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1.
Sci Rep ; 10(1): 20210, 2020 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-33214574

RESUMO

The overall prognosis for pancreatic cancer remains dismal and potent chemotherapeutic agents that selectively target this cancer are critically needed. Elevated expression of NAD(P)H:quinone oxidoreductase 1 (NQO1) is frequent in pancreatic cancer, and it offers promising tumor-selective targeting. Recently, KP372-1 was identified as a novel NQO1 redox cycling agent that induces cytotoxicity in cancer cells by creating redox imbalance; however, the mechanistic basis of KP372-1-induced cytotoxicity remains elusive. Here, we show that KP372-1 sensitizes NQO1-expressing pancreatic cancer cells and spares immortalized normal pancreatic duct cells, hTERT-HPNE. Notably, we found that KP372-1 is ~ 10- to 20-fold more potent than ß-lapachone, another NQO1 substrate, against pancreatic cancer cells. Mechanistically, our data strongly suggest that reactive oxygen species produced by NQO1-dependent redox cycling of KP372-1 cause robust DNA damage, including DNA breaks. Furthermore, we found that KP372-1-induced DNA damage hyperactivates the central DNA damage sensor protein poly(ADP-ribose) polymerase 1 (PARP1) and activates caspase-3 to initiate cell death. Our data also show that the combination of KP372-1 with PARP inhibition creates enhanced cytotoxicity in pancreatic cancer cells. Collectively, our study provides mechanistic insights into the cytotoxicity instigated by KP372-1 and lays an essential foundation to establish it as a promising chemotherapeutic agent against cancer.


Assuntos
Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Poli(ADP-Ribose) Polimerase-1/metabolismo , Tetrazóis/farmacologia , Antineoplásicos/uso terapêutico , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Humanos , NAD(P)H Desidrogenase (Quinona)/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Espécies Reativas de Oxigênio/metabolismo , Tetrazóis/uso terapêutico
2.
Int J Mol Sci ; 21(22)2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-33203141

RESUMO

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) determines the angiotensin converting enzyme 2 (ACE2) down-regulation and related decrease in angiotensin II degradation. Both these events trigger "cytokine storm" leading to acute lung and cardiovascular injury. A selective therapy for COVID-19 has not yet been identified. Clinical trials with remdesivir gave discordant results. Thus, healthcare systems have focused on "multi-targeted" therapeutic strategies aiming at relieving systemic inflammation and thrombotic complications. No randomized clinical trial has demonstrated the efficacy of renin angiotensin system antagonists in reducing inflammation related to COVID-19. Dexamethasone and tocilizumab showed encouraging data, but their use needs to be further validated. The still-controversial efficacy of these treatments highlighted the importance of organ injury prevention in COVID-19. Neprilysin (NEP) might be an interesting target for this purpose. NEP expression is increased by cytokines on lung fibroblasts surface. NEP activity is elevated in acute respiratory distress syndrome and it is conceivable that it is also high in COVID-19. NEP is implicated in the degradation of natriuretic peptides, bradykinin, substance P, adrenomedullin, and apelin that account for prevention of organ injury. Thus, NEP/angiotensin receptor type 1 (AT1R) inhibitor sacubitril/valsartan (SAC/VAL) may increase levels of these molecules and block AT1Rs required for ACE2 endocytosis in SARS-CoV-2 infection. Moreover, SAC/VAL has a positive impact on acute heart failure that is very frequently observed in deceased COVID-19 patients. The current review aims to summarize actual therapeutic strategies for COVID-19 and to examine the data supporting the potential benefits of SAC/VAL in COVID-19 treatment.


Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Neprilisina/antagonistas & inibidores , Pneumonia Viral/tratamento farmacológico , Aminobutiratos/administração & dosagem , Aminobutiratos/uso terapêutico , Antagonistas de Receptores de Angiotensina/administração & dosagem , Animais , Infecções por Coronavirus/metabolismo , Combinação de Medicamentos , Humanos , Neprilisina/metabolismo , Pandemias , Pneumonia Viral/metabolismo , Tetrazóis/administração & dosagem , Tetrazóis/uso terapêutico , Valsartana/administração & dosagem , Valsartana/uso terapêutico
3.
Open Heart ; 7(2)2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33020255

RESUMO

BACKGROUND: Sacubitril/valsartan is an effective treatment for heart failure with reduced ejection fraction (HFrEF) based on clinical trial data. However, little is known about its use or impact in real-world practice. The aim of this study was to describe our routine clinical experience of switching otherwise optimally treated patients with HFrEF to sacubitril/valsartan with respect to patient outcomes such as quality of life (QoL) and echocardiographic variables. METHODS AND RESULTS: From June 2017 to May 2019, 80 consecutive stable patients with HFrEF on established and maximally tolerated guideline-directed HF therapies were initiated on sacubitril/valsartan with bimonthly uptitration. Clinical assessment, biochemistry, echocardiography and QoL were compared pretreatment and post-treatment switching. We were able to successfully switch 89% of patients from renin-angiotensin axis inhibitors to sacubitril/valsartan (71 of 80 patients). After 3 months of switch therapy, we observed clinically significant and incremental improvements in blood pressure (systolic blood pressure 123 vs 112 mm Hg, p<0.001; diastolic blood pressure 72 vs 68 mm Hg, p=0.004), New York Heart Association functional classification score (2.3 vs 1.9, p<0.001), Minnesota Living with Heart Failure Questionnaire score (46 vs 38, p=0.016), left ventricular ejection fraction (26% vs 33%, p<0.001) and left ventricular end systolic diameter (5.2 vs 4.9 cm, p=0.013) compared with baseline. There were no significant changes in renal function or serum potassium. CONCLUSION: This study provides real-world clinical practice data demonstrating incremental improvements in functional and echocardiographic outcomes in optimally treated patients with HFrEF switched to sacubitril/valsartan. The data provide evidence beyond that observed in clinical trial settings of the potential benefits of sacubitril/valsartan when used as part of a multidisciplinary heart failure programme.


Assuntos
Aminobutiratos/uso terapêutico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Substituição de Medicamentos , Insuficiência Cardíaca/tratamento farmacológico , Inibidores de Proteases/uso terapêutico , Volume Sistólico/efeitos dos fármacos , Tetrazóis/uso terapêutico , Função Ventricular Esquerda/efeitos dos fármacos , Idoso , Aminobutiratos/efeitos adversos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/efeitos adversos , Combinação de Medicamentos , Ecocardiografia , Feminino , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Neprilisina/antagonistas & inibidores , Inibidores de Proteases/efeitos adversos , Qualidade de Vida , Recuperação de Função Fisiológica , Estudos Retrospectivos , Tetrazóis/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
4.
Am Heart J ; 230: 35-43, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32980364

RESUMO

BACKGROUND: In PARADIGM-HF, sacubitril/valsartan improved quality of life (QOL) versus enalapril in heart failure with reduced ejection fraction (HFrEF), yet limited data are available regarding QOL changes after sacubitril/valsartan initiation in routine practice. METHODS: PROVIDE-HF was a prospective study within a national research network (Patient-Centered Outcomes Research Network) of HFrEF outpatients recently initiated on sacubitril/valsartan versus controls with recent angiotensin-converting enzyme inhibitor/angiotensin receptor blocker initiation/dose change. The primary end point was mean Kansas City Cardiomyopathy Questionnaire (KCCQ) change through 12 weeks. Other end points included responder analyses: ≥5-point and ≥20-point KCCQ increase. Adjusted QOL change was estimated after propensity score weighting. RESULTS: Overall, 270 patients had both baseline and 12-week KCCQ data (151 sacubitril/valsartan; 119 control). The groups had similar demographics and HF details: median EF 28% and N-terminal pro-brain natriuretic peptide 1083 pg/mL. Sacubitril/valsartan patients had larger improvements in KCCQ (mean difference +4.76; P = .027) and were more likely to have a ≥5-point and ≥20-point response (all P < .05). Adjusted comparisons demonstrated similar numerical improvements in the change in KCCQ (+4.55; 95% CI -0.89 to 9.99; P = .101) and likelihood of ≥5-point increase (odds ratio 1.55; 95% CI: 0.84-2.86; P = .16); ≥20-point increase remained statistically significant (odds ratio 3.79; 95% CI 1.47-9.73; P = .006). CONCLUSIONS: In this prospective HFrEF study of sacubitril/valsartan initiation compared with recent angiotensin-converting enzyme inhibitor/angiotensin receptor blocker initiation/dose change, the between-group difference in the primary end point, mean KCCQ change at 12 weeks was not statistically significant following adjustment, but sacubitril/valsartan initiation was associated with early improvements in QOL and a higher likelihood of ≥20-point improvement in KCCQ at 12 weeks. These data add additional real-world evidence related to patient-reported outcomes following the initiation of sacubitril/valsartan in routine clinical practice.


Assuntos
Aminobutiratos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Medidas de Resultados Relatados pelo Paciente , Dados Preliminares , Qualidade de Vida , Tetrazóis/uso terapêutico , Idoso , Aminobutiratos/administração & dosagem , Antagonistas de Receptores de Angiotensina/administração & dosagem , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Estudos de Casos e Controles , Combinação de Medicamentos , Feminino , Insuficiência Cardíaca/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Pontuação de Propensão , Estudos Prospectivos , Tetrazóis/administração & dosagem
5.
Neurologia ; 35(9): 628-632, 2020.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-32896463

RESUMO

INTRODUCTION: In recent months, doubts have arisen among patients, general practitioners, and neurologists as to whether some drugs commonly used in patients with headaches and neuralgia may favour or complicate the disease caused by SARS-CoV-2. MATERIAL AND METHODS: We collected information on the opinions of scientific societies and medicines agencies (American, European, and Spanish) to clarify doubts regarding the use of drugs such as lisinopril, candesartan, ibuprofen, corticosteroids, carbamazepine, and monoclonal antibodies targeting the calcitonin gene-related peptide in the context of the COVID-19 pandemic. RESULTS: We make recommendations about the use of standard headache treatments in the context of the COVID-19 pandemic, based on the current scientific evidence. CONCLUSIONS: At present, there is no robust scientific argument to formally contraindicate any of the standard treatments employed for headaches and neuralgias.


Assuntos
Analgésicos/efeitos adversos , Infecções por Coronavirus/complicações , Cefaleia/tratamento farmacológico , Neuralgia/tratamento farmacológico , Pneumonia Viral/complicações , Corticosteroides/efeitos adversos , Corticosteroides/uso terapêutico , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/uso terapêutico , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/uso terapêutico , Antivirais/farmacologia , Benzimidazóis/efeitos adversos , Benzimidazóis/uso terapêutico , Betacoronavirus , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/efeitos adversos , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/uso terapêutico , Carbamazepina/efeitos adversos , Carbamazepina/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Suscetibilidade a Doenças/induzido quimicamente , Interações Medicamentosas , Indução Enzimática/efeitos dos fármacos , Cefaleia/complicações , Cefaleia/prevenção & controle , Humanos , Ibuprofeno/efeitos adversos , Ibuprofeno/farmacologia , Ibuprofeno/uso terapêutico , Lisinopril/efeitos adversos , Lisinopril/uso terapêutico , Neuralgia/complicações , Pandemias , Peptidil Dipeptidase A/biossíntese , Peptidil Dipeptidase A/genética , Receptores Virais/biossíntese , Receptores Virais/genética , Fatores de Risco , Tetrazóis/efeitos adversos , Tetrazóis/uso terapêutico
6.
G Ital Cardiol (Rome) ; 21(10): 750-756, 2020 Oct.
Artigo em Italiano | MEDLINE | ID: mdl-32968307

RESUMO

BACKGROUND: During the COVID-19 pandemic, non-urgent outpatient activities were temporarily suspended. The aim of this study was to assess the impact of this measure on the management of the heart failure outpatient clinic at our institution. METHODS: We analyzed the clinical outcome of 110 chronic heart failure patients (mean age 73 ± 9 years) whose follow-up visit had been delayed. RESULTS: At their last visit before the lockdown, 80.9% was in NYHA class II, had an ejection fraction of 37 ± 7%, and B-type natriuretic peptide level was moderately elevated (266 ± 138 pg/ml). All patients received loop diuretics, 97.2% beta-blockers, 64.9% an aldosterone antagonist, 60.9% sacubitril/valsartan (S/V), and 72.2% of the remaining patients were on angiotensin-converting enzyme inhibitor or valsartan therapy. Patients were contacted by phone during and at the end of the lockdown period to fix a new appointment and underwent a structured interview to assess their clinical conditions and ongoing therapy and to verify whether they had contracted SARS-CoV-2 infection. Twelve patients (13.2%) contracted COVID-19. None was hospitalized for worsening heart failure or reported defibrillator shocks and none changed autonomously the prescribed therapy. Overall, 75% of patients reported stable or improved general well-being from the last in-person visit, while 25% described subjective worsening due to the social effect of the pandemic. Unchanged body weight and blood pressure values were reported by 86% and 78.4% of patients, respectively. Lower blood pressure values compared to baseline were recorded in 15.2% of patients on conventional renin-angiotensin system inhibition vs 21% of those on S/V, one of whom had to down-titrate S/V for persistent but asymptomatic hypotension; 4 patients up-titrated S/V to 200 mg/day following phone indications. CONCLUSIONS: Cancellation of scheduled follow-up visits during 3 months did not have significant negative effects in a cohort of stable patients with chronic heart failure on optimized medical therapy. Telephone support was effective in keeping connections with the patients during the lockdown, allowing appropriate management and implementation of drug therapy. In particular, patients who received S/V were not affected by delays in scheduled visits, confirming the tolerability and safety of this novel therapy in terms of both clinical and biohumoral parameters.


Assuntos
Betacoronavirus , Infecções por Coronavirus/epidemiologia , Insuficiência Cardíaca/tratamento farmacológico , Pneumonia Viral/epidemiologia , Quarentena , Antagonistas Adrenérgicos beta/uso terapêutico , Idoso , Instituições de Assistência Ambulatorial , Aminobutiratos/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Doença Crônica , Continuidade da Assistência ao Paciente/organização & administração , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/psicologia , Assistência à Saúde , Progressão da Doença , Combinação de Medicamentos , Feminino , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/psicologia , Humanos , Itália/epidemiologia , Masculino , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Peptídeo Natriurético Encefálico/sangue , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/psicologia , Recidiva , Inibidores de Simportadores de Cloreto de Sódio e Potássio/uso terapêutico , Volume Sistólico , Telefone , Tetrazóis/uso terapêutico , Suspensão de Tratamento
7.
Orv Hetil ; 161(38): 1637-1645, 2020 09.
Artigo em Húngaro | MEDLINE | ID: mdl-32924968

RESUMO

INTRODUCTION: Intermittent claudication has a significant negative impact on the patients' quality of life. Revascularization procedures and noninvasive medical therapies can improve walking capacity. Cilostazol has IA recommendation for the treatment of intermittent claudication. AIM: The aim of this study was to evaluate the effect of a three-month cilostazol treatment on the health-related quality of life and on the lower-limb functional capacity in diabetic (DM) and non-diabetic patients (NDM) with intermittent claudication in the clinical practice. METHOD: The study was a multicenter, non-interventional trial; 812 patients with peripheral artery disease (Fontaine II stage, mean age: 67.17 years, male/female: 58.25/41.75%, 318 diabetics) were enrolled, who received cilostazol (50 or 100 mg twice a day) for 3 months. The quality of life was evaluated with the EQ-5D-3L questionnaire, the functional capacity with the WELCH questionnaire. Walking distances, ankle-brachial index were measured at baseline and after 3 months. RESULTS: Upon conclusion of the study, the EQ-5D index improved both in non-diabetic and diabetic patients (baseline: NDM -0.45 ± 0.22, DM -0.48 ± 0.23, 3rd month: -0,24 ± 0.18, -0,27 ± 0.19; respectively; p<0.0001) and there was a significant increase in the WELCH score as well (baseline: NDM 20 ± 14, DM 18 ± 14; 3rd month: 33 ± 19, 29 ± 16, respectively; p<0.0001). Both pain-free and maximal walking distance increased by 59.2% (median: 50.0%), 46.58 (median: 40.51%) in NDM and 42.85% (median: 43.33%), 41.61% (median: 34.68%) in DM patients, respectively (p<0.001). CONCLUSIONS: Three months of cilostazol treatment improved the quality of life and lower-limb functional capacity in diabetic and non-diabetic claudicant patients. The WELCH questionnaire is a useful tool in clinical practice for the evaluation of intermittent claudication treatment. Orv Hetil. 2020; 161(38): 1637-1645.


Assuntos
Cilostazol/uso terapêutico , Diabetes Mellitus/fisiopatologia , Claudicação Intermitente/tratamento farmacológico , Doença Arterial Periférica/complicações , Qualidade de Vida/psicologia , Tetrazóis/uso terapêutico , Vasodilatadores/uso terapêutico , Idoso , Estudos de Casos e Controles , Complicações do Diabetes , Feminino , Humanos , Claudicação Intermitente/psicologia , Extremidade Inferior/fisiopatologia , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/tratamento farmacológico , Resultado do Tratamento , Caminhada
8.
JAMA Netw Open ; 3(8): e2012252, 2020 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-32761160

RESUMO

Importance: Observational studies have suggested that angiotensin receptor blockers are associated with a unique cognitive protection. It is unclear if this is due to reduced blood pressure (BP) or angiotensin receptors type 1 blockade. Objective: To determine neurocognitive effects of candesartan vs lisinopril in older adults with mild cognitive impairment (MCI). Design, Setting, and Participants: This randomized clinical trial included participants aged 55 years or older with MCI and hypertension. Individuals were withdrawn from prior antihypertensive therapy and randomized in a 1 to 1 ratio to candesartan or lisinopril from June 2014 to December 2018. Participants underwent cognitive assessments at baseline and at 6 and 12 months. Brain magnetic resonance images were obtained at baseline and 12 months. This intent-to-treat study was double-blind and powered for a sample size accounting for 20% dropout. Data were analyzed from May to October 2019. Interventions: Escalating doses of oral candesartan (up to 32 mg) or lisinopril (up to 40 mg) once daily. Open-label antihypertensive drug treatments were added as needed to achieve BP less than 140/90 mm Hg. Main Outcomes and Measures: The primary outcome was executive function (measured using the Trail Making Test, Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research tool) and secondary outcomes were episodic memory (measured using the Hopkins Verbal Learning Test-Revised) and microvascular brain injury reflected by magnetic resonance images of white matter lesions. Results: Among 176 randomized participants (mean [SD] age, 66.0 [7.8] years; 101 [57.4%] women; 113 [64.2%] African American), 87 were assigned to candesartan and 89 were assigned to lisinopril. Among these, 141 participants completed the trial, including 77 in the candesartan group and 64 in the lisinopril group. Although the lisinopril vs candesartan groups achieved similar BP (12-month mean [SD] systolic BP: 130 [17] mm Hg vs 134 [20] mm Hg; P = .20; 12-month mean [SD] diastolic BP: 77 [10] mm Hg vs 78 [11] mm Hg; P = .52), candesartan was superior to lisinopril on the primary outcome of executive function measured by Trail Making Test Part B (effect size [ES] = -12.8 [95% CI, -22.5 to -3.1]) but not Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research score (ES = -0.03 [95% CI, -0.08 to 0.03]). Candesartan was also superior to lisinopril on the secondary outcome of Hopkins Verbal Learning Test-Revised delayed recall (ES = 0.4 [95% CI, 0.02 to 0.8]) and retention (ES = 5.1 [95% CI, 0.7 to 9.5]). Conclusions and Relevance: These findings suggest that in older adults with MCI, 1-year treatment with candesartan had superior neurocognitive outcomes compared with lisinopril. These effects are likely independent of the BP-lowering effect of candesartan. Trial Registration: ClinicalTrials.gov Identifier: NCT01984164.


Assuntos
Anti-Hipertensivos/uso terapêutico , Benzimidazóis/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Lisinopril/uso terapêutico , Tetrazóis/uso terapêutico , Administração Oral , Idoso , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/farmacologia , Benzimidazóis/administração & dosagem , Benzimidazóis/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Encéfalo/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Feminino , Humanos , Hipertensão/tratamento farmacológico , Lisinopril/administração & dosagem , Lisinopril/farmacologia , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tetrazóis/administração & dosagem , Tetrazóis/farmacologia
9.
Sci Rep ; 10(1): 13045, 2020 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-32747644

RESUMO

Cyclophosphamide (CP) is a chemotherapeutic agent that induces oxidative stress causing multiple organ damage. Sacubitril/valsartan, is a combined formulation of neprilysin inhibitor (sacubitril) and angiotensin II receptor blocker (valsartan), that induces the protective effect of brain natriuretic peptide. The aim of the current study is to investigate the prophylactic impacts of sacubitril/valsartan versus valsartan against CP-induced lung toxicity in rats. Rats were assigned randomly into 6 groups; control; received corn oil (2 ml/kg/day; p.o. for 6 days), sacubitril/valsartan (30 mg/kg; p.o. for 6 days), valsartan (15 mg/kg; p.o. for 6 days), CP (200 mg/kg; i.p. on day 5), sacubitril/valsartan + CP (30 mg/kg; p.o. for 6 days, 200 mg/kg; i.p. single dose on day 5, respectively), valsartan + CP (15 mg/kg; p.o. for 6 days, 200 mg/kg; i.p. single dose on day 5, respectively). Both sacubitril/valsartan and valsartan produced a significant decrease in the inflammation and fibrosis markers in the BALF, in comparison with the CP group. Both sacubitril/valsartan and valsartan produced an apparent decrease in the relative genes expression of miR-150-3p and NF-κB, as well as a significant decrease in the relative expression of P38 and ERK1/2 MAPKs and an increase in the relative gene expression of Nrf-2, compared to CP group. Intriguingly, sacubitril/valsartan , showed subtle superiority in almost all investigated parameters, compared to valsartan. In conclusion, sacubitril/valsartan effectively abrogated the CP induced lung inflammation and fibrosis, providing a potential promising protection that could be linked to their ability to inhibit miR-150-3p via inhibition of NF-κB and MAPK signaling pathways.


Assuntos
Aminobutiratos/uso terapêutico , Lesão Pulmonar/tratamento farmacológico , Lesão Pulmonar/genética , Sistema de Sinalização das MAP Quinases , MicroRNAs/genética , NF-kappa B/metabolismo , Substâncias Protetoras/uso terapêutico , Tetrazóis/uso terapêutico , Aminobutiratos/farmacologia , Animais , Antioxidantes/metabolismo , Líquido da Lavagem Broncoalveolar/citologia , Ciclofosfamida , Citocinas/metabolismo , Combinação de Medicamentos , Regulação da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Mediadores da Inflamação/metabolismo , L-Lactato Desidrogenase/metabolismo , Contagem de Leucócitos , Pulmão/patologia , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , MicroRNAs/metabolismo , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Peptídeo Natriurético Encefálico/metabolismo , Fosforilação/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Ratos , Tetrazóis/farmacologia
10.
Expert Opin Pharmacother ; 21(18): 2215-2223, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32812825

RESUMO

INTRODUCTION: Antiseizure drugs (ASDs) play a central and crucial role in the treatment of epilepsy patients because the majority require anticonvulsant treatment for an extended period of time. Due to the fact that 30% of patients are refractory to medical treatment, new therapeutic options are necessary. Cenobamate is the latest approved antiepileptic drug in focal epilepsy, and its mode of action is thought to be mediated by blocking voltage-gated sodium channels and interaction with the GABAergic system. AREAS COVERED: This article reviews animal studies, pharmacokinetics, pharmacodynamics, and the phase 1 to 3 trials and open-label extension data on cenobamate. EXPERT OPINION: Cenobamate has the potential to perform as an important ASD because trial data are indicative of remarkable responder and seizure freedom rates so far not seen with other ASDs. Cenobamate demonstrated significant efficacy at a dosage between 100 and 400 mg per day. The side-effect profile of this drug is comparable to other ASDs and is mainly CNS related; in particular, somnolence, dizziness, headache, diplopia, and nystagmus. However, slow titration is mandatory to decrease the risk of drug rash with eosinophilia and systemic symptoms (DRESS) that was observed in several patients with fast uptitration schemes.


Assuntos
Anticonvulsivantes/uso terapêutico , Carbamatos/uso terapêutico , Clorofenóis/uso terapêutico , Epilepsias Parciais/tratamento farmacológico , Tetrazóis/uso terapêutico , Animais , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/sangue , Carbamatos/administração & dosagem , Carbamatos/efeitos adversos , Carbamatos/sangue , Clorofenóis/administração & dosagem , Clorofenóis/efeitos adversos , Clorofenóis/sangue , Cefaleia/induzido quimicamente , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Tetrazóis/administração & dosagem , Tetrazóis/efeitos adversos , Tetrazóis/sangue , Resultado do Tratamento
11.
JACC Heart Fail ; 8(10): 789-799, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32641226

RESUMO

The PARADIGM-HF (Prospective Comparison of Angiotensin II Receptor Blocker Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial reported that sacubitril/valsartan (S/V), an angiotensin receptor-neprilysin inhibitor, significantly reduced mortality and heart failure (HF) hospitalization in HF patients with a reduced ejection fraction (HFrEF). However, fewer than 1% of patients in the PARADIGM-HF study had New York Heart Association (NYHA) functional class IV symptoms. Accordingly, data that informed the use of S/V among patients with advanced HF were limited. The LIFE (LCZ696 in Hospitalized Advanced Heart Failure) study was a 24-week prospective, multicenter, double-blinded, double-dummy, active comparator trial that compared the safety, efficacy, and tolerability of S/V with those of valsartan in patients with advanced HFrEF. The trial planned to randomize 400 patients ≥18 years of age with advanced HF, defined as an EF ≤35%, New York Heart Association functional class IV symptoms, elevated natriuretic peptide concentration (B-type natriuretic peptide [BNP] ≥250 pg/ml or N-terminal pro-B-type natriuretic peptide [NT-proBNP] ≥800 pg/ml), and ≥1 objective finding of advanced HF. Following a 3- to 7-day open label run-in period with S/V (24 mg/26 mg twice daily), patients were randomized 1:1 to S/V titrated to 97 mg/103 mg twice daily versus 160 mg of V twice daily. The primary endpoint was the proportional change from baseline in the area under the curve for NT-proBNP levels measured through week 24. Secondary and tertiary endpoints included clinical outcomes and safety and tolerability. Because of the COVID-19 pandemic, enrollment in the LIFE trial was stopped prematurely to ensure patient safety and data integrity. The primary analysis consists of the first 335 randomized patients whose clinical follow-up examination results were not severely impacted by COVID-19. (Entresto [LCZ696] in Advanced Heart Failure [LIFE STUDY] [HFN-LIFE]; NCT02816736).


Assuntos
Aminobutiratos/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Tetrazóis/uso terapêutico , Betacoronavirus , Cardiotônicos/uso terapêutico , Infecções por Coronavirus , Relação Dose-Resposta a Droga , Método Duplo-Cego , Combinação de Medicamentos , Término Precoce de Ensaios Clínicos , Taxa de Filtração Glomerular , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Transplante de Coração , Coração Auxiliar , Hospitalização/estatística & dados numéricos , Humanos , Hipotensão/induzido quimicamente , Peptídeo Natriurético Encefálico/metabolismo , Pandemias , Fragmentos de Peptídeos/metabolismo , Pneumonia Viral , Volume Sistólico
12.
Ann Intern Med ; 172(12): JC65, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32539517

RESUMO

SOURCE CITATION: Solomon SD, Vaduganathan M, Claggett BL, et al. Sacubitril/valsartan across the spectrum of ejection fraction in heart failure. Circulation. 2020;141:352-61. 31736342.


Assuntos
Antagonistas de Receptores de Angiotensina , Insuficiência Cardíaca , Aminobutiratos/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Hospitalização , Humanos , Volume Sistólico , Tetrazóis/uso terapêutico , Valsartana
14.
Cardiovasc Drugs Ther ; 34(5): 707-722, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32519065

RESUMO

An abundance of new data regarding the use of the novel drug compound sacubitril/valsartan in chronic heart failure (CHF) patients is published every year since the initial publication of the PARADIGM-HF study in 2014. This review summarises the most recent evidence (2019 and onwards) of sacubitril/valsartan in CHF patients as well as provides a critical appraisal of these data. New data are grouped in categories such as real-world data, randomised controlled trials, surrogate end-points, cost-effectiveness, use of sacubitril/valsartan as an anti-hypertensive treatment, effect on diuretic dosing and implementation of this novel compound in other populations. This review of recent literature identified important messages such as early initiation during index hospitalisation or immediately post-discharge, barriers against implementation of this novel treatment modality, analytical issues regarding measuring natriuretic peptides in patients under treatment and extrapolated use of sacubitril/valsartan in other than PARADIGM-HF populations. This update may serve as a very helpful evidence-based resource for practising clinicians, future research planning and health-related policy makers.


Assuntos
Aminobutiratos/uso terapêutico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Inibidores de Proteases/uso terapêutico , Tetrazóis/uso terapêutico , Aminobutiratos/efeitos adversos , Aminobutiratos/economia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/efeitos adversos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/economia , Análise Custo-Benefício , Custos de Medicamentos , Medicina Baseada em Evidências , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/economia , Insuficiência Cardíaca/fisiopatologia , Humanos , Neprilisina/antagonistas & inibidores , Segurança do Paciente , Inibidores de Proteases/efeitos adversos , Inibidores de Proteases/economia , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Recuperação de Função Fisiológica , Medição de Risco , Fatores de Risco , Tetrazóis/efeitos adversos , Tetrazóis/economia , Resultado do Tratamento
15.
Am J Physiol Renal Physiol ; 319(1): F63-F75, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32463726

RESUMO

Diuretics and renin-angiotensin system blockers are often insufficient to control the blood pressure (BP) in salt-sensitive (SS) subjects. Abundant data support the proposal that the level of atrial natriuretic peptide may correlate with the pathogenesis of SS hypertension. We hypothesized here that increasing atrial natriuretic peptide levels with sacubitril, combined with renin-angiotensin system blockage by valsartan, can be beneficial for alleviation of renal damage in a model of SS hypertension, the Dahl SS rat. To induce a BP increase, rats were challenged with a high-salt 4% NaCl diet for 21 days, and chronic administration of vehicle or low-dose sacubitril and/or valsartan (75 µg/day each) was performed. Urine flow, Na+ excretion, and water consumption were increased on the high-salt diet compared with the starting point (0.4% NaCl) in all groups but remained similar among the groups at the end of the protocol. Upon salt challenge, we observed a mild decrease in systolic BP and urinary neutrophil gelatinase-associated lipocalin levels (indicative of alleviated tubular damage) in the valsartan-treated groups. Sacubitril, as well as sacubitril/valsartan, attenuated the glomerular filtration rate decline induced by salt. Alleviation of protein cast formation and lower renal medullary fibrosis were observed in the sacubitril/valsartan- and valsartan-treated groups, but not when sacubitril alone was administered. Interestingly, proteinuria was mildly mitigated only in rats that received sacubitril/valsartan. Further studies of the effects of sacubitril/valsartan in the setting of SS hypertension, perhaps involving a higher dose of the drug, are warranted to determine if it can interfere with the progression of the disease.


Assuntos
Aminobutiratos/administração & dosagem , Antagonistas de Receptores de Angiotensina/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Nefropatias/tratamento farmacológico , Tetrazóis/administração & dosagem , Valsartana/administração & dosagem , Aminobutiratos/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Animais , Hipertensão/fisiopatologia , Nefropatias/fisiopatologia , Masculino , Ratos , Ratos Endogâmicos Dahl , Cloreto de Sódio na Dieta , Tetrazóis/uso terapêutico , Valsartana/uso terapêutico
16.
Medicine (Baltimore) ; 99(17): e19902, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32332668

RESUMO

BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) is a disease caused by the infiltration of blood into the subarachnoid space due to the rupture of an intracranial aneurysm. It is a serious cerebrovascular disease, with a mortality rate of about 40% worldwide, which seriously threatens human life and health. Many drugs are used to treat aSAH and its complications, and some have been tested in systematic reviews and have shown good effects. But which drug has the best effect remains unclear. This network meta-analysis (NMA) aims to assess the effectiveness and feasibility of clazosentan, cilostazol, and statins in patients with aSAH. METHODS: We will search for EMBASE.com, PubMed, the Cochrane Library, and Web of Science from inception to December 2019. Randomized controlled trials (RCTs) reporting efficacy and safety of clazosentan, cilostazol, and statins compared with the control, or compared with each other for the treatment of aSAH will be included. Two independent reviewers will assess the risk of bias of the included RCTs with the Cochrane "Risk of bias" tool. The pairwise meta-analysis will be performed with the random-effects model. The NMA will be performed in a Bayesian hierarchical framework using Markov Chain Monte Carlo method in WinBUGS 1.4.3. Egger test and funnel plot will be used to assess the publication bias. We will evaluate the quality of evidence for each outcome according to the GRADE approach. RESULTS: The results of this NMA will be submitted to a peer-reviewed journal for publication. CONCLUSION: This study will summarize up-to-date evidence to compare the efficacy and safety of clazosentan, cilostazol, and statins on aSAH.PROSPERO registration number: CRD42019147523.


Assuntos
Protocolos Clínicos , Hemorragia Subaracnóidea/tratamento farmacológico , Cilostazol/uso terapêutico , Dioxanos/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Metanálise como Assunto , Piridinas/uso terapêutico , Pirimidinas/uso terapêutico , Literatura de Revisão como Assunto , Hemorragia Subaracnóidea/fisiopatologia , Sulfonamidas/uso terapêutico , Tetrazóis/uso terapêutico
17.
Drug Des Devel Ther ; 14: 1341-1349, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32308367

RESUMO

Purpose: Fimasartan, the ninth and most recent angiotensin receptor blocker (ARB) approved by the Korea Food and Drug Administration, has shown similar efficacy and safety profiles compared to other ARBs. However, due to being predominantly excreted by the hepatobiliary system, concerns on safety have been raised regarding its use in patients with underlying liver disease. Patients and Methods: This prospective, 12-month, observational study evaluated patients with essential hypertension (HTN) receiving ≥1 dose of fimasartan. Self-reported and physician-reported events were recorded and classified according to organ class and severity. Outcomes were compared according to the absence and presence of underlying liver disease. Results: A total of 601 patients were screened, and 566 patients who met predefined inclusion criteria were grouped according to the presence of underlying liver disease. Adverse events (AE) were reported in 28.7% (128/446) of patients without prior liver disease, while 42.5% (51/120) experienced events in the group with chronic liver disease. There was no difference in discontinuations due to liver function between patients with and without baseline liver disease (1.1% [5] vs 2.5% [3], p=0.376), and only a non-significant increase was observed in events associated to the hepatobiliary system in patients with chronic liver disease (9.7% [7] vs 2.7% [9], p=0.061). There were no deaths or serious adverse drug reactions (SADR) during the study period. In multivariate regression analysis, the presence of chronic liver disease (OR 2.01), female sex (OR 1.49) and old age (OR 1.12 for every 5-year increase) were independent predictors for the development of AE. Finally, no significant difference was observed in the reduction of systolic blood pressure after 12 months of treatment (least square mean change -6.57 ± 0.80 mmHg for normal liver function group; -7.65 ± 1.59 mmHg for chronic liver disease group; p=0.546). Conclusion: Long-term use of fimasartan for treatment of HTN was associated with a low rate of adverse events overall, especially in the absence of underlying liver disease. Even for patients with chronic liver disease, fimasartan treatment was well tolerated. Fimasartan could be a safe option for long-term treatment of essential HTN. ClinicalTrials.gov identifier: NCT02385721.


Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Hipertensão/tratamento farmacológico , Hepatopatias/tratamento farmacológico , Pirimidinas/uso terapêutico , Tetrazóis/uso terapêutico , Antagonistas de Receptores de Angiotensina/administração & dosagem , Antagonistas de Receptores de Angiotensina/efeitos adversos , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/efeitos adversos , Compostos de Bifenilo/administração & dosagem , Compostos de Bifenilo/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Análise de Regressão , República da Coreia , Tetrazóis/administração & dosagem , Tetrazóis/efeitos adversos , Fatores de Tempo
18.
Rev Cardiovasc Med ; 21(1): 113-118, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32259909

RESUMO

Patients with heart failure (HF) are prone to combine with renal insufficiency. Recently, LCZ696 has been used in the treatment of HF, but whether LCZ696 is better than angiotensin converting enzyme inhibitors/angiotensin receptor antagonists (ACEI/ARB) in renal protection for HF patients has not been investigated. Therefore, we conducted a meta-analysis focusing on LCZ696 and its role in preservation of renal function in HF patients. Embase, PubMed, the Cochrane Library and ClinicalTrials.gov databases were electronically searched for available randomized controlled trials (RCTs). HF patients taking LCZ696 or ACEI/ARB were assessed for renal adverse events. The last search date was Sep 20, 2019. A total of 14959 patients from 6 trials were included in this meta-analysis. As compared to ACEI/ARB, LCZ696 significantly reduced the risk of renal function deterioration (odds ratio 0.77, 95% confidence interval 0.61-0.97, P = 0.02). In summary, LCZ696 may have superior renal protection in HF patients compared with ACEI/ARB.


Assuntos
Aminobutiratos/uso terapêutico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Rim/efeitos dos fármacos , Inibidores de Proteases/uso terapêutico , Tetrazóis/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Aminobutiratos/efeitos adversos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/efeitos adversos , Medicina Baseada em Evidências , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/fisiopatologia , Humanos , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Neprilisina/antagonistas & inibidores , Inibidores de Proteases/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Tetrazóis/efeitos adversos , Resultado do Tratamento
19.
Sci Rep ; 10(1): 6665, 2020 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-32313194

RESUMO

The aim of this study was to evaluate the effects of Sacubitril/Valsartan (S/V) on clinical, laboratory and echocardiographic parameters and outcomes in a real-world population with heart failure with reduced ejection fraction (HFrEF). This was a prospective observational study enrolling patients with HFrEF undergoing treatment with S/V. The primary outcome was the composite of cardiac death and HF rehospitalization at 12 months follow-up; secondary outcomes were all-cause death, cardiac death and the occurrence of rehospitalization for worsening HF. The clinical outcome was compared with a retrospective cohort of 90 HFrEF patients treated with standard medical therapy. The study included 90 patients (66.1 ± 11.7 years) treated with S/V. The adjusted regression analysis showed a significantly lower risk for the primary outcome (HR:0.31; 95%CI, 0.11-0.83; p = 0.019) and for HF rehospitalization (HR:0.27; 95%CI, 0.08-0.94; p = 0.039) in S/V patients as compared to the control group. A significant improvement in NYHA class, left ventricular ejection fraction, left ventricular end systolic volume and systolic pulmonary arterial pressure was observed up to 6 months. S/V did not affect negatively renal function and was associated with a significantly lower dose of furosemide dose prescribed at 6- and 12-month follow-up. In this study, S/V reduced the risk of HF rehospitalization and cardiac death at 1 year in patients with HFrEF. S/V improved NYHA class, echocardiographic parameters and need of furosemide, and preserved renal function.


Assuntos
Aminobutiratos/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Cardiotônicos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Coração/efeitos dos fármacos , Tetrazóis/uso terapêutico , Disfunção Ventricular Esquerda/tratamento farmacológico , Idoso , Pressão Arterial/efeitos dos fármacos , Estudos de Casos e Controles , Diuréticos/uso terapêutico , Ecocardiografia , Feminino , Furosemida/uso terapêutico , Coração/diagnóstico por imagem , Coração/fisiopatologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/fisiopatologia , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Readmissão do Paciente/estatística & dados numéricos , Análise de Regressão , Estudos Retrospectivos , Volume Sistólico/efeitos dos fármacos , Análise de Sobrevida , Resultado do Tratamento , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/fisiopatologia
20.
Drugs R D ; 20(2): 125-133, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32328931

RESUMO

BACKGROUND: Cenobamate is a new, Food and Drug Administration (FDA)-approved oral antiepileptic drug for treatment of focal seizures in adults. This study examined recovery of cenobamate from suspensions administered through ex vivo enteral feeding tubes. METHODS: Suspensions containing 100 and 200 mg of cenobamate were prepared (five duplicates for each dose), passed through five vertically standing tubes, and collected into flasks. The flasks containing the suspensions were rinsed with deionized water, and this content was also injected into the tubes and collected in the flasks. Acetonitrile, isopropyl alcohol, and trifluoroacetic acid were added to the flasks, followed by deionized water to a concentration of 500 (100-mg cenobamate) and 400 (200-mg cenobamate) µg/mL. A 3-mL aliquot from each suspension was placed into a 10-mL flask, diluted to volume, and mixed, resulting in final concentrations of 150 and 120 µg/mL, respectively. All suspensions were analyzed by high-performance liquid chromatography (LC). The % LC recovery of cenobamate was calculated for each suspension, and mean % LC for duplicates. RESULTS: The % LC recovery of cenobamate from the 100-mg suspensions ranged from 96.2 to 99.1%, with mean % LC recovery between 96.3 and 98.3%. The % LC recovery of cenobamate from the 200-mg suspensions ranged from 97.1 to 102.6%, with mean % LC recovery between 98.5 and 101.7%. CONCLUSION: The mean % LC recovery of cenobamate was within the predetermined acceptable range of 90.0-110.0%, suggesting no adhesion or adsorption of cenobamate to enteral feeding tubes. Delivery of cenobamate suspension via enteral feeding tubes may be a viable route of administration for patients who cannot swallow tablets.


Assuntos
Anticonvulsivantes/uso terapêutico , Carbamatos/uso terapêutico , Clorofenóis/uso terapêutico , Nutrição Enteral , Convulsões/tratamento farmacológico , Tetrazóis/uso terapêutico , Administração Oral , Anticonvulsivantes/administração & dosagem , Carbamatos/administração & dosagem , Clorofenóis/administração & dosagem , Humanos , Comprimidos/administração & dosagem , Comprimidos/uso terapêutico , Tetrazóis/administração & dosagem
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