Compositions and methods for increasing efficiency of cardiac metabolism
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Publication Number
US-12318453-B2
Publication Date
2025-06-03
Expiration Date
Abstract
Compositions and methods for increasing efficiency of cardiac metabolism are provided.
Core Innovation
The invention provides a method of treating ischemia in a subject suffering from ischemia by providing a compound represented by formula (X). The disclosed approach is associated with altering cardiac metabolism toward increased glucose oxidation versus fatty-acid oxidation, with an emphasis on myocardial mitochondrial function and mitochondrial respiration.
The material describes combinations involving mitochondrial respiration promoters and NAD+ precursors, and links these to cardiac efficiency and cardiac mechanical efficiency. In the documented examples, trimetazidine (TMZ) in combination with nicotinamide and succinate is described as providing greater preservation of coronary flow/function and greater reduction in infarct size than TMZ alone, with dose-dependent protection.
The disclosure further includes covalently linked single-molecule designs for the A/B and optionally C concept, presented as formulas I-V and VII-VIII, with cleavable linkers such as alkoxy and PEG/CH2CH2O architectures. It states that PEGylation and related ethylene-glycol-linked architectures can improve bioavailability and mitigate Parkinsonian side effects associated with trimetazidine, and includes pharmaceutical formulation formats for oral use.
Claims Coverage
The independent claim covers a method of treating ischemia in a subject by providing a compound represented by formula (X). The dependent claims add three main refinements: providing the compound in a pharmaceutical composition, administering the composition orally, and specifying selected dosage forms; one dependent claim also constrains the administered dosage range.
Treating ischemia with a compound represented by formula (X)
A method of treating ischemia in a subject suffering from ischemia by providing a compound represented by formula (X).
Providing the compound as part of a pharmaceutical composition
The method is carried out using the compound as part of a pharmaceutical composition.
Oral administration of the pharmaceutical composition
The method includes orally administering the pharmaceutical composition to the subject.
Dosage form selection for the pharmaceutical composition
The method is carried out using a pharmaceutical composition that includes a dosage form selected from tablet, troche, lozenge, fast-melt, aqueous suspension, oily suspension, dispersible powder, granule, emulsion, hard capsule, soft capsule, syrup, and elixir.
Dose range in mg/kg/day
The method is carried out by administering the compound to the subject at a dosage ranging from about 1 mg/kg/day to about 10 mg/kg/day.
Overall, the claim set centers on administering a formula (X) compound for treating ischemia, with coverage narrowed by inclusion in a pharmaceutical composition, oral administration, specified dosage forms, and a defined mg/kg/day dosage range.
Stated Advantages
PEGylation and ethylene-glycol-linked architectures may improve bioavailability.
PEGylation and ethylene-glycol-linked architectures may mitigate Parkinsonian side effects associated with trimetazidine.
Preserved coronary flow/function and reduced infarct size in ischemia-reperfusion settings, with greater effect than TMZ alone and dose-dependent protection.
Documented Applications
Heart failure treatment, as an indicated therapeutic use described in the document.
Ischemic heart disease treatment, as an indicated therapeutic use described in the document.
Diabetic cardiomyopathies treatment, as an indicated therapeutic use described in the document.
Treating ischemia in a subject, including ischemia-reperfusion contexts assessed using coronary flow, LVDP, and infarct size by TTC, as well as echocardiographic and functional readouts in models including mice.
Cardiac metabolism alteration toward increased glucose oxidation versus fatty-acid oxidation, linked to myocardial mitochondrial function and mitochondrial respiration.
Formulation and administration of the compound(s) in pharmaceutical dosage forms including aqueous or oily suspensions, dispersible powders or granules, oil-in-water emulsions, syrups or elixirs, and oral administration.
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