Human immunodeficiency virus indinavir

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. 

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)). 

Koudriakova T, latsimirskaia E, Utkin I, et al. Metabolism of the human immunodeficiency virus protease inhibitors indinavir and ritonavir by human intestinal microsomes and expressed cytochrome P4503A4/3A5 mechanism-based inactivation of cytochrome P4503A by ritonavir. Drug Metab Dispos 1998 26(6) 552-561. 

Gulick RM, Mellors JW, Havilir D, Eron JJ, et al. 1997. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. NEJM. 337 734-739. 

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. 

One of the few industrial examples of the asymmetric synthesis of halohydrins is in a process to the human immunodeficiency virus (HIV) protease inhibitor, Indinavir.190 The y,8-unsaturated carboxamide 23 is smoothly converted into iodohydrin 24 (92%, 94% de) (Scheme 9.34). (For more on the chemistry of the indanol, see Chapter 24.)191... 

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. 

Burger and his colleagues have illustrated an example of bridging different populations with PK/PD modeling to assess the dose adjustment need. They compared the PK/PD relationships of indinavir, a human immunodeficiency virus protease inhibitor, with or without ritonavir, in HIV-infected Thai patients to those in Caucasian patients, and recommended no dose adjustment despite the general lower body weight in the Thai population. ... 

De Wit S, Debier M, De Smet M, McCrea J, Stone J, Carides A, Matthews C, Deutsch P, Clumeck N. Effect of fluconazole on indinavir pharmacokinetics in human immunodeficiency virus-infected patients. Antimicrob Agents Chemother 1998 42(2) 223-7. 

Dieleman IP, in t Veld B, Borleffs JC, Schreij G. Acute respiratory failure associated with the human immunodeficiency virus (HIV) protease inhibitor indinavir in an HIV-infected patient. Clin Infect Dis I998 26(4) 1012-13. 

Kohan AD, Armenakas NA, Fracchia JA. Indinavir urohthiasis an emerging cause of renal colic in patients with human immunodeficiency virus. J Urol 1999 161(6) 1765-8. 

Hug B, Naef M, Bucher HC, Sponagel L, Lehmann K, Battegay M. Treatment for human immunodeficiency virus with indinavir may cause relevant urological side-effects, effectively treatable by rehydration. BJU Int 1999 84(6) 610-14. 

Reiter WJ, Pernerstorfer-Schon FI, Dorfinger K, Flofbauer J, Marberger M. Frequency of urolithiasis in individuals seropositive for human immunodeficiency virus treated with indinavir is higher than previously assumed. J Urol 1999 161 1082-1084. 

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... 

Antiviral effect and pharmacokinetic interaction between nevirapine and indinavir in persons infected with human immunodeficiency virus type 1. J. Infect. Dis. 179, 1116-1123. 

Indinavir sulfate is a protease inhibitor that inhibits human immunodeficiency virus (HIV) protease, the enzyme that cleaves viral polyprotein precursors into functional proteins in HIV-infected cells. Inhibition of this enzyme by indinavir results in formation of immature noninfectious viral particles. It is indicated in the treatment of HIV infection in combination with other antiretroviral agents. 

Chemical synthesis remains as important to society as it became during World War II, when the modem pharmaceutical industry originated in its efforts to develop penicillins. Ever since, organic chemists literally have made the drugs that relieve our illnesses. Further examples include the antiinflammatory cortisone, developed in the 1940s to treat arthritis, and the protease inhibitors indinavir, ritonavir, and saquyinavir, introduced in 1995 to suppress the human immunodeficiency virus (HfV). 

Piscitelli SC, Vogel S, Figg WD, Raje S, Forrest A, Metcalf JA, Baseler M, Falloon J. Alteration in indinavir clearance during interleukin-2 infusions in patients infect with the human immunodeficiency virus. Pharmacotherapy ( 99 ) 18,1212-16. 

Riddler SA, Havlir D, Squires KE, Kerr B, Lewis RH, YehK, Hawe Wynne L, Zhong L, Peng Y, Deutsch P, Saah A, Coadministration of indinavir and nelfinavir in human immunodeficiency virus type 1-infected adults safety, pharmacokinetics, and antiretroviral activity, Antimicrob Agents Chemother (2002) 46, 3877-82. 

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,... 

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