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Concept: Losartan

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Background Aortic-root dissection is the leading cause of death in Marfan’s syndrome. Studies suggest that with regard to slowing aortic-root enlargement, losartan may be more effective than beta-blockers, the current standard therapy in most centers. Methods We conducted a randomized trial comparing losartan with atenolol in children and young adults with Marfan’s syndrome. The primary outcome was the rate of aortic-root enlargement, expressed as the change in the maximum aortic-root-diameter z score indexed to body-surface area (hereafter, aortic-root z score) over a 3-year period. Secondary outcomes included the rate of change in the absolute diameter of the aortic root; the rate of change in aortic regurgitation; the time to aortic dissection, aortic-root surgery, or death; somatic growth; and the incidence of adverse events. Results From January 2007 through February 2011, a total of 21 clinical centers enrolled 608 participants, 6 months to 25 years of age (mean [±SD] age, 11.5±6.5 years in the atenolol group and 11.0±6.2 years in the losartan group), who had an aortic-root z score greater than 3.0. The baseline-adjusted rate of change (±SE) in the aortic-root z score did not differ significantly between the atenolol group and the losartan group (-0.139±0.013 and -0.107±0.013 standard-deviation units per year, respectively; P=0.08). Both slopes were significantly less than zero, indicating a decrease in the degree of aortic-root dilatation relative to body-surface area with either treatment. The 3-year rates of aortic-root surgery, aortic dissection, death, and a composite of these events did not differ significantly between the two treatment groups. Conclusions Among children and young adults with Marfan’s syndrome who were randomly assigned to losartan or atenolol, we found no significant difference in the rate of aortic-root dilatation between the two treatment groups over a 3-year period. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT00429364 .).

Concepts: Clinical trial, Cardiology, Aortic dissection, Aorta, Marfan syndrome, Pneumothorax, Beta blocker, Losartan

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Patients with Marfan syndrome have an increased risk of life-threatening aortic complications, mostly preceded by aortic dilatation. Treatment with losartan, an angiotensin-II receptor-1 blocker, may reduce aortic dilatation rate in Marfan patients.

Concepts: Randomized controlled trial, Syndromes, Aortic dissection, Aorta, Marfan syndrome, Beta blocker, Losartan

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Among children with the most severe presentation of Marfan syndrome (MFS), an inherited disorder of connective tissue caused by a deficiency of extracellular fibrillin-1, heart failure is the leading cause of death. Here, we show that, while MFS mice (Fbn1C1039G/+ mice) typically have normal cardiac function, pressure overload (PO) induces an acute and severe dilated cardiomyopathy in association with fibrosis and myocyte enlargement. Failing MFS hearts show high expression of TGF-β ligands, with increased TGF-β signaling in both nonmyocytes and myocytes; pathologic ERK activation is restricted to the nonmyocyte compartment. Informatively, TGF-β, angiotensin II type 1 receptor (AT1R), or ERK antagonism (with neutralizing antibody, losartan, or MEK inhibitor, respectively) prevents load-induced cardiac decompensation in MFS mice, despite persistent PO. In situ analyses revealed an unanticipated axis of activation in nonmyocytes, with AT1R-dependent ERK activation driving TGF-β ligand expression that culminates in both autocrine and paracrine overdrive of TGF-β signaling. The full compensation seen in wild-type mice exposed to mild PO correlates with enhanced deposition of extracellular fibrillin-1. Taken together, these data suggest that fibrillin-1 contributes to cardiac reserve in the face of hemodynamic stress, critically implicate nonmyocytes in disease pathogenesis, and validate ERK as a therapeutic target in MFS-related cardiac decompensation.

Concepts: Blood, Cardiology, Heart failure, Angiotensin II receptor antagonist, Marfan syndrome, Pneumothorax, Connective tissue, Losartan

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To the Editor: Lacro et al. (Nov. 27 issue)(1) report no benefit of losartan, an angiotensin-receptor blocker (ARB), over the beta-blocker atenolol in respect to the rate of aortic-root dilatation in Marfan’s syndrome. A possible interpretation of this study might be that ARBs are as effective as beta-blockers in the treatment of patients with Marfan’s syndrome.(2) However, such an interpretation assumes that beta-blockers are an effective treatment option. Beta-blockers are presently considered to be first-line therapy in patients with Marfan’s syndrome. However, their benefit is debatable and not supported by robust evidence. Several observational studies and only one clinical trial . . .

Concepts: Clinical trial, Hypertension, The Canon of Medicine, Angiotensin II receptor antagonist, Marfan syndrome, Beta blocker, Losartan, Atenolol

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Angiotensin receptor blockers (ARBs; including candesartan, losartan, olmesartan and valsartan) are widely used to treat hypertension, heart failure and diabetic neuropathy. There is considerable pre-clinical evidence that ARBs can reduce cancer progression, particularly for gastric cancer. Despite this, epidemiological studies have yet to assess the impact of ARB use on gastro-oesophageal cancer survival.

Concepts: Epidemiology, Hypertension, Angiotensin, Angiotensin II receptor antagonist, Olmesartan, Candesartan, Angiotensin II receptor antagonists, Losartan

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Mild biventricular dysfunction is often present in patients with Marfan syndrome. Losartan has been shown to reduce aortic dilatation in patients with Marfan syndrome. This study assesses the effect of losartan on ventricular volume and function in genetically classified subgroups of asymptomatic Marfan patients without significant valvular regurgitation.

Concepts: Genetic disorder, Mutation, Aortic dissection, Aorta, Marfan syndrome, Haploinsufficiency, Fibrillin, Losartan

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Marfan syndrome (MFS) is an autosomal dominant heritable disorder of connective tissue that affects the cardiovascular, skeletal, ocular, pulmonary, and nervous systems and is usually caused by mutations in the FBN1 gene, which encodes fibrillin-1. MFS is traditionally considered to result from the structural weakness of connective tissue. However, recent investigations on molecular mechanisms indicate that increased transforming growth factor-β (TGF-β) activity plays a crucial role in the pathogenesis of MFS and related disorders, such as Loeys-Dietz syndrome (LDS), which is caused by mutation in TGF-β signaling-related genes. In addition, recent studies show that angiotensin II type 1 receptor (AT1R) signaling enhances cardiovascular pathologies in MFS, and the angiotensin II receptor blocker losartan has the potential to inhibit aortic aneurysm formation. However, the relationship between TGF-β and AT1R signaling pathways remains poorly characterized. In this review, we discuss the recent studies on the molecular mechanisms underlying cardiovascular manifestations of MFS and LDS and the ensuing strategies for management.

Concepts: Angiotensin, Angiotensin II receptor antagonist, Aortic dissection, Aorta, Marfan syndrome, Loeys-Dietz syndrome, Fibrillin, Losartan

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The aim of the present research work is to develop carbo-protein polymeric complex based sustain release microspheres of losartan potassium and investigate the ability of this dosage form to improve the flowability, compressibility and tableting properties of losartan potassium. The influence of silk sericin, alginate and its blend on various physicochemical parameters and in vitro drug release pattern were studied to optimize the concentration of polymeric blend required for 12 h. sustain release. Optimized batch was subjected to different flowability, compressibility and tableting properties studies to observe the effects of carbo-protein microspheres on flow properties. Results indicated that the concentration of sericin was found to be the main influential factor for prolonged drug release. Different micromeritic studies revealed that the poor flowability and compressibility properties of pure losartan potassium were significantly improved by this algino-sericin microspheric dosage form. Research findings also revealed that plasticity, die filling behavior and tableting properties of the pure drug were significantly improved by this microsphere formulation. So these prospective results concluded that carbo-protein polymeric microspheres helps to sustain the drug release for prolong hours as well as improve the flowability, compressibility and tableting properties of losartan potassium.

Concepts: Better, Improve, Hypertension, Fluid dynamics, In vitro fertilisation, In vitro, Microsphere, Losartan