 HIV-1 carriers underwent a bone marrow aspiration, regardless of their symptoms. Giemsa-stained samples were searched for Leishmania amastigotes. Thirty-two (11%) patients showed visceral leishmaniasis. Thirteen (41%) patients had subclinical cases of infection. Centers for Disease Control and Prevention (CDC) clinical category C was the factor most strongly associated with this disease (adjusted odds ratio [OR], 1.88 [95% confidence interval, 1.22 to 2.88]), but patients with subclinical cases of infection were found in all CDC categories. Female sex was negatively associated with visceral leishmaniasis (adjusted OR, 0.42 [95% confidence interval, 0.18 to 0.97]). Intravenous drug users showed a higher prevalence than the remaining patients (13.3 versus 4.9%; P = 0.04), but such an association was not independent. These results show that visceral leishmaniasis is a very prevalent disease among HIV-1-infected patients in southern Spain, with a high proportion of cases being subclinical. Like other opportunistic infections, subclinical visceral leishmaniasis can be found at any stage of HIV-1 infection, but symptomatic cases of infection appear mainly when a deep immunosuppression is present. There is also an association of this disease with male sex and intravenous drug use.
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PMID:Prevalence of and factors associated with visceral leishmaniasis in human immunodeficiency virus type 1-infected patients in southern Spain. 970 66

Pharmacokinetic drug interactions with viral protease inhibitors are of potential clinical importance. An in vitro model was applied to the quantitative identification of possible interactions of protease inhibitors with substrates of cytochrome P450-2D6. Biotransformation of desipramine (DMI) to hydroxydesipramine (OH-DMI), an index reaction used to profile activity of human cytochrome P450-2D6, was studied in vitro using human liver microsomes. Quinidine and four viral protease inhibitors currently used to treat human immunodeficiency virus infection were tested as chemical inhibitors in this system. Formation of OH-DMI from DMI was consistent with Michaelis-Menten kinetics, having a mean Km value of 11.7 microM (range: 9.9-15.3 microM). Quinidine, a highly potent and relatively selective inhibitor of P450-2D6, strongly inhibited OH-DMI formation with an apparent competitive mechanism, having a mean inhibition constant of 0.16 microM (range: 0.13-0.18 microM). All four protease inhibitors impaired OH-DMI formation; the pattern was consistent with a mixed competitive-noncompetitive mechanism. Mean inhibition constants (small numbers indicating greater inhibiting potency) were as follows: ritonavir, 4.8 microM; indinavir, 15.6 microM; saquinavir, 24.0 microM; nelfinavir, 51.9 microM. In a clinical pharmacokinetic study, coadministration of ritonavir with DMI inhibited DMI clearance by an average of 59%. The in vitro findings, together with observed plasma ritonavir concentrations, provided a reasonable quantitative forecast of this interaction, whereas estimated unbound plasma or intrahepatic ritonavir concentrations yielded poor quantitative forecasts. Thus the in vitro model correctly identifies ritonavir as a potent and clinically important inhibitor of human P450-2D6. Other protease inhibitors may also inhibit 2D6 activity in humans, but with lower potency than ritonavir.
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PMID:Inhibition of desipramine hydroxylation (Cytochrome P450-2D6) in vitro by quinidine and by viral protease inhibitors: relation to drug interactions in vivo. 975 74

Factors associated with changes in HIV risk behaviors were investigated in a prospective study of 911 injecting drug users and 359 crack smokers recruited on the basis of a stratified cluster design in metropolitan San Juan, Puerto Rico, in 1992-93. The findings presented in this paper are based on the 1004 drug users (79.1%) who were available for a follow-up interview 6 months after the baseline interview. Respondents were randomly assigned to receive a standard HIV prevention intervention (pretest counseling, optional HIV testing, and provision of HIV results) or the standard intervention plus a site-specific enhanced intervention entailing access to condoms and needle hygiene equipment, development of a personal risk reduction plan and training in the skills required to implement it, and ongoing contact with outreach workers. Overall, abstinence from sexual behavior increased from 54.6% at baseline to 61.1% at follow-up (p 0.01) while condom use during vaginal sex rose from 26.4% to 36.9% (p 0.01). In multivariate analysis, significant predictors of abstinence were male gender, injecting drug use, a positive HIV test at baseline, and not having a steady partner. Significant predictors of condom use were HIV seropositivity and a sexually transmitted disease diagnosis. Participation in the enhanced compared to the standard HIV prevention program was associated with an odds ratio of 1.29 (95% confidence interval, 0.95-1.74) for abstinence and 1.97 (95% confidence interval, 1.18-3.29) for condom use in vaginal sex.
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PMID:Factors associated with changes in sex behaviour among drug users in Puerto Rico. 982 76

We studied the pharmacokinetics of intravenously and orally administered lamivudine at six dose levels ranging from 0.5 to 10 mg/kg of body weight in 52 children with human immunodeficiency virus infection. A two-compartment model with first-order elimination from the central compartment was simultaneously fitted to the serum drug concentration-time data obtained after intravenous and oral administration. The maximal concentration at the end of the 1-h intravenous infusion and the area under the concentration-time curve after oral and intravenous administration increased proportionally with the dose. The mean clearance of lamivudine (+/- standard deviation) in the children was 0.53 +/- 0.19 liter/kg/h (229 +/- 77 ml/min/m2 of body surface area), and the mean half-lives at the distribution and elimination phases were 0.23 +/- 0.18 and 2.2 +/- 2.1 h, respectively. Clearance was age dependent when normalized to body weight but age independent when normalized to body surface area. Lamivudine was rapidly absorbed after oral administration, and 66% +/- 25% of the oral dose was absorbed. Serum lamivudine concentrations were maintained above 1 microM for >/=8 h of 24 h on the twice daily oral dosing schedule with doses of >/=2 mg/kg. The cerebrospinal fluid drug concentration measured 2 to 4 h after the dose was 12% (range, 0 to 46%) of the simultaneously measured serum drug concentration. A limited-sampling strategy was developed to estimate the area under the concentration-time curve for concentrations in serum at 2 and 6 h.
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PMID:Serum and cerebrospinal fluid pharmacokinetics of intravenous and oral lamivudine in human immunodeficiency virus-infected children. 983 13

Associations between substance use and sexual behavior were examined among 3220 seronegative men who have sex with men (MSM) in a HIV vaccine preparedness study. Relationships between current and past substance use and current sexual risk were evaluated using crude odds ratios and logistic regression to adjust for confounding variables. Heroin and injection drug use were uncommon (< 2%). Substances most often used were alcohol (89%), marijuana (49%), nitrite inhalants (29%), amphetamines or similarly acting stimulants (21%), cocaine 14% and hallucinogens (14%). Increased adjusted odds for unprotected sex were significantly associated with current heavy alcohol use (OR 1.66; CI 1.18, 2.33), past alcohol problems (OR 1.25; CI 1.05, 1.48), and current drug use (OR 1.26; CI 1.08, 1.48). When associations with specific drugs and nitrite inhalants were examined separately, current use of cocaine and other stimulants (OR 1.25; CI 1.01, 1.55), hallucinogens (OR 1.40; CI 1.10, 1.77), and nitrite inhalants (some (OR 1.61; CI 1.35, 1.92); heavy (OR 2.18; CI 1.48, 3.20)), were independently associated with unprotected sex. Those with past drug use or past heavy alcohol use but not currently using demonstrated no increase in sexual risk, suggesting an important role for substance-focused interventions in risk reduction efforts among MSM.
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PMID:Non-injection substance use correlates with risky sex among men having sex with men: data from HIVNET. 1008 45

The synthesis of L-nucleoside analogues containing 2'-vinylic fluoride was accomplished by direct condensation method, and their anti-HIV and anti-HBV activities were evaluated in vitro. The key intermediate 8, the sugar moiety of our target compounds, was prepared from 1,2-O-isopropylidene-L-glyceraldehyde via (R)-2-fluorobutenolide intermediate 5 in five steps. Coupling of the acetate 8 with the appropriate heterocycles (silylated uracil, thymine, N4-benzoylcytosine, N4-benzoyl-5-fluorocytosine, 6-chloropurine, and 6-chloro-2-fluoropurine) in the presence of Lewis acid afforded a series of 2'-fluorinated L-nucleoside analogues (15-18, 23-26, 36-45). The newly synthesized compounds were evaluated for their antiviral activities against HIV-1 in human peripheral blood mononuclear (PBM) cells and HBV in 2.2.15 cells. Cytosine 23, 5-fluorocytosine 25, and adenine 36 derivatives exhibited moderate to potent anti-HIV (EC50 0.51, 0.17, and 1.5 microM, respectively) and anti-HBV (EC50 0.18, 0.225, and 1.7 microM, respectively) activities without significant cytotoxicity up to 100 microM in human PBM, Vero, CEM, and HepG2 cells.
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PMID:Synthesis and anti-HIV and anti-HBV activities of 2'-fluoro-2', 3'-unsaturated L-nucleosides. 1019 75

The present study examined the consequences of being a self-reported transsexual male and HIV risk behaviours in a state penal system. The specific research question was whether or not sexual orientation of inmates influences the level to which they evidence HIV risk behaviours. A total of 153 participants volunteered to participate in the study of which 31 described themselves as being transsexual. Based on risk ratios and using transsexual inmates (TIs) as the reference group, they were 13.7 times more likely to have a main sex partner while in prison [95% CI=5.28, 35.58]. Moreover, TIs were 5.8 times more likely than non-transsexual inmates (NTIs) to report having more than one sex partner while in prison [95% CI=2.18, 15.54]. It is obvious from these findings that TIs require more preventive support than their NTI confederates. In addition to TIs being protected from assault and battery by NTIs, they need social support and carefully developed preventive informational materials.
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PMID:Transsexual orientation in HIV risk behaviours in an adult male prison. 1021 26

To identify the risk factors for cryptococcal meningitis in patients with HIV disease we conducted a nested case-control study of 37 incident cases of cryptococcal meningitis and 74 controls, identified from a cohort of more than 2000 HIV-infected patients. Conditional logistic regression was used to study demographic and AIDS-related variables in addition to fluconazole and steroid use. No difference in demographic variables, HIV risk factors, or stage of AIDS was detected between cases and controls. Exposure to fluconazole for more than 90 days reduced the risk of cryptococcal meningitis by 82% (OR=0.18; 95% CI=0.04-0.85; p=0.03). We did not find a difference in steroid use between cases and controls for either the length or amount of steroid exposure (p=0.41). No difference in survival during follow-up in the clinic was observed by the log-rank test (p=0.74). Among the cases, a cryptococcal antigen was positive in more than 97% of the CSF or blood samples. CSF and blood cultures were positive in 81 and 44% of the samples, respectively. We conclude that demographic factors did not affect the risk of cryptococcal meningitis in an inner city United States population. While fluconazole use has a protective effect, steroid use was not associated with an increased risk of cryptococcal meningitis in HIV-infected patients.
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PMID:Risk factors for cryptococcal meningitis in HIV-infected patients. 1033 41


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