RESUMO
Sartans, as a class of antihypertensive drugs, pose a threat to human health when illegally added to herbal beverages. It is crucial to detect sartans in herbal beverages. We have developed a highly sensitive monoclonal antibody against candesartan (CAN), olmesartan medoxomil (OLM), and irbesartan (IRB), with 50% inhibitory concentrations (IC50) that were obtained via indirect enzyme-linked immunosorbent assay (ic-ELISA) as 0.178 ng mL-1, 0.185 ng mL-1, and 0.262 ng mL-1 against CAN, OLM, and IRB, respectively. Based on this monoclonal antibody, we developed a rapid screening method for CAN, OLM, and IRB in herbal beverage samples using an immunochromatographic assay (ICA) strip. Test for 15 minutes after simple and rapid sample pre-treatment and the results of this method can be obtained through naked eye observation. The detection limits (LODs) of the ICA strip for CAN, OLM, and IRB in herbal beverage samples are lower than 0.15 ng mL-1, and the results of the ICA strip and ic-ELISA are consistent in spiked samples and recovery experiments. Therefore, this method can quickly, efficiently, and reliably achieve high-throughput on-site rapid detection of illegally added CAN, OLM, and IRB in herbal beverages.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II , Benzimidazóis , Bebidas , Compostos de Bifenilo , Tetrazóis , Humanos , Olmesartana Medoxomila , Irbesartana , Anticorpos Monoclonais/químicaRESUMO
The bile acid tauroursodeoxycholic acid (TUDCA) is of natural origin and is used in traditional Chinese medicine for centuries. Earlier its use was limited to biliary disorders but owing to its pleiotropic effects dietary TUDCA supplementation is under clinical trials for diseases including type 1 and 2 diabetic complications. The current study aims to evaluate the potential and underlying molecular mechanism of the TUDCA as a monotherapy and as an add-on therapy to telmisartan, an angiotensin II type 1 receptor (AT1R) blocker against diabetic kidney disease (DKD). We employed both in-vitro and in-vivo approaches where NRK-52E cells were incubated with high glucose, and DKD was induced in Wistar rats using streptozotocin (55 mg/kg, i.p.). After 4 weeks, animals were administered with TUDCA (250 mg/kg, i.p.), telmisartan (10 mg/kg, p.o.), and their combination for 4 weeks. Plasma was collected for the biochemical estimation and kidneys were used for immunoblotting, PCR, and histopathological analysis. Similarly, for in-vitro experiments, cells were exposed to 1000 µM of TUDCA and 10 µM of telmisartan, and their combination, followed by cell lysate collection and immunoblotting analysis. We observed that the addition of TUDCA to conventional telmisartan treatment was more effective in restoring the renal function decline and suppressing the apoptotic and fibrotic signaling as compared to monotherapies of AT1R blocker and ER stress inhibitor. The results implicate the utility of traditionally used TUDCA as a potential renoprotective compound. Since, both TUDCA and telmisartan are approved for clinical usage, thus concomitant administration of them could be a novel therapeutic strategy against DKD.
Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , Ratos , Animais , Nefropatias Diabéticas/tratamento farmacológico , Telmisartan/farmacologia , Telmisartan/uso terapêutico , Estreptozocina , Ratos Wistar , Ácido Tauroquenodesoxicólico/farmacologia , Ácido Tauroquenodesoxicólico/uso terapêutico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Diabetes Mellitus/tratamento farmacológicoRESUMO
Backgrounds: Estrogen replacement therapy (ERT) and hypertension may influence females' renin-angiotensin system (RAS) and its components. The angiotensin II (Ang II) type 1 receptor (AT1R) antagonist (losartan) may promote renal blood flow (RBF), and it is widely used in the clinic to control hypertension. The main objective of this study was the effects of estradiol or induced hypertension on RBF response to Ang II in losartan-treated ovariectomized (OVX) rats. Methods: Two groups of OVX rats were treated with placebo (group 1) and estradiol (group 2) for period of four weeks, and another group of OVX rats was subjected to induce hypertension by two-kidney one clip (2K1C) model (group 3). All the groups were subjected to the surgical procedure under anesthesia, and AT1R was blocked by losartan. RBF and renal vascular resistance (RVR) responses to Ang II administration were determined and compared. Results: Mean arterial (MAP) and renal perfusion (RPP) pressures in group 3 and uterus weight (UT) in group 2 were significantly more than other groups (P < 0.05). Ang II infusion resulted in dose-related percentage change increase in RBF and decrease in RVR. However, these responses in the OVX-estradiol and OVX-hypertensive rats were significantly lower than in the OVX-control group (P < 0.05). For instance, at the dose of 1000 ng/kg/min of Ang II administration, the percentage change of RBF was 45.1 ± 10.4%, 17.9 ± 2.3%, and 16.7 ± 4.7% in the groups of 1 to 3, respectively. Conclusion: Losartan prescription in some conditions such as hypertension or ERT could worsen RBF and RVR responses to Ang II.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II , Hipertensão , Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Pressão Sanguínea , Estradiol/farmacologia , Feminino , Hipertensão/tratamento farmacológico , Losartan/farmacologia , Ratos , Receptor Tipo 1 de Angiotensina , Circulação RenalRESUMO
Importance: SARS-CoV-2 viral entry may disrupt angiotensin II (AII) homeostasis, contributing to COVID-19 induced lung injury. AII type 1 receptor blockade mitigates lung injury in preclinical models, although data in humans with COVID-19 remain mixed. Objective: To test the efficacy of losartan to reduce lung injury in hospitalized patients with COVID-19. Design, Setting, and Participants: This blinded, placebo-controlled randomized clinical trial was conducted in 13 hospitals in the United States from April 2020 to February 2021. Hospitalized patients with COVID-19 and a respiratory sequential organ failure assessment score of at least 1 and not already using a renin-angiotensin-aldosterone system (RAAS) inhibitor were eligible for participation. Data were analyzed from April 19 to August 24, 2021. Interventions: Losartan 50 mg orally twice daily vs equivalent placebo for 10 days or until hospital discharge. Main Outcomes and Measures: The primary outcome was the imputed arterial partial pressure of oxygen to fraction of inspired oxygen (Pao2:Fio2) ratio at 7 days. Secondary outcomes included ordinal COVID-19 severity; days without supplemental o2, ventilation, or vasopressors; and mortality. Losartan pharmacokinetics and RAAS components (AII, angiotensin-[1-7] and angiotensin-converting enzymes 1 and 2)] were measured in a subgroup of participants. Results: A total of 205 participants (mean [SD] age, 55.2 [15.7] years; 123 [60.0%] men) were randomized, with 101 participants assigned to losartan and 104 participants assigned to placebo. Compared with placebo, losartan did not significantly affect Pao2:Fio2 ratio at 7 days (difference, -24.8 [95%, -55.6 to 6.1]; P = .12). Compared with placebo, losartan did not improve any secondary clinical outcomes and led to fewer vasopressor-free days than placebo (median [IQR], 9.4 [9.1-9.8] vasopressor-free days vs 8.7 [8.2-9.3] vasopressor-free days). Conclusions and Relevance: This randomized clinical trial found that initiation of orally administered losartan to hospitalized patients with COVID-19 and acute lung injury did not improve Pao2:Fio2 ratio at 7 days. These data may have implications for ongoing clinical trials. Trial Registration: ClinicalTrials.gov Identifier: NCT04312009.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Tratamento Farmacológico da COVID-19 , COVID-19/complicações , Losartan/uso terapêutico , Lesão Pulmonar/prevenção & controle , Lesão Pulmonar/virologia , Adulto , Idoso , COVID-19/diagnóstico , Método Duplo-Cego , Feminino , Hospitalização , Humanos , Lesão Pulmonar/diagnóstico , Masculino , Pessoa de Meia-Idade , Escores de Disfunção Orgânica , Testes de Função Respiratória , Estados UnidosRESUMO
BACKGROUND: This study aimed to detect the effect of angiotensin receptor 1 (AT1) knock out (KO) on spermatogenesis and hypothalamic-pituitary-gonadal (HPG) axis hormone expression. METHODS: Normal C57BL/6 male mice were used as control group or treated with angiotensin receptor blocker, in addition heterozygous ± AT1KO mice were generated. After caged at a ratio of 2 to 1 with females, pregnancy rates of female mice were determined by detection of vaginal plugs. Deformity rate of spermatozoa was evaluated by eosin staining and morphology evaluation. The AT1 mRNA expression in the testes of male ± AT1KO mice was detected by quantitative real-time polymerase chain reaction (QRT-PCR). Serum GnRH level was determined by ELISA. RESULTS: Compared to control, ± AT1KO mice showed reduced expression of AT1 in testes, pituitary and hypothalamus. In addition, decreased level of GnRH, but not follicle stimulating hormone (FSH) or luteinizing hormone (LH), in ± AT1KO mice was detected. Treatment with angiotensin receptor blocker (ARB) did not have significant effects on HPG hormones. ± AT1KO mice exhibited male infertility and significant abnormality of sperm morphology. CONCLUSION: Reduced AT1 knockout resulted in male infertility, potentially by inducing abnormal spermatogenesis. Both testis and HPG axis signaling may be involved.
Assuntos
Hormônio Liberador de Gonadotropina/metabolismo , Infertilidade Masculina/genética , Receptor Tipo 1 de Angiotensina/genética , Espermatogênese/genética , Testículo/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Hormônio Liberador de Gonadotropina/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Infertilidade Masculina/metabolismo , Losartan/farmacologia , Masculino , Camundongos , Camundongos Knockout , Hipófise/efeitos dos fármacos , Hipófise/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Espermatogênese/efeitos dos fármacos , Testículo/efeitos dos fármacosRESUMO
Hypertrophic cardiomyopathy (HCM) is the most common monogenic cardiac disease with a highly variable phenotypic expression, ranging from asymptomatic to drug refractory heart failure (HF) presentation. Pharmacological therapy is the first line of treatment, but options are currently limited to nonspecific medication like betablockers or calcium channel inhibitors, with frequent suboptimal results. While being the gold standard practice for the management of drug refractory HCM patients, septal reduction therapy (SRT) remains an invasive procedure with associated surgical risks and it requires the expertise of the operating centre, thus limiting its accessibility. It is therefore with high interest that researchers look for pharmacological alternatives that could provide higher rates of success. With new data gathering these past years as well as the development of a new drug class showing promising results, this review provides an up-to-date focused synthesis of existing medical treatment options and future directions for HCM pharmacological treatment.
Assuntos
Cardiomiopatia Hipertrófica/tratamento farmacológico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Animais , Bloqueadores dos Canais de Cálcio/uso terapêutico , Cardiomiopatia Hipertrófica/fisiopatologia , Fármacos Cardiovasculares/uso terapêutico , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Reposicionamento de Medicamentos , Humanos , Miosinas/antagonistas & inibidores , Bloqueadores dos Canais de Sódio/uso terapêutico , Espironolactona/uso terapêutico , Vasodilatadores/uso terapêuticoRESUMO
Angiotensin II-type 1 receptor stimulation is recognised to promote inflammation, a state central to the development and maintenance of rheumatoid arthritis. Herein we examined the use of losartan, an angiotensin II-type 1 receptor antagonist, on vascular reactivity, knee joint diameter and behavioural assessment of pain in a Freund's complete adjuvant (FCA) mouse model of joint inflammation. Monoarthritis was induced via FCA in the presence or absence of losartan with naive mice serving as controls. Knee joint swelling, joint pain (assessed by dynamic weight bearing of limb use), knee joint artery reactivity (assessed ex vivo) and blood perfusion of the knee joint (assessed in vivo) were determined. FCA mediated a significant increase in knee joint diameter and reduced weight-bearing (a surrogate for pain sensation) of the affected limb. Notably, these phenomena were substantially reduced when mice were prophylactically treated with losartan. Assessment of arterial relaxation and blood perfusion with acetylcholine stimulation revealed that FCA resulted in significant vascular dysfunction, which was resolved to naïve levels with losartan treatment. Through the actions of losartan, these findings indicate that the angiotensin II-type 1 receptor is a likely therapeutic target of importance in the development of the physical changes, pain sensation and vascular dysfunction found in inflammatory arthritis.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Losartan/farmacologia , Acetilcolina/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Animais , Artérias/efeitos dos fármacos , Artralgia/induzido quimicamente , Artralgia/tratamento farmacológico , Circulação Sanguínea/efeitos dos fármacos , Citocinas/sangue , Adjuvante de Freund/toxicidade , Injeções Intraperitoneais , Articulação do Joelho/efeitos dos fármacos , Losartan/administração & dosagem , Masculino , Camundongos Endogâmicos C57BL , Nitroprussiato/farmacologia , Suporte de CargaRESUMO
Pulmonary regurgitation (PR) after repair of tetralogy of Fallot (rTOF) is associated with progressive right (RV) and left (LV) ventricular dysfunction and fibrosis. However, angiotensin II receptor blockade therapy has shown mixed and often disappointing results. The aim of this study was to serially assess changes in biventricular remodeling, dysfunction, and interactions in a rat model of isolated severe PR and to study the effects of angiotensin II receptor blockade. PR was induced in Sprague-Dawley rats by leaflet laceration. Shams (n = 6) were compared with PR (n = 5) and PR + losartan treatment (n = 6). In the treatment group, oral losartan (50 mg·kg-1·day-1) was started 6 wk after PR induction and continued for 6 wk until the terminal experiment. In all groups, serial echocardiography was performed every 2 wk until the terminal experiment where biventricular myocardium was harvested and analyzed for fibrosis. PR and PR + losartan rats experienced early progressive RV dilatation by 2 wk which then stabilized. RV systolic dysfunction occurred from 4 wk after insult and gradually progressed. In PR rats, RV dilatation caused diastolic LV compression and impaired relaxation. PR rats developed increased RV fibrosis compared with shams. Although losartan decreased RV fibrosis, RV dilatation and dysfunction were not improved. This suggests that RV dilatation is an early consequence of PR and affects LV relaxation. RV dysfunction may progress independent of further remodeling. Reduced RV fibrosis was not associated with improved RV function and may not be a viable therapeutic target in rTOF with predominant RV volume loading.NEW & NOTEWORTHY The time-course of RV dilatation and the mechanisms of biventricular dysfunction caused by PR have not been well characterized and the effect of losartan in volume-overloaded RV remains controversial. Our findings suggest that severe PR induces early onset of RV dilatation and dysfunction with little progression after the first 4 wk. The RV dilatation distorts LV geometry with associated impaired LV relaxation. Losartan reduced RV fibrosis but did not reverse RV dilatation and dysfunction.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Losartan/uso terapêutico , Insuficiência da Valva Pulmonar/complicações , Disfunção Ventricular Esquerda/tratamento farmacológico , Disfunção Ventricular Direita/tratamento farmacológico , Animais , Modelos Animais de Doenças , Ecocardiografia , Fibrose/tratamento farmacológico , Fibrose/etiologia , Fibrose/fisiopatologia , Insuficiência da Valva Pulmonar/fisiopatologia , Ratos , Ratos Sprague-Dawley , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/fisiopatologia , Disfunção Ventricular Direita/etiologia , Disfunção Ventricular Direita/fisiopatologiaRESUMO
Cardiac fibrosis plays an important role in hypertension-related contractile dysfunction and heart failure. Qingda granule (QDG), derived from the Qingxuan Jiangya decoction, has been used clinically for more than 60 years to treat hypertension. However, the effect of QDG on hypertensive cardiac fibrosis remains largely unknown. The objective of this study was to investigate the effect of QDG on cardiac fibrosis and explore the underlying mechanism in vivo and in vitro. For in vivo experiments, 30 male spontaneously hypertensive rats were randomly divided into groups that received no QDG or one of three doses (0.45, 0.9 or 1.8 g/kg/day). Positive-control animals received valsartan (VAL, 7.2 mg/kg/day). Treatments were administered by gavage for 10 weeks. All three doses of QDG and VAL led to significantly lower blood pressure than in SHR animals. Besides, all three doses of QDG and VAL attenuated pathological changes in SHR animals. However, only intermediate, high concentrations of QDG and VAL led to significantly lower left ventricle ejection fraction and left ventricle fractional shortening than in SHR animals. Therefore, the minimum and effective QDG dose (intermediate concentration of QDG) was selected for subsequent animal experiments in this study. Our results showed that intermediate concentration of QDG also significantly mitigated the increases in levels of α-smooth muscle actin (α-SMA), proliferating cell nuclear antigen (PCNA), collagen III, transforming growth factor-ß1 (TGF-ß1) and in the ratio of phospho-Smad2/3 to total Smad2/3 protein in cardiac tissue, based on immunohistochemistry, Western blotting, and Masson staining. For in vitro experiments, primary cardiac fibroblasts were stimulated with 100 nM angiotensin II in the presence or absence of QDG. And we tested different concentrations of QDG (3.125, 6.25, 12.5, 25, 50 µg/mL) in the cell viability experiment. Our results showed that 3.125, 6.25 and 12.5 µg/mL of QDG treatment for 24 h didn't affect the cell viability of cardiac fibroblasts. Consistently, QDG at 6.25 or 12.5 µg/mL significantly reduced cell viability and down-regulated α-SMA in primary cardiac fibroblasts were stimulated with 100 nM angiotensin II. Therefore, QDG at 12.5 µg/mL was chosen for the following cell experiment. Our results showed that QDG at 12.5 µg/mL alleviated the increase of PCNA, collagen â ¢, TGF-ß1 expression, and the ratio of phospho-Smad2/3 to total Smad2/3 protein. Our studies in vitro and in vivo suggest that QDG reduces blood pressure and cardiac fibrosis as well as protecting cardiac function, and that it exerts these effects in part by suppressing TGF-ß1/Smad2/3 signaling.
Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Miocárdio/patologia , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/efeitos dos fármacos , Proteína Smad3/efeitos dos fármacos , Fator de Crescimento Transformador beta1/efeitos dos fármacos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Animais , Pressão Sanguínea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ecocardiografia , Fibrose , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Valsartana/uso terapêuticoRESUMO
Combination therapies of compound danshen dripping pill (CDDP) and Azilsartan (AZ) represent a promising treatment option in clinical practice in China, but there are no reports on drug-drug interactions between CDDP and AZ. This study investigated the effects of CDDP on the pharmacokinetics of AZ and clarified its potential mechanism. The pharmacokinetic profiles of oral administration of AZ (2 mg/kg) in Sprague-Dawley rats, with or without pre-treatment of CDDP (81, 405, 810 mg/kg/d for 7 d) were investigated using UPLC-MS/MS. The main pharmacokinetic parameters were calculated and compared. The MS analysis was performed in positive ionization mode. The purpose of chromatographic separation of AZ and the internal standard (IS, Valsartan) was finished on a Waters XBridge BEH C18 column (2.1 × 100 mm, 2.5 µm). The mobile phase was acetonitrile and 0.1 % formic acid-water with gradient elution at a flow rate of 0.4 mL/min. The mRNA and protein levels of CYP2B1, CYP2C6, and CYP2C11 in the rat liver were detected by qRT-PCR and western blot, respectively. The results indicated that low, medium and high doses of CDDP significantly increased the Cmax (6.47 ± 2.28, 6.51 ± 1.99, 7.04 ± 1.31 vs. 3.30 ± 1.87) of AZ, compared with that in the AZ single-drug group (p<0.05). The AUC0-t of AZ (47.77 ± 23.41, 50.69 ± 25.46, 54.50 ± 11.57 vs. 26.85 ± 16.79) tended to increase in combination with CDDP. The gene and protein expression levels of CYP2B1, CYP2C6, and CYP2C11 were significantly reduced in the rat liver by CDDP. CDDP may diminish the AZ metabolism in vivo by suppressing the expression of the CYP2B1, CYP2C6, and CYP2C11 enzymes. This observation suggested the occurrence of potential interactions between CDDP and AZ when clinically administered as combination therapy, which may require adjustment of the clinical dose of AZ.
Assuntos
Medicamentos de Ervas Chinesas , Espectrometria de Massas em Tandem , Bloqueadores do Receptor Tipo 1 de Angiotensina II , Animais , Canfanos , China , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Citocromo P-450 CYP2B1 , Medicamentos de Ervas Chinesas/análise , Isoenzimas , Panax notoginseng , Ratos , Ratos Sprague-Dawley , Salvia miltiorrhizaRESUMO
Astrocytes play an essential role in the genesis, maturation and regulation of the neurovascular unit. Multiple evidence support that astrocyte reactivity has a close relationship to neurovascular unit dysfunction, oxidative stress and inflammation, providing a suitable scenario for the development of mental disorders. Ketamine has been proposed as a single-use antidepressant treatment in major depression, and its antidepressant effects have been associated with anti-inflammatory properties. However, Ketamine long-lasting effects over the neurovascular unit components remain unclear. Angiotensin II AT1 receptor (AT1 -R) blockers have anti-inflammatory, antioxidant and neuroprotective effects. The present work aims to distinguish the acute and long-term Ketamine effects over astrocytes response extended to other neurovascular unit components, and the involvement of AT1 -R, in prefrontal cortex and ventral tegmental area. Male Wistar rats were administered with AT1 -R antagonist Candesartan/Vehicle (days 1-10) and Ketamine/Saline (days 6-10). After 14 days drug-free, at basal conditions or after Ketamine Challenge, the brains were processed for oxidative stress analysis, cresyl violet staining and immunohistochemistry for glial, neuronal activation and vascular markers. Repeated Ketamine administration induced long-lasting region-dependent astrocyte reactivity and morphological alterations, and neuroadaptative changes observed as exacerbated oxidative stress and neuronal activation, prevented by the AT1 -R blockade. Ketamine Challenge decreased microglial and astrocyte reactivity and augmented cellular apoptosis, independently of previous treatment. Overall, AT1 -R is involved in the development of neuroadaptative changes induced by repeated Ketamine administration but does not interfere with the acute effects supporting the potential use of AT1 -R blockers as a Ketamine complementary therapy in mental disorders.
Assuntos
Astrócitos , Ketamina , Bloqueadores do Receptor Tipo 1 de Angiotensina II , Animais , Ketamina/toxicidade , Masculino , Estresse Oxidativo , Ratos , Ratos WistarRESUMO
Mechanical ventilation (MV) is a life-saving intervention for many critically ill patients. Unfortunately, prolonged MV results in the rapid development of inspiratory muscle weakness due to diaphragmatic atrophy and contractile dysfunction (termed ventilator-induced diaphragm dysfunction (VIDD)). Although VIDD is a major risk factor for problems in weaning patients from MV, a standard therapy to prevent VIDD does not exist. However, emerging evidence suggests that pharmacological blockade of angiotensin II type 1 receptors (AT1Rs) protects against VIDD. Nonetheless, the essential characteristics of AT1R blockers (ARBs) required to protect against VIDD remain unclear. To determine the traits of ARBs that are vital for protection against VIDD, we compared the efficacy of two clinically relevant ARBs, irbesartan and olmesartan; these ARBs differ in molecular structure and effects on AT1Rs. Specifically, olmesartan blocks both angiotensin II (AngII) binding and mechanical activation of AT1Rs, whereas irbesartan prevents only AngII binding to AT1Rs. Using a well-established preclinical model of prolonged MV, we tested the hypothesis that compared with irbesartan, olmesartan provides greater protection against VIDD. Our results reveal that irbesartan does not protect against VIDD whereas olmesartan defends against both MV-induced diaphragmatic atrophy and contractile dysfunction. These findings support the hypothesis that olmesartan is superior to irbesartan in protecting against VIDD and are consistent with the concept that blockade of mechanical activation of AT1Rs is a required property of ARBs to shield against VIDD. These important findings provide a foundation for future clinical trials to evaluate ARBs as a therapy to protect against VIDD.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Diafragma/patologia , Respiração Artificial/efeitos adversos , Animais , Atrofia/etiologia , Atrofia/prevenção & controle , Diafragma/efeitos dos fármacos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Imidazóis/administração & dosagem , Irbesartana/administração & dosagem , Ratos , Respiração Artificial/instrumentação , Tetrazóis/administração & dosagem , Ventiladores Mecânicos/efeitos adversosRESUMO
BACKGROUND: Retrospective studies on the use of Renin-Angiotensin-Aldosterone System blockade in patients with Coronavirus Disease 2019 (COVID-19) have been informative but conflicting, and prospective studies are required to demonstrate the safety, tolerability, and outcomes of initiating these agents in hospitalized patients with COVID-19 and hypertension. METHODS AND FINDINGS: This is a single center feasibility study encompassing two cohorts: (1) prospective cohort (April 21, 2020 to May 29, 2020) and (2) retrospective cohort (March 7, 2020 to April 1, 2020) of hospitalized patients with real-time polymerase chain reaction (PCR) positive SARS-CoV-2 by nasopharyngeal swab. Key inclusion criteria include BP > 130/80 and a requirement of supplemental oxygen with FiO2 of 25% or higher to maintain SpO2 > 92%. Key exclusion criteria included hyperkalemia and acute kidney injury (AKI) at the time of enrollment. Prospective cohort consisted of de novo initiation of losartan and continuation for a minimum of 7 days and assessed for adverse events (AKI, hyperkalemia, transaminitis, hypotension) and clinical outcomes (change in SpO2/FiO2 and inflammatory markers, need for ICU admission and mechanical ventilation). Retrospective cohort consisted of continuation of losartan (prior-to-hospitalization) and assessment of similar outcomes. In the prospective cohort, a total of 250 hospitalized patients were screened and inclusion/exclusion criteria were met in 16/250 patients and in the retrospective cohort, a total of 317 hospitalized patients were screened and inclusion/exclusion criteria were met in 14/317 patients. Most common adverse event was hypotension, leading to discontinuation in 3/16 (19%) and 2/14 (14%) patients in the prospective and retrospective cohort. No patients developed AKI in the prospective cohort as compared to 1/14 (7%) patients in the retrospective cohort, requiring discontinuation of losartan. Hyperkalemia occurred in 1/16 (6%) and 0/14 patients in the prospective and retrospective cohorts, respectively. In the prospective cohort, 3/16 (19%) and 2/16 (13%) patients required ICU admission and mechanical ventilation. In comparison, 3/14 (21%) required ICU admission and mechanical ventilation in the retrospective cohort. A majority of patients in both cohorts (14/16 (88%) and 13/14 (93%) patients from the prospective and retrospective cohort) were discharged alive from the hospital. A total of 9/16 (prospective) and 5/14 (retrospective) patients completed a minimum 7 days of losartan. In these 9 patients in the prospective cohort, a significant improvement in SpO2/FiO2 ratio was observed from day 1 to 7. No significant changes in inflammatory markers (initiation, peak, and day 7) were observed in either cohort. CONCLUSION: In this pilot study we demonstrate that losartan was well-tolerated among hospitalized patients with COVID-19 and hypertension. We also demonstrate the feasibility of patient recruitment and the appropriate parameters to assess the outcomes and safety of losartan initiation or continuation, which provides a framework for future randomized clinical trials.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , COVID-19/patologia , Hipertensão/tratamento farmacológico , Losartan/uso terapêutico , Idoso , Bloqueadores do Receptor Tipo 1 de Angiotensina II/efeitos adversos , Pressão Sanguínea/efeitos dos fármacos , Feminino , Humanos , Losartan/efeitos adversos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Estudos Retrospectivos , SARS-CoV-2RESUMO
The outbreak of a novel coronavirus namely SARS-CoV-2, which first emerged from Wuhan, China, has wreaked havoc not only in China but the whole world that now has been engulfed in its wrath. In a short lapse of time, this virus was successful in spreading at a blistering pace throughout the globe, hence raising the flag of pandemic status. The mounting number of deaths with each elapsing day has summoned researchers from all around the world to play their part in driving this SARS-CoV-2 pandemic to an end. As of now, multiple research teams are immersed in either scrutinizing various antiviral drugs for their efficacy or developing different types of vaccines that will be capable of providing long-term immunity against this deadly virus. The mini-review sheds light on the possible approaches that can be undertaken to curb the COVID-19 spread. Possible strategies comprise viral vector-based, nucleic acid-based, protein-based, inactivated and weakened virus vaccines; COVID-19 vaccine being developed by deploying Hyleukin-7 technology; plant-based chimeric protein and subunit vaccines; humanized nano-bodies and human antibodies; intravenous immunoglobulin (IVIG) infusion therapy; inhibitors for ACE-2, Angiotensin 1 receptor (AT1R), complement system, viral proteins, host cell protease and endocytosis; shield immunity; IL-6R, NKG2A and hACE2-SARS-CoV-2-RBD interaction blocking monoclonal antibodies; SARS-CoV RdRp-based drugs, traditional Chinese medicine, repositioned and anti-viral drugs. These vaccines and drugs are currently being screened in the clinical trials as several of them have manifested positive results, hence increasing the probability of becoming one of the potential treatments for this disease.
Assuntos
Antivirais/farmacologia , Tratamento Farmacológico da COVID-19 , Vacinas contra COVID-19/farmacologia , COVID-19/prevenção & controle , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Enzima de Conversão de Angiotensina 2/antagonistas & inibidores , Anticorpos Monoclonais/farmacologia , Ensaios Clínicos como Assunto , Reposicionamento de Medicamentos , Humanos , Vírus da Bronquite Infecciosa/imunologia , Transplante de Células-Tronco Mesenquimais/métodos , RNA Mensageiro/imunologia , Proteínas Recombinantes/genética , Anticorpos de Domínio Único/farmacologia , Vacinas Atenuadas/farmacologia , Vacinas de Subunidades Antigênicas/farmacologia , Vacinas Sintéticas/farmacologiaRESUMO
COVID-19 has proven to be particularly challenging given the complex pathogenesis of SARS-CoV-2. Early data have demonstrated how the host response to this novel coronavirus leads to the proliferation of pro-inflammatory cytokines, massive endothelial damage, and generalized vascular manifestations. While SARS-CoV-2 primarily targets the upper and lower respiratory tract, other organ systems are also affected. SARS-CoV-2 relies on 2 host cell receptors for successful attachment: angiotensin-converting enzyme 2 and transmembrane protease serine 2. Clinicopathologic reports have demonstrated associations between severe COVID-19 and viral coagulopathy, resulting in pulmonary embolism; venous, arterial, and microvascular thrombosis; lung endothelial injury; and associated thrombotic complications leading to acute respiratory distress syndrome. Viral coagulopathy is not novel given similar observations with SARS classic, including the consumption of platelets, generation of thrombin, and increased fibrin degradation product exhibiting overt disseminated intravascular coagulation-like syndrome. The specific mechanism(s) behind the thrombotic complications in COVID-19 patients has yet to be fully understood. Parenteral anticoagulants, such as heparin and low-molecular-weights heparins, are widely used in the management of COVID-19 patients. Beyond the primary (anticoagulant) effects of these agents, they may exhibit antiviral, anti-inflammatory, and cytoprotective effects. Direct oral anticoagulants and antiplatelet agents are also useful in the management of these patients. Tissue plasminogen activator and other fibrinolytic modalities may also be helpful in the overall management. Catheter-directed thrombolysis can be used in patients developing pulmonary embolism. Further investigations are required to understand the molecular and cellular mechanisms involved in the pathogenesis of COVID-19-associated thrombotic complications.
Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/complicações , Pandemias , Pneumonia Viral/complicações , Trombofilia/etiologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anticoagulantes/uso terapêutico , Arteriopatias Oclusivas/etiologia , Arteriopatias Oclusivas/fisiopatologia , Arteriopatias Oclusivas/virologia , COVID-19 , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , Cateterismo de Swan-Ganz , Terapia Combinada , Infecções por Coronavirus/sangue , Infecções por Coronavirus/tratamento farmacológico , Endotélio Vascular/fisiopatologia , Endotélio Vascular/virologia , Fibrinolíticos/uso terapêutico , Humanos , Oxigenoterapia Hiperbárica , Inibidores da Agregação Plaquetária/uso terapêutico , Pneumonia Viral/sangue , Pneumonia Viral/tratamento farmacológico , Embolia Pulmonar/etiologia , Embolia Pulmonar/terapia , Embolia Pulmonar/virologia , Síndrome do Desconforto Respiratório/etiologia , SARS-CoV-2 , Terapia Trombolítica/instrumentação , Terapia Trombolítica/métodos , Trombofilia/fisiopatologia , Trombofilia/terapia , Trombose Venosa/etiologia , Trombose Venosa/fisiopatologia , Trombose Venosa/virologia , Internalização do Vírus/efeitos dos fármacos , Tratamento Farmacológico da COVID-19RESUMO
Esaxerenone is a novel selective mineralocorticoid receptor (MR) blocker that was recently approved in Japan to treat hypertension. In phase II and III studies, esaxerenone plus a renin-angiotensin system inhibitor markedly reduced the urinary albumin-to-creatinine ratio (UACR) in hypertensive patients with diabetic nephropathy. To evaluate a direct renoprotective effect by MR blockade independent of an antihypertensive effect in the context of diabetic nephropathy, esaxerenone (3 mg/kg), olmesartan (an angiotensin II receptor blocker; 1 mg/kg), or both were orally administered to KK-Ay mice, a type 2 diabetes model, once daily for 56 days. Urinary albumin (Ualb), UACR, and markers, such as podocalyxin, monocyte chemoattractant protein-1 (MCP-1), and 8-hydroxy-2'-deoxyguanosine (8-OHdG), were measured, along with systolic blood pressure (SBP), fasting blood glucose, and serum K+ levels. Prior to the initiation of drug administration, KK-Ay mice showed higher blood glucose, insulin, Ualb excretion, and UACR levels than C57BL/6 J mice, a nondiabetic control, indicating the development of diabetic renal injury. Combined treatment with esaxerenone and olmesartan significantly reduced the change in UACR from baseline compared with the change associated with vehicle at week 8 (-1.750 vs. 0.339 g/gCre; P < 0.002) and significantly inhibited the change in Ualb from baseline compared with the change associated with vehicle at week 8 (P < 0.002). The combination treatment also reduced urinary excretion of podocalyxin and MCP-1, but did not influence 8-OHdG excretion, SBP, blood glucose, or serum K+ levels. Overall, esaxerenone plus olmesartan treatment ameliorated diabetic nephropathy in KK-Ay mice without affecting SBP, suggesting that the renoprotective effects of esaxerenone could be exerted independently of its antihypertensive effect.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Nefropatias Diabéticas/tratamento farmacológico , Imidazóis/uso terapêutico , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Pirróis/uso terapêutico , Sulfonas/uso terapêutico , Tetrazóis/uso terapêutico , Albuminúria/tratamento farmacológico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Diabetes Mellitus Tipo 2/complicações , Avaliação Pré-Clínica de Medicamentos , Quimioterapia Combinada , Imidazóis/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Pirróis/farmacologia , Sulfonas/farmacologia , Tetrazóis/farmacologiaRESUMO
The COVID-19 pandemic is an emerging threat to global public health. While our current understanding of COVID-19 pathogenesis is limited, a better understanding will help us develop efficacious treatment and prevention strategies for COVID-19. One potential therapeutic target is angiotensin converting enzyme 2 (ACE2). ACE2 primarily catalyzes the conversion of angiotensin I (Ang I) to a nonapeptide angiotensin or the conversion of angiotensin II (Ang II) to angiotensin 1-7 (Ang 1-7) and has direct effects on cardiac function and multiple organs via counter-regulation of the renin-angiotensin system (RAS). Significant to COVID-19, ACE2 is postulated to serve as a major entry receptor for SARS-CoV-2 in human cells, as it does for SARS-CoV. Many infected individuals develop COVID-19 with fever, cough, and shortness of breath that can progress to pneumonia. Disease progression promotes the activation of immune cells, platelets, and coagulation pathways that can lead to multiple organ failure and death. ACE2 is expressed by epithelial cells of the lungs at high level, a major target of the disease, as seen in post-mortem lung tissue of patients who died with COVID-19, which reveals diffuse alveolar damage with cellular fibromyxoid exudates bilaterally. Comparatively, ACE2 is expressed at low level by vascular endothelial cells of the heart and kidney but may also be targeted by the virus in severe COVID-19 cases. Interestingly, SARS-CoV-2 infection downregulates ACE2 expression, which may also play a critical pathogenic role in COVID-19. Importantly, targeting ACE2/Ang 1-7 axis and blocking ACE2 interaction with the S protein of SARS-CoV-2 to curtail SARS-CoV-2 infection are becoming very attractive therapeutics potential for treatment and prevention of COVID-19. Here, we will discuss the following subtopics: 1) ACE2 as a receptor of SARS-CoV-2; 2) clinical and pathological features of COVID-19; 3) role of ACE2 in the infection and pathogenesis of SARS; 4) potential pathogenic role of ACE2 in COVID-19; 5) animal models for pathological studies and therapeutics; and 6) therapeutics development for COVID-19.
Assuntos
Betacoronavirus , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Receptores Virais/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Enzima de Conversão de Angiotensina 2 , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/uso terapêutico , Antivirais/uso terapêutico , Betacoronavirus/química , Betacoronavirus/patogenicidade , Betacoronavirus/fisiologia , COVID-19 , Vacinas contra COVID-19 , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/terapia , Modelos Animais de Doenças , Interações entre Hospedeiro e Microrganismos/fisiologia , Humanos , Camundongos , Modelos Biológicos , Pandemias , Pneumonia Viral/terapia , Sistema Renina-Angiotensina/fisiologia , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Nanomedicina Teranóstica , Vacinas Virais/isolamento & purificação , Internalização do VírusRESUMO
BACKGROUND The aim of this study was to further clarify the effects of valsartan on restenosis in patients with arteriosclerosis obliterans of the lower extremities. MATERIAL AND METHODS Patients with arteriosclerosis obliterans of the lower extremities undergoing continuous stent implantation in the superficial femoral artery were enrolled and randomly divided into an ARB group and a control group. Patients in the ARB group received valsartan orally in a single-blind manner and were followed up for 6 months. An evaluation was performed based on the criteria for clinical efficacies designed by the Committee of Vascular Disease, Chinese Association of Integrative Medicine. The total clinical effective rate was calculated, and ankle brachial index (ABI) of the patients was assessed. The concentrations of interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hs-CRP) were measured using enzyme-linked immunosorbent assay. The in-stent restenosis of patients was examined by angiography. RESULTS One patient in the control group died due to acute cerebral hemorrhage 4 months after enrollment, and 1 patient was lost to follow-up due to acute myocardial infarction during follow-up 5 months after enrollment. Age, sex, Fontaine stage, and underlying diseases were comparable between the 2 groups. Hs-CRP (3.93±1.43) and IL-6 (11.26±2.29) levels were significant different in the ARB group compared with the control group. The postoperative follow-up showed that ABI was 0.98±0.20 in the ARB group and 0.62±0.48 in the control group. CONCLUSIONS Valsartan inhibited the increase in hs-CRP and IL-6 levels, improved clinical efficacies, increased ABI, and decreased the restenosis rate after the interventional therapy in patients with arteriosclerosis obliterans of the lower extremities.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Arteriosclerose Obliterante/terapia , Procedimentos Endovasculares , Artéria Femoral/cirurgia , Oclusão de Enxerto Vascular/epidemiologia , Doença Arterial Periférica/terapia , Stents , Valsartana/uso terapêutico , Arteriosclerose Obliterante/metabolismo , Proteína C-Reativa/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Interleucina-6/metabolismo , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/metabolismo , Método Simples-CegoRESUMO
As of April 9, 2020, a novel coronavirus (SARS-CoV-2) had caused 89,931 deaths and 1,503,900 confirmed cases worldwide, which indicates an increasingly severe and uncontrollable situation. Initially, little was known about the virus. As research continues, we now know the genome structure, epidemiological and clinical characteristics, and pathogenic mechanisms of SARS-CoV-2. Based on this knowledge, potential targets involved in the processes of virus pathogenesis need to be identified, and the discovery or development of drugs based on these potential targets is the most pressing need. Here, we have summarized the potential therapeutic targets involved in virus pathogenesis and discuss the advances, possibilities, and significance of drugs based on these targets for treating SARS-CoV-2. This review will facilitate the identification of potential targets and provide clues for drug development that can be translated into clinical applications for combating SARS-CoV-2.
Assuntos
Betacoronavirus/genética , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/uso terapêutico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Enzima de Conversão de Angiotensina 2 , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Antivirais/uso terapêutico , Basigina/metabolismo , Benzamidinas , Betacoronavirus/metabolismo , Betacoronavirus/patogenicidade , COVID-19 , Vacinas contra COVID-19 , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/terapia , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/imunologia , Ésteres , Gabexato/análogos & derivados , Gabexato/uso terapêutico , Genoma Viral , Guanidinas/uso terapêutico , Humanos , Imunização Passiva , Imunossupressores/uso terapêutico , Medicina Tradicional Chinesa , Inibidores da Síntese de Ácido Nucleico/uso terapêutico , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Pneumonia Viral/metabolismo , Inibidores de Proteases/uso terapêutico , RNA Polimerase Dependente de RNA/metabolismo , SARS-CoV-2 , Serina Endopeptidases/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Vacinas Virais , Internalização do Vírus , Replicação Viral , Tratamento Farmacológico da COVID-19 , Soroterapia para COVID-19RESUMO
We previously showed that 2 weeks of a severe food restricted (sFR) diet (40% of the caloric intake of the control (CT) diet) up-regulated the circulating renin angiotensin (Ang) system (RAS) in female Fischer rats, most likely as a result of the fall in plasma volume. In this study, we investigated the role of the central RAS in the mean arterial pressure (MAP) and heart rate (HR) dysregulation associated with sFR. Although sFR reduced basal mean MAP and HR, the magnitude of the pressor response to intracerebroventricular (icv) microinjection of Ang-[1-8] was not affected; however, HR was 57 ± 13 bpm lower 26 min after Ang-[1-8] microinjection in the sFR rats and a similar response was observed after losartan was microinjected. The major catabolic pathway of Ang-[1-8] in the hypothalamus was via Ang-[1-7]; however, no differences were detected in the rate of Ang-[1-8] synthesis or degradation between CT and sFR animals. While sFR had no effect on the AT1 R binding in the subfornical organ (SFO), the organum vasculosum laminae terminalis (OVLT) and median preoptic nucleus (MnPO) of the paraventricular anteroventral third ventricle, ligand binding increased 1.4-fold in the paraventricular nucleus (PVN) of the hypothalamus. These findings suggest that sFR stimulates the central RAS by increasing AT1 R expression in the PVN as a compensatory response to the reduction in basal MAP and HR. These findings have implications for people experiencing a period of sFR since an activated central RAS could increase their risk of disorders involving over activation of the RAS including renal and cardiovascular diseases.