CA2260892A1 - Appetite suppression - Google Patents
Appetite suppression Download PDFInfo
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- CA2260892A1 CA2260892A1 CA002260892A CA2260892A CA2260892A1 CA 2260892 A1 CA2260892 A1 CA 2260892A1 CA 002260892 A CA002260892 A CA 002260892A CA 2260892 A CA2260892 A CA 2260892A CA 2260892 A1 CA2260892 A1 CA 2260892A1
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- tryptophan
- neurotransmitter
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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
- A61K31/40—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
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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
- A61K31/495—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
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- 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
Abstract
A method and composition for reducing appetite and carbohydrate craving using precursors for the neurotransmitters serotonin, dopamine, norepinephrine and histamine, which include the precursors tryptophan, phenylalanine, tyrosine and histidine. The precursors are combined together and with xanthines for synergistic effect permitting advantageously lower doses of the precursors. Concomitant administration of histidine with any of tryptophan, phenylalanine and tyrosine produces a potentiated effect in appetite suppression. Xanthines, including theobromine, caffeine and cocoa, act as potentiators of the precursors, individually and in combinations of precursors. Separate formulations with xanthines of tyrosine and/or phenylalanine are used conjointly with a formulation of tryptophan with xanthines, each administered separately at intervals of at least 20 minutes. Hydrolyzed protein is utilized as a natural tryptophan source for the combinations, together with an insulin producing carbohydrate to remove from the blood stream other amino acids competing for transport across the blood-brain barrier. Alternatively, unhydrolyzed protein may be administered along with a proteolytic enzyme to produce tryptophan in the gastrointestinal tract.
Description
W O 98/02165 PCT~US97/12408 Description A~L 111~ SUPPRESSION
Technical Field This invention relates generally to dietary supplements for 10 reducing appetite and decreasing carbohydrate craving. There 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 15 reduction programs, artificial fats, and pharmaceutical agents to alter both appetite and carbohydrate craving. Despite the desirability of reducing weight and the proliferation of products to aide in weight reduction, the weight of the population continues to rise. It is now estimated that more than 40% of the population is significantly 20 overweight. At any given time approximately 25% of the population is on a diet, leading to undesirable "yo-yo" effects from repeated dieting.
The failure of weight reduction products to achieve and to sustain weight loss can be attributed to several factors. These include the relative ineffe-liveness of the individual approaches, side effects of 25 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.
30 B~cl~round Art One major component of a successful weight loss program is appetite sul,~ression. Appetite ~upp;ession has been achieved with administration of amphetamines, antidepressants, both soluble and 35 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 a~pelile. Dexedrine and related agents including ephedrine and pseudoephedrine reduce a~elile. These agents either produce agitation, addiction or nerve ~l~mAge (dexedrine), or produce rapid attenuation of effect (ephedrine or 5 pseudoephedrine). Phentermine, an amphetamine-like molecule, is approved for use as an appetite su~ essant, but must be ~lmini~tered by prescription. This results in increased costs associated with physician visits. Additionally, phentermine can only be used for short periods when a~minictered ~y itself. It is believed that the amphetamines, 10 including phentermine, su~press 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.
One approach, introduced ~y Wurtman and associates in 1978, was to use precursors of brain serotonin to reduce appetite for carbohydrate. Serotonin within the hypothalamic region of the brain is known to reduce craving for carbohydrates. In Wurtman, et al U.S.
Patent No. 4,210,637, a composition and method for selectively sllpl~.essing appetite for carbohydrates is described. This method includes the a~1mini~tration 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 cc~ ele with tryptophan ~or transport across the blood-brain barrier. This carbohydrate-initiated insulin effect on circulating amino acids m~imi7.es 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. When Wurtman applied tryptophan administration to humans in an amount of 2,300 mg per day, there was no consistent effect on ap~elite slly~ression. Moreover, the regulatory agency in the United States, the Food and Drug A~lmini~tration (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 ~ot~.,lially cause muscle damage. Accordingly, tryptophan is not being used alone, or administered with a carbohydrate, as an a~pelite aide.
Wurtman, et al in U.S. Patent No. 4,309,445 described a co~ osilion and method using d-fenfluramine to block intermittent 5 carbohydrate cravings. This method disclosed that d-fenfluramine and the related isomer l-fenfluramine selectively reduces carbohydrate ~avillg. Wurtman, et al, in U.S. Patent 4,687,763 disclosed that Iryptophan can increase brain serotonin levels when given with melatonin. In this patent Wurtman, et al, disclosed that oral 10 administration of tryptophan can increase brain serotonin and that increased brain serotonin leads to reduced carbohydrate craving. The amount of tryptophan used by Wurtman, et al, were consistently been between 2 and 100 mg/kg. of body weight per dose. These amounts are significantly above the current FDA safety guidelines of less than 1.6 15 mg/kg per day of supplemental tryptophan, particularly if the tryptophan comes from bacterial synthesized sources.
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 oc~ lh~g protein may be used.
20 Naturally occurring protein contains approximately 1.6 % tryptophan.
The amount of l~ tophan 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 25 present in protein. In a recent Fr)A publication, it was concluded that there was insufficient evidence that tryptophan reduces appetite in doses considered safe. There is no known prior art suggesling the use of predigested protein as a source of tryptophan for appetite su~ ession.
Tyrosine is a ~rec.ll~or of brain dopamine. Amphetamines 30 stimulate the release of dopamine. Brain dopamine is associated with the appetite sup~)resshlg 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.
35 4,673,689 disclose that lyrosille can be used to potentiate the sympathomimetic agents such as ephedrine or pseudoephedrine.
However, this patent contains no disclosure or suggestion of any CA 02260892 l999-0l-l4 usefulness or ~ynergism~for any purpose for combining tyrosine with any other agents active in the central nervous ~ysle.n.
Histidine is a precursor of histamine in the brain. It has been rel)olled that histamine and its precursor histidine will decrease the 5 food intake of experimental ~nimAl~ (rats) when administered ~y intrape~ilo~leal injection ("Manipulation of Central Nervous System Histarnine, Histaminergic Receplors (H1) Affects Food Intake in Rats,"
Mercer et al., J. of Nutrition, 1994, Vol. 24, pp 1029-1036) ) However, the e~e-:liveness of either histamine or its precursor histidine for 10 supp.ession 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 15 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 neurotransmitter precursors such as tryptophan or tyrosine. Phenylethylamines are also known to stimulate the release of 2Q 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 25 defined. Most comm~n knowledge attributes the appeal of chccolate to its taste, not to neurotransll-iller affects.
In 1992, Wientraub observed that phenle~.ine and fenfluramine when used together induced long term weight loss, reduced appetite and reduced carbohydrate craving. Fenfluramine is the mixture of the 30 dextro and levo forms of fenn-lramille. The results of using phentelll.inE and fenfluramine in combination was attributed to their separate effects on serotonin and dopamine. Using this combination of prescription drugs, weight loss could be sustained for months to years.
Accordingly, there has been a substantial increase in the use of the 35 phenterrnine-fenauramine approach to weight loss despite the l;ack of reuglatory approval of the the combination. Many regulatory agencies limit the use of either agent to short periods ranging from 7 days to 1 month. In addition, the use of fenlluf~ll,inc has been associated with the side effect of pulmonary l.~p~.l~llsion and heart valve disease in rare instances. The use of d-fenfluramine induces grogginess in many subjects and is expe. sive, often costing US$5.00 per day for the drug.
5 This cost is in addition to multiple visits to physicians for monitoring of treatment which may last many months or years. Also, 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 phellt~ ine-fenfluramine therapies that can be applied to 10 a large number of individuals without repetitive physician monitorin~.
Ideally, the components of such a program would be formulated from low cost ingredients which are not drug.
Disclosure of the Invention This invention has the object of achieving appetite SU~re5SiOn and reduced carbohydrate craving without large doses of fibers, amphetamines, antide~.ressants, or other prescription drugs. This invention also has the object of enabling use of readily available, low 20 cost, safe, plant-derived agents and to provide appetite ~ pression with such agents at reduced dosage to minimize the possibility of side effects.
This invention provides methods and compositions for su~ es~il,g appetite based upon the discovery that certain neurotransmitter precursors will act synergistically with each other and 25 with certain neur~transmitter potentiators in sup~ressing appetite and reducing carbohydrate craving. In particular, neurotransmitter precursors for the neurotransmitters serotonin, dopamine, norepinephrine and histamine, which contain an amine group and include tryptophan, phenyl~l~nine, tyrosine and histidine, are orally 30 administered in reduced doses concomitantly with one or more xanthines, and particularly caffeine and/or theobromine effectively to sulJ~ress appetite. When administered alone, these neurotransmitter precursors require unacceptably high doses in order to sullpress appetite.
In a further aspect of this invention histidine is a~lmini~tered 35 concommitantly with either tryptophan, phenylalanine or tyrosine with synergistic effect to su~ress a~~li~e, either with or without the concomitant administration of a xanthine. Tryptophan may be ., adminstered conjointly with phenylalanine or tyrosine with beneficial effect, during the same day but with administration of one se~erated by at least 20 rninutes of the other, to avoid competition between them for entry across the blood-brain barrier.
In another feature of the invention the neurotransmitter precursor and potentiators are a~lmini.stered in accordance with this invention in naturally occurring forms long considered safe for ingestion as a food stuff The neurotransmitter precursor tryptophan may be dmini~tered in the form of natural proteins which have been 10 hydrolyzed to release amino acid residues including tryptophan. The predigested protein allows delivery of free amino acids 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 15 secretion to clear from the bloodstream competing amino acids 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 acids allow~
sufficient l~ lo~han to be delivered to the brain so that the desired 20 effects are achieved In a related embodiment, rather than administering prehydrolyzed protein, 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 25 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 30 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, capulets and other forms individualized for administering the 35 ap~ropl;ate single dose quantities of the selected constituents. The amount of tryptophan in the dosage forms is from about 2.5 to 100 milli~rams, the amount of tyrosine is from about 10 to 700 milligrams, the amount of histidine ~from about 1 to 500 milli~rams. Where they present in the dosage forms, the xanthine theobromine is in the range of from about 1 mg. to 2 gm. or higher. Where cocoa is employed as the xanthine source, it may be present in the single dosage form in the 5 amount of about 1 mg. to 2 grams or higher. Where, 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 ~oteil, is selected to provide therein an amount of lr~/~tol~han of between 2.5 to 100 milligrams.
These combinations of agents, due to their surprising synergism, allows the dose of the individual neurotransmitter precursors to be reduced, thus reduce side effects and to reduce component doses to levels generally considered safe by regulatory agencies, such as the FDA.
They additional enable the use of naturally oc~ r~ g ~roleh~ and plant-15 derived subshnces instead of drugs.
Under FDA regulations supplemental tryptophan cannot be synthesized by man-made processes and thus they must be derived from naturally occurring protein, either animal or vegetable. The ~DA
further stipulates that the dose of added tryptophan cannot exceed 100 20 mg per day, or 1.43 mg/kg per day. The ~rled 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. These doses of tryptophan, which comply with the ~DA limitations, would be 25 ineffective in the absence of the xanthines Best Mode of Carlying Out The Invention The following description illustrates the manner in which the principles of the invention are applied but is not to be construed as limiting the scope of the invention.
Serotonin, dopamine, norepinephrine and histamine form a class of neurolransmitters that are active in the CNS to affect appetite, either stimulating the release of corticolro~ releasing factor (CRF), which su~ esses appetite, or su~les~ g the release and/or activity of neuropeptide Y, which stimulates a~pelile. Serotonin, norepinephrine , WO 98tO2165 PCT/US97/12408 and histamine all stimulate the release of CRF. Dopamine suppresses neuropeptide Y. Histamine additionally promotes neuron firing.
The ~re~ ors for this class of neurotransll~iller~, all of which contain an amine group, include tryptophan for serotonin, 5 phenylalanine and tyrosine for both dopamine and nore~ e~l rine and histidine for histamine. In this invention, these ~re~ rsor~ are employed in combination with each other and in combination with xanthines to potentiate the effect on appetite supl,.ession by the respective neurotransmitters of this class.
The precursors are employed in this invention to enhance the synthesis of their respe~:live neurotranmitters and since serotonin, phenylAl~nine, tyrosine and histidine all enhance synthesis of neurotransmitters that stimulate release of CRF, these p~e~llr~ors all thereby indirectly stimulate release of CRF. Additionally, phenylalanine 15 and tyrosine indirectly s~lpplesses neuropeptide Y through enhancement of the synthesis of dopamine as well. Also, histidine promotes neuron firing thereby indirectly stimulating synthesis of nore~,i"ephrine, tyrosine and serotonin.
The ~re.:~lrsors may be employed in this invention in pure form, 20 e.g. exogenous material synthesized or derived from animal or vegehble ~lotein, particularly purified extracts isolated from the amino acid residues in enzyme hydrolyzed proteins. However, a source for the precursor tryptophan particularly useful in this invention, both because it is a natural food source and because of the regulatory restrictions, are 25 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 ~,aslrointestinal tract. Cornmercial preparations of predigested proteins, typically from milk-derived protein, such as casein or whey, are 30 available and may be administered separately or in co-.lyosilion with histidine and/or a xanthine.
Where the lr~tophan is to be administered in the form of a predigested protein or a protein to be enzyme hydrolyzed upon administration, it is i~ ollant in this invention to a-lmini.~ter the 35 protein concomitantly with a carbohydrate, and particularly sugar, dextrins, starch and the like, in order to cause release of insulin to CA 02260892 l999-0l-l4 remove from the blood gtream the other amino acids competing with tryptophan for transport across the blood-brain barrier.
Where unhydrolyzed protein is administered together with a proteolytic enzyme, soluble proteins, such as albumin, are plef~l.ed, for 5 ease of breakdown. Whey, casein and soy are convenient protein sources. Proteolytic enzymes may include papain, chymopapain, bromelin, ll~sin and pepsin.
Xanthines constitute a class of non-selective adenosine antagonists and they include theobromine, caffeine and theophylline.
10 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, 15 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 citrated caffeine, theophylline ethylene~3iamine, theophylline sodium acetate, sodium glycinate, the choline salt, the theophylline derivatives 20 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 25 biogenic amines, and particularly phenylethylamine, in a form that is normally easily ingested and tolerated ~y 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 30 preliminary formulations with neurotransmitter precursors to improve flavor and because its mood enhancing effects have appealed to people for centuries. An unexpected result was that the cocoa powder significantly potentiated the effects of the neurotransmitter precursors.
This potentiating effect was determined ~y us to be produced ~y the 35 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 extract form, alone or, more inconveniently, in composition with the 5 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 10 potentiation may be achieved by administering the neurotransmitter yl e~:ulsor 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 15 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 l"~pl~.phan in this invention with advantage but as they can inhibit passage of tryptophan across the blood-brain barrier, they are 20 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 25 tryptophan take-up is avoided and enhanced effect of the precursors is attained. Additionally, neurotransmitter balance is fostered ~sr decreasing the total dose over time of any single neurotransmitter.
While it is not intended to be bound by any theory, the unexpected synergism found between these precursors may be at least 30 partially explained ~y the different mechanisms mediated by their respective neurotransmiters in stimulating release of CRF and/or sup~ressing neuropeptide Y.
The dosage of each neurotransmitter precursor is in an amount sufficient to enhance synthesis of its respective neurotransmitter(s), to 35 stimulate the release of CRF and thereby to suppress appetite i n combined administration with the other neurotransmitter and or xanthines employed. The synergistic effect of these combinations will permit a~l,elile s-lpp~ession at lower dosage levels of each of the neurol~ansmitter 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 5 groggilless.
~ For ll~tophan the desired single dose range is between 2.5 and100 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. However, doses up to 700 mg. or even to 1 gram or higher, 10 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 su~ress appetite if used alone. Histidine is desirably ad.~ ustered 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, 15 if tolerated by the subject. The dosage range for each precursor applies to combined a-lmini~tration of the precursor with another precursor, with a xanthine, or with both.
Where hydrolyzed proteins or proteins to be hydrolyzed in the gastrointestinal tract are employed as the source of tryptophan, the 20 proteins should be in an amount to provide the tryptophan dosage levels of this invention as di~cll~se~ 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 25 dosage le~ els of from about one half gram to 5 g~ams.
Xanthines are employed in this invention in dosage ranges a~l,royliate to promote release of neurotransmitters and to avoid undesired side effects. Theobromine and theophylline may each be a~minictered in a dosage of from 1 mg. to 2 grams or higher. Caffeine 30 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 a~ropriate dose of xanthines, with a pl~efe.led dose being 400 to 800 mg. Infusions such as tea or coffee may be employed, with one to two cups providing an appropriate dose~
35 Somewhat higher doses of these xanthines may be employed with some subjects without undue discomfort.
The neurotransmitter ~.~c.llaors and neurotransmitter potentiators of this invention may be administered orally separately, or, for assurance of a~,prop,;ate proportions and dosages as well as for convenience, they are a-lminictered together in the same composition.
5 The dosage forms for a~1ministration s~arately or in the same composition may be any of the conventional forms, including capsules, capulets, 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 10 caffeine. Hydrolyzed protein sources of tryptophan may be taken sel,alately in tablet form, utilizing commercially available predigested protein tablets, such as LLP Concentrated Predigested Protein sold ~y Twin Laboratories, Inc., Ronkonkoma, New York containing aproximately 18 mg. of lr~y~to~han per 1 gram tablet.
The compositions in the form of powders or liquids may be pA~ged in multiple dosage quantities with instructions to the user to extract thereLul-, for ingestion a~fop,iate individual dosage amounts, e.g. a teaspoonf-ll. However, the compositions are desirably prepared in discrete units, e.g. capsules, wafers etc., which each contain the 20 ap~roy,;ate dosage amounts of neurotransmitter precursors and/or neurotlans-niller potentiators for a single dose as discussed above.
The compositions may include the usual carriers, fillers, excipients and adjuvants. Advantageously, they include soluble fiber, insoluble fiber, neurotransmitter precursors and the potentiating agents 25 contained in coco~ powder. The inclusion of dietary fibers produces early satiety from volume distention and causes further appetite s~ ;ession by trigge.lllg the release of CCK. The a~l~etite s~ essing actions of the dietary fiber component further enhance the invention's neurotransmitter-related effects. They additionally may contain folic 30 acid and vitamin B6 to enhance conversion of tryptophan to serotonin, tyrosine to dopamine and histidine to hist~mine, respeelively.
The plefe,led amount of hlic acid is 200 mcg per dose with a range of 1- 800 mcg/dose. The ~ref~led amount of vitamin B6 is 10 mg with a range of 1- 50 mg/dose. Representative doses of soluble fibers are 35 100 mg to 1000 mg per dose. The best soluble fibers for producing appetite su~ression are pectin fibers from apple or citrus. fruits.
Representative doses of insoluble fibers are 100 mg to 1000 mg per dose.
A ~efelled 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. These concentration of S insoluble fibers would be inerfe. live 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 premi~e~l and heated to dryness will reduce the 10 effectiveness of the formulations.
It is important in carrying out the invention to administer the dosages when the subject has an empty stomach, typically at least an hour after the subject has eaten in order to avoid undesirably slow uptake across the blood-brain barrier, due to competition with other 15 amino acids from the ingested food. Administration may be repealed as desired, at intervals throughout the day.
The effects of the formations of this invention normally should be sufficiently potent that their effects can be experienced after the first dose. Their effectiveness can be detected by a given individual using a 20 questionnaire to assess hunger and carbohydrate craving. This is in contradistinction to other appetite su~l~;essants that require multiple doses or indirect methods such as weight loss to assess their effectiveness.
The various embodiments of the invention utili7.ing tryptophan, 25 phenylalanine or tyr.osine as the sole neurotransmitter precursor or combined with histidine, may be used alone. Advantageously, however, these tryptophan and phenylalanine or tyrosine formulations are given to a subject, but at different times, each to produce appetite ression, but by different modalities. The phenylalanine or 30 tyrosine-containing formulations are designed to potentiate the production and release of dopamine. A~elite su~iession 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 35 pseudoephedrine. Tryptophan-containing formulations are designed to reduce appetite for 2~ hours and are designed to potentiate the production and release of serotonin, and of histamine, if histidine is included. Aypetile sll~yression and reduced carbohydrate craving is achieved by the resulting activity of serotonin. The tryptophan-containing formulations emulate the effects of fenfluramine, d-fenfluramine and fluoxetine and are typically designed to reduce 5 al,l,etile 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 y:efe..ed that each to be taken on an empty 10 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 ~.e~llr~ors for entry across the blood brain barrier. Typically, the phenylalanine or tyrosine formulation is given before lunch to 15 suyyiess ayyelile 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. Alternately, The phenylalanine or 20 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 effects of the prescription drugs phentermine, fenfluramine, and d-fenfluramine.
If an individual undergoes a fast to induce hunger, a~lminigtration of tyrosine results in appetite suppression which begins 15 to 30 minutes after ingestion and continues for 2-4 hours. If hunger reayyear~ re-ingestion of the formulation results in suypression of hunger beginning 1~30 minutes after ingestion and continuing for 2-4 hours. Repeated ~lmini~tration of the tyrosine formulation results in reyelilive sup~ression of appelile.
Administration of the llyytoyhan-containing formulation after a self-induced fast results in appetite suyy~ession which begins 20-40 minutes after ingestion and continues for 2~ hours. A reduction of carbohydrate craving begins approximately 30 minutes after ingestion of the lr~yptoyhan formulation and continues for 18-36 hours. If the l~yytoyhan formulation is administered 30-90 minutes before the CA 02260892 1999-0l-l4 WO 98/02165 PCTrUS97/12408 topl-an, the onset of the lr~ypto~han formulation effects is reduced to 15-30 minutes.
Following Examples 1 through 7 illustrate formulations with tyrosine asthe sole neurollansmitter precursor and formulations with 5 tryptophan as the sole neurotransmitter precursor and use thereof independently and together. These examples also illustrate the use of various xanthines with the ~fe~ r~ors and the use of hydrolyzed proteill as the source of tryptophan.
Example 1 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 15 mgt and folic acid 100 mcg. 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 acid 100 mcg. Another useful tryptophan-containing formulation per dose is soluble fiber 175 mg, insoluble fiber 175 mg, predigested protein powder 2,000 mg, cocoa 20 250 mg, sugar 250 mg, vitamin B6 5 mg, and folic acid 100 mcg.. A
lJreferled dosage of the combination is 2 capsules of tyrosine formulation before lunch, 2 capsules of the lyrosille formulation at 4:00 p.m., and 2 capsules of either of the llyptophan formulations 30 minutes before dinner. Another dosage schedule includes the tyrosine 25 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.
Example 2 This example illustrates the use of tyrosine as the sole neurotransmitter ~recllr~or~ together with xanthines, for appetite su~,ression. A 53 year old male underwent a 10 hour fast to induce hunger. Two capsules of a Iyrosi~le formulation were given each 35 capsule containing soluble fiber in the form of apple pectin 175 mg, insoluble fiber in the form of bran fiber, tyrosine 295 mg, cocoa powder 200 mg, folic acid 100 mcg 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.
Example 3 This example illustrate the use of tryptophan as the sole neurotransmitter ~re~ rsor, together with xanthines~ for appetite 10 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 15 tryptophan, 250 mg of cocoa powder, 5 mg of vitamin B6, and 100 mcg of folic acid. The individual's hunger began to dissipate in 30 minutes and was completely tli~sipated in 60 minutes. The ingestion of the formulation resulted in early satiety in the following meal. There was an abolition of carbohydrate craving which lasted for 24 hours. The 20 onset of the appetite suppression following ingestion of the formulation was associated with mental grogginess that lasted for approximately 15 minutes.
Example 4 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 hst in order to induce hunger. She then 30 il.gesled 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 mcg of folic acid. She experienced a reduction of appetite and abolition of 35 carbohydrate craving. There was no mental grogginess induced ~y this formulation.
Example 5 This example illustrates the use tyrosine and tryptophan of this 5 invention together for ay~elite su~pression, 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. During the 10 day 10 period, both of the formulations reduced appetite for 24 hours after each ingestion. Carbohydrate craving was reduced for 24 hours after ingestion of the lr~tGlJhan formulation. By the third day there apl,eared to be an enhanced effect in that the duration of action of the combined doses were prolonged. By the fifth day there was complete 15 su~.ession of carbohydrate craving that lasted throughout the 10 day period. There were no observed side effect except for the 15 minutes of g,ogginess induced by the tryptophan formulation on days 1 and 2. For the first 2 days, the onset of the appetite supplession following ingestion of the tryptophan formulation was ~soci~ted with mental grogginess 20 that lasted for approximately 15 minutes. By the third day the grogginess effect was lost. The subject initially weighed 159 pounds and by the 10th day, his weight was reduced to 150 pounds.
ExO.mple 6 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 30 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 kyptopLan capsule.
Example 7 WO 98/02165 PCT/~S97/12408 This example illustrates the use of tyrosine and Iry~tolJhan formulations in a randomized double blind placebo controlled trial in 30 subjects. All 30 subjects underwent a 10 hour fast following which they complcted a questionnaire to assess hunger on a 5 point scale and 5 carbohydrate craving also measured on a 5 point scale. The subjects then il,e,esled 2 of the capsules of F.~mple 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 10 p.m. and at 10:00 a.m. the next morning. In the 15 placebo subjects, ingestion of the placebo was followed by an increase in the hunger index from 2.2 to 2.9 after the first dose of tyrosine, p<0.03. In the 15 subjects randomized to receive lylosille, the hunger index fell from 3.1 to 2.4, p<0.03. Comparison of the active to placebo group showed a 15 reduction of the hunger index with a high degree of significance, p<O~Olo The carbohydrate craving index was also significantly reduced by the tophan dose, p<.01. In the active group, 85% of the subjects either reduced their feeling of hunger or cravings for carbohydrate while only 45% of the placebo group experienced either a reduction of hunger or 20 cravings for carbohydrate, p<0.03.
Following examples 8 and 9 illustrate the formulation and use of histidine with xanthines, with histidine as the only neurotransmitter 25 precursor.
Example 8 A formulation of histidine and cocoa may be ~re~aled ~y 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. Alternatively, the blended powder may be prepared in the form WO 98/02165 PCT/US97tl2408 of a chewable wafer sized~ to contain the same dose, by combining with the powder wheat bran, apple pectin and a sweetener.
5F.YAmple 9 A formulation of histidine and caffeine may be ~;el,ared in the same manner as des~it~e~l in example 8 by blending in powder form histidine and caffeine in a proportion of 3 parts histidine and 10 parts 10 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.
15Following examples 10 through 15 illustrate practice of the invention utilizing the combination of histidine with tyrosine and of histidine with try~tol~han as neurotransmitter ~;e..lrsors, both with and without concomitant application of xanthines.
Example 10 A formulation of tryptophan and histidine may be prepared by blending these two ingredients in powder form in a proportion of 5 25 parts l~to~han and 3 parts histidine. This prcduct is then portioned into gelatin capsules so that each contains 50 mg. of tryptophan 30 mg.
histidine and the capsules are ad.,~il isteled as in Example 8.
30Example 11 A formulation as in Example 10 that contains caffeine in addition to l.y~to~han and histidine may ~re~ared by blending in powder form 10 parts of caffeine with 5 parts tr~pto~han and 3 parts histidine. Gelatin 35 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 lyrosine and histidine may be prepared ~y blending these two ingredients in powder form in a proportion of 50 parts Iy~osil~e 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 F.y~mple 8.
Example 13 A formulation as in Example 12 that contains cocoa in addition to tyrosine and histidine may ~repa~d 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.
Example 14 A formulation of histidine with I~Iol,han 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 3û 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 iri Example 14 that contains cocoa in addition to hydrolyzed milk ~lotein and histidine may p~e~ared ~y blending in powder form 50 parts of cocoa with 200 parts of the hydrolyzed milk plolei" and 3 parts histidine. Gelatin capsules are filled with the powder 5 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 a~minictered as in example 8.
Following examples 16 through 18 illustrate the practice 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 15 histidine as an additional neurollallsmitter precursor.
Example 16 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 ll~ptophan.
Specifically 10 grams of whey powder and approximately 40 mg.
of papain powder were administered to a subject orally, on an empty stomach. With this high dosage, typtophan was released in the G.I. tract in an amount to induce appetite su~ ession, without the administration of xanthine. However, the subject experienced very pronounced grogginess that lasted for several hours.
Later, to the same subject, between 1 and 2 grams of whey powder, approximately 40 mg. of papain powder and 40 mg. of cocoa were administered, on an empty stomach. This formulation induced appetite su~pression in the subject and no grogginess was experienced.
This procedure provides an easy mode of a~lmini.stering tryptophan using natural food sources together with xanthine to produce appetite su~ ession without undue grogginess.
A~1minctration of this lr~ylJto~han source without xanthine, or a synergistic neuroliansmitter p~e.ursor, required such a high dosage level to acheive a~etile sup~ression that the side effects (grogginess) were unacce~table.
l~Y~mple 17 A formulation of cocoa with lr~pl~phan in the form of 10 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 p.oteil" 4 parts papain and 50 parts cocoa. This product is then portioned into gelatin capsules 15 so that each contains 500 mg. cocoa and 2 gm. of whey and 40 mg.
papain. Hydrolysis of the whey in the gaslloil~testinal tract provides a dose of approximately 50 mg. of tryptophan. The capsules are administered as in Example 8.
Example 18 A formulation is prepared and administered as in Example 17 but with the addition thereto of 3 parts histidine, thus additionally 25 providing 30 mg. of histidine per capsule dosage.
As can be seen from the foregoing, the synergistic combinations of the invention allow reduced doses of the individual components to 30 be used to achieve the desired effects and particularly of the neurotransmitter ~rec~ll,ors. The reduced doses decrease the side effects caused by the large doses heretofore necess~ry to achieve the desired effects. Our invention allows apl,elile su~ression and reduction of carbohydrate craving to be achieved at doses levels which 35 are considered safe by regulatory authorities. Previous alle..~ts 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 groggi~ess or safety concerns associated with higher doses. The reduced dose of tyrosine allows appetite suppression without the agitation and anxiety induced 5 ~y amphetamines. The reduced dose of histidine reduces or eliminates potential side effects of histamine.
It is further seen that the combinations of the invention enable the use of naturally occurring subslances thereby enhancing their regulatory approval and market acce~tance.
Although the description above contains many specificities, these should not be construed as limiting the scope of the invention but as merely providing illustrations of some of the presently ~referl~d embodiments of this invention. Various other embodiments and ramifications are possible within it's scope.
~L5
Technical Field This invention relates generally to dietary supplements for 10 reducing appetite and decreasing carbohydrate craving. There 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 15 reduction programs, artificial fats, and pharmaceutical agents to alter both appetite and carbohydrate craving. Despite the desirability of reducing weight and the proliferation of products to aide in weight reduction, the weight of the population continues to rise. It is now estimated that more than 40% of the population is significantly 20 overweight. At any given time approximately 25% of the population is on a diet, leading to undesirable "yo-yo" effects from repeated dieting.
The failure of weight reduction products to achieve and to sustain weight loss can be attributed to several factors. These include the relative ineffe-liveness of the individual approaches, side effects of 25 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.
30 B~cl~round Art One major component of a successful weight loss program is appetite sul,~ression. Appetite ~upp;ession has been achieved with administration of amphetamines, antidepressants, both soluble and 35 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 a~pelile. Dexedrine and related agents including ephedrine and pseudoephedrine reduce a~elile. These agents either produce agitation, addiction or nerve ~l~mAge (dexedrine), or produce rapid attenuation of effect (ephedrine or 5 pseudoephedrine). Phentermine, an amphetamine-like molecule, is approved for use as an appetite su~ essant, but must be ~lmini~tered by prescription. This results in increased costs associated with physician visits. Additionally, phentermine can only be used for short periods when a~minictered ~y itself. It is believed that the amphetamines, 10 including phentermine, su~press 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.
One approach, introduced ~y Wurtman and associates in 1978, was to use precursors of brain serotonin to reduce appetite for carbohydrate. Serotonin within the hypothalamic region of the brain is known to reduce craving for carbohydrates. In Wurtman, et al U.S.
Patent No. 4,210,637, a composition and method for selectively sllpl~.essing appetite for carbohydrates is described. This method includes the a~1mini~tration 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 cc~ ele with tryptophan ~or transport across the blood-brain barrier. This carbohydrate-initiated insulin effect on circulating amino acids m~imi7.es 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. When Wurtman applied tryptophan administration to humans in an amount of 2,300 mg per day, there was no consistent effect on ap~elite slly~ression. Moreover, the regulatory agency in the United States, the Food and Drug A~lmini~tration (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 ~ot~.,lially cause muscle damage. Accordingly, tryptophan is not being used alone, or administered with a carbohydrate, as an a~pelite aide.
Wurtman, et al in U.S. Patent No. 4,309,445 described a co~ osilion and method using d-fenfluramine to block intermittent 5 carbohydrate cravings. This method disclosed that d-fenfluramine and the related isomer l-fenfluramine selectively reduces carbohydrate ~avillg. Wurtman, et al, in U.S. Patent 4,687,763 disclosed that Iryptophan can increase brain serotonin levels when given with melatonin. In this patent Wurtman, et al, disclosed that oral 10 administration of tryptophan can increase brain serotonin and that increased brain serotonin leads to reduced carbohydrate craving. The amount of tryptophan used by Wurtman, et al, were consistently been between 2 and 100 mg/kg. of body weight per dose. These amounts are significantly above the current FDA safety guidelines of less than 1.6 15 mg/kg per day of supplemental tryptophan, particularly if the tryptophan comes from bacterial synthesized sources.
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 oc~ lh~g protein may be used.
20 Naturally occurring protein contains approximately 1.6 % tryptophan.
The amount of l~ tophan 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 25 present in protein. In a recent Fr)A publication, it was concluded that there was insufficient evidence that tryptophan reduces appetite in doses considered safe. There is no known prior art suggesling the use of predigested protein as a source of tryptophan for appetite su~ ession.
Tyrosine is a ~rec.ll~or of brain dopamine. Amphetamines 30 stimulate the release of dopamine. Brain dopamine is associated with the appetite sup~)resshlg 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.
35 4,673,689 disclose that lyrosille can be used to potentiate the sympathomimetic agents such as ephedrine or pseudoephedrine.
However, this patent contains no disclosure or suggestion of any CA 02260892 l999-0l-l4 usefulness or ~ynergism~for any purpose for combining tyrosine with any other agents active in the central nervous ~ysle.n.
Histidine is a precursor of histamine in the brain. It has been rel)olled that histamine and its precursor histidine will decrease the 5 food intake of experimental ~nimAl~ (rats) when administered ~y intrape~ilo~leal injection ("Manipulation of Central Nervous System Histarnine, Histaminergic Receplors (H1) Affects Food Intake in Rats,"
Mercer et al., J. of Nutrition, 1994, Vol. 24, pp 1029-1036) ) However, the e~e-:liveness of either histamine or its precursor histidine for 10 supp.ession 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 15 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 neurotransmitter precursors such as tryptophan or tyrosine. Phenylethylamines are also known to stimulate the release of 2Q 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 25 defined. Most comm~n knowledge attributes the appeal of chccolate to its taste, not to neurotransll-iller affects.
In 1992, Wientraub observed that phenle~.ine and fenfluramine when used together induced long term weight loss, reduced appetite and reduced carbohydrate craving. Fenfluramine is the mixture of the 30 dextro and levo forms of fenn-lramille. The results of using phentelll.inE and fenfluramine in combination was attributed to their separate effects on serotonin and dopamine. Using this combination of prescription drugs, weight loss could be sustained for months to years.
Accordingly, there has been a substantial increase in the use of the 35 phenterrnine-fenauramine approach to weight loss despite the l;ack of reuglatory approval of the the combination. Many regulatory agencies limit the use of either agent to short periods ranging from 7 days to 1 month. In addition, the use of fenlluf~ll,inc has been associated with the side effect of pulmonary l.~p~.l~llsion and heart valve disease in rare instances. The use of d-fenfluramine induces grogginess in many subjects and is expe. sive, often costing US$5.00 per day for the drug.
5 This cost is in addition to multiple visits to physicians for monitoring of treatment which may last many months or years. Also, 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 phellt~ ine-fenfluramine therapies that can be applied to 10 a large number of individuals without repetitive physician monitorin~.
Ideally, the components of such a program would be formulated from low cost ingredients which are not drug.
Disclosure of the Invention This invention has the object of achieving appetite SU~re5SiOn and reduced carbohydrate craving without large doses of fibers, amphetamines, antide~.ressants, or other prescription drugs. This invention also has the object of enabling use of readily available, low 20 cost, safe, plant-derived agents and to provide appetite ~ pression with such agents at reduced dosage to minimize the possibility of side effects.
This invention provides methods and compositions for su~ es~il,g appetite based upon the discovery that certain neurotransmitter precursors will act synergistically with each other and 25 with certain neur~transmitter potentiators in sup~ressing appetite and reducing carbohydrate craving. In particular, neurotransmitter precursors for the neurotransmitters serotonin, dopamine, norepinephrine and histamine, which contain an amine group and include tryptophan, phenyl~l~nine, tyrosine and histidine, are orally 30 administered in reduced doses concomitantly with one or more xanthines, and particularly caffeine and/or theobromine effectively to sulJ~ress appetite. When administered alone, these neurotransmitter precursors require unacceptably high doses in order to sullpress appetite.
In a further aspect of this invention histidine is a~lmini~tered 35 concommitantly with either tryptophan, phenylalanine or tyrosine with synergistic effect to su~ress a~~li~e, either with or without the concomitant administration of a xanthine. Tryptophan may be ., adminstered conjointly with phenylalanine or tyrosine with beneficial effect, during the same day but with administration of one se~erated by at least 20 rninutes of the other, to avoid competition between them for entry across the blood-brain barrier.
In another feature of the invention the neurotransmitter precursor and potentiators are a~lmini.stered in accordance with this invention in naturally occurring forms long considered safe for ingestion as a food stuff The neurotransmitter precursor tryptophan may be dmini~tered in the form of natural proteins which have been 10 hydrolyzed to release amino acid residues including tryptophan. The predigested protein allows delivery of free amino acids 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 15 secretion to clear from the bloodstream competing amino acids 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 acids allow~
sufficient l~ lo~han to be delivered to the brain so that the desired 20 effects are achieved In a related embodiment, rather than administering prehydrolyzed protein, 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 25 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 30 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, capulets and other forms individualized for administering the 35 ap~ropl;ate single dose quantities of the selected constituents. The amount of tryptophan in the dosage forms is from about 2.5 to 100 milli~rams, the amount of tyrosine is from about 10 to 700 milligrams, the amount of histidine ~from about 1 to 500 milli~rams. Where they present in the dosage forms, the xanthine theobromine is in the range of from about 1 mg. to 2 gm. or higher. Where cocoa is employed as the xanthine source, it may be present in the single dosage form in the 5 amount of about 1 mg. to 2 grams or higher. Where, 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 ~oteil, is selected to provide therein an amount of lr~/~tol~han of between 2.5 to 100 milligrams.
These combinations of agents, due to their surprising synergism, allows the dose of the individual neurotransmitter precursors to be reduced, thus reduce side effects and to reduce component doses to levels generally considered safe by regulatory agencies, such as the FDA.
They additional enable the use of naturally oc~ r~ g ~roleh~ and plant-15 derived subshnces instead of drugs.
Under FDA regulations supplemental tryptophan cannot be synthesized by man-made processes and thus they must be derived from naturally occurring protein, either animal or vegetable. The ~DA
further stipulates that the dose of added tryptophan cannot exceed 100 20 mg per day, or 1.43 mg/kg per day. The ~rled 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. These doses of tryptophan, which comply with the ~DA limitations, would be 25 ineffective in the absence of the xanthines Best Mode of Carlying Out The Invention The following description illustrates the manner in which the principles of the invention are applied but is not to be construed as limiting the scope of the invention.
Serotonin, dopamine, norepinephrine and histamine form a class of neurolransmitters that are active in the CNS to affect appetite, either stimulating the release of corticolro~ releasing factor (CRF), which su~ esses appetite, or su~les~ g the release and/or activity of neuropeptide Y, which stimulates a~pelile. Serotonin, norepinephrine , WO 98tO2165 PCT/US97/12408 and histamine all stimulate the release of CRF. Dopamine suppresses neuropeptide Y. Histamine additionally promotes neuron firing.
The ~re~ ors for this class of neurotransll~iller~, all of which contain an amine group, include tryptophan for serotonin, 5 phenylalanine and tyrosine for both dopamine and nore~ e~l rine and histidine for histamine. In this invention, these ~re~ rsor~ are employed in combination with each other and in combination with xanthines to potentiate the effect on appetite supl,.ession by the respective neurotransmitters of this class.
The precursors are employed in this invention to enhance the synthesis of their respe~:live neurotranmitters and since serotonin, phenylAl~nine, tyrosine and histidine all enhance synthesis of neurotransmitters that stimulate release of CRF, these p~e~llr~ors all thereby indirectly stimulate release of CRF. Additionally, phenylalanine 15 and tyrosine indirectly s~lpplesses neuropeptide Y through enhancement of the synthesis of dopamine as well. Also, histidine promotes neuron firing thereby indirectly stimulating synthesis of nore~,i"ephrine, tyrosine and serotonin.
The ~re.:~lrsors may be employed in this invention in pure form, 20 e.g. exogenous material synthesized or derived from animal or vegehble ~lotein, particularly purified extracts isolated from the amino acid residues in enzyme hydrolyzed proteins. However, a source for the precursor tryptophan particularly useful in this invention, both because it is a natural food source and because of the regulatory restrictions, are 25 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 ~,aslrointestinal tract. Cornmercial preparations of predigested proteins, typically from milk-derived protein, such as casein or whey, are 30 available and may be administered separately or in co-.lyosilion with histidine and/or a xanthine.
Where the lr~tophan is to be administered in the form of a predigested protein or a protein to be enzyme hydrolyzed upon administration, it is i~ ollant in this invention to a-lmini.~ter the 35 protein concomitantly with a carbohydrate, and particularly sugar, dextrins, starch and the like, in order to cause release of insulin to CA 02260892 l999-0l-l4 remove from the blood gtream the other amino acids competing with tryptophan for transport across the blood-brain barrier.
Where unhydrolyzed protein is administered together with a proteolytic enzyme, soluble proteins, such as albumin, are plef~l.ed, for 5 ease of breakdown. Whey, casein and soy are convenient protein sources. Proteolytic enzymes may include papain, chymopapain, bromelin, ll~sin and pepsin.
Xanthines constitute a class of non-selective adenosine antagonists and they include theobromine, caffeine and theophylline.
10 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, 15 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 citrated caffeine, theophylline ethylene~3iamine, theophylline sodium acetate, sodium glycinate, the choline salt, the theophylline derivatives 20 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 25 biogenic amines, and particularly phenylethylamine, in a form that is normally easily ingested and tolerated ~y 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 30 preliminary formulations with neurotransmitter precursors to improve flavor and because its mood enhancing effects have appealed to people for centuries. An unexpected result was that the cocoa powder significantly potentiated the effects of the neurotransmitter precursors.
This potentiating effect was determined ~y us to be produced ~y the 35 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 extract form, alone or, more inconveniently, in composition with the 5 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 10 potentiation may be achieved by administering the neurotransmitter yl e~:ulsor 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 15 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 l"~pl~.phan in this invention with advantage but as they can inhibit passage of tryptophan across the blood-brain barrier, they are 20 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 25 tryptophan take-up is avoided and enhanced effect of the precursors is attained. Additionally, neurotransmitter balance is fostered ~sr decreasing the total dose over time of any single neurotransmitter.
While it is not intended to be bound by any theory, the unexpected synergism found between these precursors may be at least 30 partially explained ~y the different mechanisms mediated by their respective neurotransmiters in stimulating release of CRF and/or sup~ressing neuropeptide Y.
The dosage of each neurotransmitter precursor is in an amount sufficient to enhance synthesis of its respective neurotransmitter(s), to 35 stimulate the release of CRF and thereby to suppress appetite i n combined administration with the other neurotransmitter and or xanthines employed. The synergistic effect of these combinations will permit a~l,elile s-lpp~ession at lower dosage levels of each of the neurol~ansmitter 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 5 groggilless.
~ For ll~tophan the desired single dose range is between 2.5 and100 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. However, doses up to 700 mg. or even to 1 gram or higher, 10 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 su~ress appetite if used alone. Histidine is desirably ad.~ ustered 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, 15 if tolerated by the subject. The dosage range for each precursor applies to combined a-lmini~tration of the precursor with another precursor, with a xanthine, or with both.
Where hydrolyzed proteins or proteins to be hydrolyzed in the gastrointestinal tract are employed as the source of tryptophan, the 20 proteins should be in an amount to provide the tryptophan dosage levels of this invention as di~cll~se~ 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 25 dosage le~ els of from about one half gram to 5 g~ams.
Xanthines are employed in this invention in dosage ranges a~l,royliate to promote release of neurotransmitters and to avoid undesired side effects. Theobromine and theophylline may each be a~minictered in a dosage of from 1 mg. to 2 grams or higher. Caffeine 30 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 a~ropriate dose of xanthines, with a pl~efe.led dose being 400 to 800 mg. Infusions such as tea or coffee may be employed, with one to two cups providing an appropriate dose~
35 Somewhat higher doses of these xanthines may be employed with some subjects without undue discomfort.
The neurotransmitter ~.~c.llaors and neurotransmitter potentiators of this invention may be administered orally separately, or, for assurance of a~,prop,;ate proportions and dosages as well as for convenience, they are a-lminictered together in the same composition.
5 The dosage forms for a~1ministration s~arately or in the same composition may be any of the conventional forms, including capsules, capulets, 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 10 caffeine. Hydrolyzed protein sources of tryptophan may be taken sel,alately in tablet form, utilizing commercially available predigested protein tablets, such as LLP Concentrated Predigested Protein sold ~y Twin Laboratories, Inc., Ronkonkoma, New York containing aproximately 18 mg. of lr~y~to~han per 1 gram tablet.
The compositions in the form of powders or liquids may be pA~ged in multiple dosage quantities with instructions to the user to extract thereLul-, for ingestion a~fop,iate individual dosage amounts, e.g. a teaspoonf-ll. However, the compositions are desirably prepared in discrete units, e.g. capsules, wafers etc., which each contain the 20 ap~roy,;ate dosage amounts of neurotransmitter precursors and/or neurotlans-niller potentiators for a single dose as discussed above.
The compositions may include the usual carriers, fillers, excipients and adjuvants. Advantageously, they include soluble fiber, insoluble fiber, neurotransmitter precursors and the potentiating agents 25 contained in coco~ powder. The inclusion of dietary fibers produces early satiety from volume distention and causes further appetite s~ ;ession by trigge.lllg the release of CCK. The a~l~etite s~ essing actions of the dietary fiber component further enhance the invention's neurotransmitter-related effects. They additionally may contain folic 30 acid and vitamin B6 to enhance conversion of tryptophan to serotonin, tyrosine to dopamine and histidine to hist~mine, respeelively.
The plefe,led amount of hlic acid is 200 mcg per dose with a range of 1- 800 mcg/dose. The ~ref~led amount of vitamin B6 is 10 mg with a range of 1- 50 mg/dose. Representative doses of soluble fibers are 35 100 mg to 1000 mg per dose. The best soluble fibers for producing appetite su~ression are pectin fibers from apple or citrus. fruits.
Representative doses of insoluble fibers are 100 mg to 1000 mg per dose.
A ~efelled 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. These concentration of S insoluble fibers would be inerfe. live 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 premi~e~l and heated to dryness will reduce the 10 effectiveness of the formulations.
It is important in carrying out the invention to administer the dosages when the subject has an empty stomach, typically at least an hour after the subject has eaten in order to avoid undesirably slow uptake across the blood-brain barrier, due to competition with other 15 amino acids from the ingested food. Administration may be repealed as desired, at intervals throughout the day.
The effects of the formations of this invention normally should be sufficiently potent that their effects can be experienced after the first dose. Their effectiveness can be detected by a given individual using a 20 questionnaire to assess hunger and carbohydrate craving. This is in contradistinction to other appetite su~l~;essants that require multiple doses or indirect methods such as weight loss to assess their effectiveness.
The various embodiments of the invention utili7.ing tryptophan, 25 phenylalanine or tyr.osine as the sole neurotransmitter precursor or combined with histidine, may be used alone. Advantageously, however, these tryptophan and phenylalanine or tyrosine formulations are given to a subject, but at different times, each to produce appetite ression, but by different modalities. The phenylalanine or 30 tyrosine-containing formulations are designed to potentiate the production and release of dopamine. A~elite su~iession 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 35 pseudoephedrine. Tryptophan-containing formulations are designed to reduce appetite for 2~ hours and are designed to potentiate the production and release of serotonin, and of histamine, if histidine is included. Aypetile sll~yression and reduced carbohydrate craving is achieved by the resulting activity of serotonin. The tryptophan-containing formulations emulate the effects of fenfluramine, d-fenfluramine and fluoxetine and are typically designed to reduce 5 al,l,etile 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 y:efe..ed that each to be taken on an empty 10 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 ~.e~llr~ors for entry across the blood brain barrier. Typically, the phenylalanine or tyrosine formulation is given before lunch to 15 suyyiess ayyelile 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. Alternately, The phenylalanine or 20 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 effects of the prescription drugs phentermine, fenfluramine, and d-fenfluramine.
If an individual undergoes a fast to induce hunger, a~lminigtration of tyrosine results in appetite suppression which begins 15 to 30 minutes after ingestion and continues for 2-4 hours. If hunger reayyear~ re-ingestion of the formulation results in suypression of hunger beginning 1~30 minutes after ingestion and continuing for 2-4 hours. Repeated ~lmini~tration of the tyrosine formulation results in reyelilive sup~ression of appelile.
Administration of the llyytoyhan-containing formulation after a self-induced fast results in appetite suyy~ession which begins 20-40 minutes after ingestion and continues for 2~ hours. A reduction of carbohydrate craving begins approximately 30 minutes after ingestion of the lr~yptoyhan formulation and continues for 18-36 hours. If the l~yytoyhan formulation is administered 30-90 minutes before the CA 02260892 1999-0l-l4 WO 98/02165 PCTrUS97/12408 topl-an, the onset of the lr~ypto~han formulation effects is reduced to 15-30 minutes.
Following Examples 1 through 7 illustrate formulations with tyrosine asthe sole neurollansmitter precursor and formulations with 5 tryptophan as the sole neurotransmitter precursor and use thereof independently and together. These examples also illustrate the use of various xanthines with the ~fe~ r~ors and the use of hydrolyzed proteill as the source of tryptophan.
Example 1 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 15 mgt and folic acid 100 mcg. 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 acid 100 mcg. Another useful tryptophan-containing formulation per dose is soluble fiber 175 mg, insoluble fiber 175 mg, predigested protein powder 2,000 mg, cocoa 20 250 mg, sugar 250 mg, vitamin B6 5 mg, and folic acid 100 mcg.. A
lJreferled dosage of the combination is 2 capsules of tyrosine formulation before lunch, 2 capsules of the lyrosille formulation at 4:00 p.m., and 2 capsules of either of the llyptophan formulations 30 minutes before dinner. Another dosage schedule includes the tyrosine 25 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.
Example 2 This example illustrates the use of tyrosine as the sole neurotransmitter ~recllr~or~ together with xanthines, for appetite su~,ression. A 53 year old male underwent a 10 hour fast to induce hunger. Two capsules of a Iyrosi~le formulation were given each 35 capsule containing soluble fiber in the form of apple pectin 175 mg, insoluble fiber in the form of bran fiber, tyrosine 295 mg, cocoa powder 200 mg, folic acid 100 mcg 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.
Example 3 This example illustrate the use of tryptophan as the sole neurotransmitter ~re~ rsor, together with xanthines~ for appetite 10 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 15 tryptophan, 250 mg of cocoa powder, 5 mg of vitamin B6, and 100 mcg of folic acid. The individual's hunger began to dissipate in 30 minutes and was completely tli~sipated in 60 minutes. The ingestion of the formulation resulted in early satiety in the following meal. There was an abolition of carbohydrate craving which lasted for 24 hours. The 20 onset of the appetite suppression following ingestion of the formulation was associated with mental grogginess that lasted for approximately 15 minutes.
Example 4 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 hst in order to induce hunger. She then 30 il.gesled 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 mcg of folic acid. She experienced a reduction of appetite and abolition of 35 carbohydrate craving. There was no mental grogginess induced ~y this formulation.
Example 5 This example illustrates the use tyrosine and tryptophan of this 5 invention together for ay~elite su~pression, 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. During the 10 day 10 period, both of the formulations reduced appetite for 24 hours after each ingestion. Carbohydrate craving was reduced for 24 hours after ingestion of the lr~tGlJhan formulation. By the third day there apl,eared to be an enhanced effect in that the duration of action of the combined doses were prolonged. By the fifth day there was complete 15 su~.ession of carbohydrate craving that lasted throughout the 10 day period. There were no observed side effect except for the 15 minutes of g,ogginess induced by the tryptophan formulation on days 1 and 2. For the first 2 days, the onset of the appetite supplession following ingestion of the tryptophan formulation was ~soci~ted with mental grogginess 20 that lasted for approximately 15 minutes. By the third day the grogginess effect was lost. The subject initially weighed 159 pounds and by the 10th day, his weight was reduced to 150 pounds.
ExO.mple 6 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 30 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 kyptopLan capsule.
Example 7 WO 98/02165 PCT/~S97/12408 This example illustrates the use of tyrosine and Iry~tolJhan formulations in a randomized double blind placebo controlled trial in 30 subjects. All 30 subjects underwent a 10 hour fast following which they complcted a questionnaire to assess hunger on a 5 point scale and 5 carbohydrate craving also measured on a 5 point scale. The subjects then il,e,esled 2 of the capsules of F.~mple 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 10 p.m. and at 10:00 a.m. the next morning. In the 15 placebo subjects, ingestion of the placebo was followed by an increase in the hunger index from 2.2 to 2.9 after the first dose of tyrosine, p<0.03. In the 15 subjects randomized to receive lylosille, the hunger index fell from 3.1 to 2.4, p<0.03. Comparison of the active to placebo group showed a 15 reduction of the hunger index with a high degree of significance, p<O~Olo The carbohydrate craving index was also significantly reduced by the tophan dose, p<.01. In the active group, 85% of the subjects either reduced their feeling of hunger or cravings for carbohydrate while only 45% of the placebo group experienced either a reduction of hunger or 20 cravings for carbohydrate, p<0.03.
Following examples 8 and 9 illustrate the formulation and use of histidine with xanthines, with histidine as the only neurotransmitter 25 precursor.
Example 8 A formulation of histidine and cocoa may be ~re~aled ~y 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. Alternatively, the blended powder may be prepared in the form WO 98/02165 PCT/US97tl2408 of a chewable wafer sized~ to contain the same dose, by combining with the powder wheat bran, apple pectin and a sweetener.
5F.YAmple 9 A formulation of histidine and caffeine may be ~;el,ared in the same manner as des~it~e~l in example 8 by blending in powder form histidine and caffeine in a proportion of 3 parts histidine and 10 parts 10 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.
15Following examples 10 through 15 illustrate practice of the invention utilizing the combination of histidine with tyrosine and of histidine with try~tol~han as neurotransmitter ~;e..lrsors, both with and without concomitant application of xanthines.
Example 10 A formulation of tryptophan and histidine may be prepared by blending these two ingredients in powder form in a proportion of 5 25 parts l~to~han and 3 parts histidine. This prcduct is then portioned into gelatin capsules so that each contains 50 mg. of tryptophan 30 mg.
histidine and the capsules are ad.,~il isteled as in Example 8.
30Example 11 A formulation as in Example 10 that contains caffeine in addition to l.y~to~han and histidine may ~re~ared by blending in powder form 10 parts of caffeine with 5 parts tr~pto~han and 3 parts histidine. Gelatin 35 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 lyrosine and histidine may be prepared ~y blending these two ingredients in powder form in a proportion of 50 parts Iy~osil~e 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 F.y~mple 8.
Example 13 A formulation as in Example 12 that contains cocoa in addition to tyrosine and histidine may ~repa~d 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.
Example 14 A formulation of histidine with I~Iol,han 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 3û 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 iri Example 14 that contains cocoa in addition to hydrolyzed milk ~lotein and histidine may p~e~ared ~y blending in powder form 50 parts of cocoa with 200 parts of the hydrolyzed milk plolei" and 3 parts histidine. Gelatin capsules are filled with the powder 5 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 a~minictered as in example 8.
Following examples 16 through 18 illustrate the practice 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 15 histidine as an additional neurollallsmitter precursor.
Example 16 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 ll~ptophan.
Specifically 10 grams of whey powder and approximately 40 mg.
of papain powder were administered to a subject orally, on an empty stomach. With this high dosage, typtophan was released in the G.I. tract in an amount to induce appetite su~ ession, without the administration of xanthine. However, the subject experienced very pronounced grogginess that lasted for several hours.
Later, to the same subject, between 1 and 2 grams of whey powder, approximately 40 mg. of papain powder and 40 mg. of cocoa were administered, on an empty stomach. This formulation induced appetite su~pression in the subject and no grogginess was experienced.
This procedure provides an easy mode of a~lmini.stering tryptophan using natural food sources together with xanthine to produce appetite su~ ession without undue grogginess.
A~1minctration of this lr~ylJto~han source without xanthine, or a synergistic neuroliansmitter p~e.ursor, required such a high dosage level to acheive a~etile sup~ression that the side effects (grogginess) were unacce~table.
l~Y~mple 17 A formulation of cocoa with lr~pl~phan in the form of 10 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 p.oteil" 4 parts papain and 50 parts cocoa. This product is then portioned into gelatin capsules 15 so that each contains 500 mg. cocoa and 2 gm. of whey and 40 mg.
papain. Hydrolysis of the whey in the gaslloil~testinal tract provides a dose of approximately 50 mg. of tryptophan. The capsules are administered as in Example 8.
Example 18 A formulation is prepared and administered as in Example 17 but with the addition thereto of 3 parts histidine, thus additionally 25 providing 30 mg. of histidine per capsule dosage.
As can be seen from the foregoing, the synergistic combinations of the invention allow reduced doses of the individual components to 30 be used to achieve the desired effects and particularly of the neurotransmitter ~rec~ll,ors. The reduced doses decrease the side effects caused by the large doses heretofore necess~ry to achieve the desired effects. Our invention allows apl,elile su~ression and reduction of carbohydrate craving to be achieved at doses levels which 35 are considered safe by regulatory authorities. Previous alle..~ts 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 groggi~ess or safety concerns associated with higher doses. The reduced dose of tyrosine allows appetite suppression without the agitation and anxiety induced 5 ~y amphetamines. The reduced dose of histidine reduces or eliminates potential side effects of histamine.
It is further seen that the combinations of the invention enable the use of naturally occurring subslances thereby enhancing their regulatory approval and market acce~tance.
Although the description above contains many specificities, these should not be construed as limiting the scope of the invention but as merely providing illustrations of some of the presently ~referl~d embodiments of this invention. Various other embodiments and ramifications are possible within it's scope.
~L5
Claims (39)
1. A method for suppressing appetite in an animal subject by promoting synthesis and release of a first neurotransmitter selected from serotonin, norepinephrine and dopamine in the animal which comprises concomitantly administering orally to the subject at least one precursor for the first neurotransmitter, in a dose that is effective to enhance synthesis of the first neurotransmitter in the subject, at least one precursor for the neurotransmitter histamine, in a dose effective to enhance release of the first neurotransmitter, and a xanthine, in an amount effective to enhance release of the first neurotransmitter in the subject.
2. method as in claim 1 and wherein the precursor for the first neurotransmitter is selected from tyrosine and phenylalanine and the precursor for the neurotransmitter histamine comprises histidine.
3. A method as in claim 2 and wherein the histidine dose administered is between 1 and 500 mg.
4. A method as in claim 3 and wherein the precursor for the first neurotransmitter comprises tyrosine administered is in a dose of between 10 and 700 mg.
5. A method as in claim 2 and wherein the xanthine comprises caffeine.
6. A method as in claim 5 and wherein the caffeine administered is in a dose of between 1 and 200 mg.
7. A method as in claim 2 and wherein the xanthine comprises theobromine.
8. A method as in claim 7 and wherein the theobromine administered is in a dose of between 1 and 2,000 mg.
9. A method as in claim 2 and wherein the xanthine is in the form of cocoa.
10. A method as in claim 9 and wherein the cocoa administered is in a dose of between 1 mg. and 20 grams.
11. A method as in claim 1 and wherein the precursor for the first neurotransmitter is tryptophan and the precursor for the neurotransmitter histamine is histidine.
12. A method as in claim 11 and wherein the xanthine comprises caffeine.
13. A method as in claim 12 and wherein the caffeine administered is in a dose of between 1 and 200 mg.
14. A method as in claim 11 and wherein the xanthine comprises theobromine.
15. A method as in claim 14 and wherein the theobromine administered is in a dose of between 1 and 2,000 mg.
16. A method as in claim 11 and wherein the xanthine is in the form of cocoa.
17. A method as in claim 6 and wherein the cocoa administered is in a dose of between 1 and 2,000 mg.
18. A method as in claim 11 and wherein the tryptophan is administered in the form of enzyme hydrolyzed protein.
19. A method as in claim 11 and wherein the tryptophan is administered in a dose of less than 100 mg.
20. A method for suppressing appetite in an animal subject which comprises concomitantly administering to the subject protein in an amount to comprise, upon enzyme hydrolysis thereof, sufficient tryptophan effective to enhance synthesis of serotonin in the brain, a proteolyfic enzyme in an amount to hydrolyze the protein in the gastrointestinal tract to liberate the tryptophan, the histamine precursor histidine in an amount effective to enhance synthesis of histamine in the brain and a xanthine in an amount effective to increase neural release in the brain of histamine and of serotonin.
21. A composition for promoting synthesis and release of a first neurotransmitter selected from serotonin, norepinephrine and dopamine in an animal subject, in unit dosage form for oral administration, comprising at least one precursor for the first neurotransmitter in an amount effective to enhance synthesis of the first neurotransmitter in the subject, at least one precursor for the neurotransmitter histamine, in an amount effective to enhance release of the first neurotransmitter and a xanthine in an amount effective to increase release of the first neurotransmitter in the subject.
22. A composition as in claim 21 and wherein the precursor for the first neurotransmitter is selected from tyrosine and phenylalanine the precursor for histamine comprises histidine.
23. A composition as in claim 22 and wherein the amount of histidine per dose is between 1 and 600 mg
24. A composition as in claim 22 and wherein the xanthine comprises caffeine in an amount of between 1 and 200 mg. per dose.
25. A composition as in claim 22 and wherein the xanthine comprises theobromine.
26. A composition as in claim 24 and wherein the xanthine comprises theobromine in an amount of between 1 and 2,000 mg. per dose.
27. A composition as in claim 22 and wherein the xanthine is in the form of cocoa in the amount of between 1 and 2,000 mg. per dose.
28. A composition as in claim 22 and wherein the precursor comprises tyrosine in an amount per dose is between 1 and 600 mg.
29. A composition as in claim 28 and wherein the amount of tyrosine per dose is less than 500 mg.
30. A composition as in claim 21 and wherein the precursor for the first neurotransmitter comprises tryptophan and the precursor for histamine comprises histidine.
31. A composition as in claim 30 and wherein the xanthine comprises theobromine in an amount of between 1 and 2,000 mg. per dose.
32. A composition as in claim 30 and wherein the xanthine comprises caffeine in an amount of between 1 and 200 mg. per dose.
33. A composition as in claim 30 and wherein the xanthine is in the form of cocoa.
34. A composition as in claim 30 and wherein the tryptophan is present in the composition in the form of enzyme hydrolyzed protein.
35. A composition as in claim 22 and wherein the amount of histidine per dose is between 1 and 600 mg.
36. A composition for suppressing appetite in animal subject, in a dry unit dosage form, comprising powdered protein in an amount to comprise, upon enzyme hydrolysis thereof, sufficient tryptophan effective to enhance synthesis of serotonin in the brain, a proteolytic enzyme in an amount to hydrolyze the protein in the gastrointestinal tract to liberate the tryptophan, histidine in an amount effective to enhance neural release of serotonin in the brain and a xanthine in an amount effective to enhance neural release of serotonin in the brain.
37. A composition as in claim 36 and wherein the protein is in the amount of between about one half gram to 30 grams per unit dose and the enzyme is in the amount of between 30 and to 50 mg. per gram of protein.
38. A composition as in claim 37 and wherein the enzyme is papain.
39. A composition for suppressing appetite in animal subject, in a dry unit dosage form, comprising powdered protein in an amount to comprise, upon enzyme hydrolysis thereof, sufficient tryptophan effective to enhance synthesis of serotonin in the brain, a proteolytic enzyme in an amount to hydrolyze the protein in the gastrointestinal tract to liberate the tryptophan, the histamine precursor histidine in an amount effective to enhance synthesis of histamine in the brain and a xanthine in an amount effective to increase neural release in the brain of histamine and of serotonin.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US68353596A | 1996-07-17 | 1996-07-17 | |
| US08/683,535 | 1996-07-17 | ||
| PCT/US1997/012408 WO1998002165A1 (en) | 1996-07-17 | 1997-07-16 | Appetite suppression |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2260892A1 true CA2260892A1 (en) | 1998-01-22 |
Family
ID=24744444
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002260892A Abandoned CA2260892A1 (en) | 1996-07-17 | 1997-07-16 | Appetite suppression |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0912181A1 (en) |
| JP (1) | JP2000515139A (en) |
| KR (1) | KR20000023819A (en) |
| AU (1) | AU3666497A (en) |
| CA (1) | CA2260892A1 (en) |
| IL (1) | IL127684A0 (en) |
| WO (1) | WO1998002165A1 (en) |
Families Citing this family (34)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7232830B2 (en) | 1998-06-26 | 2007-06-19 | Elaine A Delack | Method for treatment of neurodegenerative diseases and effects of aging |
| 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 |
| US6610277B2 (en) * | 2000-12-27 | 2003-08-26 | Arthur Zuckerman | Appetite suppressant toothpaste |
| US6485710B2 (en) * | 2000-12-27 | 2002-11-26 | 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 |
| CA2489942A1 (en) | 2002-07-01 | 2004-01-08 | Unilever Plc | Satiety inducing composition |
| US7674482B2 (en) * | 2002-08-27 | 2010-03-09 | Targeted Medical Pharma Inc. | Method and compositions for potentiating pharmaceuticals with amino acid based medical foods |
| US7585523B2 (en) * | 2002-08-27 | 2009-09-08 | Targeted Medical Pharma | Composition and method to augment and sustain neurotransmitter production |
| US7648957B2 (en) * | 2002-09-04 | 2010-01-19 | Dsm Ip Assets B.V. | Nutritional and therapeutic composition of an insulin sensitizer and a peptide fraction |
| US7279971B2 (en) | 2002-09-06 | 2007-10-09 | Telefonaktiebolaget Lm Ericsson (Publ) | Composite power amplifier |
| EP1605764A4 (en) * | 2003-03-14 | 2008-07-23 | Eurark Llc | Composition and method for appetite and carvingsuppressission and mood enhancement |
| EP1753443A1 (en) * | 2004-05-27 | 2007-02-21 | Campina Nederland Holding B.V. | Use of protein hydrolysates for the manufacture of a medicament for prophylaxis and/or treatment of a dpp-iv mediated condition |
| WO2006053217A1 (en) * | 2004-11-12 | 2006-05-18 | Mccleary, Edward Larry | Weight loss composition and method |
| JP5068174B2 (en) | 2004-12-23 | 2012-11-07 | カンピナ ネーデルランド ホールディング ビー．ブイ． | Protein hydrolyzate concentrated in peptides inhibiting DPP-IV and uses thereof |
| GB0520917D0 (en) * | 2005-10-14 | 2005-11-23 | Zumbe Albert | Chocolate based appetite suppressant |
| EP1954299B1 (en) | 2005-11-30 | 2016-01-13 | Campina Nederland Holding B.V. | Use of a protein hydrolysate for enhancing activity of glucagon-like peptide-1 |
| JP2008094787A (en) * | 2006-10-13 | 2008-04-24 | Paq Kk | Sympathetic nerve stimulant using peanut-treated material |
| 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 (en) | 2008-01-02 | 2010-06-17 | Armando Jose Yañez Soler | COMPOSITION BASED ON COCOA AND SPIRULIN. |
| US20090214682A1 (en) * | 2008-02-22 | 2009-08-27 | Heuer Marvin A | Composition and methods for weight loss in a subject |
| JP4593639B2 (en) | 2008-03-04 | 2010-12-08 | 株式会社マルハニチロ食品 | Peptide-containing feeding regulator |
| JP4691571B2 (en) | 2008-03-04 | 2011-06-01 | 株式会社マルハニチロ食品 | Feeding regulator |
| EP2571502B1 (en) | 2010-05-19 | 2016-04-27 | Unilever N.V. | Theobromine for increasing hdl-cholesterol |
| JP6041242B2 (en) * | 2010-10-05 | 2016-12-07 | ディーエスエム アイピー アセッツ ビー．ブイ． | Peptides containing tryptophan |
| JP5886657B2 (en) * | 2012-02-29 | 2016-03-16 | 株式会社ファンケル | Formulation containing powder derived from wheat bran |
| 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 |
| US9138455B2 (en) | 2013-03-15 | 2015-09-22 | Mead Johnson Nutrition Company | Activating adiponectin by casein hydrolysate |
| 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 |
| US9352020B2 (en) | 2013-03-15 | 2016-05-31 | Mead Johnson Nutrition Company | Reducing proinflammatory response |
| US9289461B2 (en) | 2013-03-15 | 2016-03-22 | Mead Johnson Nutrition Company | Reducing the risk of autoimmune disease |
Family Cites Families (6)
| 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 |
| NL7710582A (en) * | 1977-06-03 | 1978-12-05 | Pharmaceutical Export Promotio | PROCESS FOR PREPARING A SLIMMING PREPARATION. |
| 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 (en) * | 1990-01-18 | 1992-05-15 | Medgenix Group Sa | DIETETIC COMPOSITION BASED ON POLYPEPTIDES AND AMINO ACIDS. |
-
1997
- 1997-07-16 AU AU36664/97A patent/AU3666497A/en not_active Abandoned
- 1997-07-16 EP EP97933498A patent/EP0912181A1/en not_active Withdrawn
- 1997-07-16 WO PCT/US1997/012408 patent/WO1998002165A1/en not_active Application Discontinuation
- 1997-07-16 JP JP10506277A patent/JP2000515139A/en active Pending
- 1997-07-16 IL IL12768497A patent/IL127684A0/en unknown
- 1997-07-16 CA CA002260892A patent/CA2260892A1/en not_active Abandoned
-
1999
- 1999-01-15 KR KR1019997000305A patent/KR20000023819A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| KR20000023819A (en) | 2000-04-25 |
| WO1998002165A1 (en) | 1998-01-22 |
| IL127684A0 (en) | 1999-10-28 |
| AU3666497A (en) | 1998-02-09 |
| EP0912181A1 (en) | 1999-05-06 |
| JP2000515139A (en) | 2000-11-14 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |