Human immunodeficiency virus ritonavir

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. 

Kaplan SS, Hicks CB. 2005. Safety and antiviral activity of lopinavir/ritonavir-based therapy in human immunodeficiency virus type 1 (HIV-1) infection. J Antimicrob Chemother. 56 273-276. 

Samaras K, Pett S, Gowers A, McMurchie M, Cooper DA. Iatrogenic Cushing s syndrome with osteoporosis and secondary adrenal failure in human immunodeficiency virus-infected patients receiving inhaled corticosteroids and ritonavir-boosted protease inhibitors six cases. J Clin Endocrinol Metab 2005 90(7) 4394-8. 

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. 

Hsu A, Granneman GR, Witt G, et al. Multiple-dose pharmacokinetics of ritonavir in human immunodeficiency virus-infected subjects. Antimicrob Agents Chemother 1997 41(5) 898-905. 

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. 

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. ... 

Benson CA, Deeks SG, Brun SC, Gulick RM, Eron JJ, Kessler HA, Murphy RL, Hicks C, King M, Wheeler D, Feinberg J, Stryker R, Sax PE, Riddler S, Thompson M, Real K, Hsu A, Kempf D, Japour AJ, Sun E. Safety and antiviral activity at 48 weeks of lopinavir/ritonavir plus nevirapine and 2 nucleoside reverse-transcriptase inhibitors in human immunodeficiency virus type 1-infected protease inhibitor-experienced patients. J Infect Dis 2002 185(5) 599-607. 

Mueller BU, Nelson RP Jr, Sleasman J, Zuckerman J, Heath-Chiozzi M, Steinberg SM, Bahs FM, Brouwers P, Hsu A, Saulis R, Sei S, Wood LV, Zeichner S, Katz TT, Higham C, Aker D, Edgerly M, Jarosinski P, Serchuck L, Whitcup SM, Pizzuti D, Pizzo PA. A phase FII study of the protease inhibitor ritonavir in children with human immunodeficiency virus infection. Pediatrics 1998 101(3 Pt 1) 335 3. 

Krogstad P, Lee S, Johnson G, Stanley K, McNamara J, Moye J, Jackson JB, Aguayo R, Dieudonne A, Khoury M, Mendez H, Nachman S, Wiznia A, Ballow A, Aweeka F, Rosenblatt HM, Perdue L, Frasia A, Jeremy R, Anderson M, Japour A, Fields C, Farnsworth A, Lewis R, Schnittman S, GigUotti M, Maldonaldo S, Lane B, Hernandez JE, et al. Pediatric AIDS Clinical Trials Group 377 Study Team. Nucleoside-analogue reverse-transcriptase inhibitors plus nevirapine, nehinavir, or ritonavir for pretreated children infected with human immunodeficiency virus type 1. CUn Infect Dis 2002 34(7) 991-1001. 

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. 

Ritonavir (Norvir Abbott) is a drug for treating patients infected with human immunodeficiency virus-1 (HIV-1). In solid state the compound consists exclusively of one kind of monoclinic crystals. As this form, now called form I, was not sufficiently bioavailable by the oral route, a liquid formulation containing dissolved ritonavir in a hydroalcoholic solution was developed. It gave satisfactory results during the development and early manufacturing phases. However, in 1998, 2 years after the launch, a second form (form II) precipitated during shelf life. The new form is thermodynamically more stable and about 50% less water-soluble than form I. Within weeks-days, this new form was produced in all the production lines and Abbott had to stop the production of ritonavir. Finally, after considerable effort and expense, a new formulation of ritonavir was developed. 

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... 

D. Hickman, S. Vasavanonda, G. Nequist, L. Colletti, W. M. Kati, R. Bertz, A. Hsu, and D. J. Kempf, Estimation of serum-free 50-percent inhibitory concentrations for human immunodeficiency virus protease inhibitors lopinavir and ritonavir. Antimicrob Agents Chemother 48 2911-2917 (2004). 

Ritonavir is an inhibitor of the human immunodeficiency virus (HIV) protease which, in combination with nucleoside analogs (600 mg/b.i.d. p.o.), is indicated in the treatment of HIV infection. Ritonavir is a peptidomimetic inhibitor of both the HIV-1 and HIV-2 proteases. Inhibition of HIV protease renders the enzyme incapable of processing the gag-pol polyprotein precursor, which leads to production of noninfectious immature HIV particles. 

Ritonavir 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 HIV infections 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). 

Kempf, D.J., K.C. Marsh, G. Kumar, A.D. Rodrigues, J.F. Denissen, E. McDonald et al. (1997). Pharmacokinetic enhancement of inhibitors of the human immunodeficiency virus protease by coadministration with ritonavir. Antimicrob. Agents Chemother 41, 654-660. 

Hsu A, Granneman GR, Witt G, Locke C, Denissen J, Molla A, Valdes J, Smith J, Erdman K, Lyons N, Niu P, Decourt JP, Fourtillan JB, Girault J, Leonard JM. Multiple-dose pharmacokinetics of ritonavir in human immunodeficiency virus-infected subjects. Antimicrob Agents Chemother 1997 41 898-905. 

The human immunodeficiency virus (HIV) protease inhibitor ritonavir is an inhibitor of both CYP3A4 and P-glycoprotein. Substrates of these two elimination pathways are particularly susceptible to interactions with ritonavir. 

Shelton MJ, Hewitt RG, Adams J, Della-Coletta A, Cox S, Morse GD. Pharmacokinetics of ritonavir and delavirdine in human immunodeficiency virus-infected patients. Antimicrob Agents Cbemotber (2003) 47, 1694-9. 

Duval X, Le Moing V, Longuet P, Leport C, Vilde J L, Lamotte C, Peytavin G, Farinotti R. Efavirenz-induced decrease in plasma amprenavir levels in human immunodeficiency virus-infected patients and correction hy ritonavir. Antimicrob Agents Cbemotber (2000) 44, 2593. 

Fletcher CV, Yogev Nachman SA, Wiznia A, Pelton S, McIntosh K, Stanley K. Pharmacokinetic characteristics of ritonavir, zidovudine, lamivudine, and stavudine in children with human immunodeficiency virus infection. Pharmacotherapy (2004) 24,453-9. 

Cato A, Qian J, Hsu Levy B, Leonard J, Granneman R. Multidose pharmacokinetics of ritonavir and zidovudine in human immunodeficiency virus-infected patients. Antimicrob Agents Chemoiher (1998) 42, 1788-93. 

Sekar VJ, Lefebvre E, De Paepe E, De Marez T, De Pauw M, Parys W, Hoetehnans RM. Pharmacokinetic interaction between darunavir boosted with ritonavir and omeprazole or ranitidine in human immunodeficiency virus-negative healthy volunteers. Antimicrob Agents Chemodter (p.007) 51, 958-61. 

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