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Journal of the American College of... Jan 2011The purpose of this study was to investigate predictors of bleeding in a cohort of anticoagulated patients and to evaluate the predictive value of several bleeding risk... (Comparative Study)
Comparative Study Randomized Controlled Trial
Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation: the HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) score.
OBJECTIVES
The purpose of this study was to investigate predictors of bleeding in a cohort of anticoagulated patients and to evaluate the predictive value of several bleeding risk stratification schemas.
BACKGROUND
The risk of bleeding during antithrombotic therapy in patients with atrial fibrillation (AF) is not homogeneous, and several clinical risk factors have been incorporated into clinical bleeding risk stratification schemas. Current risk stratification schemas for bleeding during anticoagulation therapy have been based on complex scoring systems that are difficult to apply in clinical practice, and few have been derived and validated in AF cohorts.
METHODS
We investigated predictors of bleeding in a cohort of 7,329 patients with AF participating in the SPORTIF (Stroke Prevention Using an ORal Thrombin Inhibitor in Atrial Fibrillation) III and V clinical trials and evaluated the predictive value of several risk stratification schemas by multivariate analysis. Patients were anticoagulated orally with either adjusted-dose warfarin (target international normalized ratio 2 to 3) or fixed-dose ximelagatran 36 mg twice daily. Major bleeding was centrally adjudicated, and concurrent aspirin therapy was allowed in patients with clinical atherosclerosis.
RESULTS
By multivariate analyses, significant predictors of bleeding were concurrent aspirin use (hazard ratio [HR]: 2.10; 95% confidence interval [CI]: 1.59 to 2.77; p < 0.001); renal impairment (HR: 1.98; 95% CI: 1.42 to 2.76; p < 0.001); age 75 years or older (HR: 1.63; 95% CI: 1.23 to 2.17; p = 0.0008); diabetes (HR: 1.47; 95% CI: 1.10 to 1.97; p = 0.009), and heart failure or left ventricular dysfunction (HR: 1.32; 95% CI: 1.01 to 1.73; p = 0.041). Of the tested schemas, the new HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) score performed best, with a stepwise increase in rates of major bleeding with increasing HAS-BLED score (p(trend) <0.0001). The c statistic for bleeding varied between 0.50 and 0.67 in the overall entire cohort and 0.68 among patients naive to warfarin at baseline (n = 769).
CONCLUSIONS
This analysis identifies diabetes and heart failure or left ventricular dysfunction as potential risk factors for bleeding in AF beyond those previously recognized. Of the contemporary bleeding risk stratification schemas, the new HAS-BLED scheme offers useful predictive capacity for bleeding over previously published schemas and may be simpler to apply.
Topics: Aged; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Blood Coagulation; Double-Blind Method; Female; Follow-Up Studies; Hemorrhage; Humans; Male; Prognosis; Risk Assessment; Risk Factors; Stroke; Warfarin
PubMed: 21111555
DOI: 10.1016/j.jacc.2010.09.024 -
Neurotherapeutics : the Journal of the... Jan 2007Safinamide (SAF) ((S)-(+)-2-(4-(3-fluorobenzyloxy) benzylamino)propanamide) was initially synthetized by Farmitalia Carlo Erba (Italy). Following initial anticonvulsant... (Review)
Review
Safinamide (SAF) ((S)-(+)-2-(4-(3-fluorobenzyloxy) benzylamino)propanamide) was initially synthetized by Farmitalia Carlo Erba (Italy). Following initial anticonvulsant screening, safinamide was selected for its potency, broad spectrum of action, and good safety margin. Pharmacodynamic properties probably relevant to its antiepileptic activity are use- and frequency-dependent block of voltage sensitive Na+ channels, block of Ca++ channels, and glutamate release inhibition. Possibly contributing mechanism are also selective and reversible monoamide oxidase B inhibition and dopamine and noradrenaline uptake inhibition. The high selectivity for the sigma-1 receptor site does not entail psychotomimetic or behavioral changes. In several experimental in vitro and in vivo conditions, SAF exerts neurorescuing and neuroprotectant effects. Safinamide is water soluble and suitable for 1 times a day oral administration in humans. In a pilot phase II study in 38 refractory epilepsy patients affected by multiple types of seizures, 41% of subjects obtained > or =50% seizure reduction during a 12-week escalating dose up to 300 mg 1 times day compared with perspective baseline. Safinamide is being developed in phase III for treatment of Parkinson's disease, whereas the development in epilepsy relates to the industrial strategy of the company.
Topics: Alanine; Animals; Anticonvulsants; Benzylamines; Brain; Clinical Trials as Topic; Epilepsy; Humans; Parkinson Disease
PubMed: 17199024
DOI: 10.1016/j.nurt.2006.11.011 -
Lakartidningen Dec 2018
Topics: Anticoagulants; Antithrombins; Atrial Fibrillation; Azetidines; Benzylamines; Dabigatran; Factor Xa Inhibitors; Humans; Safety-Based Drug Withdrawals; Stroke; Warfarin
PubMed: 30512138
DOI: No ID Found -
Molecules (Basel, Switzerland) Jul 2022A number of imines, including 12 new compounds, previously not reported in the literature, derived from variously fluorinated benzaldehydes and different anilines or...
A number of imines, including 12 new compounds, previously not reported in the literature, derived from variously fluorinated benzaldehydes and different anilines or chiral benzylamines were synthesized by a solvent-free mechanochemical method, which was based on the manual grinding of equimolar amounts of the substrates at the room temperature. In a very short reaction time of only 15 min, the method produced the expected products with good-to-excellent yields. The yields were comparable or significantly higher than those reported in the literature for the imines synthesized by other methods. Importantly, the conditions used for the reactions with aniline derivatives also resulted in the high yields of imines obtained from chiral benzylamines, and can be extended to the synthesis with other similar amines. Structures of all imines were confirmed by NMR spectroscopy: H, C and F. For four compounds, X-ray structures were also obtained. The synthetic approach presented in this paper contributes to the prevention of environmental pollution and can be easily extended for larger-scale syntheses. The mechanochemical solvent-free method provides a convenient strategy particularly useful for the preparation of fluorinated imines being versatile intermediates or starting material in the synthesis of drugs and other fine chemicals.
Topics: Amines; Benzaldehydes; Benzylamines; Imines; Magnetic Resonance Spectroscopy
PubMed: 35889430
DOI: 10.3390/molecules27144557 -
Biochemical Pharmacology Feb 2022Cholesterol biosynthesis, primarily associated with eukaryotes, occurs as an essential component of human metabolism with biosynthetic deregulation a factor in cancer... (Review)
Review
Cholesterol biosynthesis, primarily associated with eukaryotes, occurs as an essential component of human metabolism with biosynthetic deregulation a factor in cancer viability. The segment that partitions between squalene and the C-end cholesterol yields the main cholesterogenesis branch subdivided into the Bloch and Kandutsch-Russell pathways. Their importance in cell viability, in normal growth and development originates primarily from the amphipathic property and shape of the cholesterol molecule which makes it suitable as a membrane insert. Cholesterol can also convert to variant oxygenated product metabolites of distinct function producing a complex interplay between cholesterol synthesis and overall steroidogenesis. In this review, we disassociate the two sides of cholesterogenesisis affecting the type and amounts of systemic sterols-one which is beneficial to human welfare while the other dysfunctional leading to misery and disease that could result in premature death. Our focus here is first to examine the cholesterol biosynthetic genes, enzymes, and order of biosynthetic intermediates in human cholesterogenesis pathways, then compare the effect of proximal and distal inhibitors of cholesterol biosynthesis against normal and cancer cell growth and metabolism. Collectively, the inhibitor studies of druggable enzymes and specific biosynthetic steps, suggest a potential role of disrupted cholesterol biosynthesis, in coordination with imported cholesterol, as a factor in cancer development and as discussed some of these inhibitors have chemotherapeutic implications.
Topics: Animals; Anticholesteremic Agents; Antineoplastic Agents; Benzylamines; Cholesterol; Humans; Lanosterol; Neoplasms; Terbinafine; Thiophenes
PubMed: 34010597
DOI: 10.1016/j.bcp.2021.114611 -
Science Advances Jul 2023Hypertrophic cardiomyopathy (HCM) is a primary myocardial disorder characterized by left ventricular hypertrophy, hyperdynamic contraction, and impaired relaxation of... (Review)
Review
Hypertrophic cardiomyopathy (HCM) is a primary myocardial disorder characterized by left ventricular hypertrophy, hyperdynamic contraction, and impaired relaxation of the heart. These functional derangements arise directly from altered sarcomeric function due to either mutations in genes encoding sarcomere proteins, or other defects such as abnormal energetics. Current treatment options do not directly address this causal biology but focus on surgical and extra-sarcomeric (sarcolemmal) pharmacological symptomatic relief. Mavacamten (formerly known as MYK-461), is a small molecule designed to regulate cardiac function at the sarcomere level by selectively but reversibly inhibiting the enzymatic activity of myosin, the fundamental motor of the sarcomere. This review summarizes the mechanism and translational progress of mavacamten from proteins to patients, describing how the mechanism of action and pharmacological characteristics, involving both systolic and diastolic effects, can directly target pathophysiological derangements within the cardiac sarcomere to improve cardiac structure and function in HCM. Mavacamten was approved by the Food and Drug Administration in April 2022 for the treatment of obstructive HCM and now goes by the commercial name of Camzyos. Full information about the risks, limitations, and side effects can be found at www.accessdata.fda.gov/drugsatfda_docs/label/2022/214998s000lbl.pdf.
Topics: United States; Humans; Precision Medicine; Cardiomyopathy, Hypertrophic; Benzylamines; Myosins
PubMed: 37506209
DOI: 10.1126/sciadv.abo7622 -
Frontiers in Bioscience (Elite Edition) Jan 2016Burning mouth syndrome (BMS) is characterised by the presence of a burning sensation in the oral mucosa in the absence of any clinically apparent mucosal sign. It occurs... (Review)
Review
Burning mouth syndrome (BMS) is characterised by the presence of a burning sensation in the oral mucosa in the absence of any clinically apparent mucosal sign. It occurs more commonly in older women and often affects the tongue tip and lateral borders, lips, and hard and soft palates. Besides the burning sensation, patients with BMS may complain of unremitting oral mucosal pain, dysgeusia, and xerostomia. The exact pathophysiology of primary BMS remains unknown. A major challenge for the clinician is the treatment of BMS: identifying possible causative factors is the first step, but BMS is often idiopathic. Drug therapy, in addition to behavioural therapy and psychotherapy, may help to eliminate the symptoms. Considering the growing incidence of BMS in older people, further research is required to determine the true efficacy of current management strategies for patients with this disorder.
Topics: Benzylamines; Burning Mouth Syndrome; Capsaicin; Clonazepam; Humans; Lidocaine; Prevalence
PubMed: 26709657
DOI: 10.2741/E762 -
Expert Opinion on Pharmacotherapy Jun 2017The major unmet needs in the medical treatment of Parkinson disease (PD) are reduction of motor side effects from dopaminergic drugs, management of non-motor symptoms... (Review)
Review
The major unmet needs in the medical treatment of Parkinson disease (PD) are reduction of motor side effects from dopaminergic drugs, management of non-motor symptoms and disease modification. Areas covered: Motor fluctuations and OFF periods are a significant determinant of quality of life in PD and reducing their duration and severity can significantly improve motor function. This aim may be partly facilitated by the development of effective adjunctive drugs for dopamine replacement. Safinamide (Xadago), which is a first generation anticonvulsant, has pharmacological properties which are of interest in the context of neurodegenerative diseases, leading to research into its potential as an adjunct to levodopa in PD. Expert opinion: Although its mechanism has not been fully defined, safinamide provides enhanced symptom control of motor function in advanced PD and improves quality of life.
Topics: Alanine; Antiparkinson Agents; Benzylamines; Dopamine; Dopamine Agents; Humans; Levodopa; Parkinson Disease; Quality of Life; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 28504022
DOI: 10.1080/14656566.2017.1329819 -
Circulation Research Mar 2015For >50 years, it has been recognized that immunity contributes to hypertension. Recent data have defined an important role of T cells and various T cell-derived... (Review)
Review
For >50 years, it has been recognized that immunity contributes to hypertension. Recent data have defined an important role of T cells and various T cell-derived cytokines in several models of experimental hypertension. These studies have shown that stimuli like angiotensin II, deoxycorticosterone acetate-salt, and excessive catecholamines lead to formation of effector like T cells that infiltrate the kidney and perivascular regions of both large arteries and arterioles. There is also accumulation of monocyte/macrophages in these regions. Cytokines released from these cells, including interleukin-17, interferon-γ, tumor necrosis factorα, and interleukin-6 promote both renal and vascular dysfunction and damage, leading to enhanced sodium retention and increased systemic vascular resistance. The renal effects of these cytokines remain to be fully defined, but include enhanced formation of angiotensinogen, increased sodium reabsorption, and increased renal fibrosis. Recent experiments have defined a link between oxidative stress and immune activation in hypertension. These have shown that hypertension is associated with formation of reactive oxygen species in dendritic cells that lead to formation of gamma ketoaldehydes, or isoketals. These rapidly adduct to protein lysines and are presented by dendritic cells as neoantigens that activate T cells and promote hypertension. Thus, cells of both the innate and adaptive immune system contribute to end-organ damage and dysfunction in hypertension. Therapeutic interventions to reduce activation of these cells may prove beneficial in reducing end-organ damage and preventing consequences of hypertension, including myocardial infarction, heart failure, renal failure, and stroke.
Topics: Adaptive Immunity; Animals; Benzylamines; Cardiovascular Diseases; Cytokines; Drug Evaluation, Preclinical; Humans; Hypertension; Immunity, Innate; Inflammation; Kidney; Lymphocyte Activation; Mice; Mice, Knockout; Models, Animal; Models, Cardiovascular; Models, Immunological; Oxidative Stress; Reactive Oxygen Species; Signal Transduction; T-Lymphocyte Subsets; Vascular Remodeling; Vascular Stiffness
PubMed: 25767287
DOI: 10.1161/CIRCRESAHA.116.303697 -
Cardiovascular & Hematological Agents... 2023Obstructive hypertrophic cardiomyopathy results from asymmetric septal hypertrophy, which eventually obstructs the outflow of the left ventricle. Obstructive... (Review)
Review
Obstructive hypertrophic cardiomyopathy results from asymmetric septal hypertrophy, which eventually obstructs the outflow of the left ventricle. Obstructive hypertrophic cardiomyopathy is linked to mutations in genes that encode for sarcomere proteins, including actin, β-myosin heavy chain, titin, and troponin. The mutations lead to structural abnormalities in myocytes and myofibrils, causing conduction irregularities and abnormal force generation. Obstructive hypertrophic cardiomyopathy is a chronic disease that worsens over time, and patients become at higher risk of developing atrial fibrillation, heart failure, and stroke. Up until recently, there were no disease- specific medications for obstructive hypertrophic cardiomyopathy. Nevertheless, the US Food and Drug Administration approved mavacamten on April 28, 2022, for the treatment of symptomatic obstructive hypertrophic cardiomyopathy (New York Heart Association class II to III) in adults to improve functional capacity and symptoms. Its approval was based on data from EXPLORER- HCM and EXPLORER-LTE (NCT03723655). Mavacamten is a novel, first-in-class, orally active, allosteric inhibitor of cardiac myosin ATPase, which decreases the formation of actin- myosin cross-bridges, and thus, it reduces myocardial contractility, and it improves myocardial energetics. It represents a paradigm-shifting pharmacological treatment of obstructive hypertrophic cardiomyopathy. In this review, we describe its chemical and mechanistic aspects as well as its pharmacokinetics, adverse effects and warnings, potential drug-drug interactions, and contraindications.
Topics: Adult; Humans; Actins; Benzylamines; Cardiomyopathy, Hypertrophic; Myocardium; United States; United States Food and Drug Administration
PubMed: 36278454
DOI: 10.2174/1871525721666221019095218