Human immunodeficiency virus saquinavir

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. 

Fitzsimmons, M. E., Collins, J. M., Selective biotransformation of the human immunodeficiency virus protease inhibitor saquinavir by human small-intestinal cytochrome P4503A4 potential contribution to high first-pass metabolism, Drug. Metab. Dispos. 1997, 25, 256-266. 

Peptidases encoded by many viruses play essential roles at various stages of viral replication, including the coordinated assembly and maturation of virons [7a]. Viral peptidases have become important drug targets in the treatment of viral infections. Of note are inhibitors of proteases of the human immunodeficiency virus (HIV), particularly HIV-1 protease (HIV-1 retropepsin, EC 3.4.23.16) and HIV-2 protease [47-50], Drugs in this class, which include indinavir, ritonavir, and saquinavir, are useful in the treatment of AIDS, especially when administered as a cocktail together with one of the drugs that act on the viral retrotranscriptase (e.g., didanosine, stavudine, and zidovudine (AZT)). 

Collier AC, Coombs RW, Schoenfeld DA, Bassett RL. et al. 1996. Treatment of human immunodeficiency virus infection with saquinavir, zidovudine, and zalcitabine. AIDS clinical trials group. N Engl J Med 334 1011-1017. 

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. 

Khaliq Y, Gallicano K, Venance S, et al. Effect of ketoconazole on ritonavir and saquinavir concentrations in plasma and cerebrospinal fluid from patients infected with human immunodeficiency virus. Cbn Pharmacol Ther 2000 68 637-646. 

Korting HC, et al. Effects of die human immunodeficiency virus (HIV) proteinase inhibitors saquinavir and indinavir on in vitro activities of secreted aspartyl proteinases of Candida albicans isolates from HIV-infected patients. Antimicrob. Agents Chemodier. 

Maschera, B., Darby, G., Palu, G., Wright, L. L., Tisdale, M., Myers, R., Blair, E. D., and Furfine, E. S. (1996) Human immunodeficiency virus Mutations in the protease that confer resistance to saquinavir increase the dissociation rate constant of the protease-saquinavir complex. J. Biol. Chem. 271, 33,231-33,235. 

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. 

An interesting example of polymorphic structure differentiation is that of human immunodeficiency virus (HIV) protease inhibitors. The HIV protease inhibitors pose a serious problem in their bioavailability. Invirase showed only modest market performance, and it was soon superseded by drugs, such as ritonavir (Norvir) and indinavir sulfate (Crixivan ) that had better bioavailability. Three years after initial approval, saquinavir was reintroduced in a formulation with sixfold higher oral bioavailability relative to the original product. Ritonavir was originally launched as a semisolid dosage form, in which the waxy matrix contained the dispersed drug in order to achieve acceptable oral bioavailabiUty. Two years after its introduction, ritonavir... 

Saquinavir mesylate is a protease inhibitor that inhibits human immunodeficiency virus (HIV) protease, the enzyme required to form functional proteins in HIV-infected cells. It is indicated in the treatment of advanced HIV infection. Saquinavir is given in combination with nucleoside analogs (e.g., zidovudine). 

Merrill DP, Manion DJ, Chou T-C, Hirsch MS, Antagonism between human immunodeficiency virus type 1 protease inhibitors indinavir and saquinavir in vitro, J Infect Dis (1997) 176, 265-8,... 

Hsu A Granneman GR, Cao G, Carodiers L, El-Shourbagy T, Baroldi P, Erdman K, Brown F, Sun E, Leonard JM. Pharmacokinetic interactions between two human immunodeficiency virus protease inhibitors, ritonavir and saquinavir. Clin Pharmacol Ther (1998) 63,453-64. 

Gallicano K, Khaliq Y, Carignan G, Tsei A Walmsley S, CameronDW. A pharmacokinetic stu< of intermittent rifabutin dosing witii a combination of ritonavir and saquinavir in patients infected with human immunodeficiency virus. Clin Pharmacol Ther (2001) 70, 149-58. 

Simon, VA. Thiam, M.D. Lipford, L.C. Determination of serum levels of thirteen human immunodeficiency virus-suppressing drugs by high-performance hquid chromatography, J.ChromatogrA, 2001,913,447-453. [zalcitabine lamivudine stavudine didanosine zidovudine nevirapine abacavir indinavir delavirdine nelfinavir saquinavir ritonavir efavirenz]... 

SPE LOD 260 ng/mL for lamivudine zalcitabine lamivudine stavudine didanosine zidovudine nevirapine abacavir indinavir deiavirdine nelimavir saquinavir ritonavir efavirenz] Solas, C. Li, Y.-F. Xie, M.-Y. Sommadossi, J.-P. Zhou, X.-J. Intracellular nucleotides of (-)-2, 3 -deoxy-3 -thiacytidine in peripheral blood mononuclear cells of a patient infected with human immunodeficiency virus, Aratimicro6..4 erats Chemother., 1998, 42, 2989-2995. 

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