Indinavir treatment

Colson AE, Sax PE, Keller MJ, Turk BK, Pettus PT, Platt R, Choo PW. Paronychia in association with indinavir treatment. Clin Infect Dis 2001 32(l) 140-3. 

Tornero C, Sanchez P, Castejon P, RuU S. Regrassion de la lipomatosis multiple con la administration de indinavir. [Reversal of multiple lipomatosis after indinavir treatment.] Med Clin (Bare) 1999 113(7) 278-9. 

Valencia ME J-NI, Rodriguez-Rosado R, SorianoV, Carrillo deAlbornoz ME, Gonzalez Lahoz J. Incidence of nephrolithiasis in HIV infected patients under indinavir treatment, [abstract 448]. Sixth European Conference on Clinical Aspects and Treatment of HIV Infection October 1997 Hamburg October 1997. 

Preliminary results from a study in healthy subjects suggest that the concurrent use of atovaquone 750 mg twice daily and indinavir 800 mg three times daily results in a minor 5% decrease in the AUC of indinavir, and a 13% increase in the AUC of atovaquone. The UK manufacturer of atovaquone notes that concurrent use decreased the minimum level and AUC of indinavir by 23% and 9%, respectively. They recommend that caution should be exercised on concurrent use because of the potential risk of failure of indinavir treatment. However, note that the effect was small and that indinavir is often used with other antiretrovirals, which might modify the interaction by affecting indinavir levels. 

Lankisch TO, Behrens G, Ehmer U, Mobius U, Rockstroh J, Wehmeier M, Kalthoff S, Freiberg N, Manns MP, Schmidt RE, Strassburg CP. Gilbert s syndrome and hyperbilirubinemia in protease inhibitor therapy—an extended haplotype of genetic variants increases risk in indinavir treatment. J Hepatol 2009 50(5) 1010-8. 

Shulman NS, Bosch RJ, MeUors JW, Albrecht MA, Katzenstein DA (2004) Genetic correlates of efavirenz hypersusceptibility. AIDS 13 1781-1785 Staszewski S, Morales-Ramirez J, Tashima KT, Rachlis A, Skiest D, Stanford J, Stryker R, Johnson P, Labriola DE, Earina D et al (1999) Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. Study 006 Team. N Engl J Med 341 1865-1873 SteUbrink HJ (2007) Antiviral drugs in the treatment of AIDS what is in the pipeline Eur J Med Res 12 483 95... 

Therapies not recommended for initial treatment due to poor potency or significant toxicity include delavirdine, nevirapine in patients with moderate to high CD4+ T-cell counts, indinavir or saquinavir used without ritonavir ( unboosted ), ritonavir used without another protease inhibitor, and tenofovir plus didanosine with an NNRTI. 

St. John s wort, which has become very popular for the treatment of depression, has been shown to induce intestinal P-gp and intestinal and hepatic CYP3A4 in humans [140]. That mechanism explains the significant reduction in cyclosporin and anti-aids (e.g., indinavir) plasma concentrations. It is likely that similar effects will be noted with the compounds listed in Table 8 (although the effects noted in Table 8 are in the opposite direction of those seen in the presence of St. John s wort). 

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)). 

In some circumstances, the FDA processes drug reviews under the accelerated scheme. This mechanism is to review and approve drugs speedily for cases where effective therapies are lacking or in situations of rare diseases. One of the fastest approval times to date is the case of imatinib mesylate (Gleevec, Novartis—Exhibit 7.3) for the treatment of chronic myeloid leukemia (CML) it was approved in less than 3 months after the filing of an NDA with the FDA. Another example is the new AIDS drug indinavir (Crixivan, Merck), which was approved in a mere 42 days. 

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). 

Indinavir sulfate (Compound X) as the crystalline ethanolate is then prepared by treatment of the free base monohydrate with sulfuric acid in anhydrous ethanol. 

Indinavir is a protease inhibitor used in the management of HIV infection. CYP3A4 mediates the biotransformation of indinavir in vitro (85,86), and in vivo, indinavir has been shown to be a potent competitive and mechanism-based inhibitor of CYP3A4 (85,87). Piscitelli and coworkers (80) examined the effect of St. John s wort (300 mg t.i.d. x 14 days) administration on indinavir (800 mg q.i.d. x 8 hr x four doses) exposure in eight healthy volunteers (two females). The administration of St. John s wort for 14 days resulted in a significant 54 /o reduction in the indinavir eight-hour area under the concentration-time curve, from 35.8 13.0 to 15.6 5.8 pg X hr/mL. The authors conclude that the magnitude in the reduction in indinavir concentrations may result in the development of antiretroviral resistance and subsequent treatment failure. 

The high aqueous solubility and largely nonpeptidic character of indinavir may be responsible for the good oral bioavailability, respectable pharmacokinetic profile, and high antiviral activity observed with this compound. Similar to saquinavir and ritonavir, indinavir has been recently approved by the FDA for treatment of AIDS. 

HIV PR inhibitors with acceptable oral availability and pharmacokinetic properties offer great promise for the treatment of HIV infection and AIDS. Efficacy studies of indinavir, ritonavir, or nelfinavir using plasma viral RNA as a marker have demonstrated up to three log reductions in RNA copy numbers that are... 

If St. John s wort can alter levels of cyclosporin in the blood, might it not also interfere with the action of other medications Recent research indicates that it can. Not surprisingly, the affected drugs are those that, like cyclosporin, are also metabolized by cytochrome enzymes. Protease inhibitors, used in the treatment of hiv infections, are a prime example. Because of the popularity of St. John s wort as an antidepressant and the incidence of depression in patients diagnosed with HIV infections, researchers at the U.S. National Institutes of Health decided to investigate the consequences of using the herbal remedy and the protease inhibitor indinavir concurrently. Doctors prescribe indinavir to prevent the hiv virus... 

Some patients receiving indinavir exhibit nephrolithiasis/urolithiasis including flank pain that may be accompanied by hematuria. The frequency of nephrolithiasis is dependent on the period of treatment with indinavir. Other side effects associated with indinavir include insulin resistance, hyperglycemia, asymptomatic hyperbilirubinemia, HIV lipodystrophy syndrome and skin abnormalities. Indinavir should not be coadministered with drugs that affect the cytochrome P-450 system (CYP3A4). Antacids are not recommended within 2 h of its administration, specifically didano-sine containing an antacid buffer. 

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. 

Sataszewski S, Morales-Ramirez J, Tashima KT, Rachlis A, et al. 1999. Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. Study 006 team. NEJM. 341 1865-1873. 

Dyslipidemia is a common accompaniment of the lipodystrophy syndrome observed in HIV-infected patients. This syndrome presents as a combination of peripheral lipoatrophy and the metabolic syndrome (central adiposity, insulin resistance, and dyslipidemia). The term lipodystrophy syndrome was first used in two case reports to describe a clinical picture of subcutaneous fat wasting in the face and limbs of HIV infected patients treated with indinavir, reminiscent of the rare congenital lipodystrophy syndromes (138,139). In addition, benign symmetric lipomatoses on the trunk and neck were described. A systematic study of this syndrome in the Australian HIV cohort showed co-existence of peripheral lipoatrophy with abdominal visceral obesity, dyslipidemia, and insulin resistance in HIV-infected patients with or without treatment with protease inhibitors (140). 

A retrospective analysis of the development of diabetes in 1011 patients has been summarized (163). All were nondiabetic when antiretroviral treatment was started. Over 10 months, diabetes was diagnosed in 16 patients (2.06 per 100 person-years). Older age (HR = 1.1, 1.06-1.16) was associated with a higher risk. In multivariate analysis adjusted for age and sex, the onset of diabetes was not related to CD4 cell count, viral load, or type of antiviral therapy (with or without protease inhibitors). However, patients taking stavudine or indinavir were at significantly higher risks (stavudine HR = 16, 95% Cl — 3, 84 indinavir HR = 4.0,95% Cl = 1.3,13). The strong association of stavudine with diabetes is surprising and needs further confirmation. 

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. 

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