Method of treating neurological conditions with extract of Nerium species or Thevetia species
Inventors
ADDINGTON, Otis C. • Newman, Robert A.
Assignees
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Publication Number
US-10307450-B2
Publication Date
2019-06-04
Expiration Date
Abstract
A method of treating neurological condition in a subject by administration of a neuroprotective composition of a mixture of two or more triterpenes. Alzheimer's disease, Huntington's disease, stroke or Parkinson's disease are treated by administering a therapeutically effective amount of the neuroprotective composition to a subject.
Core Innovation
The invention relates to a method of treating a neurological disorder, condition or disease by administering a therapeutically effective amount of a neuroprotective composition consisting essentially of oleanolic acid, ursolic acid and betulinic acid. Oleanolic acid, ursolic acid and betulinic acid are described as the primary or sole pharmacologically active ingredients of the composition, and the composition is described as neuroprotective while emphasizing cardiac-glycoside-free compositions.
The neuroprotective composition excludes cardiac glycoside and excludes pharmacologically active polysaccharide obtained from Nerium species or of Thevetia species. The invention further discusses that molar ratios of O/UA/BA affect efficacy and safety, and that neuroprotection can be shown even when cardiac glycosides are not detected.
Oleanolic acid, ursolic acid and betulinic acid are independently selected upon each occurrence from the free acid form, salt form, derivative form, prodrug form or a combination thereof. Extensive in vitro neuroprotection evidence is described for assays including brain-slice OGD stroke assay and disease-relevant assays such as APP/Aβ and tau4R Alzheimer's assays and Huntington cortico-striatal co-culture assay, including activation of the Nrf2/ARE pathway and upregulation of ARE target genes such as Gcic, Nqo1, Srx and Hmox1.
The invention describes treating neurological diseases including Alzheimer’s disease, Huntington’s, stroke/ischemic injury, Parkinson’s and tauopathies using the specified neuroprotective compositions derived from Nerium species or Thevetia species comprising mixtures of triterpenes, especially oleanolic acid, ursolic acid and betulinic acid, optionally as extract fractions. It also describes comparative activity/toxicity of individual triterpenes versus mixtures and discusses dosing/regimen concepts and combination therapy with other standard drugs, including a time-delayed stroke administration window.
Claims Coverage
The disclosed independent claim covers a method of treating a neurological disorder by administering a therapeutically effective amount of a neuroprotective composition consisting essentially of oleanolic acid, ursolic acid and betulinic acid, with defined exclusion of cardiac glycosides and excluded pharmacologically active polysaccharides from Nerium/Thevetia, and with oleanolic acid, ursolic acid and betulinic acid allowed in multiple chemical forms. Dependent claims refine the method by adding dosage constraints, molar ratio constraints, specific neurological disease selections, and a time-delayed stroke administration window.
Neuroprotective composition consisting essentially of O/U/B as primary pharmacologically active ingredients
Administering a therapeutically effective amount of a neuroprotective composition consisting essentially of oleanolic acid, ursolic acid and betulinic acid as the primary or sole pharmacologically active ingredients.
Excluding cardiac glycosides and excluding pharmacologically active Nerium/Thevetia polysaccharides
The neuroprotective composition excludes cardiac glycoside and excludes pharmacologically active polysaccharide obtained from Nerium species or of Thevetia species.
O/U/B chemical forms independently selected from free acid, salt, derivative, prodrug
Oleanolic acid, ursolic acid and betulinic acid are independently selected upon each occurrence from the free acid form, salt form, derivative form, prodrug form or a combination thereof.
Therapeutic method optionally narrowed by specified neurological disease selections
The neurological condition is selected from Alzheimer's disease, Huntington's disease, stroke or Parkinson's disease.
Time-delayed stroke administration window
A time-delayed treatment for stroke in a subject, where a neuroprotective composition is administered within an acceptable delay period after the stroke in an amount sufficient to treat the stroke.
Across the covered independent claim and refinements described in associated dependent claims, the method is anchored on administering an O/U/B-based neuroprotective composition consisting essentially of these triterpenes while excluding cardiac glycosides and excluding pharmacologically active polysaccharides from Nerium/Thevetia, with O/U/B allowed in multiple chemical forms, and further narrowed by disease selection and a time-delayed stroke framework.
Stated Advantages
Neuroprotection is described while emphasizing compositions that exclude cardiac glycosides and exclude pharmacologically active polysaccharides from Nerium/Thevetia.
The compositions are described as showing efficacy and safety related to molar ratios of O/UA/BA.
Activation of the Nrf2/ARE pathway and upregulation of ARE target genes (Gcic, Nqo1, Srx, Hmox1) are described in connection with the neuroprotective effects.
Documented Applications
Treating neurological disorders including Alzheimer’s disease, Huntington’s disease, stroke/ischemic injury, Parkinson’s disease and tauopathies.
Time-delayed treatment of stroke in a subject after an acceptable delay period.
In vitro neuroprotection assessments are described using a brain-slice OGD stroke assay and disease-relevant Alzheimer's and Huntington assay formats, including APP/Aβ and tau4R Alzheimer's assays and Huntington cortico-striatal co-culture assay.
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