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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：
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)：心力衰竭是一种常见的心脏病，影响着近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有关。以交感神经活动增强和副交感神经活动取消为特征的心血管系统自主神经调节失调会促进心力衰竭的进展。药物阻断交感神经过度活动与降低死亡风险有关，但关于药物增强副交感神经戒断的数据很少。乙酰胆碱酯酶抑制剂通过阻断乙酰胆碱在胆碱能受体部位的酶分解来增加副交感神经传递。吡斯的明是FDA批准的一种短效、可逆乙酰胆碱酯酶抑制剂，用于治疗重症肌无力。我们现在提出了一项第二阶段的前瞻性随机双盲试验，以比较60名有症状的慢性心力衰竭伴左室收缩功能障碍的患者接受递增剂量的吡斯的明(每8小时15、30和60毫克)与匹配的安慰剂治疗12周的疗效。将针对以下每个具体目标研究吡斯的明的临床药理学：1)确定口服吡斯的明与安慰剂对慢性心力衰竭患者交感迷走神经平衡的影响；2)确定口服吡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；以及3)描述反复口服吡斯的明在慢性心力衰竭患者中的稳定药代动力学和药效学特性。混合效应模型将用于确定研究药物分配与交感迷走神经平衡的生理标记物(运动后心率恢复、心率变异性、心脏迷走神经压力感受器功能和休息/运动血儿茶酚胺水平)之间的关联，描述性统计以表征安全性/耐受性措施(运动能力、生活质量、疾病进展的生物标记物、胆碱能症状评分)，以及群体药代动力学/药效学建模，以表征研究剂量、研究药物血液水平、胆碱酯酶抑制程度以及交感神经迷走神经平衡措施与安全/耐受性之间的关系。总体目标是进一步确定吡斯的明作为治疗心力衰竭受试者的一种新疗法的潜力，并获得必要的信息，以评估未来心力衰竭患者进行第三阶段结果研究的可行性/后勤保障。拟议的研究将提供迫切需要的新数据，以指导这种有前景的药物作为一种减少心力衰竭患者发病率和死亡率的新治疗方法的未来发展。