Weight loss abstract
There is disclosed a method of treating weight loss disorders.
This method consists essentially of administering to a mammal, such
as a human, a daily dosage of at least about 10 milligrams per 37
kilogram body weight of at least one opiate antagonist. These opiate
antagonists include naloxone, naltrexone, nalorphine, diprenorphine,
levallorphan, pentazocine, metazocine, cyclozocine, etazocine, and
pharmacologically acceptable salts thereof. The use of naloxone
hydrochloride as the opiate antagonist is preferred.
Weight loss claims
I claim:
1. A method of treating weight loss disorders consisting essentially
of administering to a mammal having a weight loss disorder a daily
dosage of an effective amount which consists essentially of at least
about 10 milligrams per 37 kilogram body weight of at least one
opiate antagonist.
2. The method of claim 1 wherein said mammal is a human.
Weight loss description
BACKGROUND OF THE INVENTION
This invention relates generally to the use of narcotic antagonists,
including naloxone and naltrexone, to counteract the physiological
and/or psychological effects of starvation by food and fluid deprivation
in animals, including humans. In particular, this invention relates
to a method for treating mammals, including humans, with opiate
antagonists in order to alleviate weight loss disorders, including
anorexia nervosa and bulimia.
Deprivation of food and fluids leading to starvation with accompanying
weight loss may be imposed by "circumstances", as, for
example, famine, or by others, as, for example, a prisoner of war
situation. It may also be self imposed, as in the case of anorexia
nervosa and bulimia.
The term "anorexia" refers to a medical symptom indicating
a lack or loss of appetite for food (see Dorland's Medical Dictionary,
25th Ed.) which may occur in a variety of medical conditions and
diseases. In contrast, the term "anorexia nervosa" denotes
a diagnosis of a severe nervous condition characterized by a relentless
addiction-like pursuit of thinness to the point of cachexia by voluntarily
withholding foods and fluids, and, at times, by excessive exercising,
that results from dieting to achieve a socially pleasing slim appearance.
Anorexia nervosa is also associated with physiological changes
that include abnormal endocrine and metabolic functions, variations
from normal urine concentrations, and a lowering of body temperature,
respiratory, and cardiovascular functions. These changes appear
to be part of a universal adaptive mechanism of starvation since
they are reversible with weight gain and do not differ substantially
from those found in other forms of starvation, such as famine or
prisoner of war situations.
Bulimia is characterized by excessive intake of food and fluids
followed by, or associated with, purgatory maneuvers designed to
rid oneself of the ingested food and fluids. Such purgatory self-manipulations
include, but may not be restricted to vomiting, use of laxatives
and rectal enemas, and depletion of body fluids by diuretic agents.
Each of these methods leads to body fluid loss and disturbance of
the body's electrolyte balance. Excessive food intake and purging
behavior usually results from excessive dieting and can become an
addictive compulsive habit, especially in distressed and depressed
individuals.
Opiate antagonists are synthetic compounds which may be given to
opiate addicts to block the physical and/or psychological effects
of opiates. These opiate antagonists include naltrexone and naloxone.
Naloxone is a powerful antagonist of exogenous opiates and naturally
occurring opioid peptide hormones which have opiate like effects
on the organism. It is a relatively pure opiate antagonist and is
administered intravenously. Naltrexone is known to be a powerful
antagonist of exogenous opiates and naturally occurring opioid peptide
hormones which have opiate like effects on the organism. It may
be prepared in accordance with the teachings of U.S. Pat. No. 3,322,950
and Canadian Pat. No. 913,077. Naltrexone is a relatively pure opiate
antagonist and is effective when given orally.
Naltrexone has been used in the past to induce anorexia as discussed
in U.S. Pat. No. 4,217,353. In that patent, there is discussed certain
studies directed principally to the safety and efficacy of naltrexone
as an oral narcotic antagonist. In these studies, the patentee notes
that there are some isolated and contradictory statements concerning
the effect of naltrexone on appetite in man.
One study has suggested the use of naloxone in treating anorexia
nervosa. See Moore et al "Naloxone in the Treatment of Anorexia
Nervosa: Effect on Weight Gain and Lipolysis", 74 J. Roy. Soc.
Med. 129 (1981). This study of the effect of naloxone on anorexics
is inconclusive, however, because the naloxone treatment was coupled
with hypercaloric feeding (3000-4000 kcal dietary intake) as well
as the administration of antidepressant medication (usually amitriptylene).
A letter in that same publication suggests that the weight gain
described in the Moore et al study might be related to interference
with vomiting, both voluntary and involuntary. It also discusses
a possible role of opiate antagonists in the therapy of anorexia
nervosa. 74 J. Roy. Soc. Med. 631. The "vomiting" explanation
was subsequently discussed and dismissed by a co-author of the Moore
et al article. 74 J. Roy. Soc. Med. 945.
The search has continued for improved methods of treating weight
loss disorders such as anorexia nervosa and bulimia. This invention
was made as a result of that search.
OBJECTS AND SUMMARY OF THE INVENTION
Accordingly, it is a general object of the present invention to
avoid or substantially alleviate the above-discussed problems of
the prior art.
A more specific object of the present invention is to provide a
method for treating weight loss disorders wherein the physiological
and/or behavioral changes which result from these disorders are
reversed and the patient is not subjected to harmful side effects.
A further object of the present invention is to provide for weight
gain in a patient afflicted with anorexia nervosa.
Another object of the present invention is to eliminate the self-destructive
excessive food intake and purging behavior in patients afflicted
with bulimia, which leads to loss of body fluids and electrolyte
imbalance.
Still other objects and advantages of the present invention will
become apparent from the following summary of the invention and
description of its preferred embodiments.
The present invention provides a method of treating weight loss
disorders. This method comprises administering to a mammal, such
as a human, a daily dosage of at least about ten milligrams per
37 kilogram body weight of an opiate antagonist. The opiate antagonist
may be naloxone, naltrexone, nalorphine, diprenorphine, levallorphan,
pentazocine, metazocine, cyclozocine, etazocine, or pharmacologically
acceptable salts thereof. Mixtures of two or more opiate antogonists
may also be used.
The present invention is based, in part, on the discovery that
prolonged starvation triggers a physical and mental adaptive mechanism
that is mediated by endogenous opioid peptides or endorphins. Increased
preoccupation with food as well as a reduction of the body metabolism
and a numbing of the psychological effects of starvation appear
to be the essential features of this mechanism. Consistent with
these features, anorexia nervosa is not associated with a loss of
appetite, as earlier thought, but is characterized by an increasing
preoccupation with food and intensified food related activities
including a powerful urge to eat as dieting progresses. This urge
is resisted by anorexics for the sake of benefitting from the sense
of well-being mediated by elevated levels of endorphins.
Endorphins are powerful enforcers which produce tolerance and dependence
by mediating cellular mechanisms of addiction. In sufficient concentration,
they provide a sense of well-being. Most anorexics initiate a starvation
diet to counteract a sense of distress and/or depression. This sense
of well-being provided by the endorphins makes anorexics susceptible
to the addictive effects of the endorphins. Once the addictive mechanism
is initiated, the need to overcome tolerance to the reinforcing
effects of the endorphins causes the anorexic to seek progressively
lower weight which, absent intervention such as by the method of
the present invention, can ultimately lead to death.
The present invention is also based, in part, on the discovery
that endogenous opioid peptides are triggered by the purgatory acts
performed by bulimics. These peptides are the reinforcing substrate
which motivates and perpetuates bulimic behavior consistent with
the pattern of addiction.
Opiate antagonists, such as naloxone and naltrexone, act as powerful
antagonists of endogenous opiates and naturally occurring opioid
peptide hormones by blocking the receptor sites, and thus the euphoria-producing
effects, of opiates. Once self-starvation no longer "feels
good", as a result of this blockage, the patient may be induced
to follow a prescribed diet which, in combination with appropriate
psychotherapy, will enable weight gain and the correction of physiological
and/or behavioral problems associated with the weight loss disorder.
The use of minor amounts of opiate antagonists will not effectively
counteract the effects, including the addictive effects, of the
endorphins. While the use of minor amounts of opiate antagonists,
such as the amounts disclosed in the above-discussed Moore et al
article, may have an effect vis-a-vis lipolysis, such amounts are
substantially ineffective to counteract the addictive and other
effects of the endorphins.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
As noted above, the present invention is directed to a method of
treating weight loss disorders such as anorexia nervosa and bulimia.
The method consists essentially of administering to a mammal, such
as a human, a daily dosage of generally at least about 10, typically
from about 30 to about 200, and preferably from about 50 to about
150 milligrams of an opiate antagonist based upon a 37 kilogram
body weight.
These opiate antagonists include naloxone, naltrexone, nalorphine,
diprenorphine, levallorphan, pentazocine, metazocine, cyclozocine,
etazocine, and pharmacologically acceptable salts thereof. Mixtures
of two or more opiate antagonists may also be used.
These opiate antagonists are described above in terms of their
common names. They may also be described in terms of their chemical
names. Naloxone, for example, is also known as N-allylnoroxymorphone;
naltrexone is (-)-17-(cyclopropylmethyl)-4,5,-alpha-epoxy-3,14-dihydroxymorphinan-6-one;
nalorphine is the alkyl derivative of morphine, i.e., N-allynormorphine;
levallorphan is 1-N-allyl-3-hydroxynorphinan; and pentazocine is
2-dimethylallyl-5,9-dimethyl-2'-hydroxy-benzomorphan.
Naloxone, naltrexone and/or their pharmacologically acceptable
salts are preferred for use in the present invention. Naloxone and
its pharmacologically acceptable salts are administered intravenously
whereas naltrexone and its pharmacologically acceptable salts are
administered orally. Naloxone hydrochloride is particularly preferred.
The opiate antagonist is administered either orally or intravenously
for a time sufficient to allow the patient's weight to increase
and to break the addictive effect of the opiates. This time period
may vary widely and is dependent upon the circumstances in a particular
case.
This invention is further illustrated by the following Examples.
EXAMPLES
Nine female hospitalized adolescents, who fulfill the Research
Diagnostic Criteria for anorexia nervosa, as described in Feighner
et al in "Diagnostic Criteria For Use In Psychiatric Research",
26 Arch. Gen. Psychiatry 57 (1972), and who have a body weight of
approximately 37 kilograms, are treated with naloxone, naltrexone,
and placebo drugs commercially available from DuPont Pharmaceuticals,
Inc. Naloxone hydrochloride is dissolved in sufficient normal saline
solution to be infused over a four hour period. Four different dosages
(0.2; 0.4; 0.8; and 1.2 milligrams per kilogram of body weight)
are administered over a four hour period to each patient in the
study. One four hour administration is provided on every other day.
Each day of naloxone treatment is followed by a day of placebo treatment
in a double blind arrangement comprising a four hour intravenous
infusion of a placebo consisting of the inert ingredients of naloxone
hydrochloride dissolved in normal saline solution.
Naltrexone is orally administered to one patient having a body
weight of approximately 32 kilograms in four increasing daily dosages
of 25, 50, 75, and 100 milligrams with each of the dosages matched
by a placebo on alternate days in double blind fashion.
The endorphin dependent hormone levels measured in these subjects
show less response to endorphin receptor blockade by naloxone than
the response of the same hormones to naloxone administration in
normal healthy volunteers. Furthermore, several behavioral observations
made on days of opiate antagonist administration suggest a powerful
effect of endorphins on the regulation of coping, mood, and eating
behavior. Only for the duration of the pharmacological action of
naloxone these subjects displayed a marked change. The well-known
hypervigilant, manipulative irritable, restless, reticent and angry
behavior changed for about 12-24 hours into a state of quiet, tearful
weeping for no apparent reason, of wishing someone close for comfort
and sharing of worried thoughts, and of apparent defenselessness.
Furthermore, the usual avoidance of food and anxiety related to
a fear of obesity gave way to one of quietly accepting the prescribed
diet and enlisting encouragement from staff. These changes occur
under opiate antagonist, but not placebo, administration. Also,
these changes are more apparent with increasing opiate antagonist
dosage.
The principles, preferred embodiments, and modes of operation of
the invention have been described in the foregoing specification.
The invention which is intended to be protected herein, however,
is not to be construed as limited to the particular forms disclosed,
since these are to be regarded as illustrative rather than restrictive.
Variations and changes may be made by those skilled in the art without
departing from the spirit of the invention.
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