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: KEGG:D03833 (Indinavir)
242 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Indinavir-associated adverse dermatologic reactions are rare but do occur. A 39-year-old man who was positive for the human immunodeficiency virus and had no known allergy, developed an erythematous, maculopapular eruption several hours after switching to a new triple-drug regimen consisting of stavudine, didanosine, and indinavir. The eruption completely resolved 2 weeks after he discontinued the antiretroviral combination. To preserve future treatment options, the patient was sequentially rechallenged with each agent and confirmed indinavir as the cause. The patient tolerated and responded to a new combination of stavudine, didanosine, and nelfinavir. The rapid onset of the adverse reaction suggested that it might have been immunoglobulin-E mediated. No cross-sensitivity between indinavir and nelfinavir was apparent.
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PMID:Indinavir-associated maculopapular eruption. 1055 39

The use of human immunodeficiency virus (HIV) protease inhibitors in children has lagged behind that in adults because of the lack of suitable pediatric formulations and information on safe and effective dosing regimens. This study was designed to obtain pharmacokinetic information on indinavir, administered to HIV-infected children also receiving therapy with two nucleoside agents, and to explore relationships between pharmacokinetic parameters and anti-HIV effect. Indinavir was initiated at a dose of 500 mg/m(2) every 8 h. Plasma indinavir concentrations were measured every 4 weeks; the dose or dosing interval was adjusted to maintain trough concentrations of > or =0.1 mg/liter. All children were evaluated clinically at baseline and every 4 weeks. Plasma HIV RNA was quantitated at baseline and at weeks 4, 12, and 24. Eighteen children participated in this study. The average daily dose of indinavir was 2,043 mg/m(2); nine children received indinavir at 6-h intervals. Pharmacokinetic characteristics of indinavir (mean +/- standard deviation) were the following: oral clearance, 1.4 +/- 0.5 liters/h/kg; half-life, 1.1 +/- 0.43 h; and trough concentration, 0. 29 +/- 0.32 mg/liter. In nine children that completed 24 weeks of therapy, the baseline-to-week-24 change in HIV RNA level was related to indinavir trough concentration and didanosine area under the curve. This study illustrates the ability to obtain pharmacokinetic information from children during routine clinic visits and to use this information to provide a safeguard against underdosing. The incorporation of pharmacologic knowledge with virologic, immunologic, and behavioral considerations should result in improved clinical outcomes for children infected with HIV.
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PMID:Pharmacologic characteristics of indinavir, didanosine, and stavudine in human immunodeficiency virus-infected children receiving combination therapy. 1072 7

Indinavir is a potent protease inhibitor widely used in combination with reverse-transcriptase inhibitors to treat human immunodeficiency virus (HIV) disease. Individuals treated with indinavir are prone to develop urinary complications, including renal colic, renal calculi, lower urinary tract symptoms, and indinavir crystalluria. Although renal stones secondary to indinavir have been described and characterized, little is known about the onset, frequency, and significance of the crystalluria. To document the longitudinal characteristics of indinavir crystalluria and associated urine abnormalities, 54 asymptomatic indinavir-naive HIV-positive individuals had urinalysis testing initially weekly and then monthly during the first year of indinavir treatment. Six hundred eight urinalyses were performed (11 +/- 2 urinalysis/subject), including 579 microscopy examinations performed by a nephrologist (10 +/- 2 examinations/subject). Baseline urinalysis results were essentially normal. After the start of treatment, indinavir crystalluria was frequently observed (67% of subjects). After the first 2 weeks, indinavir crystalluria remained constant at a frequency of approximately 25% of urine sediments examined at each test point. Other urine abnormalities, principally leukocytes (>/=10/high-power field) and casts, were observed in 39% of subjects. These abnormalities were more severe in five subjects, with concomitant increasing serum creatinine levels in three of them. Additional urine findings include the predominance of low pH (</=5. 5 in 72% of urinalyses) and high specific gravity (>/=1.025 in 66% of urinalyses). In conclusion, abnormal urinalysis results were noted frequently during the first year of treatment with indinavir. The main findings were the high proportion of subjects with crystalluria and the relatively high frequency of crystalluria observed consistently throughout. These findings may occasionally be associated with other urine abnormalities, presumably secondary to indinavir crystalluria.
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PMID:Prospective study of urinalysis abnormalities in HIV-positive individuals treated with indinavir. 1097 82

In order to identify inhibitors of various drug-resistant forms of the human immunodeficiency virus protease (HIV PR), we have designed and synthesized pseudopeptide libraries with a general structure Z-mimetic-Aa1-Aa2-NH2. Five different chemistries for peptide bond replacement have been employed and the resulting five individual sublibraries tested with the HIV PR and its drug-resistant mutants. Each mutant contains amino acid substitutions that have previously been shown to be associated with resistance to protease inhibitors, including Ritonavir, Indinavir, and Saquinavir. We have mapped the subsite preferences of resistant HIV PR species with the aim of selecting a pluripotent pharmaceutical lead. All of the enzyme species in this study manifest clear preference for an L-Glu residue in the P2' position. Slight, but significant, differences in P3' subsite specificity among individual resistant PR species have been documented. We have identified three compounds, combining the most favorable features of the inhibitor array, that exhibit low-nanomolar or picomolar Ki values for all three mutant PR species tested.
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PMID:A picomolar inhibitor of resistant strains of human immunodeficiency virus protease identified by a combinatorial approach. 1105 Oct 93

To characterize steady-state indinavir pharmacokinetics in cerebrospinal fluid and plasma, 8 adults infected with human immunodeficiency virus underwent intensive cerebrospinal fluid sampling while receiving indinavir (800 mg every 8 hours) plus nucleoside reverse transcriptase inhibitors. Nine and 11 serial cerebrospinal fluid and plasma samples, respectively, were obtained from each subject. Free indinavir accounted for 94.3% of the drug in cerebrospinal fluid and 41.7% in plasma. Mean values of cerebrospinal fluid peak concentration, concentration at 8 hours, and area under the concentration-time profile calculated over the interval 0 to 8 hours [AUC(0-8)] for free indinavir were 294 nmol/L, 122 nmol/L, and 1616 nmol/L x h, respectively. The cerebrospinal fluid-to-plasma AUC(0-8) ratio for free indinavir was 14.7% +/- 2.6% and did not correlate with indexes of blood-brain barrier integrity or intrathecal immune activation. Indinavir achieves levels in cerebrospinal fluid that should contribute to control of human immunodeficiency virus type 1 replication in this compartment. The cerebrospinal fluid-to-plasma AUC(0-8) ratio suggests clearance mechanisms in addition to passive diffusion across the blood-cerebrospinal fluid barrier, perhaps by P-glycoprotein-mediated efflux.
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PMID:Steady-state pharmacokinetics of indinavir in cerebrospinal fluid and plasma among adults with human immunodeficiency virus type 1 infection. 1140 45

A theoretical study was performed on a set of 38 human immunodeficiency type 1 (HIV-1) protease inhibitors that are structurally similar to the AIDS drug Indinavir. Comparison between the computed binding energies and experimental activity data (pIC(50)) found a high degree of correlation (r(2)() = 0.82). Three-dimensional quantitative structure-activity relationship (3D-QSAR) models using comparative molecular field analysis (CoMFA) yielded predicted activities that were in excellent agreement with the corresponding experimentally determined values. Inclusion of the calculated enzyme-inhibitor binding energy as an additional descriptor in the CoMFA model yielded a significant improvement in the internal predictive ability of our model (q(2)() = 0.45 to q(2)() = 0.69). Separate CoMFA models were constructed to evaluate the influence of different alignment schemes (Atom Fit and Field Fit) and different partial atomic charge assignment schemes (Discover CVFF, Gasteiger-Marsili, and AM1-ESP) on the statistical quality of the models.
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PMID:Computational studies on HIV-1 protease inhibitors: influence of calculated inhibitor-enzyme binding affinities on the statistical quality of 3D-QSAR CoMFA models. 1108 69

To assess a possible association between antiretroviral treatment and paronychia, we conducted a retrospective cohort study of 288 human immunodeficiency virus-positive protease inhibitor recipients. Indinavir treatment-adjusted for age, sex, CD4 count, diabetes status and other antiretroviral drug exposures-was significantly associated with paronychia of the great toe (hazard ratio 4.7; 95% confidence interval 1.6-13.9).
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PMID:Paronychia in association with indinavir treatment. 1111 93

Concurrent administration of indinavir and didanosine significantly reduces the level of exposure to indinavir, but it is unclear how soon after didanosine administration indinavir may be given safely. We compared indinavir pharmacokinetics and gastric pH in 12 human immunodeficiency virus-positive patients by use of 800 mg of indinavir alone versus 800 mg of indinavir administered 1 h after didanosine administration. Median gastric pH was significantly higher when indinavir was taken after didanosine administration; however, no significant difference in the maximum concentration in plasma or the area under the concentration-time curve from time zero to 8 h was observed. Indinavir may be taken with a light meal 1 h following the administration of 400 mg of didanosine.
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PMID:If taken 1 hour before indinavir (IDV), didanosine does not affect IDV exposure, despite persistent buffering effects. 1112 Sep 81

In many patients with human immunodeficiency virus (HIV) treated with HIV protease inhibitors, a complication develops that resembles abdominal obesity syndrome, with insulin resistance and glucose intolerance that, in some cases, progresses to diabetes. In this study, we tested the hypothesis that indinavir, an HIV-protease inhibitor, directly induces insulin resistance of glucose transport in skeletal muscle. Rat epitrochlearis muscles were incubated with a maximally effective insulin concentration (12 nmol/l) and 0, 1, 5, 20, or 40 micromol/l indinavir for 4 h. In control muscles, insulin increased 3-O-[(3)H]methyl-D-glucose (3MG) transport from 0.15 +/- 0.03 to 1.10 +/- 0.05 micromol. ml(-)(1). 10 min(-)(1). Incubation of muscles with 5 micromol/l indinavir reduced the insulin-stimulated increase in 3MG transport by 40%, whereas 20 micromol/l indinavir reduced the insulin-stimulated increase in 3MG transport by 58%. Indinavir induced a similar reduction in maximally insulin-stimulated 3MG transport in the soleus muscle. The increase in glucose transport activity induced by stimulating epitrochlearis muscles to contract was also markedly reduced by indinavir. The insulin-stimulated increase in cell-surface GLUT4, assessed using the 2-N-4-(1-azi-2,2,2-trifluoroethyl)benzoyl-1,3-bis-[2-(3)H] (D-mannose-4-yloxy)-2-propylamine exofacial photolabeling technique, was reduced by approximately 70% in the presence of 20 micromol/l indinavir. Insulin stimulation of phosphatidylinositol 3-kinase activity and phosphorylation of protein kinase B were not decreased by indinavir. These results provide evidence that indinavir inhibits the translocation or intrinsic activity of GLUT4 rather than insulin signaling.
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PMID:The HIV protease inhibitor indinavir decreases insulin- and contraction-stimulated glucose transport in skeletal muscle. 1137 41

Indinavir (IDV) is a potent and selective human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) widely used in antiretroviral therapy for suppression of HIV, but its effects on the immune system are relatively unknown. Recently, it has been reported that PIs inhibit lymphocyte apoptosis. In the present study we have investigated the effects of ex vivo addition of IDV on lymphocyte activation and apoptosis in cells from HIV-infected children (n = 18) and from healthy uninfected individuals (controls, n = 5) as well as in Jurkat and PM1 T-cell lines. Pretreatment of control peripheral blood mononuclear cell (PBMC) cultures with IDV resulted in a dose-dependent inhibition of lymphoproliferative responses to different activation stimuli. Additionally, this treatment led to cell-cycle arrest in G0/G1 phase in anti-CD3 monoclonal antibody-stimulated PBMC cultures in controls and in 15 of 18 HIV-infected children. Spontaneous- or activation-induced apoptosis of PBMCs from HIV-infected or uninfected individuals or of Fas-induced apoptosis in Jurkat and PM1 T cell lines were not inhibited by IDV. Moreover, IDV did not inhibit activation of caspases-1, -3, -4, -5, -9, and -8 in lysates of Jurkat T cells undergoing Fas-induced apoptosis. The findings indicate that IDV interferes with cell-cycle progression in primary cells but does not directly affect apoptosis. It is concluded that IDV may prolong cell survival indirectly by inhibiting their entry into cell cycle. In individuals on PI therapy, PI-mediated effects could potentially modulate immunologic responses independently of antiviral activity against HIV.
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PMID:The HIV protease inhibitor Indinavir inhibits cell-cycle progression in vitro in lymphocytes of HIV-infected and uninfected individuals. 1143 7


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