Eprosartan: an angiotensin-II receptor antagonist for the management of hypertension

Eprosartan is a competitive angiotensin-II receptor antagonist with a high affinity for the angiotensin-II subtype 1 receptor. The drug has an elimination half-life of approximately 5 to 9 hours and duration of antihypertensive effect of up to 24 hours. The antihypertensive efficacy of eprosartan has been examined in a number of placebo-controlled, dose-finding, and comparative trials. Results of these clinical trials have consistently shown statistically significant differences in antihypertensive efficacy favoring eprosartan doses of 400 mg or greater per day over placebo. Eprosartan was also shown to be at least as effective as enalapril at lowering blood pressure in patients with mild to severe hypertension. The frequency of adverse events observed with eprosartan has been similar to that seen with placebo. In addition, there are no clinically significant drug interactions associated with eprosartan. Given the excellent tolerability and drug-interaction profiles of eprosartan, the use of this agent may help to improve patient compliance to a drug regimen. In addition, eprosartan may be particularly advantageous when used as a part of combination therapy for the management of hypertension.     

Eplerenone: a selective aldosterone receptor antagonist for hypertension and heart failure

Aldosterone has been implicated for many years as an important substance in the pathogenesis of heart disease. Elevated aldosterone concentrations have been documented in patients with hypertension and heart failure, leading to the use of aldosterone antagonists for the treatment of these conditions. Spironolactone has been used for nearly 2 decades for the treatment of hypertension, and more recently, has become a standard agent for the treatment of systolic heart failure. Spironolactone, however, is a nonselective antagonist of the aldosterone receptor, binding also to other steroid receptors and causing a significant percentage of patients to have sex hormone-related adverse effects such as gynecomastia. Eplerenone is the first of a new class of drugs known as selective aldosterone receptor antagonists, which selectively block the aldosterone receptor with minimal effect at other steroid receptors, thereby minimizing many of the hormonal side effects seen with spironolactone. Eplerenone has been shown to be beneficial both as monotherapy and combination therapy for lowering elevated blood pressure in patients with hypertension. The antihypertensive efficacy of eplerenone is roughly similar to that of other antihypertensive agents, although in 1 study black patients responded better with eplerenone than losartan. In addition, eplerenone has demonstrated some renoprotective effects in diabetic patients with hypertension. Recently, eplerenone was shown to significantly reduce mortality and cardiovascular morbidity in post-myocardial infarction patients with systolic heart failure currently taking standard heart failure medications. Eplerenone is generally well tolerated, although hyperkalemia with this agent is of some concern. Eplerenone is metabolized by CYP3A4 and administration with potent inhibitors of this enzyme is contraindicated because of the risk of hyperkalemia. In summary, eplerenone has proven to be beneficial in treating hypertension and post-myocardial infarction heart failure. Its exact place in therapy will in large part be determined by its cost and whether or not future studies will be able to demonstrate a clinical benefit of this agent over spironolactone or other currently available treatments.     

Endothelin-receptor antagonist treatment of portopulmonary hypertension.

BACKGROUND & AIMS: Portal hypertension leading to variceal bleeding and ascites is a severe complication of liver cirrhosis and is associated with a high mortality rate. Endogenous vasoconstrictors including endothelin might play a role in control of intrahepatic vascular tone. Few patients develop pulmonary hypertension in the setting of portal hypertension, known as portopulmonary hypertension. METHODS/RESULTS: In this case report, we describe a patient with portopulmonary hypertension in the setting of cryptogenic liver cirrhosis. The patient received the dual antagonist of receptors A and B of endothelin-1 bosentan. After 16 and 31 weeks the pulmonary arterial pressure dropped significantly from the baseline value of 88 mm Hg to 63 and 58 mm Hg, respectively. Hepatic venous portal gradient was measured before and after bosentan treatment. Hepatic venous portal gradient significantly decreased from 26 mm Hg (baseline) to 7 and 17 mm Hg at 16 and 31 weeks after treatment with bosentan, respectively. CONCLUSIONS: The present report demonstrates the efficacy of bosentan in the treatment of portopulmonary and portal hypertension in the clinical setting. There are ongoing prospective studies to confirm these data.     

Angiotensin II-receptor antagonist in the treatment of hypertension

Effective treatment of high blood pressure levels represents a crucial point in reducing global cardiovascular risk, and several studies have clearly demonstrated a significant reduction in cardiovascular and renal morbidity and mortality with a more intensive blood pressure-lowering treatment. Other factors beyond blood pressure control may be important in reducing the risk related to hypertension. Pharmacologic agents blocking the renin-angiotensin system, in particular the angiotensin II-receptor blocker (ARB), a novel class of antihypertensive agents, represent an important addition to the therapeutic options for hypertension management, and recent large, international, randomized, trials have demonstrated that ARBs have clinical benefits across the spectrum of disease severity. In this article, we provide some evidence derived from these trials, supporting a role for ARBs in primary and secondary prevention of cardiovascular and renal disease, beyond blood pressure control.     

Selection of a mineralocorticoid receptor antagonist for patients with hypertension or heart failure

Clinical trials have demonstrated morbidity and mortality benefits of mineralocorticoid receptor antagonists (MRAs) in patients with heart failure. These studies have used either spironolactone or eplerenone as the MRA. It is generally believed that these two agents have the same effects, and the data from studies using one drug could be extrapolated for the other. National and international guidelines do not generally discriminate between spironolactone and eplerenone, but strongly recommend using an MRA for patients with heart failure due to LV systolic dysfunction and post‐infarct LV systolic dysfunction. There are no major clinical trials directly comparing the efficacy of these two drugs. This article aims to compare the pharmacokinetics and pharmacodynamics of spironolactone and eplerenone, and to analyse the available data for their cardiovascular indications and adverse effects. We have also addressed the role of special circumstances including co‐morbidities, concomitant drug therapy, cost, and licensing restrictions in choosing an appropriate MRA for a particular patient, thus combining an evidence‐based approach with personalized medicine.     

Successful treatment of systemic sclerosis digital ulcers and pulmonary arterial hypertension with endothelin receptor antagonist bosentan

SIR, We read with interest the recent reports describing thepromising results of studies exploring the role of the dualendothelin receptor antagonist bosentan in pulmonary arterialhypertension (PAH) [1, 2]. We report the case of a patient withsystemic sclerosis associated with PAH and ischaemic digitalulcerations who responded successfully to bosentan. A 50-yr-old male dentist presented in 1995 with severe Raynaud'ssyndrome and acral systemic sclerosis. Over 2 yr, he had developedsevere pruritus, worsening upper and     

An endothelin receptor antagonist TAK-044 ameliorates carbon tetrachloride-induced acute liver injury and portal hypertension in rats

ABSTRACT— Hepatic levels of a powerful vasoconstrictor endothelin-1 (ET-1) and its receptors increase in human and carbon tetrachloride (CCl₄)-induced liver cirrhosis. The aim of this study was to determine whether antagonism of hepatic ET-1 receptors ameliorates CCl₄-induced hepatic injury and portal hypertension in rats. Acute liver injury was induced by a single intraperitoneal injection of CCl₄ (0.3 ml/kg), whereas cirrhosis and portal hypertension were induced by CCl₄ treatment (0.15 ml/kg twice a week) for 8 weeks. Hepatic morphology, ET-1 and its receptors, and portal venous pressures were determined. Increases in ET-1 and its receptors occurred within 24 h of CCl₄ administration, and progressively thereafter during the development of cirrhosis. The acute CCl₄-induced hepatic injury was characterized by significant increases in portal pressure (from 8.7 ± 1.8 to 17.6 ± 3.3 mmHg; p<0.01) and serum levels of liver enzymes, as well as massive hepatocellular necrosis (62±8%). Intravenous administration of an ET-1 receptor antagonist TAK-044 reduced portal pressure to 13.6±2.8 mmHg (p<0.05), and ameliorated hepatocellular necrosis by about 35% (p<0.001). TAK-044 treatment also produced significant reduction in serum levels of liver enzymes. In cirrhotic rats, portal venous infusion of TAK-044 reduced portal hypertension by about 40% (p<0.05). In conclusion, these results indicate involvement of ET-1 in acute liver injury as well as portal hypertension associated with hepatic cirrhosis, and a potential for ET-1 receptor antagonists in the treatment of these pathologic conditions.     

Device-guided breathing exercises for the treatment of hypertension: An overview

The American Heart Association considers device-guided breathing as a reasonable treatment modality in their statement on non-pharmacological options for lowering blood pressure. This review discusses all randomized controlled trials that have investigated the effects of device-guided breathing on blood pressure in patients with hypertension. Thirteen studies were included in this review. In total, 627 patients were in-cluded, of which 365 patients were allocated to device-guided breathing. Only 6 studies used acceptable control groups: listening to music, meditative relaxa-tion exercises, or a sham-device. Two sponsored trials showed beneficial effects of device-guided breathing, both used listening to music as a control group. The remaining 4 studies, which had no employees of the manufacturer listed as co-author, observed no benefi-cial effects on blood pressure. There is only 1 study that used a sham device as a control group. All other studies were to some extend methodologically flawed. Based on the studies with an acceptable methodologi-cal quality, there is no clear evidence supporting a short-term beneficial effect on blood pressure by using device-guided breathing.     

Amlodipine: effective for treatment of mild to moderate essential hypertension and left ventricular hypertrophy

This was a 20-week, open-label, uncontrolled clinical investigation of the long-acting calcium antagonist amlodipine in 33 male or female patients with essential hypertension and left ventricular hypertrophy (LVH). A once-daily dose (5-10 mg/day) of amlodipine provided a consistent antihypertensive effect, reducing the sitting diastolic (-13.8% change) and systolic (-13.0% change) blood pressures by clinically meaningful and statistically significant (p = 0.0001, n = 33) amounts. Amlodipine had no effect on heart rate. A significant regression in LVH was seen (left ventricular mass index reduced from 169.0 [SD 30.7] g/m(2) to 140.6 [SD 19.6] g/m(2), p < 0.01, n = 12). There was also a significant reduction in total peripheral resistance and improvement in left ventricular diastolic filling (E/A ratio increased from 0.86 pre-treatment to 1.03 post-treatment, p = 0.038, n = 12). These results are consistent with other studies in showing that a relatively short treatment regimen with amlodipine is associated with a significant reduction in left ventricular mass index.     

Calcitonin gene-related peptide receptor antagonist ubrogepant for the treatment of acute migraine: A meta-analysis

Background:The objective of this study is to systematically evaluate the efficacy and safety of the calcitonin gene-related peptide (CGRP) receptor antagonist ubrogepant for the treatment of acute migraine.Methods:Randomized controlled trials (RCTs) of ubrogepant for treatment of acute migraine were identified in PubMed, MEDLINE, EMBASE, and the Cochrane Library from database establishment to June 2020; we also searched ClinicalTrials.gov manually during the same period. Then, RevMan 5.3 software was used to perform a meta-analysis on each outcome measure.Results:A total of 5 RCTs involving 4903 patients were included; there were 3358 cases in the ubrogepant group and 1545 cases in the placebo group. The meta-analysis showed the following results: at 2 hours postdose, the percentages of participants reporting pain relief and the absence of photophobia, nausea, and phonophobia were significantly higher in the ubrogepant group than in the placebo group (odds ratio [OR] = 1.71, 95%CI: 1.48–1.97, P < .00001; OR = 1.33, 95%CI: 1.22–1.45, P < .00001; OR = 1.07, 95%CI: 1.03–1.11, P = .0006; OR = 1.21, 95%CI: 1.14–1.28, P < .00001). The incidence of common adverse events was similar between the 2 groups (P > .05).Conclusion:Ubrogepant is effective and safe for the treatment of acute migraine.Registration number:PROSPERO CRD42019145286.     

Calcium antagonist treatment by lercanidipine prevents hyperpolarization in essential hypertension

Essential hypertension is associated with impaired endothelium-dependent vasodilation caused by oxidative stress-induced nitric oxide (NO) breakdown and compensatory production of a hyperpolarizing factor. To test whether calcium antagonist treatment can restore NO availability and prevent hyperpolarization through antioxidant properties, in 15 healthy subjects and 15 patients with essential hypertension, we studied forearm blood flow (strain-gauge plethysmography) modifications induced by intrabrachial bradykinin (5, 15, 50 ng/100 mL per minute), an endothelium-dependent vasodilator, in basal conditions, during infusion of NG-monomethyl-l-arginine (L-NMMA, 100 microg/100 mL per minute), an NO-synthase inhibitor, and ouabain (0.72 microg/100 mL per minute), an Na+-K+ ATPase inhibitor to prevent hyperpolarization. These infusions were repeated in the presence of the antioxidant vitamin C (8 mg/100 mL/min). The response to sodium nitroprusside was also evaluated. In controls, vasodilation to bradykinin was inhibited by L-NMMA and remained unchanged by ouabain or vitamin C. In hypertensive patients, vasodilation to bradykinin was blunted and resistant to L-NMMA but sensitive to ouabain. Vitamin C increased the response to bradykinin and restored the inhibiting effect of L-NMMA while preventing the effect of ouabain. In hypertensive patients, infusions were repeated after 3-month treatment with lercanidipine (10 to 20 mg daily). Lercanidipine decreased plasma lipoperoxides, isoprostanes, and malondialdehyde and increased plasma antioxidant capacity. Moreover, lercanidipine increased the vasodilation to bradykinin and restored the inhibiting effect of L-NMMA on bradykinin-induced vasodilation while preventing the effect of ouabain. Finally, vitamin C no longer exerted its facilitating activity. These results indicate that in essential hypertension, lercanidipine increases endothelium-dependent vasodilation by restoring NO availability and preventing hyperpolarization, an effect probably determined by antioxidant activity.     

Serotonin receptor antagonist inhibits monocrotaline-induced pulmonary hypertension and prolongs survival in rats

OBJECTIVES: It has been reported that serotonin (5-HT) is involved in the development of pulmonary arterial hypertension (PAH) with pulmonary vascular remodeling. The purpose of the present study was to examine the role of a 5-HT2A receptor antagonist, sarpogrelate hydrochroride, in preventing or reversing monocrotaline (MCT)-induced PAH in rats. METHODS: Rats were injected with 40 mg/kg of MCT subcutaneously and randomized to either sarpogrelate (50 mg/kg, intraperitoneally) or placebo for 3 weeks. Animals treated with MCT and survived for 3 weeks were assigned to either sarpogrelate (50 mg/kg, intraperitoneally) or placebo for next 3 weeks. The animals had pressure measurement of the pulmonary artery, and then underwent histologic, immunohistochemical, and Western blot analyses of the lung tissue. Survival rate was also assessed after treatment. RESULTS: Sarpogrelate immediately following MCT injection suppressed PAH with severe pulmonary vascular remodeling and right-sided heart failure. The survival rate was significantly increased in the sarpogrelate-treated group compared with the placebo group (71% vs. 44%, p<0.05). Intense expression of P-selectin was found on the endothelium of the pulmonary arteries in the placebo group, and it was markedly attenuated in the sarpogrelate-treated group. The numbers of the CD45-positive cells and those of the proliferating cell nuclear antigen (PCNA)-positive cells in the lung tissue were significantly increased in the placebo group, and the increases in these cells were prevented by sarpogrelate. Endothelial nitric oxide synthase (eNOS) expression in the lung tissue was markedly decreased in the placebo group, but it was prevented by sarpogrelate (p<0.001). In contrast, late treatment with sarpogrelate failed to reverse established PAH. CONCLUSIONS: Specific 5-HT2A receptor blockade with sarpogrelate immediately after MCT inhibited PAH and prolongs survival in rats. These effects were accompanied by anti-inflammatory and anti-proliferative effects in the lung tissue and marked improvement of pulmonary vascular endothelial dysfunction and activation.     

Treatment of pulmonary arterial hypertension with the selective endothelin-A receptor antagonist sitaxsentan.

OBJECTIVES: We sought to determine the optimal dose of the selective endothelin A (ET(A)) receptor antagonist sitaxsentan for the treatment of pulmonary arterial hypertension (PAH); for observation only, an open-label (OL) bosentan arm was included. BACKGROUND: Endothelin is a mediator of PAH. In a preliminary PAH study, the selective ET(A) receptor antagonist sitaxsentan improved six-min walk (6MW) distance, World Health Organization (WHO) functional class (FC), and hemodynamics. METHODS: In this double-blind, placebo-controlled 18-week study, 247 PAH patients (idiopathic, or associated with connective tissue disease or congenital heart disease) were randomized; 245 patients were treated: placebo (n = 62), sitaxsentan 50 mg (n = 62) or 100 mg (n = 61), or OL (6MW tests, Borg dyspnea scores, and WHO FC assessments third-party blind) bosentan (n = 60). The primary end point was change in 6MW distance from baseline to week 18. Secondary end points included change in WHO FC, time to clinical worsening, and change in Borg dyspnea score. RESULTS: At week 18, patients treated with sitaxsentan 100 mg had an increased 6MW distance compared with the placebo group (31.4 m, p = 0.03), and an improved WHO FC (p = 0.04). The placebo-subtracted treatment effect for sitaxsentan 50 mg was 24.2 m (p = 0.07) and for OL bosentan, 29.5 m (p = 0.05). The incidence of elevated hepatic transaminases (>3x the upper limit of normal) was 6% for placebo, 5% for sitaxsentan 50 mg, 3% for sitaxsentan 100 mg, and 11% for bosentan. CONCLUSIONS: Treatment with the selective ET(A) receptor antagonist sitaxsentan, orally once daily at a dose of 100 mg, improves exercise capacity and WHO FC in PAH patients, with a low incidence of hepatic toxicity.