Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protease inhibitors block the protease enzyme of HIV-1. When new viral particles break off from an infected cell, protease cuts long protein strands into the parts needed to assemble a mature virus. When protease is blocked, the new viral particles cannot mature. Protease inhibitors being tested in humans include Atazanavir, GW433908, L-756,423, Mozenavir(DMP-450), Tipranavir and more. Several firms are trying to develop a new type of protease inhibitor that will be the more favorable pharmacokinetic and resistance profiles compared with currently available drugs. We cannot expect that every one of the drugs listed in this paper will be successfully developed. However, it is likely that significant clinical advancements can be made with those that are proven to be active and safe for patients in need.
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PMID:[New HIV-1 protease inhibitors in development]. 1196 88

The introduction of HIV-1 protease inhibitors in 1995 ushered in the era of highly active antiretroviral therapy. For the first time, inhibition of two key enzymes responsible for HIV replication, reverse transcriptase and protease, was possible. The combination of two nucleoside reverse transcriptase inhibitors with a single protease inhibitor proved highly effective at reducing viral burden. In resource-rich countries where such combination therapy is readily available, dramatic reductions in HIV-related morbidity and mortality have been seen. However, long-term use of highly active antiretroviral therapy has led to several issues, including development of drug resistance and metabolic complications. Atazanavir (formerly BMS-232632), a novel azapeptide protease inhibitor, is a potent protease inhibitor that is not associated with significant dyslipidaemia as seen with other protease inhibitors. In this review, the current standard approach to the treatment of HIV in the US will be discussed as background to understand the potential utility of this new antiretroviral agent.
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PMID:Atazanavir: a novel HIV-1 protease inhibitor. 1222 50

A selective, accurate, and reproducible LC-MS-MS assay was developed for the determination of the HIV protease inhibitor atazanavir (BMS-232632) in human plasma samples. The method involved automated solid-phase extraction of atazanavir and a stable isotope analog internal standard (I.S.) using Oasis HLB 10 mg 96-well SPE plates. A portion of the reconstituted sample residue was injected onto a C(18) HDO analytical column which was configured with a triple quad mass spectrometer for analyte determination by positive ion electrospray. The assay was linear from 1.00 to 1,000 ng/ml with a lower limit of quantitation of 1.00 ng/ml. The inter- and intra-day coefficients of variation (C.V.) for the assay were <4%, and the accuracy was 99-102%. Atazanavir was stable in human plasma for at least 109 h at room temperature and for at least 1 year at -20 degrees C.
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PMID:Quantitative determination of the HIV protease inhibitor atazanavir (BMS-232632) in human plasma by liquid chromatography-tandem mass spectrometry following automated solid-phase extraction. 1270 78

A selective, accurate, and reproducible LC/MS/MS assay was developed and validated for the determination of the HIV protease inhibitor atazanavir (BMS-232632) in human peripheral blood mononuclear cells (PBMC) samples. In addition to the details of the validated LC/MS/MS method, a practical procedure is described in great detail for the preparation of large supplies of control (blank) PBMC from units of blood (each unit of blood is about 500 ml) for making the calibration standards and quality control (QC) samples. The PBMC assay design, intended for high-throughput sample analysis, is also described in some detail in regards to the composition and concentration expressions of the calibration standards and QC samples, the lysing procedure of the PBMC samples, and the final analysis/quantitation procedure. The method involved automated solid-phase extraction (SPE) of atazanavir and a stable isotope analog internal standard (I.S.) using 3M Empore C2-SD 96-well plates. A portion of the reconstituted sample residue was injected onto a YMC Basic analytical column which was connected to a triple quad mass spectrometer for analyte determination by positive-ion electrospray in the selected reaction monitoring (SRM) mode. The standard curve, which ranged from 5 to 2500 fmol per one million cells (fmol/10(6) cells), was fitted to a quadratic regression model weighted by 1/concentration. The lower limit of quantitation (LLOQ) was 5 fmol/10(6) cells. The inter- and intra-run coefficients of variation (CV) for the assay were <9% and the accuracy was 94-104%. Atazanavir was stable in PBMC for at least 24h at room temperature and for at least 129 days at -15 degrees C.
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PMID:Liquid chromatography-tandem mass spectrometric quantitative determination of the HIV protease inhibitor atazanavir (BMS-232632) in human peripheral blood mononuclear cells (PBMC): practical approaches to PBMC preparation and PBMC assay design for high-throughput analysis. 1452 32

HIV caregivers face many challenges following initiation of ART. The development of jaundice is uncommon but worrisome. In this case, two distinct and contrasting episodes of jaundice were observed. In the first instance, isolated elevation of the indirect bilirubin without elevation of the alkaline phosphatase was noted. The normal PT and serum aminotransferase levels indicate the absence of intrinsic liver dysfunction. Elevations in the indirect bilirubin may result from either impaired uptake/conjugation or excess production. The latter, usually from acquired hemolysis, may be a complication of an occult NHL. A work-up for this AIDS-related malignancy was not initiated since the caregivers recognized jaundice as a complication of IDV, which inhibits UDP-glucuronyl transferase and produces a Gilbert's-like syndrome. Physicians can expect to encounter this syndrome even more frequently with ATV. Experienced patients given RTV-boosted ATV have experienced elevations of unconjugated hyper-bilirubinemia in up to 45 percent of cases in clinical trials. However, such elevations do not reflect liver dysfunction and symptomatic jaundice requiring dosage reduction that occurred infrequently (7 to 8 percent of study patients). Counseling patients about this syndrome may promote adherence and prevent self-directed interruptions of ATV that compromise efficacy. The second case of jaundice provides a more formidable diagnostic challenge. The triad of LFT abnormalities (mild elevation of aminotransferases, normal PT, and marked cholestatic jaundice) implies an acute process that is mildly toxic to hepatocytes without affecting their synthetic function. The subacute nature of the patient's cholestatic jaundice suggests either intrahepatic infiltrative disease of the liver or extrahepatic obstruction of the biliary tree, most likely due to the patient's relatively modest level of pain and lack of fever. Despite LFT abnormalities occurring 17 months after a switch in his ART, cumulative drug-related toxicities must still be considered. Ritonavir can produce significant elevations in the AST/ALT, especially with pre-existing chronic liver disease as with hepatitis C virus coinfection. The NRTIs can produce hepatic steatosis, a result of mitochondrial toxicity and impaired fatty acid oxidation. However, jaundice and cholestasis are not typical of the latter syndrome. With a negative contrast CT that excludes parenchymal liver disease, investigation of the biliary tree to assess the presence of AIDS-related cholangitis was the next step. Performing a sphincterotomy or stent placement, and obtaining brushings or biopsy specimens to determine the extent of extrahepatic obstruction may help define a pathogen and be life-saving. The negative results of the ERCP justify the final diagnostic step, a liver biopsy to evaluate microscopic infiltrative disease that might not have been detected on contrast abdominal CT. Examples might include granulomatous disease (MAC), fungal etiologies (histoplasmosis), carcinomatosis (lymphoma, hepatoma, cholangiocarcinoma), and microvascular disease (bacillary angiomatosis). The failure to observe granulomatous inflammation in the liver does not exclude MAC infection, as MAC may involve other peri-aortic or mesenteric lymph nodes. This form of IRIS is unlikely given the abdominal CT findings, lack of systemic complaints, and extended persistence of liver aminotransferases. The nonspecific results of the liver biopsy are a common outcome in advanced AIDS patients with elevated alkaline phosphatase levels. Despite not having identified a pathogen, the biopsy establishes chronic liver disease and prompts re-evaluation and change of treatment to NFV. The subsequent normalization of the patient's aminotransferase levels suggests a prior adverse effect of LPV/r in the setting of unexplained, chronic liver disease. Most importantly, this case highlights the importance of HIV caregivers to review ART for safety when noting chronic liver dysfunction. Patients need to be counseled to minimize acetaminophen use, to consume alcohol in moderation, and to avoid behavior with risk for hepatitis C. Finally, all HIV patients should receive appropriate vaccination against hepatitis A and B if serology shows lack of protective immunity.
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PMID:Clinical vignette in antiretroviral therapy: jaundice. 1498 14

In the year 2003, the basis of antiretroviral treatment comprising nucleoside and nucleotide reverse transcriptase inhibitors (NRTI, NNRTI, NtRTI) and protease inhibitors (PI) will be extended to include entry inhibitors (EI). A representative of this class of drugs, enfurvitide (T20), is about to receive official approval. In the meantime, initial data on long-term treatment with tenofovir, which has been available in Germany since February 2002, have become available. Further medications are in the pipe-line of clinical development, for example, the NRTI emtricitabine (FTC) and the Pis amdoxovir and Atazanavir. Results from studies employing immunomodulatory approaches have so far proved disappointing. In contrast, a number of smaller studies on vaccination have provided promising data. Recommendations for antiretroviral treatment of HIV infection were updated in the summer of 2002.
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PMID:[Antiretroviral therapy 2003. The current status]. 1501 74

The purpose of the study was to determine long-term efficacy, safety, and tolerability of atazanavir plus stavudine/lamivudine in 346 HIV-infected patients previously treated with atazanavir or nelfinavir. BMS AI424-044 is an ongoing, multicenter, international, open-label, rollover/switch study initiated in June 2001. Patients completing >or=48 weeks in trial BMS AI424-008 with a plasma HIV RNA viral load <10,000 copies/mL were eligible to continue on atazanavir (400 or 600 mg) or to switch from nelfinavir to atazanavir (400 mg) once daily. Antiviral efficacy, change in CD4 cell counts, and effect on lipid parameters were measured. After 24 weeks of atazanavir use in BMS AI424-044, 83%, 85%, and 87% of the atazanavir 400-mg, atazanavir 600-mg, and nelfinavir-to-atazanavir-switched patients, respectively, had HIV RNA levels <400 copies/mL compared with 76%, 76%, and 63%, respectively, at week 48 of BMS AI424-008. Atazanavir-treated patients showed minimal changes in lipid levels compared with baseline. Patients switched from nelfinavir to atazanavir showed significant mean percent decreases in total cholesterol (-16%), fasting low-density lipoprotein cholesterol (-21%), and fasting triglycerides (-28%) (P<0.0001) by week 12 of atazanavir treatment. No new safety issues were identified, and the overall incidence of treatment-emergent adverse events during BMS AI424-044 was comparable across treatment groups. Atazanavir was safe, tolerable, and effective during extended use and in patients switched from nelfinavir. Extended atazanavir use resulted in continued viral suppression and lipid changes that were not clinically relevant. In virologically suppressed nelfinavir-treated patients switched to atazanavir, virologic improvement continued, whereas nelfinavir-induced lipid elevations were reversed within 12 weeks, approaching pretreatment values.
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PMID:Long-term efficacy and safety of atazanavir with stavudine and lamivudine in patients previously treated with nelfinavir or atazanavir. 1516 87

Atazanavir is a once-a-day non-pepsidic inhibitor of HIV protease which is licensed for use in the UK and the USA. One of its major advantages is that it does not produce lipid abnormalities in patients who receive it. This feature has been widely interpreted as implying that in the future there will be no abnormalities associated with fat redistribution when the drug is administered. This article explores that view.
J HIV Ther 2004 May
PMID:Does atazanavir cause lipodystrophy? 1523 75

Protease inhibitors are potent agents against HIV but their use is constrained by poor pharmacokinetics, cross-resistance and metabolic toxicities. Atazanavir [Reyataz] is a new protease inhibitors with once-daily dosing and minimal lipid and glycemic effects. Resistance studies of clinical isolates reveal a mutational pattern distinctive from that of other protease inhibitors. Atazanavir selects for the I50L mutation in HIV protease that confers increased susceptibility to other protease inhibitors in vitro. Clinical trials have shown comparable efficacy to nelfinavir (Viracept) and efavirenz (Sustiva) in treatment-naive patients, and in preliminary studies, ritonavir-boosted atazanavir is effective in patients failing previous protease inhibitor-containing regimens. Reversible elevations in bilirubin occur in some patients but are not associated with hepatic injury. Atazanavir improves upon aspects of currently-available protease inhibitors and appears useful for initial and possibly subsequent HIV therapy.
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PMID:Atazanavir: improving the HIV protease inhibitor class. 1548 37

Atazanavir is a new human immunodeficiency virus 1 protease inhibitor that has a favorable side-effect profile and is available in once-daily dosing. We report the case of a young man with human immunodeficiency virus infection who developed acute renal failure after therapy with this drug. Renal biopsy showed acute interstitial nephritis. This is the first report of acute interstitial nephritis from atazanavir.
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PMID:Acute interstitial nephritis associated with atazanavir, a new protease inhibitor. 1549 41


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