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)

The US Food and Drug Administration (FDA) has approved the marketing of five new drugs for treatment of HIV infection. Stavudine (D4T; Zerit -- Bristol-Myers Squibb) and lamivudine (3TC; Epivir -- Glaxo Wellcome) are nucleoside analogs similar to zidovudine (AZT), didanosine (ddI) and zalcitabine (ddC). Saquinavir (Invirase -- Roche), ritonavir (Norvir -- Abbott) and indinavir (Crixivan -- Merck) are protease inhibitors, a new class of anti-HIV drugs.
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PMID:New drugs for HIV infection. 860 77

In 1995 and 1996, the Food and Drug Administration (FDA) approved three products in the new protease inhibitor class of drugs--saquinavir (Invirase), ritonavir (Norvir), and indinavir (Crixivan). Another drug in this class of agents, nelfinavir (Viracept) (Agouron Pharmaceuticals), is expected to be available soon from the manufacturer through an expanded-access program. All four drugs, which inhibit HIV protease and thus interfere with viral maturation and replication, are the most potent antiretroviral agents available to treat patients with HIV disease. However, these protease inhibitors interact with rifamycin derivatives, such as rifampin and rifabutin, which are used to treat and prevent the mycobacterial infections commonly observed in HIV-infected patients. Rifamycins accelerate the metabolism of protease inhibitors (through induction of hepatic P450 cytochrome oxidases), resulting in subtherapeutic levels of the protease inhibitors. In addition, protease inhibitors retard the metabolism of rifamycins, resulting in increased serum levels of rifamycins and the likelihood of increased drug toxicity. This report describes approaches for managing patients who are candidates for or who are undergoing protease inhibitor therapy when tuberculosis (TB) is diagnosed and presents interim recommendations for managing these patients until additional data are available and formal guidelines are issued.
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PMID:Clinical update: impact of HIV protease inhibitors on the treatment of HIV-infected tuberculosis patients with rifampin. 892 17

The humoral immune response to HIV infection plays an important role in determining disease progression. Few and discordant results correlate changes in neutralizing antibody (NtAb) titer with antiretroviral treatment. The NtAb titer against autologous-HIV was evaluated in 33 patients treated with the protease inhibitor saquinavir (SQV, Invirase) and zidovudine (ZDV) alone or in combination. Ten out of 33 (30%) patients showed a significant increase (4-fold or greater) in NtAb titer from baseline in response to the initiation of therapy. A significant correlation (P = 0.007) was found between an increase in NtAb titer and treatment with SQV alone (5 subjects) or in combination (5 subjects). A significant decrease in NtAb titer was detected in 7 patients, 5 of whom were treated with ZDV alone. After one year of therapy a significant decrease in HIV-RNA copy number (> 0.5 log) with respect to baseline value was detected only in patients treated with SQV alone or in combination. Patients with increased NtAb titer showed a significantly reduced HIV-RNA copy number and increased CD4+ cell count at week 16 of treatment which were sustained up to week 52. These data suggest that treatment with SQV can improve neutralizing activity against autologous virus as well as bring about a significant and sustained reduction in viral load.
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PMID:Increase in neutralizing antibody titer against sequential autologous HIV-1 isolates after 16 weeks saquinavir (Invirase) treatment. 940 77

Cytochrome P450 3A4 (CYP3A4), the major phase I drug metabolizing enzyme in humans, and the MDR1 gene product P-glycoprotein (P-gp) are present at high concentrations in villus tip enterocytes of the small intestine and share a significant overlap in substrate specificity. A large body of research both in vitro and in vivo has established metabolism by intestinal CYP3A4 as a major determinant of the systemic bioavailability of orally administered drugs. More recently it has been recognized that drug extrusion by intestinal P-gp can both reduce drug absorption and modulate the effects of inhibitors and inducers of CYP3A-mediated metabolism. There is relatively little data regarding the effects of CYP3A and P-gp on peptide drugs; however, studies with the cyclic peptide immunosuppresant cyclosporine as well as peptidomimetics such as the HIV-protease inhibitor saquinavir (Invirase) and a new cysteine protease inhibitor K02 (Morpholine-Urea-Phe-Hphe-Vinyl sulfone; Axys Pharmaceuticals) provide some insight into the impact of these systems on the oral absorption of peptides.
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PMID:Role of P-glycoprotein and cytochrome P450 3A in limiting oral absorption of peptides and peptidomimetics. 981 84

Therapeutic drug monitoring is essential in HIV-patients undergoing highly active antiretroviral therapy (HAART). Saquinavir (SQV) is used alone or in combination with ritonavir (RTV) or nelfinavir (NLF), respectively, in the context of the HAART drug regimen. The achievable SQV concentration range in clinical practice remains to be elucidated. A non-randomized prospecitve clinical trial 19 patients (group I) receiving SQV (1x600 mg/d Invirase or Fortovase), 29 patients (group II) receiving SQV (2x600 mg/d Fortovase) plus RTV (2x400 mg/d Norvir), and 21 patients (group III) receiving SQV (2x600 mg/d Fortovase) plus NLF (2x750 mg/d Viracept) was conducted to determine SQV plasma concentrations. SQV levels were determined as trough levels during routine outpatient visits. Analysis was performed by HPLC with UV detection. The lowest SQV plasma levels were found in group I (95% CI 89-177 ng/ml). Significantly higher SQV levels were found in group III (combination with NLF) ranging from 242 to 398 ng/ml (95% CI) and in group II (combination with RTV) ranging from 1354 to 1747 ng/ml (95% CI). The IC 50% of 54 ng/ml was not reached in at least one sample during the study (mean duration of study 16+/-10 months) in 14/19 patients of group I, 9/29 patients in group II and 13/21 patients in group III, respectively. A positive correlation between patient compliance, defined by SQV levels in the 95% CI of the used combination, and the HIV RNA plasma level was found. The presented data confirm that therapy with SQV alone may not be effective, since trough levels are near the lower limit of antiretroviral efficacy. Although the combination of SQV with NLF results in higher SQV plasma concentrations in a bid regimen, in more than 60% of the patients SQV concentrations below IC 50 level were detected during the twelve-months study period. The combination of SQV with RTV yields the highest SQV-trough levels. SQV concentrations below the IC 50 were seen in only 31% of patients with the SQV/RTV combination. In conclusion, therapeutic drug monitoring allows an efficient surveillance of patients compliance. In addition, therapeutic drug monitoring represents a valuable tool for management of HAART in patients receiving a complex comedication or suffering from advanced liver disease.
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PMID:Therapeutic drug monitoring of saquinavir in patients during protease inhibitor therapy with saquinavir alone or in combination with ritonavir or nelfinavir. 1072 May 64

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

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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