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[PMID]: 29286056 [Au] Autor: Zaid Iskandar M; Lang CC [Ad] Endereço: Ninewells Hospital and Medical School, Dundee, Scotland, UK. [Ti] Título: Sacubitril and valsartan fixed combination to reduce heart failure events in post-acute myocardial infarction patients. [So] Source: Drugs Today (Barc);53(10):545-551, 2017 Oct. [Is] ISSN: 1699-3993 [Cp] País de publicação: Spain [La] Idioma: eng [Ab] Resumo: Heart failure is a term used to define a constellation of symptoms and signs that are commonly attributed to the inability of the heart to produce a cardiac output that meets the demands of the body. It remains a deadly disease, affecting between 1-2% of the population, and is more common in the elderly, with around 6-10% of patients over 65 suffering from the condition. Sacubitril/valsartan (LCZ-696) is a combined neprilysin inhibitor and angiotensin AT1 receptor blocker approved in recent years for the treatment of chronic heart failure with reduced ejection fraction. In an area where there have been limited pharmacological advances in the last 10 years, this drug was a game changer and a much welcomed addition to contemporary heart failure therapy. It is currently being studied in patients with heart failure with preserved ejection fraction and for the reduction of heart failure events post-acute myocardial infarction. Results from the ongoing PARADISE-MI study are awaited by the global cardiology community with great interest. [Mh] Termos MeSH primário: Aminobutiratos/administração & dosagem Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem Insuficiência Cardíaca/tratamento farmacológico Infarto do Miocárdio/complicações Neprilisina/antagonistas & inibidores Tetrazóis/administração & dosagem Valsartana/administração & dosagem [Mh] Termos MeSH secundário: Aminobutiratos/farmacologia Ensaios Clínicos como Assunto Seres Humanos Tetrazóis/farmacologia Valsartana/farmacologia [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (Aminobutyrates); 0 (Angiotensin II Type 1 Receptor Blockers); 0 (LCZ 696); 0 (Tetrazoles); 80M03YXJ7I (Valsartan); EC 3.4.24.11 (Neprilysin) [Em] Mês de entrada: 1803 [Cu] Atualização por classe: 180306 [Lr] Data última revisão: 180306 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171230 [St] Status: MEDLINE [do] DOI: 10.1358/dot.2017.53.10.2722396

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[PMID]: 29324336 [Au] Autor: Staniszewska M; Gizinska M; Mikulak E; Adamus K; Koronkiewicz M; Lukowska-Chojnacka E [Ad] Endereço: National Institute of Public Health-National Institute of Hygiene, Chocimska 24, 00-791 Warsaw, Poland. Electronic address: mstaniszewska@pzh.gov.pl. [Ti] Título: New 1,5 and 2,5-disubstituted tetrazoles-dependent activity towards surface barrier of Candida albicans. [So] Source: Eur J Med Chem;145:124-139, 2018 Feb 10. [Is] ISSN: 1768-3254 [Cp] País de publicação: France [La] Idioma: eng [Ab] Resumo: A series of novel tetrazole derivatives was synthetized using N-alkylation or Michael-type addition reactions, and screened for their fungistatic potential against Candida albicans (the lack of endpoint = 100%). Among them, the selected compounds 2d, 4b, and 6a differing in substituents at the tetrazole ring were non-toxic to Galleria mellonella larvae in vivo and exerted slight toxicity against Caco-2 in vitro (CC at 256 µg/mL). An antagonistic effect of tetrazole derivatives 2d, 4b, and 6a respectively in combination with Fluconazole was shown using the checker board and colorimetric methods (fractional inhibitory concentration indexes FICIs >1). The most active 2d and 6a displayed an inverse relation between MICs in the presence of exogenous ergosterol, the effect was opposite to Itraconazole and Amphotericin B. The differences between 6a's and 2d's action mode were noted. Combining both flow cytometry and fluorescence image analyses respectively showed the complexity of planktonic and biofilm cell demise mode under the tetrazole derivatives tested. The following evidences for 6a's interaction with fungal membrane were noted: necrosis-like programmed cell death (97.03 ±â€¯0.88), DNA denaturation (no laddering), mitochondrial damage (XTT assay), reduced adhesion to human epithelium (>50% at 0.0313 µg/mL, p ≤ .05), irregular deposit of chitin, and attenuated morphogenesis in mature biofilm. The treatment with 6a reduced pathogenicity of C. albicans during infection in G. mellonella. Contrariwise, 2d enhancing fungal adhesion displayed mechanism targeted to the cell wall (due to the presence of 3-chloropropyl clubbed with aryltetrazole) in the presence of osmotic protector. Under 2d, the accidental cell death (88.60% ±â€¯4.81) was observed. In conclusion, all tetrazole derivatives were obtained in satisfactory yields (60-95%) using efficient, simple and not expensive methods. Fungistatic and slightly anticancer tetrazole derivatives with the novel action mode can circumvent an appearance of antifungal-resistant strains. These results indicate that they are worthy of further studies. [Mh] Termos MeSH primário: Antifúngicos/farmacologia Candida albicans/efeitos dos fármacos Tetrazóis/farmacologia [Mh] Termos MeSH secundário: Antifúngicos/síntese química Antifúngicos/química Células CACO-2 Candida albicans/crescimento & desenvolvimento Sobrevivência Celular/efeitos dos fármacos Relação Dose-Resposta a Droga Seres Humanos Testes de Sensibilidade Microbiana Estrutura Molecular Relação Estrutura-Atividade Tetrazóis/síntese química Tetrazóis/química [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antifungal Agents); 0 (Tetrazoles) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180227 [Lr] Data última revisão: 180227 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180112 [St] Status: MEDLINE

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[PMID]: 29382024 [Au] Autor: Park DH; Yun GY; Eun HS; Joo JS; Kim JS; Kang SH; Moon HS; Lee ES; Lee BS; Kim KH; Kim SH [Ad] Endereço: Department of Internal Medicine. [Ti] Título: Fimasartan-induced liver injury in a patient with no adverse reactions on other types of angiotensin II receptor blockers: A case report. [So] Source: Medicine (Baltimore);96(47):e8905, 2017 Nov. [Is] ISSN: 1536-5964 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: RATIONALE: Angiotensin II receptor blockers (ARBs) are widely used for patients with hypertension, and fimasartan is a recently approved ARBs. Fimasartan can cause headache, dizziness, itching, and coughing. There have been several reports of hepatotoxicity in ARBs. However, there have not yet been published reports of the hepatotoxicity of fimasartan. PATIENT CONCERNS: A 73-year-old man with hypertension experienced liver injury after fimasartan administration. He had a previous history of taking 3 types of ARBs each for more than 2 years before taking fimasartan, and there were no side effects on ARBs except for fimasartan. DIAGNOSES: Other factors that could cause liver injury were excluded in diagnostic tests, and fimasartan was suspected to be the causative agent. INTERVENTION: Fimasartan was immediately discontinued and the patient was managed with supportive care via hepatotonics. DIAGNOSES: Other factors that could cause liver injury were excluded in diagnostic tests, and fimasartan was suspected to be the causative agent. OUTCOME: The liver injury due to fimasartan was confirmed by histology and accidental redosing. LESSONS: We emphasize that liver function should be monitored during fimasartan administration because fimasartan may cause hepatotoxicity in patients who have no side effects with other types of ARBs. And fimasartan-induced liver injury may appear later than other ARBs. [Mh] Termos MeSH primário: Antagonistas de Receptores de Angiotensina/efeitos adversos Anti-Hipertensivos/efeitos adversos Compostos de Bifenilo/efeitos adversos Doença Hepática Induzida por Substâncias e Drogas/etiologia Hipertensão/tratamento farmacológico Pirimidinas/efeitos adversos Tetrazóis/efeitos adversos [Mh] Termos MeSH secundário: Idoso Seres Humanos Masculino [Pt] Tipo de publicação: CASE REPORTS; JOURNAL ARTICLE [Nm] Nome de substância: 0 (Angiotensin Receptor Antagonists); 0 (Antihypertensive Agents); 0 (Biphenyl Compounds); 0 (Pyrimidines); 0 (Tetrazoles); P58222188P (fimasartan) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180207 [Lr] Data última revisão: 180207 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 180201 [St] Status: MEDLINE [do] DOI: 10.1097/MD.0000000000008905

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[PMID]: 29180454 [Au] Autor: Engeli S; Stinkens R; Heise T; May M; Goossens GH; Blaak EE; Havekes B; Jax T; Albrecht D; Pal P; Tegtbur U; Haufe S; Langenickel TH; Jordan J [Ad] Endereço: From the Institute of Clinical Pharmacology (S.E., M.M., S.H., J.J.), Institute of Sports Medicine (U.T.), Hannover Medical School, Germany; Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism (R.S., G.H.G., E.E.B.), Division of Endocrinology, Department [Ti] Título: Effect of Sacubitril/Valsartan on Exercise-Induced Lipid Metabolism in Patients With Obesity and Hypertension. [So] Source: Hypertension;71(1):70-77, 2018 01. [Is] ISSN: 1524-4563 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Sacubitril/valsartan (LCZ696), a novel angiotensin receptor-neprilysin inhibitor, was recently approved for the treatment of heart failure with reduced ejection fraction. Neprilysin degrades several peptides that modulate lipid metabolism, including natriuretic peptides. In this study, we investigated the effects of 8 weeks' treatment with sacubitril/valsartan on whole-body and adipose tissue lipolysis and lipid oxidation during defined physical exercise compared with the metabolically neutral comparator amlodipine. This was a multicenter, randomized, double-blind, active-controlled, parallel-group study enrolling subjects with abdominal obesity and moderate hypertension (mean sitting systolic blood pressure ≥130-180 mm Hg). Lipolysis during rest and exercise was assessed by microdialysis and [1,1,2,3,3- H]-glycerol tracer kinetics. Energy expenditure and substrate oxidation were measured simultaneously using indirect calorimetry. Plasma nonesterified fatty acids, glycerol, insulin, glucose, adrenaline and noradrenaline concentrations, blood pressure, and heart rate were also determined. Exercise elevated plasma glycerol, free fatty acids, and interstitial glycerol concentrations and increased the rate of glycerol appearance. However, exercise-induced stimulation of lipolysis was not augmented on sacubitril/valsartan treatment compared with amlodipine treatment. Furthermore, sacubitril/valsartan did not alter energy expenditure and substrate oxidation during exercise compared with amlodipine treatment. In conclusion, sacubitril/valsartan treatment for 8 weeks did not elicit clinically relevant changes in exercise-induced lipolysis or substrate oxidation in obese patients with hypertension, implying that its beneficial cardiovascular effects cannot be explained by changes in lipid metabolism during exercise. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01631864. [Mh] Termos MeSH primário: Aminobutiratos Anlodipino/administração & dosagem Exercício/fisiologia Hipertensão Neprilisina Obesidade Abdominal Tetrazóis [Mh] Termos MeSH secundário: Tecido Adiposo/metabolismo Aminobutiratos/administração & dosagem Aminobutiratos/efeitos adversos Aminobutiratos/farmacocinética Antagonistas de Receptores de Angiotensina/administração & dosagem Antagonistas de Receptores de Angiotensina/efeitos adversos Antagonistas de Receptores de Angiotensina/farmacocinética Pressão Sanguínea/efeitos dos fármacos Bloqueadores dos Canais de Cálcio/administração & dosagem Método Duplo-Cego Monitoramento de Medicamentos/métodos Feminino Seres Humanos Hipertensão/diagnóstico Hipertensão/tratamento farmacológico Hipertensão/metabolismo Metabolismo dos Lipídeos/efeitos dos fármacos Metabolismo dos Lipídeos/fisiologia Masculino Meia-Idade Peptídeos Natriuréticos/metabolismo Neprilisina/antagonistas & inibidores Neprilisina/metabolismo Obesidade Abdominal/diagnóstico Obesidade Abdominal/tratamento farmacológico Obesidade Abdominal/metabolismo Tetrazóis/administração & dosagem Tetrazóis/efeitos adversos Tetrazóis/farmacocinética Resultado do Tratamento [Pt] Tipo de publicação: JOURNAL ARTICLE; MULTICENTER STUDY; RANDOMIZED CONTROLLED TRIAL; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Aminobutyrates); 0 (Angiotensin Receptor Antagonists); 0 (Calcium Channel Blockers); 0 (LCZ 696); 0 (Natriuretic Peptides); 0 (Tetrazoles); 1J444QC288 (Amlodipine); EC 3.4.24.11 (Neprilysin) [Em] Mês de entrada: 1712 [Cu] Atualização por classe: 180207 [Lr] Data última revisão: 180207 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171129 [Cl] Clinical Trial: ClinicalTrial [St] Status: MEDLINE [do] DOI: 10.1161/HYPERTENSIONAHA.117.10224

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[PMID]: 29300156 [Au] Autor: Betts JW; Abdul Momin HF; Phee LM; Wareham DW [Ad] Endereço: 1​Antimicrobial Research Group, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. [Ti] Título: Comparative activity of tedizolid and glycopeptide combination therapies for the treatment of Staphylococcus aureus infections: an in vitro and in vivo evaluation against strains with reduced susceptibility to glycopeptides. [So] Source: J Med Microbiol;67(2):265-271, 2018 Feb. [Is] ISSN: 1473-5644 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: PURPOSE: Glycopeptides are widely used for the treatment of meticillin-resistant Staphylococcus aureus (MRSA) infections. Although difficult to detect, isolates with reduced (GISA), hetero (hGISA) or complete (GRSA) resistance to glycopeptides are increasingly reported. Optimal therapy for such strains is unknown. We compared the in vitro and in vivo activity of tedizolid (TED), a recently licensed oxazolidonone, with vancomycin (VAN) and teicoplanin (TEIC) combined with fusidic acid (FD) or rifampicin (RIF) against S. aureus (SA) with reduced susceptibility to glycopeptides. METHODS: Susceptibility was determined for six (GISA, hGISA and GRSA) reference strains and 72 clinical MRSA isolates screened for hGISA/GISA-like phenotypes. Synergy and bactericidal activity were assessed using chequerboard and time-kill assays. The G. mellonella wax moth caterpillar model was used to measure the activity of TED and the combinations in vivo. RESULTS: Glycopeptide MICs (VAN/TEIC) ranged from 0.5-8/4 and 0.125-1 for TED. No significant synergy was noted when VAN/TEIC were combined with either RIF or FD. Time-kill assays confirmed that TED was bacteriostatic but superior to VAN and TEIC against GISA strains. In G. mellonella TED was more effective than TEIC monotherapy versus GISA strains. The combination of TEIC with RIF was the most effective combination overall, both in vitro and in vivo. CONCLUSIONS: TED had good in vitro activity versus MRSA including those with reduced susceptibility to glycopeptides. Although bacteriostatic, it was effective in the G. mellonella model and superior to TEIC in the treatment of GISA. Although this supports the use of TED for MRSA and GISA, the TEIC/RIF combination also warrants further study. [Mh] Termos MeSH primário: Antibacterianos/uso terapêutico Oxazolidinonas/uso terapêutico Infecções Estafilocócicas/tratamento farmacológico Staphylococcus aureus/efeitos dos fármacos Teicoplanina/uso terapêutico Tetrazóis/uso terapêutico Vancomicina/uso terapêutico [Mh] Termos MeSH secundário: Animais Antibacterianos/administração & dosagem Antibacterianos/farmacologia Quimioterapia Combinada Seres Humanos Larva/microbiologia Lepidópteros/microbiologia Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos Testes de Sensibilidade Microbiana Oxazolidinonas/administração & dosagem Oxazolidinonas/farmacologia Infecções Estafilocócicas/microbiologia Teicoplanina/administração & dosagem Teicoplanina/farmacologia Tetrazóis/administração & dosagem Tetrazóis/farmacologia Vancomicina/administração & dosagem Vancomicina/farmacologia [Pt] Tipo de publicação: COMPARATIVE STUDY; JOURNAL ARTICLE [Nm] Nome de substância: 0 (Anti-Bacterial Agents); 0 (Oxazolidinones); 0 (Tetrazoles); 61036-62-2 (Teicoplanin); 6Q205EH1VU (Vancomycin); 97HLQ82NGL (torezolid) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180206 [Lr] Data última revisão: 180206 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180105 [St] Status: MEDLINE [do] DOI: 10.1099/jmm.0.000671

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[PMID]: 29241885 [Au] Autor: Ramos IC; Versteegh MM; de Boer RA; Koenders JMA; Linssen GCM; Meeder JG; Rutten-van Mölken MPMH [Ad] Endereço: Institute for Medical Technology Assessment, Erasmus University Rotterdam, the Netherlands. Electronic address: corroramos@imta.eur.nl. [Ti] Título: Cost Effectiveness of the Angiotensin Receptor Neprilysin Inhibitor Sacubitril/Valsartan for Patients with Chronic Heart Failure and Reduced Ejection Fraction in the Netherlands: A Country Adaptation Analysis Under the Former and Current Dutch Pharmacoeconomic Guidelines. [So] Source: Value Health;20(10):1260-1269, 2017 12. [Is] ISSN: 1524-4733 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: OBJECTIVES: To describe the adaptation of a global health economic model to determine whether treatment with the angiotensin receptor neprilysin inhibitor LCZ696 is cost effective compared with the angiotensin-converting enzyme inhibitor enalapril in adult patients with chronic heart failure with reduced left ventricular ejection fraction in the Netherlands; and to explore the effect of performing the cost-effectiveness analyses according to the new pharmacoeconomic Dutch guidelines (updated during the submission process of LCZ696), which require a value-of-information analysis and the inclusion of indirect medical costs of life-years gained. METHODS: We adapted a UK model to reflect the societal perspective in the Netherlands by including travel expenses, productivity loss, informal care costs, and indirect medical costs during the life-years gained and performed a preliminary value-of-information analysis. RESULTS: The incremental cost-effectiveness ratio obtained was €17,600 per quality-adjusted life-year (QALY) gained. This was robust to changes in most structural assumptions and across different subgroups of patients. Probability sensitivity analysis results showed that the probability that LCZ696 is cost-effective at a €50,000 per QALY threshold is 99.8%, with a population expected value of perfect information of €297,128. On including indirect medical costs of life-years gained, the incremental cost-effectiveness ratio was €26,491 per QALY gained, and LCZ696 was 99.46% cost effective at €50,000 per QALY, with a population expected value of perfect information of €2,849,647. CONCLUSIONS: LCZ696 is cost effective compared with enalapril under the former and current Dutch guidelines. However, the (monetary) consequences of making a wrong decision were considerably different in both scenarios. [Mh] Termos MeSH primário: Aminobutiratos/uso terapêutico Antagonistas de Receptores de Angiotensina/uso terapêutico Farmacoeconomia Insuficiência Cardíaca/tratamento farmacológico Modelos Econômicos Tetrazóis/uso terapêutico [Mh] Termos MeSH secundário: Idoso Aminobutiratos/economia Antagonistas de Receptores de Angiotensina/economia Inibidores da Enzima Conversora de Angiotensina/economia Inibidores da Enzima Conversora de Angiotensina/uso terapêutico Doença Crônica Análise Custo-Benefício Enalapril/economia Enalapril/uso terapêutico Feminino Guias como Assunto Insuficiência Cardíaca/economia Seres Humanos Masculino Meia-Idade Neprilisina/antagonistas & inibidores Países Baixos Anos de Vida Ajustados por Qualidade de Vida Ensaios Clínicos Controlados Aleatórios como Assunto Volume Sistólico/efeitos dos fármacos Tetrazóis/economia [Pt] Tipo de publicação: COMPARATIVE STUDY; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Aminobutyrates); 0 (Angiotensin Receptor Antagonists); 0 (Angiotensin-Converting Enzyme Inhibitors); 0 (LCZ 696); 0 (Tetrazoles); 69PN84IO1A (Enalapril); EC 3.4.24.11 (Neprilysin) [Em] Mês de entrada: 1712 [Cu] Atualização por classe: 180202 [Lr] Data última revisão: 180202 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171216 [St] Status: MEDLINE

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[PMID]: 29261715 [Au] Autor: Park JB; Kim SA; Sung KC; Kim JY [Ad] Endereço: JB lab and clinic, Seoul, South Korea. [Ti] Título: Gender-specific differences in the incidence of microalbuminuria in metabolic syndrome patients after treatment with fimasartan: The K-MetS study. [So] Source: PLoS One;12(12):e0189342, 2017. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: BACKGROUND: The effect of resolving metabolic syndrome on target organ damage in hypertensive patients is not well described. We evaluated whether treating metabolic syndrome (MetS) with an angiotensin receptor blocker subsequently reduced microalbuminuria in the K-MetS cohort. METHODS: Among 10,601 total metabolic syndrome patients, 3,250 (52.2% male, 56.2±10.0 years) with sufficient data on five specific metabolic components were included in this study. Patients were divided into four groups based on MetS status at baseline and 3 months. All patients received an angiotensin receptor blocker, fimasartan, for these 3 months; thereafter, treatment was modified at the discretion of each patient's physician. Microalbuminuria and the albumin/creatine ratio were evaluated as a proxy of organ damage. RESULTS: Blood pressure and waist circumference decreased from baseline to 3 months and 1 year. The average albumin/creatinine ratio significantly improved during the first three months of the study from 36.0±147.4 to 21.0±74.9 mg/g (p<0.05) and was persistently high in patients with MetS at baseline and 3 months versus other groups. Women in comparison with men showed significantly lower ACR among patients with newly developed MetS at 3-month. CONCLUSIONS: Treatment of hypertensive patients for one year with the angiotensin receptor blocker fimasartan significantly reduced the albumin/creatine ratio, irrespective of whether the patient had MetS; however, the albumin/creatinine ratio was significantly higher in patents with persistent or newly developed MetS compared to patients without MetS. Additionally, these findings were more prominent in women than in men. [Mh] Termos MeSH primário: Albuminúria/tratamento farmacológico Albuminúria/epidemiologia Compostos de Bifenilo/uso terapêutico Síndrome Metabólica/tratamento farmacológico Síndrome Metabólica/epidemiologia Pirimidinas/uso terapêutico Caracteres Sexuais Tetrazóis/uso terapêutico [Mh] Termos MeSH secundário: Albuminas/metabolismo Albuminúria/fisiopatologia Pressão Sanguínea Creatinina/metabolismo Feminino Seres Humanos Incidência Masculino Síndrome Metabólica/fisiopatologia Meia-Idade Fatores Sexuais [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Albumins); 0 (Biphenyl Compounds); 0 (Pyrimidines); 0 (Tetrazoles); AYI8EX34EU (Creatinine); P58222188P (fimasartan) [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: 171221 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0189342

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[PMID]: 28463833 [Au] Autor: Fujimura M; Joo JY; Kim JS; Hatta M; Yokoyama Y; Tominaga T [Ad] Endereço: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan. [Ti] Título: Preventive Effect of Clazosentan against Cerebral Vasospasm after Clipping Surgery for Aneurysmal Subarachnoid Hemorrhage in Japanese and Korean Patients. [So] Source: Cerebrovasc Dis;44(1-2):59-67, 2017. [Is] ISSN: 1421-9786 [Cp] País de publicação: Switzerland [La] Idioma: eng [Ab] Resumo: BACKGROUND: Clazosentan has been explored worldwide for the prophylaxis of cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH). In a dose-finding trial (CONSCIOUS-1) conducted in Israel, Europe, and North America, clazosentan (1, 5, and 15 mg/h) significantly reduced the incidence of cerebral vasospasm, but its efficacy in Japanese and Korean patients was unknown. We conducted a double-blind comparative study to evaluate the occurrence of cerebral vasospasm in Japanese and Korean patients with aSAH. METHODS: The aim of this multicenter, double-blind, randomized, placebo-controlled, dose-finding phase 2 clinical trial, was to evaluate the efficacy, pharmacokinetics, and safety of clazosentan (5 and 10 mg/h) against cerebral vasospasm after clipping surgery in Japanese and Korean patients with aSAH. Patients aged between 20 and 75 years were administered the study drug within 56 h after the aneurysm rupture and up to day 14 post-aSAH. The incidence of vasospasm, defined as an inner artery diameter reduction of major intracranial arteries ≥34% based on catheter angiography, was compared between each treatment group. Cerebral infarction due to vasospasm at 6 weeks and patients' outcome at 3 months was also compared. RESULTS: Among 181 enrolled patients, 158 completed the study and were analyzed. The incidence of vasospasm up to day 14 after aSAH onset was 80.0% in the placebo group (95% CI 67.0-89.6), 38.5% in the 5 mg/h clazosentan group (95% CI 25.3-53.0), and 35.3% in the 10 mg/h clazosentan group (95% CI 22.4-49.9), indicating that the incidence of vasospasm was significantly reduced by clazosentan treatment (placebo vs. 5 mg/h clazosentan, p < 0.0001; placebo vs. 10 mg/h clazosentan, p < 0.0001). The occurrence of cerebral infarction due to vasospasm was 20.8% in the placebo group (95% CI 10.8-34.1), 3.8% in the 5 mg/h clazosentan group (95% CI 0.5-13.2), and 4.2% in the 10 mg/h clazosentan group (95% CI 0.5-14.3), indicating that clazosentan significantly reduced the occurrence of cerebral infarctions caused by vasospasm (placebo vs. 5 mg/h clazosentan, p = 0.0151; placebo vs. 10 mg/h clazosentan, p = 0.0165). The overall incidence of all-cause death and/or vasospasm-related morbidity/mortality was significantly reduced in the 10 mg/h clazosentan group compared with the placebo group (p = 0.0003). CONCLUSION: These results suggest that clazosentan prevents cerebral vasospasm and subsequent cerebral infarction, and could thereby improve outcomes after performing a clipping surgery for aSAH in Japanese and Korean patients. [Mh] Termos MeSH primário: Infarto Cerebral/prevenção & controle Dioxanos/uso terapêutico Antagonistas do Receptor de Endotelina A/uso terapêutico Procedimentos Neurocirúrgicos/efeitos adversos Piridinas/uso terapêutico Pirimidinas/uso terapêutico Hemorragia Subaracnóidea/cirurgia Sulfonamidas/uso terapêutico Tetrazóis/uso terapêutico Vasodilatadores/uso terapêutico Vasoespasmo Intracraniano/prevenção & controle [Mh] Termos MeSH secundário: Adulto Idoso Angiografia Digital Angiografia Cerebral/métodos Infarto Cerebral/diagnóstico por imagem Infarto Cerebral/etiologia Infarto Cerebral/fisiopatologia Dioxanos/efeitos adversos Dioxanos/farmacocinética Método Duplo-Cego Antagonistas do Receptor de Endotelina A/efeitos adversos Antagonistas do Receptor de Endotelina A/farmacocinética Feminino Seres Humanos Japão Masculino Meia-Idade Piridinas/efeitos adversos Piridinas/farmacocinética Pirimidinas/efeitos adversos Pirimidinas/farmacocinética República da Coreia Hemorragia Subaracnóidea/diagnóstico por imagem Hemorragia Subaracnóidea/fisiopatologia Sulfonamidas/efeitos adversos Sulfonamidas/farmacocinética Tetrazóis/efeitos adversos Tetrazóis/farmacocinética Fatores de Tempo Resultado do Tratamento Vasodilatadores/efeitos adversos Vasodilatadores/farmacocinética Vasoespasmo Intracraniano/diagnóstico por imagem Vasoespasmo Intracraniano/etiologia Vasoespasmo Intracraniano/fisiopatologia Adulto Jovem [Pt] Tipo de publicação: JOURNAL ARTICLE; MULTICENTER STUDY; RANDOMIZED CONTROLLED TRIAL [Nm] Nome de substância: 0 (Dioxanes); 0 (Endothelin A Receptor Antagonists); 0 (Pyridines); 0 (Pyrimidines); 0 (Sulfonamides); 0 (Tetrazoles); 0 (Vasodilator Agents); 3DRR0X4728 (clazosentan) [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: 170503 [St] Status: MEDLINE [do] DOI: 10.1159/000475824

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[PMID]: 29206849 [Au] Autor: Chancharoenthana W; Leelahavanichkul A; Taratummarat S; Wongphom J; Tiranathanagul K; Eiam-Ong S [Ad] Endereço: Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand. [Ti] Título: Cilostazol attenuates intimal hyperplasia in a mouse model of chronic kidney disease. [So] Source: PLoS One;12(12):e0187872, 2017. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Intimal hyperplasia (IH) is a common cause of vasculopathy due to direct endothelial damage (such as post-coronary revascularization) or indirect injury (such as chronic kidney disease, or CKD). Although the attenuation of coronary revascularization-induced IH (direct-vascular-injury-induced IH) by cilostazol, a phosphodiesterase III inhibitor, has been demonstrated, our understanding of the effect on CKD-induced IH (indirect-vascular-injury-induced IH) is limited. Herein, we tested if cilostazol attenuated CKD-induced IH in a mouse model of ischemic-reperfusion injury with unilateral nephrectomy (Chr I/R), a normotensive non-proteinuria CKD model. Cilostazol (50 mg/kg/day) or placebo was orally administered once daily from 1-week post-nephrectomy. At 20 weeks, cilostazol significantly attenuated aortic IH as demonstrated by a 34% reduction in the total intima area with 50% and 47% decreases in the ratios of tunica intima area/tunica media area and tunica intima area/(tunica intima + tunica media area), respectively. The diameters of aorta and renal function were unchanged by cilostazol. Interestingly, cilostazol decreased miR-221, but enhanced miR-143 and miR-145 in either in vitro or aortic tissue, as well as attenuated several pro-inflammatory mediators, including asymmetrical dimethylarginine, high-sensitivity C-reactive protein, vascular endothelial growth factor in aorta and serum pro-inflammatory cytokines (IL-6 and TNF-α). We demonstrated a proof of concept of the effectiveness of cilostazol in attenuating IH in a Chr I/R mouse model, a CKD model with predominantly indirect-vascular-injury-induced IH. These considerations warrant further investigation to develop a new primary prevention strategy for CKD-related IH. [Mh] Termos MeSH primário: Modelos Animais de Doenças Hiperplasia/tratamento farmacológico Falência Renal Crônica/complicações Tetrazóis/uso terapêutico Túnica Íntima/patologia [Mh] Termos MeSH secundário: Animais Hiperplasia/complicações Falência Renal Crônica/patologia Camundongos Nefrectomia/efeitos adversos [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Tetrazoles); N7Z035406B (cilostazol) [Em] Mês de entrada: 1712 [Cu] Atualização por classe: 171229 [Lr] Data última revisão: 171229 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171206 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0187872

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[PMID]: 28460381 [Au] Autor: Vitting KE [Ad] Endereço: From Suburban Nephrology Group, Wayne, New Jersey. [Ti] Título: Sacubitril-Valsartan in Heart Failure. [So] Source: Ann Intern Med;166(9):680, 2017 05 02. [Is] ISSN: 1539-3704 [Cp] País de publicação: United States [La] Idioma: eng [Mh] Termos MeSH primário: Aminobutiratos Tetrazóis [Mh] Termos MeSH secundário: Insuficiência Cardíaca Seres Humanos [Pt] Tipo de publicação: JOURNAL ARTICLE; COMMENT [Nm] Nome de substância: 0 (Aminobutyrates); 0 (LCZ 696); 0 (Tetrazoles) [Em] Mês de entrada: 1712 [Cu] Atualização por classe: 171208 [Lr] Data última revisão: 171208 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 170502 [St] Status: MEDLINE [do] DOI: 10.7326/L17-0049

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