Indinavir transcriptase inhibitors

TC, lamivudine ABC, abacavir APV, amprenavir AST, aspartate aminotransferase ALT, alanine aminotransferase ATV, atazanavir CBC, complete blood cell count D/C, discontinue ddl, didano-sine d4T, stavudine EFV, efavirenz FTC, emtricitabine P1BV, hepatitis B virus F1CV, hepatitis C vims HIV, human immunodeficiency virus IDV, indinavir IV, intravenous LFT, liver function tests LPV/r, lopinavir + ritonavir NNRTI, nonnucleoside reverse transcriptase inhibitor NRTI, nucleoside reverse transcriptase inhibitor NVP, nevirapine PI, protease inhibitor PT, prothrombin time T.bili, total bilirubin TDF, tenofovir disoproxiI fumarate TPV, tipranavir ULN, upper limit of normal ZDV, zidovudine. 

Cross-resistance between indinavir and HIV reverse transcriptase inhibitors is unlikely because the enzyme targets involved are different. Cross-resistance was noted between indinavir and the protease inhibitor ritonavir. Varying degrees of cross-resistance have been observed between indinavir and other HIV-protease inhibitors. 

Drugs that might affect amprenavir include abacavir, aldesleukin, antacids, anticonvulsants, azole antifungals, clarithromycin, cyclosporine, dexamethasone, buffered didanosine, disulfiram, ethanol, indinavir, methadone, metronidazole, nelfinavir, nonnucleoside reverse transcriptase inhibitors, oral contraceptives, rifamycins, ritonavir, saquinavir, St. John s wort, tacrolimus, and zidovudine. 

This class of antiretrovirals may be considered the most potent therapeutic agents for HIV to date. Protease inhibitors are used in combination regimens and combinations of reverse-transcriptase inhibitors and protease inhibitors have been proven most effective to decrease viral load and prolong survival. However, the protease inhibitors generally show poor penetration into the CNS and thus have no effect on aids dementia. The present Pis available for the treatment of HIV are indinavir, ritonavir, nel-finavir, saquinavir and (fos)amprenavir, atazanavir and lopinavir (in combination with ritonavir as ritonavir improves the bioavailability of lopinavir by inhibiting its metabolism in the liver by CYP3A). 

Haas DW, Fessel WJ, Delapenha RA, Kessler H, Seekins D, Kaplan M, Ruiz NM, Ploughman LM, Labriola DF, Manion DJ. Therapy with efavirenz plus indinavir in patients with extensive prior nucleoside reverse-transcriptase inhibitor experience a randomized, double-bhnd, placebo-controlled trial. J Infect Dis 2001 183(3) 392-400. 

At the present time, there are at least 14 compounds that have been formally approved for the treatment of human immunodeficiency virus (HIV) infections. There are six nucleoside reverse transcriptase inhibitors (NRTIs) that, after their intracellular conversion to the 5 -triphosphate form, are able to interfere as competitive inhibitors of the normal substrates (dNTPs). These are zidovudine (AZT), didanosine (ddl), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), and abacavir (ABC). There are three nonnucleoside reverse transcriptase inhibitors (NNRTIs) — nevirapine, delavirdine, and efavirenz — that, as such, directly interact with the reverse transcriptase at a nonsubstrate binding, allosteric site. There are five HIV protease inhibitors (Pis saquinavir, ritonavir, indinavir, nelfinavir, and amprenavir) that block the cleavage of precursor to mature HIV proteins, thus impairing the infectivity of the virus particles produced in the presence of these inhibitors. 

Application as a Synthetic Building Block in Pharmaceutical Compounds. The best-known application of the (lS,2/ )-enantiomer of cw-aminoindanol is as a component of Indinavir (4), the primary component of a Crixivan combination therapy (with other reverse transcriptase inhibitors) for AIDS7 An excellent account of the synthetic approach to Indinavir, as well as the use of 1 in other drugs, can be found in a recent review. ... 

Efavirenz is a non-nucleoside reverse transcriptase inhibitor with excellent inhibitory activity against HTV-l. Its most frequent adverse effects involve the central nervous system and the skin (1). At the start of therapy, dizziness, insomnia, or fatigue is observed in most patients, and headache and even psychotic reactions have also been observed. A maculopapular rash is seen in about 10%. These adverse effects usually vanish within the first 2-4 weeks of therapy (2). About 1-2% of individuals stop taking efavirenz because of neurological or dermatological adverse events. Administration of efavirenz at bedtime reduces the incidence of severe adverse effects, and the rash can be managed by short-term antihistamines or topical corticosteroids (1). Nausea and vomiting are less often observed than in patients treated with zidovudine, lamivudine, or indinavir. 

Lichterfeld M, Nischalke HD, Bergmann F, Wiesel W, Rieke A, Theisen A, Fatkenheuer G, Oette M, Carls H, Fenske S, Nadler M, Knechten H, Wasmuth JC, Rockstroh JK. Long-term efficacy and safety of ritonavir/ indinavir at 400/400 mg twice a day in combination with two nucleoside reverse transcriptase inhibitors as first line antiretroviral therapy. HIV Med 2002 3(l) 37-43. 

Patients with AIDS who are taking protease inhibitors and nonnucleoside reverse transcriptase inhibitors are at risk of being subtherapeutically treated because these drugs are metabolized by CYP3A4. Studies have shown that combined use of St. John s wort and indinavir reduced the area under the... 

Successful treatment of human immunodeficiency virus (HIV-1) infection has been achieved through successful implementation of highly active antiretroviral therapy, frequently referred to as HAART. This involves simultaneous administration of both nucleoside and nonnucleoside reverse transcriptase inhibitors and one or more protease inliibitors. The common nucleoside reverse transcriptase inhibitors are the thymidine analogs didanosine (ddl), lamivudine (3TC), and zalcitabine (ddC) and the non-thymidine analogs abacavir (Ziazen), stavudine (d4T), and zidovudine (AZT). The nonnucleoside reverse transcriptase inhibitors include delavirdine, efavirenz, and nevirapine. The protease inhibitors include indinavir, nelfinavir, ritonavir, and saquinavir. Response to therapy is monitored by quantification of HIV-RNA copies (viral load) and CD-4+ T-lymphocyte count. Successful therapy is indicated when viral load is reduced to <50 copies/mL and CD-4+ count >500 per mL. 

The FDA approves an HIV viral load test Nevirapine, the first anti-HIV drug of the non-nucleoside reverse transcriptase inhibitors (NNRTl) Ritonavir Pi Indinavir Pis... 

There is no cure for AIDS. Treatment seeks to suppress symptoms (e.g., antibiotics for the infections) and slow viral reproduction. Mortality rates have decreased since 1995 because of the introduction of a treatment protocol called highly active antiretroviral therapy (HAART) that consists of combinations of drugs from the following categories (1) nucleoside reverse transcriptase inhibitors (NRTIs) (e.g., azidothymidine, also called zidovudine or AZT), (2) non-nucleoside reverse transcriptase inhibitors (NNRTIs) (e.g., efavirenz) and protease inhibitors (e.g., indinavir). Both NRTIs and NNRTIs inhibit vDNA synthesis catalyzed by reverse transcriptase. Protease inhibitors are a class of drugs that prevent the processing of viral protein that is required for the assembly of new virions. 

Indinavir (800 mg/t.i.d.) is an inhibitor of the HIV protease, which is an enzyme required for the proteolytic cleavage of the viral polyprotein precursors into the individual functional proteins found in infectious HIV. Indinavir binds to the protease active site and inhibits the activity of the enzyme. This inhibition prevents cleavage of the viral polyproteins resulting in the formation of immature noninfectious viral particles. Cross-resistance between indinavir and HIV reverse-transcriptase inhibitors is unlikely because the enzyme targets involved are different. Cross-resistance was noted between indinavir and the protease inhibitor ritonavir. Varying degrees of cross-resistance have been noted between indinavir and other HIV protease inhibitors. Indinavir is metabolized in the liver, and seven metabolites have been identified, and 20% of indinavir is excreted unchanged in the urine. 

Combination of 16 ARVs seven HIV protease inhibitors (amprenavir, atazanavir, indinavir, lopinavir, nelfmavir, ritonavir, and saquinavir), seven nucleoside reverse transcriptase inhibitors (abacavir, didanosine, emtricitabine, lamivudine, stavudine, zalcitabine, and zidovudine), and two nonnucleoside reverse transcriptase inhibitors (efavirenz and nevirapine)... 

Marzolini, C. Telenti, A. Buclin, T. Biollaz, J. Decosterd, L.A. Simultaneous determination of the HIV protease inhibitors indinavir, amprenavir, saquinavir, ritonavir, nel-finavir and the non-nucleoside reverse transcriptase inhibitor efavirenz by high-performance liquid chromatography after solid-phase extraction. J. Chromatogr. B, 2000, 740 (1), 43-58. 

The hydrogenations in Equations 15.31 and 15.32 illustrate the reduction of more complex substrates leading to a-amino acid amides. The first example demonstrates a diaste-reoselective hydrogenation conducted by the fine chemicals company Lonza as part of the synthesis of the vitamin biotin. " The second example shows an a-amino acid product produced in quantities greater than 200 tons by Lonza using a rhodium catalyst containing the Josiphos ligand shown. This product is an intermediate in the synthesis of Indinavir (Crixivan), which was used in combination with a reverse transcriptase inhibitor to create the first effective treatment for... 

DaiUy, E. Thomas, L. Kergueris, M.F. JolUet, P. Bourin, M. High-performance liquid chromatographic assay to determine the plasma levels of HIV-protease inhibitors (amprenavir, indinavir, nelflnavir, ritonavir and saquinavir) and the non-nucleoside reverse transcriptase inhibitor (nevirapine) after liquid-liquid extraction, J.Chromatogr.B, 2001, 758, 129-135. 

Faux, J. Venisse, N. Le Motil, G. Dupuis, A. Bouquet, S. Simultaneous determination of six HIV protease inhibitors, one metabolite, and two non-nucleoside reverse transcriptase inhibitors in human plasma by isocratic reversed-phase liquid chromatography after solid-phase extraction, Chromatographia 2003, 58, 421-426. [amprenavir indinavir lopinavir nelflnavir ritonavir saquinavir efavirenz nevirapine prazepsun]... 

Villani, P. Peroggio, M. Gianelli, L. Bartoli, A. Montagna, M. Maserati, R. Regazzi, M.B. Antiretrovirals simultaneous determination of five protease inhibitors and three nonnucleoside transcriptase inhibitors in human plasma by a rapid high-performance liquid chromatography-mass spectrometry assay, Ther.Drug Morait, 2001,23, 380-388. [saquinavir indinavir ritonavir nelfinavir amprenavir nevirapine delavirdine efavirenz]... 

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