EP0912181A1 - Coupe-faim - Google Patents

Coupe-faim

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Publication number
EP0912181A1
EP0912181A1 EP97933498A EP97933498A EP0912181A1 EP 0912181 A1 EP0912181 A1 EP 0912181A1 EP 97933498 A EP97933498 A EP 97933498A EP 97933498 A EP97933498 A EP 97933498A EP 0912181 A1 EP0912181 A1 EP 0912181A1
Authority
EP
European Patent Office
Prior art keywords
amount
tryptophan
xanthine
dose
composition
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP97933498A
Other languages
German (de)
English (en)
Inventor
William E. Shell
Mark E. Jarmel
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.)
Nutracorp Scientific Inc
Original Assignee
Nutracorp Scientific Inc
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Filing date
Publication date
Application filed by Nutracorp Scientific Inc filed Critical Nutracorp Scientific Inc
Publication of EP0912181A1 publication Critical patent/EP0912181A1/fr
Withdrawn legal-status Critical Current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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/01—Hydrolysed proteins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents

Definitions

  • This invention relates generally to dietary supplements for reducing appetite and decreasing carbohydrate craving.
  • weight control has been increasing attention to weight control since obesity is associated with an increased mortality rate, diabetes mellitus, hypertension, heart disease and stroke.
  • the attention to reducing obesity has lead to the introduction of sugar-free and fat-free foods, diet plans, weight reduction programs, artificial fats, and pharmaceutical agents to alter both appetite and carbohydrate craving.
  • weight reduction programs have been introduced to alter both appetite and carbohydrate craving.
  • the weight of the population continues to rise. It is now estimated that more than 40% of the population is significantly overweight. At any given time approximately 25% of the population is on a diet, leading to undesirable "yo-yo" effects from repeated dieting.
  • weight reduction products to achieve and to sustain weight loss can be attributed to several factors. These include the relative ineffectiveness of the individual approaches, side effects of weight loss products, and the cost of a sustained weight loss program. Accordingly, there is a need for an effective program based on safe naturally occurring agents. Such a program will allow weight loss with reduced side effects and reduction of costs.
  • appetite suppression One major component of a successful weight loss program is appetite suppression. Appetite suppression has been achieved with administration of amphetamines, antidepressants, both soluble and insoluble fibers, serotonin precursors, and prescription drugs which enhance serotonin activity. All of these techniques, as currently applied, have significant disadvantages. Amphetamines are well known to reduce appetite. Dexedrine and related agents including ephedrine and pseud oephedrine reduce appetite. These agents either produce agitation, addiction or nerve damage (dexedrine), or produce rapid attenuation of effect (ephedrine or pseudoephedrine).
  • Phentermine an amphetamine-like molecule, is approved for use as an appetite suppressant, but must be administered by prescription. This results in increased costs associated with physician visits. Additionally, phentermine can only be used for short periods when administered by itself. It is believed that the amphetamines, including phentermine, suppress appetite in part through their effects on brain dopamine. Phentermine also can cause hypertension, heart irregularities and agitation. Thus, the amphetamines and related agents can be used for appetite reduction, but at substantial cost and with known, often unacceptable side effects.
  • Serotonin within the hypothalamic region of the brain is known to reduce craving for carbohydrates.
  • a composition and method for selectively suppressing appetite for carbohydrates is described. This method includes the administration of the serotonin precursor, tryptophan, along with a carbohydrate that causes insulin secretion. Secretion of insulin moves amino acids other than tryptophan from the bloodstream into the tissues. This removes amino acids from the blood which compete with tryptophan for transport across the blood-brain barrier. This carbohydrate-initiated insulin effect on circulating amino acids maximizes delivery of tryptophan to the hypothalamus.
  • the dose of tryptophan proposed by Wurtman is between 10 and 100 mg per kg. in rats. For a 70 kg man, the dose would range between 700 and 7,000 mg to potentially achieve similar effects.
  • the dose of tryptophan proposed by Wurtman is between 10 and 100 mg per kg. in rats. For a 70 kg man, the dose would range between 700 and 7,000 mg to potentially achieve similar effects.
  • the regulatory agency in the United States, the Food and Drug Administration (FDA) has found that tryptophan in doses of more than 100 mg per day may be unsafe.
  • the FDA has determined that doses of tryptophan in excess of 100 mg per day may potentially cause muscle damage. Accordingly, tryptophan is not being used alone, or administered with a carbohydrate, as an appetite aide.
  • Wurtman, et al in U.S. Patent No. 4,309,445 described a composition and method using d-fenfluramine to block intermittent carbohydrate cravings. This method disclosed that d-fenfluramine and the related isomer 1-fenfluramine selectively reduces carbohydrate craving.
  • Wurtman, et al, in U.S. Patent 4,687,763 disclosed that tryptophan can increase brain serotonin levels when given with melatonin.
  • the FDA only allows naturally occurring protein to be used as a source of supplemental tryptophan. Both intact and "predigested" (enzyme hydrolyzed), forms of naturally occurring protein may be used. Naturally occurring protein contains approximately 1.6 % tryptophan. The amount of tryptophan in naturally occurring protein has previously been considered insufficient to produce a reduction in carbohydrate craving. This is due to the presence of other amino acids which compete for absorption with the small amount of tryptophan present in protein. In a recent FDA publication, it was concluded that there was insufficient evidence that tryptophan reduces appetite in doses considered safe. There is no known prior art suggesting the use of predigested protein as a source of tryptophan for appetite suppression.
  • Tyrosine is a precursor of brain dopamine. Amphetamines stimulate the release of dopamine. Brain dopamine is associated with the appetite suppressing effects of amphetamine-like agents. To date, a food supplement has not been used to enhance the release of dopamine without using amphetamines or amphetamine-like agents such as ephedrine or pseudoephedrine. Wurtman, et al, in U.S. Patent No. 4,673,689 disclose that tyrosine can be used to potentiate the sympathomimetic agents such as ephedrine or pseudoephedrine. However, this patent contains no disclosure or suggestion of any usefulness or synergism for any purpose for combining tyrosine with any other agents active in the central nervous system.
  • Histidine is a precursor of histamine in the brain. It has been reported that histamine and its precursor histidine will decrease the food intake of experimental animals (rats) when administered by intraperitoneal injection ("Manipulation of Central Nervous System Histamine, Histaminergic Receptors (HI) Affects Food Intake in Rats," Mercer et al, J. of Nutrition, 1994, Vol. 24, pp 1029-1036) ) However, the effectiveness of either histamine or its precursor histidine for suppression of appetite by oral administration or at dosage levels at which the known side effects could be tolerated has not been elucidated.
  • Chocolate particularly the cocoa powder, contains among other active ingredients, the xanthines theobromine and caffeine; as well as biogenic amines such as phenylethylamine. These agents influence the activity of both serotonin and dopamine. Xanthines are known to increase the release of both dopamine and serotonin. Neither chocolate or cocoa powder have been used as appetite suppressants either alone or in combination with neuro transmitter precursors such as tryptophan or tyrosine. Phenylethylamines are also known to stimulate the release of serotonin and dopamine. Phenylethylamines are also known to act as inhibitors of the enzyme monoamine oxidase (MAO), which breaks down serotonin and dopamine. Chocolate has been used both directly and indirectly, knowingly and unknowingly, as a mood elevator. The mechanism of chocolate's appeal has, heretofore, not been specifically defined. Most common knowledge attributes the appeal of chocolate to its taste, not to neurotransmitter affects.
  • MAO
  • fenfluramine has been associated with the side effect of pulmonary hypertension and heart valve disease in rare instances.
  • the use of d-fenfluramine induces grogginess in many subjects and is expensive, often costing US$5.00 per day for the drug. This cost is in addition to multiple visits to physicians for monitoring of treatment which may last many months or years.
  • phentermine is an amphetamine-like drug whose long term effects are unknown. Accordingly, there is a need for a low cost program that emulates the effects of the phentermine-fenfluramine therapies that can be applied to a large number of individuals without repetitive physician monitoring. Ideally, the components of such a program would be formulated from low cost ingredients which are not drug.
  • This invention has the object of achieving appetite suppression and reduced carbohydrate craving without large doses of fibers, amphetamines, antidepressants, or other prescription drugs.
  • This invention also has the object of enabling use of readily available, low cost, safe, plant-derived agents and to provide appetite suppression with such agents at reduced dosage to minimize the possibility of side effects.
  • This invention provides methods and compositions for suppressing appetite based upon the discovery that certain neurotransmitter precursors will act synergistically with each other and with certain neurotransmitter potenriators in suppressing appetite and reducing carbohydrate craving.
  • neurotransmitter precursors for the neurotransmitters serotonin, dopamine, norepinephrine and histamine which contain an amine group and include tryptophan, phenylalanine, tyrosine and histidine, are orally administered in reduced doses concomitantly with one or more xanthines, and particularly caffeine and /or theobromine effectively to suppress appetite.
  • these neurotransmitter precursors require unacceptably high doses in order to suppress appetite.
  • histidine is administered concommitantly with either tryptophan, phenylalanine or tyrosine with synergistic effect to suppress appetite, either with or without the concomitant administration of a xanthine.
  • Tryptophan may be adminstered conjointly with phenylalanine or tyrosine with benefidal effect, during the same day but with administration of one seperated by at least 20 minutes of the other, to avoid competition between them for entry across the blood-brain barrier.
  • the neurotransmitter precursor and potentiators are administered in accordance with this invention in naturally occurring forms long considered safe for ingestion as a food stuff
  • the neurotransmitter precursor tryptophan may be administered in the form of natural proteins which have been hydrolyzed to release amino add residues including tryptophan.
  • the predigested protein allows delivery of free amino adds so that a rapid effect can be produced.
  • the hydrolyzed protein is advantageously administered concomitantly with a carbohydrate to a subject having an empty stomach (i.e. at least an hour after eating) to trigger insulin secretion to clear from the bloodstream competing amino adds that would otherwise block passage of tryptophan across the blood-brain barrier, thereby maximizing the absorption of naturally occurring tryptophan.
  • This insulin-mediated effect on amino adds allows sufficient tryptophan to be delivered to the brain so that the desired effects are achieved
  • the protein source for the tryptophan may be administered in unhydrolyzed form, together with a proteolytic enzyme, so that hydrolysis occurs in the gastrointestinal tract to release the tryptophan.
  • Xanthines are also advantageously derived from natural sources long employed in foodstuffs, such as cocoa, tea, coffee and the like. Cocoa in particular provides a unique source of a combination of both the xanthines caffeine and theobromine and phenylethylamine that is quite palatable and considered safe.
  • Dosage forms are provided to advantageously and conveniently carry out the foregoing methods with reduced dosages consistent with effective suppression of appetite.
  • the single dosage forms constitute, pills, capsulets and other forms individualized for administering the appropriate single dose quantities of the selected constituents.
  • the amount of tryptophan in the dosage forms is from about 2.5 to 100 milligrams
  • the amount of tyrosine is from about 10 to 700 milligrams
  • the amount of histidine from about 1 to 500 milligrams.
  • the xanthine theobromine is in the range of from about 1 mg. to 2 gm. or higher.
  • cocoa is employed as the xanthine source, it may be present in the single dosage form in the amount of about 1 mg. to 2 grams or higher.
  • hydrolyzed protein is the source of tryptophan
  • the amount of hydrolyzed protein may be between one half of a gram, and 30 grams or higher. Desirably, the amount of hydrolyzed protein is selected to provide therein an amount of tryptophan of between 2.5 to 100 milligrams.
  • supplemental tryptophan cannot be synthesized by man-made processes and thus they must be derived from naturally occurring protein, either animal or vegetable.
  • the FDA stipulates that the dose of added tryptophan cannot exceed 100 mg per day, or 1.43 mg/kg per day.
  • the preferred source for our invention is vegetable protein and a dose of tryptophan is 45 mg/dose or 0.71 mg/kg per day.
  • the amount of tryptophan in the embodiment using predigested protein can be as low as 15 to 40 mg per dose.
  • Serotonin, dopamine, norepinephrine and histamine form a sandy of neurotransmitters that are active in the CNS to affed appetite, either stimulating the release of corticotropin-releasing factor (CRF), which suppresses appetite, or suppressing the release and /or activity of neuropeptide Y, which stimulates appetite.
  • CRF corticotropin-releasing factor
  • Serotonin, norepinephrine and histamine all stimulate the release of CRF.
  • Dopamine suppresses neuropeptide Y. Histamine additionally promotes neuron firing.
  • the precursors for this class of neurotransmitters all of which contain an amine group, indude tryptophan for serotonin, phenylalanine and tyrosine for both dopamine and norepinephrine and histidine for histamine.
  • these precursors are employed in combination with each other and in combination with xanthines to potentiate the effect on appetite suppression by the respective neurotransmitters of this ensemble.
  • the precursors are employed in this invention to enhance the synthesis of their respective neurotranmitters and since serotonin, phenylalanine, tyrosine and histidine all enhance synthesis of neurotransmitters that stimulate release of CRF, these precursors all thereby indirectly stimulate release of CRF.
  • phenylalanine and tyrosine indiredly suppresses neuropeptide Y through enhancement of the synthesis of dopamine as well. Also, histidine promotes neuron firing thereby indirectly stimulating synthesis of norepinephrine, tyrosine and serotonin.
  • the precursors may be employed in this invention in pure form, e.g. exogenous material synthesized or derived from animal or vegetable protein, particularly purified extracts isolated from the amino acid residues in enzyme hydrolyzed proteins.
  • a source for the precursor tryptophan particularly useful in this invention are proteins, either enzyme hydrolyzed prior to administration to release tryptophan or unhydrolyzed protein to be administered along with a proteolytic enzyme that will liberate the tryptophan in the gastrointestinal tract.
  • Commercial preparations of predigested proteins typically from milk-derived protein, such as casein or whey, are available and may be administered separately or in composition with histidine an /or a xanthine.
  • tryptophan is to be administered in the form of a predigested protein or a protein to be enzyme hydrolyzed upon administration
  • soluble proteins such as albumin
  • proteolytic enzymes may include papain, chymopapain, bromelin, trypsin and pepsin.
  • Xanthines constitute a class of non-selective adenosine antagonists and they include theobromine, caffeine and theophylline. They are capable of promoting release of the neurotransmitters serotonin, dopamine and histamine. and they potentiate neurotransmitter synthesis for each when administered in accordance with this invention. Combining xanthines, and neurotransmitter precursors allows the desired effects to be achieved with reduced, safe, doses of neurotransmitter precursors.
  • the xanthines may be used in the form of their free compounds or as their salts, adducts or other derivatives, for example dtrated caffeine, theophylline ethylenediamine, theophylline sodium acetate, sodium glycinate, the choline salt, the theophylline derivatives theophylline-megumine and dyphylline, theobromine calcium salicylate, sodium acetate or sodium salicylate.
  • a particularly suitable source of xanthines for use in this invention are those from natural sources. Cocoa provides a unique combination of xanthines, including theobromine and caffeine, and biogenic amines, and particularly phenylethylamine, in a form that is normally easily ingested and tolerated by the subject. In addition to the potentiating effect of the xanthines in cocoa, the MAO-inhibiting action of the phenylethylamine prolong the effects of serotonin, histamine and /or dopamine. Cocoa powder was originally included in preliminary formulations with neurotransmitter precursors to improve flavor and because its mood enhancing effects have appealed to people for centuries.
  • cocoa powder significantly potentiated the effects of the neurotransmitter precursors.
  • This potentiating effect was determined by us to be produced by the naturally occurring xanthines and biogenic amines present in cocoa powder.
  • Infusions of caffeine from coffee beans and of caffeine and theophylline from tea leaves may be employed as a natural source of these xanthines, either in liquid form as coffee and tea, or in dried extrad form, alone or, more inconveniently, in composition with the neurotransmitter precursor.
  • chocolate, guarana and other food sources may be employed.
  • the combinations of neurotransmitter precursors of this invention may be employed with an attendant synergistic effect, without concomitant administration of xanthine, and yet further potentiation may be achieved by administering the neurotransmitter precursor combinations with a xanthine.
  • the neurotransmitter precursor combinations include histidine administered with tyrosine or with tryptophan and tyrosine followed by tryptophan after a time delay. Histidine does not compete with either tyrosine or tryptophan in crossing the blood-brain barrier so may be administered with either tyrosine or tryptophan at the same time and in the same composition.
  • Tyrosine and phenylalanine may be used conjointly with tryptophan in this invention with advantage but as they can inhibit passage of tryptophan across the blood-brain barrier, they are administered to the subject separately from the tryptophan, at time intervals of at least twenty minutes. Either the tryptophan or the tyrosine and/ or phenylalanine may be administered before the other. Administered in this fashion to first permit take up of the phenylalanine and/ or tyrosine from the blood stream, inhibition of tryptophan take-up is avoided and enhanced effect of the precursors is attained. Additionally, neurotransmitter balance is fostered by decreasing the total dose over time of any single neurotransmitter.
  • each neurotransmitter precursor is in an amount suffident to enhance synthesis of its respective neurotransmitter (s), to stimulate the release of CRF and thereby to suppress appetite in combined administration with the other neurotransmitter and or xanthines employed.
  • the synergistic effect of these combinations will permit appetite suppression at lower dosage levels of each of the neurotransmitter precursors than otherwise possible and desirably these lower dosage levels are employed to avoid possible side effects and particularly those now limiting the use of at tryptophan, including grogginess.
  • the desired single dose range is between 2.5 and 100 mg. with a typical dose of 45 mg.
  • the desired dosage range of either phenylalanine or tyrosine is between 10 and 600 mg., with a typical dose of 500 mg.
  • doses up to 700 mg. or even to 1 gram or higher, e.g. up to 3 grams may be administered without undue risk of side effects. These amounts, equivalent to from .14 to 42.2 mg/kg, would be insufficient to suppress appetite if used alone.
  • Histidine is desirably administered in a dosage range of 1 to 500 mg., with a typical dose of 30 mg. However somewhat higher doses, e.g. up to 1 gram, may be given, if tolerated by the subject.
  • the dosage range for each precursor applies to combined administration of the precursor with another precursor, with a xanthine, or with both.
  • the proteins should be in an amount to provide the tryptophan dosage levels of this invention as discussed above. Typically, this will be in a range of between around one half of a gram and 30 gm.
  • the amount of enzyme employed may be 30 to 50 mg. per gram of protein.
  • Insulin producing carbohydrates administered with the protein are desirably at dosage levels of from about one half gram to 5 grams.
  • Xanthines are employed in this invention in dosage ranges appropriate to promote release of neurotransmitters and to avoid undesired side effects.
  • Theobromine and theophylline may each be administered in a dosage of from 1 mg. to 2 grams or higher.
  • Caffeine may be administered in a dose of from 1 to 200 mg. or higher, if tolerated by the subject.
  • Cocoa may be administered in a dose of 1 mg. to 2 grams or higher up to 20 grams for an appropriate dose of xanthines, with a preferred dose being 400 to 800 mg.
  • Infusions such as tea or coffee may be employed, with one to two cups providing an appropriate dose.
  • Somewhat higher doses of these xanthines may be employed with some subjeds without undue discomfort.
  • the neurotransmitter precursors and neurotransmitter potentiators of this invention may be administered orally separately, or, for assurance of appropriate proportions and dosages as well as for convenience, they are administered together in the same composition.
  • the dosage forms for administration separately or in the same composition may be any of the conventional forms, including capsules, capsulets, chewable wafers, tablets, liquid suspensions, powders and the like.
  • Xanthine dosages may take the form of chocolate preparations, cocoa drinks, infusions, e.g. coffee and tea and cola drinks containing caffeine.
  • Hydrolyzed protein sources of tryptophan may be taken separately in tablet form, utilizing commercially available predigested protein tablets, such as LLP Concentrated Predigested Protein sold by Twin Laboratories, Inc., Ronkonkoma, New York containing aproximately 18 mg. of tryptophan per 1 gram tablet.
  • the compositions in the form of powders or liquids may be packaged in multiple dosage quantities with instructions to the user to extract therefrom for ingestion appropriate individual dosage amounts, e.g. a teaspoonful.
  • the compositions are desirably prepared in discrete units, e.g. capsules, wafers etc., which each contain the appropriate dosage amounts of neurotransmitter precursors and/ or neurotransmitter potentiators for a single dose as discussed above.
  • compositions may include the usual carriers, fillers, exdpients and adjuvants.
  • they indude soluble fiber, insoluble fiber, neurotransmitter precursors and the potentiating agents contained in cocoa powder.
  • the inclusion of dietary fibers produces early satiety from volume distention and causes further appetite suppression by triggering the release of CCK.
  • the appetite suppressing actions of the dietary fiber component further enhance the invention's neurotransmitter-related effects. They additionally may contain folic acid and vitamin B6 to enhance conversion of tryptophan to serotonin, tyrosine to dopamine and histidine to histamine, respectively.
  • the preferred amount of folic add is 200 meg per dose with a range of 1 - 800 meg/ dose.
  • the preferred amount of vitamin B6 is 10 mg with a range of 1 - 50 mg/dose.
  • Representative doses of soluble fibers are 100 mg to 1000 mg per dose.
  • the best soluble fibers for producing appetite suppression are pectin fibers from apple or dtrus. fruits.
  • Representative doses of insoluble fibers are 100 mg to 1000 mg per dose.
  • a preferred embodiment utilizes insoluble fiber in the form of wheat bran for these formulations.
  • Other suitable insoluble fibers include, but are not limited to cellulose, methyl-cellulose, chitosan, whey, whole wheat fiber, and other whole grain fiber.
  • insoluble fibers would be ineffective as appetite suppressants if given alone in these doses.
  • the fibers must be premixed with water until barely wet and dried at low heat. The premix will result in a better gel and fat binding than the use of either type of fiber alone. Fiber which has not been premixed and heated to dryness will reduce the effediveness of the formulations.
  • tryptophan, phenylalanine or tyrosine as the sole neurotransmitter precursor or combined with histidine
  • these tryptophan and phenylalanine or tyrosine formulations are given to a subject, but at different times, each to produce appetite suppression, but by different modalities.
  • the phenylalanine or tyrosine-containing formulations are designed to potentiate the production and release of dopamine. Appetite suppression is achieved by the resulting activity of dopamine, and of histamine, if histidine is included.
  • the phenylalanine or tyrosine-containing formulations emulate the effects of amphetamines, phentermine, ephedrine and pseudoephedrine. Tryptophan-containing formulations are designed to reduce appetite for 2-4 hours and are designed to potentiate the production and release of serotonin, and of histamine, if histidine is included. Appetite suppression and reduced carbohydrate craving is achieved by the resulting activity of serotonin.
  • the tryptophan- containing formulations emulate the effeds of fenfluramine, d- fenfluramine and fluoxetine and are typically designed to reduce appetite for 1-4 hours and to reduce carbohydrate craving for 16-36 hours.
  • the tryptophan and phenylalanine or tyrosine formulations may be designed for use together in varying dosage schedules depending on individual needs. It is a preferred that each to be taken on an empty stomach. When used together in accordance with this invention, typically during the same day (24 hours), one is administered separately at least 20 minutes after the other. This is done to avoid competition of the precursors for entry across the blood brain barrier.
  • the phenylalanine or tyrosine formulation is given before lunch to suppress appetite during the day and afternoon.
  • the tryptophan formulation is given before dinner to decrease appetite and reduce carbohydrate craving at dinner and during the evening. Late afternoon and evening hours are the times of day when many over-weight people crave both food and carbohydrates.
  • the phenylalanine or tyrosine formulation can be administered at 10:00 a.m. and at 3:00 p.m. with the tryptophan formulation being administered at 11:00 a.m. and 4:00 p.m..
  • the dosage schedule allows these food supplements to emulate the effeds of the prescription drugs phentermine, fenfluramine, and d-fenfluramine. If an individual undergoes a fast to induce hunger, administration of tyrosine results in appetite suppression which begins 15 to 30 minutes after ingestion and continues for 2-4 hours. If hunger reappears, re-ingestion of the formulation results in suppression of hunger beginning 15-30 minutes after ingestion and continuing for 2-4 hours. Repeated administration of the tyrosine formulation results in repetitive suppression of appetite.
  • Examples 1 through 7 illustrate formulations with tyrosine as the sole neurotransmitter precursor and formulations with tryptophan as the sole neurotransmitter precursor and use thereof independently and together. These examples also illustrate the use of various xanthines with the precursors and the use of hydrolyzed protein as the source of tryptophan.
  • a useful tyrosine formulation in one dose is tyrosine 295 mg, soluble fiber 125 mg, insoluble fiber 125 mg, cocoa 200 mg, vitamin B6 5 mg, and folic add 100 meg.
  • a useful tryptophan combination per dose is soluble fiber 175 mg, insoluble fiber 175 mg, protein powder 100 mg, tryptophan 45 mg, vitamin B6 5 mg, and folic add 100 meg.
  • Another useful tryptophan-containing formulation per dose is soluble fiber 175 mg, insoluble fiber 175 mg, predigested protein powder 2,000 mg, cocoa 250 mg, sugar 250 mg, vitamin B6 5 mg, and folic add 100 meg..
  • a preferred dosage of the combination is 2 capsules of tyrosine formulation before lunch, 2 capsules of the tyrosine formulation at 4:00 p.m., and 2 capsules of either of the tryptophan formulations 30 minutes before dinner.
  • Another dosage schedule includes the tyrosine dose at 10:00 a.m. and 3:00 p.m. with tryptophan dose at 11:00 a.m. and 4:00 p.m. Other dosage schedules can be used.
  • This example illustrates the use of tyrosine as the sole neurotransmitter precursor, together with xanthines, for appetite suppression.
  • a 53 year old male underwent a 10 hour fast to induce hunger.
  • Two capsules of a tyrosine formulation were given each capsule containing soluble fiber in the form of apple pertin 175 mg, insoluble fiber in the form of bran fiber, tyrosine 295 mg, cocoa powder 200 mg, folic add 100 meg and vitamin B6 5 mg.
  • the soluble and insoluble fibers had been premixed, wet and dried. The material had been placed into capsules.
  • the subject experienced an elimination of hunger that began 8 minutes after ingestion and lasted for 2.5 hours.
  • a second ingestion of 2 capsules of the formulation reproduced the effect.
  • This example illustrate the use of tryptophan as the sole neurotransmitter precursor, together with xanthines, for appetite suppression and carbohydrate craving.
  • a 44 year old male underwent a 10 hour fast to induce hunger. He then ingested 2 capsules of a tryptophan formulation each capsule containing 175 mg soluble fiber in the form of apple pectin and psyllium, 175 mg insoluble fiber in the form of bran fiber, 100 mg vegetable non-soy protein, 45 mg of tryptophan, 250 mg of cocoa powder, 5 mg of vitamin B6, and 100 meg of folic add.
  • the individual's hunger began to dissipate in 30 minutes and was completely dissipated in 60 minutes.
  • This example illustrates the use of a tryptophan formulation utilizing predigested proteins as the tryptophan source.
  • a 35 year old female underwent a 10 hour fast in order to induce hunger. She then ingested two capsules containing 175 mg soluble fiber in the form of apple pectin and psyllium, 175 mg insoluble fiber in the form of bran fiber, 2,000 mg of predigested protein in the form of predigested casein, 250 mg of cocoa powder, 250 mg sugar, 5 mg of vitamin B6, and 100 meg of folic add. She experienced a reduction of appetite and abolition of carbohydrate craving. There was no mental grogginess induced by this formulation.
  • This example illustrates the use tyrosine and tryptophan of this invention together for appetite suppression, decreased carbohydrate craving and weight loss.
  • the 53 year old male took 2 capsules of the formulation of daily at 10:00 am, 2 capsules of the formulation of Example 2 at 4:00 p.m. and 2 capsules of the formulation of Example 3 at 5:00 p.m..
  • This regimen was continued for 10 days.
  • both of the formulations reduced appetite for 2 hours after each ingestion.
  • Carbohydrate craving was reduced for 24 hours after ingestion of the tryptophan formulation.
  • the third day there appeared to be an enhanced effect in that the duration of action of the combined doses were prolonged.
  • By the fifth day there was complete suppression of carbohydrate craving that lasted throughout the 10 day period.
  • This example illustrates the use of tyrosine and tryptophan formulations of the invention together in an open label study of 5 subjects including 3 males and 2 females. Each subject took the tyrosine capsule of Example 2 at 10 AM and a typtophan capsule of Example 3 at 3:30 PM. All 5 subjects reported a decrease in hunger after either dose. All 5 Patients experienced a reduction of carbohydrate craving after the tryptophan capsule.
  • Example 7 This example illustrates the use of tyrosine and tryptophan formulations in a randomized double blind placebo controlled trial in 30 subjects. All 30 subjects underwent a 10 hour fast following which they completed a questionnaire to assess hunger on a 5 point scale and carbohydrate craving also measured on a 5 point scale. The subjerts then ingested 2 of the capsules of Example 2 or placebo capsules at 10:00 a.m., followed by a questionnaire at 11:00 a.m.. The subjects again took the Example 2 capsule or placebo at 4:00 p.m. and the Example 3 capsule or placebo at 5:00 p.m. They completed questionnaires at 4:00, 5:00, 6:00 p.m. and at 10:00 a.m. the next morning.
  • a formulation of histidine and cocoa may be prepared by blending these two ingredients in powder form in a proportion of 3 parts histidine and 50 parts cocoa by weight. This product is then portioned into gelatin capsules so that each contains 30 mg. of histidine and 500 mg. cocoa. A one capsule dose of this formulation is best administered on an empty stomach, at least one or two hours after eating.
  • the blended powder may be prepared in the form of a chewable wafer sized to contain the same dose, by combining with the powder wheat bran, apple pectin and a sweetener.
  • a formulation of histidine and caffeine may be prepared in the same manner as described in example 8 by blending in powder form histidine and caffeine in a proportion of 3 parts histidine and 10 parts caffeine by weight. Single dose capsules are then filled with this blend in an amount to each contain 30 mg. histidine and 100 mg. caffeine. This formulation is administered as in example 8.
  • a formulation of tryptophan and histidine may be prepared by blending these two ingredients in powder form in a proportion of 5 parts tryptophan and 3 parts histidine. This produd is then portioned into gelatin capsules so that each contains 50 mg. of tryptophan 30 mg. histidine and the capsules are administered as in Example 8.
  • a formulation as in Example 10 that contains caffeine in addition to tryptophan and histidine may prepared by blending in powder form 10 parts of caffeine with 5 parts tryptophan and 3 parts histidine. Gelatin capsules are filled with the powder blend so that each gelatin capsule contain 50 mg. of tryptophan 30 mg. histidine and 100 mg. of caffeine. This formulation is administered as in example 8.
  • Example 12
  • a formulation of tyrosine and histidine may be prepared by blending these two ingredients in powder form in a proportion of 50 parts tyrosine and 3 parts histidine. This product is then portioned into gelatin capsules so that each contains 500 mg. of tyrosine 30 mg. histidine and the capsules are administered as in Example 8.
  • a formulation as in Example 12 that contains cocoa in addition to tyrosine and histidine may prepared by blending in powder form 50 parts of cocoa with 50 parts tyrosine and 3 parts histidine. Gelatin capsules are filled with the powder blend so that each gelatin capsule contain 500 mg. of tyrosine 30 mg. histidine and 500 mg. of cocoa. This formulation is administered as in example 8.
  • a formulation of histidine with tryptophan in the form of enzyme hydrolyzed protein may be prepared as follows. Enzyme hydrolyzed milk protein (casein) in dry powder form containing approximately 18 mg. tryptophan per gram is blended with histidine in powder form in a proportion of 200 parts hydrolyzed protein and 3 parts histidine. This product is then portioned into gelatin capsules so that a single dose of 30 mg. histidine and 2 gm. of hydrolyzed milk protein, which provides approximately 32 mg. of tryptophan, is contained in three capsules. The capsules are administered as in Example 8.
  • Example 15 A formulation as in Example 14 that contains cocoa in addition to hydrolyzed milk protein and histidine may prepared by blending in powder form 50 parts of cocoa with 200 parts of the hydrolyzed milk protein and 3 parts histidine. Gelatin capsules are filled with the powder blend so that three capsules together contain a single dose of 30 mg. histidine, 2 gm. of hydrolyzed milk protein, which provides approximately 32 mg. of tryptophan, and 500 mg. of cocoa. This formulation is administered as in example 8.
  • examples 16 through 18 illustrate the pradice of the invention utilizing unhydrolyzed protein, together with a proteolytic enzyme, as the source of the neurotransmitter precursor tryptophan, both with and without concomitant application of a xanthine and /or histidine as an additional neurotransmitter precursor.
  • This example illustrates the administration of tryptophan in accordance with this invention by giving to the subject orally unhydrolyzed protein together with a proteolytic enzyme which will hydrolyze the protein when it enters the gastrointestinal tract to release the tryptophan.
  • a proteolytic enzyme which will hydrolyze the protein when it enters the gastrointestinal tract to release the tryptophan.
  • 10 grams of whey powder and approximately 40 mg. of papain powder were administered to a subject orally, on an empty stomach.
  • typtophan was released in the G.I. tract in an amount to induce appetite suppression, without the administration of xanthine.
  • the subject experienced very pronounced grogginess that lasted for several hours.
  • a formulation of cocoa with tryptophan in the form of unhydrolyzed protein together with a proteolytic enzyme to hydrolyze the protein in the G. I. tract may be prepared as follows. Whey in dry powder is blended with papain and cocoa in powder form in a proportion of 200 parts by weight of hydrolyzed protein, 4 parts papain and 50 parts cocoa. This product is then portioned into gelatin capsules so that each contains 500 mg. cocoa and 2 gm. of whey and 40 mg. papain. Hydrolysis of the whey in the gastrointestinal tract provides a dose of approximately 50 mg. of tryptophan. The capsules are administered as in Example 8.
  • a formulation is prepared and administered as in Example 17 but with the addition thereto of 3 parts histidine, thus additionally providing 30 mg. of histidine per capsule dosage.
  • the synergistic combinations of the invention allow reduced doses of the individual components to be used to achieve the desired effects and particularly of the neurotransmitter precursors.
  • the reduced doses decrease the side effects caused by the large doses heretofore necessary to achieve the desired effects.
  • Our invention allows appetite suppression and reduction of carbohydrate craving to be achieved at doses levels which are considered safe by regulatory authorities. Previous attempts to use certain of the components in isolation were either ineffective or required dosages which caused side effects.
  • the decreased dose of tryptophan for example, allows reduction of carbohydrate craving without causing feelings of grogginess or safety concerns associated with higher doses.
  • the reduced dose of tyrosine allows appetite suppression without the agitation and anxiety induced by amphetamines.
  • the reduced dose of histidine reduces or eliminates potential side effects of histamine.

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Abstract

La présente invention concerne un procédé et une composition permettant de diminuer l'appétit et l'envie de glucides à l'aide de précurseurs des neurotransmetteurs sérotonine, dopamine, noradrénaline et histamine, parmi lesquels les précurseurs tryptophane, phénylalanine, tyrosine et histidine. Les précurseurs sont combinés entre eux et avec des xanthines afin de produire un effet synergique qui permet de réduire avantageusement les doses de précurseurs. L'administration simultanée d'histidine et de tryptophane, de phénylalanine ou de tyrosine a un effet de potentialisation sur la suppression de l'appétit. Les xanthines, comprenant la théobromine, la caféine et le cacao, agissent comme agents de potentialisation des précurseurs, individuellement et dans des combinaisons de précurseurs. On utilise des formulations séparées de tyrosine et/ou phénylalanine avec des xanthines en même temps qu'une formulation de tryptophane avec des xanthines, chacune étant administrée séparément à des intervalles d'au moins 20 minutes. Dans ces combinaisons, on utilise une protéine hydrolysée comme source naturelle de tryptophane, ainsi qu'un glucide produisant de l'insuline afin d'éliminer de la circulation sanguine les acides aminés qui pourraient sinon entrer en compétition avec le tryptophane pour traverser la barrière hémato-encéphalique. Selon une variante, une protéine non hydrolysée peut être administrée en même temps qu'une enzyme protéolytique afin de produire du tryptophane dans le tube digestif.
EP97933498A 1996-07-17 1997-07-16 Coupe-faim Withdrawn EP0912181A1 (fr)

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US68353596A 1996-07-17 1996-07-17
US683535 1996-07-17
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Families Citing this family (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ509198A (en) 1998-06-26 2002-11-26 Elaine A Treatment for multiple sclerosis using a histamine H2 agonist in combination with a phosphodiesterase inhibitor
US7232830B2 (en) 1998-06-26 2007-06-19 Elaine A Delack Method for treatment of neurodegenerative diseases and effects of aging
US6485710B2 (en) * 2000-12-27 2002-11-26 Arthur Zuckerman Appetite suppressant toothpaste
US6610277B2 (en) * 2000-12-27 2003-08-26 Arthur Zuckerman Appetite suppressant toothpaste
US7048941B2 (en) 2001-03-30 2006-05-23 New World Enterprizes, Inc. Chocolate composition as delivery system for nutrients and medications
ATE349918T1 (de) 2002-07-01 2007-01-15 Unilever Nv Zusammensetzung, die ein sättigungsgefühl hervorruft
US7585523B2 (en) * 2002-08-27 2009-09-08 Targeted Medical Pharma Composition and method to augment and sustain neurotransmitter production
US7674482B2 (en) * 2002-08-27 2010-03-09 Targeted Medical Pharma Inc. Method and compositions for potentiating pharmaceuticals with amino acid based medical foods
EP1534314B1 (fr) * 2002-09-04 2014-10-22 DSM IP Assets B.V. Composition nutritionnelle et thérapeutique d'un agent sensibilisant à l'insuline et d'une fraction peptidique
EP1540815B1 (fr) 2002-09-06 2006-12-27 Telefonaktiebolaget LM Ericsson (publ) Amplificateur de puissance composite
US7115285B2 (en) * 2003-03-14 2006-10-03 Eurark, Llc Composition and method for appetite and craving suppression and mood enhancement
WO2005117933A1 (fr) * 2004-05-27 2005-12-15 Campina Nederland Holding B.V. Utilisation d'hydrolysats proteiques pour preparer un medicament destine a prevenir et/ou traiter un etat pathologique induit par dpp-iv
WO2006053217A1 (fr) * 2004-11-12 2006-05-18 Mccleary, Edward Larry Composition et procede de perte de poids
DK1831361T3 (da) 2004-12-23 2012-05-14 Campina Nederland Holding Bv Proteinhydrolysat beriget med peptider, som inhiberer DPP-IV, og deres anvendelse
GB0520917D0 (en) * 2005-10-14 2005-11-23 Zumbe Albert Chocolate based appetite suppressant
US8431531B2 (en) 2005-11-30 2013-04-30 Campina Nederland Holding B.V. Methods for stimulating glucagon-like peptide-1(GLP-1) secretion and treatments comprising same
JP2008094787A (ja) * 2006-10-13 2008-04-24 Paq Kk 落花生処理物を用いた交感神経興奮剤
GB0719545D0 (en) 2007-10-08 2007-11-14 Barry Callebaut Ag Novel use of cocoa extract
GB0719542D0 (en) 2007-10-08 2007-11-14 Barry Callebaut Ag Use of cocoa extract
GB0719544D0 (en) 2007-10-08 2007-11-14 Barry Callebaut Ag Cocoa extract and use thereof
ES2325435B1 (es) * 2008-01-02 2010-06-17 Armando Jose Yañez Soler Composicion a base de cacao y espirulina.
US20090214682A1 (en) * 2008-02-22 2009-08-27 Heuer Marvin A Composition and methods for weight loss in a subject
JP4691571B2 (ja) 2008-03-04 2011-06-01 株式会社マルハニチロ食品 摂食調節剤
JP4593639B2 (ja) 2008-03-04 2010-12-08 株式会社マルハニチロ食品 ペプチド含有摂食調節剤
CA2798911C (fr) 2010-05-19 2018-07-03 Unilever Plc Theobromine pour l'elevation de hdl-cholesterol
CN103153326B (zh) * 2010-10-05 2015-08-19 帝斯曼知识产权资产管理有限公司 含有色氨酸的肽
JP5886657B2 (ja) * 2012-02-29 2016-03-16 株式会社ファンケル 小麦フスマ由来の粉末を含有する製剤
US20140129484A1 (en) * 2012-11-02 2014-05-08 Dsm Ip Assets B.V. Method of marketing protein hydrolysate for high energy sensation
US9345727B2 (en) 2013-03-15 2016-05-24 Mead Johnson Nutrition Company Nutritional compositions containing a peptide component and uses thereof
US9345741B2 (en) 2013-03-15 2016-05-24 Mead Johnson Nutrition Company Nutritional composition containing a peptide component with adiponectin simulating properties and uses thereof
US9289461B2 (en) 2013-03-15 2016-03-22 Mead Johnson Nutrition Company Reducing the risk of autoimmune disease
US9138455B2 (en) 2013-03-15 2015-09-22 Mead Johnson Nutrition Company Activating adiponectin by casein hydrolysate
US9352020B2 (en) 2013-03-15 2016-05-31 Mead Johnson Nutrition Company Reducing proinflammatory response
US8889633B2 (en) 2013-03-15 2014-11-18 Mead Johnson Nutrition Company Nutritional compositions containing a peptide component with anti-inflammatory properties and uses thereof

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3867539A (en) * 1973-04-27 1975-02-18 Us Health Method of producing anorexia as a treatment for obesity
FI772858A (fi) * 1977-06-03 1978-12-04 Pharmaceutical Export Promotio Avmagningsmedel och foerfarande foer framstaellning daerav
US4210637A (en) * 1978-07-31 1980-07-01 Massachusetts Institute Of Technology Composition and method for suppressing appetite for calories as carbohydrates
US4897380A (en) * 1985-08-30 1990-01-30 Pollack Robert L Method and composition for relieving dietary-related disorders
US5019594A (en) * 1989-11-28 1991-05-28 Interneuron Pharmaceuticals, Inc. Method for decreasing appetite
FR2657013B1 (fr) * 1990-01-18 1992-05-15 Medgenix Group Sa Composition dietetique a base de polypeptides et acides amines.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9802165A1 *

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JP2000515139A (ja) 2000-11-14
AU3666497A (en) 1998-02-09

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