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)

HIV-derived vectors are of potential clinical relevance due to their ability to transduce nondividing cells in vitro and in vivo. However, the generation of cell lines stably and reproducibly expressing high amounts of defined subviral particles, capable of packaging and transducing HIV-derived vectors, has been hampered by the cytotoxicity of some of the required gene products, in particular of the HIV-1 protease. The successful use of regulatable gene expression systems to overcome this problem requires that the remaining basally expressed gene product activity is below the threshold for cytotoxicity. To try to achieve this, we have consecutively introduced appropriate plasmids, encoding HIV rev and HIV gag/pol gene products, each under the control of separate ecdysone-inducible promoters, into human 293 cells. Using a protocol in which a specific HIV protease inhibitor, Saquinavir, was continuously present in the culture medium during selection, we could generate stable cell lines inducibly expressing high amounts of subviral particles. A cell line, termed 293-Rev/Gag/Pol(i), which has been characterized in more detail, inducibly releases, within 48 h postinduction, high amounts of HIV Gag/Pol particles (about 10 microg CA/ml). These HIV Gag/Pol particles can package and transduce third-generation HIV vectors to high titers. Thus, in addition to other applications, the 293-Rev/Gag/Pol(i) cell line represents a "founder" packaging cell line which, depending on the requirement, can be further modified to include specific transgene-encoding vector and targeting glycoprotein genes.
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PMID:Generation of a flexible cell line with regulatable, high-level expression of HIV Gag/Pol particles capable of packaging HIV-derived vectors. 1131 23

This study assessed the activity and tolerability of an HIV-protease inhibitor, saquinavir, alone or in combination with zidovudine. A total of 92 previously untreated HIV-infected patients with CD4 cell counts < 300 cells/mm3 participated in a parallel, randomized double-blind study. Patients were randomized to receive one of five treatments, each three times a day: 600 mg of saquinavir; 200 mg of zidovudine; 75, 200 or 600 mg of saquinavir in combination with 200 mg of zidovudine. The primary treatment period was 16 weeks, with monthly extensions in patients who did not show major disease progression or toxicity. The main measures of the efficacy of therapy used were changes in CD4 cell counts and in the concentration of HIV-1 RNA in the plasma (as determined by quantitative polymerase chain reaction). The 600 mg dose of saquinavir in combination with zidovudine induced a 1.6 log (after 4 weeks) and a 0.7 log (after 16 weeks) median reduction in plasma RNA concentration; this reduction was greater than those seen in the other four treatment groups. The combination of 600 mg of saquinavir with zidovudine also resulted in a larger and more sustained improvement in the CD4 cell count than either saquinavir or zidovudine monotherapy or the other combination therapies. In the group receiving 200 mg of saquinavir in combination with zidovudine, the maximal median change in CD4 cell count occurred at week 2 (85 cells/mm3), and by week 16 had fallen to 15 cells/mm3. In the group receiving 600 mg of saquinavir plus zidovudine, the median change in CD4 cell count remained high for the 16-week period (median change of 48 cells/mm3 at week 2 and 61 cells/mm3 at week 16). Saquinavir was safe and very well tolerated, either alone or in combination with zidovudine. The incidence of adverse events was greater in the four groups receiving zidovudine therapy, and all the most commonly reported adverse events have previously been associated with zidovudine therapy. Few changes in laboratory values occurred during the study, except for known zidovudine-associated toxicities. The most frequent abnormalities were raised aspartate aminotransferase and alanine aminotransferase levels, depressed calcium levels, and abnormally high or low phosphate levels. Despite the low oral bioavailability of saquinavir, combined virological and immunological data show definite antiviral activity in vivo for the combination of saquinavir at 600 mg plus zidovudine at 200 mg (each three times daily). The combination of drugs with different mechanisms of action represents an advance in the treatment of HIV infection.
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PMID:A randomized controlled trial of a protease inhibitor (saquinavir) in combination with zidovudine in previously untreated patients with advanced HIV infection. 1132 46

Saquinavir is a peptidomimetic inhibitor of HIV protease. Initially marketed as Invirasetrade mark, the effectiveness of saquinavir was greatly hindered by its nearly complete first pass metabolism by cytochrome P450 3A4. A new formulation, Fortovasetrade mark, appears to yield some six times the drug exposure and has been demonstrated to yield virological and immunological results similar to those of other protease inhibitors (PIs) when used in conjunction with two nucleoside reverse transcriptase inhibitors (nRTIs). Emerging data suggest it is safe to use twice daily. Co-administration of either formulation of saquinavir with nelfinavir and especially ritonavir yields greatly increased blood levels, with corresponding superior magnitude and durability of viral suppression in first line therapy, albeit with increased adverse effects. The combination of ritonavir and saquinavir has also yielded the most promising results published for second line therapy, after virological breakthrough on previous PI-containing therapy. In addition, preliminary data suggests the possibility of once daily dosing of ritonavir and saquinavir, which would be expected to increase compliance and allow for direct observed therapy.
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PMID:Pharmacology and clinical experience with saquinavir. 1133 88

New clinical trial developments surrounding anti-HIV compounds, known as protease inhibitors, are discussed for the following drugs: Merck (MK-639), Searle (SC512151), Abbott (ABT-538), Hoffman LaRoche (Saquinavir), Agouron (AG-1343), and Vertex (VX-478). Merck's MK-639 shows marked reductions of HIV in blood, but resistance appears after six months. Side effects have been minimal, the most severe of which is the brief appearance of hyperbilirubinemia. Searle is stopping clinical development of SC512151 because of the drug's lack of anti-viral effect. Preliminary clinical data on Abbott's ABT-538 are promising, based on trials showing rises in CD4 counts, and evidence of very good bioavailability compared with other protease inhibitors. Saquinavir, the longest tested protease inhibitor, shows an ability to cause a two-fold reduction in HIV RNA plasma levels. Supplies of saquinavir are low. Roche intends to apply for accelerated approval of saquinavir in 1995. AG-1343 and VX-478 are just starting clinical trials, however, preclinical trials of AG-1343 show excellent bioavailability and pharmacokinetics.
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PMID:Protease inhibitor update. 1136 40

The Inter-Company Collaboration for AIDS Drug Development (ICC), formed in April 1993, is a consortium of international pharmaceutical companies that have agreed to conduct combination and comparative studies of antiviral agents for the treatment of HIV infection and AIDS. Members at the May 11, 1995 meeting discussed the start of the first triple-combination study of antiretroviral drugs conducted under the Collaboration's master multi-drug protocol. The trial (001) has been delayed by almost a year due to disagreement about its design. Protocol 001 will examine the antiviral and immunologic effects of two different three-drug combinations--AZT plus ddC plus saquinavir and AZT plus ddC plus nevirapine--and compare the three-drug combination to the two-drug combination of AZT plus ddC. Protocol 002 will compare the three-drug combination AZT plus ddI plus nevirapine to AZT plus ddI plus 3TC. These protocols, however, do not include the most promising new experimental treatments for HIV infection--the Merck and Abbott protease inhibitor drugs. The protocols use traditional study design. Researchers and activists are asking for uncontrolled, small, quick studies to screen new multi-drug combinations to discover the strongest possible antiviral effect as measured by polymerase chain reaction (PCR) and CD4 cell testing. Also vital to the AIDS community, is a clinical study combining two protease inhibitor drugs--Roche's saquinavir (Invirase) and Merck's indinavir sulfate (Crixivan).
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PMID:The Inter-Company Collaboration for AIDS Drug Development: boon or bust? 1136 48

Hoffmann-La Roche and Agouron Pharmaceuticals are establishing large clinical studies in the United States of their protease inhibitors. La Roche is set to begin its Phase III trial of Invirase (saquinavir), which will study the drug alone and in combination with other antiretrovirals. The trial, NV14256, includes 1,000 patients with advanced HIV disease who are no longer tolerant to zidovudine (AZT, Retrovir) and who have a CD4 count between 50 and 300. A concurrent international Phase III trial of saquinavir will involve 3,300 patients who have had little or no AZT treatment. Roche will also begin a compassionate-treatment program that will supply saquinavir to patients unable to meet the stringent requirements of the clinical trials. Agouron is expected to enter Phase III trials for its protease inhibitor, AG1343. A monotherapy trial will look at optimal dosing, durability, and resistance patterns of the drug. A second trial will combine AG1343 with the antiretroviral, stavudine (D4T). A third trial will look at the stavudine-AG1343 combination in late-stage patients, and will compare standard-of-care treatment with AG1343 to standard-of-care treatment and placebo. In Agouron's Phase I/II trials for AG1343, results showed up to a 95 percent reduction in viral load throughout the first 4 weeks of treatment for patients. CD4 counts rose as much as 120 in some patients in the first 9 days. Although there is excitement about the four protease inhibitors currently being tested, questions about resistance continue.
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PMID:Protease inhibitor trials moving to next phase. 1136 75

The Inter-Company Collaboration for AIDS Drug Development (ICC) was created to foster cooperation between pharmaceutical companies with antiviral drugs in clinical development so as to more rapidly develop therapies for people with AIDS. Recent activities, reported at the May 11, 1995 meeting, include an agreement by the participating companies to extend their collaboration into basic research to share developed animal models, share biologic data for drug resistance studies, exchange biochemical assays, and share data on compounds that failed in pre-clinical development. In addition, ICC-001 is the first study evaluating the effect of two separate three-drug combinations, AZT/ddC/Invirase and AZT/ddC/nevirapine compared to AZT/ddC, in 225 patients. The trial is fully enrolled although the number of female participants is low. ICC-002 is scheduled to begin enrolling June 12, 1995, to compare AZT/ddI/nevirapine and AZT/ddI/3TC to AZT/ddI, again in 225 patients. Also at the meeting, two new clinical trial designs were proposed. Jules Levin recommended that the collaborative run combination protease inhibitor studies, specifically of Merck's MK-639 and Roche's invirase (saquinavir). Bill Bahlman proposed that the ICC run open-label studies of a new three-drug combination in thirty patients every month in order to quickly discover more potent combination therapies. Finally, David Barry, M.D., of the Burroughs Wellcome Co. (and chair of the ICC's clinical trials subcommittee) proposed to establish an observational database that would gather data on every person with HIV under treatment by a physician.
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PMID:Future of ICC debated. Inter-Company Collaboration for AIDS Drug Development. 1136 92

In September 1995, Hoffmann-LaRoche submitted its protease inhibitor Invirase (saquinavir) to the Food and Drug Administration (FDA) for approval. Clinical data are showing saquinavir is unlikely to cause cross-resistance to most compounds in its class; when resistance does develop, it is at a lower rate than seen with other AIDS drugs, even after prolonged treatment; and it is well tolerated (even at higher dosages) and shows activity against HIV as monotherapy and in combination with ddC and/or ZDV. Currently there are approximately 3,600 patients enrolled in Invirase phase III trials, and additional studies are underway to further define the potential of saquinavir.
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PMID:Roche submits NDA for Invirase. 1136 96

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

Glaxo Wellcome presented results from evaluation studies on their new protease drug, VX-478, at the Consensus Symposium on Combined Antiviral Therapy in 1995. Results show that VX-478 appears to be synergistic with Roche's Invirase (saquinavir), and additive with Merck's Crixivan (indinavir sulfate), and Abbott's ritonavir. VX-478 has been shown to be a potent inhibitor of both AZT-sensitive and AZT-resistant viruses. Studies with Merck's Crixivan, another protease inhibitor, indicate problems with cross-resistance; and data on Hoffman-LaRoche's Invirase suggest no cross-resistance problems. It is believed that combination therapy strategies with various protease inhibitors may keep HIV replication in check for a prolonged period, and delay emergence of resistant strains of the virus.
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PMID:New protease drug shows early promise. 1136 87


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