UMLS:C0019693 - FACTA Search

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Query: UMLS:C0019693 (HIV)
170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

HIV protease inhibitors decrease mortality and improve quality of life in patients with HIV infection. However, these drugs have been associated with serum lipid elevations, which may pose an increased risk of cardiovascular disease and pancreatitis. Treatment of protease inhibitor-related hyperlipidaemia (PIH) is complicated by drug interactions, which significantly increase concentrations of most 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins). Although pravastatin and atorvastatin effectively lower cholesterol and triglyceride concentrations in HIV-infected patients, a significant number of patients did not achieve their National Cholesterol Education Program low density lipoprotein concentration goals. Nonetheless, due to the increased risk of rhabdomyolysis with elevated statin concentrations, atorvastatin should be considered a second-line agent. The limited available PIH data supports the fact that pravastatin and atorvastatin are well-tolerated in HIV-infected individuals. More data are needed on the appropriate starting doses, maximum safe doses, role of combination statin-fibrate therapy, documentation of coronary heart disease benefit and incidence of myotoxicity and hepatotoxicity. Pravastatin has an acceptable risk-benefit ratio in PIH, while theoretical toxicity concerns exist with atorvastatin.
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PMID:Risk-benefit of HMG-CoA reductase inhibitors in the treatment of HIV protease inhibitor-related hyperlipidaemia. 1290 55

Elevating women from the nadir of ovarian hypofunction has been a major driving force in developing hormonal strategies for the management of menopause. As indicated by recent evidence, however, this may have resulted in unacceptable morbidity in several women. Likewise, the use of menstrual cessation as the hallmark of menopause may have served the counterproductive effect of delaying the onset of appropriate preventive pharmacologic and non-pharmacologic strategies until the later years of life. Preventive and therapeutic strategies that target the menopausal phase of life exclusively are grossly inadequate. Unquestionably, the controversies that surround the precise health implications of menopause deal mainly with the risk of chronic disease. Health professionals are best advised to develop menopausal intervention strategies that parallel the continuum of a woman's life, beginning in adolescence and extending into later life. Preventive screening includes the following: History Relevant medical history Develop risk profile of chronic diseases (e.g., cardiovascular disease, cancer, osteoporosis) Dietary history Sexual history Physical exercise history Medication history Physical examination Body mass index evaluation Breast examination and instruction in examination technique Bimanual pelvic examination Nutritional assessment Investigation Cholesterol levels Stool for occult blood Thyroid function tests Papanicolaou smears HIV testing if positive risk factors Psychosocial evaluation Family relationships Job satisfaction Sexuality High-risk social behaviors Review perception of self-health Annual health examination is encouraged in all perimenopausal women. Additionally, preventive screening should be instituted, as appropriate, in all women of reproductive age.
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PMID:Menopause. 1456 3

Lopinavir (LPV)/ritonavir (RTV) used in combination, is a potent antiretroviral drug. However, its benefit is limited by its inherent effect on lipid metabolism, causing dislypemia in a large proportion of treated patients. Fasting triglyceride (TG) and cholesterol levels were assessed in 126 HIV-infected patients who initiated salvage therapy based on LPV/RTV. Both TG and cholesterol significantly increased from baseline to month 3. A positive correlation was found between the percentage increase in TG and LPV trough levels (r = 0.32; p = 0.003). Moreover, patients with TG elevations above the median (27%) showed higher LPV Ctrough levels than those with lower TG elevations (7.1 vs. 4.7 microg/ml, p = 0.004). In contrast, no correlation was found between LPV Ctrough and increases in cholesterol levels. Cholesterol elevations were positively correlated with RTV Ctrough concentrations (r = 0.32; p = 0.003).
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PMID:Correlation between lopinavir plasma levels and lipid abnormalities in patients taking lopinavir/ritonavir. 1458 81

To determine the site of insulin exocytosis in the pancreatic beta cell plasma membrane, we analyzed the interaction between the docking/fusion of green fluorescent protein-tagged insulin granules and syntaxin 1 labeled by TAT-conjugated Cy3-labeled antibody (Ab) using total internal reflection fluorescence microscopy (TIRFM). Monoclonal Ab against syntaxin 1 was labeled with Cy3 then conjugated with the protein transduction domain of HIV-1 TAT. TAT-conjugated Cy3-labeled anti-syntaxin 1 Ab was transduced rapidly into the subplasmalemmal region in live MIN6 beta cells, which enabled us to observe the spatial organization and distribution of endogenous syntaxin 1. TIRFM imaging revealed that syntaxin 1 is distributed in numerous separate clusters in the intact plasma membrane, where insulin secretory granules were docked preferentially to the sites of syntaxin 1 clusters, colocalizing with synaptosomal-associated protein of 25 kDa (SNAP-25) clusters. TIRFM imaging analysis of the motion of single insulin granules demonstrated that the fusion of insulin secretory granules stimulated by 50 mm KCl occurred exclusively at the sites of the syntaxin 1 clusters. Cholesterol depletion by methyl-beta-cyclodextrin treatment, in which the syntaxin 1 clusters were disintegrated, decreased the number of docked insulin granules, and, eventually the number of fusion events was significantly reduced. Our results indicate that 1) insulin exocytosis occurs at the site of syntaxin 1 clusters; 2) syntaxin 1 clusters are essential for the docking and fusion of insulin granules in MIN6 beta cells; and 3) the sites of syntaxin 1 clusters are distinct from flotillin-1 lipid rafts.
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PMID:Site of docking and fusion of insulin secretory granules in live MIN6 beta cells analyzed by TAT-conjugated anti-syntaxin 1 antibody and total internal reflection fluorescence microscopy. 1467 8

Dyslipidemia, characterized by elevated serum levels of triglycerides and reduced levels of total cholesterol, low-density lipoprotein-cholesterol (LDL-C) and high-density lipoprotein-cholesterol, has been recognized in patients with human immunodeficiency virus (HIV) infection. It is thought that elevated levels of circulating cytokines, such as tumor necrosis factor-alpha and interferon-alpha, may alter lipid metabolism in patients with HIV infection. Protease inhibitors, such as saquinavir, indinavir and ritonavir, have been found to decrease mortality and improve quality of life in patients with HIV infection. However, these drugs have been associated with a syndrome of fat redistribution, insulin resistance, and hyperlipidemia. Elevations in serum total cholesterol and triglyceride levels, along with dyslipidemia that typically occurs in patients with HIV infection, may predispose patients to complications such as premature atherosclerosis and pancreatitis. It has been estimated that hypercholesterolemia and hypertriglyceridemia occur in greater than 50% of protease inhibitor recipients after 2 years of therapy, and that the risk of developing hyperlipidemia increases with the duration of treatment with protease inhibitors. In general, treatment of hyperlipidemia should follow National Cholesterol Education Program guidelines; efforts should be made to modify/control coronary heart disease risk factors (i.e. smoking; hypertension; diabetes mellitus) and maximize lifestyle modifications, primarily dietary intervention and exercise, in these patients. Where indicated, treatment usually consists of either pravastatin or atorvastatin for patients with elevated serum levels of LDL-C and/or total cholesterol. Atorvastatin is more potent in lowering serum total cholesterol and triglycerides compared with other hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, but it is also associated with more drug interactions compared with pravastatin. Simvastatin and lovastatin are significantly metabolized by cytochrome P450 enzymes (CYP3A4) and are therefore not recommended for coadministration with protease inhibitors. A fibric acid derivative (gemfibrozil or fenofibrate) should be used in patients with primary hypertriglyceridemia. However, it must be kept in mind that protease inhibitors, such as nelfinavir and ritonavir, induce enzymes involved in the metabolism of the fibric acid derivatives and may, therefore, reduce the lipid-lowering activity of coadministered gemfibrozil or fenofibrate. In certain patients HMG-CoA reductase inhibitors may be used in combination with fibric acid derivatives but patients should be carefully monitored for liver and skeletal muscle toxicity. Select patients may experience improvements in serum lipid levels when their offending protease inhibitor(s) is/are exchanged for efavirenz, nevirapine, or abacavir; however each patient's virologic and immunologic status must be taken closely into consideration.
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PMID:Management of protease inhibitor-associated hyperlipidemia. 1472 85

Cholesterol-labeled oligonucleotides were found several years ago to inhibit HIV-1 in tissue culture at nanomolar concentrations. We present evidence that this is mainly due to an electrostatic interaction between polyanionic oligonucleotide concentrated at the cell surface and a positively charged region in the V3 loop of the HIV-1 envelope protein. When added to tissue culture, cholesterol-labeled oligonucleotides became concentrated at the plasma membrane and potently inhibited virus entry and cell fusion mediated by the envelope protein of some X4 strains of HIV-1, but had little effect on fusion mediated by R5 strains of HIV-1, amphotropic MLV envelope protein, or VSV-G protein. Noncholesterol-labeled oligonucleotides did not bind to the cell surface or inhibit fusion. The pattern of susceptibility to cholesterol-labeled oligonucleotides among HIV-1 strains was the same as reported for nonmembrane-associating polyanions such as dextran sulfate, but the cholesterol-labeled oligonucleotides were effective at lower concentrations. Substitution of a basic 33 amino acid V3 loop sequence from the envelope protein of a resistant strain into a susceptible strain made the envelope protein resistant to inhibition. Inhibition by cholesterol-labeled oligonucleotides was abrogated by the polycation DEAE-dextran. Cholesterol-labeled oligonucleotides bound to nonraft regions of the plasma membrane and did not inhibit HIV virus binding to cells. Many infectious agents first associate with target cells via relatively nonspecific charge interactions; our data suggest that molecules that combine a membrane-targeting motif with multiple negative charges might be useful to modify these interactions.
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PMID:Inhibition of certain strains of HIV-1 by cell surface polyanions in the form of cholesterol-labeled oligonucleotides. 1552 33

Pneumocystis can transiently colonize healthy individuals without causing adverse symptoms, and most people test positive for exposure to this organism early in life. However, it can cause Pneumocystis pneumonia (PcP) in people with impaired immune systems and is a major cause of death in HIV/AIDS. Although it has close affinities to the Ascomycetes, Pneumocystis has features unlike those of any single group of fungi. For example, Pneumocystis does not synthesize ergosterol, which is consistent with the inefficacy of amphotericin B and some triazoles in clearing PcP. Pneumocystis sterols include distinct delta7 24-alkylsterols. Metabolic radiolabeling experiments demonstrated that P. carinii synthesizes sterols de novo. Cholesterol is the most abundant sterol in Pneumocystis; most, if not all, is scavenged from the mammalian host lung by the pathogen. The P. carinii erg7, erg6, and erg11 genes have been cloned, sequenced, and expressed in heterologous systems. The recombinant P. carinii S-adenosyl-L-methionine:C-24 sterol methyl transferase (SAM:SMT) has a preference for lanosterol over zymosterol as substrate, and the enzyme can catalyze the transfer of either one or two methyl groups to the C-24 position of the sterol side chain. Two different sterol compositions were detected among human-derived P. jirovecii; one was dominated by C28 and C29 sterols, and the other had high proportions of higher molecular mass components, notably the C32 sterol pneumocysterol. The latter phenotype apparently represents organisms blocked at 14alpha-demethylation of the sterol nucleus. These studies suggest that SAM:SMT is an attractive drug target for developing new chemotherapy for PcP.
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PMID:Sterol metabolism in the opportunistic pathogen Pneumocystis: advances and new insights. 1563 43

The HIV lipodystrophy syndrome, a condition characterized by subcutaneous fat loss sometimes associated with relative or absolute accumulation of central fat, has a high prevalence in the treatment of HIV infection. Associated metabolic alterations include peripheral and hepatic insulin resistance, impaired glucose tolerance, type 2 diabetes, hypertriglyceridemia, hypercholesterolemia, increased free fatty acids, and decreased HDL. Often, these metabolic abnormalities appear or deteriorate before the manifestation of fat redistribution. Hypertriglyceridemia is the leading lipid abnormality after initiation of HIV therapy frequently observed together with low HDL cholesterol. Raised levels of tissue plasminogen activator and plasminogen activator inhibitor-1 have been found in these patients, and there are reports about hypertension associated with antiretroviral therapy. Thus, the lipodystrophy syndrome in HIV therapy resembles a clinical situation that is known as the "metabolic syndrome" in HIV-negative patients. There is now good evidence that the metabolic abnormalities of HIV-infected patients harbor a significant risk for cardiovascular disease with as yet unknown consequences. In addition, several studies report a reduced quality of life in patients with body habitus changes leading to reduced therapy adherence. Current data indicate a rather multifactorial pathogenesis where HIV infection, its therapy, and patient-related factors are major contributors. Therapeutic and preventive strategies have, so far, been of only limited or no success. For reduction of the cardiovascular risk, recommendations proposed for non-HIV-infected patients like the National Cholesterol Education Program (NECP) have been adapted for HIV-infected patients. These should be regarded as rather preliminary and need to be evaluated in further clinical trials. General recommendations include dietary changes and physical activity, switch of antiretroviral drugs (replacement of protease inhibitors), and, finally, use of metabolically active drugs. Lipid-lowering agents can be considered for the treatment of severe hypertriglyceridemia, elevated LDL, or a combination of both. Some HMG-CoA reductase inhibitors, however, share common hepatic metabolization pathways with protease inhibitors (cytochrome P450 3A4 system), thereby potentially leading to additional liver and muscle toxicity. Although clinicians should assess cardiovascular risk factors and target risk reduction in HIV-infected patients, the primary goal in HIV therapy remains to be the effective suppression of viral replication leading to reduced morbidity and mortality.
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PMID:[Metabolic syndrome and hyperlipidemia in HIV-positive patients]. 1617 Jun 75

This retrospective and longitudinal study evaluated the long-term hepatic tolerance of a nelfinavir (NFV)-antiretroviral combined regimen in 82 patients of the HCV-HIV Cohort of CISIH-Sud of Marseilles. Follow-up data (liver enzyme levels, CD4 cell count, HIV viral load, and metabolic parameters) of patients treated with NFV on inclusion or during the follow-up of the cohort were analyzed under treatment over 24 months. Comparisons were performed with X2 or Kruskal-Wallis tests. At baseline (n = 82), the median exposure to NFV was 4.1 months; 58 patients received NFV combined with NRTI and 24 with NNRTI. The median CD4 cell count was 337/mm3 [interquartile range (IR): 216-480) and 39.7% had an undetectable HIV RNA level. Qualitative HCV PCR was positive in 91% of the patients and 19/51 patients with liver biopsy were F3-F4. Median alanine and aspartate aminotransferase (ALAT, ASAT), gamma-glutamyltransferase (GT), and alkaline phosphatase (ALP) were 46 UI/liter (IR: 36-76), 55 UI/liter (IR: 32-97), 97 UI/liter (IR: 50-194), and 88 UI/liter (IR: 72-104), respectively, with 76% of the patients with ALAT/ASAT grade <2. Median follow-up was 23 months (IR: 13.8-37). No significant difference was observed in the distribution of ALAT, ASAT, GT, and ALP as well as of ALAT/ASAT grades over the 24-month study period. Patients treated with NFV + NNRTI had significantly higher GT and ALP levels at baseline with no significant increase during follow-up. Cholesterol, triglyceride, and glycemia distributions remained stable over time. In conclusion, this study showed a good hepatic and metabolic tolerance of a long-term NFV-combined regimen in HIV-HCV coinfected patients.
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PMID:Nelfinavir in HIV-HCV coinfected patients: a 24-month follow-up in a cohort of 82 patients. 1622 10

The recommendations made in this review are based on the current clinical knowledge with regard to the origin and therapy of lipodystrophy. They should be regarded as provisional and will change with expanding knowledge. The recommendations for treating dyslipidaemia in particular are oriented closely on the American recommendations of the National Cholesterol Education Program (NCEP III), and may be regarded both by HIV practitioners and patients as excessive and too rigid. The therapeutic goals of the NCEP in the first intervention studies in HIV-positive individuals were only achieved for a small proportion of the HIV patients. In addition, preliminary results suggest a potentially higher risk of adverse events in HIV-patients under statins or fibrates. The clinical efficacy of interventions with lipid lowering drugs has not been validated in HIV-seropositive patients. However, therapeutic decisions so far have been based on data obtained in non-HIV cardiovascular intervention studies. With more and more results becoming available from the HIV patient population a revision of these recommendations will be required.
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PMID:Appendix to the German-Austrian HIV Therapeutic Guidelines: strategies for treating morphological and metabolic alterations under antiretroviral treatment (current as of December 2004). 1650 61

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