US20060088607A1 - Nutritional supplement compositions - Google Patents

Nutritional supplement compositions Download PDF

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Publication number
US20060088607A1
US20060088607A1 US11/241,248 US24124805A US2006088607A1 US 20060088607 A1 US20060088607 A1 US 20060088607A1 US 24124805 A US24124805 A US 24124805A US 2006088607 A1 US2006088607 A1 US 2006088607A1
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Prior art keywords
morphine
composition
glucuronide
mammal
reticuline
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Inventor
George Stefano
Patrick Cadet
Kirk Mantione
Wei Zhu
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Research Foundation of the State University of New York
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Individual
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Priority to US11/241,248 priority Critical patent/US20060088607A1/en
Assigned to RESEARCH FOUNDATION OF STATE UNIVERSITY OF NEW YORK, THE reassignment RESEARCH FOUNDATION OF STATE UNIVERSITY OF NEW YORK, THE ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CADET, PATRICK, MATIONE, KIRK J., STEFANO, GEORGE B., ZHU, WEI
Publication of US20060088607A1 publication Critical patent/US20060088607A1/en
Assigned to NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT reassignment NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT EXECUTIVE ORDER 9424, CONFIRMATORY LICENSE Assignors: STATE UNIVERSITY OF NEW YORK
Assigned to NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT reassignment NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT CONFIRMATORY LICENSE (SEE DOCUMENT FOR DETAILS). Assignors: THE RESEARCH FOUNDATION OF THE STATE UNIVERSITY OF NEW YORK
Priority to US14/152,536 priority patent/US20140128420A1/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P25/00—Drugs for disorders of the nervous system
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the document relates to nutritional supplement compositions.
  • this document relates to nutritional supplement compositions containing one or more compounds such as arginine, selenium, calcium, calcium sources, morphine precursors (e.g., reticuline), morphine, and morphine-6 ⁇ -glucuronide.
  • Analgesic compounds such as morphine are routinely used to reduce pain in humans. For example, surgery patients are typically instructed to take 5 to 10 mg of morphine per person to alleviate pain caused by the surgical procedure. In some cases, patients suffering from extreme pain (e.g., bum victims or cancer patients) are instructed to take higher doses of morphine.
  • compositions containing one or more compounds such as arginine, selenium, calcium, calcium sources, morphine precursors (e.g., reticuline), morphine, and morphine-6 ⁇ -glucuronide.
  • morphine precursors e.g., reticuline
  • morphine-6 ⁇ -glucuronide e.g., a low dose of morphine (e.g., a dose that is below that which is given to relieve a mammal of pain).
  • the compositions provided herein can be used as nutritional supplement compositions.
  • the compositions provided herein can be used to provide a mammal with a long-term, low level of morphine that can allow the mammal to experience behavioral changes (e.g., a general overall calm feeling).
  • compositions provided herein can be used to provide a mammal with a long-term, low level of morphine that can allow the mammal to experience reduced *inflammatory responses and can allow the mammal to maintain an increased, basal level of constitutive nitric oxide release.
  • the compositions provided herein can be used to down regulate immune, vascular, neural, and gastrointestinal tissues via nitric oxide produced within a mammal.
  • the compositions provided herein can be used to reduce the excited state of inflamed gastrointestinal tissues in mammals having Crohn's disease.
  • compositions provided herein can be used to treat (e.g., reduce the severity of symptoms) neural conditions (e.g., schizophrenia, chronic pain, mania, depression, psychosis, paranoia, autism, stress, Alzheimer's disease, or Parkinson's disease), immune conditions (e.g., pro-inflammatory diseases, autoimmune disorders, histolytic medullary reticulosis, lupus, or arthritis), vascular conditions (e.g., atherosclerosis or neuronal vasculopathy), gastrointestinal conditions (e.g., colitis, Crohn's disease, or irritable bowel syndrome), or addiction (e.g., opiate addiction).
  • neural conditions e.g., schizophrenia, chronic pain, mania, depression, psychosis, paranoia, autism, stress, Alzheimer's disease, or Parkinson's disease
  • immune conditions e.g., pro-inflammatory diseases, autoimmune disorders, histolytic medullary reticulosis, lupus, or arthritis
  • vascular conditions e.g
  • a nutritional supplement composition containing morphine or a morphine precursor such as reticuline, norlaudanosoline, L-DOPA, or codeine can be used to treat neural conditions such as neurovascular alterations involving hypothalamic hormone secretion (e.g., reproductive and growth hormones).
  • compositions provided herein can include one or more of the following: arginine, selenium, calcium, calcium sources, morphine precursors (e.g., reticuline), morphine, and morphine-6 ⁇ -glucuronide.
  • morphine precursors e.g., reticuline
  • morphine-6 ⁇ -glucuronide e.g., a long-term, low level of morphine can be achieved in a mammal by administering a low dose of morphine, by administering a morphine precursor, or by administering a combination of morphine and morphine precursors.
  • inhibitors such as dopamine ⁇ -hydroxylase inhibitors can be used to inhibit the dopamine to norepinephrine step in adrenaline synthesis, which can result in an endogenous dopamine level increase as well as an endogenous morphine level increase.
  • morphine can result the continued positive effects of morphine such as nitric oxide release, without the need to escalate morphine dosages with time to achieve the same beneficial effects.
  • the use of low doses of morphine can allow mammals to experience the beneficial effects of morphine, while not experiencing possible negative effects of morphine (e.g., addiction or powerful analgesia).
  • providing mammals with a morphine precursor such as reticuline can allow mammals to experience the beneficial effects of morphine, while not experiencing possible negative effects of morphine (e.g., addiction or powerful analgesia).
  • a morphine precursor such as reticuline can allow patients to receive a low dose of morphine indirectly with a reduced risk of overdosing.
  • one aspect of this document features a dietary supplement composition
  • a dietary supplement composition comprising, or consisting essentially of, morphine or morphine-6 ⁇ -glucuronide in an amount that results in less than 0.05 mg of the morphine or morphine-6 ⁇ -glucuronide being administered to a human per kg of body weight of the human.
  • the composition can comprise less than 4.0 mg (e.g., 3.0, 2.0, 1.0, 0.5, 0.1, 0.05 mg) of the morphine or morphine-6 ⁇ -glucuronide.
  • the composition can comprise less than 1.0 mg of the morphine or morphine-6 ⁇ -glucuronide.
  • the composition can comprise a morphine precursor.
  • the composition can be in the form of a tablet.
  • the composition can comprise selenium.
  • the composition can comprise L-arginine.
  • the composition can comprise a calcium source.
  • the morphine or morphine-6 ⁇ -glucuronide can be in an amount that results in less than 0.025 mg of the morphine or morphine-6 ⁇ -glucuronide being administered to the human per kg of body weight of the human.
  • the morphine or morphine-6 ⁇ -glucuronide can be in an amount that results in less than 0.01 mg of the morphine or morphine-6 ⁇ -glucuronide being administered to the human per kg of body weight of the human.
  • the composition can comprise morphine.
  • the composition can comprise morphine and morphine-6 ⁇ -glucuronide.
  • the composition can comprise thebaine, codeine, reticuline, norlaudanosoline, salutaridine, dopamine, L-DOPA, tyrosine, tyramine, phenylalanine, 3,4 dihydroxyphenyl pyruvate, dihydroxyphenyl acetaldehyde, or combinations thereof.
  • compositions comprising, or consisting essentially of, morphine and a compound selected from the group consisting of selenium and arginine.
  • the composition can comprise between 35 ⁇ g and 700 ⁇ g of morphine.
  • the composition can comprise between 55 ⁇ g and 300 ⁇ g of selenium.
  • the composition can comprise between 1 mg and 500 mg of arginine.
  • the composition can comprise a calcium source.
  • the composition can comprise between 1 g and 1.3 g of the calcium source.
  • the calcium source can be calcium citrate.
  • This document provides methods and materials related to nutritional supplement compositions containing one or more of the following compounds: arginine, selenium, morphine, morphine precursors (e.g., tyrosine, tyramine, phenyl alanine, 3,4 dihydroxyphenyl pyruvate, dihydroxyphenyl acetaldehyde, dopamine, L-DOPA, reticuline, norlaudanosoline, salutaridine, thebaine, or codeine), morphine-6 ⁇ -glucuronide, inhibitors of morphine synthesis or activity, or inhibitors of dopamine synthesis.
  • Such nutritional supplement compositions can be used to treat diseases, to reduce inflammation, or to restore normal function.
  • this document provides compositions containing morphine, morphine precursors, morphine-6 ⁇ -glucuronide, or combinations thereof.
  • Morphine or morphine-6 ⁇ -glucuronide can be formulated into compositions designed to deliver a low dose of morphine or morphine-6 ⁇ -glucuronide to a mammal.
  • a low dose of morphine is a dose that is below that which is given to relieve a mammal of pain.
  • a low dose of morphine can be between 0.5 and 10 ⁇ g (e.g., between 1 and 9 ⁇ g, between 1 and 8 ⁇ g, between 1 and 7 ⁇ g, between 1 and 6 ⁇ g, between 1 and 5 ⁇ g, between 2 and 10 ⁇ g, between 3 and 10 ⁇ g, between 4 and 10 ⁇ g, or between 5 and 10 ⁇ g) per kg of body weight per day.
  • a low level of morphine-6 ⁇ -glucuronide can be similar to those of morphine.
  • a low dose of morphine-6 ⁇ -glucuronide can be between 1 and 10 ⁇ g (e.g., between 1 and 9 ⁇ g, between 1 and 8 ⁇ g, between 1 and 7 ⁇ g, between 1 and 6 ⁇ g, between 1 and 5 ⁇ g, between 2 and 10 ⁇ g, between 3 and 10 ⁇ g, between 4 and 10 ⁇ g, or between 5 and 10 ⁇ g) per kg of body weight per day.
  • morphine or morphine-6 ⁇ -glucuronide can be formulated to deliver between 35 and 700 ⁇ g of morphine or morphine-6 ⁇ -glucuronide for a 70 kg individual.
  • a low dose can be any amount that is high enough to cause cells within the mammal to release nitric oxide yet low enough to not cause the mammal to experience analgesia.
  • a dose can be, without limitation, about 5 ⁇ g per kg of body weight per day.
  • morphine or morphine-6 ⁇ -glucuronide can be formulated into a pill or tablet that contains between 10 and 1000 ⁇ g (e.g., between 10 and 900 ⁇ g, between 10 and 800 ⁇ g, between 10 and 700 ⁇ g, between 10 and 600 ⁇ g, between 10 and 500 ⁇ g, between 30 and 1000 ⁇ g, between 35 and 1000 ⁇ g, between 40 and 1000 ⁇ g, between 50 and 1000 ⁇ g, between 35 to 700 ⁇ g, or between 35 and 500 ⁇ g) of morphine or morphine-6 ⁇ -glucuronide.
  • a tablet can be designed to contain 100 ⁇ g of morphine.
  • a mammal weighing about 70 kg can be instructed to take between one and three pills or tablets per day. Mammals weighing more or less than 70 kg can be instructed to take the appropriate number of pills or tablets to achieve a similar final concentration.
  • morphine as used herein includes dihydromorphine, morphine sulfate, morphine hydrochloride, and morphine acetate.
  • compositions provided herein can contain one or more than one (e.g., two, three, four, five, or more) morphine precursors without containing morphine or morphine-6 ⁇ -glucuronide.
  • morphine precursors include, without limitation, tyrosine, tyramine, dopamine, L-DOPA, 3,4 dihydroxyphenyl pyruvate, dihydroxyphenyl acetaldehyde, phenylalanine, reticuline, norlaudanosoline, salutaridine, thebaine, and codeine.
  • a composition can be designed to contain tyrosine, tyramine, dopamine, L-DOPA, 3,4 dihydroxyphenyl pyruvate, dihydroxyphenyl acetaldehyde, phenylalanine, reticuline, norlaudanosoline, salutaridine, thebaine, codeine, or combinations thereof.
  • Such compositions can contain any amount of the morphine precursors such as an amount between 1 and 10 mg per person weighing about 70 kg.
  • a composition can contain between 1 and 10 mg of reticuline.
  • compositions provided herein can contain one or more (e.g., two, three, four, five, or more) morphine precursors in addition to morphine or morphine-6 ⁇ -glucuronide or in addition to a combination of morphine and morphine-6 ⁇ -glucuronide.
  • a composition can contain morphine and reticuline.
  • compositions containing morphine and a morphine precursor as well as compositions containing morphine-6 ⁇ -glucuronide and a morphine precursor can contain any amount of the morphine precursor such as between 0.1 and 100 mg (e.g., between 0.1 and 90 mg, between 0.1 and 75 mg, between 0.1 and 50 mg, between 0.1 and 25 mg, between 0.1 and 10 mg, between 0.5 and 100 mg, between 1 and 100 mg, between 1 and 50 mg, or between 1 and 10 mg) of the morphine precursor.
  • a composition can contain between 10 and 100 ⁇ g of morphine, between 10 and 100 ⁇ g of morphine-6 ⁇ -glucuronide, and between 1 and 10 mg of reticuline.
  • a composition designed to deliver a low dose of morphine, designed to deliver a low dose of morphine-6 ⁇ -glucuronide, designed to contain one or more morphine precursors, or designed to contain any combination thereof (e.g., both morphine and one or more morphine precursors) can be formulated to contain additional components such as L-arginine, selenium, and Ca ++ .
  • L-arginine can be included to promote a cell's ability to release nitric oxide in response to morphine via nitric oxide synthesis from L-arginine metabolism.
  • Selenium can be added to enhance mu3 opiate receptor gene expression.
  • Calcium sources such as calcium citrate or CaCO 3 can be added to help facilitate the metabolism of L-arginine into nitric oxide via a calcium-dependent constitutive nitric oxide synthase.
  • CaCO 3 can be used as a calcium source.
  • a pill or tablet designed to deliver a low dose of morphine can be formulated to contain 35 to 700 ⁇ g morphine (e.g., 0.1 mg morphine), 1 mg to 500 mg L-arginine (e.g., 300 mg L-arginine), 55 ⁇ g to 200 ⁇ g selenium (e.g., 100 ⁇ g selenium), and 1000 to 1300 mg Ca ++ (e.g., 1000 mg Ca ++ ).
  • a pill or tablet can be formulated to contain 1 to 10 mg reticuline (e.g., 5 mg reticuline), 1 mg to 500 mg L-arginine (e.g., 300 mg L-arginine), 55 ⁇ g to 200 ⁇ g selenium (e.g., 100 ⁇ g selenium), and 1000 to 1300 mg Ca ++ (e.g., 1000 mg Ca ++ ).
  • Other components that can be included in a composition provided herein include, without limitation, pharmaceutically acceptable aqueous vehicles, pharmaceutically acceptable solid vehicles, steroids, antibacterial agents, anti-inflammatory agents, immunosuppressants, dilators, vaso-constrictors, anti-cholinergics, anti-histamines, antioxidant, and combinations thereof.
  • a composition designed to deliver a low dose of morphine, designed to deliver a low dose of morphine-6 ⁇ -glucuronide, designed to contain one or more morphine precursors, or designed to contain any combination thereof (e.g., both morphine and one or more morphine precursors) can be formulated to contain one or more inhibitors of morphine synthesis (e.g., a CYP2D6 or CYP2D7 inhibitor) or activity (e.g., naloxone), one or more inhibitors of dopamine synthesis or activity, or combinations thereof.
  • a composition e.g., pill or tablet designed to deliver a low dose of morphine, designed to deliver a low dose of morphine-6 ⁇ -glucuronide, designed to contain one or more morphine precursors, or designed to contain any combination thereof (e.g., both morphine and one or more morphine precursors)
  • one or more inhibitors of morphine synthesis e.g., a CYP2
  • CYP2D6 inhibitors include, without limitation, amiodarone, chloroquine, cimetidine, clomipramine, diphenhydramine, duloxetine, fluoxetine, hydroxychloroquin, paroxetine, propafenone, propoxyphene, and quinidine, terbinafine.
  • a pharmaceutically acceptable aqueous vehicle can be, for example, any liquid solution that is capable of dissolving morphine or a morphine precursor (e.g., reticuline) and is not toxic to the particular individual receiving the composition.
  • pharmaceutically acceptable aqueous vehicles include, without limitation, saline, water, and acetic acid.
  • pharmaceutically acceptable aqueous vehicles are sterile.
  • a pharmaceutically acceptable solid vehicle can be formulated such that morphine or a morphine precursor is suitable for oral administration.
  • capsules or tablets can contain reticuline in enteric form. The dose supplied by each capsule or tablet can vary since an effective amount can be reached by administrating either one or multiple capsules or tablets.
  • a pharmaceutically acceptable solid vehicle can be a solid carrier including, without limitation, starch, sugar, or bentonite.
  • a tablet or pill formulation of morphine or a morphine precursor can follow conventional procedures that employ solid carriers, lubricants, and the like.
  • Steroids can be any compound containing a hydrocyclopentanophenanthrene ring structure.
  • steroids include, without limitation, prednisone, dexamethasone, and hydrocortisone.
  • An antibacterial agent can be any compound that is active against bacteria, such as penicillin, erythromycin, neomycin, gentamicin, and clindamycin.
  • An anti-inflammatory agent can be any compound that counteracts inflammation, such as ibuprofen and salicylic acid.
  • An immunosuppressant can be any compound that suppresses or interferes with normal immune function, such as cyclosporine.
  • a dilator can be any compound that causes the expansion of an orifice, such as albuterol.
  • a vaso-constrictor can be any compound that constricts or narrows blood vessels, such as phenylephrine hydrochloride, cocaine, and epinephrine.
  • An anti-cholinergic can be any compound that blocks parasympathetic nerve impulses, such as ipratropium bromide.
  • An anti-histamine can be any compound that opposes the action of histamine or its release from cells (e.g.,.mast cells), such as terfenadine and astemizole.
  • any method can be used to obtain morphine, morphine-6 ⁇ -glucuronide, morphine precursors, or any additional component of a composition provided herein.
  • the components of the compositions provided herein can be obtained using common chemical extraction, isolation, or synthesis techniques. For example, reticuline can be obtained as described elsewhere (Brochmann-Hanssen and Nielsen, Tetrahedron Lett., 18:1271-4 (1965) and U.S. Pat. No. 3,894,027).
  • the components of the compositions provided herein can be obtained from commercial vendors.
  • morphine, morphine-6 ⁇ -glucuronide, codeine, norlaudanosoline, and salutaridine can be ordered from Sigma, Inc.
  • compositions provided herein can be in any form.
  • a composition provided herein can be in the form of a solid, liquid, and/or aerosol including, without limitation, powders, crystalline substances, gels, pastes, ointments, salves, creams, solutions, suspensions, partial liquids, sprays, nebulae, mists, atomized vapors, tinctures, pills, capsules, tablets, and gelcaps.
  • the composition can be a dietary supplement.
  • a composition containing morphine, one or more morphine precursors, or a combination thereof can be prepared for oral administration by mixing the components with one or more of the following: a filler, a binder, a disintegrator, a lubricant, and a coloring agent.
  • a filler a filler, a binder, a disintegrator, a lubricant, and a coloring agent.
  • Lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose, silicon dioxide, or the like can be used as the filler.
  • Polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, acacia, tragacanth, gelatin, shellac, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, calcium citrate, dextrin, or pectin can be used as the binder.
  • Magnesium stearate, talc, polyethylene glycol, silica, or hardened plant oil can be used as the lubricant.
  • a pharmaceutically acceptable coloring agent can be used as the coloring agent. Cocoa powder, mentha water, aromatic acid, mentha oil, borneol, or powdered cinnamon bark also can be added.
  • a composition containing morphine, one or more morphine precursors, or a combination thereof can be prepared for injection by mixing the components with one or more of the following: a pH adjusting agent, a buffer, a stabilizer, and a solubilizing agent.
  • compositions provided herein can be administered to any mammal (e.g., rat, mouse, dog, cat, horse, cow, goat, pig, monkey, or human).
  • any route of administration e.g., oral or parenteral administration
  • a composition containing morphine or reticuline can be administered orally or parenterally (e.g., a subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrastemal, or intravenous injection).
  • compositions provided herein can be used to increase or maintain a basal level of nitric oxide release by cells (e.g., cells expressing mu3 opiate receptors).
  • the administration of morphine precursors such as reticuline to a mammal can lead to the conversion of the morphine precursor into morphine.
  • the morphine produced from the morphine precursor or the morphine provided directly by a composition containing morphine or the morphine-6 ⁇ -glucuronide provided directly by a composition containing morphine-6 ⁇ -glucuronide can activate mu3 opiate receptors, which are coupled to nitric oxide release, and can down regulate the activated state of tissues within the mammal making them less excitable.
  • administering morphine or reticuline can limit undesired excitation and restore basal activity levels within a mammal.
  • certain mammals may not produce enough endogenous morphine to fulfill the needs of processes normally using this material to down regulate their excitatory state (e.g., a run-away pro-inflammatory state, mental disorders, vascular disorders).
  • Administering a morphine precursor such as reticuline can provide mammals with the morphine needed to down regulate excitatory states without administering a controlled substance.
  • Administering morphine or morphine-6 ⁇ -glucuronide directly at a low dose can provide mammals with the morphine needed to down regulate excitatory states without triggering tolerance to the administered morphine or morphine-6 ⁇ -glucuronide.
  • morphine can be administered chronically (e.g., a long duration) at a low dose without observing a reduction of morphine's effects (e.g., nitric oxide release) over time.
  • administering morphine-6 ⁇ -glucuronide can provide mammals with nitric oxide release in the periphery as opposed to the brain since morphine-6 ⁇ -glucuronide exhibits a limited ability to cross the blood brain barrier.
  • compositions provided herein can be administered to a mammal in any amount, at any frequency, and for any duration.
  • a composition provided herein can be administered to a mammal in an amount, at a frequency, and for a duration effective to induce nitric oxide release in the mammal.
  • a composition provided herein can be administered to a mammal in an amount, at a frequency, and for a duration effective to reduce the severity of a symptom of a disease or condition (e.g., schizophrenia, mania, depression, psychosis, chronic pain, paranoia, autism, stress, Alzheimer's disease, Parkinson's disease, pro-inflammatory diseases, autoimmune disorders, histolytic medullary reticulosis, lupus, arthritis, atherosclerosis, neuronal vasculopathy, or addiction).
  • a symptom of a disease or condition e.g., schizophrenia, mania, depression, psychosis, chronic pain, paranoia, autism, stress, Alzheimer's disease, Parkinson's disease, pro-inflammatory diseases, autoimmune disorders, histolytic medullary reticulosis, lupus, arthritis, atherosclerosis, neuronal vasculopathy, or addiction.
  • an effective amount of a composition provided herein or of morphine or of a morphine precursor can be any amount that induces cells to release nitric oxide without producing significant toxicity to the mammal.
  • an effective amount of a composition provided herein or of morphine or of a morphine precursor can be any amount that reduces, prevents, or eliminates a symptom of a disease or condition upon administration to a mammal without producing significant toxicity to the mammal.
  • an effective amount can be any amount that results in the production of detectable amounts of morphine within a tissue sample.
  • a composition provided herein can be administered to a mammal in any amount.
  • the amount of a composition provided herein or of morphine or of a morphine precursor can be greater than 0.01 mg/kg of body weight.
  • the amount of a composition provided herein or of morphine or of a morphine precursor can be between about 0.01 and about 50 mg/kg (e.g., between about 0.01 and about 45 mg/kg; between about 0.1 and about 25 mg/kg; or between about 1 and about 5 mg/kg) of body weight.
  • the effective amount can vary depending upon the disease to be treated (if any), the site of administration, and the mammal to be treated. Such effective amounts can be determined using the methods and materials provided herein. For example, the level of morphine production can be assessed using routine experimentation in vitro or in vivo. For example, a patient having a particular condition can receive 5 mg/kg body weight of reticuline. If the patient fails to respond or produce morphine, then the amount can be increased by, for example, ten fold. After receiving this higher concentration, the patient can be monitored for both responsiveness to the treatment and toxicity symptoms, and adjustments made accordingly.
  • the frequency of administration, duration of treatment, combination of other agents, site of administration, stage of disease (if present), and the anatomical configuration of the treated area may require an increase or decrease in the actual amount administered.
  • the frequency of administration of a composition provided herein can be any frequency.
  • the frequency of administration can be from about four times a day to about once a month, or more specifically, from about twice a day to about once a week.
  • the frequency of administration can remain constant or can be variable during the duration of treatment.
  • various factors can influence the actual frequency of administration used for a particular application.
  • the amount, duration of treatment, combination of agents, site of administration, stage of disease (if present), and the anatomical configuration of the treated area may require an increase or decrease in administration frequency.
  • a composition containing reticuline can be administered daily at a dose of about 1 to about 5 mg of reticuline per kg of body weight.
  • the duration of administration of a composition provided herein can be any duration.
  • a duration of administration of a composition provided herein can be longer than a week, month, three months, six months, nine months, a year, two years, or three years.
  • an effective duration can be any duration that reduces, prevents, or eliminates a symptom of a disease upon administration to a mammal without producing significant toxicity to the mammal.
  • Such an effective duration can vary from several days to several weeks, months, or years.
  • an effective duration for the treatment of an acute disease can range in duration from several days to several months.
  • an effective duration can vary with the frequency of administration, the amount administered, combination of multiple agents, site of administration, state of disease (if present), and anatomical configuration of the treated area.
  • a composition provided herein e.g., a composition containing reticuline
  • the mammal can be treated with a combination of L-DOPA and dopamine to inhibit the production of morphine that results from the administered composition.
  • a combination of L-DOPA and dopamine can be used to reduce that amount of morphine produced from a composition containing a morphine precursor such that only 95, 90, 80, 70, 60, 50, 40, 30, 20, 10, or less percent of the morphine normally produced following administration of the composition is actually produced.
  • compositions provided herein can be administered as described herein.
  • a composition containing morphine can be administered to a mammal in an amount and at a frequency such that the mammal receives between 0.5 ⁇ g and 10 ⁇ g of morphine per kg of body weight per day for a duration of more than one month (e.g., more than two, three, four, five, six, seven, eight, nine, or more months).
  • this document provides methods for treating a mammal having a disease or condition using a composition provided herein.
  • diseases or conditions that can be treated using the compositions provided herein include, without limitation, rheumatoid arthritis, systemic lupus erythematosus, systemic scleroderma, Behcet disease, periarteritis, ulcerative colitis, Crohn's disease, active chronic hepatitis, glomerular nephritis, autoimmune diseases, osteoarthritis, gout, atherosclerosis, psoriasis, atopic dermatitis, pulmonary diseases with granuloma, encephalitis, endotoxin shock, sepsis, inflammatory colitis, diabetes, acute myelocytic leukemia, pneumonia, heart transplantation, encephalomylitis, anorexia, acute hepatitis, chronic hepatitis, drug-induced hepatic injury, alcoholic hepatitis, viral he
  • compositions provided herein can be administered as described herein.
  • a composition containing morphine can be administered to a mammal in an amount and at a frequency such that the mammal receives between 0.5 ⁇ g and 10 ⁇ g of morphine per kg of body weight per day for a duration of more than one month (e.g., more than two, three, four, five, six, seven, eight, nine, or more months).
  • the compositions provided herein can be used to reduce the severity of a symptom of the disease or condition, or to prevent the development or onset of the disease or condition.

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US8865696B2 (en) 2004-10-01 2014-10-21 The Research Foundation For The State University Of New York Morphine and morphine precursors
RU2607497C2 (ru) * 2010-11-15 2017-01-10 Нейродерм Лтд Непрерывное введение l-допа, ингибиторов допа-декарбоксилазы, ингибиторов катехол-о-метилтрансферазы и предназначенные для этого композиции
US10022320B2 (en) 2014-03-13 2018-07-17 Neuroderm, Ltd. Dopa decarboxylase inhibitor compositions
US10258585B2 (en) 2014-03-13 2019-04-16 Neuroderm, Ltd. DOPA decarboxylase inhibitor compositions
US11213502B1 (en) 2020-11-17 2022-01-04 Neuroderm, Ltd. Method for treatment of parkinson's disease
US11331293B1 (en) 2020-11-17 2022-05-17 Neuroderm, Ltd. Method for treatment of Parkinson's disease
US11844754B2 (en) 2020-11-17 2023-12-19 Neuroderm, Ltd. Methods for treatment of Parkinson's disease
US12161612B2 (en) 2023-04-14 2024-12-10 Neuroderm, Ltd. Methods and compositions for reducing symptoms of Parkinson's disease

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CN101766622A (zh) * 2009-12-16 2010-07-07 昆明理工大学 Morphine作为保护PC12细胞免于帕金森病毒性物损伤剂的应用
US10813901B2 (en) 2013-10-22 2020-10-27 Yamo Pharmaceuticals Llc Compositions and methods for treating autism
US9326962B2 (en) 2013-10-22 2016-05-03 Steven Hoffman Compositions and methods for treating intestinal hyperpermeability
US10751313B2 (en) 2013-10-22 2020-08-25 Yamo Pharmaceuticals Llc Compositions and methods for treating autism
MX2017013176A (es) * 2015-04-14 2018-01-30 Hoffman Steven Composiciones y metodos para tratar autismo.
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US8865696B2 (en) 2004-10-01 2014-10-21 The Research Foundation For The State University Of New York Morphine and morphine precursors
US9474749B2 (en) 2004-10-01 2016-10-25 The Research Foundation For The State University Of New York Morphine and morphine precursors
RU2607497C2 (ru) * 2010-11-15 2017-01-10 Нейродерм Лтд Непрерывное введение l-допа, ингибиторов допа-декарбоксилазы, ингибиторов катехол-о-метилтрансферазы и предназначенные для этого композиции
US10022320B2 (en) 2014-03-13 2018-07-17 Neuroderm, Ltd. Dopa decarboxylase inhibitor compositions
US10258585B2 (en) 2014-03-13 2019-04-16 Neuroderm, Ltd. DOPA decarboxylase inhibitor compositions
US10624839B2 (en) 2014-03-13 2020-04-21 Neuroderm, Ltd. Dopa decarboxylase inhibitor compositions
US10813902B2 (en) 2014-03-13 2020-10-27 Neuroderm, Ltd. DOPA decarboxylase inhibitor compositions
US11213502B1 (en) 2020-11-17 2022-01-04 Neuroderm, Ltd. Method for treatment of parkinson's disease
US11331293B1 (en) 2020-11-17 2022-05-17 Neuroderm, Ltd. Method for treatment of Parkinson's disease
US11458115B2 (en) 2020-11-17 2022-10-04 Neuroderm, Ltd. Method for treatment of Parkinson's disease
US11844754B2 (en) 2020-11-17 2023-12-19 Neuroderm, Ltd. Methods for treatment of Parkinson's disease
US12161612B2 (en) 2023-04-14 2024-12-10 Neuroderm, Ltd. Methods and compositions for reducing symptoms of Parkinson's disease

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Effective date: 20110923

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