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Estudo da atividade e polimorfismos da Paraoxonase-1 em indivíduos infectados pelo vírus da imunodeficiência humana tipo-1 (HIV-1) tratados com inibidores de protease; Study of activity and polymorphisms of Paraoxonase-1 in individuals infected with human immunodeficiency vírus type-1 (HIV-1) treated with protease inhibitors

Cunha, Joel da
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 31/08/2012 Português
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A enzima Paraoxonase-1 (PON1) possui atividades paraoxonase, arilestearase e lactonase, entre outras. É a mais estuda da família das PONs que é composta pela PON1, PON2 e PON3. Sugere-se, que todas atuam inibindo o processo de peroxidação lipídica de moléculas como a lipoproteína de baixa densidade (LDL) e alta densidade (HDL), caracterizando assim um possível papel anti-aterogênico. O gene da PON1 apresenta dois sítios polimórficos, com a troca de uma Gln192Arg (Q/R) e Met55Leu, que estão associados com diferenças na atividade e concentrações séricas da enzima. Por sua vez, indivíduos soropositivos para o HIV-1 apresentam alterações do metabolismo lipídico, que poderiam estar associados a alterações na atividade da PON1 e a terapia antirretroviral (TARV) com inibidores de protease (IP). O objetivo do estudo foi determinar as atividades séricas da PON1 e da arilestearase (ARE), e as freqüências alélicas dos polimorfismos genéticos da PON1 192QR e 55LM, e ainda, avaliar a correlação destes parâmetros com as alterações lipídicas em indivíduos soropositivos para o HIV-1 tratados com IP. No período de Setembro de 2009 até Junho de 2012, 174 indivíduos soropositivos e 46 soronegativos para o HIV-1 foram estudados. Foi realizada a genotipagem dos polimorfismos da PON1 192QR e 55LM através de PCR-RFLP. A atividade sérica da PON1/ARE foi avaliada por espectrofotometria empregando-se como substratos o paraoxon e o fenilacetato...

Hyperlipidemia related to the use of HIV-protease inhibitors : natural history and results of treatment with fenofibrate

Caramelli, Bruno; Bernoche, Claudia Y.S.M. de; Sartori, Ana M.C; Spósito, Andrei Carvalho; Santos, Raul D.; Monachini, Maristela C.; Strabelli, Tania; Uip, Davi
Fonte: Universidade de Brasília Publicador: Universidade de Brasília
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
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7 f.; Hyperlipidemia has been frequently recorded as a side effect of treating HIV patients with protease inhibitors (PI). This study was initiated to analyze the modifications on blood lipids in HIV-patients receiving PI and the safety and efficacy of the treatment with fenofibrate. Total (TC) and HDL-cholesterol, triglycerides (TG), and CD4+ T-cell counts were measured in 30 HAART-naive patients (Group I) before and after PI introduction. In a second phase of the study, the effects of fenofibrate on lipids, CPK, CD4+, and viral load were determined in 13 patients (Group II) with elevated TC or TG. In Group I, 60% of the patients showed TC or TG elevations. Average increments of 31% and 146% in TC and TG respectively (p<0.0006 and p<0.0001) were observed. In Group II, fenofibrate treatment was associated with decrements of 6.6% (TC) and 45.7% (TG) (p=0.07 and 0.0002) and no modifications on CPK, CD4+, and viral load. In conclusion, hyperlipidemia is common during the treatment of HIV with protease inhibitors, and fenofibrate appears to be an effective and safe choice for its treatment.

Hyperlipidemia related to the use of HIV-protease inhibitors: natural history and results of treatment with fenofibrate

Caramelli,Bruno; Bernoche,Claudia Y.S.M. de; Sartori,Ana M. C.; Sposito,Andrei C.; Santos,Raul D.; Monachini,Maristela C.; Strabelli,Tania; Uip,Davi
Fonte: Brazilian Society of Infectious Diseases Publicador: Brazilian Society of Infectious Diseases
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/12/2001 Português
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68.65374%
Hyperlipidemia has been frequently recorded as a side effect of treating HIV patients with protease inhibitors (PI). This study was initiated to analyze the modifications on blood lipids in HIV-patients receiving PI and the safety and efficacy of the treatment with fenofibrate. Total (TC) and HDL-cholesterol, triglycerides (TG), and CD4+ T-cell counts were measured in 30 HAART-naive patients (Group I) before and after PI introduction. In a second phase of the study, the effects of fenofibrate on lipids, CPK, CD4+, and viral load were determined in 13 patients (Group II) with elevated TC or TG. In Group I, 60% of the patients showed TC or TG elevations. Average increments of 31% and 146% in TC and TG respectively (p<0.0006 and p<0.0001) were observed. In Group II, fenofibrate treatment was associated with decrements of 6.6% (TC) and 45.7% (TG) (p=0.07 and 0.0002) and no modifications on CPK, CD4+, and viral load. In conclusion, hyperlipidemia is common during the treatment of HIV with protease inhibitors, and fenofibrate appears to be an effective and safe choice for its treatment.

Prevalence and factors associated with darunavir resistance mutations in multi-experienced HIV-1-infected patients failing other protease inhibitors in a referral teaching center in Brazil

Vidal,Jose E; Freitas,Angela C; Song,Alice TW; Campos,Silvia V; Dalben,Mirian; Hernandez,Adrian V
Fonte: Brazilian Society of Infectious Diseases Publicador: Brazilian Society of Infectious Diseases
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/06/2011 Português
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Information about resistance profile of darunavir (DRV) is scarce in Brazil. Our objectives were to estimate the prevalence of DRV resistance mutations in patients failing protease inhibitors (PI) and to identify factors associated with having more DRV resistance mutations. All HIV-infected patients failing PI-based regimens with genotyping performed between 2007 and 2008 in a referral teaching center in São Paulo, Brazil, were included. DRV-specific resistance mutations listed by December 2008 IAS-USA panel update were considered. Two Poisson regression models were constructed to assess factors related to the presence of more DRV resistance mutations. A total of 171 HIV-infected patients with available genotyping were included. The number of patients with lopinavir, saquinavir, and amprenavir used in previous regimen were 130 (76%), 83 (49%), and 35 (20%), respectively. The prevalence of major DRV resistance mutations was 50V: 5%; 54M: 1%; 76V: 4%; 84V: 15%. For minor mutations, the rates were 11I: 3%; 32I: 7%; 33F: 23%; 47V: 6%; 54L: 6%; 74P: 3%; 89V: 6%. Only 11 (6%) of the genotypes had > 3 DRV resistance mutations. In the clinical model, time of HIV infection of > 10 years and use of amprenavir were independently associated with having more DRV resistance mutations. In the genotyping-based model...

ESTROGEN RECEPTOR-ALPHA MEDIATES GENDER DIFFERENCES IN ATHEROSCLEROSIS INDUCED BY HIV PROTEASE INHIBITORS

Allred, Kimberly F.; Smart, Eric J.; Wilson, Melinda E.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Português
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As part of highly active antiretroviral therapy, protease inhibitor treatment has significantly increased the lifespan of HIV infected individuals. Many patients, however, develop negative side effects including premature atherosclerosis. We have previously demonstrated that in male low-density lipoprotein receptor (LDL-R) null mice, HIV protease inhibitors induce atherosclerotic lesions and cholesterol accumulation in macrophages in the absence of changes in plasma lipid levels. We determined that these increases were due to an up-regulation of the scavenger receptor, CD36. In the present study, we examined the effects of HIV protease inhibitors in female LDL-R null mice. Female mice given ritonavir and amprenavir (23 and 10 μg/mouse/day, respectively) developed fewer atherosclerotic lesions than males. Furthermore, peritoneal macrophages isolated from ritonavir-treated females had reduced levels of cholesterol accumulation as compared to males, and CD36 protein levels were increased to a significantly lesser degree in females than in males. To investigate the molecular mechanisms of this gender difference, we examined the effect of genetically removing estrogen receptor-alpha (ERα). In female mice lacking both LDL-R and ERα, the protective effect of gender was lost. Additionally...

A Structural Basis for the Acute Effects of HIV Protease Inhibitors on GLUT4 Intrinsic Activity*

Hertel, Johann; Struthers, Heidi; Horj, Christal Baird; Hruz, Paul W.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Português
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Human immunodeficiency virus (HIV) protease inhibitors (PIs) act as reversible noncompetitive inhibitors of GLUT4 with binding affinities in the low micromolar range and are known to contribute to alterations in glucose homeostasis during treatment of HIV infection. As aspartyl protease inhibitors, these compounds all possess a core peptidomimetic structure together with flanking hydrophobic moieties. To determine the molecular basis for GLUT4 inhibition, a family of related oligopeptides containing structural elements found in PIs was screened for their ability to inhibit 2-deoxyglucose transport in primary rat adipocytes. The peptide oxybenzylcarbonyl-His-Phe-Phe-O-ethyl ester (zHFFe) was identified as a potent inhibitor of zero-trans glucose flux with a Ki of 26 μM. Similar to PIs, transport inhibition by this peptide was acute, noncompetitive, and reversible. Within a Xenopus oocyte expression system, zHFFe acutely and reversibly inhibited GLUT4-mediated glucose uptake, whereas GLUT1 activity was unaffected at concentrations as high as 1 mM. The related photoactivatable peptide zHFF-p-benzoylphenylalanine-[125I]Tyr-O-ethyl ester selectively labeled GLUT4 in rat adipocytes and indinavir effectively protected against photolabeling. Furthermore...

Gender-specific effects of HIV protease inhibitors on body mass in mice

Wilson, Melinda E; Allred, Kimberly F; Kordik, Elizabeth M; Jasper, Deana K; Rosewell, Amanda N; Bisotti, Anthony J
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
Publicado em 01/05/2007 Português
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Protease inhibitors, as part of highly active anti-retroviral therapy (HAART), have significantly increased the lifespan of human immunodeficiency virus (HIV) infected patients. Several deleterious side effects including dyslipidemia and lipodystrophy, however, have been observed with HAART. Women are at a higher risk of developing adipose tissue alterations and these alterations have different characteristics as compared to men. We have previously demonstrated that in mice the HIV protease inhibitor, ritonavir, caused a reduction in weight gain in females, but had no effect on male mice. In the present study, we examined the potential causes of this difference in weight gain. Low-density lipoprotein receptor (LDL-R) null mice or wild-type C57BL/6 mice, were administered 15 μg/ml ritonavir or vehicle (0.01% ethanol) in the drinking water for 6 weeks. The percent of total body weight gained during the treatment period was measured and confirmed that female LDL-R gained significantly less weight with ritonavir treatment than males. In wild type mice, however, there was no effect of ritonavir treatment in either sex. Despite the weight loss in LDL-R null mice, ritonavir increased food intake, but no difference was observed in gonadal fat weight. Serum leptin levels were significantly lower in females. Ritonavir further suppressed leptin levels in (p < 0.05). Ritonavir did not alter serum adiponectin levels in either gender. To determine the source of these differences...

HIV protease inhibitors block the zinc metalloproteinase ZMPSTE24 and lead to an accumulation of prelamin A in cells

Coffinier, Catherine; Hudon, Sarah E.; Farber, Emily A.; Chang, Sandy Y.; Hrycyna, Christine A.; Young, Stephen G.; Fong, Loren G.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
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HIV protease inhibitors (HIV-PIs) target the HIV aspartyl protease, which cleaves the HIV gag-pol polyprotein into shorter proteins required for the production of new virions. HIV-PIs are a cornerstone of treatment for HIV but have been associated with lipodystrophy and other side effects. In both human and mouse fibroblasts, we show that HIV-PIs caused an accumulation of prelamin A. The prelamin A in HIV-PI-treated fibroblasts migrated more rapidly than nonfarnesylated prelamin A, comigrating with the farnesylated form of prelamin A that accumulates in ZMPSTE24-deficient fibroblasts. The accumulation of farnesyl-prelamin A in response to HIV-PI treatment was exaggerated in fibroblasts heterozygous for Zmpste24 deficiency. HIV-PIs inhibited the endoproteolytic processing of a GFP-prelamin A fusion protein. The HIV-PIs did not affect the farnesylation of HDJ-2, nor did they inhibit protein farnesyltransferase in vitro. HIV-PIs also did not inhibit the activities of the isoprenyl-cysteine carboxyl methyltransferase ICMT or the prenylprotein endoprotease RCE1 in vitro, but they did inhibit ZMPSTE24 (IC50: lopinavir, 18.4 ± 4.6 μM; tipranavir, 1.2 ± 0.4 μM). We conclude that the HIV-PIs inhibit ZMPSTE24, leading to an accumulation of farnesyl-prelamin A. The inhibition of ZMPSTE24 by HIV-PIs could play a role in the side effects of these drugs.

Additivity in the Analysis and Design of HIV Protease Inhibitors

Jorissen, Robert N.; Kiran Kumar Reddy, G. S.; Ali, Akbar; Altman, Michael D.; Chellappan, Sripriya; Anjum, Saima G.; Tidor, Bruce; Schiffer, Celia A.; Rana, Tariq M.; Gilson, Michael K.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 12/02/2009 Português
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We explore the applicability of an additive treatment of substituent effects to the analysis and design of HIV protease inhibitors. Affinity data for a set of inhibitors with a common chemical framework were analyzed to provide estimates of the free energy contribution of each chemical substituent. These estimates were then used to design new inhibitors, whose high affinities were confirmed by synthesis and experimental testing. Derivations of additive models by least-squares and ridge-regression methods were found to yield statistically similar results. The additivity approach was also compared with standard molecular descriptor-based QSAR; the latter was not found to provide superior predictions. Crystallographic studies of HIV protease-inhibitor complexes help explain the perhaps surprisingly high degree of substituent additivity in this system, and allow some of the additivity coefficients to be rationalized on a structural basis.

Ultra-Fast Analysis of Plasma and Intracellular Levels of HIV Protease Inhibitors in Children: A Clinical Application of MALDI Mass Spectrometry

van Kampen, Jeroen J. A.; Reedijk, Mariska L.; Burgers, Peter C.; Dekker, Lennard J. M.; Hartwig, Nico G.; van der Ende, Ineke E.; de Groot, Ronald; Osterhaus, Albert D. M. E.; Burger, David M.; Luider, Theo M.; Gruters, Rob A.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 01/07/2010 Português
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HIV protease inhibitors must penetrate into cells to exert their action. Differences in the intracellular pharmacokinetics of these drugs may explain why some patients fail on therapy or suffer from drug toxicity. Yet, there is no information available on the intracellular levels of HIV protease inhibitors in HIV infected children, which is in part due to the large amount of sample that is normally required to measure the intracellular concentrations of these drugs. Therefore, we developed an ultra-fast and sensitive assay to measure the intracellular concentrations of HIV protease inhibitors in small amounts of peripheral blood mononuclear cells (PBMCs), and determined the intracellular concentrations of lopinavir and ritonavir in HIV infected children. An assay based on matrix-assisted laser desorption/ionization (MALDI) - triple quadrupole mass spectrometry was developed to determine the concentrations of HIV protease inhibitors in 10 µL plasma and 1×106 PBMCs. Precisions and accuracies were within the values set by the FDA for bioanalytical method validation. Lopinavir and ritonavir did not accumulate in PBMCs of HIV infected children. In addition, the intracellular concentrations of lopinavir and ritonavir correlated poorly to the plasma concentrations of these drugs. MALDI-triple quadrupole mass spectrometry is a new tool for ultra-fast and sensitive determination of drug concentrations which can be used...

HIV Protease Inhibitors: Effect on the Opportunistic Protozoan Parasites

Alfonso, Yenisey; Monzote, Lianet
Fonte: Bentham Open Publicador: Bentham Open
Tipo: Artigo de Revista Científica
Publicado em 09/03/2011 Português
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The impact of highly active antiretroviral therapy (HAART) in the natural history of AIDS disease has been allowed to prolong the survival of people with HIV infection, particularly whose with increased HIV viral load. Additionally, the antiretroviral therapy could exert a certain degree of protection against parasitic diseases. A number of studies have been evidenced a decrease in the incidence of opportunistic parasitic infections in the era of HAART. Although these changes have been attributed to the restoration of cell-mediated immunity, induced by either non-nucleoside reverse transcriptase inhibitors or HIV protease inhibitors, in combination with at least two nucleoside reverse transcriptase inhibitors included in HAART, there are evidence that the control of these parasitic infections in HIV-positive persons under HAART, is also induced by the inhibition of the proteases of the parasites. This review focuses on the principal available data related with therapeutic HIV-protease inhibitors and their in vitro and in vivo effects on the opportunistic protozoan parasites.

HIV Protease Inhibitors Impact on Apoptosis

Rizza, Stacey A.; Badley, Andrew D.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /01/2008 Português
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HIV protease inhibitors are the backbone of HIV therapy. In addition to blocking intracellular HIV protease and dramatically decreasing viral burden, the protease inhibitors also regulate apoptosis. A growing body of data has confirmed the immunomodulatory effects of HIV protease inhibitors which block CD4+ and CD8+ T cell death in models of HIV infection. The mechanism of this apoptosis inhibition is still under active investigation and supported by several proposed hypothesis for how they alter the fate of the cell. More recently, the anti-apoptotic effects of the HIV protease inhibitors has been extended to the non-HIV, non-immune cell, whereby protease inhibitors prevent apoptosis, and disease, in animal models of sepsis, hepatitis and stroke. Interestingly, when HIV protease inhibitors are used at supra-therapeutic concentrations, they exert pro-apoptotic effects. This has been demonstrated in a number of tumor models. Although it is unclear how HIV protease inhibitors can induce apoptosis at increased concentrations, future research will define the targets of the immunomodulation and reveal the full clinical potential of this intriguing class of drugs.

Validation of Simultaneous Quantitative Method of HIV Protease Inhibitors Atazanavir, Darunavir and Ritonavir in Human Plasma by UPLC-MS/MS

Mishra, Tulsidas; Shrivastav, Pranav S.
Fonte: Hindawi Publishing Corporation Publicador: Hindawi Publishing Corporation
Tipo: Artigo de Revista Científica
Publicado em 23/01/2014 Português
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Objectives. HIV protease inhibitors are used in the treatment of patients suffering from AIDS and they act at the final stage of viral replication by interfering with the HIV protease enzyme. The paper describes a selective, sensitive, and robust method for simultaneous determination of three protease inhibitors atazanavir, darunavir and ritonavir in human plasma by ultra performance liquid chromatography-tandem mass spectrometry. Materials and Methods. The sample pretreatment consisted of solid phase extraction of analytes and their deuterated analogs as internal standards from 50 μL human plasma. Chromatographic separation of analytes was performed on Waters Acquity UPLC C18 (50 × 2.1 mm, 1.7 μm) column under gradient conditions using 10 mM ammonium formate, pH 4.0, and acetonitrile as the mobile phase. Results. The method was established over a concentration range of 5.0–6000 ng/mL for atazanavir, 5.0–5000 ng/mL for darunavir and 1.0–500 ng/mL for ritonavir. Accuracy, precision, matrix effect, recovery, and stability of the analytes were evaluated as per US FDA guidelines. Conclusions. The efficiency of sample preparation, short analysis time, and high selectivity permit simultaneous estimation of these inhibitors. The validated method can be useful in determining plasma concentration of these protease inhibitors for therapeutic drug monitoring and in high throughput clinical studies.

HIV protease inhibitors: a review of molecular selectivity and toxicity

Lv, Zhengtong; Chu, Yuan; Wang, Yong
Fonte: Dove Medical Press Publicador: Dove Medical Press
Tipo: Artigo de Revista Científica
Publicado em 08/04/2015 Português
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Highly active antiretroviral therapy (HAART) is recognized as the most effective treatment method for AIDS, and protease inhibitors play a very important role in HAART. However, poor bioavailability and unbearable toxicity are their common disadvantages. Thus, the development of safer and potentially promising protease inhibitors is eagerly needed. In this review, we introduced the chemical characteristics and associated side effects of HIV protease inhibitors, as well as the possible off-target mechanisms causing the side effects. From the chemical structures of HIV protease inhibitors and their possible off-target molecules, we could obtain hints for optimizing the molecular selectivity of the inhibitors, to provide help in the design of new compounds with enhanced bioavailability and reduced side effects.

β-strand mimicry as the basis for a universal approach to protease inhibition.

Jones, Seth Adam
Fonte: Universidade de Adelaide Publicador: Universidade de Adelaide
Tipo: Tese de Doutorado
Publicado em //2011 Português
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This thesis describes the design, preparation, and testing of a range of protease inhibitors. Chapter One introduces the concept of peptidomimetics, and discusses how proteases almost universally bind their ligands in a β-strand conformation. The idea of constraining a compound into a biologically active conformation by the introduction of a ring or bridge is discussed. The technique of ring closing metathesis as a strategy for macrocyclisation is introduced. The chapter also discusses calpain and HIV proteases and their structures and implications in human disease. Chapter Two surveys the acyclic calpain inhibitors reported in the literature. A series of N-heterocyclic peptidic calpain inhibitors were docked in silico into an ovine m-calpain homology model using Glide, which revealed that compounds 2.60 – 2.67 all adopted a β-strand conformation upon binding. The modelling revealed low energy conformations of 2.60, 2.61 and 2.66 not in a β-strand geometry. The synthesis and testing of these inhibitors is described, with 2.63 displaying an IC₅₀ of 40 nM against m-calpain in an in vitro assay. Chapter Three describes the design and synthesis of the β-strand mimic macrocycle 3.8, which was prepared using ring closing metathesis. The chapter also describes the design of a number of calpain and HIV protease inhibitors that incorporate 3.8. Each inhibitor is designed to bind and inhibit a specific protease target. Chapter Four describes the synthesis and testing of a series of macrocyclic calpain and proteasome 20S inhibitors. The preparation of the aldehydes 3.9 and 3.10 by elaboration of the macrocycle 3.8 is described. As well...

Entwicklung polymerer Carbanionen-Äquivalente zur Anwendung in milden C-C-Verknüpfungen und deren Einsatz in der Synthese von Aspartylprotease-Inhibitoren des Norstatin-Typs; Development of polymer carbanion equivalents for application in smooth CC-couplings and their use in the synthesis of aspartic protease inhibitors of the norstatine type

Weik,Steffen
Fonte: Universidade de Tubinga Publicador: Universidade de Tubinga
Tipo: Dissertação
Português
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Der erste Teil der Dissertation beschreibt die Verwendung polymerer (Cyanmethylen)phosphorane zur Synthese von Norstatinen. Dazu wurde zunächst durch Alkylierung von Triphenylphosphin-Harz mit Bromacetonitril ein polymeres WITTIG-Salz hergestellt, das sehr leicht zum WITTIG-Ylid deprotoniert werden konnte. Entgegen der bisher üblichen Art und Weise wurde das Phosphoran-Harz nicht zur Carbonyl-Olefinierung im Sinne eines polymeren Reagenzes eingesetzt, sondern wie aus der Lösungssynthese bekannt durch Fmoc-Aminosäuren unter Aktivierung mit EDC/DMAP acyliert. Nach erfolgreicher Peptidsynthese am Phosphoran-Linker konnten alpha-Ketoester, -säuren und -amide durch ozonolytische Phosphoran-Spaltung und Abfangen intermediärer, hochreaktiver alpha,beta-Diketonitrile mit Alkoholen, Wasser und Aminen erhalten werden. Durch anschließende Reduktion wurden entsprechend alpha-Hydroxyester und -amide zugänglich. Nachteile der zunächst in Analogie zur Lösungssynthese präsentierten Reaktionssequenz wurden durch sukzessive Optimierung beseitigt. Dabei konnte eine zunächst bei der ozonolytischen Abspaltung beobachtete Decarbonylierung durch Umstellung auf DMDO verhindert werden. Weiterhin wurden als Zwischenprodukte alpha-Hydroxytrimethylsilylethylester synthetisiert...

Oral candidiasis in HIV+ patients under treatment with protease inhibitors

WITZEL, Andréa Lusvarghi; SILVEIRA, Fernando Ricardo Xavier da; PIRES, Maria de Fátima Costa; LOTUFO, Mônica Andrade
Fonte: Sociedade Brasileira de Pesquisa Odontológica Publicador: Sociedade Brasileira de Pesquisa Odontológica
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
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The purpose of this work was to evaluate the influence of Protease Inhibitors (PI) on the occurrence of oral candidiasis in 111 HIV+ patients under PI therapy (Group A). The controls consisted of 56 patients that were not using PI drugs (Group B) and 26 patients that were not using any drugs for HIV therapy (Group C). The patient's cd4 cell counts were taken in account for the correlations. One hundred and ninety three patients were evaluated. The PI did not affect the prevalence of oral candidiasis (p = 0.158) or the frequency of C. albicans isolates (p = 0.133). Patients with lower cd4 cell counts showed a higher frequency of C. albicans isolates (p = 0.046) and a greater occurrence of oral candidiasis (p = 0.036).; State of São Paulo Research Foundation (FAPESP)

In vitro inhibition of human immunodeficiency virus (HIV) type 1 replication by C2 symmetry-based HIV protease inhibitors as single agents or in combinations.

Kageyama, S; Weinstein, J N; Shirasaka, T; Kempf, D J; Norbeck, D W; Plattner, J J; Erickson, J; Mitsuya, H
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /05/1992 Português
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C2 symmetry-based human immunodeficiency virus (HIV) protease inhibitors were examined in vitro as single agents or in combination with 3'-azido-2',3'-dideoxythymidine (AZT) or 2',3'-dideoxyinosine for activity against HIV type 1 (HIV-1). Ten C2 symmetry-based or pseudo-C2 symmetry-based HIV protease inhibitors were active against a laboratory strain (HIV-1IIIB) in the HIV-1 cytopathic effect inhibition assay. Three inhibitors, A75925, A76928, and A77003, selected to represent a range of aqueous solubility and antiviral activity, were active against four different HIV-1 strains tested. These three inhibitors exhibited a significant inhibition of the cytopathic effect of HIV-1 against the CD4+ ATH8 cell line, with 90% inhibitory concentrations ranging from 0.1 to 4 microM. Cellular toxicity was negligible at up to 20 microM. Furthermore, they completely inhibited the replication of monocytotropic strain HIV-1Ba-L in purified monocytes and macrophages at 0.75 to 2 microM. Potent inhibitory activity against a primary HIV-1 isolate and an AZT-resistant HIV-1 variant was also observed for all three inhibitors in phytohemagglutinin-activated peripheral blood mononuclear cells. When these three HIV protease inhibitors and AZT or 2',3'-dideoxyinosine were used in combinations against a primary HIV isolate in phytohemagglutinin-activated peripheral blood mononuclear cells and the results were analyzed with the COMBO program package...

In vitro anti-human immunodeficiency virus (HIV) activities of transition state mimetic HIV protease inhibitors containing allophenylnorstatine.

Kageyama, S; Mimoto, T; Murakawa, Y; Nomizu, M; Ford, H; Shirasaka, T; Gulnik, S; Erickson, J; Takada, K; Hayashi, H
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /04/1993 Português
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Transition state mimetic tripeptide human immunodeficiency virus (HIV) protease inhibitors containing allophenylnorstatine [(2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid] were synthesized and tested for activity against HIV in vitro. Two compounds, KNI-227 and KNI-272, which were highly potent against HIV protease with little inhibition of other aspartic proteases, showed the most potent activity against the infectivity and cytopathic effect of a wide spectrum of HIV strains. As tested in target CD4+ ATH8 cells, the 50% inhibitory concentrations of KNI-227 against HIV type 1 LAI (HIV-1LAI), HIV-1RF, HIV-1MN, and HIV-2ROD were 0.1, 0.02, 0.03, and 0.1 microM, respectively, while those of KNI-272 were 0.1, 0.02, 0.04, and 0.1 microM, respectively. Both agents completely blocked the replication of 3'-azido-2',3'-dideoxythymidine-sensitive and -insensitive clinical HIV-1 isolates at 0.08 microM as tested in target phytohemagglutinin-activated peripheral blood mononuclear cells. The ratios of 50% cytotoxic concentrations to 50% inhibitory concentrations for KNI-227 and KNI-272 were approximately 2,500 and > 4,000, respectively, as assessed in peripheral blood mononuclear cells. Both compounds blocked the posttranslational cleavage of the p55 precursor protein to generate the mature p24 Gag protein in stably HIV-1-infected cells. The n-octanol-water partition coefficients of KNI-227 and KNI-272 were high...

Oral candidiasis in HIV+ patients under treatment with protease inhibitors

Witzel,Andréa Lusvarghi; Silveira,Fernando Ricardo Xavier da; Pires,Maria de Fátima Costa; Lotufo,Mônica Andrade
Fonte: Sociedade Brasileira de Pesquisa Odontológica - SBPqO Publicador: Sociedade Brasileira de Pesquisa Odontológica - SBPqO
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/12/2008 Português
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The purpose of this work was to evaluate the influence of Protease Inhibitors (PI) on the occurrence of oral candidiasis in 111 HIV+ patients under PI therapy (Group A). The controls consisted of 56 patients that were not using PI drugs (Group B) and 26 patients that were not using any drugs for HIV therapy (Group C). The patient's cd4 cell counts were taken in account for the correlations. One hundred and ninety three patients were evaluated. The PI did not affect the prevalence of oral candidiasis (p = 0.158) or the frequency of C. albicans isolates (p = 0.133). Patients with lower cd4 cell counts showed a higher frequency of C. albicans isolates (p = 0.046) and a greater occurrence of oral candidiasis (p = 0.036).