Fast Skeletal Muscle Troponin and Tropomyosin as a Dietary Source of Antidiabetic and Antihypertensive Bioactive Peptides: An In Silico Study / Troponina y Tropomiosina de Músculo Esquelético como Fuente Alimentaria de Péptidos Bioactivos Antidiabéticos y Antihipertensivos: Estudio In Silico

Background: The nutraceutical properties of food hydrolysates rely on multiple biochemical interactions involving the modulation of enzymes and cellular receptors. Numerous bioactive peptides released from troponin and tropomyosin digestion have been identified. Their characterization has mostly been performed by hydrolysis catalyzed by proteases unrelated to the human digestive system. Objective: This study aimed to determine the bioactive profile of beef, pork, and chicken meat by analyzing the frequency and pharmacokinetics of biopeptides released from troponin and tropomyosin. Methods:In silico digestion and biopeptide release frequency were studied by three parameters; bioactive fragments release frequency (AE), frequency percentage (W), and mean occurrence (AS), all stated on the BIOPEP-UWM platform. Further on, hydrolysis end-products were screened based on gastrointestinal-absorption probability and pharmacokinetic profiling performed on SwissADME, SwissTargetPrediction, and ADME/Tlab bioinformatics web tools. Statistical analyses were performed using a one-way ANOVA test. Results: Dipeptidyl peptidase-IV (DPP-IV) and angiotensin-converting enzyme (ACE) inhibiting biopeptides exhibited the highest release frequency. Moreover, W and ASparameters showed no significant difference (p>0.05) between the myofibrillar isoforms assessed. Seven biopeptides were classified as highly absorbable and reported optimal drug-likeness compliance. Although biopeptides hold good pharmacokinetic properties, the therapeutic potency of biopeptides showed to be lower than those of DPP-IV and ACE-inhibiting drugs. Conclusions: Troponin and tropomyosin are rich dietary sources of bioactive peptides, mainly DPP-IV and ACE inhibitors. Digestion end-products are mainly dipeptides with optimal pharmacokinetic and drug-like properties, suggesting a potential therapeutic application in hypertensive and hyperglycemic disorders

Antecedentes: Las propiedades nutracéuticas de los hidrolizados de alimentos dependen de múltiples interacciones bioquímicos que involucran la modulación de enzimas y receptores celulares. Se han identificado numerosos péptidos bioactivos liberados de la digestión de troponina y tropomiosina, pero su caracterización se ha llevado a cabo principalmente por hidrólisis catalizada por proteasas ajenas al sistema digestivo humano. Objetivo: Este estudio tuvo como objetivo determinar el perfil bioactivo de la carne de res, cerdo y pollo mediante el análisis de la frecuencia y farmacocinética de los biopéptidos liberados de la troponina y la tropomiosina. Métodos: Se estudió la digestión in silico y la frecuencia de liberación de biopéptidos mediante dos parámetros; frecuencia de liberación de fragmentos bioactivos (AE), frecuencia porcentual (W) y ocurrencia media (AS), ambos indicados en la plataforma BIOPEP-UWM. Más adelante, los productos finales de la hidrólisis se examinaron en función de la probabilidad de absorción gastrointestinal y el perfil farmacocinético realizado en las herramientas bioinformáticas SwissADME, SwissTargetPrediction y ADME/Tlab. El análisis estadístico se llevó a cabo mediante una prueba ANOVA de una vía. Resultados: Los biopéptidos inhibidores de la dipeptidil peptidasa IV (DPP-IV) y la enzima convertidora de angiotensina (ECA) exhibieron la mayor frecuencia de liberación. Además, los parámetros W y ASno mostraron diferencias significativas (p> 0.05) entre las isoformas miofibrilares evaluadas. Siete biopéptidos se clasificaron como altamente absorbibles e informaron un cumplimiento óptimo de similitud con el fármaco. Aunque los biopéptidos tienen propiedades farmacocinéticas adecuadas, su potencia terapéutica demostró ser menor que la de los fármacos inhibidores de la DPP-IV y la ACE. Conclusiones: La troponina y la tropomiosina son una fuente dietética rica en péptidos bioactivos, principalmente DPP-IV e inhibidores de la ACE. Los productos finales de la digestión son principalmente dipéptidos con propiedades farmacocinéticas óptimas y similares a la de los fármacos, lo que sugiere una aplicación terapéutica factible en trastornos hipertensivos e hiperglicémicos

Role of Brain Angiotensin-II in Development of Experimental Diabetic Nephropathy in Wistar Rats

Abstract The renin-angiotensin-aldosterone system (RAAS) plays a key role in diabetic nephropathy (DN). Angiotensin-II secreted during the RAAS pathway increases nephropathy. It stimulates oxidative stress which can quench nitric oxide. Reduced nitric oxide level aggravates Ang-II-induced vasoconstriction. Ang-II has also emerged as a central mediator of the glomerular hemodynamic changes that are associated with renal injury. Deletion of ACE2 is also noted due to increased Ang-II level which leads to the development of DN. We hypothesize that nephropathy caused by Ang-II in the periphery may be controlled by brain RAAS. ACE inhibitors and ARBs may show the renoprotective effect when administered through ICV without crossing the blood-brain barrier. DN was observed after 8 weeks of diabetes induction through alloxan. Administration of captopril and valsartan once and in combined therapy for 2 weeks, significantly reduced urine output, blood urea nitrogen, total protein in the urine, serum cholesterol, serum creatinine, serum triglycerides, and kidney/body weight ratio as compared to diabetic control rats. Further, combination therapy significantly increased the body weight and serum nitrate level as compared to diabetic control animals. However, increased ACE2 levels in the brain may reduce the sympathetic outflow and might have decreased the peripheral activity of Ang-II which shows beneficial effects in DN.

Endothelial expression of the receptor for advanced glycation end products in experimental diabetes / Expresión endotelial del receptor para productos finales de glicación avanzada en diabetes experimental

The receptor for advanced glycation end products (RAGE) is implicated in the pathogenesis of several chronic diseases including diabetes. The interaction between RAGE and advanced glycation end products (AGEs) promotes gene expression, enhances the release of proinflammatory molecules and causes the generation of oxidative stress in numerous cell types. The aim of this investigation was to evaluate the effect of enalapril and losartan on RAGE expression in abdominal aortic endothelium of rats with experimentally induced diabetes. Male Sprague-Dawley rats, weighing approximately 150 - 200 g, were used. Diabetes was induced in 30 rats by intravenous administration of a single dose of 55 mg/kg body weight of streptozotocin (ETZ). The following groups were studied: control (n=10), diabetic (n=10), losartan-treated diabetic (n=10) and enalapril-treated diabetic (n=10) rats. RAGE expression in aortic endothelium was determined by indirect immunofluorescence. A significant increase in RAGE expression was observed in diabetic animals versus controls (p<0.001), there was a decrease in RAGE expression, in animals treated with losartan versus controls (p<0.01) and in those treated with enalapril (p<0.05) versus control and versus diabetes + vehicle. In conclusion, in the experimental model of ETZ-induced diabetes, there is an increase in RAGE expression at the level of the abdominal aortic endothelium, which can be reversed by treatment with losartan and/or enalapril, two drugs that block the renin-angiotensin system, suggesting its involvement in the molecular events related to vascular damage during diabetes.

El receptor para productos finales de glicación avanzada (RAGE) está implicado en la patogénesis de varias enfermedades crónicas incluyendo la diabetes. La interacción entre RAGE y los productos finales de glicación avanzada (AGEs), promueve la expresión génica, potencia la liberación de moléculas proinflamatorias y provoca la generación de estrés oxidativo en numerosos tipos de células. El objetivo de esta investigación fue evaluar el efecto del enalapril y el losartán sobre la expresión de RAGE en el endotelio de la aorta abdominal de ratas con diabetes inducida experimentalmente. Se utilizaron ratas Sprague-Dawley machos, con un peso aproximado de entre 150 - 200 g. La diabetes se indujo en 30 ratas mediante la administración intravenosa de una sola dosis de 55 mg/Kg de peso corporal de estreptozotocina (ETZ). Se estudiaron los siguientes grupos: ratas control (n=10), diabéticas (n=10), diabéticas tratadas con losartán (n=10) y diabéticas tratadas con enalapril (n=10). La expresión de RAGE en el endotelio aórtico se determinó por inmunofluorescencia indirecta. Se observó un incremento significativo en la expresión de RAGE en los animales diabéticos versus los controles (p<0.001), hubo una disminución en la expresión de RAGE, en los animales tratados con losartán versus los controles (p<0.01) y en los tratados con enalapril (p<0.05) versus control y versus diabetes + vehículo. En conclusión, en el modelo experimental de diabetes inducida por ETZ, existe un incremento en la expresión de RAGE a nivel del endotelio de la aorta abdominal, la cual puede revertirse mediante el tratamiento con losartán y/o enalapril, dos fármacos bloqueadores del sistema renina-angiotensina, lo cual sugiere la participación del mismo en los acontecimientos moleculares relacionados con el daño vascular durante la diabetes.

Perfil de medicamentos descartados nas farmácias públicas de um município do leste de Minas Gerais / Profile of medicines discarded in the public pharmacies of an eastern municipality of Minas Gerais

O descarte inadequado de medicamentos pode levar a impactos ambientais negativos e deve ser considerado um problema de saúde pública. O presente estudo teve como objetivo levantar dados quantitativos e qualitativos relacionados ao perfil dos medicamentos descartados no município de Governador Valadares - MG. O trabalho foi desenvolvido nas UAPS/ESF que possuíam farmácias, e também na Farmácia Central/Policlínica Municipal. Nesses locais, foi realizada uma análise dos medicamentos descartados no período de julho de 2017 a maio de 2018. Por meio dos dados obtidos nesse período foi possível perceber que as principais classes de medicamentos descartadas foram os inibidores da enzima conversora de angiotensina, antagonistas da angiotensina II, agentes betabloqueadores, diuréticos, hipoglicemiantes, contraceptivos hormonais e agentes modificadores de lipídeos. Além disso, foi realizada uma ação de educação em saúde e aplicado um questionário semiestruturado aos usuários participantes dos grupos operativos. Dos 34 usuários respondentes do questionário, 23 (69,70%) não tinham acesso a informação sobre o local correto de descarte e armazenamento de medicamentos. Após a ação de educação em saúde verificou-se um aumento no quantitativo de medicamentos descartados pelos usuários nas UAPS/ESF Mãe de Deus I e II, Altinópolis III e IV, Santa Rita II, São Pedro I e II e Esperança e Nossa Senhora das Graças. O trabalho desenvolvido permitiu apresentar dados relevantes para a gestão municipal demonstrando a importância do farmacêutico no cuidado em saúde e o caráter epidemiológico local da prevalência das doenças crônico não transmissíveis.

The inadequate disposal of drugs can lead to negative environmental impacts and should be treated as a public health problem. This study aimed at surveying quantitative and qualitative data related to the profile of drugs discarded in the city of Governador Valadares - MG. The work was developed in the UAPS / ESF that had pharmacies, and also in the Central Pharmacy/Municipal Polyclinic. In these locations, an analysis of the drugs discarded between July 2017 and May 2018 was carried out. Through the data obtained in this period, it was possible to notice that the main classes of drugs discarded were angiotensin-converting enzyme inhibitors, angiotensin II antagonists, beta-blocking agents, diuretics, hypoglycemic agents, hormonal contraceptives, and lipid-modifying agents. In addition, a health education action was carried out and a semi-structured questionnaire was applied to users participating in the operating groups. From the 34 users who responded the questionnaire, 23 (69.70%) did not have access to information on the correct place to dispose and store medicines. After the health education action, there was an increase in the amount of drugs discarded by users in the UAPS/ESF Mãe de Deus I and II, Altinópolis III and IV, Santa Rita II, São Pedro I and II, and Esperança and Nossa Senhora das Graças. The work carried out made it possible to present relevant data for municipal management, demonstrating the importance of the pharmacist in health care and the local epidemiological character of the prevalence of chronic non-communicable diseases.

Diferenças Raciais no Controle da Pressão Arterial em Usuários de Anti-Hipertensivos em Monoterapia: Resultados do Estudo ELSA-Brasil / Racial Differences in Blood Pressure Control from Users of Antihypertensive Monotherapy: Results from the ELSA-Brasil Study

Resumo Fundamento Aparentemente, a pior resposta a algumas classes de anti-hipertensivos, especialmente inibidores da enzima conversora da angiotensina e bloqueadores de receptor de angiotensina, pela população negra, explicaria, pelo menos parcialmente, o pior controle da hipertensão entre esses indivíduos. Entretanto, a maioria das evidências vêm de estudos norte-americanos. Objetivos Este estudo tem o objetivo de investigar a associação entre raça/cor da pele autorrelatadas e controle de PA em participantes do Estudo Longitudinal de Saúde do Adulto (ELSA-Brasil) utilizando várias classes de anti-hipertensivos em monoterapia. Métodos O estudo envolveu uma análise transversal, realizada com participantes da linha de base do ELSA-Brasil. O controle de pressão arterial foi a variável de resposta, participantes com valores de PA ≥140/90 mmHg foram considerados descontrolados em relação aos níveis de pressão arterial. A raça/cor da pele foi autorrelatada (branco, pardo, negro). Todos os participantes tiveram que responder perguntas sobre uso contínuo de medicamentos. A associação entre o controle de PA e raça/cor da pele foi estimada por regressão logística. O nível de significância adotado nesse estudo foi de 5%. Resultados Do total de 1.795 usuários de anti-hipertensivos em monoterapia na linha de base, 55,5% se declararam brancos, 27,9%, pardos e 16,7%, negros. Mesmo depois de padronizar em relação a variáveis de confusão, negros em uso de inibidores da enzima conversora de angiotensina (IECA), bloqueadores de receptor de angiotensina (BRA), diuréticos tiazídicos (DIU tiazídicos) e betabloqueadores (BB) in monoterapia tinham controle de pressão arterial pior em comparação a brancos. Conclusões Os resultados deste estudo sugerem que, nesta amostra de brasileiros adultos utilizando anti-hipertensivos em monoterapia, as diferenças de controle de pressão arterial entre os vários grupos raciais não são explicadas pela possível eficácia mais baixa dos IECA e BRA em indivíduos negros.

Abstract Background It seems that the worst response to some classes of antihypertensive drugs, especially angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, on the part of the Black population, would at least partially explain the worse control of hypertension among these individuals. However, most of the evidence comes from American studies. Objectives This study aims to investigate the association between self-reported race/skin color and BP control in participants of the Longitudinal Study of Adult Health (ELSA-Brasil), using different classes of antihypertensive drugs in monotherapy. Methods The study involved a cross-sectional analysis, carried out with participants from the baseline of ELSA-Brasil. Blood pressure control was the response variable, participants with BP values ≥140/90 mmHg were considered out of control in relation to blood pressure levels. Race/skin color was self-reported (White, Brown, Black). All participants were asked about the continuous use of medication. Association between BP control and race/skin color was estimated through logistic regression. The level of significance adopted in this study was of 5%. Results Of the total of 1,795 users of antihypertensive drugs in monotherapy at baseline, 55.5% declared themselves White, 27.9% Brown, and 16.7% Black. Even after adjusting for confounding variables, Blacks using angiotensin converting enzyme inhibitors (ACEI), angiotensin receptor blocker (ARB), thiazide diuretics (thiazide DIU), and beta-blockers (BB) in monotherapy had worse blood pressure control compared to Whites. Conclusions Our results suggest that in this sample of Brazilian adults using antihypertensive drugs in monotherapy, the differences in blood pressure control between different racial groups are not explained by the possible lower effectiveness of ACEIs and ARBs in Black individuals.

Role of ACE and ACE-2 in abrogated cardioprotective effect of ischemic preconditioning in ovariectomized rat heart

Abstract Ischemic heart disease is the leading cause of death in postmenopausal women. The activity of heart ACE increases whereas the activity of ACE-2 decreases after menopause. The present study was designed to investigate the role of ACE and ACE-2 in the abrogated cardioprotective effect of IPC in OVX rat heart. The heart was isolated from OVX rat and mounted on Langendorff's apparatus for giving intermittent cycles of IPC. The infarct size was estimated using TTC stain, and coronary effluent was analyzed for LDH, CK-MB, and nitrite release. IPC induced cardioprotection was significantly attenuated in the ovariectomized rat heart as compared to the normal rat heart. However, this attenuated cardioprotection was significantly restored by perfusion of DIZE, an ACE-2 activator, and captopril, an ACE inhibitor, alone or in combination noted in terms of decrease in myocardial infarct size, the release of LDH and CK-MB, and also increase in the release of NO as compared to untreated OVX rat heart. Thus, it is suggested that DIZE and captopril, alone or in combination restore the attenuated cardioprotective effect of IPC in OVX rat heart which is due to an increase in ACE-2 activity and decrease in ACE activity after treatment.

Comparison on the clinical characteristics of patients with Takotsubo syndrome from China and from Europe/North America / 中华心血管病杂志

Objective: To summarize the clinical characteristics of patients with Takotsubo syndrome (TTS) from China and compare these features with patients from Europe/North America. Methods: We reviewed case reports published between 1990 and 2020 with the key words of "Takotsubo syndrome" "stress cardiomyopathy" "apical balloon syndrome" and "broken heart syndrome", in Wanfang, CNKI, Pubmed and Web of Science databases, and 1 294 articles were identified, including 128 articles reporting 163 cases in China and 1 166 articles reporting 1 256 cases in Europe/North America. The characteristics of demographics, triggers, symptoms, electrocardiogram, echocardiography, left ventriculogram,coronary angiography, treatment and prognosis were analyzed and compared between Chinese and European/North American cases. Results: A total of 1 294 articles (1 419 cases: 163 from China, 1 256 from Europe/North America) were included in the final analysis. The characteristics of Chinese cases included: (1) demographic:the age was (59.6±16.9) years, which was similar with that of European/North American ((59.7±17.4) years, P=0.90), and female accounting for 78.5% (128/163), which was lower than that of European/North American (85.4% (1 073/1 256), P=0.02). (2) Triggers:mental triggers accounted for 48.5% (79/163), physical triggers accounted for 43.6% (71/163), and no triggers accounted for 7.9% (13/163), respectively. Compared with Europe/North America, the ratio of patients with mental triggers was higher in China, while the ratio of patients with physical triggers and no triggers was lower (P<0.05). (3) Symptoms: chest pain (52.8% (86/163)), chest tightness (35.0% (57/163)), shortness of breath (33.1% (54/163)), dizziness (16.0% (26/163)), sweating (15.3% (25/163)), palpitations (12.3% (20/163)), syncope (9.2% (15/163)) abdominal pain/diarrhea (8.6% (14/163)), hypotension (7.4% (12/163)), and fatigue (1.2% (2/163)) were illustrated in sequence. Compared with patients in Europe/North America, the ratio of patients with chest tightness, dizziness, sweating, palpitations, abdominal pain/diarrhea was higher in Chinese patients, while the ratio of patients with hypotension was lower in Chinese patients (P<0.05). (4) Electrocardiogram: main manifestations were myocardial ischemia symptoms, such as ST-segment elevation (63.8% (104/163)), T wave inversion (46.0% (75/163)), ST-segment depression (8.6% (14/163)). Compared with European/North American, the ratio of patients with ST-segment elevation, T wave inversion, and atrioventricular block was higher in Chinese patients (P<0.05). (5) Echocardiography and imaging:apical dyskinesia (59.5% (97/163)) and apical/left ventricular bulbar dilation (36.2%(59/163)) dominated the echocardiography findings. Compared with European/North American, the ratio of patients with apical dyskinesia, apical/left ventricular bulbar dilation, and mitral regurgitation was higher in Chinese patients, while the ratio of patients with dyskinesia in other parts and left ventricular ejection fraction<50% was lower in Chinese patients (P<0.05). Left ventricular angiography showed 36.2% (59/163) of apical dyskinesia in Chinese patients, which was higher than that reported in European/North American patients, and 38.7% (63/163) of apical/left ventricular bulbar dilation was reported in Chinese patients, which was similar to that reported in European/North American patients. Coronary angiography showed percent of no stenosis or stenosis less than 50% was 87.1% (142/163), which was similar to that reported in European/North American patients (P>0.05). The typical type of TTS accounted for 96.3% (157/163), which was significantly higher than that reported in European/ American patients, while the ratio of basal type and midventricular type was lower (P<0.01). (6) Treatment and prognosis:the applied drugs in China were listed in order as following, β-blockers (41.1% (67/163)), antiplatelet agents (37.4%(61/163)), ACEI/ARB (36.2%(59/163)), anticoagulants (27.0%(44/163)), diuretics (19.6% (32/163)), etc. Compared with Europe/North America, the ratio of antiplatelet agents, anticoagulants, statins, diuretics, and nitrates use was higher in China (P<0.05), while the use of oxygen therapy and IABP was similar (P>0.05). The hospital mortality in China was 5.5% (9/163), during 1-year follow-up the recurrence rate was 3.7% (6/163) and the mortality was 0. The prognosis was similar with that in Europe/North America. Conclusions: Compared with TTS cases in Europe/North America, TTS cases in China also occur usually in middle-aged and elderly women, most of whom have mental/physical triggers and typical imaging manifestations, followed by a low hospital mortality rate and recurrence rate.

Efficacy and safety of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation and hypertrophic cardiomyopathy / 中华心血管病杂志

Objective: To evaluate the efficacy and safety of non-vitamin K antagonist oral anticoagulants (NOAC) in patients with atrial fibrillation (AF) and hypertrophic cardiomyopathy (HCM). Methods: This study was a prospective cohort study. The data of this study were based on the Chinese Atrial Fibrillation Registry (CAFR) Study, which was a prospective, multicenter registry study. The CAFR Study enrolled inpatients and outpatients with AF from 31 hospitals. Patients with AF and HCM were selected from August 2011 to December 2018. The patients were divided into NOAC-treated group and warfarin-treated group. General clinical data, echocardiographic results and treatment options were collected and compared between the two groups. Patients were followed up every 6 months; outcome events included effective endpoint events(thromboembolism)and safety endpoint events(major bleeding). The incidence of endpoint events in both groups was calculated and compared. Cox proportional hazards regression models and Kaplan-Meier survival analysis were performed to determine the association between NOAC use and endpoint events. Results: A total of 393 patients were included (average age: (60.5±11.8) years, 252 men (64.1%)). There were 133 (34.0%) patients in the NOAC-treated group and 260 (66.0%) patients in the warfarin-treated group. Compared with the warfarin-treated group, the patients in the NOAC-treated group had a higher proportion of paroxysmal AF, catheter ablation of AF, a lower proportion of hypertension, ischemic stroke/transient ischemic attack (TIA), lower heart rate, lower usage rate of angiotensin-converting enzyme inhibitors(ACEI)/angiotensin receptor blockers(ARB), β-blockers, non-dihydropyridine calcium channel blockers(NDH-CCB)(P<0.05). There were no significant differences on the echocardiographic results, including interventricular septal thickness, left ventricular posterior wall thickness, left ventricular end-diastolic diameter, left atrial diameter, left ventricular ejection fraction(P>0.05). After a follow-up of 42 (24, 60)months, the incidence rates of thromboembolism were 1.63 and 2.10 events per 100 person-years for NOAC-and warfarin-treated group, and those of major bleeding were 0.66 and 1.03 events per 100 person-years. Kaplan-Meier survival analysis showed survival rates free from endpoint events were similar between NOAC-treated group and warfarin-treated group(thromboembolism-free survival comparison, P=0.476; major bleeding-free survival comparison, P=0.855). Cox multivariate regression analysis revealed that there was no significant difference on risk of thromboembolism(HR=1.21, 95%CI: 0.42-3.50, P=0.720) and major bleeding(HR=1.50, 95%CI: 0.27-8.41, P=0.642) between NOAC-treated and warfarin-treated group. Conclusion: Patients with AF and HCM can be safely and effectively treated with NOAC.

Clinical comprehensive evaluation of Huangkui Capsules in treatment of chronic kidney diseases / 中国中药杂志

Based on Guidelines for the Management of Clinical Comprehensive Evaluation of Drugs(trial version 2021), this study aims to sort out the clinical evidence of Huangkui Capsules(HC) in the treatment of chronic kidney diseases in aspects of safety, effectiveness, economy, innovation, suitability, accessibility, and characteristics of traditional Chinese medicine( "6+1" dimensions) from real-world data, secondary literature evaluations, questionnaires, and public data, with the methods in evidence-based medicine, epidemiology, pharmacoeconomics, and health technology. Furthermore, with multi-criteria decision analysis(MCDA) model and CSC v2.0, the clinical value of the medicine is comprehensively assessed. All the above are to highlight the advantages and characteristics of HC and lay a basis for scientific decision-making by the medical management department. The dimensions are graded A, B, C, or D. According to the conclusions from phase Ⅳ clinical trial, spontaneous reporting system(SRS), systematic review and Meta-analysis, acute toxicity and long-term toxicity tests, it mainly results in the adverse reactions of nausea, abdominal distension, vomiting, pruritus, rash, and good prognosis in patients. According to the available research, the safety evidence is sufficient and the risk is controllable, so the safety of this medicine is grade B. According to Meta-analysis, HC in combination with conventional drugs in the treatment of chronic kidney disease is superior to conventional drugs alone in reducing urinary protein, serum creatinine concentration, and blood urea nitrogen. In addition, HC combined angiotensin receptor blocker(ARB) or angiotensin converting enzyme inhibitor(ACEI) is outstanding in improving total clinical effective rate, reducing 24 h urinary protein quantity, urinary albumin excretion rate, serum creatinine concentration, triglyceride, and total cholesterol in the treatment of diabetic nephropathy as compared with ARB or ACEI alone. As for chronic nephritis, the application together with ARB or ACEI can raise the total effective rate, reduce 24 h urinary protein content, serum creatinine concentration, and blood urea nitrogen, and delay the progress of the disease. HC boasts high-quality evidence in treating chronic kidney disease, diabetic nephropathy, and chronic nephritis. It has obvious clinical significance in treating chronic kidney disease and thus its efficacy in this aspect is grade B. It has outstanding clinical significance for diabetic nephropathy and chronic nephritis and corresponding and the effectiveness is grade A. As for the pharmacoeconomic value, HC combined with ARB or ACEI is more economical in the treatment of chronic kidney disease than Bailing Capsules combined with ARB or ACEI, with high-quality evidence, and thus the economy of the formula is grade B. HC is a key solution to the high urinary protein in patients with hypotension and chronic kidney disease. The innovation is evidenced by the methods to ensuring drug supply, community-level supply, drug safety, effectiveness, and reasonable price, as wells as the aspects of enterprise philosophy, equipment management, research and development in process and technology, enterprise management and marketing. Thus, the prescription is grade A in innovation. The suitability, as evidenced in drug administration, technical management, drug storage, information service, and medication, is grade B. The course of the medicine is affordable, and it is accessible in a wide range of areas and hospitals. Thus, the accessibility is grade A. HC was developed from an in-hospital preparation, with application in numerous patients and thus large-scale real-world data. As a result, HC is grade B in terms of characteristics of traditional Chinese medicine. After comprehensive evaluation, the clinical value of HC in treating chronic kidney disease is class B, and that for diabetic nephropathy and chronic nephritis is class A. The result is of great reference value for the basic clinical medication management.

Renin-angiotensin system inhibitor is associated with the reduced risk of all-cause mortality in COVID-19 among patients with/without hypertension / 医学前沿

Consecutively hospitalized patients with confirmed coronavirus disease 2019 (COVID-19) in Wuhan, China were retrospectively enrolled from January 2020 to March 2020 to investigate the association between the use of renin-angiotensin system inhibitor (RAS-I) and the outcome of this disease. Associations between the use of RAS-I (angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB)), ACEI, and ARB and in-hospital mortality were analyzed using multivariate Cox proportional hazards regression models in overall and subgroup of hypertension status. A total of 2771 patients with COVID-19 were included, with moderate and severe cases accounting for 45.0% and 36.5%, respectively. A total of 195 (7.0%) patients died. RAS-I (hazard ratio (HR)= 0.499, 95% confidence interval (CI) 0.325-0.767) and ARB (HR = 0.410, 95% CI 0.240-0.700) use was associated with a reduced risk of all-cause mortality among patients with COVID-19. For patients with hypertension, RAS-I and ARB applications were also associated with a reduced risk of mortality with HR of 0.352 (95% CI 0.162-0.764) and 0.279 (95% CI 0.115-0.677), respectively. RAS-I exhibited protective effects on the survival outcome of COVID-19. ARB use was associated with a reduced risk of all-cause mortality among patients with COVID-19.

Infarto De Miocardio Sin Lesiones Coronarias. Subanálisis Del Registro CONAREC XVII / Myocardial infarction without coronary arteries lesions. Insights from the CONAREC XVII Registry

Los síndromes coronarios agudos sin lesiones coronarias han cobrado relevancia en los últimos años, pero aún no se dispone de datos locales. Analizamos un registro de pacientes con infarto agudo de miocardio, en 45 centros del país con residencias de cardiología. Se analizaron 1182 participantes de los cuales 33 (2.8%) no presentaron lesiones coronarias en angiografía, mientras que 89.5% tenían lesiones graves y 7.7% lesiones intermedias. La edad promedio de los pacientes sin lesiones coronarias fue 64.5 ± 13.0 años, 69.7% eran varones, sin diferencias respecto a aquellos con enfermedad epicárdica. La presentación electrocardiográfica más frecuente fue la desviación del segmento ST (13 supradesnivel y 10 infradesnivel del segmento). Además, este subgrupo presentó biomarcadores más bajos (CPK pico 203.5 UI/l, rango [RIC] 102- 422.5 vs. 895.5 UI/l RIC 350-1891, p < 0.0001). La mediana de días de internación fue 4.0 (RIC 3-5.5), siendo menor que la del grupo con enfermedad coronaria intermedia y grave (5.5 días, RIC 4-7, y 6 RIC 4-7, p = 0.003). Al alta, aquellos sin lesiones coronarias recibieron menor prescripción de IECA/ARA II (54.6% vs. 78.0% y 79.7%, p = 0.002) y estatinas (78.8% vs. 87.9% y 91.9%, p = 0.017). Ninguno de este subgrupo falleció durante la inter nación. Nuestros datos sugieren que los infartos sin lesiones coronarias significativas son frecuentes en nuestro medio, aunque probablemente se encuentren subdiagnosticados. Si bien su pronóstico parece más favorable, resulta importante señalar que recibieron menos fármacos para prevenir su recurrencia. Nuevos estudios son necesarios para profundizar el conocimiento de esta enfermedad.

Abstract Acute coronary syndromes without coronary lesions have gained relevance in recent years. However, local data on this condition is scarce. We aimed to explore this entity in a National registry of acute myocardial infarction that was carried out prospectively in hospitals with cardiology residence programs from Ar gentina. We included 1182 patients from 45 centers, where 33 did not present coronary lesions on angiography. The mean age was 64.5 ±13.0 and 69.7% were male, without differences compared to participants with epicardial disease. The most common electrocardiographic presentation was ST segment deviation. In addition, presented lower biomarkers (peak CPK 203.5 IU / l, range [IQR] 102-422.5 vs. 895.5 IU / l IQR 350-1891, p < 0.0001). The median hospitalization was 4.0 days (IQR 3-5.5), lower than the group with intermediate and severe coronary disease (5.5 days, RIC 4-7, and 6, RIC 4-7, p = 0.003). At discharge, less use of ACE/ARB (54.6% vs.78.0% y 79.7%, p = 0.002) and statins (78.8% vs. 87.9% y 91.9%, p = 0.017). No deaths during hospitalization were reported. Our data suggested that infarcts without significant coronary lesions are frequent, although they are probably underdiagnosed. Their prognosis seems to be more favorable, but they receive fewer drugs to prevent recurrence. New studies are necessary to deepen the knowledge of the disease.

Na covid-19 é real a não suspensão dos inibidores do sistema renina angiotensina aldosterona? / In covid-19, the non-suspension of inhibitors of the renina angiotensin aldosterone system is real?

A interação dos bloqueadores do sistema renina angiotensina com o SARS-CoV-2 permanece obscura. Os inibidores do sistema renina angiotensina aldosterona (IECAs) e os bloqueadores do receptor AT1 da angiotensina 2 (BRAs) são fármacos com evidências robustas para terapia farmacológica de pacientes portadores, principalmente de hipertensão arterial e insuficiência cardíaca, além de outras comorbidades cardiovasculares. Os pacientes que se beneficiam desta terapêutica são considerados grupos de risco para má evolução desta virose e não há na literatura um consenso a respeito desta questão, em vista do vírus utilizar a expressão da ECA2 para penetração no ser humano. Apesar destas considerações fisiopatológicas da biologia do vírus, as principais diretrizes recomendam não suspender a terapia dos pacientes em uso dos bloqueadores do sistema renina angiotensina aldosterona no curso da infecção com o COVID-19. Aditivamente, o estudo BRACE-CORONA trouxe evidências mais consistentes para não suspensão desses fármacos

The interaction of blockers of the renin angiotensin system with SARS-COV-2 remains unclear. Inhibitors of the renin angiotensin aldosterone system (ACE inhibitors) and angiotensin 2 AT1 receptor blockers (BRAs) are drugs with robust evidence for pharmacological therapy for patients with mainly arterial hypertension and heart failure, and other cardiovascular comorbidities. Patients who benefit from this therapy are considered groups at risk for poor evolution of this virus and the literature still does not have a consensus on this issue, in view of the virus using the expression of ECA2 to penetrate in humans. Despite these athophysiological considerations of the biology of the virus, the main guidelines recommend not to suspend therapy for patients using blockers of the renin angiotensin aldosterone system in the course of infection with COVID-19. In addition, the BRACE corona study has more consistent evidence for not suspending these drugs.

O papel dos inibidores da enzima conversora de angiotensina e dos antagonistas dos receptores de angiotensina em pacientes com Covid-19: uma revisão narrativa / The role of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Antagonists in patients with Covid-19: a narrative review

O objetivo deste trabalho é reunir e discutir os principais achados científicos, opiniões de especialistas e considerações de comunidades médicas a respeito da continuação do tratamento de pacientes hipertensos diagnosticados com Covid-19 em uso de anti-hipertensivos. Trata-se de uma revisão narrativa de literatura, restringida a publicações até abril de 2020, utilizando as bases de dados Medline e Embase e consulta a quatro sociedades científicas de Cardiologia. Um total de 93 publicações foram encontradas nas bases de dados consultadas, e, destas, nove publicações foram elegíveis para análise, sendo que seis publicações se mostraram favoráveis à continuação do tratamento com inibidores da enzima conversora de angiotensina e antagonistas dos receptores de angiotensina, o que foi ao encontro das recomendações das sociedades de Cardiologia; outras três publicações sugeriram que essas classes de anti-hipertensivos podem aumentar a gravidade da infecção. A continuação do tratamento com anti-hipertensivos durante a pandemia de coronavírus ou após o diagnóstico da infecção apresenta um paradoxo entre o potencial aumento da patogenicidade viral e a proteção pulmonar conferida pelo equilíbrio do sistema renina-angiotensina.

The objective of this work is to gather and discuss the main scientific findings, opinions and specialists in medical communities and respect for the continuation of treatment with antihypertensive drugs in hypertensive patients diagnosed with Covid-19. This is a narrative review of the literature, restricted to publications until April 2020, using Medline and Embase as a database and consulting four scientific societies of cardiology. A total of 93 publications were found in the databases consulted and of these, 9 publications were eligible for analysis, with six publications being considered favorable for the continuation of treatment with angiotensin-converting enzyme inhibitors and receptor antagonists angiotensin, which met the decisions of cardiology societies; three other publications suggested that these classes of antihypertensives may increase the severity of the infection. The continuation of treatment with antihypertensive drugs during a coronavirus pandemic or after the diagnosis of infection presents a paradox between the potential increase in viral pathogenicity and the pulmonary protection provided by the balance of the renin-angiotensin system.

O uso de inibidores do Sistema Renina-Angiotensina pode aumentar a suscetibilidade à infecção pelo SARS-CoV-2 (COVID-19)? / Can the use of Renin-Angiotensin System inhibitors increase the susceptibility to SARSCoV-2 infection (COVID-19)?

Diante do contexto pandêmico da COVID-19, esforços têm sido direcionados ao desenvolvimento de medidas terapêuticas seguras e eficazes no combate à doença. Entretanto, divergências entre as condutas adotadas nesses pacientes tem sido frequentes. Em especial, fármacos inibidores do Sistema Renina-Angiotensina, como os Inibidores da Enzima Conversora de Angiotensina e Bloqueadores do Receptor da Angiotensina, são foco de grande discussão. Diversos autores questionam uma possível relação de risco aumentado entre o uso de tais medicações e o desenvolvimento de formas mais graves da doença, ao correlacionar a regulação positiva da Enzima Conversora de Angiotensina 2 induzida por esses fármacos com o fato do SARS-CoV-2 usar essa enzima como receptor celular. Enquanto isso, outros autores defendem que essa modulação atue como fator protetor à gravidade da infecção, levando em consideração a promoção de efeitos vasodepressores, anti-fibróticos e anti-inflamatórios. Dada a alta prevalência do uso desses anti-hipertensivos, a presente revisão analisa o funcionamento do Sistema Renina-Angiotensina; aspectos moleculares do novo coronavírus; e a inibição da Angiotensina 2 no contexto dessa infecção, para discutir qual conduta seria mais adequada no manejo da hipertensão arterial e doenças cardiovasculares, dada a pandemia da COVID-19.

In the face of the pandemic context of the COVID-19, efforts have been directed to the development of safe and effective therapeutic actions in combating the disease. However, divergences between management of these patients have been frequent. Especially, Renin-Angiotensin System inhibitors, as Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers, are the focus of great discussion. Several authors question a possible increased risk relation between the use of that medication and the development of the most severe disease form, when correlating AngiotensinConverting Enzyme 2 upregulation induced by those drugs with the fact that SARS-CoV-2 uses this enzyme as its cellular receptor. Meanwhile, other authors defend that the referred modulation acts as a protective factor to infection severity, considering the induction of vasodepressor, antifibrotic and anti-inflammatory effects. Given the high prevalence of the use of those antihypertensive drugs, the present review analyses the Renin-Angiotensin System functionning; molecular aspects of the novel coronavirus; and the Angiotensin 2 inhibition in the context of this infection, in order to discuss which conduct would be more appropriate in the management of arterial hypertension and cardiovascular diseases, given the COVID-19 pandemic.

Chronic and acute effects of kefir: the role of angiotensin converting enzyme inhibition instead of nitric oxide balance

Probiotic consumption promotes numerous health benefits. The aim of this study is 1) to evaluate the antihypertensive effect of kefir in a hypertension rat model caused by the administration of the nitric oxide synthesis inhibitor, L-NAME, and 2) to evaluate the acute angiotensin converting enzyme (ACE) inhibitory activity of the soluble nonbacterial fraction (SNBF) of kefir. To develop the first aim, male rats were separated into three groups: control group (C) treated with 0.3 mL/100 g of milk; L-NAME group (LN) received 10 mg/kg of said inhibitor; and Kefir group (K) treated with 0.3 mL/100 g of kefir plus L-NAME (10 mg/kg of said inhibitor). The treatments were given by oral gavage twice a day for four weeks. For the second aim"instead additionally, male rats received angiotensin I (in bolus) in three doses (Ang I: 0.03, 3 and 300 µg/kg) and were separated into two groups: a) received captopril (30 mg/kg i.v.) and b)received SNBF of kefir (5 mL/kg i.v.). Blood pressure were evaluated before and after Ang I. After treatment, hemodynamic parameters were evaluated, heart weight was recorded, and body weight gain was calculated. SNBF of kefir did not decrease the blood pressure for L-NAMEtreated animals, and no changes were observed in the cardiac parameters. However, the SNBF of kefir demonstrated acute inhibition of ACE in vivo similar to that of captopril. Thus, our results suggest that kefir may improve human cardiovascular systems by using mechanisms independent of nitric oxide syntheses. Additionally, the renin angiotensin system is probably the most important system involved in kefir effect regarding hypertension.

Renin-Angiotensin-Aldosterone System Inhibitors in COVID-19: A Review

Among the multiple uncertainties surrounding the novel coronavirus disease (COVID-19) pandemic, a research letter published in The Lancet implicated drugs that antagonize the renin-angiotensin-aldosterone system (RAAS) in an unfavorable prognosis of COVID-19. This report prompted investigations to identify mechanisms by which blocking angiotensin-converting enzyme 2 (ACE2) could lead to serious consequences in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The possible association between RAAS inhibitors use and unfavorable prognosis in this disease may have been biased by the presence of underlying cardiovascular diseases. As the number of COVID-19 cases has increased worldwide, it has now become possible to investigate the association between RAAS inhibitors and unfavorable prognosis in larger cohorts. Observational studies and one randomized clinical trial failed to identify any consistent association between the use of these drugs and unfavorable prognosis in COVID-19. In view of the accumulated clinical evidence, several scientific societies recommend that treatment with RAAS inhibitors should not be discontinued in patients diagnosed with COVID-19 (unless contraindicated). This recommendation should be followed by clinicians and patients.

Hereditary angioedema: how to approach it at the emergency department? / Angioedema hereditário: como abordar na emergência?

ABSTRACT Angioedema attacks are common causes of emergency care, and due to the potential for severity, it is important that professionals who work in these services know their causes and management. The mechanisms involved in angioedema without urticaria may be histamine- or bradykinin-mediated. The most common causes of histamine-mediated angioedema are foods, medications, insect sting and idiopathic. When the mediator is bradykinin, the triggers are angiotensin-converting enzyme inhibitors and factors related to acquired angioedema with deficiency of C1-inhibitor or hereditary angioedema, which are less common, but very important because of the possibility of fatal outcome. Hereditary angioedema is a rare disease characterized by attacks of edema that affect the subcutaneous tissue and mucous membranes of various organs, manifesting mainly by angioedema and abdominal pain. This type of angioedema does not respond to the usual treatment with epinephrine, antihistamines and corticosteroids. Thus, if not identified and treated appropriately, these patients have an estimated risk of mortality from laryngeal edema of 25% to 40%. Hereditary angioedema treatment has changed dramatically in recent years with the development of new and efficient drugs for attack management: plasma-derived C1 inhibitor, recombinant human C1-inhibitor, bradykinin B2 receptor antagonist (icatibant), and the kallikrein inhibitor (ecallantide). In Brazil, plasma-derived C1 inhibitor and icatibant have already been approved for use. Proper management of these patients in the emergency department avoids unnecessary surgery and, especially, fatal outcomes.

RESUMO As crises de angioedema são causas comuns de atendimentos nas emergências, e devido ao potencial de gravidade, é importante que os profissionais que atuam nesses serviços conheçam suas causas e abordagem. Os mecanismos envolvidos no angioedema sem urticas podem ser histaminérgicos ou mediados por bradicinina. As causas mais comuns de angioedema mediado por histamina são alimentos, medicamentos, ferroada de insetos e idiopática. Quando o mediador é a bradicinina, os desencadeantes são os inibidores da enzima conversora de angiotensina e fatores relacionados ao angioedema adquirido com deficiência do inibidor de C1 ou angioedema hereditário que são menos comuns, mas muito importantes pela possibilidade de desfecho fatal. O angioedema hereditário é uma doença rara, caracterizada por crises de edema que acometem o tecido subcutâneo e mucosas de vários órgãos, manifestando-se principalmente por crises de angioedema e dor abdominal. Esse tipo de angioedema não responde ao tratamento usual com adrenalina, anti-histamínicos e corticosteroides. Assim, se não identificados e tratados adequadamente, esses pacientes têm risco de morte por edema de laringe estimado em 25% a 40%. O tratamento do angioedema hereditário mudou drasticamente nos últimos anos, com o desenvolvimento de novos e eficientes fármacos para as crises: inibidor de C1 derivado de plasma, inibidor de C1 recombinante humano, antagonista do receptor B2 da bradicinina (icatibanto) e o inibidor da calicreína (ecalantide). No Brasil, até o momento, estão liberados para uso o inibidor de C1 derivado de plasma e o icatibanto. O manejo correto desses pacientes na emergência evita cirurgias desnecessárias e, principalmente, desfechos fatais.