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WO2009073942A1 - Combinaisons d'alcaloïdes tropaniques et de trigonelline et procédés d'administration de celles-ci - Google Patents

Combinaisons d'alcaloïdes tropaniques et de trigonelline et procédés d'administration de celles-ci Download PDF

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Publication number
WO2009073942A1
WO2009073942A1 PCT/CA2007/002243 CA2007002243W WO2009073942A1 WO 2009073942 A1 WO2009073942 A1 WO 2009073942A1 CA 2007002243 W CA2007002243 W CA 2007002243W WO 2009073942 A1 WO2009073942 A1 WO 2009073942A1
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WO
WIPO (PCT)
Prior art keywords
trigonelline
composition
tropane alkaloids
catuabin
phase
Prior art date
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Ceased
Application number
PCT/CA2007/002243
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English (en)
Inventor
Michele Molino
Joseph Macdougall
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Iovate T&P Inc
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Iovate T&P Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Iovate T&P Inc filed Critical Iovate T&P Inc
Priority to PCT/CA2007/002243 priority Critical patent/WO2009073942A1/fr
Publication of WO2009073942A1 publication Critical patent/WO2009073942A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system

Definitions

  • the present invention relates to a nutritional composition and method for improving the consistency of muscular contractions with respect to applied force and relaxation cycles over time and reducing the onset of central fatigue. Specifically, the present invention relates to a composition and method comprising a synergistic combination of trigonelline and tropane alkaloids which substantially simultaneously increases dopaminergic transmission and blocks potassium channels.
  • Muscle cells constitute the contractile tissues of the body, and are classified into three distinct types; skeletal, cardiac and smooth.
  • Skeletal muscle or voluntarily controlled muscle, is muscle which is anchored to the bone and plays a role in locomotion, maintaining posture and other voluntary movements.
  • actin and myosin results in a contraction of a muscle, and thus a movement results.
  • Muscle contractions are induced by electrical impulses which are transmitted by nerves, e.g. motor neurons, however only skeletal muscle contractions can be controlled voluntarily. Theses motor neurons interact with muscles at synapses referred to as neuromuscular junctions.
  • the neurons enter the muscle and split into many unmyelinated branches, which occupy depressions in the sarcolemma.
  • the sarcolemma is the cell membrane of muscle cells, which is responsible for receiving and conducting stimuli from neurons at neuromuscular junctions. Signals from the neurons are conducted by the sarcolemma into the inner portion of the muscle fiber to induce contraction.
  • a non- exhaustive list of these physiological responses includes; promotion of energy availability to support the force-requiring demands of high-intensity resistance exercise, facilitation of the contractile characteristics of skeletal muscle, and redirection of blood flow to areas of the body where larger amounts are required at a given time.
  • acetylcholine stimulates muscle contraction
  • dopamine acts to reduce involuntary muscle contraction, such that muscles are "steadied", thereby readying muscles for further contractions.
  • muscular contractions resulting in fatigue are accompanied by a marked decrease in the release of catecholamines such as dopamine. It would be desirable in certain situations, namely physical endeavors, for an individual to be able to maintain consistent levels of dopaminergic transmission to facilitate in muscle relaxation following contraction in repetitive circumstances.
  • the present invention relates to a nutritional composition and method for improving the consistency of muscular contractions with respect to applied force and relaxation cycles over time and reducing the onset of central fatigue.
  • the nutritional composition comprising at least an effective amount of trigonelline or derivative of trigonelline and an effective amount of tropane alkaloids functioning synergistically to increase dopaminergic transmission and block potassium channels to improve the consistency of muscular contractions with respect to applied force and relaxation cycles over time.
  • the present invention is directed towards a nutritional composition and method for improving the consistency of muscular contractions with respect to applied force and relaxation cycles over time and reducing the onset of central fatigue.
  • the nutritional composition comprising at least an effective amount of trigonelline or derivative of trigonelline and an effective amount of tropane alkaloids functioning synergistically to increase dopaminergic transmission and block potassium channels.
  • 'trigonelline' refers to the chemical 3 -carboxy-1 -methyl -pyridinum inner salt, (CAS Registry No. 535-83-1), also known as, nicotinic acid N-methylbetaine, coffearine, caffearine, gynesine, or trigenolline. Additionally, as used herein, the term 'trigonelline' also includes derivatives of trigonelline such as esters, and amides, and salts, as well as other derivatives, including derivatives having pharmacoproperties upon metabolism to an active form.
  • central fatigue' refers to fatigue resulting from reduced cognitive performance or the lowering of the excitation ability of motor neurons.
  • 'nutritional composition' includes dietary supplements, diet supplements, nutritional supplements, supplemental compositions and supplemental dietary compositions or those similarly envisioned and termed compositions not belonging to the conventional definition of pharmaceutical interventions as is known in the art. Furthermore, 'nutritional compositions' as disclosed herein belong to the category of compositions having at least one physiological function when administered to a mammal by conventional routes of administration.
  • 'potassium leakage' refers to the passive movement of potassium, down its electrochemical gradient, out of the cell. Furthermore, 'potassium leakage' as disclosed herein includes the increased movement of potassium out of the sarcolemma during periods of repetitive muscular stimulation. Trigonelline
  • Trigonelline is an alkaloid which is a salt formed by the addition of a methyl group to the nitrogen of niacin. Trigonelline is produced in the body as a metabolite of niacin and is excreted from the body in the urine. Various plant sources, for example, the green coffee bean, are significant sources of trigonelline.
  • trigonelline is capable of eliciting central nervous system stimulating effects (Natarajan B, Muralidharan A, Satish R, Dhananjayan R. Neuropharmacological activity of Trigonella foenum graecum Linn. Seeds. J Nat Remedies. 2007;7(l): 160-5), when orally administered to rats. Additionally, trigonelline has shown promise in mice models of Alzheimer's disease (Tohda C, Kuboyama T, Komatsu K. Search for natural products related to regeneration of the neuronal network. Neurosignals. 2005;14(l-2):34-45), as it has been shown to induce regenerative effects in dendrites and axons.
  • trigonelline has been shown to exert neuroprotective and neurotrophic effects, as it increases the excitability of the rat dorsal gangliae (Temraz TA, Houssen WE, Jaspars M, Woolley DR, Wease KN, Davies SN, Scott RH.
  • a pyridinium derivative from Red Sea soft corals inhibited voltage-activated potassium conductances and increased excitability of rat cultured sensory neurons. BMC Pharma. 2006 JuI 6;6:10).
  • the observed increase in the excitability of rat neurons was attributed to the inhibition of potassium channels.
  • the administration of a crude sample of Sarcophyton glaucum was later shown to contain trigonelline, which induced a dramatic increase in action potential firing.
  • the crude sample was shown to reduce the amplitudes of the current stimuli that were required to reach the threshold for action potential firing.
  • the number of action potentials over a period of 100 ms was increased from 1, in the control, to 4 in the treated
  • a serving of the present nutritional composition comprises from about
  • a serving of the present nutritional composition comprises from about 0.0001 g to about 0.25 g of trigonelline or derivatives of trigonelline.
  • a serving of the present nutritional composition most preferably comprises from about 0.0001 g to about 0.1 g of trigonelline or derivatives of trigonelline.
  • Tropane alkaloids are alkaloids, which are naturally occurring amines produced by plants.
  • the tropane alkaloids contain a tropane group being defined by a nitrogenous bicyclic organic compound, which may further contain additional functional groups bound via ester linkages.
  • a typical example of a tropane alkaloid is atropine, which is a highly competitive antagonist of acetylcholine receptors and is an extremely potent central nervous system stimulant.
  • Tropane alkaloids have been shown to possess dopamine uptake inhibitory characteristics (Hemby SE, Lucki I, Gatto G, Singh A, Thornley C, Matasi J, Kong N, Smith JE, Davies HM, Dworkin SI. Potential antidepressant effects of novel tropane compounds, selective for serotonin or dopamine transporters. J Pharmacol Exp Ther. 1997 Aug;282(2):727-33), as they are able to interact with various binding domains on dopamine transporters. Dopamine transporters are responsible for the inactivation of dopamine following synapses.
  • dopamine is responsible for inducing relaxation of contracted muscle, and decreases in dopamine levels result in extended periods of contraction, the prolonged presence of dopamine in the synaptic cleft would increase the sensitivity of the muscle to a subsequent signal by returning the muscle to the normal state. Essentially, proliferation of dopamine in the synaptic cleft would result in a greater number of possible muscular contractions during a period of exercise.
  • tropane alkaloids for example those being provided by plants of the Erythroxylum genus, will act to increase dopaminergic transmission thus prolonging the presence of dopamine in a synaptic cleft via inhibition of dopamine transporters.
  • the increased presence of dopamine in the synaptic cleft will increase the speed at which a contracted muscle can return to the relaxed state; making it available for a subsequent contraction.
  • an increase in dopaminergic transmission acts to improve the consistency of muscular contractions with respect to applied force and relaxation cycles over time.
  • an increased presence of dopamine will result in increased oxygen delivery to working muscle, as a result of increased blood flow, causing a reduction in free radical formation and less muscle damage, and thereby reducing central fatigue.
  • a serving of the present nutritional composition comprises from about 3.2 ⁇ g to about 3.2 mg of tropane alkaloids. More preferably, a serving of the present nutritional composition comprises from about 3.2 ⁇ g to about 1.5 mg of tropane alkaloids. A serving of the present nutritional composition most preferably comprises from about 3.2 ⁇ g to about 1 mg of tropane alkaloids.
  • the nutritional composition of the present invention comprises trigonelline and tropane alkaloids.
  • the nutritional composition is provided in any acceptable and suitable oral dosage form as known in the art. Improvement in the consistency of muscular contractions with respect to applied force and relaxation cycles over time via substantially simultaneously increasing dopaminergic transmission and blocking potassium channels is induced and carried out in an individual by administration of the composition of the present invention.
  • the nutritional composition of the present invention may be administered in a dosage form having controlled release characteristics, e.g. time-release.
  • the controlled release may be in forms such as a delayed release of active constituents, gradual release of active constituents, or prolonged release of active constituents.
  • the nutritional composition may be administered in the form of a multicompartment capsule which combines both immediate release and time-release characteristics.
  • Individual components of the nutritional composition may be contained in differential compartments of such a capsule such that the specific components may be released rapidly while others are time-dependently released.
  • a uniform mixture of the various components of the present invention may be divided into both immediate release and time-release compartments to provide a multi-phasic release profile.
  • Embodiments of the present invention of the present invention having multi-phasic release profiles may do so according the methods disclosed in U.S.
  • the aforementioned discloses a method of providing a multi -phasic dissolution profile through the use of differentially-sized milled particles.
  • the present invention is comprised of trigonelline or derivatives of trigonelline, which have been shown to inhibit potassium channels.
  • This inhibition of potassium channels will act to minimize the refractory period, as is known in the art, which accompanies the firing of an action potential, by minimizing potassium leakage.
  • This minimization of potassium leakage will reduce the amplitude of stimuli which is required to reach the threshold for another action potential, thereby leading to improved consistency of muscular contractions with respect to applied force and relaxation cycles over time
  • the present invention comprises tropane alkaloids that have been shown to increase dopaminergic transmission, prolonging the presence of dopamine in a synaptic cleft, via inhibition of dopamine transporters.
  • the increased presence of dopamine in the synaptic cleft will increase the speed at which a contracted muscle fibre can return to the relaxed state, making it available for a subsequent contraction.
  • the increase in dopaminergic transmission will act to improve the consistency of muscular contractions with respect to applied force and relaxation cycles over time.
  • Additional embodiments of the present invention may also include portions of the composition as fine-milled ingredients.
  • the nutritional composition may be consumed in any form.
  • the dosage form of the nutritional composition may be provided as, e.g.
  • a powder beverage mix a liquid beverage, a ready-to-eat bar or drink product, a capsule, a liquid capsule, a tablet, a caplet, or as a dietary gel.
  • the preferred dosage forms of the present invention are provided as a caplet or as a liquid capsule.
  • the dosage form of the nutritional composition may be provided in accordance with customary processing techniques for herbal and nutritional compositions in any of the forms mentioned above.
  • the nutritional composition set forth in the example embodiment herein disclosed may contain any appropriate number and type of excipients, as is well known in the art.
  • a nutritional composition comprising the following ingredients per serving is prepared for consumption by a mammal as a caplet to be consumed twice daily:
  • a nutritional composition comprising the following ingredients per serving is prepared for consumption by a mammal as a liquid capsule to be consumed once daily:

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  • Health & Medical Sciences (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Alternative & Traditional Medicine (AREA)
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Abstract

L'invention concerne une composition nutritionnelle comprenant au moins une quantité efficace de trigonelline ou d'un dérivé de trigonelline et une quantité efficace d'alcaloïdes tropaniques. Les substances agissant sensiblement simultanément améliorent la cohérence de contractions musculaires par rapport à une force appliquée et de cycles de relaxation dans le temps et retardent la survenu d'une fatigue centrale. L'invention concerne aussi un procédé associé.
PCT/CA2007/002243 2007-12-12 2007-12-12 Combinaisons d'alcaloïdes tropaniques et de trigonelline et procédés d'administration de celles-ci Ceased WO2009073942A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/CA2007/002243 WO2009073942A1 (fr) 2007-12-12 2007-12-12 Combinaisons d'alcaloïdes tropaniques et de trigonelline et procédés d'administration de celles-ci

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Application Number Priority Date Filing Date Title
PCT/CA2007/002243 WO2009073942A1 (fr) 2007-12-12 2007-12-12 Combinaisons d'alcaloïdes tropaniques et de trigonelline et procédés d'administration de celles-ci

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010142750A1 (fr) * 2009-06-11 2010-12-16 Dsm Ip Assets B.V. Stimulants musculaires de niacine et/ou de trigonelline
EP2269607A1 (fr) * 2009-06-11 2011-01-05 DSM IP Assets B.V. Trigonelline en tant que stimulant musculaire

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050176827A1 (en) * 2002-05-10 2005-08-11 Lee Steve S. Compositions and methods for glycogen synthesis
US20050226948A1 (en) * 2004-03-02 2005-10-13 Lee Steve S Methods for enhancing the transport of glucose into muscle

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050176827A1 (en) * 2002-05-10 2005-08-11 Lee Steve S. Compositions and methods for glycogen synthesis
US20050226948A1 (en) * 2004-03-02 2005-10-13 Lee Steve S Methods for enhancing the transport of glucose into muscle

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
HEMBY ET AL.: "Potential Antidepressant Effects of Novel Tropane Compounds, Selective for Serotonin or Dopamine Transporters", J. PHARM. EXPER. THER., vol. 282, 1997, pages 727 - 733 *
NATARAJAN, B. ET AL.: "Neuropharmacological activity of Trigonella foenum graecum Linn. seeds", J. NAT. REM., vol. 7, 2007, pages 160 - 165 *
TEMRAZ ET AL.: "A pyridinium derivative from Red Sea soft corals inhibited voltage-activated potassium conductances and increased excitability of rat cultured sensory neurones", BMC PHARMACOLOGY, vol. 6, 2006, pages 10, XP021015139, DOI: doi:10.1186/1471-2210-6-10 *
ZANOLARI ET AL.: "Tropane Alkaloids from the Bark of Erythroxylum vacciniifolium", J. NAT. PROD., vol. 66, 2003, pages 497 - 502 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010142750A1 (fr) * 2009-06-11 2010-12-16 Dsm Ip Assets B.V. Stimulants musculaires de niacine et/ou de trigonelline
EP2269607A1 (fr) * 2009-06-11 2011-01-05 DSM IP Assets B.V. Trigonelline en tant que stimulant musculaire
US20120190617A1 (en) * 2009-06-11 2012-07-26 Angelika Friedel Niacin and/or trigonelline as a muscle stimulant
US8323707B2 (en) 2009-06-11 2012-12-04 Dsm Ip Assets B.V. Trigonelline as a muscle stimulant
US8772230B2 (en) * 2009-06-11 2014-07-08 Dsm Ip Assets B.V. Niacin and/or trigonelline as a muscle stimulant
US9241938B2 (en) 2009-06-11 2016-01-26 Dsm Ip Assets B.V. Trigonelline as a muscle stimulant

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