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US 2011 O1891 61A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0189161 A1 Blum et al. (43) Pub. Date: Aug. 4, 2011 (54) NUTRIGENOMICS METHODS AND A633/24 (2006.01) COMPOSITIONS A633/10 (2006.01) A6II 35/60 (2006.01) (76) Inventors: Kenneth Blum, San Diego, CA (US); Roger L. Waite, San Diego, (52) U.S. Cl. .................... 424/94.65: 514/17.6: 514/17.5; CA (US); B. William Downs, 514/17.7: 514/18.3; 424/725; 424/548; 424/764: Lederach, PA (US); William J. 424/752; 424/728; 424/734; 424/547: 424/733; Heaney, Huntington Beach, CA 424/730; 424/655; 424/687; 424/523 (US) (57) ABSTRACT (21) Appl. No.: 13/000,623 The present invention provides a proprietary compositions (22) PCT Filed: Jun. 22, 2009 and systems to modulate genetic and metabolomic contribut ing factors affecting disease diagnosis, stratification, and (86). PCT No.: PCT/USO9/48074 prognosis, as well as the metabolism, efficacy and/or toxicity associated with specific vitamins, minerals, herbal Supple S371 (c)(1), ments, homeopathic ingredients, and other ingredients for the (2), (4) Date: Dec. 21, 2010 purposes of customizing a Subject's nutritional Supplement formulation to optimize specific health outcomes. Specific to Related U.S. Application Data this invention the utilization of certain known polymorphic genes associated with Substance Use Disorder (SUD) are (60) Provisional application No. 61/074,629, filed on Jun. analyzed to target certain genetic anomalies that lead to a high 21, 2008. risk and predisposition to SUD. The genotypic patterns are O O then utilized to provide certain nutritional customized solu Publication Classification tions especially related to the attenuation of aberrant abuse of (51) Int. Cl. physician prescribed narcotic pain medication across all pain A6 IK 38/48 (2006.01) conditions. A priority GENOPROFILE is measured and A6 IK 38/02 (2006.01) directs the customization of a Subsequent nutraceutical to act A6 IK 36/41 (2006.01) as a therapeutic modality. Specifically the treatment includes A6 IK 35/32 (2006.01) slow attenuation of the pain medication by incorporating A6IP 25/24 (2006.01) orals (shakes, liquid beverages, pills, tablets, troche, oint A6IP 25/22 (2006.01) ments etc.). Intramuscular, Intravenous, intra-rectal and any A6IP 25/00 (2006.01) form necessary to deliver a Sufficient amount of an anti A6IP 9/02 (2006.01) craving and anti-stress nutraceutical. Moreover, the invention A6 IK 36/28 (2006.01) includes examples of novel analgesic ointments coupling A6 IK 36/16 (2006.01) Synaptamine and Such analgesic and other anesthetic com A6 IK 36/258 (2006.01) pounds including but not limited to Gabapentin, Ketamine, A6 IK 36/67 (2006.01) Baclofen, Ketoprofen, Amitriptyline, Lidocaine, Cycloben A6 IK 35/56 (2006.01) Zapine, Diclofenac, Menthol, Camphor and Capsaicin. The A6 IK 36/84 (2006.01) GENOPROFILE will be used to determine pain sensitivity A6 IK 36/38 (2006.01) Intolerance. Patent Application Publication Aug. 4, 2011 Sheet 1 of 13 US 2011/O1891.61 A1 FIGURE 1. The Brain Reward Cascade .83: Patent Application Publication Aug. 4, 2011 Sheet 2 of 13 US 2011/O1891.61 A1 FIGURE 2 Reward Deficiency Syndrome and the DRD2 Dopamine Receptor wered D2 Receptors sassessister kitiki assetsyistra ties strike Patent Application Publication Aug. 4, 2011 Sheet 3 of 13 US 2011/01891.61 A1 FIGURE 3A Mesolimbic System The Deep Structures Residing in the Mesolimbic System of the Brain emisection of the Brain Showing Anatomical Sites Crucial to the Reward C NCEUS ACCUMBENSOM HPPOCAMPS VI, Wil, EX LOCUS Frus A6) \ REGIONl AIO SOURCE: K. BLUM WI HJ. PAYNE) ALCOHOLAND THE ADDICTIVE BRAIN THE FREE FRESS. WITH PERMISSION 1991 Patent Application Publication Aug. 4, 2011 Sheet 4 of 13 US 2011/01891.61 A1 FIGURE 3B Neurotransmitter Relations in the Reward Cascade Ers Nisrepairs. " isassissists Wi is . arra-------------see-earera Soutfits: it. $iifiti --. fMette adoff. Afifi is: {{Krfews aftart-terrise trusses, it f:RSSK at Patent Application Publication Aug. 4, 2011 Sheet 5 of 13 US 2011/O1891.61 A1 FIGURE 4 Brain Reward Cascade Hypothalamus (1) Wentral Tegmental Region (A10) (2) Sustantia aparine """ Amygdala (5) Hippocampus 6 pairie A S. Patent Application Publication Aug. 4, 2011 Sheet 6 of 13 US 2011/O1891.61 A1 FIGURE 5 Brain reward chemistry is a critical treatment target. deparine ticipatite Y eteti s S S. - When a signal comes down the neuron, dopamine is released into the synapse. It then crosses to the second neuron where it binds to and stimulates dopamine receptors. It then crosses back to the first neuron where it is picked back up by dopamine transporters (reuptake molecules) for re-use. S Š S S & Patent Application Publication Aug. 4, 2011 Sheet 7 of 13 US 2011/O1891.61 A1 FIGURE 6 Natural "Rewards' Patent Application Publication Aug. 4, 2011 Sheet 8 of 13 US 2011/O1891.61 A1 FIGURE 7 DRD2 Receptor-Levels in Addiction : Dopamine D2 Recent wer in Addiction x: ss s: s x: k Patent Application Publication Aug. 4, 2011 Sheet 9 of 13 US 2011/O1891.61 A1 FIGURE 8 Drawing 8... Represents the significant differences (P<0.045; P C 0.049) between the DRD2A1 (n=9) and the DRD2A1 (n=14) with regard to days on Genotrim treatment in Dutch descent self-identified obese subjects in the D.I.E.T. pilot study. A1 = (A1/A1/A1/A2) and A1 = A2/A2. Meso-limbic system FIGURE 9 Ca?TiOUS A substantia L. Coeruleus Nigra (A6) Patent Application Publication Aug. 4, 2011 Sheet 10 of 13 US 2011/O1891.61 A1 FIGURE 10 Neutransmitter Adequacy Patent Application Publication Aug. 4, 2011 Sheet 11 of 13 US 2011/O1891.61 A1 FIGURE 11 Neutotransmitter Deficiency Patent Application Publication Aug. 4, 2011 Sheet 12 of 13 US 2011/O1891.61 A1 FIGURE 12 GnAP Program outline Physician (HCP) Suspicion of Narcotic Addiction Genetic Test (Cheek Swab) Confirmation by DNA test of HCP Analysis to suspicion 8 Customize Tx (Synaptamine) Survey results ompounds Device Regimen GnAP & S& Phase 2 Phase 3 - 2 Weeks of 6 Weeks of Patent Application Publication Aug. 4, 2011 Sheet 13 of 13 US 2011/O1891.61 A1 FIGURE 13 Bygstastica Cisc: fixiec. 3' jewers for 'tag Axistic US 2011/O 1891 6 1 A1 Aug. 4, 2011 NUTRGENOMICS METHODS AND 0.014 Diuretic therapy. There is a gene known as COMPOSITIONS C825T involved with a second messenger G-protein {beta}3 whereas polymorphisms in this gene predict RELATED APPLICATIONS responsiveness to the anti-diuretic drug (used to treat 0001. This application is a national stage filing of PCT hypertension), hydrochlorothiazide. patent application no. PCT/US2009/048.074, filed 22 Jun. 0.015 Lipid response Genetic variation of the apoli 2009, and this application hereby claims the benefit of and poprotein constituents of the lipoprotein molecules priority to PCT/US2009/048.074, of which this application is (APOE gene locus) predicts plasma low-density lipo a continuation-in-part of, and U.S. provisional patent appli protein cholesterol (LDL-C) concentrations. Interesting cation Ser. No. 61/074,629, filed 21 Jun. 2008, the contents of carrying one form of the APOE (E4) seems to be more each of which are herein incorporated by reference in their responsive to dietary modification than carriers of E3 entirety for any and all purposes. and or E2 forms of the same gene. 0016 Nicotine patch Variation of the CT and TT BACKGROUND OF INVENTION allele of the dopamine D2 receptor gene confirms a 0002 Nutragenomics differential response to the nicotine patch. At the eight 0003. It is well know that individuals respond differently year mark, 12% of women with the CT or TT allele of the to medications and certain nutraceuticals in terms of both dopamine D2 receptor gene who had received the patch toxicity and treatment efficacy. Potential causes for such vari had remained abstinent. Only 5% of women with the CC ability in drug (nutrient) effects include the pathogenesis and allele had maintained their non-Smoking status. No dif severity of the disease being treated: drug (nutrient) interac ference based on genetics was noted in men. tions; the individual’s age, nutritional status; kidney and liver (0.017. The polymorphic CYP2D6 regulates the O-dem function; and concomitant illnesses. Despite the potential importance of these clinical variables in determining drug/ ethylation of codeine and other weak opioids to more nutrient effects, it is now recognized that inherited differences potent metabolites with poor metabolizers having in the metabolism and disposition of drugs/nutrients, and reduced antinociception in some cases. genetic variants (polymorphisms) in the targets of drug/nu 0018. In the broadest terms, the interface between the trient therapy (Such as receptors like the dopamine D2 recep nutritional environment and cellular/genetic processes is tor DRD2), can have even greater influence on the efficacy being referred to as “nutrigenomics’. While nutrigenomics in and toxicity of either medications or nutraceuticals. this sense seeks to provide a molecular genetic understanding 0004 Many genes encoding drug targets exhibit genetic for how common dietary chemicals i.e. nutrition) influences polymorphism (variants), which in many cases alters their health by altering the expression and/or structure of an indi sensitivity to specific medications and/or offer specific tar vidual's genetic makeup, the more restricted view is governed geted therapy. by the same principles as seen with advent of pharmacoge 0005 Such examples include the following: nomics in clinical medicine which involves DNA based— 0006 Asthma Polymorphisms in Beta-adrenergic targeted response to biologically active compounds. receptors (adrenalin-like) impart differential sensitivity 0019. In terms of dietary intervention based in individual to Substances that stimulate these receptors (beta-ago ized nutrition Such examples of a number of gene-disease nists) in asthmatics.
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