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1.
Pharmacoepidemiol Drug Saf ; 33(4): e5777, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38511239

RESUMO

BACKGROUND: Valsartan is commonly used for cardiac conditions. In 2018, the Food and Drug Administration recalled generic valsartan due to the detection of impurities. Our objective was to determine if heart failure patients receiving valsartan at the recall date had a greater likelihood of unfavorable outcomes than patients using comparable antihypertensives. METHODS: We conducted a cohort study of Optum's de-identified Clinformatics® Datamart (July 2017-January 2019). Heart failure patients with commercial or Medicare Advantage insurance who received valsartan were compared to persons who received non-recalled angiotensin receptor blockers (ARBs) and angiotensin converting enzyme-inhibitors (ACE-Is) for 1 year prior and including the recall date. Outcomes included a composite for all-cause hospitalization, emergency department (ED), and urgent care (UC) use and a measure of cardiac events which included hospitalizations for acute myocardial infarction and hospitalizations/ED/UC visits for stroke/transient ischemic attack, heart failure or hypertension at 6-months post-recall. Cox proportional hazard models with propensity score weighting compared the risk of outcomes between groups. RESULTS: Of the 87 130 adherent patients, 15% were valsartan users and 85% were users of non-recalled ARBs/ACE-Is. Valsartan use was not associated with an increased risk of all-cause hospitalization/ED/UC use six-months post-recall (HR 1.00; 95% CI 0.96-1.03), compared with individuals taking non-recalled ARBs/ACE-Is. Similarly, cardiac events 6-months post-recall did not differ between individuals on valsartan and non-recalled ARBs/ACE-Is (HR 1.04; 95% CI 0.97-1.12). CONCLUSIONS: The valsartan recall did not affect short-term outcomes of heart failure patients. However, the recall potentially disrupted the medication regimens of patients, possibly straining the healthcare system.


Assuntos
Inibidores da Enzima Conversora de Angiotensina , Insuficiência Cardíaca , Humanos , Idoso , Estados Unidos , Valsartana/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Antagonistas de Receptores de Angiotensina/efeitos adversos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/efeitos adversos , Estudos de Coortes , Medicare , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/induzido quimicamente , Tetrazóis/efeitos adversos
2.
Proc Natl Acad Sci U S A ; 121(8): e2306936121, 2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-38349873

RESUMO

Accumulating evidence suggests that the brain renin angiotensin system (RAS) plays a pivotal role in the regulation of cognition and behavior as well as in the neuropathology of neurological and mental disorders. The angiotensin II type 1 receptor (AT1R) mediates most functional and neuropathology-relevant actions associated with the central RAS. However, an overarching comprehension to guide translation and utilize the therapeutic potential of the central RAS in humans is currently lacking. We conducted a comprehensive characterization of the RAS using an innovative combination of transcriptomic gene expression mapping, image-based behavioral decoding, and pre-registered randomized controlled discovery-replication pharmacological resting-state functional magnetic resonance imaging (fMRI) trials (N = 132) with a selective AT1R antagonist. The AT1R exhibited a particular dense expression in a subcortical network encompassing the thalamus, striatum, and amygdalo-hippocampal formation. Behavioral decoding of the AT1R gene expression brain map showed an association with memory, stress, reward, and motivational processes. Transient pharmacological blockade of the AT1R further decreased neural activity in subcortical systems characterized by a high AT1R expression, while increasing functional connectivity in the cortico-basal ganglia-thalamo-cortical circuitry. Effects of AT1R blockade on the network level were specifically associated with the transcriptomic signatures of the dopaminergic, opioid, acetylcholine, and corticotropin-releasing hormone signaling systems. The robustness of the results was supported in an independent pharmacological fMRI trial. These findings present a biologically informed comprehensive characterization of the central AT1R pathways and their functional relevance on the neural and behavioral level in humans.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II , Sistema Renina-Angiotensina , Humanos , Sistema Renina-Angiotensina/genética , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Transdução de Sinais , Pressão Sanguínea , Perfilação da Expressão Gênica , Receptor Tipo 1 de Angiotensina/genética , Angiotensina II/metabolismo
3.
Med. clín (Ed. impr.) ; 162(4): 163-169, Feb. 2024. tab, ilus, graf
Artigo em Inglês | IBECS | ID: ibc-230572

RESUMO

Objectives: COVID-19, caused by SARS-CoV-2, has spread around the world since 2019. In severe cases, COVID-19 can lead to hospitalization and death. Systemic arterial hypertension and other comorbidities are associated with serious COVID-19 infection. Literature is unclear whether antihypertensive therapy with angiotensin receptor blockers (ARBs) and angiotensin converting enzyme (ACE) inhibitors affect COVID-19 outcomes. We aim to assess whether ACEI/ARB therapy is a risk factor for worse respiratory outcomes related to COVID-19 in hospitalized patients. Methods: Retrospective study enrolling admitted COVID-19-diagnosed patients by RT-PCR at the Hospital Geral de Fortaleza, Brazil, during 2021. Patient medical records, sociodemographic, and clinical data were analyzed. Chest CT images were analyzed using CAD4COVID-CT/Thirona™ software. Results: A total of 294 patients took part in the study. A cut-off point of 66% of pulmonary involvement was found by ROC curve, with patients having higher risk of death and intubation and lower 60-day survival. Advanced age (RR 1.025, P=0.001) and intubation (RR 16.747, P<0.001) were significantly associated with a higher risk of death. Advanced age (RR 1.023, P=0.001) and the use of noninvasive ventilation (RR 1.548, P=0.037) were associated with a higher risk of intubation. Lung involvement (>66%) increased the risk of death by almost 2.5-fold (RR 2.439, P<0.001) and by more than 2.3-fold the risk of intubation (RR 2.317, P<0.001). Conclusions: Altogether, our findings suggest that ACEI or ARB therapy does not affect the risk of death and disease course during hospitalization.(AU)


Objetivos: La COVID-19, causada por el SARS-CoV-2, se ha extendido por todo el mundo desde 2019. En casos graves, la COVID-19 puede provocar hospitalización y muerte. La hipertensión arterial sistémica y otras comorbilidades se asocian con una infección grave por COVID-19. La literatura no está clara si la terapia antihipertensiva con bloqueadores de los receptores de angiotensina (BRA) e inhibidores de la enzima convertidora de angiotensina (ECA) afecta los resultados de la COVID-19. Nuestro objetivo fue evaluar si la terapia BRA/ECA es un factor de riesgo de peores resultados respiratorios relacionados con COVID-19 en pacientes hospitalizados. Métodos: Estudio retrospectivo que incluyó pacientes ingresados con diagnóstico de COVID-19 mediante RT-PCR en el Hospital General de Fortaleza, Brasil, durante 2021. Se analizaron las historias clínicas de los pacientes, datos sociodemográficos y clínicos. Las imágenes de TC de tórax se analizaron utilizando el software CAD4COVID-CT/ThironaTM. Resultados: Participaron en el estudio un total de 294 pacientes. Mediante curva ROC se encontró un punto de corte del 66% de afectación pulmonar, teniendo los pacientes mayor riesgo de muerte e intubación y menor supervivencia a 60 días. La edad avanzada (RR 1,025; P=0,001) y la intubación (RR 16,747; P<0,001) se asociaron significativamente con un mayor riesgo de muerte. La edad avanzada (RR 1,023; P=0,001) y el uso de ventilación no invasiva (RR 1,548; P=0,037) se asociaron con un mayor riesgo de intubación. La afectación pulmonar (>66%) aumentó el riesgo de muerte casi 2,5 veces (RR 2,439; P<0,001) y más de 2,3 veces el riesgo de intubación (RR 2,317, P<0,001). Conclusiones: Se concluyó que el tratamiento con BRA o ECA no afecta el riesgo de muerte y el curso de la enfermedad durante la hospitalización.(AU)


Assuntos
Humanos , Masculino , Feminino , /diagnóstico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Hipertensão , Comorbidade , /epidemiologia , Medicina Clínica , Estudos Retrospectivos , Brasil , Anti-Hipertensivos/efeitos adversos , Inteligência Artificial
4.
Biomed Pharmacother ; 171: 116169, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38228033

RESUMO

Telmisartan is an antagonist of the angiotensin II receptor used in the management of hypertension (alone or in combination with other antihypertensive agents. It belongs to the drug class of angiotensin II receptor blockers (ARBs). Among drugs of this class, telmisartan shows particular pharmacologic properties, including a longer half-life than any other angiotensin II receptor blockers that bring higher and persistent antihypertensive activity. In hypertensive patients, telmisartan has superior efficacy than other antihypertensive drugs (losartan, valsartan, ramipril, atenolol, and perindopril) in controlling blood pressure, especially towards the end of the dosing interval. Telmisartan has a partial PPARγ-agonistic effect whilst does not have the safety concerns of full agonists of PPARγ receptors (thiazolidinediones). Moreover, telmisartan has an agonist activity on PPARα and PPARδ receptors and modulates the adipokine levels. Thus, telmisartan could be considered as a suitable alternative option, with multi-benefit for all components of metabolic syndrome including hypertension, diabetes mellitus, obesity, and hyperlipidemia. This review will highlight the role of telmisartan in metabolic syndrome and the main mechanisms of action of telmisartan are discussed and summarized. Many studies have demonstrated the useful properties of telmisartan in the prevention and improving of metabolic syndrome and this well-tolerated drug can be greatly proposed in the treatment of different components of metabolic syndrome. However, larger and long-duration studies are needed to confirm these findings in long-term observational studies and prospective trials and to determine the optimum dose of telmisartan in metabolic syndrome.


Assuntos
Hipertensão , Síndrome Metabólica , Humanos , Telmisartan/farmacologia , Antagonistas de Receptores de Angiotensina/farmacologia , Síndrome Metabólica/tratamento farmacológico , PPAR gama/farmacologia , Estudos Prospectivos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Benzimidazóis/farmacologia , Hipertensão/tratamento farmacológico , Anti-Hipertensivos/farmacologia , Pressão Sanguínea , Benzoatos/farmacologia
5.
Aliment Pharmacol Ther ; 59(4): 432-444, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38185985

RESUMO

BACKGROUND: Although enteropathy due to angiotensin II receptor blockers (ARBs) has been known for over 10 years, clinicians' awareness of this condition is still low. AIMS: To systematically review the literature about clinical phenotypes, distribution of mucosal changes throughout the gastrointestinal tract and prognosis of enteropathy due to ARBs. METHODS: According to PRISMA guidelines, we searched PubMed and Embase for relevant articles up to November 6, 2023. We included full-text papers, letters, case reports and case series describing enteropathy due to ARBs. Patients were classified into subgroups based on endoscopic and histological findings of different regions of the gastrointestinal tract. The protocol was registered with Open Science Framework (https://doi.org/10.17605/OSF.IO/TK67C). RESULTS: We included 94 articles reporting 183 cases (101 female, mean age at diagnosis 69 ± 10 years). The clinical picture at diagnosis was characterised by severe diarrhoea (97%) and weight loss (84%, median -13 kg), leading to hospital admission in 167 (95%) patients. Olmesartan (90%) was most frequently implicated. Villous atrophy (VA) was reported in 164/183 (89%) patients. One hundred and nine had only VA, 12 had pan-gastrointestinal involvement, 23 had VA and gastric involvement and 19 had VA and colon involvement (predominantly microscopic colitis). Outcomes were reported for 178/183 (97%) patients, who all recovered clinically on ARBs withdrawal. Histological recovery occurred in all 96 patients with VA at baseline who underwent follow-up duodenal biopsy. CONCLUSIONS: Enteropathy due to ARBs is characterised by severe malabsorption often requiring hospital admission and can involve the entire gastrointestinal tract. Clinician awareness can lead to prompt diagnosis and excellent prognosis.


Assuntos
Antagonistas de Receptores de Angiotensina , Enteropatias , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Bloqueadores do Receptor Tipo 1 de Angiotensina II/efeitos adversos , Antagonistas de Receptores de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Prognóstico , Tetrazóis
6.
Ann Pharm Fr ; 82(1): 72-83, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37567559

RESUMO

Nitrosamines (NAs) are molecules that include the nitroso functional group. In 2018, the US Food and Drug Administration (FDA) received its first report of NAs in pharmaceuticals. The fact that NA impurities are likely human carcinogens is relevant to these compounds. Furthermore, prolonged exposure to NA contaminants above safe limits may raise the risk of cancer. The goal of this article was to assess the amounts of six different NAs in Sartan group medicines purchased from formal pharmacies in Istanbul, Türkiye, using a validated LC-MS/MS assay. An LC-MS/MS-based analytical assay was undertaken. The separation was performed with a HR ODS 150mm×3.0mm and 5-analytical columns, providing effective separation of major peaks from NA impurities. In mobile phase A, formic acid was 0.10% in water, while in mobile phase B, formic acid was 0.10% in methanol. The flow rate was 0.4mL/minute, and the total runtime was 18minutes with the gradient elution mode. The validation was conducted in line with ISO/IEC 17025 requirements. Up to 100µg/L, linearity was determined using correlation coefficients (r2>0.995) for all NAs. The limit of quantification values for all NAs analyses were below 1.0µg/L. The mean recovery value obtained during the spike experiment was 95.18%, demonstrating the accuracy of the procedure. In addition, the accuracy was shown by a certified reference analysis, which yielded relative standard deviation and relative error values of 1.82% and 3.34%, respectively. During the intermediate precision testing, bias and relative standard deviation were 0.96 and 2.87%, respectively. Of the 75 study samples involving Sartan group medical products, no nitrosamine impurities were detected, demonstrating that pharmaceutical companies have adequate medication safety precautions in place in accordance with FDA and European Medicines Agency (EMA) regulations published to prevent NA contaminants in human medicinal products.


Assuntos
Nitrosaminas , Humanos , Bloqueadores do Receptor Tipo 1 de Angiotensina II , Cromatografia Líquida/métodos , Turquia , Espectrometria de Massas em Tandem/métodos , Preparações Farmacêuticas , Cromatografia Líquida de Alta Pressão/métodos
7.
Arch Biochem Biophys ; 751: 109851, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-38065251

RESUMO

In diabetes, increased oxidative stress and impaired trace element metabolism play an important role in the pathogenesis of diabetic nephropathy. The objective of this research was to examine the outcomes of blocking the renin-angiotensin system, using either the angiotensin-converting enzyme inhibitor (ACEI), perindopril, or the angiotensin II type 1 (AT1) receptor blocker, irbesartan, on oxidative stress and trace element levels such as Zn, Mg, Cu, and Fe in the kidneys of diabetic rats that had been induced with streptozotocin. Thirty-two Wistar albino male rats were equally divided into four groups. The first group was used as a control. The second group of rats developed diabetes after receiving a single intraperitoneal dose of STZ. The third and fourth groups of rats had STZ-induced diabetes and received daily dosages of irbesartan (15 mg/kg b.w/day) and perindopril (6 mg/kg b.w/day) treatment, respectively. Biochemical analysis of the kidneys showed a distinct increase in oxidative stress, indicated by heightened levels of malondialdehyde (MDA) and decreased superoxide dismutase (SOD) activities, as well as reduced glutathione (GSH) levels in the kidneys of diabetic rats. In the kidneys of diabetic rats, the mean levels of Fe and Cu were found to be significantly higher than those of the control group. Additionally, the mean levels of Zn and Mg were significantly lower in the diabetic rats compared to the control rats. Both perindopril and irbesartan decreased significantly MDA content and increased SOD activities and GSH levels in the kidneys of rats with diabetes. The Zn and Mg concentrations in the kidneys of diabetic rats treated with perindopril and irbesartan were markedly higher than in untreated STZ-diabetic rats, while the Cu and Fe concentrations were significantly lower. The urinary excretion of rats treated with perindopril and irbesartan showed a pronounced increase in Cu levels, along with a significant reduction in Zn and Mg levels. Although diabetic rats demonstrated degenerative morphological alterations in their kidneys, both therapies also improved diabetes-induced histopathological modifications in the kidneys. Finally, the present results suggest that manipulating the levels of Zn, Mg, Cu, and Fe - either through ACE inhibition or by blocking AT1 receptors - could be advantageous in reducing lipid peroxidation and increasing antioxidant concentration in the kidneys of diabetic rats.


Assuntos
Diabetes Mellitus Experimental , Nefropatias Diabéticas , Oligoelementos , Ratos , Animais , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Irbesartana/metabolismo , Irbesartana/farmacologia , Irbesartana/uso terapêutico , Antagonistas de Receptores de Angiotensina/metabolismo , Antagonistas de Receptores de Angiotensina/farmacologia , Antagonistas de Receptores de Angiotensina/uso terapêutico , Perindopril/metabolismo , Perindopril/farmacologia , Perindopril/uso terapêutico , Estreptozocina/metabolismo , Estreptozocina/farmacologia , Estreptozocina/uso terapêutico , Ratos Wistar , Diabetes Mellitus Experimental/metabolismo , Oligoelementos/metabolismo , Oligoelementos/farmacologia , Oligoelementos/uso terapêutico , Rim/patologia , Nefropatias Diabéticas/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/metabolismo , Estresse Oxidativo , Superóxido Dismutase/metabolismo
8.
Biochem Pharmacol ; 220: 115978, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38081369

RESUMO

Despite its known importance in the cardiovascular system, the specific role and impact of the angiotensin type 2 receptor (AT2R) in lung physiology and pathophysiology remain largely elusive. In this study, we highlight the distinct and specialized lung-specific roles of AT2R, primarily localized to an alveolar fibroblast subpopulation, in contrast to the angiotensin type 1 receptor (AT1R), which is almost exclusively expressed in lung pericytes. Evidence from our research demonstrates that the disruption of AT2R (AT2R-/y), is associated with a surge in oxidative stress and impaired lung permeability, which were further intensified by Hyperoxic Acute Lung Injury (HALI). With aging, AT2R-/y mice show an increase in oxidative stress, premature enlargement of airspaces, as well as increased mortality when exposed to hyperoxia as compared to age-matched WT mice. Our investigation into Losartan, an AT1R blocker, suggests that its primary HALI lung-protective effects are channeled through AT2R, as its protective benefits are absent in AT2R-/y mice. Importantly, a non-peptide AT2R agonist, Compound 21 (C21), successfully reverses lung oxidative stress and TGFß activation in wild-type (WT) mice exposed to HALI. These findings suggest a possible paradigm shift in the therapeutic approach for lung injury and age-associated pulmonary dysfunction, from targeting AT1R with angiotensin receptor blockers (ARBs) towards boosting the protective function of AT2R.


Assuntos
Lesão Pulmonar Aguda , Receptor Tipo 2 de Angiotensina , Camundongos , Animais , Receptor Tipo 2 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/agonistas , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Antagonistas de Receptores de Angiotensina , Inibidores da Enzima Conversora de Angiotensina , Receptor Tipo 1 de Angiotensina/genética , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/prevenção & controle
9.
Mol Pharm ; 21(1): 18-37, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-38108281

RESUMO

Sartans (angiotensin II receptor blockers, ARBs), drugs used in the treatment of hypertension, play a principal role in addressing the global health challenge of hypertension. In the past three years, their potential use has expanded to include the possibility of their application in the treatment of COVID-19 and neurodegenerative diseases (80 clinical studies worldwide). However, their therapeutic efficacy is limited by their poor solubility and bioavailability, prompting the need for innovative approaches to improve their pharmaceutical properties. This review discusses methods of co-crystallization and co-amorphization of sartans with nonpolymeric, low molecular, and stabilizing co-formers, as a promising strategy to synthesize new multipurpose drugs with enhanced pharmaceutical properties. The solid-state forms have demonstrated the potential to address the poor solubility limitations of conventional sartan formulations and offer new opportunities to develop dual-active drugs with broader therapeutic applications. The review includes an in-depth analysis of the co-crystal and co-amorphous forms of sartans, including their properties, possible applications, and the impact of synthetic methods on their pharmacokinetic properties. By shedding light on the solid forms of sartans, this article provides valuable insights into their potential as improved drug formulations. Moreover, this review may serve as a valuable resource for designing similar solid forms of sartans and other drugs, fostering further advances in pharmaceutical research and drug development.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II , Anti-Hipertensivos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Antagonistas de Receptores de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/química , Anti-Hipertensivos/química , Solubilidade
10.
Ter Arkh ; 95(9): 810-817, 2023 Nov 03.
Artigo em Russo | MEDLINE | ID: mdl-38158926

RESUMO

The activity of the renin-angiotensin-aldosterone system is one of the main pathogenetic mechanisms underlying cardiovascular diseases at all stages of the cardiovascular continuum. This article discusses the role of telmisartan and azilsartan as the most powerful sartans in modern cardiology. Azilsartan and especially telmisartan have a significant organoprotection and are superior to other antihypertensive drugs in terms of lowering blood pressure. However, the effect of azilsartan on hard endpoints has not been studied while the efficacy of telmisartan on hard endpoints has been evaluated in plenty clinical trials including 3 large randomized clinical trials with several thousand patients. The article also presents calculations showing the better cost-effectiveness of telmisartan compared to azilsartan.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II , Hipertensão , Humanos , Telmisartan/farmacologia , Telmisartan/uso terapêutico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Hipertensão/tratamento farmacológico , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea
11.
Int J Mol Sci ; 24(24)2023 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-38139391

RESUMO

Quantum pharmacology introduces theoretical models to describe the possibility of ultra-high dilutions to produce biological effects, which may help to explain the placebo effect observed in hypertensive clinical trials. To determine this within physiology and to evaluate novel ARBs, we tested the ability of known angiotensin II receptor blockers (ARBs) (candesartan and telmisartan) used to treat hypertension and other cardiovascular diseases, as well as novel ARBs (benzimidazole-N-biphenyl tetrazole (ACC519T), benzimidazole-bis-N,N'-biphenyl tetrazole (ACC519T(2)) and 4-butyl-N,N0-bis[[20-2Htetrazol-5-yl)biphenyl-4-yl]methyl)imidazolium bromide (BV6(K+)2), and nirmatrelvir (the active ingredient in Paxlovid) to modulate vascular contraction in iliac rings from healthy male New Zealand White rabbits in responses to various vasopressors (angiotensin A, angiotensin II and phenylephrine). Additionally, the hemodynamic effect of ACC519T and telmisartan on mean arterial pressure in conscious rabbits was determined, while the ex vivo ability of BV6(K+)2 to activate angiotensin-converting enzyme-2 (ACE2) was also investigated. We show that commercially available and novel ARBs can modulate contraction responses at ultra-high dilutions to different vasopressors. ACC519T produced a dose-dependent reduction in rabbit mean arterial pressure while BV6(K+)2 significantly increased ACE2 metabolism. The ability of ARBs to inhibit contraction responses even at ultra-low concentrations provides evidence of the existence of quantum pharmacology. Furthermore, the ability of ACC519T and BV6(K+)2 to modulate blood pressure and ACE2 activity, respectively, indicates their therapeutic potential against hypertension.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II , Hipertensão , Coelhos , Masculino , Animais , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Telmisartan/farmacologia , Enzima de Conversão de Angiotensina 2/farmacologia , Antagonistas de Receptores de Angiotensina/farmacologia , Artéria Ilíaca , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Benzimidazóis/uso terapêutico , Tetrazóis/farmacologia , Tetrazóis/uso terapêutico , Hipertensão/tratamento farmacológico , Pressão Sanguínea
12.
Exp Mol Med ; 55(11): 2346-2356, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37907743

RESUMO

Spondyloarthritis (SpA) is a chronic inflammatory disease that results in bone ankylosis. The tissue renin-angiotensin system (RAS) is an emerging pathway potentially implicated in SpA-associated bone changes. The aim of the present study was to determine the mechanisms underlying this relationship. Sakaguchi (SKG) mice injected with curdlan (SKGc), animal models for SpA, were treated with RAS modulators, angiotensin II receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors (ACEis). Disease activity was assessed using clinical scores and computed tomography scans. Mouse primary bone marrow monocytes (BMMs), osteoblast (OB) progenitor cells, peripheral blood monocytes (PBMCs), and bone-derived cells (BdCs) from patients with radiographic axial SpA (r-axSpA) were used to investigate the role of RAS in SpA pathogenesis. The expression of RAS components was significantly increased in SKGc mouse joints, and ARBs significantly reduced erosion and systemic bone loss, whereas ACEis did not. Osteoclast (OC) differentiation from primary BMMs, mediated by TRAF6, was inhibited by ARBs but promoted by ACEis; the modulators also exerted opposite effects on OB differentiation. Expression of RAS molecules was higher in PBMCs and BdCs of patients with r-axSpA than in control participants. ARBs inhibited OB differentiation in the BdCs of patients with r-axSpA, whereas ACEis did not. Neither ARBs nor ACEis affected OB differentiation in the control participants. In SpA, a condition characterized by RAS overexpression, ARBs, but not ACEis, inhibited OC and OB differentiation and bone progression. The findings should be taken into account when treating patients with SpA using RAS modulators.


Assuntos
Espondiloartrite Axial , Espondilartrite , Humanos , Animais , Camundongos , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Espondilartrite/tratamento farmacológico
13.
Am Heart J ; 266: 198-200, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37980092

RESUMO

PURPOSE: To identify the cause of discrepancy between the INHERIT trial and VANISH trial in regards to disease modification of angiotensin receptor II blockers in hypertrophic cardiomyopathy (HCM). METHODS: We replicated the data analysis used in VANISH, converting individual change in each component of the composite endpoint into a z-score and applying this z-score to the INHERIT results. RESULTS: No significant improvement was identified in the composite z-score between the 2 groups at 12-month follow-up (P = .4). With the exception of tissue Doppler systolic (s') velocity, we found no significant benefit or harm from losartan compared to placebo for any of the individual components of the composite score at 12-month follow-up. Results were similar in analyses without imputed data or when restricted to patients with sarcomeric HCM. CONCLUSION: Despite applying the potentially more sensitive composite z-score endpoint as in the VANISH trial, no statistically significant benefits from the use of losartan compared to placebo could be detected at 12-month follow-up in patients with overt HCM participating in the INHERIT trial.


Assuntos
Cardiomiopatia Hipertrófica , Losartan , Humanos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Cardiomiopatia Hipertrófica/tratamento farmacológico , Losartan/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto
14.
Georgian Med News ; (342): 152-155, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37991972

RESUMO

The data on the polycontamination of multimedication in polymorbid patients with a heterogeneous class of carcinogens/nitrosamines, NDSRIs (classified according to the FDA regulation to the companies of 2023 to those with a carcinogenic potency between 1 and 5), are one of the most important steps to clarify the concept of skin cancer nitrosogenesis/ pathogenesis. The FDA is the first regulatory institution in the world to courageously declare that a problem exists and should be addressed. The main and currently unexplained and somewhat controversial issue lies in 1) the sporadic nature of polycontamination in different geographical regions, and 2) the lack of official data from the established international, but also regional pharmaceutical market regulators on the results of the checks conducted for nitrosamine contamination of the respective batches. It is this that leads scientists to the idea of (albeit seemingly) speculative but entirely possible controlled contamination of the production in certain geographical regions. This (hypo)thesis is supported, albeit indirectly, by the fact that: a recent regional check for possible contamination of sartans in a particular geographical region was not indicative of the presence of any nitrosamines/NDSRIs. But this fact is indicative of several extremely important things: 1) contamination is not ubiquitous, its genesis is heterogeneous; 2) contamination could be completely avoided at production level in certain geographical regions; 3) ˝controlled contamination˝ or carelessness of a heterogeneous nature should be excluded by the relevant regulators. Regular inspection and certification of medicinal products in relevant geographical regions to exclude contamination with nitrosamines/NDSRIs would be the surest method to protect public health globally. The initial parameters of the restrictive processes for the availability of nitrosamines in medicines have been established by the most powerful regulator globally in the face of the FDA, with the hope being that manufacturers will find a short-term solution to the problem. We report another patient who simultaneously developed 2 cutaneous tumors under potentially/actually nitrosamine contaminated drugs such as: beta blockers- atenolol, calcium antagonists- nifedipine/amlodipine, sartans- valsartan and antiarrhythmics- propafenone. One of the tumors was localized in the upper lip area (keratoacanthoma) and the other in the right shoulder area (basal cell carcinoma). Successful surgical treatment of the tumors was performed in the form of upper lip advancement rotation flap and elliptical excision of the second lesion. The evolution/growth rate of the tumors in relation to the potential mutagens/carcinogens heterogeneous in their potency contained in the drugs is commented.


Assuntos
Ceratoacantoma , Neoplasias , Nitrosaminas , Humanos , Valsartana , Bloqueadores do Receptor Tipo 1 de Angiotensina II , Propafenona , Bloqueadores dos Canais de Cálcio/uso terapêutico , Nifedipino/uso terapêutico , Anlodipino , Ombro , Carcinógenos , Antiarrítmicos/uso terapêutico , Retalhos Cirúrgicos
15.
Arterioscler Thromb Vasc Biol ; 43(12): 2256-2264, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37855126

RESUMO

Blood pressure management involves antihypertensive therapies blocking the renin-angiotensin system (RAS). Yet, it might be inadequate due to poor patient adherence or the so-called RAS escape phenomenon, elicited by the compensatory renin elevation upon RAS blockade. Recently, evidence points toward targeting hepatic AGT (angiotensinogen) as a novel approach to block the RAS pathway that could circumvent the RAS escape phenomenon. Removing AGT, from which all angiotensins originate, should prevent further angiotensin generation, even when renin rises. Furthermore, by making use of a trivalent N-acetylgalactosamine ligand-conjugated small interfering RNA that specifically targets the degradation of hepatocyte-produced mRNAs in a highly potent and specific manner, it may be possible in the future to manage hypertension with therapy that is administered 1 to 2× per year, thereby supporting medication adherence. This review summarizes all current findings on AGT small interfering RNA in preclinical models, making a comparison versus classical RAS blockade with either ACE (angiotensin-converting enzyme) inhibitors or AT1 (angiotensin II type 1) receptor antagonists and AGT suppression with antisense oligonucleotides. It ends with discussing the first-in-human study with AGT small interfering RNA.


Assuntos
Angiotensinogênio , Hipertensão , Humanos , Acetilgalactosamina , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Angiotensinogênio/genética , Angiotensinogênio/metabolismo , Pressão Sanguínea , Hipertensão/terapia , Hipertensão/tratamento farmacológico , Renina/metabolismo , Sistema Renina-Angiotensina/fisiologia , RNA Interferente Pequeno/farmacologia
16.
Chem Biodivers ; 20(11): e202301157, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37796134

RESUMO

There has been a significant shift in the perception of hypertension as an important contributor to the global disease burden. Approximately 6 % and 8 % of pregnancies are affected by hypertension, which can adversely affect the mother and the fetus. Furthermore, a hypertensive individual is at increased risk of developing kidney disease, arterial hardening, eye damage, and strokes. Using angiotensin receptor blockers (ARBs) is widespread in treating hypertension, heart failure, coronary artery disease, and diabetic nephropathy. Despite this, some ARBs have limited use due to their poor oral bioavailability and water solubility. To tackle this, a variety of nanoparticle (NP)-based systems, such as polymeric NPs (i. e., dendrimers), polymeric micelles, polymer-drug conjugates, lipid NPs, nanoemulsions, self-emulsifying drug delivery systems (SEDDS), solid lipid NPs (SLNs), nanostructured lipid carriers (NLCs), carbon-based nanocarriers, inorganic NPs, and nanocrystals, have been recently developed for efficient delivery of losartan, Valsartan (Val), Olmesartan (OLM), Telmisartan (TEL), Candesartan, Eprosartan, Irbesartan, and Azilsartan to target cells. This review article provides a literature-based comparison of the various classes of ARBs, their mechanisms of action, and an overview of the nanoformulations developed for ARB delivery and successfully applied to managing hypertension, diabetic complications, and other conditions.


Assuntos
Antagonistas de Receptores de Angiotensina , Hipertensão , Humanos , Antagonistas de Receptores de Angiotensina/uso terapêutico , 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 , Tetrazóis/uso terapêutico , Hipertensão/tratamento farmacológico , Nanotecnologia , Lipídeos
17.
Int Immunopharmacol ; 124(Pt B): 110995, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37801970

RESUMO

As angiotensin II is associated with inflammation, type I angiotensin II receptor blockers (ARBs) exibit anti-inflammatory effects in patients with hypertension as well as inflammatory disease animal models including arthritis models. The present study aimed to investigate whether ARBs exert anti-inflammatory effects in vivo in skin disorders. We tested effects of ARBs on 1-chloro-2,4-dinitrobenzene(CDNB)-induced atopic dermatitis-like and imiquimod-induced psoriasis-like skin models. CDNB-induced atopic dermatitis-like skin lesions were suppressed by administration of candesartan or telmisartan. The suppressive effect of telmisartan was blocked by the presence of GW9662, a selective PPARγ inhibitor, but not that of candesartan. Both ARBs suppressed increases in pro-inflammatory cytokine (IL-4, IL-13, IFN-γ, and IL-17A) levels, and GW9662 inhibited telmisartan-induced suppression but not candesartan. Candesartan significantly inhibited in vitro differentiation of naïve T cells into Th17 cells to a greater extent than telmisartan. In the imiquimod-induced psoriasis model, whose primary etiology is activation of IL-23/IL-17 axis, candesartan significantly suppressed psoriasis-like skin lesions and Th17 cell populations in both lymph nodes and spleens to a greater extent than telmisartan. Overall, certain ARBs may have anti-inflammatory effects in skin diseases. Candesartan may have therapeutic implications in inflammatory skin disorders by suppressing Th17 differentiation, while telmisartan might have therapeutic potential by activating PPARγ.


Assuntos
Dermatite Atópica , Psoríase , Animais , Humanos , Telmisartan/uso terapêutico , Células Th17 , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Dermatite Atópica/tratamento farmacológico , Antagonistas de Receptores de Angiotensina , PPAR gama , Imiquimode/uso terapêutico , Benzoatos/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Pele/patologia , Psoríase/induzido quimicamente , Psoríase/tratamento farmacológico , Psoríase/patologia , Diferenciação Celular , Anti-Inflamatórios/uso terapêutico
18.
Behav Brain Res ; 454: 114639, 2023 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-37652238

RESUMO

Post-traumatic stress disorder (PTSD) is a neuropsychiatric disorder that not only entails alterations in fear behavior and anxiety but also includes neuroendocrine dysfunctions involving the hypothalamic pituitary adrenal (HPA) axis and the renin-angiotensin system. Recent preclinical studies demonstrate that activation of the angiotensin type 1 receptor (AT1R) in the paraventricular region of the hypothalamus (PVR) promotes anxiety-like behaviors and enables microglia proliferation. An increase in microglia and anxiety-like behavior also occurs in the PTSD animal model single-prolonged stress (SPS). In the present study, we tested whether AT1Rs contribute to the effects of SPS on behavior and microglia in brain structures important for HPA axis regulation and fear behavior. To test this, male and female animals were exposed to SPS and then given the oral AT1R antagonist candesartan beginning one week later. Candesartan did not alter auditory fear conditioning or extinction in SPS-exposed male or female animals. However, we found that the male animals exposed to SPS showed increased anxiety-like behavior, which was reversed by candesartan. In contrast, neither SPS nor candesartan altered anxiety-like behavior in the female animals. At the molecular level, SPS increased the cellular expression of AT1Rs in the PVR of male animals and candesartan reversed this effect, whereas AT1Rs in the PVR of females were unaltered by either SPS or candesartan. Iba1-expressing microglia increased in the PVR after SPS exposure and was reversed by candesartan in both sexes suggesting that SPS stimulates AT1Rs to increase microglia in the PVR. Collectively, these results suggest that the contribution of AT1Rs to the molecular and behavioral effects of SPS is sex-dependent.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II , Sistema Hipotálamo-Hipofisário , Feminino , Masculino , Animais , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Sistema Hipófise-Suprarrenal , Benzimidazóis/farmacologia
19.
Int Immunopharmacol ; 123: 110761, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37544025

RESUMO

Astrocytes are crucially involved in neuroinflammation. Activated astrocytes exhibit at least two phenotypes, A1 (neurotoxic) and A2 (neuroprotective). The A1 phenotype is the major reactive astrocyte phenotype involved in aging and neurodegenerative diseases. Telmisartan, which is an antihypertensive agent, is a promising neuroprotective agent. This study aimed to investigate the effects of telmisartan on the phenotype of reactive astrocytes. Astrocytes were activated by culturing with the conditioned medium derived from lipopolysaccharide-stimulated microglia. This conditioned medium induced early, transient A2 astrocyte conversion (within 24 h) and late, sustained A1 conversion (beginning at 24 h and lasting up to 7 days), with a concomitant increase in the production of pro-inflammatory cytokines (interleukin [IL]-1ß, tumor necrosis factor [TNF]α, and IL-6) and phosphorylation of nuclear factor-κB (NF-κB)/p65. Telmisartan treatment promoted and inhibited A2 and A1 conversion, respectively. Telmisartan reduced total and phosphorylated p65 protein levels. Losartan, a specific angiotensin II type-1 receptor (AT1R) blocker, did not influence the reactive state of astrocytes. Additionally, AT1R activation by angiotensin II did not induce the expression of pro-inflammatory cytokines and A1/A2 markers, indicating that the AT1R signaling pathway is not involved in the astrocyte-mediated inflammatory response. A peroxisome proliferator-activated receptor γ (PPARγ) antagonist reversed the effects of telmisartan. Moreover, telmisartan-induced p65 downregulation was reversed by the proteasome inhibitor MG132. These results indicate that telmisartan suppresses activated microglia-induced neurotoxic A1 astrocyte conversion through p65 degradation. Our findings contribute towards the elucidation of the anti-inflammatory activity of telmisartan in brain disorders.


Assuntos
NF-kappa B , PPAR gama , Telmisartan/farmacologia , NF-kappa B/metabolismo , PPAR gama/metabolismo , Astrócitos/metabolismo , Microglia , Angiotensina II/metabolismo , Meios de Cultivo Condicionados/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Citocinas/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
20.
Georgian Med News ; (339): 24-32, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37522769

RESUMO

The Nitrosogenesis of skin cancer is a newly introduced concept in medical science, the significance of which is yet to be the subject of detailed analyses and discussions. Contamination of the most commonly used drugs for systemic treatment worldwide (such as Angiotensin receptor II blockers/ARBs, ACE inhibitors, Beta blockers, Thiazide diuretics, Metformin, Ranitidine, Nizatidine, tricyclic antidepressants, anticoagulants/dabigatran, Rifampicin, calcium channel blockers, SSRIs/ selective serotonin reuptake inhibitors, Varenicline) is already a fact and is more than worrying but also indicative. It is "this relationship" that has been repeatedly described in the medical literature (initially) as an association, and subsequently now increasingly as a causal relationship, a pathogenetic relationship. Observational data from clinicians over the past year increasingly speak in favour of a pathogenetic link and associate every single drug declared as contaminated with the development of heterogeneous forms of skin cancer gradually and surely. New drugs are added monthly that have not yet been declared as actually/potentially contaminated but are probably known to regulatory authorities or are in the process of being clarified. In parallel, the number of nitrosamines identified as contaminants in medicines is growing. This should not be surprising to anyone: ˝You take 3 drugs contaminated with mutagens- you subsequently develop skin cancer˝. Polymorbidity and multimedication against the background of polycontamination with nitrosamines appears to be the most serious problem at present. While until recently polymorbidity was considered to be a key factor in carcinogenesis (generator, trigger, inducer), today this dogma should be re-examined or looked at from another, radically different angle: from the angle of polycontamination to multimedication within polymorbidity. It is this that could provide a good explanation for the pandemic concerning skin cancer, for example. The development of relatively identical patterns of manifestation of skin tumors after concomitant intake of drugs declared as contaminated (drugs from the classes already mentioned above/ with radically different mechanism of action) supports unequivocally the thesis that: the nitrosogenesis of skin cancer is an undeniable fact that should be studied in detail. Studied because it could be eliminated. The analysis presented within this scientific thesis concerns 4 polymorbid patients who developed skin tumors within the framework of the multimedication they were assigned. The concomitant intake of medications declared as contaminated (in the presented patients) led to the manifestation of single or multiple skin neoplasms that were successfully treated surgically. Once again, the importance of potential/actual contamination of beta blockers, ACE inhibitors, oral antidiabetic drugs, and sartans in the generation of 1) non-melanocytic forms of skin cancer, and 2) melanoma precursor lesions or so-called dysplastic moles is established and validated. The possible contamination with nitrosamines of 1) other types of tricyclic antidepressant- Melitracen; 2) antidepressant of the selective serotonin reuptake inhibitor (SSRI) class: Paroxetine; 3) antidepressant of the serotonin and noradrenaline reuptake inhibitor (SNRIs) class: Venlafaxine, as well as of the systemic anticoagulant: apixaban is highlighted for the first time in the world literature.


Assuntos
Metformina , Inibidores da Recaptação de Serotonina e Norepinefrina , Neoplasias Cutâneas , Humanos , Inibidores Seletivos de Recaptação de Serotonina , Inibidores da Enzima Conversora de Angiotensina , Bloqueadores do Receptor Tipo 1 de Angiotensina II , Bloqueadores dos Canais de Cálcio , Bisoprolol , Cloridrato de Venlafaxina , Paroxetina , Enalapril , Antidepressivos Tricíclicos , Perindopril , Losartan , Anlodipino , Valsartana , Antagonistas de Receptores de Angiotensina , Incidência , Neoplasias Cutâneas/induzido quimicamente , Neoplasias Cutâneas/tratamento farmacológico
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