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)

Proteases play a pivotal role in epidermal differentiation and desquamation. Separation of a total protein extract from human reconstructed epidermis by two-dimensional gel electrophoresis and subsequent peptide analysis of a specific protein spot identified a new protein exhibiting similarities with the retroviral aspartic protease family. Cloning of the corresponding full-length cDNA revealed an open reading frame encoding for a new protease of 343 amino acids, containing a putative aspartic protease catalytic domain. We named this protein Skin ASpartic Protease (SASPase). RT-PCR and northern blot analysis of various human tissues revealed that SASPase was specifically expressed within the epidermis. Immunohistochemical analysis showed a particularly intense expression restricted to the granular layers, whereas in diseased skin, its expression was changed. Western blot analysis, using a monoclonal antibody, revealed the expression of two forms of the enzyme: a 28 kDa putative proform and the active 14 kDa form. Recombinant truncated SASPase (SASP28) was generated from a prokaryotic expression system in Escherichia coli as a fusion protein with GST. SASP28 degraded insulin and to a lesser extent casein with a pH optimum of 5. As seen for retroviral proteases, an auto-activation processing was evidenced, generating a 14 kDa protein (SASP14). Site-directed mutagenesis inhibited auto-activation of the enzyme. Indinavir, a potent HIV protease inhibitor used in AIDS therapy, had a significant inhibitory effect on rSASPase auto-activation, which could explain its side effects on skin.
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PMID:Identification and characterization of a novel retroviral-like aspartic protease specifically expressed in human epidermis. 1609 38

Cis (1S,2R) indanediol is a potential precursor to (-)-cis (1S,2R)-1-aminoindan-2-ol, a key chiral synthon for a leading HIV protease inhibitor, Crixivan (Indinavir). A potential route to the biosynthesis of this important precursor, the microbial asymmetric direduction of 1,2-indanedione to its corresponding diol, cis (1S,2R) indanediol, was investigated. The screening of 32 yeast strains yielded Trichosporon cutaneum MY 1506 as a suitable biocatalyst. At the 2-l shake-flask scale, 1,2-indanedione (charged at 1.0 g/l) was bioconverted to cis (1S,2R) indanediol at a final bioconversion yield of 99.1% and an enantiomeric excess of >99%. When scaled up in a 23-l bioreactor, T. cutaneum produced 8.4 g of pure cis (1S,2R) indanediol, and the isolated yield of cis (1S,2R) indanediol was 52%. Purification of the scale-up also yielded 0.9 g of the more polar trans (1S,2R) indanediol diastereomer, a minor bioreduction product. Supercritical fluid chromatography analyses of the purified cis (1S,2R) and trans (1S,2S) indanediol demonstrated that the enantiomeric excesses during this bioconversion scale-up were 99% and 26%, respectively.
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PMID:Asymmetric direduction of 1,2-indanedione to cis (1S,2R) indanediol by Trichosporon cutaneum MY 1506. 1623 51

Indinavir is a potent HIV-1 protease inhibitor included in current antiretroviral therapeutic regimens. It is associated with renal and urological complications ascribed to indinavir crystalluria. We have previously reported that indinavir crystalluria is frequently observed soon after initiation of therapy. In a cohort of 54 asymptomatic indinavir-naive HIV-1-infected individuals during their first year of treatment with indinavir, approximately 25% of urinalyses (U/A) contained indinavir crystals. Because the determinants of the crystalluria are unknown, we examined the relationship between urine specific gravity (SG) and pH, singly and in combination, and indinavir crystalluria in these subjects. A total of 579 U/A were obtained from the study subjects at their scheduled monthly outpatient medical assessments. The frequency of indinavir crystalluria was lower in U/A with lower pH, irrespective of the SG. Conversely, U/A with high pH (> or = 6.0) had a higher frequency of indinavir crystalluria, which was further influenced by the urine SG. As a result, nearly half of the U/A (46.7%) with high pH (> or = 6.0) and intermediate-high SG (> or = 1.015) contained indinavir crystals. In conclusion, the frequency of indinavir crystalluria in asymptomatic HIV-1 infected individuals during their first year of treatment with indinavir was markedly influenced by the urine pH and SG. Our findings suggest that low urine pH may have a protective effect against indinavir crystalluria across the entire range of urine SG.
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PMID:Low urine pH is associated with reduced indinavir crystalluria in indinavir-treated HIV-infected individuals. 1642 37

HIV protease inhibitors are antiretroviral drugs able to prevent production of infectious particles. It has been shown that these protease inhibitors are able to inhibit cancer-promoted angiogenesis in patients affected by Kaposi's sarcoma. A preliminary phase I study on dogs with stage III splenic hemangiosarcoma was designed in order to evaluate the efficacy and toxicity of the protease inhibitor Indinavir to delay the progression of this advanced neoplasm. The results suggest that Indinavir is potentially beneficial in dogs affected by microscopic residual disease.
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PMID:Effects of indinavir in a preliminary phase I study on dogs with stage III slenic hemangiosarcoma. 1643 40

Drug-induced renal calculi represent 1-2% of all renal calculi. They include two categories: those resulting from the urinary crystallisation of a highly excreted, poorly soluble drug or metabolite, and those due to the metabolic effects of a drug. Indinavir, used in HIV-infected patients, sulfonamides, especially sulfadiazine, and triamterene, which is less prescribed today, are the most frequent. Besides these drugs, about twenty other molecules, among them silicate-containing drugs and some antibiotics have been reported in patients receiving high doses or long-term treatments. Calculi analysis by physical methods such as infrared spectroscopy or x-ray diffraction can demonstrate the presence of the drug or its metabolites inside the calculi. In those calculi due to the metabolic effects of a drug, diagnosis relies on both stone analysis and clinical inquiry. Incidence of such calculi is probably underestimated, especially those due to calcium/vitamin D supplements or carbonic anhydrase inhibitors. Drug-induced calculi occur more often during high-dose or long term treatments, but there are also patient-related risk factors in relation to urine pH, urine output and other parameters, which can provide a basis for preventive treatment of such calculi. A better knowledge of these lithogenic complications of treatments and of solubility characteristics of drugs should reduce the incidence of drug-induced nephrolithiasis, especially in patients with identified risk factors.
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PMID:[Drug-induced renal calculi]. 1670 5

In HIV-infected persons on highly active antiretroviral therapy, residual virus is found in lymphoid tissues. Indinavir concentrations in lymph node mononuclear cells of patients on highly active antiretroviral therapy were approximately 25% to 35% of those in blood mononuclear cells, suggesting that drug insufficiency contributes to residual virus in lymphoid tissues. Therefore, we developed novel lipid-indinavir nanoparticles targeted to lymphoid tissues. Given subcutaneously, these nanoparticles provided indinavir concentrations 250% to 2270% higher than plasma indinavir concentrations in both peripheral and visceral lymph nodes. Improved indinavir delivery was reflected in reduced viral RNA and CD4(+) T-cell rebound. This study optimized lipid nanoparticle formulation with respect to indinavir in lymphoid tissues of HIV-infected macaques. Regardless of lipid characteristic tested (charge, fluidity, and steric modification), indinavir binds completely to lipid at pH 7.4 but is reversed at pH 5.5 or lower. Compared with previous formulations, nanoparticles composed of disteroyl phosphatidylcholine and methyl polyethylene glycol-disteroyl phosphatidylethanolamine (DSPC:mPEG-DSPE) provided 6-fold higher indinavir levels in lymph nodes and enhanced drug exposure in blood. Enhanced anti-HIV activity paralleled improved intracellular drug accumulation. Collectively, these data suggest that indinavir nanoparticles composed of DSPC:mPEG-DSPE provided the most effective lymphoid delivery and could maximally suppress the virus in lymphoid tissues.
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PMID:Optimization of lipid-indinavir complexes for localization in lymphoid tissues of HIV-infected macaques. 1676 Jul 97

The effect of p-glycoprotein inhibition on tissue distribution of indinavir, an anti-HIV (human immunodeficiency virus) protease inhibitor drug, has been evaluated. Indinavir was co-administered intravenously in rats along with a p-glycoprotein inhibitor, PSC833, and the drug concentrations in plasma and various tissues were determined using a HPLC method. Additionally, initial uptake clearance of indinavir was evaluated in the brain and testes. The highest increasing effect of p-glycoprotein inhibition on the tissue uptake ratios of indinavir was found in central nervous system (CNS). The estimated tissue extraction the drug was indicative of (i) limited drug entry to brain parenchyma, which was increased significantly by p-glycoprotein inhibition, (ii) non-restricted drug entry to testes, heart and spleen, which was increased significantly in the case of heart and decreased in the case of testes and spleen as a result of p-glycoprotein inhibition, and (iii) drug accumulation in liver and small intestine and, to a lesser extent, kidney, which was not affected by p-glycoprotein inhibition. The uptake clearances of indinavir by brain parenchyma in PSC833-treated and control rats were 68.80+/-8.65 and 21.63+/-4.28 micro/min/g and the corresponding values for the testes were 39.84+/-4.90 and 36.65+/-2.54 microl/min/g. The difference was significant only in the case of brain parenchyma (P<0.001). These data showed that p-glycoprotein inhibition increases the CNS uptake of indinavir markedly and has some transient minor effects on drug uptake by some other tissues.
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PMID:Role of P-glycoprotein in tissue uptake of indinavir in rat. 1679 66

HIV-associated cardiovascular diseases have been widely described, but clinical studies aimed at establishing cause-effect relationships between HIV-associated cardiovascular disease and either the HIV infection or antiretroviral therapy have been problematic. Endothelial dysfunction is a sensitive marker and early event in atherosclerosis, and many have suggested that protease inhibitors promote endothelial dysfunction indirectly by inducing elevations in circulating lipids. To determine whether nucleoside reverse transcriptase inhibitors and/or protease inhibitors induce endothelial dysfunction, and to test whether this effect is dependent upon drug-mediated alteration in plasma lipid concentrations, we treated male Sprague-Dawley rats with pharmacological doses of azidothymidine (AZT), indinavir, or AZT plus indinavir through their drinking water for 1 month and assessed endothelial function in aortic rings using an isometric force measurement. Circulating levels of plasma lipids and endothelin-1, a marker for endothelial injury and/or dysfunction, were also determined. We found that AZT and AZT plus indinavir treatments dramatically reduced endothelium-dependent vessel relaxation. However, AZT treatment did not significantly alter plasma levels of cholesterol or triglyceride. In addition, plasma endothelin-1 levels were elevated in rats treated with AZT plus indinavir. Indinavir treatment alone increased plasma cholesterol levels but had no effect on endothelial function. These findings suggest that in addition to modulating plasma lipid levels, antiretrovirals, particularly AZT and perhaps other nucleoside reverse transcriptase inhibitors, may have direct effects on the vascular endothelium. Together with other increased risk factors for atherosclerosis in HIV patients, AZT-induced endothelial dysfunction may contribute to the cardiovascular diseases associated with HIV antiretroviral therapy.
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PMID:Antiretrovirals induce direct endothelial dysfunction in vivo. 1681 Jan 7

Fonsecaea pedrosoi is the principal causative agent of chromoblastomycosis, which is a chronic, often debilitating, suppurative and granulomatous mycosis. Very little is known about the hydrolytic enzymes produced by this human fungal pathogen. In the present study, we have identified extracellular proteolytic activity from F. pedrosoi mycelial forms when grown in chemically defined conditions. Secretory aspartyl peptidase activity was measured during 15 days of fungal growth in vitro using bovine serum albumin (BSA) as the soluble substrate and extreme acidic pH (2.0). This activity was totally inhibited by pepstatin A, a classic aspartyl peptidase inhibitor. Conversely, metallo (o-phenanthroline), cysteine (E-64) and serine (PMSF) proteolytic inhibitors failed to restrain proteolytic activity. We also evaluated the effect of four distinct HIV aspartyl peptidase inhibitors on the secretory proteolytic activity of F. pedrosoi mycelia. Indinavir, ritonavir and nelfinavir powerfully inhibited extracellular aspartyl proteolytic activity by approximately 97, 96 and 87%, respectively, whereas saquinavir did not significantly interfere with BSA hydrolysis. Mycelial-derived secretory aspartyl peptidase activity cleaved other proteinaceous substrates, including human albumin, fibrinogen, fibronectin, laminin and type I collagen. As previously reported by our group, conidia also produce secretory aspartyl peptidase. In this sense, we investigated the effect of pepstatin A on F. pedrosoi development. Pepstatin A was able to inhibit the growth of conidium and its transformation into mycelium. Taken together, our results suggest a possible participation of aspartyl peptidases in the essential fungal processes, such as growth, differentiation, nutrition and cleavage of relevant host proteinaceous components.
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PMID:Secretory aspartyl peptidase activity from mycelia of the human fungal pathogen Fonsecaea pedrosoi: effect of HIV aspartyl proteolytic inhibitors. 1695 73

Large intra-individual variability in plasma levels may limit the interest of therapeutic drug monitoring based on a single determination. Indinavir concentrations were determined both in plasma and hair samples, and correlated with concomitant plasma HIV-RNA in 43 HIV-infected patients. In multivariate analysis, significant association was found between HIV-RNA below 50 copies/ml and indinavir concentrations in hair but not in plasma, suggesting that hair concentrations gave more extensive information on drug exposure than a single plasma sample.
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PMID:Hair versus plasma concentrations as indicator of indinavir exposure in HIV-1-infected patients treated with indinavir/ritonavir combination. 1714 76


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