Compositions and methods for treating or preventing atrial fibrillation

a technology of atrial fibrillation and compositions, applied in the direction of drug compositions, cardiovascular disorders, biocide, etc., can solve the problems of irregular heart rate, irregular heart rate, and af is a major risk factor for stroke and other embolic events, so as to prevent atrial fibrillation and prevent atrial fibrillation

Inactive Publication Date: 2011-11-17
NORTHWESTERN UNIV
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  • Description
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AI Technical Summary

Benefits of technology

[0008]The present invention provides compositions and methods for treating or preventing atrial fibrillation (AF) for therapeutic or research purposes. In some embodiments, the present invention provides targeted autonomic inhibition of sympathetic activity in the pulmonary vein (PV) and/or posterior left atrium (PLA) to treat and/or prevent atrial fibrillation. In some embodiments, muscarini...

Problems solved by technology

Cardiac arrhythmias represent a diverse set of conditions characterized by abnormal electrical activity in the heart, resulting in heart rates that are too fast, too slow, or irregular.
AF is caused by disorganized electrical impulses originating in the atria and pulmonary veins that propagate as irregular electrical signals to the ventricles, resulting in irregular heart rates.
AF is a major risk factor for stroke and other embolic events, as it predisposes to the formation of clots in the left atrial appenda...

Method used

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  • Compositions and methods for treating or preventing atrial fibrillation
  • Compositions and methods for treating or preventing atrial fibrillation
  • Compositions and methods for treating or preventing atrial fibrillation

Examples

Experimental program
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example 1

[0054]Canine CHF Model. Sterile surgery for pacemaker implantation was performed in canine subjects. The pacemaker was programmed to pace the right ventricle for 3 weeks at a rate of 240 beats per minute. CHF was confirmed by left ventricular dysfunction assessed by serial echocardiogram and by clinical assessment (e.g. ascites, tachypnea, reduced physical activity).

[0055]Experimental Setup. After the 3 weeks of pacing, the subjects were intubated and a median sternonomy was performed under general anesthesia with isoflurane. High density plaques were applied to the left inferior pulmonary vein (PV; 8×5 electrodes; 2.5 mm spacing), the posterior left atrium (PLA; 7×3 electrodes, 5 mm spacing) and the left atrial appendage (LAA; 7×3 electrodes, 5 mm spacing) for bipolar electrogram recordings and pacing. The PV plaque was placed circumferentially around the vein while the other two plaques were laid flat on the PLA and LAA epicardium. The left cervical vagus nerve was isolated and at...

example 2

[0070]Canines were subjected to heart failure (HF) by rapid ventricular pacing (240 / min for 3 weeks). Vagal stimulation induced ERP shortening (VS-ΔERP)(ms) was assessed in the test canines as well as controls at multiple sites in the LA. VS-ΔERP was reassessed in the presence of an acetylcholineesterase (AChE) inhibitor (physostigmine). Explanted LA were subjected to 1) ELISA for acetylcholinesterase (AChE) activity, 2) AChE immunostaining and 3) radioactive M2 receptor binding assay.

[0071]VS-ΔERP was significantly reduced in HF, but was restored by physostigmine (from 10±4 to 28±4). The number of parasympathetic ganglia in the LA was increased in HF (HF vs. control=3.8±3 cm−2 vs. 0.95±1.5 cm−2). AChE activity was also greater in HF. There was no change in M2 binding activity in HF compared to control. There was a profound increase in parasympathetic innervation, and a decrease in parasympathetic responsiveness in the HF LA, despite intact M2 receptor binding. Experiments conducted...

example 3

[0072]Canine Arrhythmia Model. Methoctramine, a muscarinic receptor blocker that is selective for blocking the M2 receptor subtype (Tumiatti, V. et al. Bioorg. Med. Chem. 2007, 15, 2312-2321), was evaluated for its ability to decrease effective refractory period and atrial fibrillation induced by vagal stimulation. Open chest electrophysiological mapping was performed in a canine model as previously described (Arora, R. et al. Am. J. Physiol. Heart Circ. Physiol. 2008, 294, H134-H144). Recording plaques were placed on the posterior left atrium (PLA), left superior pulmonary vein (PV) and the left atrial appendage (LAA). At baseline, effective refractory periods (ERPs) were obtained at multiple sites on each plaque in the absence and presence of vagal stimulation (VS). AF inducibility was also assessed under each of these conditions i.e. with and without VS. After baseline measurements had been made, methoctramine tetrahydrochloride hydrate (20 microgram / kg), dissolved in normal sali...

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Abstract

The present invention provides compositions and methods for treating or preventing atrial fibrillation (AF). In particular, the present invention provides administration of muscarinic receptor antagonists (e.g., M2-selective muscarinic receptor blockers), administered alone or in combination with other therapeutic agents (e.g., beta-adrenergic receptor blockers) to treat and/or prevent atrial fibrillation.

Description

[0001]This application claims priority to Provisional Patent Application Ser. No. 61 / 334,023, filed May 12, 2010, and Provisional Patent Application Ser. No. 61 / 409,691, filed Nov. 3, 2010, which are herein incorporated by reference in their entireties.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT[0002]This invention was made with government support under Grant Number R01 HL093490 awarded by the National Institutes of Health (National Heart, Lung, and Blood Institute). The government has certain rights to the invention.FIELD OF THE INVENTION[0003]The present invention provides compositions and methods for treating or preventing atrial fibrillation (AF). In particular, the present invention provides administration of muscarinic receptor antagonists (e.g., M2-selective muscarinic receptor blockers), administered alone or in combination with other therapeutic agents (e.g., beta-adrenergic receptor blockers) to treat and / or prevent atrial fibrillation.BACKGROUND[0004]C...

Claims

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Application Information

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IPC IPC(8): A61K31/551A61K31/135A61K31/404A61K31/22A61K31/5377A61K31/18A61K31/24A61K31/16A61K31/165A61K31/352A61K31/437A61K31/44A61K31/522A61K31/215A61K31/445A61K31/4725A61K31/4025A61K31/4545A61P9/06A61K31/47
CPCA61K31/135A61K31/165A61K31/551A61K31/5377A61K31/522A61K31/4725A61K31/47A61K31/4545A61K31/445A61K31/18A61K31/215A61K31/22A61K31/24A61K31/352A61K31/4025A61K31/404A61K31/437A61K31/44A61K2300/00A61K31/132A61K31/137A61K31/138A61K31/46A61P9/04A61P9/06
Inventor ARORA, RISHIZEMBOWER, DAVID E.
Owner NORTHWESTERN UNIV
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