WO2005072714A1

WO2005072714A1 - Oral administration of r-albuterol against obesity

Info

Publication number: WO2005072714A1
Application number: PCT/CA2005/000086
Authority: WO
Inventors: Alexander Zolotoy
Original assignee: Alexander Zolotoy
Priority date: 2004-01-29
Filing date: 2005-01-26
Publication date: 2005-08-11
Also published as: CA2455248A1

Abstract

A formulation for use in reducing total body fat mass while increasing muscle mass or strength in an obese or superobese person comprising an effective amount of at least one compound selected from salbutamol, its optical and other isomers, analogs, active metabolites, and salts thereof.

Description

TITLE OF THE INVENTION

Oral administration of R-albuterol against obesity

FIELD OF THE INVENTION

The present invention is related to a compound for reducing fat and increasing muscle strength of obese and superobese people.

BACKGROUND OF THE INVENTION

Obesity is a tremendous problem in countries having a high standard of life. For example, 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 classification of obesity in 2000.

This problem is not limited to the United States. In Australia 31 per cent of Aborigines and 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 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 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. 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 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 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 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 valvular 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 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 vomiting (Clin Ther. 2003, 25(2): 422-43).

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 aberrantly activated in the most common solid tumors, including non-small cell lung cancer and cancers of the breast, prostate, and colon (Oncologist 2003;8(6):531-8.)

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).

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).

Patent WO 0103725A1 indicates use of IL-6 or agonists and mimetics of IL-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-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 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 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-albuterol 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 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 low efficacy 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. 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).

Beta-2 agonist clenbuterol is a well-known agent with respect to increase in muscles and reduction of fat in livestock animals. It has been found a parallel effect of clenbuterol and salbutamol with respect to all characteristics of growth promotion in veals and clenbuterol was about 30 times more potent that salbutamol. (Meat Science, 1995, 40, 337-50).

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).

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 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% 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 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 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):615-21 ).

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-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 89: 430-436, 2000).

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. Intravenous infusion of beta-1/2 agonist isoprenaline 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 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.

1 μM 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 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 negative correlation (1^=0.76, p<0.01 ) between lipolytic noradrenaline sensitivity and BMI (body mass index), physical characteristic of obesity. It was found that the lipolytic 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 a reason of impairment of lipolysis at the first group (Diabetologia. 1994, 37(4):428-35).

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-adrenergic density in adipose tissue were significantly higher after losing weight versus baseline (J, Lipid Res. 1999, 40, 1559-71 ). Basic pharmacology recommends developing beta-3, not beta-1/2 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- 251S)

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 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 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 salbutamol (albuterol) and R-albuterol (its active metabolite) in livestock animals (veals, pigs, poltry) results in increase in muscles and 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: a) Only 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 c) Three studies that have found increase in muscle strength did not find reduction 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.

SUMMARY OF THE INVENTION

The invention discloses that oral administration of R-albuterol for 6 months significantly reduces fat and increases muscles in human. Thus oral administration of R-albuterol 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 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 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.

Example:

Patients are selected that have a body mass index (BMI) of 30 or greater. Selected 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 (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.

Claims

What is claimed is:

1. Use of at least one compound selected from salbutamol, its optical and other isomers, analogs, active metabolites, and salts thereof as an agent for reducing total body fat mass while increasing muscle mass or strength in an obese person.

2. The use as set forth in claim 1 , wherein the obese person is morbidly obese.

3. The use as set forth in claim 1 , wherein the active compound is levalbuterol.

4. Use of at least one compound selected from salbutamol, its optical and other isomers, analogs, active metabolites, and salts thereof as an agent for increasing mobility in an obese person.

The use as set forth in claim 4, wherein the obese person is morbidly obese. The use as set forth in claim 4, wherein the active compound is levalbuterol.

7. A formulation for use in reducing total body fat mass while increasing muscle mass or strength in an obese person comprising an effective amount of at least one compound selected from salbutamol, its optical and other isomers, analogs, active metabolites, and salts thereof.

8. A formulation according to claim 7, wherein the obese person is morbidly obese.

9. A formulation according to claim 7, wherein the active compound is levalbuterol.

10. A formulation for use in increasing mobility in an obese person comprising an effective amount of at least one compound selected from salbutamol, its optical and other isomers, analogs, active metabolites, and salts thereof.

11. A formulation according to claim 10, wherein the obese person is morbidly obese.

12. A formulation according to claim 10, wherein the active compound is levalbuterol.

13. Use of at least one compound selected from salbutamol, its optical and other isomers, analogs, active metabolites, and salts thereof for preparing a medicament for reducing total body fat mass while increasing muscle mass or strength in an obese person.

14. The use as set forth in claim 13, wherein the obese person is morbidly obese.

15. The use as set forth in claim 13, wherein the active compound is levalbuterol.

16. Use of at least one compound selected from salbutamol, its optical and other isomers, analogs, active metabolites, and salts thereof for preparing a medicament for increasing mobility in an obese person.

17. The use as set forth in claim 16, wherein the obese person is morbidly obese.

18. The use as set forth in claim 16, wherein the active compound is levalbuterol.

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