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[PMID]:28453836
[Au] Autor:Margot NA; Wong P; Kulkarni R; White K; Porter D; Abram ME; Callebaut C; Miller MD
[Ad] Endereço:Gilead Sciences, Foster City, California, USA.
[Ti] Título:Commonly Transmitted HIV-1 Drug Resistance Mutations in Reverse-Transcriptase and Protease in Antiretroviral Treatment-Naive Patients and Response to Regimens Containing Tenofovir Disoproxil Fumarate or Tenofovir Alafenamide.
[So] Source:J Infect Dis;215(6):920-927, 2017 03 15.
[Is] ISSN:1537-6613
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Background: The presence of transmitted drug resistance mutations (TDRMs) in antiretroviral treatment (ART)-naive patients can adversely affect the outcome of ART. Methods: Resistance testing was conducted in 6704 ART-naive subjects predominantly from the United States and Europe in 9 clinical studies conducted by Gilead Sciences from 2000 to 2013. Results: The presence of TDRMs increased during this period (from 5.2% to 11.4%), primarily driven by an increase in nonnucleoside reverse-transcriptase (RT) inhibitor (NNRTI) resistance mutations (from 0.3% to 7.1%), particularly K103N/S (increase from 0.3% to 5.3%). Nucleoside/nucleotide RT inhibitor mutations were found in 3.1% of patients. Only 1 patient had K65R (0.01%) and 7 had M184V/I (0.1%), despite high use of tenofovir disoproxil fumarate (TDF), emtricitabine, and lamivudine and potential transmission of resistance to these drugs. At least 1 thymidine-analogue mutations was present in 2.7% of patients with 0.07% harboring T215Y/F and 2.7% harboring T215 revertant mutations (T215rev). Patients with the combination of M41L + L210W + T215rev showed full human immunodeficiency virus RNA suppression while receiving a TDF- or tenofovir alafenamide-containing regimen. Conclusions: There was an overall increase of TDRMs among patients enrolling in clinical trials from 2000 through 2013, driven primarily by an increase in NNRTI resistance. However, the presence of common TDRMs, including thymidine-analogue mutations/T215rev, showed no impact on response to TDF- or tenofovir alafenamide-containing regimens.
[Mh] Termos MeSH primário: Adenina/análogos & derivados
Fármacos Anti-HIV/uso terapêutico
Farmacorresistência Viral/genética
Infecções por HIV/tratamento farmacológico
HIV-1/genética
Tenofovir/uso terapêutico
[Mh] Termos MeSH secundário: Adenina/uso terapêutico
Adulto
Emtricitabina/uso terapêutico
Europa (Continente)
Feminino
HIV-1/efeitos dos fármacos
Seres Humanos
Lamivudina/uso terapêutico
Masculino
Mutação de Sentido Incorreto
Inibidores da Transcriptase Reversa/uso terapêutico
Timidina/análogos & derivados
Estados Unidos
[Pt] Tipo de publicação:JOURNAL ARTICLE; MULTICENTER STUDY
[Nm] Nome de substância:
0 (Anti-HIV Agents); 0 (GS-7340); 0 (Reverse Transcriptase Inhibitors); 2T8Q726O95 (Lamivudine); 99YXE507IL (Tenofovir); G70B4ETF4S (Emtricitabine); JAC85A2161 (Adenine); VC2W18DGKR (Thymidine)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.1093/infdis/jix015


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[PMID]:29480838
[Au] Autor:Cheng Y; Nickman NA; Jamjian C; Stevens V; Zhang Y; Sauer B; LaFleur J
[Ad] Endereço:Biomedical Informatics Center, George Washington University, Washington, DC.
[Ti] Título:Predicting poor adherence to antiretroviral therapy among treatment-naïve veterans infected with human immunodeficiency virus.
[So] Source:Medicine (Baltimore);97(2):e9495, 2018 Jan.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Previous studies suggested that human immunodeficiency virus (HIV) infected patients at risk of poor adherence were not distinguishable only based on the baseline characteristics. This study is to identify patient characteristics that would be consistently associated with poor adherence across regimens and to understand the associations between initial and long-term adherence. HIV treatment-naïve patients initiated on protease inhibitors, nonnucleoside reverse transcriptase inhibitors, or integrase strand transfer inhibitors were identified from the Veteran Health Administration system. Initial adherence measured as initial coverage ratio (ICR) and long-term adherence measured as thereafter 1-year proportion days covered (PDC) of base agent and complete regimen were estimated for each patient. The patients most likely to exhibit poor adherence were African-American, with lower socioeconomic status, and healthier. The initial coverage ratio of base agent and complete regimen were highly correlated, but the correlations between ICR and thereafter 1-year PDC were low. However, including initial adherence as a predictor in predictive model would substantially increase predictive accuracy of future adherence.
[Mh] Termos MeSH primário: Infecções por HIV/tratamento farmacológico
Inibidores de Integrase de HIV/uso terapêutico
Adesão à Medicação
Inibidores de Proteases/uso terapêutico
Inibidores da Transcriptase Reversa/uso terapêutico
[Mh] Termos MeSH secundário: Análise de Variância
Feminino
Infecções por HIV/diagnóstico
Infecções por HIV/epidemiologia
Integrase de HIV
Nível de Saúde
Seres Humanos
Modelos Logísticos
Masculino
Meia-Idade
Prognóstico
Estudos Retrospectivos
Fatores de Risco
Fatores Socioeconômicos
Estados Unidos
United States Department of Veterans Affairs
Veteranos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (HIV Integrase Inhibitors); 0 (Protease Inhibitors); 0 (Reverse Transcriptase Inhibitors); EC 2.7.7.- (HIV Integrase)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180302
[Lr] Data última revisão:
180302
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180227
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000009495


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[PMID]:29353724
[Au] Autor:Jin K; Yin H; De Clercq E; Pannecouque C; Meng G; Chen F
[Ad] Endereço:Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, People's Republic of China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, People's Republic of China.
[Ti] Título:Discovery of biphenyl-substituted diarylpyrimidines as non-nucleoside reverse transcriptase inhibitors with high potency against wild-type and mutant HIV-1.
[So] Source:Eur J Med Chem;145:726-734, 2018 Feb 10.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:A novel series of diarylpyrimidine (DAPY) derivatives bearing the biphenyl motif with multiple substituted groups was synthesized as human immunodeficiency virus (HIV)-1 non-nucleoside reverse transcriptase inhibitors. All of the target compounds were evaluated for their in vitro activity against HIV in MT-4 cells. Most of the compounds exhibited excellent activity with low nanomolar EC values against wild-type, single and double mutant HIV-1 strains. Compound 4b displayed an EC value of 1 nM against HIV-1 IIIB, 1.3 nM against L100I, 0.84 nM against K103 N, 1.5 nM against Y181C, 11 nM against Y188L, 2 nM against E138K, 10 nM against K103 N + Y181C, and almost 110 nM against F227L + V106. The improvement in the selectivity and potency of the target molecules against the wild-type and mutant HIV-1 strains validated our hypothesis. The biphenyl ring in the DAPY derivatives could strengthen the π-π stacking effect between the target molecule and the non-nucleoside inhibitor-binding pocket in the reverse transcriptase by extending the conjugating systems. This research represented a significant step toward the discovery of novel therapeutic DAPYs for treating acquired immunodeficiency syndrome in patients infected with HIV-1.
[Mh] Termos MeSH primário: Fármacos Anti-HIV/farmacologia
Compostos de Bifenilo/farmacologia
Transcriptase Reversa do HIV/antagonistas & inibidores
HIV-1/efeitos dos fármacos
Pirimidinas/farmacologia
Inibidores da Transcriptase Reversa/farmacologia
[Mh] Termos MeSH secundário: Fármacos Anti-HIV/síntese química
Fármacos Anti-HIV/química
Compostos de Bifenilo/química
Sobrevivência Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Descoberta de Drogas
Transcriptase Reversa do HIV/metabolismo
HIV-1/genética
Seres Humanos
Testes de Sensibilidade Microbiana
Simulação de Acoplamento Molecular
Estrutura Molecular
Mutação
Pirimidinas/síntese química
Pirimidinas/química
Inibidores da Transcriptase Reversa/síntese química
Inibidores da Transcriptase Reversa/química
Relação Estrutura-Atividade
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-HIV Agents); 0 (Biphenyl Compounds); 0 (Pyrimidines); 0 (Reverse Transcriptase Inhibitors); 2L9GJK6MGN (diphenyl); EC 2.7.7.49 (HIV Reverse Transcriptase)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180302
[Lr] Data última revisão:
180302
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180123
[St] Status:MEDLINE


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[PMID]:29335203
[Au] Autor:Li Y; Pan G; Chen Y; Yang Q; Hao T; Zhao L; Zhao L; Cong Y; Diao A; Yu P
[Ad] Endereço:School of Biotechnology, Tianjin University of Science and Technology, Key Lab of Industrial Fermentation Microbiology of the Ministry of Education, Tianjin, 300457, China.
[Ti] Título:Inhibitor of the human telomerase reverse trancriptase (hTERT) gene promoter induces cell apoptosis via a mitochondrial-dependent pathway.
[So] Source:Eur J Med Chem;145:370-378, 2018 Feb 10.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Telomerase is aberrantly expressed in many cancers and plays an important role in the development of cellular immortality and oncogenesis, which makes it a potential cancer therapeutic target for drug discovery. Here, we constructed a firefly luciferase reporter driven by the human telomerase reverse trancriptase (hTERT) gene promoter to screen for inhibitory compounds. Compound 5c was discovered and shown to significantly inhibit the promoter activity of hTERT gene. Furthermore, five analogs of compound 5c were synthesized, and compound 8b was shown to be a more potent inhibitor of hTERT gene promoter activity and subsequent expression of hTERT mRNA and protein. The viability of HeLa cells was inhibited by a knockdown of hTERT gene expression, and the same effect was also observed by treating with compound 8b. Moreover, our results indicated that compound 8b induced apoptosis of HeLa cells, and activated caspase-9 and caspase-3 enzymes. Taken together, these results suggested that compound 8b down-regulates the expression of hTERT and induces mitochondrial-dependent apoptosis.
[Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos
Mitocôndrias/efeitos dos fármacos
Regiões Promotoras Genéticas/efeitos dos fármacos
Inibidores da Transcriptase Reversa/farmacologia
Telomerase/antagonistas & inibidores
[Mh] Termos MeSH secundário: Sobrevivência Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Células HeLa
Seres Humanos
Mitocôndrias/metabolismo
Estrutura Molecular
Regiões Promotoras Genéticas/genética
Inibidores da Transcriptase Reversa/síntese química
Inibidores da Transcriptase Reversa/química
Relação Estrutura-Atividade
Telomerase/genética
Telomerase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Reverse Transcriptase Inhibitors); EC 2.7.7.49 (TERT protein, human); EC 2.7.7.49 (Telomerase)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180302
[Lr] Data última revisão:
180302
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180117
[St] Status:MEDLINE


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[PMID]:29244809
[Au] Autor:Coetzee J; Hunt G; Jaffer M; Otwombe K; Scott L; Bongwe A; Ledwaba J; Molema S; Jewkes R; Gray GE
[Ad] Endereço:Perinatal HIV Research Unit (PHRU), Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
[Ti] Título:HIV-1 viraemia and drug resistance amongst female sex workers in Soweto, South Africa: A cross sectional study.
[So] Source:PLoS One;12(12):e0188606, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: HIV drug resistance (HIVDR) poses a threat to future antiretroviral therapy success. Monitoring HIVDR patterns is of particular importance in populations such as sex workers (SWs), where documented HIV prevalence is between 34-89%, and in countries with limited therapeutic options. Currently in South Africa, there is a dearth in evidence and no ongoing surveillance of HIVDR amongst sex work populations. This study aims to describe the prevalence of HIVDR amongst a sample of female sex workers (FSWs) from Soweto, South Africa. METHODOLOGY: A cross-sectional, respondent driven sampling (RDS) recruitment methodology was used to enrol FSWs based in Soweto. Participants were tested for HIV and undertook a survey that included HIV knowledge and treatment status. Whole blood specimens were collected from HIV positive FSWs to measure for CD4 counts, viral load (VL) and perform HIVDR genotyping. Frequencies were determined for categorical variables and medians and interquartile ranges (IQR) for the continuous. RESULTS: Of the 508 enrolled participants, 55% (n = 280) were HIV positive and of median age 32 (IQR: 20-51) years. Among the HIV positive, 51.8% (132/269) were defined as virologically suppressed (VL < 400 copies/ml). Of the 119 individuals with unsuppressed viral loads who were successfully genotyped for resistance testing 37.8% (45/119) had detectable drug resistance. In this group, HIVDR mutations were found amongst 73.7% (14/19) of individuals on treatment, 27.4% (26/95) of individuals who were treatment naïve, and 100% (5/5) of defaulters. One phylogenetic cluster was found amongst treatment naïve FSWs. The K103N mutation was detected most commonly in 68.9% (31/45) individuals with HIVDR mutations, with 20/26 (76.9%) of treatment naïve FSW with detectable resistance having this mutation. The M184V mutation was found in both FSWs on treatment (12/14, 85.7%) and those defaulting (1/5, 20.0%). DISCUSSION: More than one third (45/119) of the genotyped sample had HIVDR, with resistance to the NNRTI class being the most common. Almost half of HIV positive FSWs had unsuppressed viral loads, increasing the likelihood for onward transmission of HIV. Disturbingly, more than 1:4 treatment naïve women with unsuppressed viral loads had HIVDR suggesting that possible sexual transmission of drug resistance is occurring in this high-risk population. Given the high burden of HIVDR in a population with a high background prevalence of HIV, it is imperative that routine monitoring of HIVDR be implemented. Understanding transmission dynamics of HIVDR in FSW and its impact on treatment success should be urgently elucidated.
[Mh] Termos MeSH primário: Farmacorresistência Viral/genética
Infecções por HIV/epidemiologia
Infecções por HIV/transmissão
HIV-1/genética
Profissionais do Sexo
[Mh] Termos MeSH secundário: Adulto
Fármacos Anti-HIV/uso terapêutico
Contagem de Linfócito CD4
Estudos Transversais
Feminino
Genótipo
Infecções por HIV/tratamento farmacológico
Infecções por HIV/virologia
HIV-1/classificação
HIV-1/isolamento & purificação
Seres Humanos
Meia-Idade
Filogenia
Prevalência
Inibidores da Transcriptase Reversa/uso terapêutico
África do Sul/epidemiologia
Carga Viral
Viremia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-HIV Agents); 0 (Reverse Transcriptase Inhibitors)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180108
[Lr] Data última revisão:
180108
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171216
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0188606


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[PMID]:29216208
[Au] Autor:Cuzin L; Pugliese P; Allavena C; Rey D; Chirouze C; Bani-Sadr F; Cabié A; Huleux T; Poizot-Martin I; Cotte L; Isnard Bagnis C; Flandre P; Dat'AIDS study group
[Ad] Endereço:INSERM, UMR 1027, Toulouse, France; Université de Toulouse III, Toulouse, France; CHU Toulouse, COREVIH Toulouse, France.
[Ti] Título:Antiretroviral therapy as a risk factor for chronic kidney disease: Results from traditional regression modeling and causal approach in a large observational study.
[So] Source:PLoS One;12(12):e0187517, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: We investigated whether patients receiving selected antiretroviral combinations had a higher risk of chronic kidney disease (CKD) using traditional regression modeling and a causal approach in a large prospective cohort. PATIENTS AND METHODS: For the purpose of this study, we selected 6301 patients who (i) started their first antiretroviral regimen after 1st January 2004, (ii) had at least one serum creatinine measurement within 6 months before ART initiation (study entry), and (iii) had at least two measurements after study entry. Baseline eGFR was defined from the last serum creatinine measurement before study entry. All eGFR values were calculated using the Modification of Diet and Renal Disease (MDRD) equation. Both traditional Cox proportional hazards model and Cox marginal structural models were applied. Distinct coding for antiretroviral therapy exposure were investigated as well as double robust estimators. RESULTS: Overall we showed that patients receiving tenofovir (TDF) with a ritonavir boosted protease inhibitor (rbPI) exhibited a higher risk of CKD compared with patients who received TDF with a non-nucleosidic reverse transcriptase inhibitor (NNRTI). Such an increased risk was observed considering both initial and current regimens. Our analysis revealed a clinician-driven switch away from TDF among persons experiencing a decline in renal function while receiving this drug. CONCLUSION: Our results show that combination of TDF and boosted protease inhibitor is associated with a higher CKD risk than TDF and a NNRTI.
[Mh] Termos MeSH primário: Fármacos Anti-HIV/efeitos adversos
Infecções por HIV/tratamento farmacológico
Falência Renal Crônica/complicações
Inibidores da Transcriptase Reversa/efeitos adversos
[Mh] Termos MeSH secundário: Adulto
Fármacos Anti-HIV/uso terapêutico
Feminino
França
Infecções por HIV/complicações
Seres Humanos
Falência Renal Crônica/induzido quimicamente
Masculino
Meia-Idade
Modelos Teóricos
Análise de Regressão
Inibidores da Transcriptase Reversa/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE; MULTICENTER STUDY; OBSERVATIONAL STUDY
[Nm] Nome de substância:
0 (Anti-HIV Agents); 0 (Reverse Transcriptase Inhibitors)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180105
[Lr] Data última revisão:
180105
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171208
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0187517


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[PMID]:29197735
[Au] Autor:Venkatraj M; Salado IG; Heeres J; Joossens J; Lewi PJ; Caljon G; Maes L; Van der Veken P; Augustyns K
[Ad] Endereço:Laboratory of Medicinal Chemistry, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium.
[Ti] Título:Novel triazine dimers with potent antitrypanosomal activity.
[So] Source:Eur J Med Chem;143:306-319, 2018 Jan 01.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Human African trypanosomiasis (HAT), also known as sleeping sickness is a parasitic disease transmitted by the bite of the 'Glossina' insect, commonly known as the tsetse fly. This disease affects mostly poor populations living in remote rural areas of Africa. Untreated, it is usually fatal. Currently, safe and effective treatments against this disease are lacking. Phenotypic screening of triazine non-nucleoside HIV-1 reverse transcriptase inhibitors (monomers) resulted in potent and selective antitrypanosomal compounds. This serendipitous discovery and the presence of dimers in many compounds active against these neglected tropical diseases prompted us to investigate antitrypanosomal activity of triazine dimers. Optimization of the triazine dimers resulted in 3,3'-(((ethane-1,2-diylbis(azanediyl))bis(4-(mesityloxy)-1,3,5-triazine-6,2-diyl))bis(azanediyl))dibenzonitrile (compound 38), a compound with very potent in vitro and moderate in vivo antitrypanosomal activity.
[Mh] Termos MeSH primário: Antiprotozoários/farmacologia
Inibidores da Transcriptase Reversa/farmacologia
Triazinas/farmacologia
Trypanosoma brucei brucei/efeitos dos fármacos
Trypanosoma brucei rhodesiense/efeitos dos fármacos
Trypanosoma cruzi/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Antiprotozoários/síntese química
Antiprotozoários/química
Proliferação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Dimerização
Relação Dose-Resposta a Droga
Descoberta de Drogas
Fibroblastos/efeitos dos fármacos
Seres Humanos
Leishmania infantum/efeitos dos fármacos
Masculino
Camundongos
Estrutura Molecular
Inibidores da Transcriptase Reversa/síntese química
Inibidores da Transcriptase Reversa/química
Relação Estrutura-Atividade
Triazinas/síntese química
Triazinas/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antiprotozoal Agents); 0 (Reverse Transcriptase Inhibitors); 0 (Triazines)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180101
[Lr] Data última revisão:
180101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171204
[St] Status:MEDLINE


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[PMID]:29190729
[Au] Autor:Tan Z; Jia X; Ma F; Feng Y; Lu H; Jin JO; Wu D; Yin L; Liu L; Zhang L
[Ad] Endereço:Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
[Ti] Título:Increased MMAB level in mitochondria as a novel biomarker of hepatotoxicity induced by Efavirenz.
[So] Source:PLoS One;12(11):e0188366, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Efavirenz (EFV), a non-nucleoside reverse transcriptase inhibitor (NNRTI), has been widely used in the therapy of human immunodeficiency virus (HIV) infection. Some of its toxic effects on hepatic cells have been reported to display features of mitochondrial dysfunction through bioenergetic stress and autophagy, etc. However, alteration of protein levels, especially mitochondrial protein levels, in hepatic cells during treatment of EFV has not been fully investigated. METHODS: We built a cell model of EFV-induced liver toxicity through treating Huh-7 cells with different concentrations of EFV for different time followed by the analysis of cell viability using cell counting kit -8 (CCK8) and reactive oxygen species (ROS) using 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) and MitoSox dye. Proteomic profiles in the mitochondria of Huh-7 cells stimulated by EFV were analyzed. Four differentially expressed proteins were quantified by real time RT-PCR. We also detected the expression of mitochondrial precursor Cob(I)yrinic acid a,c-diamide adenosyltransferase (MMAB) by immunohistochemistry analysis in clinical samples. The expression levels of MMAB and ROS were detected in EFV-treated Huh-7 cells with and without shRNA used to knock down MMAB, and in primary hepatocytes (PHC). The effects of other anti-HIV drugs (nevirapine (NVP) and tenofovirdisoproxil (TDF)), and hydrogen peroxide (H2O2) were also tested. Amino acid analysis and fatty aldehyde dehydrogenase (ALDH3A2) expression after MMAB expression knock-down with shRNA was used to investigate the metabolic effect of MMAB in Huh-7 cells. RESULTS: EFV treatment inhibited cell viability and increased ROS production with time- and concentration-dependence. Proteomic study was performed at 2 hours after EFV treatment. After treated Huh-7 cells with EFV (2.5mg/L or 10 mg/L) for 2 h, fifteen differentially expressed protein spots from purified mitochondrion that included four mitochondria proteins were detected in EFV-treated Huh-7 cells compared to controls. Consistent with protein expression levels, mRNA expression levels of mitochondrial protein MMAB were also increased by EFV treatment. In addition, the liver of EFV-treated HIV infected patients showed substantially higher levels of MMAB expression compared to the livers of untreated or protease inhibitor (PI)-treated HIV-infected patients. Furthermore, ROS were found to be decreased in Huh-7 cells treated with shMMAB compared with empty plasmid treated with EFV at the concentration of 2.5 or 10 mg/L. MMAB was increased in EFV-treated Huh-7 cells and primary hepatocytes. However, no change in MMAB expression was detected after treatment of Huh-7 cells and primary hepatocytes with anti-HIV drugs nevirapine (NVP) and tenofovirdisoproxil (TDF), or hydrogen peroxide (H2O2), although ROS was increased in these cells. Finally, knockdown of MMAB by shRNA induced increases in the ß-Alanine (ß-Ala) production levels and decrease in ALDH3A2 expression. CONCLUSIONS: A mitochondrial proteomic study was performed to study the proteins related to EFV-inducted liver toxicity. MMAB might be a target and potential biomarker of hepatotoxicity in EFV-induced liver toxicity.
[Mh] Termos MeSH primário: Alquil e Aril Transferases/metabolismo
Benzoxazinas/toxicidade
Mitocôndrias/enzimologia
Inibidores da Transcriptase Reversa/farmacologia
[Mh] Termos MeSH secundário: Aldeído Desidrogenase/genética
Alquil e Aril Transferases/genética
Western Blotting
Linhagem Celular
Perfilação da Expressão Gênica
Técnicas de Silenciamento de Genes
Seres Humanos
Fígado/efeitos dos fármacos
Fígado/metabolismo
Proteínas Mitocondriais/genética
Estresse Oxidativo
Reação em Cadeia da Polimerase Via Transcriptase Reversa
Transcrição Genética
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Benzoxazines); 0 (Mitochondrial Proteins); 0 (Reverse Transcriptase Inhibitors); EC 1.2.1.3 (Aldehyde Dehydrogenase); EC 2.5.- (Alkyl and Aryl Transferases); EC 2.5.1.17 (cob(I)alamin adenosyltransferase); JE6H2O27P8 (efavirenz)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171226
[Lr] Data última revisão:
171226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171201
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0188366


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[PMID]:28465101
[Au] Autor:Wei L; Wang HL; Huang L; Chen CH; Morris-Natschke SL; Lee KH; Xie L
[Ad] Endereço:Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing 100850, China.
[Ti] Título:Drug-like property-driven optimization of 4-substituted 1,5-diarylanilines as potent HIV-1 non-nucleoside reverse transcriptase inhibitors against rilpivirine-resistant mutant virus.
[So] Source:Bioorg Med Chem Lett;27(12):2788-2792, 2017 06 15.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:On the basis of our prior structure-activity relationship (SAR) results, our current lead optimization of 1,5-diarylanilines (DAANs) focused on the 4-substituent (R ) on the central phenyl ring as a modifiable position related simultaneously to improved drug resistance profiles and drug-like properties. Newly synthesized p-cyanovinyl-DAANs (8a-8g) with different R side chains plus prior active p-cyanoethyl-DAANs (4a-4c) were evaluated not only for anti-HIV potency against both wild-type HIV virus and rilpivirine-resistant (E138K, E138K+M184I) viral replication, but also for multiple drug-like properties, including aqueous solubility, lipophilicity, and metabolic stability in human liver microsomes and human plasma. This study revealed that both ester and amide R substituents led to low nanomolar anti-HIV potency against wild-type and rilpivirine-resistant viral strains (E138K-resistance fold changes<3). The N-substituted amide-R side chains were superior to ester-R likely due to improved aqueous solubility, lipophilicity, and higher metabolic stability in vitro. Thus, three amide-DAANs 8e, 4a, and 4b were identified with high potency against wild-type and rilpivirine-resistant viral strains and multiple desirable drug-like properties.
[Mh] Termos MeSH primário: Compostos de Anilina/farmacologia
Fármacos Anti-HIV/farmacologia
Transcriptase Reversa do HIV/antagonistas & inibidores
HIV-1/efeitos dos fármacos
Inibidores da Transcriptase Reversa/farmacologia
Rilpivirina/farmacologia
[Mh] Termos MeSH secundário: Compostos de Anilina/síntese química
Compostos de Anilina/química
Fármacos Anti-HIV/química
Relação Dose-Resposta a Droga
Farmacorresistência Viral/efeitos dos fármacos
Transcriptase Reversa do HIV/metabolismo
HIV-1/genética
Testes de Sensibilidade Microbiana
Estrutura Molecular
Mutação
Inibidores da Transcriptase Reversa/síntese química
Inibidores da Transcriptase Reversa/química
Rilpivirina/química
Relação Estrutura-Atividade
Replicação Viral/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Aniline Compounds); 0 (Anti-HIV Agents); 0 (Reverse Transcriptase Inhibitors); EC 2.7.7.49 (HIV Reverse Transcriptase); FI96A8X663 (Rilpivirine)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171124
[Lr] Data última revisão:
171124
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE


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[PMID]:28871337
[Au] Autor:Du Jeong I; Jung SW; Park BR; Lee BU; Park JH; Kim BG; Bang SJ; Shin JW; Park NH
[Ad] Endereço:Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, 887 Bangeojinsunhwando-ro, Dong-gu, Ulsan, 44033, Republic of Korea.
[Ti] Título:Clinical Course of Partial Virologic Response with Prolonged Tenofovir Therapy in Nuclos(t)ides-Naïve Patients with Chronic Hepatitis B.
[So] Source:Dig Dis Sci;62(10):2908-2914, 2017 Oct.
[Is] ISSN:1573-2568
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIMS: The clinical course of chronic hepatitis B (CHB) patients with partial virologic response (PVR) during tenofovir disoproxil fumarate (TDF) therapy remains unclear. METHODS: We retrospectively investigated the long-term clinical outcomes of TDF treatment in nucleos(t)ides-naïve CHB patients, particularly in those with PVR. RESULTS: A total of 391 patients treated with TDF therapy for more than 12 months were included. Virologic response (VR) was achieved in 341 patients (87.2%). PVR was evident in 127 (45.3%) of the 391 patients. Multivariate logistic regression analysis using selected baseline factors identified absolute HBV DNA levels at baseline (OR 0.496; 95% CI 1.369-1.969) and HBeAg positivity (OR 0.622; 95% CI 1.096-3.167) as factors significantly associated with PVR. During continuous prolonged TDF therapy, 127 (71.8%) of 177 patients with PVR achieved VR. The cumulative rates of VR in patients with PVR at 12, 24, and 36 months were 42.4, 79.7, and 90.2%, respectively. Serum HBV DNA level at week 24 was significantly associated with VR in patients with PVR. CONCLUSIONS: The vast majority of CHB patients with PVR achieved VR through prolonged TDF therapy, although the time to achieve VR was delayed in those with PVR. This suggests that adjustment of TDF therapy in patients with PVR is unnecessary.
[Mh] Termos MeSH primário: Vírus da Hepatite B/efeitos dos fármacos
Hepatite B Crônica/tratamento farmacológico
Inibidores da Transcriptase Reversa/administração & dosagem
Tenofovir/administração & dosagem
[Mh] Termos MeSH secundário: Adulto
Biomarcadores/sangue
DNA Viral/sangue
DNA Viral/genética
Esquema de Medicação
Feminino
Vírus da Hepatite B/genética
Hepatite B Crônica/sangue
Hepatite B Crônica/diagnóstico
Hepatite B Crônica/virologia
Seres Humanos
Modelos Logísticos
Masculino
Meia-Idade
Análise Multivariada
Razão de Chances
Estudos Retrospectivos
Inibidores da Transcriptase Reversa/efeitos adversos
Tenofovir/efeitos adversos
Fatores de Tempo
Resultado do Tratamento
Carga Viral
[Pt] Tipo de publicação:JOURNAL ARTICLE; OBSERVATIONAL STUDY
[Nm] Nome de substância:
0 (Biomarkers); 0 (DNA, Viral); 0 (Reverse Transcriptase Inhibitors); 99YXE507IL (Tenofovir)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170906
[St] Status:MEDLINE
[do] DOI:10.1007/s10620-017-4737-1



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