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

Indinavir, N-[2(R)-hydroxy-1(S)-indanyl]-5-[2(S)-tertiary- butylaminocarbonyl-4-(3-pyridylmethyl)piperazino]-4(S)- hydroxy-2(R)-phenylmethylpentanamide (L-735,524,MK-639, ayl-4- Crixivan), is a potent and specific inhibitor of the HIV-1(3 protease for the treatment of AIDS. Disposition of [14C]indinavir was investigated in six healthy subjects after single oral administration of 400 mg. AUC, Cmax, and Tmax values for indinavir were 492 microM x min, 4.7 microM, and 50 min, respectively. The AUC value for the total radioactivity in plasma was 1.9 times higher than that of indinavir, indicating the presence of metabolites. The major excretory route was through feces, and the minor through urine. Mean recovery of radioactivity in the feces was 83.4%. In the urine, mean recoveries of the total radioactivity and unchanged indinavir were 18.7% and 11.0% of the dose, respectively. HPLC radioactivity and LC-MS/MS analyses of urine showed the presence of indinavir and low levels of quaternary pyridine N-glucuronide (M1), 2',3'-trans-dihydroxyindanylpyridine N-oxide (M2), 2',3'-trans-dihydroxyindan (M3) and pyridine N-oxide (M4a) analogs, and despyridylmethyl analogs of M3 (M5) and indinavir (M6). M5 and M6 were the major metabolites in urine. The metabolic profile in plasma was similar to that in urine. Quantitatively, the metabolites in feces accounted for >47% of the dose, which along with the urinary excretion of approximately 19%, suggested that the absorption of the drug was appreciable. In the feces, radioactivity was predominantly due to M3, M5, M6, and the parent compound. Thus, in urine and feces, the prominent metabolic pathways were oxidations and oxidative N-dealkylations. Excretion of the quaternary N-glucuronide metabolite in the urine, which is a minor metabolite in human, was specific to primates.
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PMID:Disposition of indinavir, a potent HIV-1 protease inhibitor, after an oral dose in humans. 897 Nov 47

Recent results from human clinical trials have established the critical role of HIV protease inhibitors in the treatment of acquired immune-deficiency syndrome (AIDS). However, the emergence of viral resistance, demanding treatment protocols, and adverse side effects have exposed the urgent need for a second generation of HIV protease inhibitors. The continued exploration of our hydroxylaminepentanamide (HAPA) transition-state isostere series of HIV protease inhibitors, which initially resulted in the identification of Crixivan (indinavir sulfate, MK-639, L-735,524), has now yielded MK-944a (L-756,423). This compound is potent, is selective, and competitively inhibits HIV-1 PR with a K(i) value of 0.049 nM. It stops the spread of the HIV(IIIb)-infected MT4 lymphoid cells at 25.0-50.0 nM, even in the presence of alpha(1) acid glycoprotein, human serum albumin, normal human serum, or fetal bovine serum. MK-944a has a longer half-life in several animal models (rats, dogs, and monkeys) than indinavir sulfate and is currently in advanced human clinical trials.
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PMID:Identification of MK-944a: a second clinical candidate from the hydroxylaminepentanamide isostere series of HIV protease inhibitors. 1097 86

A reversed-phase high-performance liquid chromatographic assay for the determination of the HIV protease inhibitors amprenavir (Agenerase) and indinavir (Crixivan) in human plasma is described, using a mobile phase consisting of 0.50 M phosphate buffer (adjusted to pH 5,5) - Milli-Q water - acetonitrile (120: 1,080: 800, v/v/v). A solid-phase extraction using C18 extraction columns (Discovery columns 100 mg, 1 ml Supelco) and a liquid-liquid extraction with 0.5 ml hydrogenocarbonate/carbonate buffer (adjusted to pH 10.6) and 6 ml methyl ter-butyl ether have been compared. The liquid-liquid extraction has been chosen to be easier and cheaper. The method has been validated over the range of 60 to 3,000 ng/ml for amprenavir and 20 to 3,000 ng/ml for indinavir using a 0.5 ml sample volume. The specificity, linearity, accuracy and precision have been studied. The limit of detection was respectively for amprenavir and indinavir 15 and 4 ng, and the limit of quantification was 60 and 20 ng/ml. Stability tests under various conditions were performed. This assay can readily be used in a hospital laboratory for the routine monitoring of plasma concentrations of amprenavir in HIV-infected patients. The trough plasma concentrations average has been determined in patients treated by amprenavir and indinavir for seven months.
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PMID:[Simultaneous quantitative determination of amprenavir and indinavir in human plasma by high-performance liquid chromatography]. 1128 20

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

Merck has announced a compassionate use lottery of Crixivan (formerly known as MD-639 and L-735, 524), a protease inhibitor for the treatment of HIV disease. Crixivan will be made available without cost to 1,400 eligible people in the United States, of which 1,100 will be randomly selected using specific criteria. The patient must be clinically stable, be able to follow directions, and have stable laboratory status. Outside the United States, Crixivan will be made available to approximately 750 patients from 29 countries in Europe, South America, Canada, and Australia. Merck will pay for the drug (including shipping), the post-selection central laboratory tests, and the urine pregnancy test, if needed. No other costs will be borne by the company.
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PMID:Merck announces compassionate-treatment lottery for Crixivan. 1136 30

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

Hoffman LaRoche and Merck have agreed to expand enrollment in their Invirase and Crixivan programs if the drug availability increases. The Roche program offers Invirase to HIV-positive individuals with CD4 cell counts under 300. The Merck program provides Crixivan to people with AIDS who have fifty or fewer CD4 cells. Originally, both programs were open only to individuals who were intolerant to, or had failed, standard treatments for HIV infection.
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PMID:Roche and Merck begin expanded access programs for protease inhibitor drugs. 1136 90

Indinavir (Crixivan) is one of the protease inhibitors approved for HIV treatment by the Food and Drug Administration (FDA). All studies to date have been limited to examining its effect on T4 cell changes and HIV viral load levels. Current studies are looking at indinavir in combination with AZT and 3TC. After sixteen weeks of combination therapy, viral loads in patients dropped to levels below those that can be measured with standard tests. However, these studies were done on small groups, and there are larger tests currently being held. Reducing the amount of virus also reduces the risk of disease progression and death. HIV can become resistant to the effects of indinavir, but this resistance occurs more slowly than with the other protease inhibitors. Using it in combination with a nucleoside analog drug seems to significantly delay resistance.
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PMID:Indinavir (Crixivan). 1136 98


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