Effect of multi-glycosides of Tripterygium wilfordii on renal injury in diabetic kidney disease rats through NLRP3/caspase-1/GSDMD pyroptosis pathway / 中国中药杂志

This study investigated the effect of multi-glycosides of Tripterygium wilfordii(GTW) on renal injury in diabetic kidney disease(DKD) rats through Nod-like receptor protein 3(NLRP3)/cysteine-aspartic acid protease-1(caspase-1)/gsdermin D(GSDMD) pyroptosis pathway and the mechanism. To be specific, a total of 40 male SD rats were randomized into the normal group(n=8) and modeling group(n=34). In the modeling group, a high-sugar and high-fat diet and one-time intraperitoneal injection of streptozotocin(STZ) were used to induce DKD in rats. After successful modeling, they were randomly classified into model group, valsartan(Diovan) group, and GTW group. Normal group and model group were given normal saline, and the valsartan group and GTW group received(ig) valsartan and GTW, respectively, for 6 weeks. Blood urea nitrogen(BUN), serum creatinine(Scr), alanine ami-notransferase(ALT), albumin(ALB), and 24 hours urinary total protein(24 h-UTP) were determined by biochemical tests. The pathological changes of renal tissue were observed based on hematoxylin and eosin(HE) staining. Serum levels of interleukin-1β(IL-1β) and interleukin-18(IL-18) were detected by enzyme-linked immunosorbent assay(ELISA). Western blot was used to detect the expression of pyroptosis pathway-related proteins in renal tissue, and RT-PCR to determine the expression of pyroptosis pathway-related genes in renal tissue. Compared with the normal group, the model group showed high levels of BUN, Scr, ALT, and 24 h-UTP and serum levels of IL-1β and IL-18(P<0.01), low level of ALB(P<0.01), severe pathological damage to kidney, and high protein and mRNA levels of NLRP3, caspase-1, and GSDMD in renal tissue(P<0.01). Compared with the model group, valsartan group and GTW group had low levels of BUN, Scr, ALT, and 24 h-UTP and serum levels of IL-1β and IL-18(P<0.01), high level of ALB(P<0.01), alleviation of the pathological damage to the kidney, and low protein and mRNA levels of NLRP3, caspase-1, and GSDMD in renal tissue(P<0.01 or P<0.05). GTW may inhibit pyroptosis by decreasing the expression of NLRP3/caspase-1/GSDMD in renal tissue, thereby relieving the inflammatory response of DKD rats and the pathological injury of kidney.

Sacubitril/valsartan attenuates left ventricular remodeling and improve cardiac function by upregulating apelin/APJ pathway in rats with heart failure / 中华心血管病杂志

Objective: To investigate the effect and mechanism of sacubitril/valsartan on left ventricular remodeling and cardiac function in rats with heart failure. Methods: A total of 46 SPF-grade male Wistar rats weighed 300-350 g were acclimatized to the laboratory for 7 days. Rats were then divided into 4 groups: the heart failure group (n=12, intraperitoneal injection of adriamycin hydrochloride 2.5 mg/kg once a week for 6 consecutive weeks, establishing a model of heart failure); heart failure+sacubitril/valsartan group (treatment group, n=12, intragastric administration with sacubitril/valsartan 1 week before the first injection of adriamycin, at a dose of 60 mg·kg-1·d-1 for 7 weeks); heart failure+sacubitril/valsartan+APJ antagonist F13A group (F13A group, n=12, adriamycin and sacubitril/valsartan, intraperitoneal injection of 100 μg·kg-1·d-1 APJ antagonist F13A for 7 weeks) and control group (n=10, intraperitoneal injection of equal volume of normal saline). One week after the last injection of adriamycin or saline, transthoracic echocardiography was performed to detect the cardiac structure and function, and then the rats were executed, blood and left ventricular specimens were obtained for further analysis. Hematoxylin-eosin staining and Masson trichrome staining were performed to analyze the left ventricular pathological change and myocardial fibrosis. TUNEL staining was performed to detect cardiomyocyte apoptosis. mRNA expression of left ventricular myocardial apelin and APJ was detected by RT-qRCR. ELISA was performed to detect plasma apelin-12 concentration. The protein expression of left ventricular myocardial apelin and APJ was detected by Western blot. Results: Seven rats survived in the heart failure group, 10 in the treatment group, and 8 in the F13A group. Echocardiography showed that the left ventricular end-diastolic diameter (LVEDD) and the left ventricular end-systolic diameter (LVESD) were higher (both P<0.05), while the left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were lower in the heart failure group than in the control group (both P<0.05). Compared with the heart failure group, rats in the treatment group were featured with lower LVEDD and LVESD (both P<0.05), higher LVEF and LVFS (both P<0.05), these beneficial effects were reversed in rats assigned to F13A group (all P<0.05 vs. treatment group). The results of HE staining showed that the cardiomyocytes of rats in the control group were arranged neatly and densely structured, the cardiomyocytes in the heart failure group were arranged in disorder, distorted and the gap between cells was increased, the cardiomyocytes in the treatment group were slightly neat and dense, and cardiomyocytes in the F13A group were featured similarly as the heart failure group. Masson staining showed that there were small amount of collagen fibers in the left ventricular myocardial interstitium of the control group, while left ventricular myocardial fibrosis was significantly increased, and collagen volume fraction (CVF) was significantly higher in the heart failure group than that of the control group (P<0.05). Compared with the heart failure group, the left ventricular myocardial fibrosis and the CVF were reduced in the treatment group (both P<0.05), these effects were reversed in the F13A group (all P<0.05 vs. treatment group). TUNEL staining showed that the apoptosis index (AI) of cardiomyocytes in rats was higher in the heart failure group compared with the control group (P<0.05), which was reduced in the treatment group (P<0.05 vs. heart failure group), this effect again was reversed in the F13A group (P<0.05 vs. treatment group). The results of RT-qPCR and Western blot showed that the mRNA and protein levels of apelin and APJ in left ventricular myocardial tissue of rats were downregulated in heart failure group (all P<0.05) compared with the control group. Compared with the heart failure group, the mRNA and protein levels of apelin and APJ were upregulated in the treatment group (all P<0.05), these effects were reversed in the F13A group (all P<0.05 vs. treatment group). ELISA test showed that the plasma apelin concentration of rats was lower in the heart failure group compared with the control group (P<0.05); compared with the heart failure group, the plasma apelin concentration of rats was higher in the treatment group (P<0.05), this effect was reversed in the F13A group (P<0.05 vs. treatment group). Conclusion: Sacubitril/valsartan can partially reverse left ventricular remodeling and improve cardiac function in rats with heart failure through modulating Apelin/APJ pathways.

Efecto del Sacubitril / Valsartan sobre las variables clínicas, de laboratorio y ecocardiográficas utilizadas para el control de la insuficiencia cardíaca con fracción de eyección del ventrículo izquierdo reducida (FEVIr) de los pacientes activos del Programa de Insuficiencia Cardíaca (PIC) del Hospital Clínica Bíblica / Effect of Sacubitril / Valsartan on the clinical, laboratory and echocardiographic variables used for the control of heart failure with reduced left ventricular ejection fraction (LVEFr) in active patients of the Heart Failure Program (HFP) of the Hospital Clínica Bíblica

Resumen Introducción y objetivos: La Insuficiencia Cardíaca (IC) es un síndrome frecuente en la población adulta. Sacubitril / Valsartán (S/V) es un tratamiento novedoso para esta patología. El presente estudio pretende analizar el efecto de este medicamento sobre las variables clínicas, de laboratorio y ecocardiográficas en pacientes con IC con FEVIr. Metodología: Se realizó un estudio observacional retrospectivo de los expedientes de los pacientes del PIC que tuvieran prescrito S/V. De estos, se recopilaron datos basales y de seguimiento de los principales parámetros de relevancia pronóstica, para estos pacientes. Luego se cuantificaron los cambios generados en el tiempo una vez establecido el tratamiento y se hicieron análisis estadísticos para validar si los cambios fueron significativos. Resultados: De la totalidad de pacientes del PIC, 27 cumplieron los criterios de inclusión, con una edad promedio de 70 años y en donde 37.0% se encontraron en la dosis meta después de un seguimiento promedio de 16.4 meses. A través del estudio fue posible encontrar una diferencia estadísticamente significativa para el cambio en la FEVI para 17 pacientes (p=0.016). En los pacientes en los que se pudo recopilar la información se observó que el NT-proBNP mejoró en un 68.75%, por su parte la caminata de 6 minutos mejoró en un 77.8%. Además, solamente 7.4% de los pacientes empeoraron en su escala funcional NYHA, 7.4% fallecieron y 3.7% sufrieron hospitalización durante el estudio. Conclusiones: Basados en los parámetros estudiados y a través de los cambios generados durante el tiempo de seguimiento, fue posible definir una mejoría en los pacientes tras el uso de S/V, asociado también a una baja mortalidad e incidencia de hospitalizaciones.

Abstract Effect of Sacubitril / Valsartan on the clinical, laboratory and echocardiographic variables used for the control of heart failure with reduced left ventricular ejection fraction (LVEFr) in active patients of the Heart Failure Program (HFP) of the Hospital Clínica Bíblica Introduction and objectives: Heart failure (HF) is a common syndrome in the adult population. Sacubitril /Valsartan (S/V) is a novel treatment for this pathology. This study aims to analyze the effect of this medication on clinical, laboratory and echocardiographic variables in patients with HF and left ventricular eyección fracción reduced (LVEFr). Methodology: A retrospective observational study was conducted on patients records who are enrolled in the Heart Failure Program (HFP) and have been prescribed with S/V. For these patients, baseline and follow-up data was collected for relevant parameters. Changes over time were then quantified once the treatment with S/V was initiated, and a statistical analysis was conducted to validate whether the changes were significant. Results: Of all HFP patients, 27 met the inclusion criteria, with an average age of 70 years and where 37.0% of them were at the target dose after an average follow- up of 16.4 months. Through the study it was possible to find a statistically significant difference in a change for the ejection fraction in 17 patients (p.0.016). In patients with available clinical data, it was observed that NT-proBNP improved by 68.75%, meanwhile the 6-minute walk improved by 77.8%. In addition, only 7.4% of patients worsened their NYHA functional scale, 3.7% were hospitalized and 7.4% died during the time. Conclusions: Based on the studied parameters and throughout all the clinical changes during the follow-up time, it was possible to establish an improvement in patients after the S/V therapy, which is also associated with a low hospitalization incidence and a low mortality rate.

Esofagitis por píldoras / Pill-induced esophageal injury

Si bien no se encuentra entre las principales causas de disfagia u odinofagia, la lesión de la mucosa del esófago a causa de la medicación administrada como píldoras debe ser tenida en cuenta, en particular en algún grupo etario con patologías crónicas. Presentamos el caso de una mujer con dolor retroesternal de confuso diagnóstico y buena evolución con tratamiento conservador. El mecanismo preciso por el cual se producen las lesiones no está bien claro. La videoendoscopia digestiva alta es la herramienta clave para observar las lesiones producidas y realizar diagnóstico diferencial; además puede resolver algunas complicaciones. En la mayoría de los casos, el tratamiento es médico. Esta situación debe tenerse presente para realizar un correcto interrogatorio y examen endoscópico.

Dysphagia and odynophagia should be considered as symptoms of pill-induced esophageal injury, particularly in age groups with chronic diseases. We report a case of a female patient with retrosternal chest pain of unclear diagnosis and favorable outcome with conservative treatment. The precise mechanism of esophageal injury remains uncertain. Upper gastrointestinal videoendoscopy is the essential tool to examine the lesions, make differential diagnosis and treat some complications. Medical treatment is useful in most cases. This condition should be kept in mind for proper interrogation and endoscopic examination.

Experiencia con sacubitril/valsartán en una clínica de falla cardiaca / Experience with sacubitril/valsartan in a heart failure clinic

Resumen Objetivo: describir las características y el comportamiento clínico de pacientes tratados con sacubitril/valsartán en una clínica de falla cardiaca de un hospital de alta complejidad. Métodos: se analizaron en retrospectiva 56 pacientes en manejo con sacubitril/valsartán, entre enero de 2017 y mayo de 2018. A los tres meses de inicio del tratamiento, 87% de los pacientes fueron evaluados. Se determinaron cambios en clase funcional, fracción de eyección ventricular izquierda (FEVI) y presión arterial sistólica y diastólica. Se registraron reingresos hospitalarios por falla cardiaca, mortalidad cardiovascular y eventos adversos asociados a la medicación. Resultados: la edad promedio fue 71,3 años; 51,7% correspondían al sexo masculino, 73% tenía etiología isquémica, 35% clase funcional NYHA II y 60% NYHA III antes de iniciar el tratamiento con sacubitril/valsartán. Al finalizar el seguimiento, 57% mejoró su clase funcional y 81,7% se encontraba en clase funcional NYHA II (IC95%, -0,52 a-0,18; p=0,0002). Hubo mejoría significativa en los valores de FEVI respecto a los basales (IC95%, 4,27 a 11,86; p=0,0002). Se observó una disminución significativa de la presión arterial tanto sistólica como diastólica (p<0,01). Un paciente presentó muerte súbita (2%) y uno hospitalización por falla cardiaca (2%). Ningún paciente descontinuó la terapia por efectos adversos. Conclusión: sacubitril/valsartán es una terapia útil en pacientes con falla cardiaca sintomática y FEVI reducida. La población evaluada tenía un perfil demográfico y clínico semejante al del ensayo clínico PARADIGM-HF, lo cual sugiere que los desenlaces clínicos son similares en la población colombiana.

Abstract Objective: The aim of this study is to describe the characteristics and clinical behaviour of patients treated with sacubitril/valsartan in a heart failure clinic of a high complexity hospital. Methods: A retrospective analysis was performed on a total of 56 patients on treatment with sacubitril/valsartan, between January 2017 and May 2018. At three months from the start of the treatment, 87% of the patients were evaluated. Changes were observed in functional class, left ventricular ejection fraction (LVEF), and systolic and diastolic arterial pressure. A record was made of hospital re-admissions due to heart failure, cardiovascular mortality, and adverse events associated with the medication. Results: The mean age of the patients was 71.3 years, of which 51.7% were male. An ischaemic origin was found in 73%. NYHA II and NYHA III functional class was observed 35% and 60%, respectively, before starting the treatment with sacubitril/valsartan. At the end of follow-up, 57% improved their functional class, and 81.7% were found to be in NYHA II functional class (95% CI; -0.52 to -0.18:=0.0002). There was a significant improvement in the LVEF values compared to baseline (95% CI; 4.27 to 11.86; P=0.0002). A significant decrease was observed in both systolic and diastolic blood pressure (P<0.01). There was sudden death in one (2%) patient and one (2%) patient admitted due to heart failure. None of the patients stopped the therapy due to secondary effects. Conclusion: Sacubitril/valsartan is a useful therapy in patients with symptomatic heart failure and a decreased LVEF. The population evaluated had a demographic and similar clinical signs and symptoms to the PARADIGM-HF clinical trial, which suggests that the clinical outcomes are similar in the Colombian population.

Efficacy and safety of early initiation of sacubitril-valsartan therapy in patients with acute decompensated heart failure / 中华心血管病杂志

Objective: To assess the efficacy and safety of the initiation of sacubitril-valsartan （ARNI） therapy, as compared with ACEI therapy, after hemodynamic stabilization among patients hospitalized for acute decompensated heart failure （ADHF）. Methods: A total of 199 hospitalized patients for ADHF in our department from January 2017 to June 2019 were included in this retrospective analysis. According to the medication early after hemodynamic stabilization, patients were divided into ARNI group (n=92) and ACEI group (n=107). Among the included patients, 61 patients with newly diagnosed heart failure at the time of admission were also divided into ARNI group (n=30) and ACEI group (n=31) according to the applied medication. Clinical baseline data and follow-up results of enrolled patients were collected through the electronic medical records at admission, outpatient and telephone follow-up. The primary effectiveness observation index was left ventricular ejection fraction (LVEF) and left ventricular end diastolic dimension (LVEDD) measured by echocardiography; the secondary observation index was death from any causes and hospitalization for heart failure. Safety outcomes were the incidences of symptomatic hypotension, worsening renal function, hyperkalemia, and angioedema. Results: The clinical baseline characteristics were similar between ARNI group and ACEI group（all P>0.05）. The duration of follow up was (15.2±6.5) months in all patients enrolled, (12.3±5.0) months in ARNI group, and (18.2±6.5) months in ACEI group. At the end of follow-up, prevalence of an absolute LVEF increase of more than 5% was 48.9% (45/92) in ANRI group and 25.2% (27/107) in ACEI group (P=0.001). Percent of LVEF increase to more than 50% was 17.4% (16/92) in ANRI group and 3.7% (4/107) in ACEI group (P=0.001). Percent of patients with more than 10 mm LVEDD reduction was 14.1% (13/92) in ANRI group and 3.7% (4/107) in ACEI group (P=0.009). All-cause mortality rate was 5.7% (5/88) in ARNI group and 15.3% (13/85) in ACEI group (P=0.038). Rate of re-hospitalization due to heart failure was 50% (46/92) in ARNI group and 71% (76/107) in ACEI group（P=0.002）.The rates of symptomatic hypotension, worsening renal function, hyperkalemia, and angioedema were similar between ARNI group and ACEI group (all P>0.05). In patients with first diagnosed heart failure，percent of LVEF increase to more than 50% was 30% (9/30) in ANRI group and 6.5% (2/31) in ACEI group (P=0.017). Percent of more than 10 mm LVEDD reduction was 26.7%(8/30) in ANRI group and 3.2%(1/31) in ACEI group (P=0.012). Percent of an absolute LVEF increase of more than 5% was 53.3% (16/30) in ANRI group and 51.6% (16/31) in ACEI group (P=0.893). Re-hospitalization due to heart failure was 23.3% (7/30） in ARNI group and 73.3% (11/31) in ACEI group（P<0.01）. Rate of all-cause death tended to be lower in patients receiving ARNI (3.4% (1/29)) as compared to patients receiving ACEI (13.0% (3/23), P=0.197）. Conclusions: Among patients with heart failure with reduced ejection fraction hospitalized for ADHF, the initiation of ARNI therapy after hemodynamic stabilization is associated with a more significant improvement of cardiac remodeling and pump function than ACEI therapy and satisfactory safety. In ADHF patients with first diagnosed heart failure, initiation of ARNI therapy after hemodynamic stabilization can more effectively improve cardiac remodeling and pump function than treatment with ACEI.

Prevenção secundária e doenças cardiovascular: onde estamos? / Secondary prevention and cardiovascular disease: where are we?

As doenças cardiovasculares, principalmente as decorrentes de casos de acidente vascular cerebral e infarto agudo do miocárdio, têm importante impacto na mortalidade global e nas internações hospitalares em todo o mundo. A despeito do vasto conhecimento dos diversos fatores de risco implicados na gênese da doença cardiovascular, o número de eventos ainda se mantém elevado e a instituição de medidas de prevenção primária e secundária são essenciais e complementares. Nos últimos anos, importantes avanços no campo do tratamento farmacológico de aterosclerose e insuficiência cardíaca, predominantemente em decorrência de cardiopatia isquêmica, foram publicados e seus principais resultados são destacados no presente artigo

Cardiovascular diseases, particularly those arising from cases of stroke and acute myocardial infarction, have a significant impact on global mortality and hospital admissions around the world. Despite the vast knowledge of the various risk factors involved in the genesis of cardiovascular disease, the number of events remains high and institution of primary and secondary prevention measures is essential and complementary. In recent years, important advances in the field of pharmacological treatment of atherosclerosis and heart failure, particularly those arising from ischemic heart disease, have been published. The main results are highlighted in this article

Circulating microparticles and central blood pressure according to antihypertensive strategy

OBJECTIVES: This prospective, randomized, open-label study aimed to compare the effects of antihypertensive treatment based on amlodipine or hydrochlorothiazide on the circulating microparticles and central blood pressure values of hypertensive patients. METHODS: The effects of treatments on circulating microparticles were assessed during monotherapy and after the consecutive addition of valsartan and rosuvastatin followed by the withdrawal of rosuvastatin. Each treatment period lasted for 30 days. Central blood pressure and pulse wave velocity were measured at the end of each period. Endothelial, monocyte, and platelet circulating microparticles were determined by flow cytometry. Central blood pressure values and pulse wave velocity were recorded at the end of each treatment period. RESULTS: No differences in brachial blood pressure were observed between the treatment groups throughout the study. Although similar central blood pressure values were observed during monotherapy, lower systolic and diastolic central blood pressure values and early and late blood pressure peaks were observed in the amlodipine arm after the addition of valsartan alone or combined with rosuvastatin. Hydrochlorothiazide-based therapy was associated with a lower number of endothelial microparticles throughout the study, whereas a higher number of platelet microparticles was observed after rosuvastatin withdrawal in the amlodipine arm. CONCLUSIONS: Despite similar brachial blood pressure values between groups throughout the study, exposure to amlodipine was associated with lower central blood pressure values after combination with valsartan, indicating a beneficial interaction. Differences between circulating microparticles were modest and were mainly influenced by rosuvastatin withdrawal in the amlodipine arm.

Combinação dose fixa de hidroclorotiazida (12, 5 mg) e valsartana (160 mg): Desenvolvimento de metodologia de dissolução in vitro e in silico para avaliar os perfis de dissolução dos produtos comercializados no Brasil e Peru / Fixed dose combination of hydrochlorothiazide (12. 5 mg) and valsartan (160 mg): Development of in vitro and in silico dissolution methodology to evaluate the dissolution profiles of products marketed in Brazil and Peru

Hidroclorothiazida (HTZ) e valsartana (VAL) são fármacos pouco solúveis em meio aquoso e pertencem às classes IV e II do Sistema de Classificação Biofarmacêutica (SCB), respectivamente. O objetivo deste trabalho foi desenvolver um método para avaliar o perfil de dissolução de formas farmacêuticas sólidas de dose fixa combinada contendo HTZ (12,5 mg) e VAL (160 mg) usando ferramentas in silico para avaliar os perfis de dissolução de produtos comercializados no Brasil e Peru. O presente trabalho foi dividido em 4 capítulos. No Capítulo I, foi determinada a solubilidade da HTZ e VAL pelo método shake-flask e potenciométrico, no qual foi possível demonstrar que existe correlação entre ambos os métodos e que HTZ e VAL são solúveis em tampão fosfato pH 6,8. No Capítulo II, um método cromatográfico em HPLC foi desenvolvido com base em Quality by Design (QbD), com auxílio do software Fusion®, no qual foi estabelecido uma zona de confiança dos parâmetros, que garantiu a robustez do método. O Capítulo III descreve o desenvolvimento de um método de dissolução utilizando ferramenta in silico (DDDplus®) na qual foi definido um delineamento experimental do tipo fatorial completo 33 usando como fatores a formulação, utilização de âncora e velocidade de agitação. Para os ensaios de dissolução in vitro, foi proposto um outro delineamento fatorial 3(3-1) com o intuito de obter as constantes de calibração das simulações in silico. Através de uma análise estatística das eficiências de dissolução obtidas nas simulações, foram avaliados os efeitos e as interações entre os fatores. Assim, as condições finais do método de dissolução estabelecidas foram: 900 mL de tampão fosfato pH 6,8 como meio de dissolução, 75 rpm de velocidade de agitação, e utilização de âncora para evitar a flutuação das formulações. O método desenvolvido foi empregado, no contexto do Capítulo IV, para avaliar o perfil de dissolução dos produtos contendo HTZ e VAL comercializados no Brasil e no Peru. Por análise multivariada, a eficiência de dissolução (ED), tempo médio de dissolução (MDT) e as porcentagens de dissolução de 5 até 60 minutos foram utilizadas para agrupar as formulações em grupos distintos. Embora os perfis de dissolução mostrem similaridade entre todas as formulações avaliadas, o produto referência se destacou por apresentar uma maior ED comparado com as outras formulações, devido à maior liberação nos primeiros 5 minutos de ensaio. Concluiu-se que o método proposto, além de garantir a liberação total de HTZ e VAL a partir das formulações, possui adequado poder discriminativo

Hydrochlorothiazide (HTZ) and valsartan (VAL) are poorly soluble drugs in aqueous medium and belong to classes IV and II of the Biopharmaceutical Classification System (BCS), respectively. The objective of this study was to develop a dissolution method to evaluate the dissolution profile of solid pharmaceutical forms of combined dose containing HTZ (12.5 mg) and VAL (160 mg) using in silico tools to evaluate the dissolution profiles of products sold in Brazil and Peru. The present study was divided into four chapters. In Chapter I, the HTZ and VAL solubility were determined by the shake-flask and potentiometric methods, in which it was possible to demonstrate that there is a correlation between both methods and that HTZ and VAL are soluble in pH 6.8 phosphate buffer. In Chapter II, a chromatographic method in HPLC was developed based on Quality by Design (QbD), using the Fusion® software, in which a zone of confidence of the parameters was established, which ensured the robustness of the method. Chapter III presents the development of a dissolution method using in silico (DDDplusTM) as a tool, in which an experimental design of the complete factorial type 33 was defined using as factors: the formulation, use of sinker and agitation speed. For in vitro dissolution assays, another factor design 3(3-1) was proposed to obtain the calibration constants of the in silico simulations. Through a statistical analysis of the dissolution efficiencies obtained in the simulations, the effects and interactions between the factors were evaluated. Thus, the final conditions of the dissolution method established were: 900 mL of pH 6.8 phosphate buffer as a dissolution medium, 75 rpm of stirring speed, and use of sinker to avoid the fluctuation of the formulations. The method developed was used, in the context of Chapter IV, to evaluate the dissolution profile of HTZ and VAL products marketed in Brazil and Peru. By multivariate analysis, the dissolution efficiency (ED), mean dissolution time (MDT) and the dissolution percentages from 5 to 60 minutes were used to group the formulations in different groups. Although the dissolution profiles show a similarity between all the evaluated formulations, the reference product stood out for presenting a higher ED compared to the other formulations, due to the higher release in the first 5 minutes of the test. It was concluded that the proposed method, besides guaranteeing the total release of HTZ and VAL from the formulations, has adequate discriminatory capacity

Issues on carcinogen contaminated antihypertensive drugs and constructing drug safety management system

European Medicines Agency withdrew valsartan from European market in July 2018 because it was contaminated with carcinogen, N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA). Medicines and Healthcare Products Regulatory Agency also found the same contamination and withdrew it from England market. US Food and Drug Administration followed the action after confirming its contamination. Ministry of Food and Drug Safety (MFDS) conducted testing all the valsartans at Korean market and withdrew some of them from market after confirming the contamination with NDMA. MFDS provided the pharmaceutical companies and laboratory institutions with the manual for testing both NDMA and NDEA and educated relevant personnels. MFDS also evaluated the health impact of the contaminated valsartan on the hypertensive patients who took the valsartan, which was shown to be very low risk of additional cancer incidence. MFDS pronounced strengthening of the safety management for the raw materials of the medicines. For guaranteeing the safety of medicines, more comprehensive drug safety management system from developing new drugs to consuming the medicines should be established. For achieving such a goal, active participation of all the stakeholders of the medicines including governmental agencies including MFDS and Ministry of Health and Welfare, the National Assembly, healthcare professionals, pharmaceutical companies, mass media, and general population including patients should be needed.

Sacubitril/Valsartan in Asian Patients with Heart Failure with Reduced Ejection Fraction

The Prospective comparison of Angiotensin Receptor-neprilysin inhibitor (ARNI) with Angiotensin converting enzyme inhibitor (ACEI) to Determine Impact on Global Mortality and morbidity in Heart Failure (HF) trial (PARADIGM-HF) showed that adding a neprilysin inhibitor (sacubitril) to a renin-angiotensin system blocker (and other standard therapy) reduced morbidity and mortality in ambulatory patients with chronic HF with reduced ejection fraction (HFrEF). In PARADIGM-HF, valsartan combined with sacubitril (a so-called ARNI) was superior to the current gold standard of an ACEI, specifically enalapril, reducing the risk of the primary composite outcome of cardiovascular (CV) death or first HF hospitalization by 20% and all-cause death by 16%. Following the results of PARADIGM-HF, sacubitril/valsartan was approved by American and European regulatory authorities for the treatment of HFrEF. The burden of HF in Asia is substantial, both due to the huge population of the region and as a result of increasing CV risk factors and disease. Both the prevalence and mortality associated with HF are high in Asia. In the following review, we discuss the development of sacubitril/valsartan, the prototype ARNI, and the available evidence for its efficacy and safety in Asian patients with HFrEF.

Actualización en el uso de inhibidores de la neprilisina y del receptor de angiotensina II: onda expansiva en el beneficio sobre distintas entidades / Update on the use of neprilysin inhibitors and angiotensin II receptor: shock wave for the benefit of different entities

Resumen La insuficiencia cardiaca es una de las principales enfermedades a nivel cardiaco debido a su mayor riesgo de mortalidad y de hospitalizaciones por descompensaciones agudas o por presencia de novo de falla cardiaca, por eso en los últimos años se desarrollaron a partir de estudios clínicos randomizados, medicamentos que mejoraran estos eventos, a partir del estudio PARADIGM-HF. Con el surgimiento de sacubitril/valsartan se evaluó su efecto en diferentes escenarios, así el enfoque de este artículo se basa en la revisión de artículos con el objetivo de analizar la importancia de los efectos be neficiosos del sacubitril/valsartan en comparación con enalapril en diferentes análisis y subestudios basado en el estudio PARADIGM-HF, en los cuales se evaluó el impacto del sacubitril/valsartan en diabetes mellitus tipo 2, en la función renal, hipertensión arterial, a nivel de mortalidad y seguridad, a nivel de edad, de hiperkalemia e hiperkalemia severa, en los factores asociados con la falta de cumplimiento durante el período de ejecución antes de la aleatorización y la influen cia en el beneficio estimado de sacubitril/valsartan en el ensayo PARADIGM-HF, eficacia de sacubitril/valsartan con dosis metas bajas, tolerabilidad y seguridad en el inicio de sacubitril/valsartan en insuficiencia cardiaca, efectos de sacubitril/ valsartan asociado a antagonistas de receptores de mineralocorticoides en la reducción de hiperkalemia, implicaciones en el pronóstico de los pacientes con insuficiencia cardiaca con fracción de eyección reducida con los cambios de pépti dos natriuréticos, eficacia y seguridad de sacubitril/valsartan en distintos rangos de edades, efecto del fármaco sobre la terapia de fondo utilizada en insuficiencia cardiaca y eficacia e influencia de sacubitril/valsartan en la fracción de eyección y desenlace primario.

Abstract Descriptores: sacubitril/valsartan, enalapril, insuficiencia cardiaca, péptidos natriureticos Heart failure is one of the main diseases at the cardiac level due to its higher risk of mortality and hospitalizations due to acute decompensation or de novo heart failure, which is why in recent years they were developed from randomized clinical trials. medicines that will improve these events, from there and from the PARADIGM-HF study. From the emergence of sacubitril / valsartan its effect was evaluated in different scenarios, hence the focus of this article was based on the review of articles and with the aim of analyzing the importance of the beneficial effects of sacubitril / valsartan compared to enalapril in different analyzes and substudies from the PARADIGM-HF study, which will evaluate the impact of sacubitril / valsartan in type 2 diabetes mellitus, in renal function, arterial hypertension, in terms of mortality and safety, in terms of age, hyperkalemia and severe hyperkalemia, in the factors associated with non-compliance during the execution period before randomization and the influence on the estimated benefit of sacubitril / valsartan in the PARADIGM-HF trial, efficacy of sacubitril / valsartan with low target doses , tolerability and safety at the onset of sacubitril / valsartan in heart failure, effects of sacubitril / valsartan associated with antag of mineralocorticoid receptors in the reduction of hyperkalemia, implications in the prognosis of patients with heart failure with reduced ejection fraction with changes in natriuretic peptides, efficacy and safety of sacubitril / valsartan in different age ranges, effect of the drug on the background therapy used in heart failure and the efficacy and influence of sacubitril / valsartan on the ejection fraction and primary outcome.

Un novedoso agente en el tratamiento de la insuficiencia cardiaca con función sistólica deprimida / A novel agent in the treatment of heart failure with depressed systolic function

Resumen Introducción: Se revisará la evolución del tratamiento farmacológico de la insuficiencia cardiaca (IC) en los últimos 25 an˜os, desde el concepto de tratamiento con vasodilatadores, pasando por el bloqueo o inhibición del sistema renina-angiotensina-aldosterona y la inhibición betaadrenérgica y su importante contribución en la disminución de la morbimortalidad por IC, el papel de los péptidos natriuréticos y, finalmente, se conocerá uno de los estudios más importantes en el área cardiológica y específicamente en el manejo de la IC, en el cual se demuestra un enfoque modulador de los sistemas neuro humorales que se activan en estos pacientes. Objetivos: La IC constituye la etapa final de la mayoría de las enfermedades cardiovasculares, con una alta tasa de hospitalización y de morbimortalidad cardiovascular, siendo, por lo tanto, de interés constante la necesidad de encontrar un agente terapéutico innovador que disminuya significativamente estas complicaciones y también que mejore la calidad de vida de los que la presentan. Metodología: Se realizará una descripción del PARADIGM-HF Clinical Trial, que utilizó un compuesto sacubitrilo/valsartán para el manejo de la IC con un mecanismo modulador diferente del concepto de bloqueador de sistemas deletéreos que se activan cuando un paciente presenta síntomas y signos de IC. Conclusiones: La muerte por causas cardiovasculares u hospitalización por IC (el punto final primario) se produjo en 914 pacientes (21.8%) en el grupo sacubitrilo/valsartán y 1,117 pacientes (26.5%) en el grupo de enalapril (razón de riesgo en el grupo sacubitrilo/valsartán, 0.80; intervalo de confianza (IC) del 95%: 0.73 a 0.87; p < 0.001 (exacta p = 4.0 × 10 - 7)). De los pacientes que recibieron sacubitrilo/valsartán, 537 (12.8%) fueron hospitalizados por IC, en comparación con los 658 pacientes (15.6%) que recibieron enalapril (razón de riesgo, 0.79; IC del 95%, 0.71 a 0.89; p < 0.001). Un total de 711 pacientes (17.0%) en el grupo sacubitrilo/valsartán y 835 pacientes (19.8%) en el grupo de enalapril murió (razón de riesgo de muerte por cualquier causa, 0.84; IC del 95%, 0.76 a la 0.93; p < 0.001).

Abstract Introduction: A review is presented on the evolution of the pharmacological treatment of heart failure (HF) in the last 25 years, from the concept of treatment with vasodilators to the blocking or inhibition of the renin angiotensin aldosterone system. Beta-adrenergic inhibition and its important contribution in the reduction of morbidity and mortality due to HF will be discussed along with the role of the natriuretic peptides. One of the most important studies in the cardiology area, and specifically in the management of HF, is presented, in which an approach is demonstrated of the modulator of the neurohumoral systems that are activated in these patients. Objectives: HF is the final stage of most cardiovascular diseases, and has a high rate of hospital admission, as well as cardiovascular morbidity and mortality. Therefore, there is constant interest in the need to find an innovative therapeutic agent that significantly reduces these complications and that improves the quality of life of those who suffer from it. Methods: A description will be presented of the PARADIGM-HF Clinical Trial using a sacubitril/valsartán compound for the management of HF with a modulating mechanism different from the concept of a deleterious system blocker that is activated when a patient has symptoms and signs of heart failure. Conclusions: Death due to cardiovascular causes, or hospital admission due to heart failure (the primary endpoint) occurred in 914 patients (21.8%) in the Sacubitril / valsartán group, and 1117 patients (26.5%) in the enalapril group (risk ratio in the sacubitril / valsartán group, 0.80, with a 95% confidence interval [CI]: 0.73 to 0.87, P<0.001 ;exact P= 4.0 × 10 --7;). Of the patients receiving sacubitril / valsartán, 537 (12.8%) were hospitalised due to heart failure, compared with 658 patients (15.6%) receiving enalapril (hazard ratio 0.79, 95% CI: 0.71 to 0.89, P<.001). A total of 711 patients (17.0%) in the sacubitril / valsartán group, and 835 patients (19.8%) in the enalapril group, died (all-cause death rate, 0.84, 95% CI: 0.76 to 0.93, P<.001)

Remodelación inversa del miocardio y reducción de marcadores inflamatorios en pacientes con insuficiencia cardíaca tratada con sacubitrilo/valsartán / Remodelamento reverso do miocárdio e redução de marcadores inflamatórios em pacientes com insuficiência cardíaca tratados com sacubitrilo/valsartan / Reverse myocardial remodeling and reduction of inflammatory markers in patients with heart failure treated with sacubitril/valsartan

Objetivo. Evaluar la evolución de la clase funcional (CF), marcadores de inflamación y función ventricular izquierda en pacientes con miocardiopatía de etiología variada y deterioro severo de la función sistólica luego de seis meses de tratamiento con sacubitrilo/valsartán (S/V). Métodos. Pacientes con fracción de eyección (FE) ≤40%, CF II-IV según NYHA, medicados con S/V y que se encontraban en tratamiento farmacológico instaurado al menos por 3 meses. Se tituló S/V a dosis máxima tolerada junto con beta bloqueantes y antagonistas de los mineralocorticoides. Se realizaron ecocardiograma con medición de FE por método de Simpson's biplano, dosaje de proteína C reactiva (PCR), eritrosedimentación (ES) y un test de caminata de 6 minutos (TC6M) al inicio y a los 6 meses. Se aplicó la prueba estadística T student y la prueba de normalidad Kolmogorov-Smirnov & Shapiro-Wilk. Resultados. Se incluyeron 18 pacientes. El promedio de dosis de S/V fue de 275 mg. Se observó una disminución del diámetro diastólico del ventrículo izquierdo (DDVI) a los 6 meses de 64,54 a 61,41 mm; p=0,05 (3,128; 0,29 a 6,285; IC 95%). El diámetro sistólico del ventrículo izquierdo (DSVI) disminuyó de 51,20 a 43,69 mm; p=0,002 (7,511; 3,292 a 11,730; IC 95%). La FE aumentó de 27,78 a 38,94%; p=0,003 (11,167; 18,081 a 4,252; IC 95%). Los pacientes mejoraron su CF a los 6 meses; p=0,001 (1,111; 0,821 a 1,401; IC 95%). El TC6M aumentó a los 6 meses de 332,22 a 495,00 metros; p=0,001 (162,778; 201,01 a 124,455; IC 95%). También disminuyeron significativamente los niveles de PCR, ES y el números de internaciones. Conclusión. En nuestra población, S/V detuvo la remodelación ventricular generando mejoría de la FE, con reducción de la inflamación sistémica y mejoría en la CF. Estos resultados (prometedores de nuestra pequeña muestra) requieren una nueva evaluación (confirmación) a través de estudios más grandes con períodos de seguimiento más prolongados.

Objective. To evaluate functional class (FC), markers of inflammation and left ventricular function in patients with myocardiopathy of varied etiology and severe deterioration of systolic function after six months of treatment with sacubitril/valsartan (S/V). Methods. Patients with ejection fraction (EF) ≤40% NYHA FC II-IV medicated with S / V and who are in pharmacological treatment established for at least 3 months. It was titled S / V at maximum tolerated dose together with beta-blockers and mineralocorticoid antagonists. We were made echocardiogram with EF measurement by Simpson's biplane method, C-reactive protein (CRP) dose, erythrosedimentation (ES) and a 6-minute walk test (6MWT) at baseline and at 6 months of treatment with S/V. The student's T test and the Kolmogorov-Smirnov & Shapiro-Wilk normality test were applied. Results. We included 18 patients. The mean dose was of S/V 275 mg. A decrease in left ventricular diastolic diameter (LVDD) was observed at 6 months from 64.54 to 61.41 mm; p=0.05 (3.128, 0.29 to 6.285, 95% CI). The left ventricular systolic diameter (LVSD) decreased from 51.20 to 43.69 mm; p=0.002 (7.511, 3.292 to 11.730, 95% CI). The EF increased from 27.78 to 38.94%; p=0.003 (11.167; 18.081 to 4.252; 95% CI). The patients improved their FC at 6 months; p=0.001 (1,111, 0.821 to 1.401, 95% CI). The 6MWT increased after 6 months from 332.22 to 495.00 meters; p=0.001 (162.778; 201.01 to 124.455; 95% CI). Also, the levels of CRP, ES and numbers of hospitalizations decreased significantly. Conclusion. In our population, S/V stopped the ventricular remodeling generating improvement of the EF, with reduction of systemic inflammation and improvement in FC. Promising results from our small sample that requires confirmation larger studies with longer follow-up periods.

Objetivo. Avaliar a evolução da classe funcional (CF), marcadores de inflamação e função ventricular esquerda em pacientes com miocardiopatia de etiologia variada e grave deterioração da função sistólica após seis meses de tratamento com sacubitrilo/valsartan (S/V). Métodos. Pacientes com fração de ejeção (FE) ≤40%, CF II-IV de acordo com a NYHA, medicados com S/V e que estão em tratamento farmacológico estabelecido há pelo menos 3 meses. Foi intitulado S/V na dose máxima tolerada juntamente com beta-bloqueadores e antagonistas mineralocorticoides. Se realizaram ecocardiograma com a medida da FE pelo método biplano de Simpson, dose de proteína C reativa (PCR), eritrosedimentação (ES) e teste de caminhada de 6 minutos (TC6M) no início e aos 6 meses de tratamento com S/V. O teste t de Student e o teste de normalidade de Kolmogorov-Smirnov e Shapiro-Wilk foram aplicados. Resultados. Nós incluímos 18 pacientes. A dose média foi de S/V 275 mg. Observou-se diminuição do diâmetro diastólico do ventrículo esquerdo (DDVE) aos 6 meses de 64,54 para 61,41 mm; p=0,05 (3,128, 0,29 a 6,285, IC 95%). O diâmetro sistólico do ventrículo esquerdo (DSVE) diminuiu de 51,20 para 43,69 mm; p=0,002 (7,511, 3,292 a 11,730, IC 95%). A FE aumentou de 27,78 para 38,94%; p=0,003 (11,167; 18,081 a 4,252; IC 95%). Os pacientes melhoraram sua CF aos 6 meses; p=0,001 (1,111, 0,821 a 1,401, IC 95%). O TC6M aumentou após 6 meses, de 332,22 para 495,00 metros; p=0,001 (162.778; 201,01 a 124,455; IC 95%). Além disso, os níveis de PCR, ES e número de hospitalizações diminuíram significativamente. Conclusão. Em nossa população, a S/V interrompeu o remodelamento ventricular gerando melhora da FE, com redução da inflamação sistêmica e melhora da CF. Estes resultados promissores da nossa pequena amostra exige uma confirmação através de estudos maiores com períodos de acompanhamento mais longos.

Insuficiência cardíaca - fisiopatologia atual e implicações terapêuticas / Heart failure - current pathophysiology and terapeutic implications

Conhecer a fisiopatologia da insuficiência cardíaca propiciou uma evolução terapêutica em seu manejo, que se traduziu em melhora de desfechos clínicos relevantes, incluindo redução da mortalidade. O conceito do remodelamento ventricular, associado à ativação neuro-humoral descrita inicialmente, via ativação do sistema renina-angiotensina-aldosterona, e posteriormente via ativação simpática, levou ao uso de inibidores da ECA e de betabloqueadores, respectivamente, que mudaram o curso da história da insuficiência cardíaca. Ainda na categoria farmacológica, mais recentemente a modulação da rota da neprilisina, através do uso do composto sacubitril/valsartan, trouxe impacto adicional de redução de mortalidade em pacientes com insuficiência cardíaca. Por fim, dispositivos que também interfiram no processo de remodelamento ventricular, como marcapassos de ressincronização biventricular, demonstraram benefícios clínicos significativos. Novos alvos moleculares, microRNAs ou moléculas de sinalização intracelular, devem crescer como potenciais áreas de investigação na progressão da doença e, potencialmente, se transformarem em alvos terapêuticos

Knowledge of the pathophysiology of heart failure has led to a therapeutic evolution in its management that has resulted in improved clinical outcomes, including a reduction in mortality. The concept of ventricular remodeling associated with neurohumoral activation, initially described via activation of the renin-angiotensin-aldosterone system and later, via sympathetic activation, led to the use of ACE inhibitors and beta blockers, respectively, altering the course of history of heart failure. Also in the pharmacological category, more recently, modulation of the neprilysin route, through the use of the compound sacubitril/valsartan, brought additional impacts in reducing mortality in patients with heart failure. Finally, devices that also interfere in the process of ventricular remodeling, such as biventricular resynchronization pacemakers, have demonstrated significant clinical benefits. New molecular targets, microRNAs, or intracellular signaling molecules should increase as potential areas of research on disease progression, and could potentially become therapeutic targets

Continuous wavelet transform methods for the simultaneous determinations and dissolution profiles of valsartan and hydrochlorothiazide in tablets

ABSTRACT Continuous wavelet transform (CWT) was proposed for the simultaneous determination and dissolution profiles of valsartan (VAL) and hydrochlorothiazide (HCT) in tablets, without the use of a chemical separation procedure. The CWT approach was applied to the original UV spectra and their ratio spectra in the optimal wavelength ranges. After testing several wavelet families, Mexican hat function-CWT and Daubechies7-CWT (mexh-CWT and db7-CWT, respectively) were found to be suitable for the transformation of the original UV spectra. In the following procedure, mexh-CWT and Coiflets3-CWT (coif3-CWT) were found to be appropriate for the signal analysis of ratio spectra (RS) of VAL/HCT and HCT/VAL. Calibration graphs for VAL and HCT were obtained by measuring db7-CWT and mexh-CWT amplitudes in the transformation of the original absorption spectra and RS-coif-CWT and RS-mexh-CWT amplitudes in the transformation of the ratio spectra. The validity and applicability of the proposed CWT methods were evaluated through the analysis of an independent set of synthetic binary mixtures consisting of VAL and HCT. The proposed signal processing methods were then successfully applied to the simultaneous quantitative evaluation and simultaneous dissolution profiles of the related drugs in commercial tablets, with good agreement reported for the experimental results.