Weight loss abstract
Materials derived from Citrus plants can be administered orally
to humans for the purpose of producing or maintaining weight loss
as well as improving the person's physical performance and increasing
the person's lean muscle mass. The Citrus materials include those
portions of the plant that are normally considered waster or inedible,
such as the leaves, peel and immature, unripe fruit. The materials
contain as least one of the alkaloids from the group consisting
of synephrine, hordenine, octopamine, tyramine and N-methylamine.
Two species, Citrus aurantium and Citrus reticulata, are particularly
useful. The materials can be administered in their natural form
or as extracts, and can be administered in various ways including
capsules and tablets. The Citrus materials may also be used as a
tea. For weight loss and weight control, the materials can be administered
concurrently with caloric restriction or in the absence of caloric
restriction. The materials may also be administered for the purpose
of increasing muscle mass concurrently with a high protein diet
as well as with an exercise program.
Weight loss claims
I claim:
1. A method for inducing weight loss in a human by suppressing
hunger, which comprises administering by mouth to a human a composition
containing at least one adrenergic amine or amines selected from
the group consisting of synephrine, hordenine, octopamine, tyramine
and N-methyltyramine.
2. The method of claim 1, wherein the adrenergic amine or amines
are administered in an amount of from 0.16 to 1.0 mg per day per
kilogram of ideal body weight.
3. The method of claim 1, wherein synephrine is 50% to 100% of
the adrenergic amine or amines administered.
4. The method of claim 1, wherein the adrenergic amine or amines
are incorporated in a plant material of the genus Citrus.
5. The method of claim 4, wherein the adrenergic amine or amines
are administered in the form of a concentrate or extract of a Citrus
material, in either dry or liquid form.
6. The method of claim 5, wherein the Citrus material is obtained
from a Citrus species which contains the adrenergic amine or amines
in an amount in excess of 0.1% of the dry mass of the material.
7. The method of claim 5, wherein the Citrus material is obtained
from a species selected from the group consisting of Citrus reticulata,
Citrus aurantium, Citrus medica, Citrus maxima, Citrus limon, Citrus
aurantiifolia, Citrus paradisi, Citrus sinensis, and Poncirus trifoliate.
8. The method of claim 4, wherein the plant material is in the
form of an oriental herb selected from the group consisting of Zhi
shi, Zhi Qiao, Chen pi, Qing pi, Fo Shou, or a concentrate or extract
thereof.
9. A method for inducing weight loss in a human by suppressing
hunger, which comprises administering by mouth to a human a plant
material of the genus Citrus containing at least one adrenergic
amine or amines selected from the group consisting of synephrine,
hordenine, octopamine, tyramine and N-methyltyramine in an amount
in excess of 0.1% of the dry mass of the plant material.
10. The method of claim 9, wherein the adrenergic amine or amines
are administered in an amount of from 0.16 to 1.0 mg per day per
kilogram of ideal body weight.
11. The method of claim 9, wherein synephrine is 50% to 100% of
the adrenergic amine or amines administered.
12. The method of claim 9, wherein the adrenergic amine or amines
are administered in the form of a concentrate or extract of a Citrus
material, in either dry or liquid form.
13. The method of claim 12, wherein the Citrus material is obtained
from a species selected from the group consisting of Citrus reticulata,
Citrus aurantium, Citrus medica, Citrus maxima, Citrus limon, Citrus
aurantiifolia, Citrus paradisi, Citrus sinensis, and Poncirus trifoliate.
14. The method of 13, wherein the Citrus material is selected from
the leaves, bark, fruit, or peel of the species Citrus aurantium
or Citrus reticulata.
15. The method of claim 9, wherein the plant material is in the
form of an oriental herb selected from the group consisting of Zhi
shi, Zhi Qiao, Chen pi, Qing pi, Fo Shou, or a concentrate or extract
thereof.
16. The method of claim 12, wherein the Citrus material is administered
in the form of a tablet, capsule, or powder, in admixture with a
food product, or in the form of a tea or tisane.
Weight loss description
TECHNICAL FIELD
The present invention relates to the use of materials derived from
Citrus plants in inducing weight loss, improving physical performance
and increasing muscle mass.
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BACKGROUND ART
It has long been known that natural and synthetic substances may
facilitate weight loss in those who are overweight or obese. Such
substances as have found utility in this respect may act by a variety
of mechanisms. For example, some such substances act by mimicking
the effects of endogenous neurotransmitters, and are capable of
directly replacing these neurotransmitters in their actions on receptors.
This, in turn, leads to increased activity of the cells which possess
the receptors. Where the receptors concerned are normally responsive
to the endogenous hormones adrenaline (epinephrine) and noradrenaline
(norepinephrine), which mediate the activities of the sympathetic
nervous system, such substances are termed direct-acting sympathicomimetic
agents. Typical examples are the amphetamines. Other substances
that produce similar effects on the sympathetic nervous system do
so by stimulating the release of the endogenous hormones adrenaline
and noradrenaline, and are thus termed indirect-acting sympathicomimetic
agents. Ephedrine is a typical example of an indirect-acting sympathicomimetic
agent. The term adrenergic may also be used, and is synonymous with
the term sympathicomimetic. Such substances may also be referred
to as agonists, where the name agonist is qualified by a descriptor
of the receptor stimulated, for example, a beta-agonist.
While the formal distinction between direct-acting and indirect-acting
sympathicomimetic action is clear, it is realized that many substances
which act by causing sympathetic stimulation do so by both mechanisms,
depending on intake levels and the receptors involved. Thus amphetamines
act mainly directly, but also have some indirect actions, while
ephedrine acts indirectly, but if given in higher dosage, may also
stimulate receptors directly, particularly in the brain. It has
been demonstrated that the main perceived actions of sympathicomimetic
agents depend both on their differing specificities for the various
receptors and on the pharmacokinetic behaviors of the agents in
the body.
Thus the amphetamines, which are direct agents and readily cross
the blood-brain barrier, mainly cause central nervous system stimulation,
while ephedrine, and particularly pseudoephedrine, are indirect
agents which do not cross the blood-brain barrier so readily, and
thus are mainly seen to exert peripheral effects.
Another class of substances of value in assisting weight loss modulates
other neurotransmitters, namely those involved in serotoninergic
systems, and particularly 5-hydroxytryptamine (5-HT; otherwise known
as serotonin) itself. These substances, of which fenfluramine and
its optical isomer, dexfenfluramine, are typical, act by preventing
the re-uptake of serotonin into storage granules in neurones. Levels
of 5-HT in the synaptic gap thus remain elevated for longer periods,
exciting receptors on responsive cells to greater activity.
Other aids to weight loss have been proposed, such as substances
which prevent the absorption of nutrients from the digestive system,
but the value of such approaches is minimal, and in general, the
accepted substances of value in weight loss act by modulating neurotransmitter
function in the central nervous system or peripherally.
Substances which modulate neurotransmitter function in the central
nervous system are known to act by increasing the availability of
catecholamines, in particular noradrenaline, in certain areas of
the brain, thus resulting in perceived suppression of hunger. By
suppressing hunger, less food is eaten, and caloric intake is lowered.
Examples of such substances include phenylpropanolamine, phentermine
and the amphetamines.
Substances which act by increasing the availability of 5-hydroxytryptamine
(serotonin), on the other hand, are known to increase perceptions
of satiety. An example of such a substance is dexfenfluramine.
Irrespective of mechanism, substances of either of these types
result in reduced food intake. But their use can be attended by
various unwanted effects characteristic of interference with other
hormone-regulated systems in the body. It has furthermore been noted
that the effects of these types of substances are transient, requiring
progressively greater dosage to elicit desired effects, until the
body finally becomes unresponsive. This progressive decrease in
sensitivity is termed tachyphylaxis.
More recently, attention has been focused on ephedrine, which was
originally thought to suppress the hunger center in the brain. However,
during the last 30 years, research has shown that ephedrine acts
mainly by stimulating thermogenesis. That is, it increases the metabolic
rate and stimulates lipolysis (fat breakdown).
The effect of ephedrine on the peripheral metabolic rate is derived
from actions on energy-generating tissues combined with stimulation
of the release of fat from stored fat depots (adipose tissue). This
not only increases the generation of energy but also increases the
availability of substrates to be utilized for this energy generation.
A valuable consequence of these two actions is the sparing of body
protein, which in certain cases, depending on the composition of
the diet, may even result in a gain of body protein (anabolic effect).
The effects of ephedrine can often be intensified by concomitant
use of methylxanthines such as caffeine.
Empirical studies have shown that ephedrine, whether as the pure
substance or in the form of Ephedra herb:
(a) Improves rates of weight loss in patients on low calorie diets,
spares lean body mass (Pasquali et al., 1992; Kaats and Adelman,
1994), increases the proportion of fat in the weight lost (Astrup
et al., 1992b) and prevents the decline in Resting Metabolic Rate
usually seen with reduced caloric intake (Astrup et al., 1992b;
Astrup and Toubro, 1993).
(b) Gives results, through increased thermogenesis and stimulation
of lipolysis (fat breakdown) at dosage levels below those required
to elicit stimulant or hunger suppressant effects (Astrup and Toubro,
1993).
(c) Shows synergism in the effects on weight loss when combined
with caffeine (Daly et al., 1993; Astrup and Toubro, 1993).
(d) Is not associated with significant adverse effects. Thermogenic
effects became more pronounced as treatment continues (Astrup et
al., 1985, 1986) while initial adrenergic effects (which are not
pronounced) exhibit tachyphylaxis and rapidly disappear (Astrup
et al., 1992a).
It has even been suggested that ephedrine may be an example of
a trace substance that belongs in the human diet, and that it provides
an opportunity to attack obesity at a level that is close to causative
(Landsberg and Young, 1993).
Based on the clinical observations, ephedrine may therefore be
considered an ideal pharmacological aid in the treatment of obesity.
Though it has some central stimulant effect, and thus mediates
suppression of hunger, ephedrine's main mode of action appears to
be peripheral and, in part, causative since it offsets the decline
in metabolic rate that normally occurs on caloric restriction. The
decline in metabolic rate that accompanies caloric restriction,
therefore, is well known to those schooled in the art to defeat
the initial weight loss benefits associated with caloric restriction.
The body, in effect, recognizes the "starvation" period,
becomes more efficient in utilizing caloric resources, and simply
waits until normal caloric intake is resumed. This explains the
"plateau" effect seen in caloric restriction diets. When
normal caloric intake is resumed, the body's increased efficiency
actually restores the fat lost in the caloric restriction period.
This is commonly known as the "yo-yo dieting" effect.
The thermogenic action which results from ephedrine's effects on
metabolic rate and lipolysis persists throughout its use period,
and may intensify as use continues.
Ephedrine's classical adrenergic actions, which are undesirable
in a weight loss context, cease rapidly due to tachyphylaxis.
The classical uses of ephedrine and pseudoephedrine for a variety
of conditions are well illustrated by reference to standard works
on Pharmacology and Therapeutics. For example, Govoni and Hayes
(1985) describe use of ephedrine as a decongestant in allergic rhinitis,
sinusitis and chronic asthma (often combined for such indications
with theophylline, a methylxanthine closely related to caffeine
in structure and effect), in the treatment of narcolepsy, to combat
hypotensive states (especially those associated with spinal anesthesia),
in the management of enuresis, as adjunctive therapy for myasthenia
gravis, as a mydriatic, as temporary support of ventricular rate
in Adams-Stokes syndrome, to relieve dysmenorhoea, and for management
of peripheral edema secondary to diabetic neuropathy. Streeten (1975)
adds idiopathic edema to the list of conditions where ephedrine
(150-200 mg per day) has beneficial activity, and other uses verified
have included ketotic hypoglycaemia (Court et al., 1974), urological
syndromes caused by prostaglandin El (Lowe and Jarow, 1993) and
insulin-induced edema (Hopkins et al., 1993). Matthews (1983) discusses
the action of ephedrine on the internal sphincter of the bladder
and urethra in relation to its use in treating urinary incontinence.
Govoni and Hayes (1985) note that maximum parenteral dosage should
not exceed 150 mg/day by sub-cutaneous (s.c.), intramuscular (i.m.)
or intravenous (i.v.) routes and comment that unwanted effects (all
of which are consequent on the pharmacology involved) usually only
occur with large doses. The same textbook teaches that pseudoephedrine
essentially shares these properties, but is mainly used for relief
of rhinitis in doses up to 240 mg/day for adults; Southon and Buckingham
(1989) concur that pseudoephedrine and ephedrine have similar pharmacological
profiles, but that pseudoephedrine is less potent.
Naturally occurring ephedrine is the 1R,2S(-)-erythro form, which
is the most active pharmacologically. Pseudoephedrine is the threo
form.
Acting indirectly, the main action of ephedrine is to elicit release
of noradrenaline (norepinephrine) from presynaptic sites. This in
turn activates both alpha- and beta-adrenoceptors. The perceived
effects on different organs and tissues depend on the relative proportions
of the two types of receptors, which mediate different responses.
At a basal level, classical pharmacology teaches that alpha-activation
results in contraction of smooth muscle (except for intestinal smooth
muscle) while beta-activation causes relaxation of smooth muscle
and stimulation of the myocardium. But this picture is complicated
by the fact that both alpha- and beta-receptors can be subdivided
into further types with differing distributions and sensitivities.
At a cellular level, activation of beta-receptors results in stimulation
of adenylate cyclase. This leads to increases in intracellular levels
of cyclic adenosine monophosphate (cAMP). The precise sequence of
events (Munson, 1995) is believed to be:
(1) The beta-agonist binds to the beta-receptor.
(2) The receptor-agonist complex has high affinity for a stimulatory
guanine nucleotide regulatory protein termed the Gs protein, and
binds to this protein.
(3) Formation of the receptor-agonist-Gs complex facilitates the
exchange of guanine diphosphate (GDP) for guanine triphosphate (GTP)
on the Gs protein.
(4) The Gs-GTP complex dissociates from the receptor-agonist complex
and then interacts with the catalytic subunit of adenylate cyclase,
promoting the conversion of adenosine triphosphate to cAMP.
(5) The cAMP activates a cAMP-dependent protein kinase, which can
then phosphorylate a variety of intracellular proteins, ultimately
leading to a pharmacological response.
Feedback inhibition control is achieved by phosphorylation of receptor
proteins, which results in their desensitization.
Activation of most alpha-2 receptors has an opposite effect, the
first step being inhibition of adenylate cyclase through a guanine
nucleotide regulatory protein termed Gi. The Gi protein, by inhibiting
the catalytic activity of the adenylate cyclase, leads to a reduction
in cellular levels of cAMP, which decreases the activation of the
cAMP-dependent protein kinases. However, in some alpha-2 receptors,
the Gi protein may act through other mechanisms which have not yet
been elucidated, but possibly lead to activation of membrane calcium
channels.
The alpha-1 receptors have a different mechanism. It does not appear
to involve cAMP, but apparently relies instead on diacyl glycerols
and inositol-1,4,5-triphosphate.
It is readily understood that the beta-receptors can also be further
subdivided based upon their mechanism of action. The known subdivision
of beta-receptors into beta-1, beta-2, and beta-3 types is of particular
interest for this invention since the beta-3-receptor is strongly
believed to be responsible for the lipolytic and thermogenic effects
of ephedrine while interactions with the other two types of beta-receptors
are known to control cardiac effects of ephedrine.
Effects on blood pressure, however, are in part due to the stimulation
of alpha-2-receptors, where such stimulation produces peripheral
vasoconstriction.
Central nervous system effects of ephedrine appear to depend on
activation both alpha- and beta-receptors (with the exception of
beta-3-receptors). The multi-receptor response to ephedrine is also
important in explaining observed synergistic effects of caffeine
on certain actions of ephedrine.
The overall response to ephedrine, reflected in perceived effects,
is governed by the distribution of receptors in terms of types and
populations. As an example, the activation of beta-receptors causes
vasodilation of vessels in the heart and skeletal muscle while simultaneous
alpha-2-activation results in vasoconstriction in other vascular
beds. This is effectively the classical "fight or flight"
response, which together with other metabolic results of adrenoceptor
activation is intended to put the body into an optimal state for
physical exertion.
The metabolic results of adrenoceptor activation also include effects
on lipolysis and thermogenesis. In the case of lipolysis, activation
of alpha-2-receptors inhibits the process, while activation of beta-receptors
(believed to be the beta-3-subtype) stimulates lipolysis and at
same time, possibly in part due to increased availability of substrate,
induces a thermogenic response. The overall response of the adipose
tissue thus depends on the relative proportions of alpha-2 and beta-3
receptors. A high ratio of alpha-2 to beta-3 receptors would produce
a comparatively lower thermogenic response than a low ratio. Indeed,
the predicted diminishment of thermogenic response associated with
increasing proportion of alpha-2 compared to beta-3 receptors may
explain why some studies of thermogenic responses to ephedrine have
found two populations: responders and relative non-responders.
Attention has been paid to the unexpected finding that thermogenic
properties of ephedrine do not exhibit tachyphylaxis. Landsberg
and Young (1993) adopt the position that since the activity of the
sympathetic nervous system may be reduced in obesity, improvement
of sympathetic nervous system activity to normal levels is physiological
rather than pharmacological, and that the use of ephedrine in obese
persons does nothing more than restore normal catecholamine function.
In this respect, therefore, ephedrine differs in no way from the
effects of high protein diets or consumption of foods containing
natural thermogenic substances. Lansdberg and Young also suggest
that ephedrine may be particularly useful in combating the weight
gain that usually follows cessation of smoking since smoking cessation
is also associated with impaired catecholamine function.
Dulloo (1993) concurs with Lansdberg and Young's point of view.
He notes that at levels compatible with therapeutic doses, ephedrine
has little or no direct agonist activity but mediates its effects
via endogenous release of noradrenaline and adrenaline. Essentially,
therefore, ephedrine does nothing more than increase the efficiency
of the system already in place in the body. He notes that this has
potential positive implications for ephedrine's use in the treatment
of obesity, and also explains some of the obscure clinical observations
reported:
1) The fact that tolerance rapidly develops to the very mild cardiovascular
effects of ephedrine, but not to its thermogenic effects, suggests
that adrenaline and noradrenaline released by ephedrine activate
the beta-3-adrenoceptors.
2) The adrenaline released is a preferential agonist for the beta-2-adrenoceptors
which stimulate protein synthesis and thus can counteract loss of
lean body mass during use of low calorie diets.
In this respect, Pasquali et al. (1992) have shown that ephedrine
enhances fat loss in diet-restricted obese patients and reduces
loss of nitrogen.
3) Chronic stimulation of postsynaptic alpha-adrenoceptors by the
adrenaline and noradrenaline released in response to ephedrine therapy
may activate thyroxine deiodinases, leading to peripheral conversion
of T4 (thyroxine) to T3 (triiodothyronine), which may, in turn,
increase adrenoceptor sensitivity to the thermogenic effects of
the catecholamines since T3 is much more active than T4.
This mechanism may also partially explain why the thermogenic effect
of ephedrine is increased after chronic administration.
4) Single dose studies have shown that skeletal muscle and visceral
organs contribute most of the thermogenic activity after ephedrine
administration, with a minor contribution from adipose tissue. These
tissues can all be reactivated and even proliferate in response
to chronic catecholamine activation, which may explain the enhanced
thermogenesis seen with prolonged ephedrine treatment.
Dulloo suggests that ephedrine, with chronic administration, exerts
its effects indirectly via adrenaline and noradrenaline and thereby
generates its own selectivity for desirable anti-obesity effects.
This is accomplished by the down-regulation of adrenoceptor types
or subtypes associated with unwanted cardiac or pressor effects
and with sustained activation of adrenoceptor types that mediate
thermogenesis, lipolysis and protein retention.
Arner (1993) approaches the mechanism of ephedrine action from
the lipolysis aspect. He notes that catecholamines have both lipolytic
and antilipolytic effects, so that at any time there is a balance
between these effects. However, it has been suggested that lipid
metabolism in man is mainly controlled by inhibitory modulators,
and adenosine has been shown to reduce the sensitivity of lipolytic
beta-adrenoceptors, particularly in subcutaneous fat depots. Several
prostaglandins of the E-type are also potent antilipolytic agents.
Thus the potentiation of the ephedrine effect by caffeine (which
may affect adenosine dynamics) and aspirin (which can inhibit prostaglandin
synthysis) may not be restricted to the synaptic gap, but may also
extend into the actual fat-mobilizing mechanism.
Dulloo (1993) noted that in early investigations of ephedrine use
as an anti-obesity agent, attention focused on the main action of
ephedrine in reducing appetite (the anorexic effect). It now appears
that the thermogenic and lipolytic effects are the main properties
that make ephedrine so suitable for use as a weight loss aid. Indeed,
significant improvements of rates of weight loss occur at ephedrine
dosage levels far below those required to achieve detectable main
effects, and increasing dosage to the level at which main effects
occur does not necessarily give better rates of weight loss (Daly
et al., 1993).
While the actions of ephedrine makes it an ideal adjunct for regulating
and controlling weight problems, it will be obvious to those skilled
in the art that it may also be useful as an ergogenic aid to improve
physical performance. The acute action is to increase energy availability
and, thus, increase the capacity for physical exertion, while the
longer-term actions result in an increase in muscle mass, particularly
when combined with appropriate diet programs and training exercises.
Indeed, Yang and McElligott (1989) have commented that beta-adrenergic
agents may act as very effective anabolic agents when given over
long periods of time. Both the beneficial ergogenic effects and
the valuable effects on weight loss stem from the combination of
the effects of ephedrine on lipolysis and its thermogenic effects.
Thus by increasing the rate at which fat is released from body stores
(lipolysis) while simultaneously increasing the metabolic rate (thermogenesis),
those wishing to lose weight may accelerate the removal of unwanted
fat stores.
At the same time, since the administration of ephedrine means there
is increased availability of substrates (the free fatty acids which
are released from the fat stores) for oxidation, the body has access
to greater amounts of energy. The body's use of these substrates
spares protein that might otherwise be oxidized for energy. Therefore,
the use of ephedrine in conjunction with additional favorable circumstances,
namely a high protein intake and an exercise program, will also
result in increased availability of amino acids for incorporation
into protein in the muscle mass.
From the foregoing, it will be obvious to those skilled in the
art that the agents most suitable for inducing weight loss in those
with excess weight, or, for persons of normal weight, increasing
energy availability and/or muscle mass, would be sympathicomimetic
(adrenergic) agents whose mechanism of action is mainly indirect,
resembling that of ephedrine, and whose pharmacokinetics favor retention
of the agents in the periphery rather than passage into the brain.
Agents whose profiles match these requirements would be less likely
to cause central nervous system stimulation under normal conditions
of use, but would still possess enough central action to suppress
the hunger center. The partition in favor of peripheral tissues
would result in increased levels of these agents at the sites of
the beta-3-receptors, which mediate lipolysis and thermogenesis.
It is also widely believed that sympathicomimetic agents possessing
mainly an indirect mechanism of action would be less likely to cause
unwanted side effects and less likely to result in addictive situations.
Hitherto, the only such agent which has been shown to act in the
optimized ideal fashion has been ephedrine itself. Ephedrine has
some drawbacks, however. It is primarily provided in pharmaceutical
forms which allow quick release in the body for the alleviation
of acute respiratory ailments whereas, for the purposes of inducing
lipolysis and thermogenesis, a slower release is desirable. Furthermore,
many of those who are overweight prefer not to use agents which
are presented as drugs. In addition, for a variety of health conditions,
such use will often be contraindicated because of the risk of potentially
hazardous side effects, which risk could be increased because of
the weight problem.
Prior to this invention, those wishing to avail themselves of natural
products for eliciting weight loss or increasing muscle mass have
had no choice other than to use products containing Ephedra herb
(Ephedraceae), which contains ephedrine together with related alkaloids.
However, because of concerns about the use of Ephedra herb products,
many do not avail themselves of this opportunity.
The provision of a natural product that acts in the ideal fashion
noted above would therefore provide major benefits to those seeking
to lose weight or improve their physical fitness, or both, and would
be especially useful to those who prefer not to take either drug-like
products or natural products containing ephedrine alkaloids.
SUMMARY OF THE INVENTION
The present invention relates to the discovery that certain plants
contain adrenergic amines of the group consisting of synephrine,
hordenine, octopamine, tyramine and N-methyltyramine that are useful
to assist in weight loss, adding muscle mass, and/or increasing
physical performance. More particularly, the present invention relates
to the discovery that useful and exploitable levels of these adrenergic
amines only occur in plant species of Citrus.
In still greater detail, the invention relates to the discovery
that these useful levels only occur in parts of the plant that are
not normally eaten, including the leaves and bark, or in the fruit
in certain stages of maturity. In yet further detail, the invention
relates to a composition in which the plant parts are used in various
forms to provide therapeutically effective doses of these adrenergic
amines and to a composition in which the adrenergic amines are extracted
from the plant parts using methods well known to those schooled
in the art.
In further detail, the invention relates to the use of the composition
to stimulate beta-receptors in a predominantly indirect fashion
thereby stimulating thermogenesis, increased metabolic rate and
lipolysis. In yet additional detail, the invention relates to the
use of the composition to control appetite by suppressing hunger.
In further detail, the composition of the invention has utility
in regulating or treating weight problems as well as increasing
vitality, energizing, and in the long term increasing muscle mass.
In still further detail, the amounts of the adrenergic amines of
this invention needed to be effective can be as low as one mg ingested
three times daily, and the low dosage effective range is from one
to five mg ingested up to 3 or 4 times daily. Still further, the
preferred use of this invention is to administer single doses of
from 8 to 30 mg up to 4 times daily, making a total daily dose of
about 100 to 120 mg per day.
In a further aspect, the present invention relates to a method
for weight loss and a method for ergogenesis to aid in improved
physical performance and to aid in adding lean muscle mass to the
body.
An object of the present invention is to provide a composition
containing an effective weight control/weight loss amount of at
least one of the group of adrenergic amines synephrine, hordenine,
octopamine, tyramine and N-methyltyramine.
Another object of the present invention is to provide a composition
containing an effective amount of at least one of these adrenergic
amines to stimulate the addition of lean muscle mass.
Yet another object of the present invention is to provide a composition
containing an effective amount of at least one of these adrenergic
amines to enhance physical performance.
Still another object of the invention is a method for promoting
weight control, weight loss, enhanced physical performance, and/or
the addition of lean muscle mass which includes the step of administering
to a subject an effective amount of at least one of the group of
five adrenergic amines.
Another object of the invention is to obtain the adrenergic amines
from the plant material of the genus Citrus, and more specifically
from the leaves, bark, unripe fruit, ripe fruit and peel of the
species Citrus aurantium and/or Citrus reticulata.
In achieving the above and other objects, one feature of the invention
is that the composition can be administered in the form of the plant
material in a tablet, capsule or other pharmacologically appropriate
carrier, in the form of a tea, or in the form without plant material
in a tablet, capsule or other pharmacological carrier which contains
at least one of the group of five adrenergic amines extracted from
the plant material.
DESCRIPTION OF DRAWINGS
FIG. 1 shows the chemical structures of the five alkaloids: synephrine,
hordenine, octopamine, tyramine and N-methyltyramine.
DETAILED EMBODIMENTS OF THE INVENTION INCLUDING BEST MODE
It has now surprisingly been found that agents present in plants
other than Ephedraceae may also act as sympathicomimetic agents
with suitable mechanisms of action in the body, and use of these
plants can therefore result in benefits as outlined with regard
to body weight regulation and physical performance.
The value of the use of such plants in body weight regulation and
physical performance has not been suspected prior to this invention.
Though the plants concerned have acknowledged uses and long histories
as foods, they have not been used to induce weight loss or for ergogenic
purposes. The agents these plants contain have likewise not previously
been related to weight loss or ergogenic applications. Furthermore,
the agents are generally only present in significant amounts in
parts of the plant which are considered as inedible waste for normal
consumption, or are only present during certain stages of the growth
cycle when the plant would not normally be consumed. While it is
true that the plants or their parts harvested during a particular
stage of growth have also been used as medicinal herbs or traditional
remedies, particularly in the Orient, these uses have also not included
applications in either weight loss or for ergogenic purposes, and
the uses according to the invention are therefore novel and surprising.
The agents contained in the plants which are used in accordance
with the invention include synephrine, hordenine, octopamine, tyramine
and N-methyltyramine, and they may be found in various species of
plants, both food plants and otherwise, as detailed by Wheaton and
Stewart (1970), including, but not limited to, Amaryllidaceae, Leguminosae,
Liliaceae, Rutaceae, Cyperaceae, Solanaceae and Berberidaceae. FIG.
1 shows the chemical structures of synephrine, hordenine, octopamine,
tyramine and N-methyltyramine.
However, in terms of practical utility, the levels of these agents
generally only reach useful values, that is to say levels in excess
of 0.1% of dry mass, in certain species of Rutaceae. Furthermore,
these useful levels are only achieved during phases of growth where
the plant would not normally be used for food, or in parts of the
plant which are not considered part of the edible portion such as
the leaves. In particular, relatively high levels of synephrine
and related substances (such as octopamine, hordenine, tyramine
and N-methyltyramine) can be found in various Citrus species, including
in particular, but not restricted to, strains of Citrus reticulata
(also known as tangerine or mandarin orange), Citrus aurantium (also
known as C. florida, C. vulgaris, C. bigaradia, Sour orange, Bitter
orange, Seville orange, Neroli orange), Citrus medica, Citrus maxima,
Citrus limon, Citrus aurantiifolia, Citrus paradisi, Citrus sinensis
and Poncirus trifoliate (trifoliate orange).
These various Citrus species have been used, and continue to be
used, for a variety of food purposes and for their health benefits,
but have hitherto not been revealed as herbs or plants which have
value in the treatment of weight problems or for improving physical
performance and fitness.
Herbs based on Citrus materials have long been used for a variety
of medicinal applications unrelated to weight loss. In this respect,
for example, the literature discloses a number of Oriental herbs
for medicinal applications, including the following:
Zhi shi: The immature (dried) fruit of Citrus aurantium is used
for the treatment of digestive disorders, to induce diuresis, and
as a mucolytic agent to relieve chest congestion (Ou Ming, 1989).
It may contain levels of the desired active agents of up to 0.9%.
Reid (1986) describes Zhi shi as the unripe fruit of the trifoliate
orange, indicated for digestive disorders and as an expectorant,
while Huang (1993) implies that this herb is derived from mature
fruits of Citrus aurantium.
Zhi Qiao: This herb is also the immature fruit of Citrus aurantium,
and is used to treat indigestion and to correct mild ptosis of the
uterus (Huang, 1993). Levels of active substances are similar to
those in the herb Zhi shi, and the distinction between these two
herbs appears to be based on degree of maturity (of the fruit) and
the area in which traditionally used.
Chen pi: The herb Chen pi is dried peel of Citrus reticulata. This
may also be called Jiu Hong, and is used as a digestive aid, antiemetic,
antitussive and antiflatulant (Huang, op. cit.). The herb also has
anti-infective properties (Ou Ming, op. cit.).
Qing pi: This herb is immature Citrus reticulata, or in some cases
the peel thereof. It is used to treat digestive disturbances and
to alleviate pain, as an expectorant, and to relax smooth muscle
(Ou Ming, op. cit.).
Fo Shou: Also known as Fructus Citri Sarcodactyli, the fruit of
Citrus medica var. sarcodactylus, it is used for treatment of digestive
disorders, for dysmenorrhea, chest congestion and as an expectorant
(Ou Ming, op. cit.).
According to Bown (1995), Citrus aurantium and Citrus reticulata
are known by different Chinese names in part according to their
uses. For example, the whole fruit, peel, unripe fruit, unripe peel
and seeds of C. reticulata are referred to as "Chen pi"
("dried ripe peel") to treat indigestion, flatulence,
vomiting and wet coughs, but as "Qing pi" ("unripe
peel") when used to treat liver and gall bladder disorders,
bronchial congestion, mastitis, breast cancer, and pain in liver,
chest or breasts, while the form "Ju he" (Jiu hong; normally
the seeds) is used to treat lumbago, orchitis and mastitis.
In Western traditional medicine, Wichtl (1994) describes use of
the mature or immature fruit of Citrus limon for the treatment of
digestive problems and phlebitis, and notes that the flowers of
Citrus aurantium and occasionally Citrus sinensis are also used
for their sedative effects. Wichtl also reports that dried peel
of Citrus aurantium, or the dried whole immature fruit, is used
in gastrointestinal remedies, tonics, roborants and cholagogues.
Grieve (1992) describes use of lemon juice for the treatment of
rheumatism, and of the oils from various oranges for alleviation
of chronic bronchitis. Font Quer (1982) refers to the antispasmodic
and hypnotic properties of Citrus aurantium flowers, and to the
use of the dried peel as a gastric tonic and antiflatulant.
Numerous other standard textbooks of herbology refer to Citrus
material of various types and its use for the alleviation of gastric
disorders. However, neither the use of such materials to induce
weight loss nor their use to increase physical performance or muscle
mass are described, and these uses are therefore surprising, novel
and not anticipated.
The active agents synephrine, hordenine, octopamine, tyramine and
N-methyltyramine are known to be adrenergic agents, and synephrine
is still used under the synonym oxedrine in some countries for the
treatment of hypotension (Reynolds, 1982). However, apart from occasional
use of tyramine as a diagnostic agent in suspected cases of phaeochromocytoma,
their use has been abandoned in favor of newer, synthetic adrenergic
agents, and no indication of their value in weight loss or physical
performance can be found in the literature. Their valuable properties
in these respects are therefore unanticipated, surprising and novel.
The Citrus material used in accordance with the invention may consist
of any portion of the plant which contains useful amounts of the
agents as defined above, which may vary depending on the species,
stage of growth, season, and agronomic conditions. For example,
leaves of Citrus reticulata are preferred to other parts of this
plant, and may show levels of synephrine and related alkaloids of
1.1% or more, based on dry matter, while the peel of the immature
fruit shows levels of only 0.2%-0.4%. In the case of Citrus aurantium,
the preferred form is the whole immature fruit of the amara variety,
though the peel of the mature fruit can also be used. In both Citrus
aurantium cases, total levels of 0.2%-0.9% of synephrine and the
related agents are regularly found. Both the peel and the whole
fruit (immature or mature) of the dolce variety also have utility,
though levels generally do not exceed 0.4%.
Though it is possible to use a variety of Citrus materials in accordance
with the invention, it is more convenient to utilize Citrus materials
which already exist in appropriate form and which are generally
available as traditional herbs and remedies. For example, the agents
are present in the residues remaining after steam distillation of
Citrus aurantium fruits to obtain the essential oils. In this respect,
various Chinese herbs, or materials from other geographic locations
prepared in the same way, are particularly useful, as are Citrus
reticulata leaves.
The Chinese herbs which are most convenient for use are:
Zhi shi, which is the immature (dried) fruit of Citrus aurantium,
but may also consist of the peel of the mature fruit, or the peel
of either. This herb contains 0.2%-0.9% total alkaloids with synephrine
predominating.
Zhi Qiao, which is also the immature fruit of Citrus aurantium
has levels of active substances similar to those in the herb Zhi
shi.
Chen pi, the dried peel of Citrus reticulata, may also be called
Jiu Hong. This herb contains 0.1%-0.4% total alkaloids.
Qing pi is the dried immature Citrus reticulata, or in some cases
the peel thereof This herb contains 0.1%-0.4% total alkaloids.
Fo Shou, also known as Fructus Citri Sarcodactyli, is the fruit
of Citrus medica var. sarcodactylus. This herb contains 0.1%-0.3%
total alkaloids.
In addition to the above, peel of the mature or immature fruit
of Citrus limon may conveniently be obtained, since it is also an
item of commerce, while tangerine leaves are also readily obtained
at certain seasons.
In a preferred embodiment of the invention, therefore, material
from Citrus species is given to humans by the oral route, either
concurrently with caloric restriction or in the absence of caloric
restriction, for the purpose of controlling body weight. The invention
works predominantly by increasing thermogenesis, that is, by increasing
the metabolic rate and facilitating lipolysis. The invention also
exhibits a hunger-suppressing effect which may become more obvious
in higher doses as well as in individuals in which the active agents
pass the blood-brain barrier more readily. Thus, most users will
benefit mainly from the thermogenic effect and additionally may
also experience mild suppression of hunger such that both mechanisms
operate simultaneously, thereby providing an added benefit. In addition,
the said material can be given to humans, either with or without
a high protein diet (>1.25 gm protein/kg ideal body weight/day),
for the purpose of increasing physical performance in the short-term
and to increase muscle mass and functionality in the long term.
The Citrus material so used is selected for its content of active
agents as defined above such that the total amount of Citrus material
ingested provides a sufficient amount of the active agents to achieve
the desired effects. In this respect, the preferred embodiment consisting
of a sufficient amount would be defined as at least 0.04 mg of active
agents per kilogram ideal body weight per dose at any one time.
In practical terms this corresponds to 2.8 mg for a person of 70
kg ideal body weight.
Ingestion of active agents in the range of 0.01 mg to 0.10 mg per
kilogram of ideal body weight per serving will be effective in accomplishing
the desired goal of weight loss, though more preferred is a range
of 0.02 mg to 0.06 mg per kilogram of ideal body weight, and most
preferred is 0.05 mg per kilogram of ideal body weight. Though ingestion
of larger amounts of the agents will not diminish the beneficial
effects, the effects may not necessarily be increased while the
possibility of side-effects due to activation of other adrenergic
systems would be increased. Thus, at an intake level of 1 mg per
kilogram of ideal body weight per serving, it is possible that the
adrenergic receptors in the cardiovascular and central nervous system
could be activated thereby resulting in increases in blood pressure
as well as tachycardia, nervousness, agitation, tremors, and insomnia.
Daily intake of the active agents for effective body weight loss
according to the invention is in the range of 0.16 mg to 1 mg per
kilogram of ideal body weight. Thus, an adult male whose desired
body weight is 176 pounds would lose weight according to this invention
with servings of 4 mg, with total daily intake in the amount of
32 mg.
In this context, the active agents are deemed to be any one or
more of synephrine, hordenine, octopamine, tyramine and N-methyltyramine,
whereby the sufficient amount may be any one singly, or a combination
of the agents that together provide a sufficient amount.
Because levels of the said agents are often relatively low and
variable, and also because in their natural state the agents are
associated with parts of the plant that are unpalatable, it may
be difficult to achieve an intake of Citrus material in a volume
sufficient to provide a suitable amount of the agents as defined
above.
To enhance edibility, the Citrus material may be consumed as a
concentrate or as an extract in either dry or liquid form. By producing
a concentrate or extract, the levels of the agents in the material
are increased to an effective level. There are several ways readily
known to those schooled in the art which permit production of a
concentrate or extract. The Citrus material may be enriched in the
agents, for example, by extraction of the Citrus material with water,
dilute acids or certain organic solvents, including mixtures thereof
with water, followed by drying on a carrier of unconcentrated Citrus
material, or by drying on a carrier of another suitable material.
Such a suitable material may include, but is not limited to, maltodextrins,
starch, protein or other carrier material, the nature of which will
be obvious to those skilled in the art of manufacturing extracts
of botanical materials. The Citrus material may also be extracted
and concentrated without drying to give a liquid extract that can
also be consumed.
When prepared as an extract or concentrate, the Citrus material
is preferably dried so that it may be given in the form of tablets,
capsules, powders or other convenient form, or it may be admixed
with foods or special food products, or it may be given in the form
of a tea or tisane. When prepared as a liquid extract, the Citrus
material may be consumed as drops, or from an appropriate liquid
measure (teaspoon), or it may be admixed with other liquids or incorporated
into solid food products. Preparation as an extract or concentrate
permits production of standardized amounts of the active agents
so as to produce a less variable response in terms of desired weight
loss and/or the desired increase in muscle mass.
If it is not prepared as an extract or concentrate, the Citrus
material may be given fresh, but is preferably dried so that it
may be given in the form of tablets, capsules, powders or other
convenient form, or it may be admixed with foods or special food
products, or it may be given in the form of a tea or tisane.
For example, the dried leaves of Citrus reticulata var. Blanco
may be filled into tea bags to give a refreshing vitalizing drink
that enervates and suppresses hunger for long periods, while dried
immature fruits of Citrus aurantium var. amara are best milled to
a fine powder and either tabletted or filled into capsules for repeated
oral administration to achieve similar effects over a period of
weeks or months.
The Citrus materials may also be admixed with other ingredients
to form the basis of a dietary product, which may either be a nutritional
drink or a nutritional bar. One such nutritional bar can provide
15 grams of protein, 26 grams of carbohydrate and 5 grams of fat
in addition to a quantity of the Citrus material. Such products
may thus be used as meal replacements by those seeking to lose weight,
or by those requiring nutritional support during sporting activities,
whereby the benefits of the Citrus material are supported by the
nutritional content of the food product.
The Citrus material, either in the form of an extract or as the
natural material, may also be given in combination with other herbs
that possess beneficial effects for humans, and particularly in
respect to weight loss or improvements in physical performance.
In this connection, suitable herbs and foods include those herbs
and foods that contain methylxanthines such as caffeine, theobromine
and theophylline, which by virtue of their inhibition of the enzyme
phosphodiesterase may potentiate the thermogenic actions of the
Citrus materials and increase the actions at the level of the beta-3-receptors.
At the same time, the actions of methylxanthines on alpha-receptors
may serve to reduce or eliminate any unwanted cardiovascular effects,
such as peripheral vasoconstriction and increase in blood pressure,
that would be undesirable within the context of weight loss or improved
physical performance. Suitable herbs and foods in this respect include,
but are not limited to, Paullinia cupana (Guarana), Ilex paraguariensis
(Mate), Cola nitida, Cola acuminata, Camellia sinensis (Tea), Coffea
arabica (Coffee) and Theobroma cacao (Cocoa), whereby the herb or
food may be used as the natural material or an extract thereof.
In such cases, the herb so chosen is admixed with the Citrus material
in a suitable form to provide a solid or liquid dosage unit.
The invention is further exemplified and illustrated by the following
examples which are not limiting.
EXAMPLE 1
Tea-bags containing each 2.5 grams dried tangerine leaves (Citrus
reticulata var. Blanco) were prepared. The tangerine leaves had
a synephrine content of 1.1% and approximately 0.5% of the related
alkaloids, which did not resolve completely on HPLC analysis, thus
providing a total amount of 40 mg of alkaloids per serving. The
tea bags were infused for 5 minutes in hot water at 85.degree. C.,
and the resulting tisane was given to 5 volunteers (GL, RE, NS,
CS, PS). All volunteers reported increased energy, which in one
case was perceptible as agitation and nervousness, persisting for
8-10 hours. During this period, subjects did not feel hungry and
refrained from eating snacks or meals.
EXAMPLE 2
A Zhi shi powder (Citrus aurantium, var. amara, whole immature
fruit dried) was obtained from a Chinese source. This powder contained
0.49% synephrine and approximately 0.5% of the related alkaloids.
It was mixed with 2% magnesium stearate and 1% silicon dioxide to
confer flowability and filled into white size 0 snap-fit capsules.
Capsule fill weight was 490 mg, plus or minus 5%. Subjects DJ and
HAF then took 3 capsules 3 times daily for four weeks, corresponding
to an intake of 14 mg total alkaloids per serving, or 42 mg per
day, without deliberate restriction of food intake. Subject DJ,
initial weight 105.4 kg, showed a fall in body weight to 100.9 kg,
while the body weight decrease in subject HAF was from 74.5 kg to
72.0 kg. Upon ceasing use of capsules, subjects showed slow increases
in body weight at a rate of approximately 0.4 kg per week.
EXAMPLE 3
A portion of the Zhi shi powder used in Example 2 was concentrated
by extraction with water and redrying on a portion of the original
material to give a dry extract with a total alkaloid content of
3.77%, of which approximately 1.9% was synephrine itself This material
was filled into capsules as in Example 2 to provide a product with
18 mg alkaloids of the synephrine group per capsule. Subjects DJ
and HAF then took 1 capsule of this product 3 times daily for four
weeks, providing a daily intake of 54 mg synephrine and related
alkaloids. During this time, subject DJ, without deliberate restriction
of food intake, showed a decrease in weight from 93.2 kg to 90.4
kg, but subject HAF had to cease use after the first day because
of unpleasant sensations of agitation and nervousness.
EXAMPLE 4
Two batches of nutrition bars were prepared using the Thermobar
concept, that is, chocolate-flavored taffy bars weighing 57 grams
providing 15 grams protein, 26 grams carbohydrate, 5 grams fat and
200 kilocalories. One batch of the bars additionally contained 0.5
grams of the extract from Example 3 per bar. Subject RE was given
two of the placebo bars. Respired gases were collected by the Douglas
bag technique starting 30 minutes before ingestion of the bars and
for a 90 minute period thereafter. The respiratory quotient (RQ)
was initially 0.78 and rose to 0.86 during the 60 minutes after
bar consumption. Two days later following the identical protocol,
the subject consumed two of the bars containing the Zhi shi extract,
corresponding to about 38 mg of synephrine and related alkaloids;
respiratory quotient rose from 0.77 to 0.89 during the 60 minutes
after bar consumption. Conversion of these results of indirect calorimetry
to energy expenditure showed that the Zhi shi extract had increased
the energy expenditure and the thermic response to the food by about
2.5%, thus indicating a thermogenic effect of the ingested alkaloids.
EXAMPLE 5
A group of 9 women, of whom 6 were mildly obese, 1 moderately obese
and 2 slightly overweight, with Body Mass Indices ranging from 23.1
to 33.4 were placed on a diet providing 900-1000 kilocalories per
day, more than 100 g protein per day and less than 100 g carbohydrate
per day. From day 8 of this dietary regime, they were additionally
given a product in capsules identified as "Herbal Balance Z-4",
providing each 325 mg of a dried Citrus aurantium (immature whole
fruit) extract, 125 mg of a dried Paullinia cupana extract, 5 mg
of Ginkgo biloba extract and 5 mg Panax ginseng extract. They were
instructed to take 1-3 capsules 1-3 times per day, and to remain
at a comfortable intake level within these parameters; 2 subjects
stabilized at 2 capsules per day, 2 at 3 capsules per day, 2 at
4 capsules per day and 3 at 5 capsules per day. The Citrus aurantium
extract contained 4.14% total alkaloids by HPLC, with approximately
2.8% as synephrine itself The daily use recorded thus corresponds
to a total alkaloid intake of 27.0 to 67.5 mg.
Starting weights, weights at day 8, and weights at day 15 were
determined. In addition, each subject completed a daily mood, appetite
and satiety rating questionnaire.
Height Weights (kg): Subject Age: (m) BMI: Day 0 Day 8 Day 15 HS
38 1.57 24.9 61.4 60.5 57.3 GA 40 1.67 29.7 82.7 81.6 80.0 CB 25
1.65 23.1 62.7 62.7 60.0 CA 46 1.61 26.7 69.1 68.2 64.5 LG 30 1.60
25.7 65.8 64.5 62.8 AW 41 1.64 33.4 90.1 88.6 85.4 AEM 31 1.67 23.8
66.6 65.4 64.1 CRT 23 1.73 25.9 77.5 76.8 74.5 LB 29 1.62 26.0 68.2
67.3 65.4
A statistical analysis showed a mean of 0.94 kg during the first
week when no product was given and 2.40 kg during the second week
when product was taken, the Z-4 product significantly increased
weight loss (P<0.05) during the second week.
Statistical Analysis
Means.+-.standard deviations:
Body Weight (kg) Weight Loss (kg): Day 0 71.57 .+-. 9.75 Day 8
70.62 .+-. 9.54 0.94 .+-. 0.43 Day 15 68.22 .+-. 9.54 2.40 .+-.
0.84
Full data on body weight indicated:
Day: Mean: SD: Median: Minimum: Maximum: 0 71.57 9.75 68.20 61.40
90.10 8 70.62 9.54 67.30 60.50 88.60 15 68.22 9.54 64.50 57.30 85.40
Full data on weight loss indicated:
Day: Mean: SD: Median: Minimum: Maximum: 8 0.94 0.43 0.90 0.00
1.50 15 2.40 0.84 2.30 1.30 3.70
This result is particularly interesting, since part of the observed
weight loss during the first week was due to water loss as a result
of changes in electrolyte and water balance (adaptation to reduced
caloric intake).
The foregoing description represents the best mode presently known
to the inventor of practicing the invention, and is not intended
to limit the scope of the present invention which is set forth in
the following claims. Likewise, those skilled in the art, given
the present disclosure, will recognize that equivalent methods and
materials may also be used in practicing the invention. It is contemplated
that such equivalents are also within the scope of the present invention. |