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)

Calpains (EC 3.4.22.17) are intracellular calcium-activated cysteine proteases that mediate tissue injury following post-ischemic and post-traumatic stress. Both human HIV protease and calpains share a similar secondary structure, where the active site is flanked by hydrophobic regions. The present study demonstrates that ritonavir, a hydrophobic HIV protease inhibitor, also inhibits calpain activity. In PC12 cell extracts assayed for calpain at maximal activity (2mM calcium), ritonavir exhibited competitive inhibition with a K(i) of 11+/-7.0 microM. Experiments with purified enzymes showed inhibition for both m- and mu-calpain isoforms (m-calpain, K(i)=9.2+/-1.2 microM; mu-calpain, K(i)=5.9+/-1.4 microM). Ritonavir also inhibited calcium-stimulated calpain activity in PC12 cells in situ. These results suggest that ritonavir or analogues of the drug should be investigated as cytoprotective agents in conditions where cell death or injury is mediated via calpain activation.
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PMID:Ritonavir inhibition of calcium-activated neutral proteases. 1199 89

Although treatment of children infected with HIV with protease inhibitors has improved the survival of these patients, various adverse side effects have been reported, including metabolic abnormalities, such as hyperlipidaemia. We describe a case of hip osteonecrosis in an adolescent with AIDS who was being treated with protease inhibitors. There is a possible relation with hyperlipidemia. F.M.G., white, 11 years old, AIDS A2, started to receive AZT and DDI when he was 7 years old. In April 1999, the patient had a significant increase in viral load and so the antiretroviral therapy was switched to d4T, 3TC and Ritonavir. Triglyceride plasma levels reached 460mg/dl after this switch and were always above the reference value. In December 1999, the patient complained of pain in the right hip. On physical examination, he had limited movement of this joint. Magnetic resonance imaging of the right hip showed flattening, deformity and fragmentation of the femoral head, compatible with osteonecrosis. Few cases of femoral head osteonecrosis have been associated with HIV infection, in the absence of the classic risk factors for osteonecrosis. Metabolic risk factors include hypertriglyceridaemia. The immunological disorders that occur in the HIV infection may predispose the patient to avascular osteonecrosis and metabolic disorders, particularly hypertriglyceridemia, while the use of protease inhibitors, may be considered an additional risk factor for osteonecrosis. Given the importance of premature diagnosis and to avoid complications of osteonecrosis, we recommend evaluation of musculoskeletal symptoms in children receiving protease inhibitors.
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PMID:Hyperlipidaemia a risk factor for femoral head osteonecrosis (Legg-Calv -Perthes-like disease) in children with AIDS: case report. 1214 52

HIV infection and psychotic illnesses frequently coexist. The atypical antipsychotic olanzapine is metabolized primarily by CYP1A2 and glucuronosyl transferases, both of which are induced by the HIV protease inhibitor ritonavir. The purpose of this study was to determine the effect of ritonavir on the pharmacokinetics of a single dose of olanzapine. Fourteen healthy volunteers (13 men; age range, 20-28 years) participated in this open-label study. Subjects received olanzapine 10 mg and blood samples were collected over a 120-hour post-dose period. Two weeks later, subjects took ritonavir 300 mg twice daily for 3 days, 400 mg twice daily for 4 days, and 500 mg twice daily for 4 days. The next morning, after 11 days of ritonavir, olanzapine 10 mg was administered and blood sampling was repeated. Plasma samples were analyzed for olanzapine with HPLC. We compared olanzapine noncompartmental pharmacokinetic parameter values before and after ritonavir with a paired Student t test. Ritonavir reduced the area under the plasma concentration-time curve of olanzapine from 501 ng. hr/mL (443-582) to 235 ng. hr/mL (197-294) (p < 0.001), the half-life from 32 hours (28-36) to 16 hours (14-18) (p = 0.00001), and the peak concentration from 15 ng/mL (13-19) to 9 ng/mL (8-12) (p = 0.002). Olanzapine oral clearance increased from 20 L/hr (18-23) to 43 L/hr (38-51) (p < 0.001) after ritonavir. Ritonavir significantly reduced the systemic exposure of olanzapine in volunteers. Patients receiving this combination may ultimately require higher olanzapine doses to achieve desired therapeutic effects.
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PMID:Influence of ritonavir on olanzapine pharmacokinetics in healthy volunteers. 1217 35

The role of macrophages in the pathogenesis and progression of human immunodeficiency virus (HIV)-related infection is substantiated by in vitro and in vivo evidence. The unique ability to survive HIV infection and produce viral particles for long periods is postulated. Detailed studies of this phenomenon are lacking. The dynamics of HIV-1 replication and cumulative virus production was studied in long-term cultures of macrophages in the presence or in the absence of antiviral drugs. Multiply spliced and unspliced HIV-RNA production was assessed by quantitative PCR, and the number of infected cells was monitored by FACS analysis. Cumulative HIV-1 production was determined by a trapezoidal equation, including such parameters as times of collection and experimental values of genomic-RNA and p24 gag antigen. Unspliced and multiply spliced HIV-RNA increased linearly after macrophage infection; reached levels of 1.5 x 10(8) and 2.8 x 10(5) copies/10(5) cells, respectively, at day 10; and then remained stable throughout the course of the experiment. Cumulative production of genomic-RNA and p24 gag antigen was 10(10) copies/10(6) cells and 10(7) pg/10(6) cells, respectively, with an average of >200 virus particles produced daily by each macrophage. AZT decreased the cumulative production of both genomic-RNA and p24 gag antigen down to 2.5 x 10(9) copies and 1.1 x 10(6) pg/10(6) cells (73.8% and 88.9% inhibition, respectively) up to day 50 without virus breakthrough. Ritonavir had a limited, but consistent, efficacy on the release of mature virus proteins (about 40% inhibition), but not on HIV-RNA production. In conclusion, the long-term dynamics and the high cumulative virus production that characterize HIV-1 infection of macrophages underscore the peculiar role of these cells as a persistently infected reservoir of HIV.
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PMID:Long-term survival and virus production in human primary macrophages infected by human immunodeficiency virus. 1237 54

Oxidative stress plays an important role in many neurodegenerative conditions including Alzheimer's disease and Parkinson's disease. 4-Hydroxynonenal (HNE), a lipid-soluble aldehydic product of membrane peroxidation, has been known to decrease neuronal survival by impairing Na+, K+, and -ATPase activity. HNE also increases neuronal vulnerability to excitotoxic injury and disrupts homeostasis by activating proteases which mediate the destruction of cellular protein and structure. The present study demonstrated that the hydrophobic HIV protease inhibitor, ritonavir inhibited HNE-mediated apoptosis in hippocampal primary neurons. In neurons exposed to oxidative stress induced by HNE (1 microM), ritonavir at 100 pM increased cell survival and completely abolished the apoptotic effects of HNE (P < 0.01). Ritonavir and its analogues might have useful cytoprotective effects for use in limiting the natural course of tissue injury after conditions where oxidative stress plays a role.
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PMID:Ritonavir protects hippocampal neurons against oxidative stress-induced apoptosis. 1238 58

Treatment of HIV infection with potent combination antiretroviral therapy has resulted in major improvement in overall survival, immune function and the incidence of opportunistic infections. However, HIV infection and treatment has been associated with the development of metabolic complications, including hyperlipidaemia, diabetes mellitus, hypertension, lipodystrophy and osteopenia. Safe pharmacological treatment of these complications requires an understanding of the drug-drug interactions between antiretroviral drugs and the drugs used in the treatment of metabolic complications. Since formal studies of most of these interactions have not been performed, predictions must be based on our understanding of the metabolism of these agents. All HIV protease inhibitors are metabolised by and inhibit cytochrome P450 (CYP) 3A4. Ritonavir is the most potent inhibitor of CYP3A4. Ritonavir and nelfinavir also induce a host of CYP isoforms as well as some conjugating enzymes. The non-nucleoside reverse transcriptase inhibitor delavirdine potently inhibits CYP3A4, whereas nevirapine and efavirenz are inducers of CYP3A4. Drug interaction studies have been performed with HIV protease inhibitors and HMG-CoA reductase inhibitors. Coadministration of ritonavir plus saquinavir to HIV-seronegative volunteers resulted in increased exposure to simvastatin acid by 3059%. Atorvastatin exposure increased by 347%, but exposure to active atorvastatin increased by only 79%. Conversely, pravastatin exposure decreased by 50%. Similar results have been obtained with combinations of simvastatin and atorvastatin with other HIV protease inhibitors. Thus, the lactone prodrugs simvastatin and lovastatin should not be used with HIV protease inhibitors. Atorvastatin may be used with caution. Although there are no formal studies available, calcium channel antagonists and repaglinide may have significant interactions and toxicity when used with HIV protease inhibitors because of their metabolism by CYP3A4. Sulfonylurea drugs utilise mainly CYP2C9 for metabolism, and this isoenzyme may be induced by ritonavir and nelfinavir with a resulting decrease in efficacy of the sulfonylurea. Losartan may have increased effect when coadministered with ritonavir and nelfinavir because of the induction of CYP2C9 and the expected increase in formation of the active metabolite, E-3174. Overall, well-designed drug-drug interaction studies at steady state are needed to determine whether antiretroviral drugs may be safely coadministered with many of the drugs used in the treatment of the metabolic complications of HIV infection.
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PMID:Interactions between antiretroviral drugs and drugs used for the therapy of the metabolic complications encountered during HIV infection. 1240 66

The structural elucidation of metabolites of ritonavir and indinavir, HIV-protease inhibitor drugs, by liquid chromatography-electrospray ionization mass spectrometry is described. Ritonavir and indinavir were biotransformed separately by incubation with transplant quality human liver microsomes. The incubation mixture was then analyzed by HPLC coupled to ion trap (ITMS) and triple quadrupole mass analyzers. The metabolites retained most of the structural features of the parent molecules. Baseline chromatographic resolution of isobaric species by gradient elution HPLC permitted rapid structural identification of these metabolites. Both drugs were biotransformed primarily by oxidative and hydrolytic pathways to numerous metabolites that retained many of the features of the parent molecules. Triple quadrupole and ion trap mass spectrometry were applied jointly to thoroughly detect and thoroughly characterize these metabolites. Furthermore, retention-time and data-dependent scanning assured acquisition of detailed MS-MS spectra for rapid detection of metabolic pathways of ritonavir and indinavir. Comparison of the ITMS and triple quadrupole data showed qualitative and quantitative differences in the mass spectral patterns, suggesting that these instruments should be used in parallel to ensure comprehensive metabolite detection and characterization by LC-MS.
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PMID:Structural elucidation of metabolites of ritonavir and indinavir by liquid chromatography-mass spectrometry. 1245 29

Ritonavir is an HIV protease inhibitor used in the therapy of HIV infection. Ritonavir has also been shown to inhibit the chymotrypsin-like activity of isolated 20S proteasomes. Here, we demonstrate that ritonavir, like classical proteasome inhibitors, has antitumoral activities. In vitro, ritonavir strongly reduced the rate of proliferation of several tumor cell lines and induced their apoptosis. Nontransformed cell lines and terminally differentiated bone-marrow macrophages were comparatively resistant to the apoptosis-inducing effect. In vivo, ritonavir, administered p.o. for a week at doses of 6-8.8 mg/mouse/day, caused significant growth inhibition (76-79% after 7 days of treatment) of established EL4-T cell thymomas growing s.c. in syngeneic C57BL/6 mice. Unexpectedly, we found that ritonavir activates the chymotrypsin-like activity of isolated 26S proteasomes, in strong contrast to its effect on isolated 20S proteasomes. The net effect of low micromolar concentrations of ritonavir on the chymotrypsin-like activity in cells and cell lysates was a weak inhibition, consistent with marginal alterations of polyubiquitinated proteins, marginal alterations in acid-soluble proteolytic peptide levels, and a small accumulation of the tumor suppressor protein p53, in cells treated with ritonavir. In contrast, we found a relatively strong accumulation of the cyclin-dependent kinase inhibitor p21(WAF-1), a sign of deregulation of cell-cycle progression typical for apoptosis induction in transformed cells by classical proteasome inhibitors. We demonstrate that p21 accumulation in the presence of ritonavir is attributable to the inhibition of proteolytic degradation. Accumulation of p21 most likely reflects a selective inhibition of proteasomes, in line with the atypical degradation of p21, which does not require ubiquitination. These findings suggest that selective perturbation of proteasomal protein degradation may play a role in the antitumoral activities of ritonavir.
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PMID:Antitumor effect of the human immunodeficiency virus protease inhibitor ritonavir: induction of tumor-cell apoptosis associated with perturbation of proteasomal proteolysis. 1246 Sep 5

Low dose-ritonavir boosted protease inhibitors are increasingly being used for the first-line antiretroviral treatment, though their virological efficacy has just poorly been compared to alternative antiretroviral therapies. Here, we retrospectively investigated the virological responses of 316 protease inhibitor-naive HIV patients receiving highly active antiretroviral treatment based on a single (n = 256) or a ritonavir-boosted protease inhibitor (n = 60), both in the background of two nucleoside analogues. - By intent-to-treat analysis, a complete initial virological response was achieved in 71.8% of all patients in the single protease inhibitor group (indinavir: 76%, ritonavir: 67.5%, nelfinavir: 70.6%) and in 88.3% (p = 0.008) of patients treated with a boosted protease inhibitor (saquinavir/r: 71.4%, indinavir/r: 92.1%, lopinavir/r: 86.6%). The multivariate risk analysis identified boosted PI treatment as an independent predictor of a complete virological response (OR = 2.8, p=0.02). Viral rebound after an initial complete virological response was observed in 28% and 17% (p = 0.06) of patients receiving a single or a dual protease inhibitor, respectively. The rate of durable viral suppression over 12 months was 44.5% and 56.7% (p = 0.09) in the respective study cohorts. Ritonavir-boosted protease inhibitors therefore seem to induce a superior virological response rate and a higher degree of sustained virological suppression.
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PMID:Superior virological efficacy of ritonavir-boosted protease inhibitor regimens compared to single protease inhibitor therapy. 1262 82

An in vitro study to evaluate the antifungal effect and activity of aspartyl proteinases of the HIV-proteinase inhibitors ritonavir and saquinavir was conducted. Ritonavir diminished the growth rate of Candida albicans as well as the activity of its secreted aspartyl proteinases (Saps) in a nitrogen-limited medium, yeast carbon base and bovine serum albumin (YCB-BSA). This inhibition occurred in a dose-dependent fashion; with 8 mg l(-1) of ritonavir a partial growth inhibition (44%) was produced. The growth rate of C. albicans in medium with saquinavir was similar to that seen in the control, and Sap activity was inhibited only at high concentrations. In conventional medium (RPMI-1640), which does not induce the production of yeast proteases, no inhibitory effect was detected with either HIV-protease inhibitor.
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PMID:Effect of ritonavir and saquinavir on Candida albicans growth rate and in vitro activity of aspartyl proteinases. 1296 50


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