Compositions and methods for increasing efficiency of cardiac metabolism
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Publication Number
US-11844840-B2
Publication Date
2023-12-19
Expiration Date
Abstract
Compositions and methods for increasing efficiency of cardiac metabolism are provided.
Core Innovation
The invention is directed to treating heart failure in a subject suffering from heart failure by providing a compound represented by formula (X). The described approach increases cardiac metabolic efficiency and modulates cardiac metabolism toward glucose oxidation, while promoting mitochondrial respiration and improving cardiac mitochondrial energy metabolism. The disclosures also link the compound to effects on fatty acid oxidation and mitochondrial function.
The document describes testing of mitochondrial activity using Seahorse OCR/ECAR flux measurements, including oxygen consumption rate (OCR), extracellular acidification rate (ECAR), and the mitochondrial stress test concept. These measurements support the stated mitochondrial function and metabolic shifts relevant to oxidative phosphorylation (OXPHOS) and glycolysis in the treatment context.
The disclosure further summarizes ischemia-reperfusion and transverse aortic constriction studies in mice and rats, including coronary flow, cardiac functional recovery metrics, and infarct-size reduction using triphenyltetrazolium chloride (TTC) staining. It also includes compound combinations, structural examples, and utility for heart diseases, including heart failure, ischemic heart disease, and diabetic cardiomyopathies.
Claims Coverage
The independent claim is directed to treating heart failure by providing a compound represented by formula (X) to a subject suffering from heart failure. The claim set further includes refinements to pharmaceutical composition form, oral administration, selectable dosage-form formats, and a dosage range constraint, and one item also describes covalently linked NAD+ precursors and cleavable linkers in the compound framework.
Treating heart failure by providing formula (X)
A method of treating heart failure in a subject suffering from heart failure by providing a compound represented by formula (X).
Providing as a pharmaceutical composition
The compound is provided as a pharmaceutical composition.
Oral administration of the pharmaceutical composition
The pharmaceutical composition is provided to the subject by oral administration.
Selected pharmaceutical format for the composition
The pharmaceutical composition includes a format selected from tablets, troches, lozenges, fast-melts, aqueous suspensions, oily suspensions, dispersible powders, granules, emulsions, hard capsules, soft capsules, syrups, and elixirs.
Dosage range constraint
The compound is administered at a dosage ranging from about 1 mg/kg/day to about 10 mg/kg/day.
Covalently linked NAD+ precursors and cleavable linkers
The compound framework includes optional covalently linked NAD+ precursors selected from nicotinic acid, nicotinamide, or nicotinamide riboside, together with cleavable linkers.
Across the claims, the core coverage centers on providing a compound represented by formula (X) to treat heart failure, with further scope limited by pharmaceutical composition form, oral administration, specified oral formulation formats, a defined dosage range, and, in one item, covalently linked NAD+ precursors and cleavable linkers.
Stated Advantages
Improved cardiac efficiency and cardiac mechanical efficiency.
Modulation of cardiac metabolism toward glucose oxidation.
Increase cardiac metabolic efficiency by shifting cardiac metabolism from fatty-acid oxidation to glucose oxidation and promoting mitochondrial respiration.
Mitochondrial function or mitochondrial activity outcomes supported by OCR/ECAR and mitochondrial stress test concept measurements.
Reported reduction in infarct size in ischemia-reperfusion and transverse aortic constriction studies.
Documented Applications
Treatment of heart failure in a subject suffering from heart failure.
Treatment of ischemic heart disease.
Treatment of diabetic cardiomyopathies.
Ischemia-reperfusion and transverse aortic constriction study evaluation, including coronary flow, cardiac functional recovery, and infarct-size reduction using TTC staining.
Mitochondrial activity and metabolism evaluation using Seahorse OCR/ECAR flux measurements and a mitochondrial stress test concept, including OXPHOS and glycolysis-related outcomes.
Use with pharmaceutical oral dosage forms.
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