Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Highly active antiretroviral therapy that includes human immunodeficiency virus (HIV) aspartyl protease inhibitors (PIs) causes a decline in the incidence of some opportunistic infections in AIDS, and this decline is currently attributed to the restoration of specific immunity. The effect of two PIs (indinavir and ritonavir) on the enzymatic activity of a secretory aspartyl protease (Sap) of Candida albicans (a major agent of mucosal disease in HIV-infected subjects) and on growth and experimental pathogenicity of this fungus was evaluated. Both PIs strongly (>/=90%) and dose dependently (0.1-10 microM) inhibited Sap activity and production. They also significantly reduced Candida growth in a nitrogen-limited, Sap expression-dependent growth medium and exerted a therapeutic effect in an experimental model of vaginal candidiasis, with an efficacy comparable to that of fluconazole. Thus, besides the expected immunorestoration, patients receiving PI therapy may benefit from a direct anticandidal activity of these drugs.
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PMID:In vitro and in vivo anticandidal activity of human immunodeficiency virus protease inhibitors. 1112 Sep 36

We retrospectively reviewed the charts of 54 human immunodeficiency virus (HIV) infected patients or acquired immunodeficiency syndrome (AIDS), who were hospitalized at the Bronx-Lebanon Hospital Center with acute pancreatitis between January 1993 and December 1995. Nineteen were female and 35 were male patients. Thirty-five (65%) of 54 patients were younger than 40 years (average age, 42 years). Forty-eight (89%) of the patients had a CD4 count of <200 units/ml of blood. Seventeen (32%) patients died either of complications of acute pancreatitis or of underlying disease. The conventional prognostic criteria used to assess the severity of pancreatitis, including Ranson's and Imrie's criteria and the APACHE II system, were applied. We determined that these criteria were not appropriate to our HIV/AIDS patients. Only serum calcium levels at 48 h after admission and serum creatinine and blood urea nitrogen (BUN) at admission and at 48 h after admission had significant p values (<0.05). We believe that the predictors commonly used to identify the severity of pancreatitis were not useful in these patients because of their low CD4 counts and preexisting liver and renal disease.
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PMID:Predictors of the severity of acute pancreatitis in patients with HIV infection or AIDS. 1043 59

Emivirine (EMV), formerly known as MKC-442, is 6-benzyl-1-(ethoxymethyl)-5-isopropyl-uracil, a novel nonnucleoside reverse transcriptase inhibitor that displays potent and selective anti-human immunodeficiency virus type 1 (HIV-1) activity in vivo. EMV showed little or no toxicity towards human mitochondria or human bone marrow progenitor cells. Pharmacokinetics were linear for both rats and monkeys, and oral absorption was 68% in rats. Whole-body autoradiography showed widespread distribution in tissue 30 min after rats were given an oral dose of [(14)C]EMV at 10 mg/kg of body weight. In rats given an oral dose of 250 mg/kg, there were equal levels of EMV in the plasma and the brain. In vitro experiments using liver microsomes demonstrated that the metabolism of EMV by human microsomes is approximately a third of that encountered with rat and monkey microsomes. In 1-month, 3-month, and chronic toxicology experiments (6 months with rats and 1 year with cynomolgus monkeys), toxicity was limited to readily reversible effects on the kidney consisting of vacuolation of kidney tubular epithelial cells and mild increases in blood urea nitrogen. Liver weights increased at the higher doses in rats and monkeys and were attributed to the induction of drug-metabolizing enzymes. EMV tested negative for genotoxic activity, and except for decreased feed consumption at the high dose (160 mg/kg/day), with resultant decreases in maternal and fetal body weights, EMV produced no adverse effects in a complete range of reproductive toxicology experiments performed on rats and rabbits. These results support the clinical development of EMV as a treatment for HIV-1 infection in adult and pediatric patient populations.
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PMID:Safety assessment, in vitro and in vivo, and pharmacokinetics of emivirine, a potent and selective nonnucleoside reverse transcriptase inhibitor of human immunodeficiency virus type 1. 1060 32

The purpose of this study was to investigate whether resting energy expenditure (REE) is elevated in early, asymptomatic human immunodeficiency virus (HIV)-infected females and to study the contribution of a cytokine, tumor necrosis factor-alpha (TNF-alpha), to hypermetabolism. Cross-sectional comparison of REE in asymptomatic HIV+ females and a control group matched for age, body mass index (BMI), and fat-free mass (FFM). Twenty-six females aged 35 +/- 7 years (10 HIV+ [mean CD4+ T cell count 636/mm3] and 16 healthy controls) participated in this study. REE was measured by indirect calorimeter using a Deltatrac ventilated hood with a continuous rate of 40 L/min for 30 minutes after a 40-minute equilibrium period. All tests were performed after a 12-hour overnight fast. Twenty-four-hour urinary nitrogen was calculated to correct for respiratory quotient. Body composition was measured by bioelectrical impedance (BioAnalogics, Beaverton, OR). TNF-alpha was measured by ELISA (R & D Systems, Minneapolis, MN). Absolute REE was 17% higher (1755 kcal/kg +/- 410 versus 1497 kcal/kg +/- 197) in the HIV+ group compared with the control group (p < 0.05). REE remained significantly higher in the HIV+ group when REE was adjusted for body composition differences (p = 0.04). Results revealed a 23% higher level of TNF-alpha in the HIV+ subjects (p < 0.01); however, only a weak correlation existed between TNF-alpha and REE (r = .352). This study documented that hypermetabolism and elevated TNF-alpha exist in HIV+ females in the early stages of disease.
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PMID:Resting energy expenditure in asymptomatic HIV-infected females. 1078 29

Despite the worldwide application of embryo-freezing technology as the means of preserving germplasm of mammalian species, there is no information available on the possible transmission of infectious agents to cryopreserved embryos via contaminated liquid nitrogen (LN). Recently, it has been reported that new methods of cryopreservation which employ ultrarapid freezing or vitrification require direct contact between the freezing medium containing oocytes or embryos and liquid phase nitrogen (LPN). As models for human and animal viral pathogens three bovine viruses, bovine viral diarrhea virus (BVDV), bovine herpesvirus-1 (BHV), and bovine immunodeficiency virus (BIV), were employed to study the potential for their transmission by experimentally contaminated LN to embryos frozen and stored in open freezing containers. Bovine embryos in a mixture of 20% ethylene glycol, 20% ME(2)SO, and 0.6% sucrose were vitrified in either unsealed standard 0.25 ml or modified open pulled straws or in plastic cryovials and then plunged into contaminated LPN. After 3-5 weeks of storage in LN, embryos were thawed and sequentially washed and only those with intact ZP were pooled together and tested in batches of three for viral contamination. From this pool of 83 batches, 13 of 61 (21.3%) batches exposed to BVDV and BHV-1 tested positive for viral association while all 22 batches exposed to BIV in unsealed containers tested negative. All control embryos vitrified in sealed cryovials and straws were free from viral contamination.
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PMID:Viral contamination of embryos cryopreserved in liquid nitrogen. 1078 10

Some novel phosphoramidate derivatives of the nucleoside analogue stavudine have been prepared as membrane-soluble prodrugs of the bioactive free phosphate forms. Phenyl phosphates linked via nitrogen to methyl esterified amino acid analogues were studied, where the amino acid was an unnatural alpha-alkyl (or aryl) glycine or an alpha,alpha-dialkyl glycine. All compounds were characterized by a range of spectroscopic, spectrometric and analytical methods and were subjected to in vitro evaluation of their anti-human immunodeficiency virus efficacy. It is notable that certain unnatural amino acid derivatives could substitute for alanine with only a relatively small loss of activity and, moreover, that this activity did not fall-off with increasing alkyl chain length for the C2-C4 mono-alkyl series. These data are further probed by the application of our recently reported 31P-NMR-based carboxyl esterase assay, with informative results.
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PMID:Phosphoramidate derivatives of stavudine as inhibitors of HIV: unnatural amino acids may substitute for alanine. 1081 35

1. Elevated proinflammatory cytokines within the central nervous system (CNS) of individuals infected with human immunodeficiency virus (HIV) may contribute to altered CNS processes prior to the onset of AIDS. Most studies of HIV-induced alterations in cytokine expression within the CNS have focused on interleukin (IL)-1 and tumor necrosis factor (TNF). 2. We used a ribonuclease protection assay (RPA) to elucidate further the pattern of cytokine mRNA expression in the rat CNS in response to HIV envelope glycoprotein 160 (gp160). Male Sprague-Dawley rats were surgically implanted with a guide cannula directed into a lateral cerebral ventricle. HIV gp160 was injected intracerebroventricularly and rats were sacrificed immediately (time = 0) or at 1, 2, or 4 hr postinjection. Discrete brain regions were dissected, and peripheral glands removed. All tissues were frozen in liquid nitrogen until RNA extraction and assay. 3. IL-1beta IL-1alpha, TNF-alpha, and TNFbeta mRNAs were constitutively expressed in brain tissues. Central administration of gp160 dramatically increased mRNA expression for IL-1beta and TNFalpha in the hypothalamus, hippocampus, brainstem, and cerebellum. Furthermore, although mRNA expression for IL-5, IL-6, and IL-10 was never detected under basal conditions, these mRNAs were increased in brain tissue after administration of gp160. Peak expression in each brain region was detected 2 hr after administration. Multiple cytokine mRNAs were detected in peripheral tissues, but their expression was not altered by central administration of gp160. 4. Our results indicate that gp160 induces mRNA expression in brain for cytokines other than IL-1 and TNF. Screening for multiple cytokine mRNA in this manner provides extensive information concerning the particular cytokines that may be involved in HIV-induced pathologies and alterations in CNS processes.
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PMID:Human immunodeficiency virus glycoprotein 160 induces cytokine mRNA expression in the rat central nervous system. 1090 Dec 64

Human immunodeficiency virus (HIV) protease inhibitors (PI) may alter lipid metabolism in patients with acquired immunodeficiency syndrome (AIDS). However, the influence of dietary fat on the metabolic effects of PI therapy remains unknown. AKR/J mice were fed high or low fat diets and treated with the PI indinavir (IDV), nelfinavir (NFV), saquinavir (SQV) or amprenavir (APV) by subcutaneous delivery for 2 wk. Serum concentrations of glucose, insulin, triglyceride, free fatty acid, glycerol, pancreatic lipase, bilirubin, alkaline phosphatase, blood urea nitrogen and PI, and interscapular and epididymal fat weights were determined. Some metabolic effects of PI were dependent on diet. IDV- and NFV-treated mice had greater serum glucose concentration and body weight; IDV-treated mice had lower serum insulin; NFV-treated mice had greater interscapular fat mass; and SQV treated mice had lower serum triglyceride concentration than control mice fed the low but not the high fat diet. In contrast, NFV- and IDV-treated mice had greater triglyceride concentration and blood urea nitrogen, and SQV treated mice had greater serum cholesterol than control mice fed the high but not the low fat diet. The serum concentration of SQV was lower in mice fed the high fat compared with the low fat diet. Other effects were not dependent on diet. IDV- and NFV-treated mice had greater fatty acids, and IDV-treated mice had greater pancreatic lipase, bilirubin and alkaline phosphatase than control mice fed either diet. APV treatment had little effect on these serum measurements. Thus, changes in dietary fat can influence some but not all of the effects of PI on metabolism. Furthermore, each PI produces different effects in vivo, indicating that various PI affect distinct metabolic pathways.
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PMID:Dietary fat alters HIV protease inhibitor-induced metabolic changes in mice. 1095 36

This is a brief review of human immunodeficiency virus (HIV)-associated wasting with expanded discussion of one treatment agent, oxandrolone. HIV-associated wasting is the involuntary loss of more than 10% of baseline body weight in the presence of chronic diarrhea, weakness, or fever lasting longer than 30 days. For patients, this clinical syndrome has special importance because it affects not only their survival but also their physical appearance and social interactions. Pharmacologic treatment is only one of the many approaches that need to be explored in every patient who presents with this condition. In 1964, oxandrolone became the first drug approved for the treatment of wasting. Since then its role has expanded to HIV-associated wasting. As an anabolic agent oxandrolone reverses many of the metabolic abnormalities characteristic of HIV-associated wasting leading to dose dependent increase in nitrogen retention. Similar to many other HIV treatments, gaps exist in our knowledge of the role of oxandrolone in HIV-associated wasting. These gaps will be filled only by years of field exposure and further clinical research.
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PMID:HIV-associated wasting: brief review and discussion of the impact of oxandrolone. 1097 71

More than 60 human immunodeficiency virus protease inhibitors were examined for the structure-activity relationship between metabolic stability, CYP3A4 inhibitory potency, and substrate-induced binding spectra with a ferric form of P450 in human liver microsomes. A positive relationship was found between CYP3A4 inhibitory potency and metabolic stability; namely, compounds that were more potent for the CYP3A4 inhibition generally were more metabolically stable. In addition, the compounds formed two clusters defined by the distinct type of substrate-induced P450 binding spectra: the compounds with type II binding spectra were more stable metabolically and more potent for the CYP3A4 inhibition than those with type I binding spectra. The structure-activity relationship suggested that the presence and position of heterocyclic nitrogen on the pyridine moiety play an important role in determining the manner of interaction with P450 and the magnitude of CYP3A4 inhibition/metabolic stability in the series of structurally related human immunodeficiency virus protease inhibitors under development.
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PMID:P450 interaction with HIV protease inhibitors: relationship between metabolic stability, inhibitory potency, and P450 binding spectra. 1112 21


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