Note: Descriptions are shown in the official language in which they were submitted.
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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.
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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
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~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
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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
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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
.,
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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,
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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
,
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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
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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.
. .,
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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
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11
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.
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12
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.
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13
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
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14
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
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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
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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.
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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
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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
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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.
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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
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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.
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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.
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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
