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: UMLS:C0021051 (immunodeficiency)
71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

PNU-140690 (sulfonamide-containing 5,6-dihydro-4-hydroxy-2-pyrone) is a potent, nonpeptidic inhibitor of the human immunodeficiency virus type 1 (HIV-1) protease currently under clinical evaluation. PNU-140690 and ritonavir were studied in two-drug combinations against the replication of HIV-1 clinical isolates in peripheral blood mononuclear cells. A ritonavir-sensitive (301-1x) and -resistant (301-6x) isolate pair derived from an individual before and after monotherapy with ritonavir were used. These isolates showed no significant difference in sensitivity to PNU-140690, but isolate 301-6x was more than 50-fold less sensitive to ritonavir than isolate 301-1x. Mathematical analysis showed that the combination of various concentrations of PNU-140690 with ritonavir yielded additive to moderately synergistic antiviral effects against the ritonavir-sensitive isolate and stronger synergy against the ritonavir-resistant isolate. The mechanism of synergy was not investigated, but the results suggested that both the virological and the observed in vitro pharmacological effects may have contributed to the observed synergy. Importantly, no significant antagonism was observed with the drug combinations studied. These data suggest that PNU-140690 may be useful in combination regimens with a structurally unrelated protease inhibitor such as ritonavir.
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PMID:In vitro combination of PNU-140690, a human immunodeficiency virus type 1 protease inhibitor, with ritonavir against ritonavir-sensitive and -resistant clinical isolates. 937 35

The human immunodeficiency virus-1 protease inhibitor SD894 was evaluated as an inhibitor and inducer of cytochromes P450 (CYPs) in rats. After addition of 10 microM SD894 and 2 mM NADPH to liver microsomes from dexamethasone-treated rats, a type II spectrum appeared. Within 2 min, it was replaced by a type III spectrum, with absorbance maxima at 426 and 456 nm, similar to those observed with alkylamines (SKF-525A) and arylamines (p-chloroaniline). Preincubation of microsomes from dexamethasone-treated rats with SD894 and NADPH resulted in a time-dependent inhibition of testosterone 6beta-hydroxylation (CYP 3A1/2 activity), which was decreased to 25% of controls after 30 min. Testosterone 16beta-hydroxylation (CYP 2B1/2 activity) was unaffected under these conditions. Testosterone 6beta-hydroxylation rates in liver microsomes from pregnenolone 16alpha-carbonitrile-treated rats incubated with 10 microM SD894 and NADPH, washed, and reisolated by ultracentrifugation were reduced by 71%, whereas 16beta-hydroxylation was unaffected by SD894. Immunoblots of liver microsomes from rats dosed iv with SD894 or ip with TAO displayed increased CYP 2B1 and CYP 3A1 levels, respectively. Testosterone 6beta-hydroxylase activity in microsomes from TAO-treated rats was greater than controls. Preincubation of these microsomes with potassium ferricyanide produced an additional 50% increase, consistent with disruption of a metabolite-CYP complex. Microsomes from SD894-treated rats displayed a 3-fold increase in testosterone 16beta-hydroxylation. Potassium ferricyanide preincubation did not increase activity. Thus, although SD894 appears to inhibit CYP in vitro in a manner typical of other amine-containing, mechanism-based inhibitors, in vivo induction by 10 mg/kg daily doses of SD894 affects a different isozyme than does inhibition. The mechanism of induction is unknown.
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PMID:In vitro and in vivo effects of the arylamine human immunodeficiency virus protease inhibitor 4R-(4alpha,5alpha,6beta, 7beta)-1-[(3-(1-imidazoylcarbamoyl)phenyl)methyl]-3-[(3-aminophenyl)m ethyl]hexahydro-5,6-dihydroxy-4,7-bis(phenylmethyl)-2H-1, 3-diazepin-2-one (SD894) on rat hepatic cytochrome P450 2B and 3A. 939 33

We report 2 cases of maculopapular eruption and fever in patients infected with human immunodeficiency virus (HIV) on the 2nd day of first administration of ritonavir, a protease inhibitor. In the 1st patient, clinical improvement occurred despite continuation of therapy, and in the 2nd the treatment was stopped with remission and rechallenge resulting in recurrence. Ritonavir should be added to the list of drugs that can induce adverse cutaneous reactions in HIV patients.
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PMID:Early ritonavir-induced maculopapular eruption. 940 88

The effect of antiretroviral therapy on both T-cell numbers and T-cell function in peripheral blood was studied. CD4+ and CD8+ T-cell numbers, T-cell reactivity to CD3 monoclonal antibodies (mAb), and viral RNA load date were obtained from patients treated for at least 28 weeks with either the HIV-1 protease inhibitor ritonavir, the nonnucleoside HIV-1 reverse transcriptase (RT) inhibitor nevirapine, or the nucleoside-analogue RT inhibitor zidovudine. Compared with both RT inhibitors, treatment with the protease inhibitor ritonavir resulted in the most significant and persistent elevation of CD4+ and CD8+ T-cell counts. However, in vitro T-cell functional improvement was of limited duration in the ritonavir-treated group and was inversely correlated with viral RNA load changes during the entire follow-up period. Thus, despite what can be assumed of responses during RT inhibitor therapy, quantitative responses on therapy did not necessarily correlate with qualitative immunologic responses, as can be seen during treatment with ritonavir. For optimal immune reconstitution, both numeric and functional immunologic improvements are essential. During antiretroviral therapy, measurement of in vitro improvement in immune function will be useful as a correlate for transient drug-induced alteration of immunodeficiency.
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PMID:Patterns of T-cell repopulation, virus load reduction, and restoration of T-cell function in HIV-infected persons during therapy with different antiretroviral agents. 942 Mar 8

Plasma human immunodeficiency virus type 1 (HIV-1) populations were genetically analyzed at their most variable locus, the envelope gene, during the rapid emergence of resistance to protease inhibitor monotherapy. Plasma virus populations remained genetically constant prior to drug treatment and during the 1 to 2 weeks following initiation of therapy, while viremia fell 10- to 100-fold. Concomitant with rapid plasma viremia rebounds associated with the emergence of drug-resistant virus, marked alterations were then detected at the env locus. Plasma population changes lasted only a few weeks before the reappearance of the pretreatment envelope variants. The emergence of resistance to single protease inhibitors was therefore associated with major but transient changes at a nonselected locus. Selection for resistance to single protease inhibitors thus appears to be more complex than the continued replication of a large, random, and therefore genetically representative sampling of the pretreatment plasma population. The possibility that drug-privileged anatomical sites containing distinct envelope variants and/or a small effective HIV-1 population size account for these results is discussed.
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PMID:Rapid, transient changes at the env locus of plasma human immunodeficiency virus type 1 populations during the emergence of protease inhibitor resistance. 949 2

We report three cases of frozen shoulder (including one with bilateral involvement) in human immunodeficiency virus (HIV)-positive patients under triple antiretroviral therapy. In each case, the diagnosis was confirmed by arthrography, and the classic causes of frozen shoulder were ruled out. We suggest that protease inhibitor therapy may have contributed to the development of frozen shoulder in these patients. Long-term follow-up of the increasing numbers of patients under triple antiretroviral therapy will confirm or refute this hypothesis.
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PMID:Frozen shoulder: a new delayed complication of protease inhibitor therapy? . 992 53

We examined the viral replicative capacity and protease-mediated processing of Gag and Gag-Pol precursors of human immunodeficiency virus (HIV) variants selected for resistance to protease inhibitors. We compared recombinant viruses carrying plasma HIV RNA protease sequences obtained from five patients before protease inhibitor therapy and after virus escape from the treatment. Paired pretherapy-postresistance reconstructed viruses were evaluated for HIV infectivity in a quantitative single-cycle titration assay and in a lymphoid cell propagation assay. We found that all reconstructed resistant viruses had a reproducible decrease in their replicative capacity relative to their parental pretherapy counterparts. The extent of this loss of infectivity was pronounced for some viruses and more limited for others, irrespective of the inhibitor used and of the level of resistance. In resistant viruses, the efficiency of Gag and Gag-Pol precursor cleavage by the protease was impaired to different extents, as shown by the accumulation of several cleavage intermediates in purified particle preparations. We conclude that protease inhibitor-resistant HIV variants selected during therapy have an impaired replicative capacity related to multiple defects in the processing of Gag and Gag-Pol polyprotein precursors by the protease.
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PMID:Loss of viral fitness associated with multiple Gag and Gag-Pol processing defects in human immunodeficiency virus type 1 variants selected for resistance to protease inhibitors in vivo. 952 57

To evaluate a potential pharmacokinetic interaction of coadministration of fluconazole, and indinavir, a human immunodeficiency virus (HIV) protease inhibitor, 13 patients were enrolled in a multiple-dose, three-period, placebo-controlled, crossover study. Patients were randomly assigned to receive indinavir at 1,000 mg every 8 h for 7 1/3 days (with fluconazole placebo), fluconazole at 400 mg once daily for 8 days (with indinavir placebo), and indinavir with fluconazole in combination. The pharmacokinetics of both drugs were measured on day 8 of each treatment period. The peak concentration in plasma (Cmax) and the time to reach Cmax were obtained by inspection, and the area under curve (AUC) was calculated for indinavir and fluconazole for each treatment period in which the respective drugs were administered. There was a marginally (P = 0.08) statistically significant decrease in the AUC from 0 to 8 h (AUC(0-8)) for indinavir when it was administered with fluconazole. However, the magnitudes of the decreases in Cmax and the concentration at 8 h postdosing (C8) were not as great as the decrease in AUC(0-8). Although the 90% confidence interval for the geometric mean ratio was within the hypothesized limits, the clinical significance is not clear. Indinavir coadministration with fluconazole had no statistically (P > 0.5) or clinically significant effect on the Cmax and C8 of indinavir. Fluconazole coadministration with indinavir had no statistically or clinically significant effect on the pharmacokinetics of fluconazole. One patient was discontinued because of mild to moderate abdominal pain and diarrhea while on indinavir and fluconazole in combination. No serious adverse experience according to the results of laboratory tests was noted. Total bilirubin levels in serum were mildly increased in most patients treated with indinavir. This was not clinically significant and was not affected by the coadministration of fluconazole. Although the values of the pharmacokinetic parameters for indinavir decrease in the presence of fluconazole, indinavir and fluconazole can be administered concomitantly to HIV-infected patients without adjustment of the dose of either drug, and both drugs are generally well tolerated.
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PMID:Effect of fluconazole on indinavir pharmacokinetics in human immunodeficiency virus-infected patients. 998 36

Indinavir sulfate is a human immunodeficiency virus type 1 (HIV-1) protease inhibitor indicated for treatment of HIV infection and AIDS in adults. The purpose of this report is to summarize single-dose studies which characterized the pharmacokinetics of the drug and the effect of food in healthy volunteers. Indinavir concentrations in plasma and urine were obtained by high-pressure liquid chromatography and UV detection assay methods. The results indicate that indinavir was rapidly absorbed in the fasting state, with the time to the maximum concentration in plasma occurring at approximately 0.8 h for all doses studied. Over the 40- to 1,000-mg dose range studied, concentrations in plasma and urinary excretion of unchanged drug increased greater than dose proportionally. The nonlinear pharmacokinetics were attributed to the dose-dependent oxidative metabolism of first-pass metabolism as well as to metabolism in the systemic circulation. Renal clearance slightly exceeded the glomerular filtration rate, suggesting a net tubular secretion component. At high concentrations in plasma, tubular secretion appeared to be lowered because there was a trend for a decreased renal clearance. Administration of 400 mg of indinavir sulfate following a high-fat breakfast resulted in a blunted and decreased absorption (areas under the concentration-time curves [AUCs], 6.86 microM.h in the fasted state versus 1.54 microM.h in the fed state; n = 10). However, two types of low-fat meals were found to have no significant effect on the absorption of 800 mg of indinavir sulfate (AUCs, 23.15 microM.h in the fasted state versus 22.71 and 21.36 microM.h, respectively, in the fed state; n = 11). Immediately following dosing, the concentrations of indinavir in urine often exceeded its intrinsic solubility. To reduce the risk of nephrolithiasis, it is recommended that indinavir sulfate be administered with water.
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PMID:Single-dose pharmacokinetics of indinavir and the effect of food. 952 81

While CD4 cell counts are widely used to predict disease progression in human immunodeficiency virus (HIV)-infected patients, they are poorly explanatory of the progression to AIDS or death after the introduction of chemotherapy. Changes in HIV load (as measured by RNA PCR) have been shown to be a much better predictor of the risk of disease progression. Since the interrelationship of these markers is of great clinical interest, we modeled the time-averaged return of CD4 cell count and change in viral load subsequent to therapy with the HIV protease inhibitor indinavir. We found that CD4 cell return was significantly related to both the baseline CD4 count (r2 = 0.86, P < 0.001) and the decline in HIV RNA PCR-determined viral load (also referred to in this work as the HIV RNA PCR decline) (r2 = 0.60, P < 0.01). Simultaneously modeling both influences in a linked nonlinear model (r2 = 0.93, P < 0.001) demonstrated that (i) the starting number of CD4 cells accounted for the majority of the change in CD4 cell return and (ii) the return of CD4 cells attributable to viral load decrease was 50% of maximal with only a decrease of approximately 0.2 log of HIV RNA as modeled from the first 12 weeks of therapy. Much greater viral inhibition beyond that necessary for maximal CD4 cell return is possible. Given that HIV RNA PCR decline is more strongly linked to ultimate clinical course in HIV disease, our findings indicate that CD4 return is potentially misleading as an indicator of antiviral effect, since it is determined more by the starting CD4 value than by viral load decline and since near-maximal changes occur with minimal antiviral effect.
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PMID:Mathematical modeling of the interrelationship of CD4 lymphocyte count and viral load changes induced by the protease inhibitor indinavir. 952 86


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