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Trials of Angiotensin Receptor Blockers in Patients With Hypertension and Cardiovascular Disease

Trials of Angiotensin Receptor Blockers in Patients With Hypertension and Cardiovascular Disease

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To differentiate angiotensin II receptor blockers (ARBs) by vascular effects and outcomes in trials on cardio-protective endpoints. MEDLINE searches were conducted from January 2003 to March 2009 using the following search terms: renin-angiotensin-aldosterone system (RAAS) blockade or inhibition; angiotensin II receptor blocker (ARBs); cardio-prote...

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... clinical trials have shown the efficacy of ARBs in vascular protection in patients with high-risk hypertension for CVD, left ventricular dysfunction, acute MI, and heart failure (Table 3), [46][47][48][49]51,54-58 yet comparative-effectiveness studies of ARBs on vascular outcomes are limited. Although not all of the clinical trials evaluating the efficacy of ARBs were designed to evaluate the cardioprotective ef fects of these drugs in- dependent of BP control, each trial examined cardiovascular outcomes. ...

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... However, AT1R blockade attenuates various pathological pathways associated with AngII/AT1R signaling and manages AngII-induced cardiac hypertrophy (Kawai et al., 2017). Treatment with selective AT1R blockers (ARBs) provides cardioprotection through an increased antioxidant capacity and regulation of MAPK pathway in the cardiomyocyte leading to reduce the cardiovascular mortality and morbidity rates (Ararat and Brozovich, 2009;Munger, 2011;Streicher et al., 2010). Therefore, this study was conducted to identify the role of RAS in gefitinib-induced cardiac hypertrophy and investigate if AT1R blockade via valsartan can attenuate cardiac hypertrophy induced by gefitinib via assessment of cardiac enzymes include creatine kinase-MB (CK-MB), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and cardiac troponin I (cTnI). ...
... AT1R blockers (ARBs) are classified chemically into bi-phenyl tetrazole analogs (azilsartan, candesartan, irbesartan, losartan, olmesartan and valsartan) or non-biphenyl tetrazole analogs (eprosartan and telmisartan) (Singh et al., 2018). ARBs provide a cardioprotective role in various pathological conditions through downregulation of AngII-mediated pathways causing oxidative stress, inflammation and apoptosis in the cardiomyocyte (Munger 2011, Escobales et al., 2019. Valsartan is a potent AT1R blocker that showed a beneficial effect in the prevention of cardiotoxicity and cardiovascular diseases (Goyal et al., 2011, Akolkar et al., 2015, Zhang et al., 2016. ...
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Gefitinib is a tyrosine kinase inhibitor (TKI) of the epidermal growth factor receptor (EGFR), used for the treatment of advanced or metastatic non-small cell lung cancer. Recently, studies proved that Gefitinib-induced cardiotoxicity through induction of oxidative stress leads to cardiac hypertro-phy. The current study was conducted to understand the mechanisms underlying gefitinib-induced cardiac hypertrophy through studying the roles of angiotensin II (AngII), oxidative stress, and mitogen-activated protein kinase (MAPK) pathway. Male Wistar albino rats were treated with valsartan, gefitinib, or both for four weeks. Blood samples were collected for AngII and cardiac markers measurement, and hearts were harvested for histological study and biochemical analysis. Gefitinib caused histological changes in the cardiac tissues and increased levels of cardiac hypertro-phy markers, AngII and its receptors. Blocking of AngII type 1 receptor (AT1R) via valsartan protected hearts and normalized cardiac markers, AngII levels, and the expression of its receptors during gefitinib treatment. valsartan attenuated gefitinib-induced NADPH oxidase and oxidative stress leading to down-regulation of JNK/p38-MAPK pathway. Collectively, AT1R blockade adjusted AngII-induced NADPH oxidase and JNK/p38-MAPK leading to attenuation of gefitinib-induced cardiac hypertrophy. This study found a pivotal role of AngII/AT1R signaling in gefitinib-induced cardiac hypertrophy, which may provide novel approaches in the management of EGFRIs-induced cardiotoxicity. Ó 2022 The Author(s). Published by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
... Captopril and enalpril have been shown to increase endogenous oxidant scavengers in mouse tissue. 45 Decreasing the synthesis and/or blocking the action of ANG II slows the progression of atherosclerosis in diabetic patients, 46 which may be due in part to a reduction in the formation of ROS. In addition, ACE inhibition improves insulin sensitivity in those with hypertension and impaired glucose metabolism because of the improvement of blood flow and therefore delivery of insulin and glucose. ...
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Diabetes mellitus (DM) is believed to promote oxidative stress, which potentially provokes and accelerates complications in conditions such as atherosclerotic cardiovascular, peripheral arterial, and cerebrovascular diseases. In this study, we evaluated the antioxidant therapeutic value of adding an angiotensin-converting enzyme (ACE) inhibitor-a low dose of captopril-as adjunct therapy to the treatment regimen of Type 2 diabetes mellitus (T2DM). Participants were distributed among two different groups: control and treated. T2DM patients in the treated group (group 2) were given a supplement of the ACE inhibitor capotopril, 12.5 mg/day, in addition to standard treatment. All subjects were interviewed for clinical examination. All patients in group 2 were re-examined monthly for 3 months to evaluate FBS, HbA1c, MDA, total GSH, reduced GSH, GSSG, and ox-LDL. All parameters were repeated for patients in group 2 after 1 and 3 months. The study showed improvements in the glycemic and oxidative stress status with the addition of a low dose of captopril-not very prominent but statistically significant. Reduced GSH decreased by 73.6% (P = 0.016) and the TBARS level was decreased by 58.3% (P = 0.018) after 3 months of treatment, while ox-LDL was decreased by 26.4% (P = 0.036) at the end of treatment. In summary, the clinical improvements in the disease indices toward normal levels make the use of low doses of ACE inhibitors as adjunct therapy in T2DM worth pursuing. Thus, investigations directed at preventing or protecting against oxidative damage may open a new window for treatment of diabetes mellitus.
... Therefore, the inhibition of AT 1 R, which is ubiquitous in all cells of the cardiovascular system (Dasgupta & Zhang, 2011) and is expressed on the surface of platelets (Kalinowski et al., 2002), is considered a strategy of high potential for the prevention of CVDs. Angiotensin II receptor blockers (ARBs) are widely used in cardiovascular medicine due to their pleiotropic properties, as they possess antiatherogenic and antioxidant effects, they can treat hypertension and heart failure (Munger, 2011), they may prevent new or recurrent strokes in hypertensive patients and they inhibit platelet aggregation (Suresh, 2016). The utilization of ARBs as antihypertensive agents, inducing antiplatelet effects, has been reported as an important factor for the prevention of ischemic stroke (Dahlof, 2002). ...
Article
Despite the scientific progression in the prevention and treatment of cardiovascular diseases (CVDs) they remain the leading cause of mortality and disability worldwide. The classic treatment involves the simultaneous dosing of two antiplatelet drugs, aspirin and clopidogrel/prasugrel. However, besides drug resistance, severe side effects have been also manifested including acute bleeding and toxicity. Thus, new therapeutic agents with enhanced efficacy and diminished side effects are of importance. Towards this end, omega-3 (ω-3) fatty acids have demonstrated potent efficacy against CVDs through inhibiting platelet aggregation that bears a pivotal role in atherothrombosis. Another factor that displays a critical role in the pathogenesis of cardiovascular diseases is the renin-angiotensin system (RAS), and especially the AT1R blocker losartan that has been reported to exert antiplatelet activity mediated by this receptor. Along these lines, we envisaged developing a molecular hybrid consisted of docosahexaenoic acid (ω-3 fatty acid) and losartan, that could exert a notable antiplatelet effect against CVDs. The design and synthesis of the new DHA-losartan hybrid, designated DHA-L, bestowed with the additive properties of the parent compounds, is reported. In silico studies were first exploited to validate the potential of DHA-L to retain losartan’s ability to bind AT1R. The antiplatelet activity of DHA-L was evaluated against in vitro platelet aggregation induced by several platelet agonists. Notably, the hybrid illustrated a pleiotropic antiplatelet profile inhibiting platelet aggregation through multiple platelet activation pathways including P2Y12, PAR-1 (Protease-Activated Receptor-1), PAF (Platelet Activating Factor), COX-1 (cyclooxygenase-1) and collagen receptors. The stability of DHA-L in human plasma and in a wide range of pH values was also evaluated over time using an HPLC protocol. The hybridization approach described herein could pave the way for the development of novel potent multitargeted therapeutics with enhanced antiplatelet profile.
... Therefore, reducing DOX-induced cardiomyopathy is needed for the clinical success of this anticancer chemotherapy, which has been a challenge for pharmacologists and oncologists. Accumulating evidence has demonstrated the potential protective effects of ACEIs on the heart (29)(30)(31)(32). In particular, the protective function of benazepril-HCl against heart failure has been confirmed in an isoproterenol-induced chronic heart failure model via amelioration of hypertrophy and dysfunction of heart ventricles (33,34). ...
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Doxorubicin (DOX) stimulates the generation of reactive oxygen species, thereby impairing mitochondrial functions. Angiotensin-converting enzyme inhibitors (ACEIs) have been identified to exhibit protective effects on cardiovascular diseases. The present study aimed to test the hypothesis that an ACEI benazepril hydrochloride (HCl) may protect against DOX-induced cardiotoxicity. The DOX injury model was established using rat embryonic cardiac myoblast cells (H9c2 cell line) treated with DOX in vitro. H9c2 cells were treated with benazepril-HCl, DOX or a mixture of DOX and benazepril-HCl to measure the activities of myocardial enzymes including lactate dehydrogenase (LDH), superoxide dismutase, catalase and glutathione peroxidase, in addition to the concentration of malondialdehyde in the culture medium. Cells without any treatment were used as a control. DOX treatment increased the levels of activity of myocardial enzymes in H9c2 cells compared with those in the untreated control cells. Additionally, co-treatment with benazepril-HCl significantly reduced the levels of apoptosis occurring due to DOX-mediated cellular damage. The mechanistic experiment revealed that pretreatment with benazepril-HCl counteracted the DOX-induced oxidative stress and suppressed the activation of apoptosis via the PI3K/Akt signaling pathway. By contrast, an Akt inhibitor (MK2206) inhibited the protective effects of benazepril-HCl against DOX-induced H9c2 cell injury, as revealed by increased LDH release in H9c2 cells. These results suggested that benazepril-HCl may potentially be administered as an adjuvant for DOX in long-term clinical use.
... Among those who did not receive ASi, the risk of ABI discontinuation was significantly higher than in the ASi group. This observation can be partially explained by the fact, drugs which block RAAS, play a protective role for the CV system (28). For example, both ACE-I or ARB reduce the risk of myocardial infarct, stroke, or CV-related death (29,30). ...
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Background Abiraterone acetate (ABI) therapy improves overall survival in metastatic prostate cancer (PC) patients; however, this effect may be diminished by concurrent comorbidities. We aimed to evaluate the influence of pre-existing chronic diseases and concomitant medications on the course of ABI treatment among post-chemotherapy patients with metastatic castration-resistant prostate cancer patients (mCRPC). Methods From the Polish National Health Fund database, we identified 93 post-chemotherapy, mCRPC patients, who were qualified for ABI treatment in our oncology center between 2014 and 2018. Survival curves and Cox proportional hazard models (univariate and multivariate) were used to determine the predictors for longer time to treatment failure (TTF) of ABI therapy. Results Median TTF was 9,8 months (IQR: 0,6–56,5) Factors associated with longer TTF were: well controlled hypertension (HR, 0.59; 95% CI. 0.38–0.90; p = 0.02), stable coronary artery disease (HR, 0.56; 95% CI, 0.33–0.95; p=0.03), the use of angiotensin system inhibitor (ASi) (HR, 0.61; 95% CI 0.4–0.94; p = 0,02). Patients who were receiving ASi had median TTF of 12.2 months versus 5.8 months in men who did not receive ASi before ABI initiation. At the start of ABI therapy, the aforementioned groups did not differ in terms of well-known prognostic factors: Gleason score, PSA level, or the number of patients with visceral metastases. In a multivariate analysis, the use of ASi remained statistically significant, even after adjustment for well-known oncological factors (HR, 0.57; 95% CI, 0.34–0.98; p = 0.04). Conclusions The use of ASi may enhance and prolong ABI therapy in post-docetaxel mCRPC patients and may potentially be considered a new, non-oncological, predictive factor for longer TTF. This association requires a prospective validation.
... Наиболее распространенной была гипертония, за которой следовали СД и ишемическая болезнь сердца [26,98]. Поскольку ось Ang II-AT 1 уже гиперактивна при этих заболеваниях [10,99], SARS-CoV-2 еще больше снижает выработку функционального ACE2. Следовательно, у пациентов с этими основными заболеваниями гораздо легче развивается тяжелое течение болезни, быстро трансформирующееся в критическое состояние. ...
Article
Пандемия коронавируса — тяжелого острого респираторного синдрома SARS-CoV2 — COVID‑19 диктует необходимость безотлагательного изучения и глубинного фундаментального понимания общей патофизиологии нового заболевания, потенциально определяющего выбор терапевтической стратегии у больных с сахарным диабетом (СД), пораженных коронавирусной инфекцией. Из-за быстрого распространения COVID‑19 с манифестацией тяжелого острого респираторного синдрома, в настоящее время в мировом на- учном сообществе ведутся серьезные дебаты по ряду актуальных тем, связанных с наиболее оптимальными способами лечения пациентов с СД во время коронавирусной пандемии, включая проблемы восприимчивости к этой новой инфекции, наличия коморбидной патологии, тяжести течения заболевания, рисков развития осложнений и летальности, а также роли лекарственных препаратов, используемых для контроля гликемии. Имеющиеся на данный момент эпидемиологические данные по COVID‑19 не подтверждают гипотезу о том, что пациенты с СД подвержены повышенному риску инфицирования по сравнению с общей популяцией. На сегодняшний день установлено, что декомпенсированный СД является независимым фактором, отягощающим течение коронавирусной инфекции и достоверно повышающим риски фатального исхода заболевания. Наши знания о новой коронавирусной инфекции растут день ото дня, и уроки, извлеченные из этой пандемии в разных странах, крайне важны и очень ценны для определения наилучшего подхода в борьбе с этой болезнью. Таким образом, существует научная и клиническая необходимость получения новых данных о методах лечения, применяемых до настоящего времени у пациентов с СД и COVID‑19, для выяснения их эффективности и выбора оптимального вида терапевтической стратегии, обеспечения менее тяжелого течения и лучшего прогноза заболевания. В данном обзоре представлено краткое резюме общих характеристик COVID‑19, а также на основе литературных источников дана аналитическая характеристика связи между этим новым инфекционным заболеванием и СД для того, чтобы способствовать лучшему пониманию патогенетических и клинических аспектов данного патологического тандема, а также выбору наиболее эффективных терапевтических стратегий лечения пациентов с COVID‑19 и СД.
... В таких пацієнтів підвищений ризик смерті. Оскільки вісь Ang II-AT1 при згаданих захворюваннях вже гіперактивна [7,78], SARS-CoV-2 ще більше знижує продукцію функціонального АПФ-2. Отже, в таких пацієнтів наба-гато легше розвивається важкий перебіг хвороби, який швидко трансформується в критичний стан. ...
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Currently, due to the rapid spread of COVID-19 with the manifestation of severe acute respiratory syndrome, extensive discussions are underway on a number of topical issues related to the best optimal ways to treat patients with diabetes mellitus (DM) during coronavirus pandemic, including problems of susceptibility to this new infection, presence of comorbid pathology, the disease severity and its course, the risks of complications and mortality, as well as the role of drugs used to control glycemia. The coronavirus pandemic is a severe acute respiratory syndrome SARS-CoV2 (COVID-19) dictates the need for immediate study and deep fundamental understanding of the general pathophysiology of the new disease, potentially determines the choice of therapeutic strategy in patients with DM, affected by coronavirus infection.Currently available epidemiological data on COVID-19 do not support the hypothesis that patients with diabetes are at increased risk of infection compared to the general population. To date, it has been established that decompensated DM is an independent factor that aggravates coronavirus infection and significantly increases the risk of fatal disease outcome. Thus, there are the scientific and clinical needs to obtain new data on the methods of treatment currently used in patients with DM infected with COVID-19 to determine their effectiveness and select the optimal treatment strategy, provide a less severe course and better prognosis of disease.Our knowledge of the new coronavirus infection is deepening day by day and the lessons dealing with this new pandemic around the world are extremely important and very valuable in determining the best approach to fighting against this disease. This review provides a brief summary of the general characteristics of COVID-19, and also based on the literature data provides an analytical characteristics of the relationship between this new infectious disease and DM in order to promote a better understanding of the pathogenetic and clinical aspects of this pathological combination, as well as the selection of the most effective therapeutic strategies for patients with COVID-19 and DM
... An oral administration of ACE-I, perindopril, inhibited adipocyte differentiation and lipogenesis due to the reduction of plasma and tissue angiotensin levels in rats 33,34) . Moreover, a previous study 42) showed that activated PPAR-ɤ, induced by administration of ARBs, lowered serum TG and LDL-C concentrations. According to the previous studies 33,34,42) , the lowered TG concentration in the OLETF-Capt group observed in this study might be induced by the enhancement of lipids and energy metabolism caused by inhibited Ang II activity due to Capt administration, although it did not lead to a significant reduction of BW and serum LDL-C concentration. ...
... Moreover, a previous study 42) showed that activated PPAR-ɤ, induced by administration of ARBs, lowered serum TG and LDL-C concentrations. According to the previous studies 33,34,42) , the lowered TG concentration in the OLETF-Capt group observed in this study might be induced by the enhancement of lipids and energy metabolism caused by inhibited Ang II activity due to Capt administration, although it did not lead to a significant reduction of BW and serum LDL-C concentration. ...
Article
Our previous studies used type-2 diabetic model Otsuka Long-Evans Tokushima fatty (OLETF) rats, and showed that both exercise and diet regimen decreased body weight (BW) and improved glucose intolerance (GI), and dyslipidemia. However, exercise regimenwas also associated with increased blood pressure (BP), diabetic nephropathy (DN) progression characterized by an increase in urinary albumin excretion (UAlb), and morphological abnormalities of the kidneys. This study examined the effects of an exercise regimen alone and the combined treatment of exercise and an antihypertensive medication, captopril (Capt), on systemic BP, DN progression, BW, GI, and dyslipidemia in OLETF rats. Twenty-four male OLETF rats were divided into the following groups: voluntary exercise alone (OLETF-Ex), Capt administration alone (OLETF-Capt), Capt and exercise (OLETF-Capt & Ex), and sedentary control (OLETF-Sed) groups. Six male Long-Evans Tokushima Otsuka (LETO) rats were used as a normal sedentary control (LETO-Sed). These treatments were conducted from 21 to 30 weeks of age. Approximately 20 mg/kg/day of Capt was administered daily. After the treatment, the OLETF-Ex group experienced decreased BW and improved GI and dyslipidemia; however, it was associated with diastolic BP elevation and DN progression. The OLETF-Capt group experienced decreased BP and serum TG concentration and inhibited DN progression. The OLETF-Capt & Ex group experienced decreased BW and BP, and improved GI and dyslipidemia without the progression of DN. This study demonstrated that a combined treatment of exercise and antihypertensive agents, such as Capt, is recommended as an ideal regimen for hypertensive diabetic patients in the pre-nephropathy stage to avoid DN progression induced by an exercise regimen alone.
... [5][6][7] Drugs modulating the renin-angiotensin-aldosterone system, most commonly angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs), are most often prescribed for treating hypertension because of their high efficacy and low side effect profile with a tolerability similar to that of placebo. [8][9][10][11] Telmisartan is a US Food and Drug Administration (FDA)-approved drug for the treatment of hypertension. It is an orally active, safe, long-acting ARB, with the longest half-life (24 h) compared with all other hypertension drugs. ...
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Background: Few studies have compared the safety and efficacy of azilsartan medoxomil (AZL-M) and telmisartan in hypertensive patients, especially using ambulatory blood pressure monitoring (ABPM). Objective: The objective of this study was to compare the efficacy and safety profile of AZL-M and telmisartan in hypertensive patients using ABPM and clinic blood pressure (BP) monitoring. Materials and Methods: This prospective, randomized, open-label, blinded endpoint, parallel-arm study included 700 patients, aged 18–70 years, with clinic and 24-h mean ambulatory systolic BP (SBP) of 150–180 mmHg and 130–170 mmHg, respectively. They were randomized equally into two groups: Group A received AZL-M 40 mg and Group T received telmisartan 40 mg; the dose was force titrated to 80 mg after 2 weeks if the response rate was not achieved. BP (clinical and ambulatory) was measured after 12 weeks and compared with baseline measurements. Results: AZL-M significantly reduced the 24-h mean ambulatory SBP (Group A: 112.74 ± 7.58 mmHg; Group T: 113.96 ± 8.52 mmHg;P < 0.0001) and diastolic BP (Group A: 71.39 ± 5.89 mmHg; Group T: 67.29 ± 6.79 mmHg;P < 0.0001) compared with telmisartan at week 12. The clinic SBP significantly decreased in Group A at weeks 4 (−30.69± −0.33 mmHg) and 12 (−39.69± −1.09 mmHg) (for both, P = 0.0001). Dose titration was done in 99 and 128 patients from Group A and Group T, respectively (P = 0.012). Headache was the most common adverse drug reaction (Group A: 21; Group T: 27) and fatigue the least. Conclusion: This study found that AZL-M has greater antihypertensive efficacy than telmisartan, with comparable side effects. In addition, ABPM was shown to be a feasible method for such studies.
... Hypertension was the most common, followed by diabetes and coronary heart disease [21,45]. Since the Ang II-AT1 axis is hyperactive in these diseases already [46,47], SARS-CoV-2 further decreases the production of functional ACE2. Therefore, in patients with those underlying diseases it is much easier to develop severe and critical conditions. ...
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Recently, the SARS-CoV-2 induced disease COVID-19 has spread all over the world. Nearly 20% of the patients have severe or critical conditions. SARS-CoV-2 exploits ACE2 for host cell entry. ACE2 plays an essential role in the renin–angiotensin–aldosterone system (RAAS), which regulates blood pressure and fluid balance. ACE2 also protects organs from inflammatory injuries and regulates intestinal functions. ACE2 can be shed by two proteases, ADAM17 and TMPRSS2. TMPRSS2-cleaved ACE2 allows SARS-CoV-2 cell entry, whereas ADAM17-cleaved ACE2 offers protection to organs. SARS-CoV-2 infection-caused ACE2 dysfunction worsens COVID-19 and could initiate multi-organ failure. Here, we will explain the role of ACE2 in the pathogenesis of severe and critical conditions of COVID-19 and discuss auspicious strategies for controlling the disease.