Note: Descriptions are shown in the official language in which they were submitted.
CA 02455248 2004-O1-29
TITLE OF THE INVENTION
Oral administration of R-albuterol against obesity
s
FIELD OF THE INVENTION
The present invention is related to a compound for reducing fat and increasing
muscle
strength of obese and superobese people.
io
BACKGROUND OF THE INVENTION
Obesity is a tremendous problem in countries having a high standard of life.
For example,
is the prevalence of obesity among U.S. adults was 19.8 percent in 2000, which
reflects a 61
percent increase since 1991. A total of 38.8 million American adults met the
class~cation
of obesity in 2000.
This problem is not limited to the United States. In Australia 31 per cent of
Aborigines and
2o Torres Strait Islanders were obese in 2001 and half of the Australian
population was either
overweight or obese.
Incidence of obesity among Australian children (7-11 years) has been
increasing at an
alarming rate: in 1985, 1.5% of boys were obese versus 9.9°!° in
2000. There was also an
2s increase for girls: in 1985, 1.9% of girls were obese versus 7.1 % in 2000.
Given all of the health complications associated with obesity, this increase
in the numbers
of obese people is cause for alarm. The development of drugs to combat obesity
has
become highly important with a large number of patents relating to inventions
addressing
3o this problem. However, the practical application of many of the disclosed
prior art anti-
obesity agents as a rule is accompanied by adverse effects or may lead to
dangerous
consequences.
i
CA 02455248 2004-O1-29
US Patent No. 6,015,558 indicates the presence of TNF-alpha in four models of
obese
animals. Thus, the patent claims use of TNF-alpha antagonists as anti-obese
agents that
increase peripheral uptake of glucose as a response to insulin. However,
reduction of
s TNF-alpha level in mammals significantly reduces resistance to infections.
This presents a
significant risk in the population of northern countries and a high risk for
the population of
areas with a tropical climate.
US Patent No. 5,055,460 claims a combination of aspirin, ephedrine, and
caffeine to
io reduce body weight. However, permanent administration of aspirin leads to
ulcer and
gastro-intestinal bleeding. It was indicated that half of people with peptic
ulcer bleeding
were using NSAIDS or aspirin (Am J Gastroenterol. 2003, 98(7):1494-9).
US Patent No. 5,795,880 claims a combination of dehydroepiandrosterone and an
is anorectic agent (specifically fenfluramine) to reduce body weight.
Fenfluramine and
dexfenfluramine are considered to be potent causal factors in the development
of both
aortic and mitral valwlar heart disease. Specifically the appearance of new
aortic
regurgitation highly correlates (R2=0.75, p<0.00001 ) with duration of
exposure to drugs
(BMC Cardiovasc Disord. 2003, 3(1 ):5; Am J Med. 2002, 112(9):710-5). Use of
2o fenfluramine is also associated with primary pulmonary hypertension and
neurotoxicity
(Tex Med. 2000, 96(2): 48-56)
US Patent No. 5,498,424 claims use of megadose of macrolide antibiotics,
specifically
clarithromycin, to reduce weight. Clarithromycin may induce diarrhea, nausea,
and
2s vomiting (Clin Ther. 2003, 25(2): 422-4.3).
US Patent No. 5,723,115 claims use of epidermal growth factor, its activators
and mimetics
against obesity. Epidermal growth factor receptor tyrosine kinase (EGFR)-TK is
a
transmembrane receptor TK that is overexpressed or aben-antly activated in the
most
3o common solid tumors, including non-small sell lung cancer and cancers of
the breast,
prostate, and colon (Oncologist 2003;8(6):531-8.)
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CA 02455248 2004-O1-29
US Patent No. 6,033,656 suggests administration of bisphenol A diglycidyl
ether to reduce
obesity. Literature indicates that this compound is mutagenic (J Endod. 1999,
25(5): 359-
63) and induces allergy (Contact Dermatitis. 1999, 41 (4): 235; Contact
Dermatitis. 2001,
44(2):98-9).
s
US Patent No. 4,673,691 suggests a combination of 2,4-dinitrophenol and
thyroid hormone
to reduce obesity. Literature indicates that 2,4-dinitrophenol is a mutagen
(Genetika. 2002,
38(10): 1337-44. Russian) and that the compound induces lassitude and malaise
(Tidsskr
Nor Laegeforen. 2002, 122(14): 1363-4).
io
Patent WO 0103725A1 indicates use of IL-6 or agonists and mimetics of fL-6
against
obesity. Increased serum levels of interleukin 6 is associated with severe
intraventricular
haemorrhage in infants (Arch Dis Child Fetal Neonatal Ed. 2003, 88(6): F501-
4). In ill
people an increase in IL-6 level is usually associated with adverse effects
such as cancer-
is related anorexia and cachexia (Clin Cancer Res. 2003, 9(13): 4653-65),
fever after surgery
(Clin Orthop. 2003, (415): 221-31) and the late graft failure in renal
transplant recipients
(Transplantation. 2003, 76(8): 1190-4).
Salbutamol (albuterol) and its active enantiomer R-albuterol increases muscles
and
2o reduces fat in livestock animals. Application of salbutamol results in
increase in muscles in
veals and pigs from 14 to 24% versus control and decrease in back fat from 16
to 25%
(Proceedings of 38th Int. Cong. Meat Sci Technol. (ICoMST), Clermont-Ferrand,
France,
1992, 69-72 ; J. D. Wood et al Control and regulation of animal growth : In
proc. Eur.
Assoc. Anim. Prod. -Seminar, Center for agricultural publishing and
documentation
2s Netherlands, 1988, pp.176-81; Cole D. J. A. et al Effect of beta-agonist
GAH/034 on
growth, carcass quality and meat quality in pigs. In: J. P. Hanrahan (Ed.),
Beta-agonists
and their effects on animal growth and carcass quality. pp. 137-42. Elseveier,
Applied
Science, London, N. Y.; Warris P. D, et al. J. Anim. Sci. 1990, 68, 3669-76).
For the
enantiomers of salbutamol, R-albuterol has been shown to be the eutomer,
whereas S-
3o afbuterol is the distomer. Therefore R-albuterol may be considered for
reduction of fat and
for increase in muscles of obese and superobese individuals. Increase in
muscles in the
last category of patients is highly important and necessary because it permits
them to be
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CA 02455248 2004-O1-29
physically active, for example enabling them to walk and be active, thereby
prolonging their
life expectancy and improving their quality of life.
However prior art of in vivo studies of beta-2 agonists against obesity
indicate tow efficacy
s of such drugs in humans.
High doses of inhaled salbutamol (5 mg, 4 times a day) for 8 months in
patients with
chronic airflow limitations did not result in change of any obesity
characteristic versus
baseline including fat, body weight, hand grip strength and resting energy
expenditure.
io Authors concluded that the clinical use of regular high-doses of beta-2
agonists by
nebulizer is not likely to contribute to the weight loss seen in patients with
COPD.
Suggestion of the literature, that beta-2 agonist therapy increases Resting
Energy
Expenditure in some COPD patients was not confirmed (Chest 1998; 113:1588-94).
is Beta-2 agonist clenbuterol is a well-known agent with respect to increase
in muscles and
n3duction of fat in livestock animals. It has been found a parallel effect of
clenbuterol and
salbutamol with respect to afl characteristics of growth promotion in veals
and clenbuterol
was about 30 times more potent that salbutamol. (Meat Science, 1995, 40, 337-
50).
20 Application of inhaled clenbuterol in patients with COPD did not change
body weight or
increase in muscles in either a 2 week placebo-controlled trial (Sridhar M. K.
Studies on
metabolic rate in patients with chronic lung disease. University of Glasgow
PhD thesis,
1995) or after month of studies (Sridhar MK et al Abstract American Thoracic
Society,
1996).
2s
High doses of albuterol, namely 4 mg, 4 times a day were administered to
patients with
fluctuating Parkinson disease for 14 weeks. Cross-sectional area of thigh
muscle was
increased by 5.3%, that corresponded in no increase in muscle strength test.
Fat-free
mass was increased by 9.5% (Clin. Neuropharmacology 2003, 26(4), 207-12).
Thus, in humans, there was only a small effect of albuterol on increase in
muscles, no
effect on muscle strength, and only a moderate effect on reduction of fat
caused by a huge
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CA 02455248 2004-O1-29
dose of the drug. Taken together, these and similar data did not support
further
development of this or related compounds for use in humans to combat obesity.
For
comparison, use of a significantly lower dose of albuterol in pigs in a 10
week study with an
initial dose of 3.3 mg/day in week 1 increasing to 8.1 mg/day in week 10
resulted in a 14°!°
s increase in longissmus dorsi (LD) muscles and a 16°~ reduction of
back fat versus controls.
In the white-line genotype (50°!° of full cohort of pigs),
albuterol induced a 21 °!° increase in
LD muscles and 25.6% reduction of back fat (J. Anim. Sci. 1990, 68, 3669-76).
Some studies have found an increase in muscle strength in humans on albuterol.
However
io in all the studies researchers did not note a reduction of fat and/or body
weight, the
necessary characteristic of a drug against obesity.
For example, a high dose of 8 mg/day of slow-release salbutamol was
administered orally
for 3 weeks to healthy young men. It was found that there was a 12
°!° increase in strength
is of both quadriceps muscles and 22°!° increase in strength of
the hamstring muscles of
dominant leg. The strength of the non-dominant hamstring muscles however
returned to
baseline values at the end of the trial. No effect in body weight, skinfold
thickness, lean
body mass or limb circumferences were found. No significant change in the grip
strength of
either hand in these subjects were found during the trial (Clin Sci (Lond).
1992, 83(5):615-
20 21 ).
In another study, a high dose of albuterol, 16 mg!day was administered for 6
weeks versus
a placebo. It was found that there was an improvement in the albuterol group
with respect
to exercises in the quadriceps muscles. No effect was found with respect to
the cross-
2s sectional area of the thigh (Med Sci Sports Exerc. 1995, 27(11 ):1471-6).
Salbutamol, 12 mg/day versus placebo, was administered to young athletes for 3
weeks
who conducted exercise. Salbutamol significantly increased time to exhaustion
during
exercise. Body weight did not change in salbutamol group versus placebo (J
Appl Physiol
30 89: 430-436, 2000).
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CA 02455248 2004-O1-29
Men and women after 15 weeks of a weight reduction program lost an average 10
and 9 kg
respectively. Beta-2 lipolytic sensitivity and beta-adrener~gic density in
adipose tissue were
significantly higher after losing weight versus baseline (J, Lipid Res. 1999,
40, 1559-71 ).
s Basic pharmacology recommends developing beta-3, not beta-112 agonists with
respect to
anti-obesity. The idea was confirmed by clinical trials of BRL 26830A, beta-3
agonist in
obese subjects. An average reduction of weight in the treated group was 15.4
kg versus
10.0 kg in placebo (p<0.02). The drug was not moved to the market because of
induction
of tremor (Am. J. Clin. Nutr. 1992, 55 (suppl):258S-251 S)
io
Thus prior art of in vivo studies of effects of beta-2 agonists against
obesity indicated low
efficacy in human. Specifically:
a) Only one out of six long term studies showed both increase in muscle and
reduction of
is fat in treated patients;
b) In this study increase in muscles was weak, reduction of fat was moderate
and no
increase in muscle strength was found;
c) three studies that have found increase in muscle strength did not find
reduction of fat
or body weight; and
2o d) lipolysis induced by beta-2 agonists is impaired in obese versus lean
human that
disfavor use of drugs in obese individuals.
Oral administration of beta-2 agonist safbutamol (albuterol) and R-albuterol
(its active
metabolite) in livestock animals (veals, pigs, poltry) results in increase in
muscles and
2s significant reduction of fat. Thus R-albuterol could be recommended for
reduction of fat of
obese people and increase in muscles of obese and superobese individuals.
Increase in
muscles in the latter category of patients is highly important and necessary
because it
permits them to be physically active and able to walk and be active,
prolonging their life
expectancy and improving their quality of life.
Prior art of in vivo studies of effects of beta-2 agonists against obesity
indicated Low
efficacy in human. Specifically:
CA 02455248 2004-O1-29
A number of studies in vivo with beta-agonists indicated that lipolysis
(reduction of fat)
related with beta-2 adrenergic stimulation is impaired in obese versus lean
human. Thus,
the use of beta-2 agonists with respect to lipolysis in obese and superobese
individuals
should be of no value.
s
Intravenous infusion of beta-1/2 agonist isoprenatine in lean and obese men
resulted in a
decrease in plasma level of free fatty acids (FFA) and glycerol in the obese
group.
Decrease in FFA and glycerol meant decrease in lipolysis in obese group, since
esterified
fatty acid is fat. The second effect of infusion of isoprenaline was a
significant decrease of
io expiratory exchange ratio in the lean group that indicated pronounced fat
oxidation in these
subjects versus obese ones (Am. J. Physiol. 1994, 267 (2 Pt 1 ), 306-15).
Effect of abdominal subcutaneous administration of terbutaline (selective beta-
2 agonist) in
adipose tissue was studied in lean versus obese girls and lean versus obese
women.
is
1 wM of terbutaline resulted in 100% increase of glycerol release (increase in
lipolysis) in
lean versus obese girls and in lean versus obese women. It must be noted that
the effect of
dobutamine (selective beta-1 agonist) resulted in no difference in the release
of glycerol in
lean versus obese girls and lean versus obese women. Thus prior art had found
that an
2o impairment in lipolysis of obese girls and women is related with beta-2
adrenergic
stimulation (Diabetes 2000, 49, 2149-53).
Study of abdominal subcutaneous fat cells of obese and lean women has found
that
lipolytic noradrenaline sensitivity is 10 times reduced in obese women. It was
found a
2s negative correlation (rz=0.76, p<0.01 ) between lipolytic noradrenaline
sensitivity and BMI
(body mass index), physical characteristic of obesity. It was found that the
lipotytic
sensitivity of beta 1- and alpha 2-adrenergic receptors was normal in the
obese women.
The beta 1-receptor density was also normal. A 70% reduction in the cell
surface density
of beta 2-adrenoceptors was observed in obese versus control subjects (p <
0.01 ) that was
3o a reason of impairment of lipolysis at the first group {Diabetologia. 1994,
37(4);428-35).
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CA 02455248 2004-O1-29
a) Oniy one out of six long term studies showed both increase in muscle and
reduction of
fat in treated patients,
b) In this study increase in muscles was weak, reduction of fat was moderate
and no
increase in muscle strength was found
s c) Three studies that have found increase in muscle strength did not find
naduction of fat or
body weight,
d) Lipolysis induced by beta-2 agonists is impaired in obese versus lean
human, thereby
indicating its use of drug in obese individuals would not be favourable.
io
SUMMARY OF THE INVENTION
The invention discloses that oral administration of R-albuterol for 6 months
signficantly
reduces fat and increases muscles in human. Thus oral administration of R-
albuterol is
is claimed for reduction of obesity and increase in muscle strength of obese
and superobese
people.
Other aspects of the invention will be appreciated by reference to the
detailed description
of the preferred embodiment and to the claims that follow.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
In the preferred embodiment of the invention R-albuterol is used to combat
obesity in
2s humans. Preferably, 4mg of R-albuterol is administered orally twice a day
for 6 months.
This use results in significant reduction of fat (up to 17%) and increase in
muscles (up to
12%) in human.
Thus oral R-albuterol should be used for reduction of fat and increase in
muscles strength
3o in obese and superobese patients. Increase in muscles in the latter
category of patients is
highly important and necessary because it permits them to be physically active
and able to
walk and be active, prolonging their life expectancy and improving their
quality of life.
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CA 02455248 2004-O1-29
Example:
Patients are selected that have a body mass index (BMI) of 30 or greater.
Selected
s patients are stratified by age, gender, and body weight and randomly
assigned to receive
either levalbuterol (2 mg 3 times daily) or a matched placebo in a double-
blinded trial. All
patients are advised regarding a hypocaloric diet and an exercise regimen.
Primary
outcomes include changes in body weight (kg), BMI, waist circumference, blood
pressure,
glucose, lipids, insulin sensitivity (insulin clamp technique), and/or body
composition
io (magnetic resonance imaging), measured one time per month during six
months.
Secondary endpoints include strength and mobility tests such as the timed up
and go, 50-
foot walk, and walking up and down 8 stairs. Favourable changes are seen in
both groups
for many of the endpoints, but differences between the outcomes for the
levalbuterol and
the placebo group are statistically significant. ,
is
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