Augmentation of Parasympathetic Signaling with Pyridostigmine in Heart Failure

吡啶斯的明在心力衰竭中增强副交感信号传导

基本信息

批准号：
8775005
负责人：
STUART D KATZ
金额：
$ 30.16万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-19 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8775005
关键词：
Acetylcholine Acetylcholinesterase Inhibitors Adrenergic Receptor Adverse effects Adverse event Affect American Autonomic nervous system Biochemical Markers Biological Markers Blood Blood drug level result Brain natriuretic peptide Cardiac Cardiovascular system Catecholamines Cessation of life Chemistry Cholinergic Receptors Cholinesterases Chronic Clinical Clinical Pharmacology Clinical Trials Data Development Disease Progression Dose Double-Blind Method Drug Interactions Drug Kinetics Electrophysiology (science)Equilibrium Erythrocytes Exercise FDA approved Functional disorder Future Goals Heart Diseases Heart Rate Heart failure Hospitalization Hour Interleukin-6 Left Logistics Measures Modeling Monitor Morbidity - disease rate Myasthenia Gravis Nervous System Physiology Neuromuscular Diseases Neurosecretory Systems Oral Outcome Study Patients Pharmaceutical Preparations Pharmacodynamics Phase Physiological Placebos Plasma Play Population Pressoreceptors Property Quality of life Randomized Recovery Regulation Renal function Rest Risk Role Safety Serum Severity of illness Signal Transduction Site Spirometry Symptoms Testing Therapeutic Tumor Necrosis Factor-alpha Ventricular Withdrawal cholinergic heart rate variability high risk improved liver function mortality neurotransmission novel novel therapeutic intervention pharmacodynamic model prospective pyridostigmine statistics

项目摘要

DESCRIPTION (provided by applicant): Heart failure is a common form of heart disease affecting nearly 6 million Americans. Despite recent advances in therapy, heart failure is associated with a high risk for hospitalization and death. Autonomic dysregulation of the cardiovascular system, characterized by heightened sympathetic activity and withdrawal of parasympathetic activity promotes progression of heart failure. Pharmacological blockade of sympathetic overactivity is associated with reduced mortality risk, but there are few data on pharmacologic augmentation of parasympathetic withdrawal. Acetylcholinesterase inhibitors augment parasympathetic neurotransmission by blocking the enzymatic breakdown of acetylcholine at cholinergic receptor sites. Pyridostigmine is a short-acting, reversible acetylcholinesterase inhibitor approved by the FDA for the treatment of myasthenia gravis. We now propose a Phase II prospective randomized, double-blind trial to compare 12 weeks of treatment with ascending doses of pyridostigmine (15, 30, and 60 mg every 8 hours) vs. matching placebo in 60 patients with symptomatic chronic heart failure associated with left ventricular systolic dysfunction. The clinical pharmacology of pyridostigmine will be investigated for each of the following specific aims: 1) To characterize the effects of oral pyridostigmine vs. placebo on sympathovagal balance in patients with chronic heart failure; 2) To characterize the safety and tolerability of oral pyridostigmine vs. placebo in patients with chronic heart failure; and 3) To characterize the steady state pharmacokinetic and pharmacodynamic properties of repeated oral dosing of pyridostigmine in patients with chronic heart failure. Mixed effects models will be used to determine the association between study drug assignment and physiological markers of sympathovagal balance (post-exercise heart rate recovery, heart rate variability, cardiovagal baroreceptor function, and rest/exercise blood catecholamine levels), descriptive statistics to characterize safety/tolerability measures (exercise capacity, quality of life, biomarkers of disease progression, cholinergic symptoms score), and population pharmacokinetic/pharmacodynamic modeling to characterize the relationship between study dosing, study drug blood levels, the degree of cholinesterase inhibition and the measures of sympathovagal balance and safety/tolerability. The overall goal is to further characterize the potential of pyridostigmine as a novel treatment in heart failure subjects and obtain information necessary to evaluate the feasibility/logistics of a future Phase III outcomes study in heart failure patients. The proposed studies will provide new data that are critically needed to direct the future development of this promising drug as a novel therapeutic approach for reduction of morbidity and mortality in heart failure patients.

描述（由申请人提供）：心力衰竭是影响近600万美国人的心脏病的常见形式。尽管治疗最近进展，但心力衰竭与住院和死亡的高风险有关。心血管系统的自主性失调，其特征是增强交感神经活动和副交感神经的戒断会促进心力衰竭的进展。交感神经过度活动的药理阻滞与死亡率降低有关，但是关于副交感神经戒断的药理学增强数据的数据很少。乙酰胆碱酯酶抑制剂通过阻断胆碱能受体部位的乙酰胆碱的酶促分解来增强副交感神经传递。吡啶斯汀类是一种短作用，可逆的乙酰胆碱酯酶抑制剂，该抑制剂已获得FDA批准用于治疗肌无力的肌无力。现在，我们提出了一项II期前瞻性随机，双盲试验，以将12周的治疗与60名与左心室心脏功能障碍相关的有症状性心力衰竭的患者与匹配的安慰剂相比，将12周的治疗与上升剂量的吡啶斯替甘氨酸（每8小时15、30和60 mg）进行比较。将针对以下每个特定目的研究吡ido虫的临床药理学：1）表征口服吡啶斯汀类与安慰剂对慢性心力衰竭患者交感平衡的影响； 2）表征慢性心力衰竭患者口服吡啶斯汀与安慰剂的安全性和耐受性； 3）表征慢性心力衰竭患者中吡ido骨的重复口服剂量的稳态药代动力学和药效学特性。 Mixed effects models will be used to determine the association between study drug assignment and physiological markers of sympathovagal balance (post-exercise heart rate recovery, heart rate variability, cardiovagal baroreceptor function, and rest/exercise blood catecholamine levels), descriptive statistics to characterize safety/tolerability measures (exercise capacity, quality of life, biomarkers of disease progression, cholinergic symptoms score), and population药代动力学/药效学建模，以表征研究剂量，研究药物水平，胆碱酯酶抑制程度以及交感神经平衡和安全性/耐受性之间的关系。总体目标是进一步将吡啶斯汀甘氨酸作为心力衰竭受试者的新型治疗的潜力，并获得评估心力衰竭患者未来III期结果研究的可行性/物流所必需的信息。拟议的研究将提供新的数据，这些数据是指导这种有前途的药物的未来开发，作为一种新型治疗方法，用于降低心力衰竭患者的发病率和死亡率。