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)

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

The drug interactions between four human immune deficiency virus (HIV-1) protease inhibitors have been characterized by in-vitro metabolic studies using rat liver microsomal fractions and in-vivo oral administration. In this study, a new HPLC analytical method developed by us was used for the simultaneous determination of saquinavir and nelfinavir in rat plasma and microsomes. The metabolic clearance rates (Vmax/Km) of saquinavir, nelfinavir, and indinavir were 170.9 +/- 10.9, 126.1 +/- 4-4, and 73.0 +/- 2.0 microL min(-1) (mg protein)(-1), respectively. Ritonavir was the strongest inhibitor with inhibition constants (Ki) of 1.64 microM for saquinavir, 0.95 microM for indinavir, and 1.01 microM for nelfinavir. Nelfinavir was the second strongest inhibitor with Ki's of 2.35 microM for saquinavir and 2.14 microM for indinavir. Indinavir was the third strongest inhibitor with Ki's of 2.76 microM for nelfinavir and 3.55 microM for saquinavir. Saquinavir was the weakest inhibitor for the other three HIV- 1 protease inhibitors. After oral co-administration in combination with another HIV-1 protease inhibitor, the AUCs of saquinavir, indinavir, and nelfinavir were significantly increased compared with mono-treatment. The AUCs of saquinavir were increased about 10.1-, 3.1- and 45.9-fold in the presence of indinavir, nelfinavir and ritonavir, respectively. The AUCs of indinavir were increased about 6.8-, 5.9- and 9.4-fold in the presence of nelfinavir, saquinavir and ritonavir, respectively. The AUCs of nelfinavir were increased about 2.2-, 6.6- and 8.5-fold in the presence of indinavir, saquinavir and ritonavir, respectively. The in-vivo effects observed after co-administration of two kinds of HIV-1 protease inhibitor were not always expected from in-vitro data, suggesting the presence of other interaction processes besides metabolism in the liver. These results provide useful information for the treatment of AIDS patients receiving combination therapy with two HIV-1 protease inhibitors.
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PMID:Pharmacokinetic interactions between HIV-1 protease inhibitors in rats: study on combinations of two kinds of HIV-1 protease inhibitors. 1109 68

The use of reduced doses of Ritonavir (RIT) and Saquinavir (SQV) is considered a potent alternative in treating patients infected by HIV-1. We tested a combination of 300mg of RIT plus 600mg of SQV, twice daily, in association with two reverse transcriptase inhibitors to treat AIDS patients for a period of 6 months. Evaluation of HIV-1 RNA plasma levels, CD4+/CD8+ cell count and biochemical/hematological parameters (liver enzymes, serum electrolytes, creatinin, blood glucose, uric acid, white blood cell count, platelet count, and hemoglobin level) were performed after 30, 90 and 180 days of therapy. Clinical failure and adverse reactions were also recorded in order to assess safety and efficacy of the treatment. A total of 30 AIDS patients (25 male; 5 female) were enrolled in the study. Eight patients discontinued the therapy due to intolerance, 2 patients presented clinical failure (onset of AIDS-defining events during the study period), 2 patients werc excluded due to protocol violation. Five patients tolerated only a lower dose of RIT (400mg/day). Patients who completed 6 months of therapy had a drop in viral load from 4.8+/-.7 log(10) median 4.9 log) to 3.4 +/- 1.0 log(10) (median 2.6 log), and an increase in CD4+ count from 109 +/- 86cells/ml (median 84cells/ml) to 249+/- 114 cells/ml (median 265 cells/ml), compared to baseline values. However, patients who used a lower dose of RIT (400mg/day) had a less impressive drop in viral load values (mean 0.6 log(10) NA copies/ml) when compared with those using the 600mg/day of the drug (mean 2.4 log(10)). The percentage of patients presenting undetectable levels of HIV-1 RNA in plasma was quite different for the 2 groups: 92% of patients with a viral load <400 RNA copies/ ml were using 600mg of RIT. The combination of reduced doses of RIT and SQV reduced viral load >1.0 log(10) after 6 months in 83% of study patients. The dose of 600mg/day of RIT was morc effective in reducing viral load than 400mg/day, but was less well-tolerated. CD4+ cell counts increased in all patients regardless of the RIT dose used.
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PMID:Safety and Efficacy of Reduced Doses of Ritonavir (RTV) Plus Saquinavir (SQV) in the Treatment of AIDS Patients in Brazil. 1109 12

Ritonavir is a potent, orally bioavailable inhibitor of HIV-1 protease. Our investigators undertook a retrospective study to compare the effectiveness of ritonavir (600mg twice daily) associated with 2 reverse transcriptase inhibitors (RTIs) in 38 patients in 3 situations. Group I patients previously treated with 2 RTIs, Group II treatment-naive patients, and Group III patients previously treated with 2 RTIs and saquinavir. Routine hematological and biochemical studies, HIV-1 viremia, and CD4+ lymphocyte counts were performed before and after ritonavir. In Group I, the median of HIV-1 RNA plasma levels decreased from 4.8 to 3.4 log(10) copies/mL, in Group II from 5.9 to 2.9 log(10) copies/mL, and in Group III from 5.2 to 4.1 log(10) copies/mL. (p=0.003, p=0.014, p=0.002, respectively, Wilcoxon signed rank test). The median increases of CD4(+) cells occurred as follows: in Group I from 173 to 282 cells/mm(3), in Group II from 92 to 254 cell/mm(3), and in Group III from 68 to 133 cell/mm(3) (p=0.002, p=0.008, p<0.001, respectively, Wilcoxon signed rank test). In Group II the mean weight increased from 55.2 +/-14.3 kg to 59.4+/-15.7 kg and, in Group III, from 62.2+/-10.5 kg to 67.5+/-12 kg (p = 0.026, p = 0.002, respectively, paired T test). Patients in Group I presented no weight gain. Mild reversible hypertriglyceridemia occurred in 6 of 38 patients. The results of this study showed that ritonavir is a good choice for treatment naive patients and as a sequential option, not only after 2 RTIs, but also after a 3 drug regimen with saquinavir.
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PMID:Comparison of Ritonavir in a First Choice Three Drug Regimen, After Two Nucleoside Analogues and in Saquinavir Experienced Patients. 1110 13

ISS-IP1, a multicenter, randomized, 48-week open trial, was designed to compare the introduction of ritonavir or indinavir in patients with previous nucleoside experience and CD4+ cell counts below 50/mm3. Concomitant antiretroviral treatment with nucleoside analogs was allowed. Primary efficacy measures were survival and time to a new AIDS-defining event or death, analyzed through the whole period of observation by the intention-to-treat approach. Primary toxicity measures were time to treatment discontinuation and adverse events, grade at least 3/serious, analyzed by an on-treatment approach. Evaluation-of efficacy also included CD4+ cell and RNA response. The trial enrolled 1251 patients in 5 months. At baseline, mean CD4+ cell count was about 20 cells/mm3 and mean HIV RNA copy number was 4.9 log10/ml in both groups. Overall, 402 patients in the ritonavir group and 250 patients in the indinavir group permanently discontinued the assigned treatment (relative risk, 1.96; 95% CI, 1.68-2.30; p = 0.0001), with most of this difference dependent on a higher number of discontinuation for adverse events in the ritonavir group. After a mean follow-up of 307 days (ritonavir, 304; indinavir, 309), 124 deaths (ritonavir, 61; indinavir, 63; relative risk, 0.96; 95% CI, 0.67-1.36; p = 0.80) and 330 new AIDS-defining events (ritonavir, 170; indinavir, 160; relative risk, 1.05; 95% CI, 0.85-1.31; p = 0.60) were observed. CD4+ cell counts increased in both groups in patients still receiving treatment, with about 100 cells gained by week 24 and 150 cells gained by week 48. Body weight also increased over time in both groups. Analysis of RNA response showed a decrease of 1.5 log10 or higher in both treatment groups. Overall, 400 patients in the ritonavir group and 338 patients in the indinavir group developed at least one grade 3/serious new adverse event during follow-up (relative risk, 1.48; 95% CI, 1.28-1.72; p = 0.0001). Favorable CD4+ cell and RNA responses at 24 and 48 weeks were observed in both groups of patients remaining on treatment. Indinavir showed slightly better effects in sustaining RNA, CD4+ cell, and body weight responses. Ritonavir and indinavir results were comparable in terms of clinical outcome (survival and AIDS-defining events).
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PMID:A randomized trial comparing the introduction of ritonavir or indinavir in 1251 nucleoside-experienced patients with advanced HIV infection. 1111 67

Lopinavir is a protease inhibitor with high specificity for HIV-1 protease. Ritonavir strongly inhibits lopinavir metabolism; coadministration of lopinavir and ritonavir in healthy volunteers increased the area under the lopinavir plasma concentration-time curve >100-fold. Trough plasma concentration: antiviral 50% effective concentration ratio for lopinavir was >75 for wild-type HIV at the dose used in clinical trials, compared to values of < or = 4 for other commonly used protease inhibitors. Coformulated lopinavir and ritonavir (lopinavir/ ritonavir) 400/100mg twice daily for 48 weeks suppressed HIV replication in significantly more antiretroviral-naive patients than nelfinavir 750mg 3 times daily (all patients also received stavudine and lamivudine). Suppression of viral replication was observed in most protease inhibitor-experienced patients with lopinavir/ ritonavir (400/100, 400/200 or 533/133mg twice daily for 48 or 96 weeks) in combination with > or = 2 nucleoside reverse transcriptase inhibitors (NRTIs) and either efavirenz or nevirapine. 48 weeks of treatment with twice daily lopinavir/ ritonavir (230/57.5 or 300/75 mg/m2 for the first 12 weeks and then 300/75 mg/m2) in combination with 1 or2 NRTIs, with or without nevirapine, suppressed viral replication in the majority of antiretroviral-naive and -experienced paediatric patients (aged 6 months to 12 years). Diarrhoea, nausea and asthenia were the most frequently reported adverse effects in patients receiving lopinavir/ritonavir-based regimens. Elevated total cholesterol, triglyceride and hepatic enzyme levels were also reported.
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PMID:Lopinavir. 1115 17

In early 1996, Abbott Pharmaceutical plans to establish a global compassionate use program for Ritonavir (ABT-538), its candidate protease inhibitor for the treatment of HIV/AIDS. Fifteen hundred people with advanced AIDS will be enrolled in the program, limited to patients with CD4+ counts of fifty or less who are failing other available antiretroviral drugs, and who have not enrolled in any other protease inhibitor trials. A formal announcement on the details of the program is expected in early November 1995.
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PMID:Abbott agrees to implement a compassionate use program for Ritonavir. 1136 98

When HIV replicates, it forms large precursor proteins that are cleaved and processed by HIV protease to generate smaller viral proteins. HIV protease inhibitors interfere with this process, causing viral particles that are formed to be structurally disorganized, nonfunctional, and non-infectious. All of the HIV protease inhibitors in clinical trials, or nearing clinical development, are active against HIV-1 and HIV-2 at nanomolar concentrations, require no intracellular processing for activation, and are effective both in acutely and chronically infected cells. However, two pharmacokinetic problems have been identified: suboptimal oral bioavailability of peptidic inhibitors; and reduced cellular uptake of inhibitor that has become bound to alpha-acid glycoprotein. Three of the ten aforementioned protease inhibitors are in advanced development: saquinavir (Ro-31 8959), indinavir (MK-639), and ritonavir (ABT-538). Saquinavir has been extensively tested. It increases CD4 cell counts, reduces viral load, and its effects are magnified when administered in combination with AZT and ddC. Saquinavir recently entered accelerated approval procedures in the United States. Indinavir, an orally bioavailable protease inhibitor, engenders viral resistance after 12-24 weeks when administered at low doses, but higher doses may produce sustained effects lasting 52 weeks. Ritonavir, like indinavir, is an orally bioavailable protease inhibitor that is effective for a short time before viral mutants emerge. The emergence of resistance is the greatest problem with protease inhibitors.
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PMID:Update on HIV protease inhibitors. 1136 32

The combination of Abbott's ritonavir and Roche's saquinavir, two protease inhibitors, must be used with caution. The saquinavir dose must be drastically reduced, but by how much is not yet known. It is hoped that by using the combination, HIV drug resistance will be delayed. Ritonavir's ability to block a liver enzyme responsible for metabolizing and eliminating saquinavir, thus increasing its concentration in the blood to potentially dangerous levels, is the reason the combination should cautiously be used.
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PMID:Ritonavir, saquinavir combination--& warning. 1136 71

Ritonavir, a protease inhibitor, demonstrated strong antiviral activity when combined with AZT and ddC at dosage levels of 1200, 600 and 2.25 mg respectively. Six-month therapy resulted in a median CD4 count increase that was nearly double from baseline, and significant viral load reductions that were sustained throughout the study. Ritonavir was generally well tolerated. A study using AZT and 3TC with an experimental protease inhibitor, indinavir, also greatly reduced viral loads. The effects lasted throughout the six-month treatment period. A specific HIV protease gene that contributes to the emergence of resistance during treatment with ritonavir has also been identified.
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PMID:Protease inhibitors shine in triple combinations. 1136 43


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