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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：
8477959
负责人：
STUART D KATZ
金额：
$ 73.35万
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/8477959
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）：心力衰竭是一种常见的心脏病，影响近600万美国人。尽管最近在治疗方面取得了进展，但心力衰竭与住院和死亡的高风险相关。以交感神经活动增强和副交感神经活动消退为特征的心血管系统的自主神经失调促进心力衰竭的进展。交感神经过度活跃的药理学阻断与降低死亡风险相关，但关于副交感神经退缩的药理学增强的数据很少。乙酰胆碱酯酶抑制剂通过阻断乙酰胆碱在胆碱能受体位点的酶促分解来增强副交感神经传递。吡斯的明是一种短效、可逆的乙酰胆碱酯酶抑制剂，经FDA批准用于治疗重症肌无力。我们现在提出一项II期前瞻性随机双盲试验，比较60例伴有左心室收缩功能障碍的症状性慢性心力衰竭患者接受递增剂量吡啶斯的明（每8小时15、30和60 mg）与匹配安慰剂治疗12周的效果。将针对以下特定目的研究吡啶斯的明的临床药理学：1）描述口服吡啶斯的明与安慰剂相比对慢性心力衰竭患者交感迷走神经平衡的影响; 2）描述口服吡啶斯的明与安慰剂相比在慢性心力衰竭患者中的安全性和耐受性; 3）研究慢性心力衰竭患者反复口服吡啶斯的明的稳态药代动力学和药效学特征。将使用混合效应模型确定研究药物分配与交感迷走神经平衡生理标志物之间的相关性（运动后心率恢复、心率变异性、心迷走神经压力感受器功能和静息/运动血儿茶酚胺水平），描述性统计量，以表征安全性/耐受性指标（运动能力、生活质量、疾病进展的生物标志物、胆碱能症状评分）和群体药代动力学/药效学建模，以表征研究给药之间的关系，研究药物血液水平、胆碱酯酶抑制程度和交感迷走神经平衡和安全性/耐受性的测量。总体目标是进一步表征吡啶斯的明作为心力衰竭受试者新型治疗的潜力，并获得必要的信息，以评估未来心力衰竭患者III期结局研究的可行性/逻辑。拟议的研究将提供指导这种有前途的药物作为降低心力衰竭患者发病率和死亡率的新型治疗方法的未来发展所急需的新数据。