WO2017004436A2 - Système thérapeutique comprenant des produits pharmaceutiques combinés à une amélioration métabolique pour traiter la neurodégénérescence - Google Patents

Système thérapeutique comprenant des produits pharmaceutiques combinés à une amélioration métabolique pour traiter la neurodégénérescence Download PDF

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WO2017004436A2
WO2017004436A2 PCT/US2016/040518 US2016040518W WO2017004436A2 WO 2017004436 A2 WO2017004436 A2 WO 2017004436A2 US 2016040518 W US2016040518 W US 2016040518W WO 2017004436 A2 WO2017004436 A2 WO 2017004436A2
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therapeutic system
system comprises
supplementation
alzheimer
drug
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PCT/US2016/040518
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Varghese John
Dale E. Bredesen
Patricia R. SPILMAN
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The Regents Of The University Of California
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/30—Dietetic or nutritional methods, e.g. for losing weight
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    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
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Definitions

  • Alzheimer's disease is the major cause of age-related cognitive decline, with approximately 5.4 million American patients and 30 million affected globally (Prince et al. (2014) World Alzheimer Report 2014 United Kingdom: Alzheimer's Disease International). In the absence of effective prevention and treatment, the prospects for the future are of great concern, with 13 million Americans and 160 million globally projected for 2050, leading to potential bankruptcy of the Medicare system. Unlike several other chronic illnesses, Alzheimer's disease (AD) prevalence is on the rise, which makes the need to develop effective prevention and treatment increasingly pressing. Recent estimates suggest that AD has become the third leading cause of death in the United States (James et al. (2014) Neurology. 82: 1045-1050), behind cardiovascular disease and cancer.
  • Embodiment 4 The method of embodiment l,wherein said method is for the treatment of subject cognitive impairment (SCI).
  • SCI subject cognitive impairment
  • Embodiment 16 The method of embodiment 15, wherein said therapeutic system comprises sleep and/or lifestyle modification.
  • Embodiment 27 The method according to any one of embodiments 1-26, wherein said therapeutic system comprises dietary supplementation comprising coenzyme Q10 supplementation at about 200 mg/day.
  • Embodiment 35 The method of embodiment 34, wherein said ashwagandha is provided at about 500mg daily.
  • Embodiment 36 The method of embodiment 34, wherein said curcumin is provided at about 400mg daily.
  • Embodiment 37 The method according to any one of embodiments 1-36, wherein said therapeutic system comprises dietary supplementation comprising
  • Embodiment 42 The method according to any one of embodiments 1-41, wherein said therapeutic system comprises nutritional modification comprising substantial elimination of simple carbohydrates.
  • Embodiment 54 The method according to any one of embodiments 1-53, wherein said therapeutic system comprises consumption of probiotic capsules or food.
  • Embodiment 56 The method according to any one of embodiments 1-55, wherein said therapeutic system comprises sleep and/or lifestyle modification comprising increasing sleep duration to at least about 7-8 hours, but not more than 9 hours.
  • Embodiment 68 The method according to any one of embodiments 1-67, wherein said therapeutic system comprises maintenance of bone density.
  • Embodiment 80 The method of embodiment 79, wherein said drug is donepezil (e.g. ARICEPT®).
  • Embodiment 81 The method of embodiment 79, wherein said drug is galantamine (e.g., RAZADYNE®).
  • Embodiment 109 The method of embodiment 108, wherein said vitamin B supplementation comprises supplementation with methylcobalamin (vitamin B 12).
  • Embodiment 110 The method according to any one of embodiments 108-
  • said therapeutic system comprises H. erinaceus and/or ALCAR.
  • Embodiment 144 The method according to any one of embodiments 100- 143, wherein said therapeutic system comprises consumption of probiotic capsules or food.
  • TRANDATE® central-acting agents
  • central-acting agents e.g., clonidine (CATAPRES®, KAPVAY®), etc.
  • guanfacine INTUNIV®, TENEX®
  • methyldopa etc.
  • vasodilators e.g., spironolactone (ALDACTONE®), eplerenone (INSPRA®), etc.
  • aldosterone antagonists e.g., spironolactone (ALDACTONE®), eplerenone (INSPRA®), etc.
  • a method of evaluating a drug for the treatment of MCI, dementia, and/or Alzheimer's disease comprises providing a population of subjects having or at risk for MCI, dementia, and/or Alzheimer's disease; administering to the subjects a therapeutic system comprising a comprehensive Metabolic Enhancement for Neurodegeneration (MEND) program or a subset thereof; administering to the subjects said drug that is to be evaluated; and evaluating over time the response of said subjects to said drug.
  • MEND Metabolic Enhancement for Neurodegeneration
  • Illustrative, but non-limiting markers of neuronal injury include, but are not limited to (1) elevated CSF tau or phospho- tau, (2) hypometabolism in an AD-like pattern ⁇ e.g., posterior cingulate, precuneus, and/or temporoparietal cortices) on FDG-PET, and (3) cortical thinning/gray matter loss in a specific anatomic distribution ⁇ e.g., lateral and medial parietal, posterior cingulate, and lateral temporal cortices) and/or hippocampal atrophy on volumetric MRI.
  • Other markers include, but are not limited to fMRI measures of default network connectivity.
  • MCI Mild Cognitive Impairment
  • amnestic MCI patients may not meet neuropathologic criteria for Alzheimer's disease, patients may be in a transitional stage of evolving Alzheimer's disease; patients in this hypothesized transitional stage demonstrated diffuse amyloid in the neocortex and frequent neurofibrillary tangles in the medial temporal lobe (see, e.g., Petersen et al, (2006) Arch. Neurol, 63(5): 665-72).
  • cerebrospinal fluid analysis and (2) research criteria that could be used in clinical research settings, including clinical trials.
  • the second set of criteria incorporate the use of biomarkers based on imaging and cerebrospinal fluid measures.
  • the final set of criteria for mild cognitive impairment due to AD has four levels of certainty, depending on the presence and nature of the biomarker findings.
  • neuropsychological measures are available to assess these cognitive domains, including (but not limited to the Trail Making Test (executive function), the Boston Naming Test, letter and category fluency (language), figure copying (spatial skills), and digit span forward (attention).
  • PiB PET imaging is used to clearly show the sites and shapes of beta amyloid deposits in living subjects using a CI 1 tracer that binds selectively to such deposits (see, e.g., Jack et al, (2008) Brain 131 (Pt 3): 665-680).
  • a CDR rating of -0.5 or -0.5 to 1.0 is often considered clinically relevant
  • the use of the MEND program in combination with a drug for the treatment of MCI, dementia, and/or Alzheimer's disease is deemed effective when there is a reduction in the CSF of levels of one or more components selected from the group consisting of Tau, phospho-Tau (pTau), APPneo, soluble ⁇ 40, soluble ⁇ 42, and/or ⁇ 42/ ⁇ 40 ratio, and/or when there is a reduction of the plaque load in the brain of the subject, and/or when there is a reduction in the rate of plaque formation in the brain of the subject that is greater than or longer lasting than the reduction that would be obtained with the use of the drug alone, and/or when there is an improvement in the cognitive abilities of the subject that is greater than or longer lasting than would be obtained with the use of the drug alone, and/or when there is a perceived improvement in quality of life by the subject that is
  • Table 4 Illustrative stages of Alzheimer's disease.
  • kits are provided for the practice of the methdos described herein.
  • the kits contain one or more nutritional/dietary supplement components of the Metabolic Enhancement for Neurodegeneration (MEND) program as described herein.
  • the kits can additionally comprise one or more drugs including, but not limited to drug(s) for the treatment of MCI, dementia, and/or Alzheimer's disease.
  • the therapeutic system described in this example derives from basic studies of the role of APP signaling and proteolysis in plasticity, and the imbalance in this receptor proteolysis that reproducibly occurs in Alzheimer's disease.
  • There are numerous physiological parameters that feed into this balance such as hormones (Lan et al. (2015) J. Alzheimers Dis. 43(4): 1137-1148; Shi et al. (2014) J. Steroid Biochem. Mol. Biol. 144PB: 280-285), trophic factors (Lourenco et al. (2009) Cell Death Differ . 16: 655-663), glucose metabolism (Yang et al. (2013) PLoS One, 8: e69824), inflammatory mediators (Sutinen et al. (2012) J.
  • the therapeutic system is designed to reverse the self-reinforcing ⁇ i.e., prionic) signaling imbalance that we have hypothesized to mediate Alzheimer's disease pathophysiology (Bredesen (2009) Mol. Neurodegener, 4:27).
  • results for these patients show greater improvements than have been reported for other patients treated for Alzheimer's disease.
  • the results provide further support for the suggestion that such a comprehensive approach to treat early Alzheimer's disease and its precursors, MCI and SCI, is effective.
  • the results also support the need for a large-scale, personalized clinical trial using this protocol.
  • His neuropsychological testing was compatible with a diagnosis of MCI. His hs-CRP was 9.9 mg/1, albumin: globulin ratio was 1.6, homocysteine 15.1 ⁇ / ⁇ , fasting glucose 96 mg/dl, hemoglobin Ale 5.5%, fasting insulin 32 mIU/1, 25-hydroxychole-calciferol 21 ng/ml, TSH 2.21 mIU/1, and testosterone 264 ng/dl.
  • neuropsychological testing well documented decline on longitudinal quantitative neuropsychological testing, and progression of symptoms. After two years on the protocol, his symptoms and neuropsychological testing improved markedly. The neuropsychologist who performed and evaluated his testing pointed out that his improvement was beyond that which had been observed in the neuropsychologist's 30 years of practice.
  • Her ApoE genotype was 4/4, homocysteine 7.5 ⁇ 1/1, hs-CRPO.26 mg/1, albumimglobulin ratio 2.0, hemoglobin Ale 5.3%, fasting insulin 2.7 mIU/1, fasting glucose 81 mg/dl, alpha-tocopherol 18.3 mg/1, and 25- hydroxycholecalciferol 188ng/ml.
  • On-line quantitative neuropsychological testing disclosed a composite memory score at the 32nd percentile, visual memory at 10th percentile, and verbal memory at 73rd percentile. This testing was repeated after four months on the protocol, at which time the composite memory score was at the 61st percentile, visual memory score at the 25th percentile, and verbal memory score at the 84th percentile.
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WO2018188771A1 (fr) * 2017-04-11 2018-10-18 Nestec S.A. Taux d'acides gras oméga-3 et de vitamine d pour identifier et atténuer le vieillissement cognitif chez des individus
CN110381935A (zh) * 2017-04-11 2019-10-25 雀巢产品有限公司 用于识别和减轻个体的认知衰老的ω-3脂肪酸和维生素D水平
WO2020008359A1 (fr) * 2018-07-03 2020-01-09 Inpha Duemila S.R.L. Formulation utilisée pour la prévention et en tant que traitement co-adjuvant de maladies neurodégénératives
WO2021102423A1 (fr) * 2019-11-22 2021-05-27 Brown University Compositions et procédés pour traiter, prévenir ou supprimer une inflammation et des troubles associés à l'âge

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* Cited by examiner, † Cited by third party
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JP2020516864A (ja) * 2017-04-11 2020-06-11 ソシエテ・デ・プロデュイ・ネスレ・エス・アー 個体における認知的加齢を特定及び軽減するためのオメガ−３脂肪酸、ホモシステイン及びビタミンｄのレベル。
JP7270547B2 (ja) 2017-04-11 2023-05-10 ソシエテ・デ・プロデュイ・ネスレ・エス・アー 個体における認知的加齢を特定及び軽減するためのオメガ－３脂肪酸、ホモシステイン及びビタミンｄのレベル。
JP7270546B2 (ja) 2017-04-11 2023-05-10 ソシエテ・デ・プロデュイ・ネスレ・エス・アー 個体における認知的加齢を特定及び軽減するためのオメガ３脂肪酸及びビタミンｄレベル
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