Saquinavir transcriptase inhibitors

APV, amprenavir ATV, atazanavir CNS, central nervous system CVD, cardiovascular disease D/C, discontinue ddC, zalcitabine ddl, didanosine DEXA, dual-energy x-ray absorptiometry d4T, stavudine EFV, efavirenz HDL, high-density lipoprotein HIV, human immunodeficiency virus HTN, hypertension IDV, indinavir LDL, low-density lipoprotein LPV/r, lopinavir+ ritonavir MRI, magnetic resonance imaging NNRTI, nonnucleoside reverse transcriptase inhibitor NRTI, nucleoside reverse transcriptase inhibitor NVP, nevirapine PI, protease inhibitor RTV, ritonavir SQV, saquinavir TDF, tenofovir disoproxil fumarate TG, triglyceride TPV/r, tipranivir + ritonavir ZDV, zidovudine. 

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). 

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. 

The HIV protease inhibitor saquinavir has hmited and variable oral systemic availability and ritonavir, an inhibitor of CYP450 and P glycoprotein, is widely used to increase its systemic exposure. A small pilot study in three HIV-infected patients has suggested that oral itraconazole can have similar effects on the oral availability of saquinavir (109). Concomitant use of itraconazole 200 mg/day with a combination of saquinavir and two nucleoside reverse transcriptase inhibitors led to a 2.5-to 6.9-fold increase in the AUC of saquinavir, a 2.0- to 5.4-fold increase in peak plasma concentrations, and a 1.6-to 17-fold increase in trough plasma concentrations. The effect of itraconazole on saquinavir was comparable to that of ritonavir. 

Gynecomastia has been reported in a series of men taking saquinavir (5). In these cases the association was clear (particularly since there was positive dechallenge), but this is a rare effect and has not previously been reported with either this or other protease inhibitors, although it has been associated with the nucleoside analogue reverse transcriptase inhibitor stavudine. 

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. 

Antiviral drags come eleventh and seventeenth. They are an important research area, but progress has been slow. Acyclovir and related drags for herpes simplex and varicella-zoster are now well established. AIDS cannot be cured but its progression can be dramatically slowed by combination therapy of two reverse transcriptase inhibitors (e.g. azidothymidine and lamivudine) plus a protease inhibitor (e.g. saquinavir). Unfortunately, viruses have the ability to modify themselves in unpredictable ways. An... 

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. 

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]... 

Protease inhibitor drugs as amprenavir, nelfinavir, indinavir, lopinavir, saquinavir, ritonavir, and atazanavir, and nonnucleoside reverse transcriptase inhibitors drugs nevirapine and efavirenz... 

Treatment of AIDS often combines reverse transcriptase inhibitors with protease inhibitors such as saquinavir (Invirase), indinavir (Crixivan), fosamprenavir (Lexiva), nelfinavir (Viracept), and ritonavir (Norvir). The inhibition of a protease enzyme prevents the proper cutting and formation of proteins used by viruses to make more copies. Researchers are not yet certain how long protease inhibitors will be beneficial for a person with AIDS. 

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