Monoglyceride of acetoacetate and derivatives for the treatment of neurological disorders
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Publication Number
US-9125881-B2
Publication Date
2015-09-08
Expiration Date
Abstract
This invention relates to methods of using the monoglyceride of acetoacetate and metabolic precursors for the treatment, prevention, inhibition or alleviation of neurological diseases associated with neuronal hypometabolism, such as Alzheimer's disease, Parkinson's disease, Friedreich's Ataxia (FRDA), GLUT1-deficient Epilepsy, Leprechaunism and Rabson-Mendenhall Syndrome, Coronary Arterial Bypass Graft (CABG) dementia, anesthesia induced memory loss, age associated memory impairment (AAMI), Traumatic Brain Injury (TBI), Huntington's disease and many others.
Core Innovation
The invention relates to methods of treatment and prevention of neurological diseases associated with neuronal hypometabolism by administering monoglycerides and acetoacetate-derived metabolic precursors to induce hyperketonemia through elevation of circulating ketone bodies. The approach uses compositions that lack a source of D-β-hydroxybutyric acid or its corresponding salt, while providing acetoacetate precursors such as monoacetoacetin (MA, AC-0523).
The background problem addressed is reduced cerebral glucose utilization associated with neuronal hypometabolism, and the limitations of prior approaches such as ketogenic diet and medium chain triglycerides (MCT) in delivering ketone bodies without certain constraints. The invention positions ketone-body elevation as a strategy for neurological diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), while using metabolic precursors derived from acetoacetate rather than including D-β-hydroxybutyric acid as a component.
In preferred embodiments, the method includes selecting patients and determining ApoE status, and administering an effective amount of monoacetoacetin (or a pharmaceutically acceptable salt thereof) to patients having an absence of ApoE4. The described compositions are formulated to elevate blood ketone bodies, with targeted physiologic relationships between D-β-hydroxybutyrate and acetoacetate, and may optionally include a carbohydrate source such as glucose and metabolic adjuvants such as L-carnitine and derivatives.
Claims Coverage
The partial content identifies one independent claim with additional dependent refinements, for a total of five claim points in the provided claim set. The independent claim centers on ApoE status-based patient selection and administration of a monoacetoacetin composition lacking a source of D-β-hydroxybutyric acid to elevate blood ketone bodies.
ApoE status selection for Parkinson's treatment using monoacetoacetin lacking D-β-hydroxybutyric acid
Selecting a patient having Parkinson's disease; determining the ApoE status of the patient; administering to the patient having an absence of ApoE4 a composition comprising an effective amount of monoacetoacetin, or a pharmaceutically acceptable salt thereof, wherein the composition lacks a source of D-β-hydroxybutyric acid or its corresponding salt, in an amount effective to elevate the patient's blood level of ketone bodies.
Monoacetoacetin dosing range
Administering monoacetoacetin at a dose ranging from 0.1 g/kg/day to 10 g/kg/day.
Target blood ketone body elevation timing and range
Elevating a patient's blood ketone body level to 0.2 mM–20 mM at about two hours after administration.
Composition additionally including a carbohydrate source
Using a composition that additionally includes a carbohydrate source.
Glucose as carbohydrate source
Using glucose as the carbohydrate source.
Across the provided claim set, the core coverage is the treatment of Parkinson's disease by ApoE4-negative selection and administration of monoacetoacetin compositions that lack a source of D-β-hydroxybutyric acid, with dependent features specifying a monoacetoacetin dosing range, target blood ketone-body levels at about two hours post-administration, and optional inclusion of a carbohydrate source (specifically glucose).
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treatment and prevention of neurological diseases associated with neuronal hypometabolism, including Parkinson's disease (PD) and Alzheimer's disease (AD).
Application in the context of neurological diseases discussed in the document: Friedreich's Ataxia (FRDA), GLUT1-deficient epilepsy, Leprechaunism, Rabson-Mendenhall syndrome, CABG dementia, anesthesia induced memory loss, age associated memory impairment (AAMI), Traumatic brain injury (TBI), and Huntington's disease.
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