TW200840590A - Compositions and methods for prevention and treatment of cachexia - Google Patents

Abstract

Compositions and methods for preventing and treating wasting disorders, such as cachexia and anorexia, are provided. In one aspect, the present invention provides a method for preventing and treating a wasting disorder in a mammal. In one embodiment, the method of the invention comprises administering to such mammal a macrolide and a β 2-adrenergic agonist in combination such that the macrolide and said β 2-agonist are administered in amounts effective to prevent or at least alleviate said wasting disorder.

Description

200840590 IX. INSTRUCTION DESCRIPTION CROSS REFERENCE RELATED APPLICATIONS This application claims US Provisional Application No. 60/75 3,11 8 (filed on December 22, 2005) in accordance with 35 USC 119(e); and 60/7 Priority of 72,752 (proposed on February 13, 2006). The disclosure of these applications is hereby incorporated by reference in its entirety for all purposes. TECHNICAL FIELD OF THE INVENTION The present invention relates to a composition and method for preventing and treating metabolic diseases, and in particular, a disease characterized by pathological loss of appetite, adipose tissue, and carcass quality. More specifically, the present invention relates to a composition and method for preventing and treating cachexia, particularly a cachexia associated with cancer and chronic renal insufficiency (CRI). The invention relates to the fields of biology, medicine, oncology and pharmacy. [Prior Art] Catabolic consumption or cachexia is characterized by involuntary progressive consumption of fat and skeletal muscle, refractory weight loss to increase nutrient input, increase in static energy expenditure (REE), decreased protein synthesis, and carbon water. Compound metabolism changes (increased Cori cycle activity), muscle ubiquitin-dependent proteasome pathway over-catabolism through protein solubilization, and asymmetry of adipose tissue through fat dissolution and excessive catabolism (Body JJ, Curr Opin Oncol 11: 255-60, 1999,

Muscaritoli M, et al: Eur J Cancer 42: 31-41, 2006). Usually 200840590 ' is diagnosed as cachexia only after the patient has reduced at least 5% or 5 pounds of pre-clinical weight. About half of all cancer patients experience some degree of catabolic consumption, and higher incidences are seen in cases of lung, pancreas, and gastrointestinal malignancies (Dewys WD, et al: Am J Med 69:491-7, 1980). . The syndrome can also be found in patients with immunodeficiency diseases such as AID S and those suffering from bacterial and parasitic diseases, rheumatoid arthritis, and chronic diseases of the intestines, liver, kidneys, lungs and heart. Cachexia is also associated with anorexia, which can be caused by aging or by physical injuries and burns. Cachexia syndrome reduces the patient's functional ability and quality of life, exacerbating the underlying condition and reducing tolerance to the drug. The degree of cachexia is inversely proportional to the patient's survival time, which usually represents a poor prognosis. In recent years, age-related diseases and disability have become major health concerns and importance. Anorexia (a medical term for loss of appetite) is a manifestation of the malignant manifestations of many malignant diseases, found in cancer, infectious diseases, chronic organ failure, and traumatic patients. Anorexia is a serious syndrome because it leads to reduced calorie intake and malnutrition. Anorexia manifests itself in the taste and smell of food, early satiety, reduced hunger and even total aversion to food, as well as symptoms of nausea and vomiting. Little is known about the causes of anorexia; effective treatment options are limited. Some studies have pointed out that the combination of hormonal, social and psychological factors may be an important factor in the occurrence and progression of this syndrome. Although in fact, cachexia is often associated with cancer, it has not been confirmed that there is a consistent relationship between the occurrence of cachexia and the size or stage of tumor size, stage of disease, and malignant disease. However, cancer cachexia is often associated with decreased calorie intake, increased static energy expenditure, and metabolic changes in protein, fat, and carbohydrates. For example, some significant abnormalities in carbohydrate metabolism include increased total glucose conversion rate, increased liver gluconeogenesis, glucose intolerance, and elevated blood glucose. Increased fat solubilization, increased conversion of free fatty acids and glycerol, hyperlipidemia, and lipoprotein lipase activity are also frequently observed. Importantly, weight loss associated with cancer cachexia is not only due to reduced body fat storage, but also to total body protein loss and extensive skeletal muscle consumption. Increased protein turnover and poor regulation of amino acid oxidation may also be important factors in the deterioration of this syndrome. In addition, in response to specific host-derived factors produced by cancer, for example, pre-inflammatory cytokines (tumor necrosis factor-a (TNF-a), interleukin-1, interleukin-6, and γ-interferon), Acute phase proteins (such as C-reactive protein), as well as specific prostaglandins, also appear to be associated with cancer cachexia. We know very little about the basic pathophysiology of cachexia associated with kidney dysfunction. Chronic renal insufficiency (CRI) may originate from any major cause of renal dysfunction. The most common cause of end-stage renal disease is diabetic nephropathy, followed by hypertensive renal arteriosclerosis and various primary and secondary glomerulopathy. Protein energy malnutrition has a high prevalence in non-dialysis patients with advanced chronic renal failure and end-stage renal disease patients undergoing maintenance hemodialysis or chronic peritoneal dialysis. The prevalence of cachexia and malnutrition is a serious problem because the labeling of protein energy malnutrition is a strong predictor of morbidity and mortality. The report indicates that in patients with chronic renal failure requiring hemodialysis or long-term peritoneal dialysis, up to 40% of them experience weight loss and have a higher morbidity and mortality. Nitrogen storage and body weight loss and organ protein storage loss of albumin and transferrin were observed. Causes of nutrition not 200840590 Good causes are multifactorial, including blood loss, loss of protein and other nutrients during dialysis, catabolism of chronic diseases, and anorexia caused by changes in taste, reduced food intake and depression (Kalantar-Zadeh K: Semin Dial 18:365-9, 2005). Current methods for treating cachexia and anorexia have only limited benefits. As described by Yavuzsen (Yavuzsen T, et al: J Clin Oncol 23: 8500-1, 2005), examples of randomized controlled clinical trials that produce negative, mixed or uncertain results include tests using the following drugs: bismuth sulfate ( Hydrazine sulfate, cyproheptadine, pentoxifylline, melatonin, erythropoietin plus or without indomethacin, twenty carbon five Eicosapentaenoic acid, male steroids, ghrelin, interferon and dronabinol. Of all the drugs tested, only corticosteroids and progestins showed consistent positive results in multiple randomized clinical trials. In particular, the progesterone derivative megestrol acetate has been shown to increase the appetite and body weight of cancer cachexia patients (but not related to quality of life, survival or functional ability). Megestrol acetate and/or its metabolites may directly or indirectly stimulate appetite leading to weight gain, or may alter metabolic pathways by interfering with the production or action of a vector substance such as tumor necrosis factor alpha. Evidence from clinical trials indicates that the weight gain observed during megestrol acetate treatment is related to the appetite stimulating or metabolic effects of the drug, rather than its glucocorticoid-like effect or edema. -8- 200840590 The administration of β2_adrenergic agonists (“β2-agonists”) is known to be involved in the anabolic effects of humans (Choo JJ, Horan ΜΑ,

Little RA, et al, Am J Physiol 263: E50-6, 1992). 22-agonists increase lean body mass by increasing protein synthesis and by interfering with the ATP-dependent-ubiquitin-proteasome pathway (Lambert CP, Uc EY, Evans WJ: Pharmacotherapy of Cachexia: 3 1 1 -324, 2005) . Clinical trials have shown that β2-agonists can increase healthy athletes (Caruso J, Hamill J, Y amauchi M, et al: J Appl Physiol 98:1 705-1 1,205, Caruso JF, et al: Med Sci Sports Exerc 27:1471-6, 1995, Martineau L, et al: Clin Sci (Lond) 83: 615-21, 1992) and patients with muscular dystrophy (Kissel JT5 et al: Neurology 57: 1434-40, 200 1 ) Carcass quality. Β2-agonists administered by injection into rats and mice with highly cachectic tumors are reported to reduce or reverse muscle wasting (Busquets S et al., Cancer Res 64:6725-3 1 (2004); Carbo N et al., Cancer Lett 1 1 5:1 1 3 -8 (1 997); Costelli P et al., J Clin Invest 95: 2367-72 (1995); Piffar PM et al., Cancer Lett 20 1: 1 3 9-48 (2003)). Surprisingly, however, beta2-agonists have not been used in humans for the prevention or treatment of cancer or cachexia in CRI. In addition, the β2-agonist formoterol fumarate (especially oral administration) has not been used in animal or human prevention or treatment of cancer, CRI or cachexia in aging sarcopenia. test. This latter observation is surprising because formoterol fumarate is known to have oral bioavailability, while the oral route of administration is more convenient than other routes of administration (such as intraperitoneal injection or inhalation) for patient convenience 200840590 and There are significant benefits in terms of compliance. It is also surprising that fumarate fumarate has not been investigated as a preventive measure against cachexia in mammals or humans because the anabolic effects of the drug should be effective in increasing the risk of cachexia or the metabolic imbalance of "cachexia" but The carcass quality and intensity of individuals who did not experience significant involuntary consumption. Since cancer cachexia is associated with increased concentrations of pre-inflammatory cytokines (TNF-α, IL6, CRP, etc.), previous clinical trials have indicated that non-steroidal anti-inflammatory agents (NSAIDS) such as ibuprofen (McMillan DC, Et al: Br J Cancer 79: 495-500, 1 999) and indomethacin (Lundholm K, et al: Cancer Res 54:5602-6, 1994) may have beneficial effects. Macrolide antibiotics associated with erythromycin structure are also known to have anti-inflammatory properties (Amsden GW: J Ant imicrob Chemother 55: 10-21, 2005). Anti-inflammatory macrolides include clarithromycin, roxithromycin, and azithromycin. In small, non-randomized, and uncontrolled clinical trials, Sakamoto and colleagues (Mikas a K, et al: Chemotherapy 43: 288-96, 1997, Sakamoto M et al., Chemotherapy 47:444-5 1 2001) Clarithromycin in patients with non-small cell lung cancer increased median survival time, decreased IL6 serum concentration, and increased body weight. However, randomized controlled clinical trials using macrolides in cancer cachexia patients have not been conducted, nor have there been any reports of the effects of macrolides on the performance status, quality of life, and functional performance of cancer cachexia patients. In the case of CRI, Kalantar-Zadeh K, Stenvinkel P, Bross R, et al: Kidney insufficiency -10- 200840590 and nutrient-based modulation of inflammation. Curr Opin Clin Nutr Metab Care 8:3 88-96, 2005) showed that patients had higher cardiovascular mortality, and protein energy malnutrition and inflammation were cited as the main cause of cachexia and high mortality in these patients. These investigators have found that there is no consensus in this medical field on how to correct malnutrition and inflammatory CRI patients, and the complexity of the disease may require multiple interventions. Review of Basaria S (Basaria S, Wahlstrom JT, Dobs AS. Clinical review 138: Anabolic-androgenic steroid therapy in the treatment of chronic diseases. J Clin Endocrinol Metab. 200 1 Nov; 86( 1 1 ): 5 1 08- 1 7) It is recommended to treat severe weight loss associated with chronic kidney disease with anabolic male steroids. Therefore, cachexia and anorexia are still a frustrating and fatal problem for clinicians and patients. Both animal and human trials have shown that nutritional support alone is largely ineffective in restoring the lean body mass of a cancer host. A randomized trial explored the effectiveness of total intravenous nutrition as an adjunct to cytotoxic anti-tumor therapy, which showed little improvement in treatment outcomes. See, for example, Brennan, M. F. ? and Burt, Μ. Ε·, 1981, Cancer Treatment

Reports 65 (Suppl· 5)··67-68. This and the conclusion that total venous nutrition can stimulate tumor growth in animals shows that there is not enough reason to routinely use total venous nutrition in cancer treatment (Visner, D.  L., 1981, Cancer Treatment Reports 65 (Suppl 5): 1-2) o The general dissatisfaction of cancer cachexia tests over the past 15 years, and the growing understanding of tumors at the molecular level before significant weight loss occurs - and / Or the importance of host-driven metabolic imbalance, which together shows that advanced cancer-11-200840590 patients should take cachexia/anorexia intervention at the initial diagnosis, regardless of whether the patient initially experienced significant weight loss. Muscaritoli et al. (2006) explained this view: "Some of the metabolic, biochemical, and molecular changes that are currently thought to contribute to the phenotypic characteristics of cachexia have occurred in the diagnosis of primary cancer, even if there is no significant weight loss. Therefore, the comprehensive view is recognized. It is considered an "early phenomenon" for cancer cachexia. In recent years, it has become increasingly important to understand the negative effects of cancer cachexia not only on patient mortality, but also on surgical risk, first-line and second-line chemical-/radiotherapy responses, and not only in quality of life. Unfortunately, the main characteristic of cancer cachexia is the gradual loss of muscle mass and function, which has been shown to be minimally responsive with currently available nutritional, metabolic or medical tools. Therefore, the development of an early and effective intervention to prevent, rather than reverse, the metabolic disorder that ultimately leads to muscle wasting and cachexia is considered to be a mandatory requirement in the scientific community. Therefore, there is still a need for better treatment options to help those who suffer from cachexia and anorexia. At the same time, there is a need to prevent the clinical manifestations of anorexia and cachexia from becoming apparent in individuals who have not experienced significant involuntary weight loss but are suffering from cachexia-related metabolic imbalances. The present invention satisfies these and other needs. SUMMARY OF THE INVENTION The present invention provides methods and compositions for the prevention and treatment of cachexia, anorexia, and other mammalian wasting diseases. The method and composition of the present invention reduces the pre-inflammatory cytokines (IL-6 and TNF) and acute phase protein (C-reactive protein) concentrations in patients without being limited to any particular effect -12-200840590. It also increases protein synthesis and interferes with catabolic protein solubilization to increase carcass quality, which is expected to improve the health of those suffering from cachexia, anorexia and other wasting diseases or those at risk of developing these wasting diseases. The present invention also provides a means of improving the quality of life of patients suffering from this condition in terms of improving well-being, promoting appetite, reducing burnout, and enhancing strength, persistence, clinical manifestation, and drug tolerance. In the first aspect, the present invention provides a method for preventing or treating a wasting disease in a mammal. In one embodiment, the method of the invention comprises administering a composition of a macrolide and a beta2-agonist to the mammal, wherein the macrolide and the beta2-agonist are administered as a composition It is administered in an amount effective to prevent or at least alleviate the wasting disease. In other embodiments, the methods of the invention comprise administering a pharmaceutically effective amount of a non-sterol anti-inflammatory agent in addition to the macrolide and the beta2-agonist. In some of these embodiments, the non-sterol anti-inflammatory agent is a non-selective cyclooxygenase inhibitor such as aspirin, diclofenac, naproxen, or 卩 美 美 美(indomethacin), or ibuprofen; or selective cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib, valdecoxib, rofecoxib (rofecoxib) or meloxicam. Thus, in some embodiments, the methods of the present invention provide a combination of anti-inflammatory and anabolic agents as an adjunct to an appetite stimulating agent to assist a mammal in receiving appropriate nutrient intake. -13- 200840590 In a more specific embodiment, the method of the invention further comprises administering a pharmaceutically effective amount of an appetite stimulating retention. The "appetite stimulating mites" used herein are synthetic natural hormones that promote appetite. In some embodiments, the appetite-stimulated A ring has a non-aromatic A ring and a keto group at position 3 of the carbocyclic carbon skeleton. The steroid can be modified to facilitate delivery via oral, transdermal patch, buccal or nasal transmission. In a more specific embodiment, the appetite stimulates the steroidal megestrol acetate. In some embodiments, the megestrol acetate is between about 1 mg/day to about 1,200 mg/day; more specifically between about 1 mg/day to about 1,000 mg/day. And more particularly, a dose of between about 400 mg/day and about 1,200 mg/day. In some embodiments, the macrolide and the β2-agonist have no substantial pharmacological interaction. In a more specific embodiment, the difference in serum half-life 値 of the macrolide and the β2-agonist is less than about 70%, less than about 50%, and less than about 30%. In other embodiments, the macrolide and the beta2-agonist have substantially different clearance mechanisms. The macrolide and the β2-agonist can be administered in the same or different pharmaceutical carriers. In some embodiments, the macrolide is roxithromycin, clarithromycin or azithromycin. In a more specific embodiment, the macrolide is roxithromycin. In a more specific embodiment, the macrolide is a rhodamine, and the roxithromycin is administered at a dose of between about 25 mg/day and about 750 mg/day. In other embodiments, the macrolide lactose, and the roxithromycin, is administered at a dose of from about 50 mg/day to about 300 mg/day -14 to 200840590. In other embodiments, the macrolide is roxithromycin, and the roxithromycin is administered in an amount of from about 50 mg/day to about 200 mg/day. In other embodiments, the macrolide lactose, and the erythromycin, are administered at a dose of from about 150 mg/day to about 75 mg/day. In some embodiments, the β2-agonist is formoterol fumarate, bambuterol or albuterol. In a more specific embodiment, the β2_agonist is formoterol fumarate. In embodiments in which the β2-agonist is formoterol fumarate, some embodiments of the invention include wherein the formoterol fumarate is between about 5 micrograms/day to about 500 micrograms/day. And administered at a dose of between about 5 micrograms/day to about 240 micrograms/day. In a second aspect, the present invention provides a pharmaceutical composition for preventing and treating a wasting disease in a mammal comprising a macrolide and a β2-agonist in a pharmaceutically acceptable carrier combination. The macrolide and the β2-agonist are administered in the form of a composition in an amount effective to prevent or at least alleviate the wasting disease. In some embodiments, the macrolide and the β2-agonist have no substantial pharmacological interaction. In a more specific embodiment, the difference in serum half-life 値 of the macrolide and the β2-agon is less than about 70%, less than about 50%, and less than about 30%. In other embodiments, the macrolide and the beta2-agonist have substantially different clearance mechanisms. The macrolide and the β2-agonist can be administered in the same or different pharmaceutical carriers. In some embodiments, the macrolide is roxithromycin -15-200840590, clarithromycin or azithromycin. In a more specific embodiment, the macrolide is roxithromycin. In a more specific embodiment, the macrolide is roxithromycin, and the roxithromycin is sufficient to deliver to the mammal between about 25 mg/day to about 750 mg/day. The amount of the dose is provided. In other embodiments, the macrolide lactose erythromycin and the roxithromycin are in a dose sufficient to deliver to the mammal between about 5 mg/day to about 300 mg/day. Quantity provided. In other embodiments, the macrolide is roxithromycin, and the roxithromycin is in a dose sufficient to deliver to the mammal from about 50 mg/day to about 200 mg/day. The amount provided. In other embodiments, the macrolide system roxithromycin' and the roxithromycin are in a dose sufficient to deliver to the mammal at a dose of from about i5 mg/day to about 750 mg/day. Quantity provided. In some embodiments, the β2-agonist is formoterol fumarate, bambuterol or albuterol. In a more specific embodiment, the β2_agonist is formoterol fumarate. In embodiments in which the β2-agonist is formoterol fumarate, some embodiments of the invention include wherein the formoterol fumarate is sufficient to deliver to the mammal at about 5 micrograms per day. Provided to an amount of about 500 micrograms per day and a dose of from about 5 micrograms per day to about 240 micrograms per day. In a third aspect, the present invention provides a method for preventing and treating a wasting disease in a mammal comprising administering a macrolide such as Rosin in an amount effective to prevent or at least alleviate the wasting disease Toxins to the mammal. -16- 200840590 In a fourth aspect, the present invention provides a method and composition for preventing and treating a wasting disease in a mammal comprising administering a dosage form suitable for oral administration and effective prevention or A beta 2 agonist such as formoterol fumarate to reduce the amount of the wasting disease to the mammal will be apparent upon reading the following description and accompanying drawings. DETAILED DESCRIPTION OF THE INVENTION In a first aspect, the present invention provides a method for preventing or treating a wasting disease in a mammal, the method comprising administering a composition of a macrolide and a β2-agonist to the lactation animal. When the macrolide and the β2-agonist are administered in the form of a composition, they are administered in an amount effective to prevent or at least alleviate the consumptive disease. In some embodiments of the methods just recited, the macrolide and the beta2-agonist are administered as separate pharmaceutically acceptable carriers. In other embodiments of the methods just recited, the macrolide and the beta2-agonist are administered in the same pharmaceutically acceptable carrier. The selection and preparation of the two agents suitable for use in the pharmaceutical compositions of the present invention, either separately or in combination, will be known to those of ordinary skill in the art. In other embodiments, the methods of the invention comprise administering a pharmaceutically effective amount of a non-sterol anti-inflammatory agent in addition to the macrolide and the beta 2 agonist. In some of these embodiments, the non-sterol anti-inflammatory agent is a non-selective cyclooxygenase inhibitor, such as aspirin, diclofenac, naproxen, or indomethacin, or ibuprofen; Or selective cyclooxygenase-2 (COX-2) -17- 200840590 inhibitors such as celecoxib, valdecoxib, rofecoxib or meloxicam. Thus, in some embodiments, the methods of the present invention provide a combination of anti-inflammatory and anabolic agents as an adjunct to an appetite stimulating agent to assist a mammal in receiving appropriate nutrient intake. Suitable macrolides include those known to have effective anti-inflammatory properties. Examples of suitable macrolides include roxithromycin, clarithromycin or azithromycin. A specific example is erythromycin. In some embodiments of the invention, the macrolide lactose is roxithromycin, and the roxithromycin is administered at a dose of between about 25 mg/day to about 750 mg/day. In other embodiments, the macrolide lactose is roxithromycin, and the roxithromycin is administered at a dose of from about 50 mg/day to about 3 晕0 halo; g/day. In other embodiments, the macrolide is roxithromycin, and the roxithromycin is administered at a dose of between about 50 mg/day and about 200 mg/day. In other embodiments, the macrolide lactose, and the roxithromycin, are administered at a dose of between about 150 mg/day and about 750 mg/day. The sources and methods of identifying, obtaining, and preparing suitable dosage forms of the macrolide for use in the methods of the present invention will be apparent to those of ordinary skill in the art. Suitable β2-agonists include bambuterol, albuterol, bitolterol, formoterol fumarate, isoetharine, isoproterenol (isoproterenol), metaproterenol, pirbuterol, ritodrine, salmeterol, benzenedimethanol, and terbutaline ). In some embodiments, the β2-agonist is formoterol fumarate, bambu -18-200840590 terro or salbutamol. In a more specific embodiment, the β2-agonist is formoterol fumarate. In a more specific embodiment, the β2_ agonist is formoterol fumarate administered at a dose of from about 5 micrograms/day to about 500 micrograms/day. In a more specific embodiment, the β2-agonist is formoterol fumarate administered at a dose of between about 5 micrograms/day to about 240 micrograms/day. The source and method of identifying, obtaining, and preparing a suitable dosage form of the β2-agonist for use in the methods of the present invention will be apparent to those of ordinary skill in the art. In some embodiments, the macrolide and the β2-agonist have no substantial pharmacological interaction. In a more specific embodiment, the difference in serum half-life enthalpy of the two components is less than about 70%. In other more specific embodiments, the difference in serum half-life enthalpy of the two components is less than about 50%. In other more specific embodiments, the difference in serum half-life enthalpy of the two components is less than about 30%. In other more specific embodiments, the two components have substantially different clearance mechanisms. The determination of appropriate serum half-life and clearance mechanisms can be performed by one of ordinary skill in the art. In other embodiments, the methods of the invention comprise administering any of the above combinations while administering a pharmaceutically effective amount of an appetite stimulating steroid. In a more specific embodiment, the method of the invention comprises administering one or more of the above combinations while administering a pharmaceutically effective amount of megestrol acetate. In some embodiments including administration of any of the above combinations and megestrol acetate, the megestrol acetate is administered at a dose of from about 100 mg/day to about 1,200 mg/day. In other embodiments comprising administering any of the above combinations and megestrol acetate, the megestrol acetate is between about 1 mg/day to about -19-200840590 1,000 mg/day. The dose is taken. In other embodiments including administration of any of the above combinations and megestrol acetate, the megestrol acetate is administered at a dose of from about 400 mg/day to about 1,200 mg/day. The megestrol acetate, macrolide and beta2-agonist can be administered in a single pharmaceutically acceptable carrier or in separate, separate pharmaceutical carriers. In other aspects, the invention provides a pharmaceutical composition for the prevention and treatment of a wasting disease in a mammal comprising a combination of a macrolide and a β2-agonist in a pharmaceutically acceptable carrier. The macrolide and the β2·agonist are administered in the form of a composition in an amount effective to prevent or at least reduce the wasting disease. The macrolide and β2-agonist are selected in accordance with the considerations set forth above. In some embodiments, the macrolide and the β2-agonist have no substantial pharmacological interaction. More specific embodiments include those in which the difference in serum half-life 値 of the macrolide and the β2-agonist is less than about 70%. Other embodiments include those in which the difference in serum half-life 値 of the macrolide and the β2-agonist is less than about 50%. Still other embodiments include those in which the difference in serum half-life 値 of the macrolide and the β2-agonist is less than about 30%. In other embodiments, the macrolide and the beta2-agonist have substantially different clearance mechanisms. Sources and methods for identifying, obtaining, and preparing suitable dosage forms of macrolides and beta2-agonists for use in the methods of the invention will be apparent to those of ordinary skill in the art. In some embodiments of the compositions of the invention, the macrolide is -20-200840590 roxithromycin, azithromycin or clarithromycin. In a more specific embodiment, the macrolide is roxithromycin. In a more specific embodiment, the macrolide lactose is roxithromycin, and the roxithromycin is in a dose sufficient to deliver to the mammal from about 50 mg/day to about 75 mg/day. Quantity provided. In other more specific embodiments, the macrolide lactose is roxithromycin, and the roxithromycin is sufficient to deliver to the mammal between about 5 mg/day to about 3 mg/day. The amount of the dose is provided. In other more specific embodiments, the macrocyclic lactone is roxithromycin, and the roxithromycin is sufficient to deliver to the mammal between about 50 mg/day to about 200 mg/day. The amount of the dose is provided. In other more specific embodiments, the macrolide lactose is roxithromycin, and the roxithromycin is sufficient to deliver to the mammal between about 15 mg/day to about 75 mg/day. The amount of the dose is provided. The source and method of identifying, obtaining and preparing the appropriate dosage form will be apparent to those of ordinary skill in the art. Suitable β2-agonists include albuterol, bitolterol, formoter〇i fuinarate, isoetharine, isoproterenol, isopr〇terenol, Metaproterenol, pirbuterol, ritodrine, salmeterol, benzenedimethanol, and terbutaline. In some embodiments of the compositions of the invention, the β2-agonist is formoterol fumarate, bambuterol or albuterol. However, beta blockers are not suitable agents. In a more specific embodiment, the β2_agonist is formoterol fumarate. In a more specific embodiment, the β2-agonist is Fuhu-21 - 200840590 Formoterol fumarate and the formoterol fumarate is sufficient to deliver to the mammal at about 5 μg/day Provided in an amount to a dose of about 240 micrograms per day. In other more specific embodiments, the β2-agonist is formoterol fumarate, and the formoterol fumarate is sufficient to deliver to the mammal from about 5 micrograms/day to about 40 micrograms/day. The amount of the dose is provided. The sources and methods of identifying, obtaining and preparing appropriate dosage forms will be apparent to those of ordinary skill in the art. In a third aspect, the present invention provides a method for preventing and treating a wasting disease in a mammal comprising administering roxithromycin in an amount effective to prevent or at least alleviate the wasting disease to the lactation animal. The methods and compositions described herein are applicable to humans and animals, particularly animals having high economic or emotional valence, such as, but not limited to, horses, cows, sheep, goats, pigs, cats, dogs, and the like, regardless of maturity. Or immature (meaning adults and children). The compositions and methods described herein are administered in an amount and frequency sufficient to prevent or at least alleviate the wasting disease. In one embodiment, a patient suffering from or at risk of developing a wasting disease is treated once a day using the methods and compositions described herein. In other embodiments, a patient suffering from or at risk of developing a wasting disease is treated twice a day using the methods and compositions described herein. The dosage form can be any form suitable for delivering a therapeutically effective amount, i.e., a dosage sufficient to at least alleviate the wasting disease, including an amount of the active pharmaceutical ingredient as described herein. Patient progression can be measured and observed by the patient's appearance (eg visible and measurable changes in body mass), body composition (eg carcass mass), patient-22- 200840590 functional (eg muscle strength and persistent movement) The relative change in the test) and the determination by relative clinical markers. Examples of such markers include, but are not limited to, pre-inflammatory cytokines (IL-6 and TNF) and acute phase protein (C-reactive protein) concentrations, lean body mass, ergonomics, muscle strength, clinical status, and quality of life. . The determination, measurement, and evaluation of features and markers associated with clinical progression are known to those of ordinary skill in the art. In other aspects, the invention also provides for the presence of a potentially morbid state (cancer, AIDS, CRI, etc.) or because of metabolic processes (such as excessive muscle catabolism) or inflammatory conditions (such as elevated concentrations of IL6, TNF, or CRP). A mammal having a risk of entering a cachectic and/or anorexia state to prevent significant weight loss. In these embodiments, any of the compositions and dosing schedules provided by the present invention are administered to a mammal that is susceptible to entering or undergoing metabolic and inflammatory imbalances associated with a cachexia or anorexia state, thereby delaying cachexia in the individual or Anorexia symptoms occur or impede the progression of cachexia or anorexia. The determination of any of these conditions can be determined by knowledge of those of ordinary skill in the art, such as detecting significant weight loss (e.g., reducing more than about 5% average normal body weight), and increasing the concentration of inflammatory markers above normal sputum (e.g., IL6, TNF- Ct, C-reactive protein) or an increase in the concentration of mRNA associated with ubiquitin-proteasome protein solubilization, or some combination thereof in an individual. In these embodiments, patients treated by the methods and compositions provided by the present invention are expected to better tolerate treatment plans for treating the underlying causes of cachexia or anorexia, such as chemotherapy, radiation therapy, Bone marrow transplantation and the analogs, treatment plans known to those of ordinary skill in the art, must be administered according to strict plans to achieve maximum therapeutic benefit. -23- 200840590 In some embodiments, the β2-agonist and the macrolide are co-administered in separate pharmaceutical carriers. In the embodiment in which the β2-agonist is administered separately, the pharmaceutical carrier is suitable for a liquid (solution, syrup, emulsion or suspension) which is orally administered or administered by the nasogastric tube. In other embodiments, the pharmaceutical carrier is suitable for parenteral injection of a liquid (solution, suspension or emulsion) of a β2_agonist. In other embodiments, the pharmaceutical carrier is suitable for oral ingestion to provide a solid or semi-solid (e.g., powder, powder, lozenge or capsule) dosage form for direct release of the beta2-agonist into the gastric compartment. In other embodiments, the pharmaceutical carrier is suitable for oral or ingestion to provide a solid or semi-solid (powder, powder, lozenge or capsule) dosage form for prolonged or controlled or sustained release of the beta2-agonist into the gastric compartment. . In the embodiment in which the macrolide is administered separately, the pharmaceutical carrier is suitable for a liquid (solution, syrup, emulsion or suspension) which is orally administered or administered by the nasogastric tube. In other embodiments, the pharmaceutical carrier is suitable for parenteral injection of a macrolide (solution, emulsion or suspension). In other embodiments, the pharmaceutical carrier is suitable for oral ingestion to provide a solid or semi-solid (powder, powder, lozenge or capsule) dosage form for direct release of macrolide into the gastric compartment. In other embodiments, the pharmaceutical carrier is suitable for oral ingestion to provide a solid or semi-solid (powder, powder, lozenge or capsule) for prolonged or controlled or sustained release of macrolide into the gastric compartment. Dosage form. Methods and materials for accomplishing such blends are known to those of ordinary skill in the art. In a more specific embodiment, the pharmaceutical carrier pH 値 of the liquid oral dosage form comprising the β2_agonist is adjusted to between about 4 mM and about 5 mM to about -24 - 200840590 2 0 OmM buffer (acetate) An aqueous solution of citrate, phosphate or succinate comprising from 3 to 6% of a sugar such as sorbitol, sucrose, glucose, lactose or mannitol plus from about 1% to about 1% Microbial preservatives such as sodium benzoate or potassium sorbate plus various flavoring and/or sweetening ingredients known to those skilled in the art and soluble in concentrations ranging from about 1 mg/ml to about 10 mg/ml. 2-2-agonist. In a more specific embodiment, the pharmaceutical carrier pH 値 comprising the oral solution dosage form of the β2-agonist is adjusted to be between about 5. 5 to about 6. An aqueous solution of from about 1 OmM to about 30 mM citrate buffer, comprising from about 4% to about 5% mannitol plus about 0. 05% to about 0. 2% potassium sorbate and various sweet and/or flavoring ingredients. Methods and materials for accomplishing the compositions are known to those of ordinary skill in the art. In a more specific embodiment, the parenteral injection form of the pharmaceutical carrier comprising the β2-agonist is adjusted to a pH of between about 4 and about 7 to about 200 mM to about 200 mM buffer (acetate, citric acid). An aqueous solution of a salt, phosphate or succinate comprising from about 3% to about 6% of a sugar such as sorbitol, sucrose, glucose, lactose or mannitol and soluble in excess of about 0. A range of β2-agonists ranging from 001 mg/ml to about 1 mg/ml. In a more specific embodiment, the pharmaceutical carrier pH of the parenteral solution comprising the β2-agonist is adjusted to a pH of about 5. 5 to about 6. 5 of an aqueous solution of from about 1 OmM to about 30 mM citrate buffer comprising from about 4% to about 5% mannitol. Methods and materials for accomplishing the compositions are known to those of ordinary skill in the art. In a more specific embodiment, the pharmaceutical carrier of the oral liquid dosage form comprising macrolides is adjusted to a pH of from about 4 to about 7 to about 5 mM to about -25 to 200840590 2 00 mM buffer (acetate) An aqueous solution of citrate, succinate or phosphate comprising from about 3% to about 6% of a sugar such as sorbitol, sucrose, glucose, lactose or mannitol plus about 0. 01% to about 1% of an antimicrobial preservative such as sodium benzoate or potassium sorbate plus a variety of sweet and/or flavoring ingredients known to those skilled in the art and soluble above about 0. Macrolides ranging from 5 mg/ml to about 10 mg/ml. In a more specific embodiment, the pharmaceutical carrier of the liquid oral dosage form comprising macrolides is adjusted to a pH of about 5. 5 to about 6. 5 of an aqueous solution of from about 10 mM to about 30 mM citrate buffer, comprising from about 4% to about 5% mannitol plus about 0. 05% to about 0. 2% potassium sorbate plus sweet and/or flavoring ingredients. Methods and materials for accomplishing the compositions are known to those of ordinary skill in the art. In a more specific embodiment, the pharmaceutical carrier of the parenteral injection form comprising macrolide is pH adjusted to between about 4 and about 7 mM to about 200 mM buffer (acetate, lemon) An aqueous solution of an acid salt, succinate, phosphate) comprising from about 3% to about 6% of a sugar such as sorbitol, sucrose, glucose, lactose or mannitol and soluble in excess of about 0. A macrolide from 5 mg/ml to a concentration range of about 1 mg/ml. In a more specific embodiment, the pharmaceutical carrier system comprising a macrolide lactone in a parenteral solution dosage form is adjusted to be between about 5. 5 to about 6. An aqueous solution of about 1 〇 111]\4 to about 3 〇1111^ lemon acid buffer comprising from about 4% to about 5% mannitol. Methods and materials for accomplishing such blends are known to those of ordinary skill in the art. In a more specific embodiment, the pharmaceutical carrier comprising a solid oral dosage form of a β2-agonist is sucrose microparticles or microcrystalline cellulose (MCC) which has been coated with a β2-agonist and comprises a polymer such as hydroxypropyl. a binder of methylcellulose-26-200840590 (HPMC) or polyvinylpyrrolidone (PVP) and a polymer which is substantially immediately released (completely dissolved in about 60 minutes) to the stomach contents, such as a polymer The HPMC was coated again. Direct release microparticles comprising a beta2-agonist can be loaded into a capsule or compressed into a tablet using methods known to those of ordinary skill in the art. Tablets and capsules comprising the immediate release beta2-agonist granules may also comprise inert, pharmaceutically acceptable excipients known to those skilled in the art, which may include, but are not necessarily limited to, lactose, starch, Talc or magnesium stearate. Methods and materials for accomplishing the compositions are known to those of ordinary skill in the art. In other specific embodiments, the pharmaceutical carrier comprising a solid oral dosage form of a β2-agonist is sucrose microparticles or microcrystalline cellulose (MCC) which has been coated with a β2-agonist and comprises a polymer such as hydroxypropyl. A binder of methylcellulose (HPMC) or polyvinylpyrrolidone (PVP) and optionally coated with a suitable polymer to provide sustained or prolonged or controlled release of the beta 2 agonist to the stomach contents. Control- or sustained- or extended-release microparticles comprising a β2_agonist can be loaded into a capsule or compressed into a tablet using methods known to those of ordinary skill in the art. Tablets and capsules comprising the sustained or extended or controlled release of the β2-agonist granules may also comprise inert, pharmaceutically acceptable excipients known to those skilled in the art, which may include, but are not necessarily limited to, Lactose, starch, talc or magnesium stearate. Methods and materials for accomplishing the compositions are known to those of ordinary skill in the art. In other specific embodiments, the pharmaceutical carrier comprising a macrocyclic lactone solid oral dosage form is coextruded with MCC and a polymeric binder such as HPMC comprising from about 50% to about 90% of the macrolide. Microparticles, which can be used to directly release macrolides into the stomach contents, -27-200840590. The direct release microparticles comprising macrolides can be filled into capsules or compressed into tablets using methods known to those of ordinary skill in the art. Tablets and capsules comprising the sustained or extended or controlled release of the β2-agonist granules may also comprise inert, pharmaceutically acceptable excipients known to those skilled in the art, which may include, but are not necessarily limited to, Lactose, starch, talc or magnesium stearate. Methods and materials for accomplishing the compositions are known to those of ordinary skill in the art. In other specific embodiments, the pharmaceutical carrier comprising a solid oral dosage form of macrolide comprises from about 50% to about 90% of the macrolide co-extruded with MCC and a suitable polymeric binder such as HPMC. The microparticles are recoated with a suitable polymer that provides sustained or extended or controlled release of the macrolide to the stomach contents. Controlled or sustained or extended release of microparticles comprising macrolides can be incorporated into capsules or compressed into tablets using methods known to those of ordinary skill in the art. Tablets and capsules comprising the sustained or extended or controlled release of the β2-agonist granules may also comprise inert, pharmaceutically acceptable excipients known to those skilled in the art, which may include, but are not necessarily limited to, Lactose, starch, talc or magnesium stearate. Methods and materials for accomplishing the compositions are known to those of ordinary skill in the art. In some embodiments, the β2-agonist and the macrolide are combined in a single pharmaceutical carrier. In the embodiment in which the β2-agonist and the macrolide are combined, the pharmaceutical carrier is suitable for oral ingestion or use of a nasogastrically administered liquid (solution, syrup, suspension) Or emulsion). In other embodiments, the pharmaceutical carrier is a liquid (solution, suspension -28-200840590 or emulsion) for parenteral injection of a combination of a β2-agonist and a macrolide. In other embodiments, the pharmaceutical carrier is suitable for oral ingestion to provide direct release of the β2-agonist and the solid or semi-solid (powder, powder, lozenge or into the gastric compartment) of the macrolide. Capsule) dosage form. In other embodiments, the pharmaceutical carrier is suitable for oral ingestion to provide extended or controlled or sustained release of the β2-agonist and macrolide into the stomach compartment of a solid or semi-solid (powder, powder, ingot) Agent or capsule) dosage form. Methods and materials for accomplishing the compositions are known to those of ordinary skill in the art. In a more specific embodiment, the pharmaceutical carrier pH of the oral liquid dosage form comprising both the β2-agonist and the macrolide is adjusted to a pH of from about 4 to about 7 mM to about 200 mM buffer. An aqueous solution of (acetate, citrate, succinate or phosphate) comprising from about 3% to about 6% of a sugar such as sorbitol, sucrose, glucose, lactose or mannitol plus about 0. 0% to about 1% of an antimicrobial preservative such as sodium benzoate or potassium sorbate plus various flavoring and/or sweetening ingredients known to those skilled in the art and soluble more than about 0. A β2-agonist in a concentration range of 001 mg/ml to about 10 mg/ml and may also dissolve above about 0. A macrolide of a concentration ranging from 5 mg/ml to about 10 mg/ml. In a more specific embodiment, the pH of the pharmaceutical carrier containing the oral solution form of both the β2-agonist and the macrolide is adjusted to be about 5. 5 to about 6. 5 of an aqueous solution of about 10 mM to about 30 mM citrate buffer, comprising from about 4% to about 5% mannitol plus about 0. 05% to about 0. 2% potassium sorbate and various sweet and/or flavored ingredients. Methods and materials for accomplishing the compositions are known to those of ordinary skill in the art. In a more specific embodiment, the parenteral injection form of the pharmaceutical vehicle comprising both the β2-agonist and the macrocyclic 29-200840590 lactone is adjusted to a pH of between about 4 and about 7. An aqueous solution of 5 mM to about 200 mM buffer (acetate, citrate, succinate or phosphate) comprising from about 3% to about 6% sugar such as sorbitol, sucrose, glucosamine, lactose or mannitol And soluble more than about 0. a range of β2-agonists ranging from 001 mg/ml to about 10 mg/ml and soluble above about 0. A macrolide of a concentration ranging from 5 mg/ml to about 1 mg/ml. In a more specific embodiment, the pH of the pharmaceutical carrier comprising the β2-energic agent and the macrolide lactone is adjusted to be about 5. 5 to about 6. An aqueous solution of from about 10 mM to about 30 mM citrate buffer, comprising from about 4% to about 5% mannitol. Methods and materials for accomplishing the compositions are known to those of ordinary skill in the art. In a more specific embodiment, a pharmaceutical carrier comprising a solid oral dosage form comprising both a β2-agonist and a macrolide comprises a direct release microparticle comprising a β2-agonist (as described above) and also comprising a macro A capsule or lozenge of a cyclic release of microparticles (as described above). The ratio and amount of the direct release microparticles comprising the β2-agonist or the macrolide can be adjusted to give each of the desired doses in each capsule or lozenge. The direct release microparticles can be filled into capsules or compressed into tablets by methods known to those skilled in the art. Tablets and capsules comprising the immediate release beta2-agonist granules may also comprise inert, pharmaceutically acceptable excipients known to those skilled in the art, which may include, but are not necessarily limited to, lactose, starch, Talc or magnesium stearate. Methods and materials for accomplishing the compositions are known to those of ordinary skill in the art. In other more specific embodiments, a pharmaceutical carrier comprising a solid oral dosage form comprising both a β2-agonist and a -30-200840590 macrolide comprises a control- or sustained-or prolongation comprising a β2-agonist The microparticles (as described above) are also released and also contain capsules or lozenges containing controlled- or sustained- or extended-release microparticles (as described above) of the macrolide. The proportion and amount of control- or sustained- or extended-release microparticles comprising a β2-agonist or macrolide can be adjusted to give each dose of the desired dose in each capsule or lozenge. The sustained- or extended- or controlled release of the microparticles can be filled into capsules or compressed into tablets by methods known to those of ordinary skill in the art. Tablets and capsules containing such sustained- or extended- or controlled granules may also contain inert, pharmaceutically acceptable excipients known to those skilled in the art, which may include, but are not necessarily limited to, lactose, starch , talc or magnesium stearate. Methods and materials for accomplishing the compositions are known to those of ordinary skill in the art. In all embodiments in which the pharmaceutical carrier is described, the dosage form can be prepared using methods and techniques known to those skilled in the art. Representative methods and techniques may include, but are not necessarily limited to: mixing (mixing, stirring, ultrasonic shock, honing, emulsification, homogenization), comminution, milling, heating/cooling, filtration, hydration (liquid Or powder), coating (spray or fluidized bed), drying (air flow, heating, spraying, fluidized bed or vacuum), extrusion, spheronization and tableting. Methods and materials for accomplishing the compositions are known to those of ordinary skill in the art. The methods and compositions of the present invention, while not wishing to be bound by any particular theory of practice, have shown that the breakdown of skeletal muscle proteins is associated with the ubiquitin proteasome system. The ubiquitin-proteasome pathway is a ruthenium-dependent regulatory system that controls the half-life of proteins, which is involved in cell cycle, signal transmission, immune system response, apoptosis, and tumorigenesis (Camps C, Iranzo V? Et al. 9 Support Care Cancer.  2006 Dec; 14(12): 1173-83. Epub 2006 Jul 4). This is especially true for muscle consumption, also known as sarcopenia, which reduces the quality of life, increases morbidity and shortens lifespan of the elderly (Inui A.  "Feeding-related disorders in

Medicine, with special reference to cancer anorexia-cachexia syndrome", Rinsho Byori. 2006 Oct; 5 4( 1 0) : 1 044 - 5 1 ; Argiles JM? Busquets S? et al.5 Int J Biochem Cell Biol. 2005 May 37(5): 1 084- 1 04. Epub 2004 Dec 30). Therefore, in view of biochemical and metabolic evidence, those having ordinary skill in the art will appreciate that the methods and compositions provided by the present invention may also be For the treatment of senile sarcopenia and other diseases associated with ubiquitin proteasome system disorders. [Embodiment] The following examples are provided to illustrate specific aspects of the invention and to assist those skilled in the art to practice the invention. The examples should not be construed as limiting the scope of the invention in any way. Example 1: Comparison of randomized, double-blind, pre-existing studies comparing the safety and efficacy of the present invention with placebo in the prevention and treatment of cachexia in terminal cancer patients The study determines the effects of the combination of formoterol fumarate and roxithromycin on the following effects: • Eastern Joint Cancer Research Group (ECOG) performance status, • Weight, -32- 200840590 • The body composition of the dual energy X-ray absorptiometry (DEXA) and bioelectrical impedance analysis (BIA), • the quality of life assessed using the questionnaire (Q〇L), • the grip strength, the grip strength, the up/down time and The 6-minute walking time measures the muscle strength and persistence assessed, and • serum concentrations of C-reactive protein, IL6 and TNF, and • various safety parameters (eg blood chemistry, ECG, and clinical chemistry). Adults with limited sex are suffering from non-cure non-small cell lung cancer at the end of the period. Patients must have a life expectancy of more than 6 months after initial clinical evaluation by the investigator. Patients with abnormal renal or hepatic function symptoms are also excluded. The two-week group of placebo-controlled trials were performed in 18 weeks. Each group had 30 patients. The patients were divided into two groups: • The first group: standard carboplatin dual chemotherapy plus nutritional counseling Garo Erythromycin plus formoterol fumarate; • Group 2: standard carboplatin dual chemotherapy plus nutritional counseling plus erythromycin placebo plus fumarate fumarate placebo. Roxithromycin will be 80 mg twice a day Oral administration, and Formoterol was administered twice a day. Example 2: Comparison of a combination of single roxithromycin, single formoterol, roxithromycin and formoterol at the end of prevention and treatment A randomized, double-blind, pre-existing study of the safety and efficacy of cachexia in cancer patients to determine the combination of formoterol fumarate and roxithromycin - 33 - 200840590 Effects of the following on: Study Group (ECOG) performance status, • Weight, • Body composition determined by dual energy X-ray absorptiometry (DEXA) and Bioelectrical Impedance Analysis (BIA), • Quality of life assessed using a questionnaire (Q〇L) • Measured muscle strength and persistence by grip strength, grip strength, up/down time and 6-minute walking time, and • serum concentrations of C-reactive protein, IL6 and TNF, and • various safety parameters (eg blood chemistry) , ECG, and clinical chemistry). The test patients must be adults of unlimited gender and suffer from end-stage non-cancerous non-small cell lung cancer. The patient must have a life expectancy of more than 6 months after initial clinical evaluation by the investigator. Patients with abnormal kidney or liver function symptoms were also excluded. The study was a four-week, four-week, placebo-controlled trial with 30 patients in each group. The patients were divided into four groups: • The first group: standard carboplatin dual chemotherapy plus nutritional counseling plus erythromycin plus fumarate fumarate; • the second group: standard carboplatin dual chemotherapy plus nutritional counseling rosin Plus formoterol fumarate placebo; • third group · standard carboplatin dual chemotherapy plus nutritional counseling rosin erythromycin placebo plus fumarate fumarate; • fourth group: standard card lead double chemotherapy plus nutrition counseling Garro erythromycin placebo plus fumarate fumarate placebo. -34- 200840590 Roxithromycin will be administered orally twice a day with 150 mg, and Formoterol will be administered orally twice a day at its highest tolerated dose. Example 3: Muscle protection of roxithromycin and formoterol fumarate in an animal model of cancer cachexia in accordance with the method of Basques et al. (Busquets S, et al: Cancer Res 64:6725 -3 1,2004 ), Wistar mothers received 2 x 107 cells/animals of Yoshida AH-130 ascites hepatoma (AH) cells inoculated intraperitoneally (ip) (day )). Control animals were inoculated with an equal volume of sterile saline solution. From the first day, the animals were given once a day of formoterol fumarate (i.p.), roxithromycin (i.p.) or a compatible inactive carrier. The animals died on the 5th day. The wet weight of the heart and gastrocnemius muscles was measured at the time of sacrifice, and the weight of the cadaver (after removal of the gastrocnemius, heart and ascites) was also determined. -35- 200840590 Table 1 Experimental design of AH 1 30 ascites hepatoma model of cancer cachexia

Test number group inoculum dose (mg/kg) 1 # fumarate fumarate erythromycin 1 1 ΑΗ* 0 0 1 2 saline 0 0 I 3 ΑΗ* 1 0 1 4 ΑΗ* 0 5 2 5 ΑΗ* 0 0 2 6 saline 0 0 2 7 ΑΗ* 1 0 2 8 ΑΗ* 1 5 2 9 saline 0 5 2 10 saline 1 0 3 11 AH* 0 0 3 12 saline 0 0 3 13 AH * 1 0 3 14 AH* 1 40 3 15 saline 0 40 4 16 AH* 0 0 4 17 brine 0 0 4 18 AH* 1 0 4 19 AH* 1 25 4 20 AH* 1 50 4 21 AH* 0 50 2χ107 ΑΗ130 ascites hepatoma cells/animal Table 2 shows the results of the weight measurement of Test 1. Table 3 shows the results of the measurement of the weight of the test 2. Table 4 shows the results of the weight measurement of Test 3. Table 5 shows the results of the weight measurement of Test 4. In the following, the treatment group is indicated by the following conventions: treatment group = inoculum type / carrier, or treatment group = inoculum type - 36 - 200840590 /F(x)R(y), wherein the inoculum type is not AH ready salt water, F is the form of formoterol fumarate, R-line roxithromycin, and the number of lanthanide fumarate fumarate and roxithromycin in the brackets (mg/kg ip).

Table 2 Rat AH test 1 weight data group inoculum dose N heart weight, gastrocnemius weight, corpse weight, (mg / kg) * g ** g: g 4 | e FR average 値 standard deviation mean 値 standard deviation mean 値Standard deviation 1 AH 0 0 7 0.320 0.008 0.503 0.005 93.96 0.70 2 Saline solution 0 0 7 0.359 0.010 0.588 0.007 96.26 0.75 3 AH 1 0 7 0.337 0.009 0.551 0.012 95.35 0.86 4 AH 0 5 9 0.320 0.009 0.493 0.004 94.35 0.71 *F = Formoterol fumarate, R: = roxithromycin* *Assess the number of animals. Animals with less than 1 ml of ascites were not included in the analysis. * * * The sample weight was normalized to the total weight of the 5th day. 0 0 g. Table 3 Rat AH130 test 2 Weight data group Inoculum dose N heart weight, gastrocnemius weight, Corpse weight, (10) g/kg) * g** g** g: ** FR mean 値 standard deviation mean 値 standard deviation mean 値 standard deviation 5 AH 0 0 10 0.349 0.0060 0.487 0.0090 92.5 0.91 6 saline 0 0 10 0.398 0.0080 0.565 0.0100 98.2 0.27 7 AH 1 0 10 0.348 0.0090 0.499 0.0050 89.7 0.53 8 AH 1 5 10 0.358 0.0100 0.514 0.0090 90.7 0.83 9 Salined water 0 5 10 0.390 0.0110 0.575 0.0070 97.6 0.48 10 Saline 1 0 7 0.410 0.0100 0.613 0.0080 97.6 0.26 * F = formoterol fumarate, R = roxithromycin * * sample weight: normalized to day 5, total weight 100 g -37 - 200840590 Table 4 mouse AH test 3 weight data group inoculum Dosage N heart weight, gastrocnemius weight, corpse weight, (mg/kg)*g*氺克*本克: *氺FR average 値 standard deviation mean 値 standard deviation mean 値 standard deviation 11 AH 0 0 10 0.341 0.0070 0.431 0.0040 93. 6 0.52 12 saline 0 0 10 0.417 0.0120 0.536 0.0060 95.2 0.83 13 AH 1 0 10 0.376 0.0140 0.489 0.0090 93.1 0.69 14 AH 1 40 10 0.350 0.0360 0.528 0.0100 95.9 0.58 15 brine 0 40 10 0.400 0.0070 0.529 0.0080 96.5 0.52

F = formoterol fumarate, R = roxithromycin * sample weight normalized to the total weight of 100 grams on day 5 Table 5 mouse AH test 4 weight data group inoculum dose N heart weight ** gastrocnemius weight ** Corpse weight** (mg/kg)* FR average 値 standard deviation mean 値 standard deviation mean 値 standard deviation 16 AH 0 0 10 0.323 0.0080 0.453 0.0051 97.2 0.59 17 saline 0 0 10 0.405 0.0069 0.556 0.0080 96.5 0.84 18 AH 1 0 10 0.367 0.0160 0.502 0.0120 97.8 0.35 19 AH 1 25 10 0.344 0.0085 0.477 0.0080 97.1 0.45 20 AH 1 50 10 0.373 0.0106 0.520 0.0097 97.4 0.25 21 AH 0 50 10 0.338 0.0130 0.500 0.0092 94.1 0.68 Formoterol fumarate, R = = Luo The erythromycin* sample weight was normalized to 100 g of the total weight on day 5. In Test 1 (see Table 2), the gastrocnemius muscle loss in the AH/vehicle group was significantly greater than that in the saline/vehicle group, indicating that the ascites liver tumor had Highly cachectic. The loss of gastrocnemius muscle in the AH/F(1)R(0) group was significantly lower than in the AH/carrier group. The amount of gastrocnemius muscle loss in the AH/F(0)R(5) group was approximately equal to -38-200840590 AH/carrier group animals. The trend of changes in gastrocnemius weight observed in each treatment group was approximately the same as that observed for heart and cadaver weight (see Table 3-6), indicating that the effects of AH vaccination and treatment are universal and not limited to gastrocnemius. In Experiment 2, the effect of AH and formoterol fumarate on the weight of the gastrocnemius was similar to that observed in Test 1. In Trial 2, there was no significant difference in the muscle weight of the animals between the eight 11/?(1)11(5) animals and the muscle weight of the eight 11/?(1)11(0) animals. The rats in the saline/F(0)R(5) and saline/F(1)R(0) groups had approximately the same weight of the gastrocnemius as the rats in the saline/vehicle group. In Experiment 3, the effect of AH and formoterol fumarate on the weight of the gastrocnemius was similar to that observed in Experiment 1. In Trial 3, the weight of the gastrocnemius muscle of AH/F(1)R(40) rats was much higher than that of AH/F(1)R(0) rats. Surprisingly, there was no significant difference in the gastrocnemius muscle weight of the animals in the AH/F(1)R(40) and the muscle weight of the animals in the saline/vehicle control group. There was no difference in the weight of the gastrocnemius between the saline/F(0)R(40) group and the saline/vehicle control group. The effect of AH and formoterol fumarate on the weight of the gastrocnemius muscle in Test 4 was similar to that observed in Test 1. The effect. In Experiment 4, there was no significant difference in the muscle weight of the AH/F(1)R(25) rat's gastrocnemius muscle and the AH/F(1)R(0) rat muscle. The weight of the gastrocnemius of the animals in AH/F(1)R(50) was higher than the muscle weight of the animals in the AH/F(1)R(0) group. Animals in the AH/F(0)R(50) group showed significantly higher gastrocnemius muscle weight compared to animals in the AH/vehicle group. Similarly for AH/F(0)R(50) rats, the gastrocnemius weight is essentially the same as the muscle weight of AH/F(1)R(0) rats and slightly lower than AH/F(1)R ( 50) -39 - * 200840590 Rat muscle weight. Figure 1 shows the effect of 40 and 50 mg/kg roxithromycin (with or without 1 mg/kg fumarate fumarate) on the gastrocnemius muscle of AH-inoculated rats. In summary, the scientific literature confirms that muscle loss is very rapid in the cancer cachexia model of rat ascites hepatoma, and that fumarate fumarate administered by intraperitoneal injection prevents cancer cachexia. Surprisingly, we found that roxithromycin also prevented muscle consumption associated with the AH mouse model. In fact, we have demonstrated that roxithromycin administered alone is as effective in preventing AH-induced loss of gastrocnemius muscle from using formoterol fumarate alone. The muscle protection of roxithromycin and formoterol fumarate is higher than when they are administered separately at the same dose. These data show that roxithromycin works in combination with formoterol fumarate to prevent cachexia and increase protein synthesis. Without being bound by any theory of action, this data is consistent with the mechanism in which formoterol fumarate reduces the action of protein by ubiquitin-proteasome pathway to prevent cachexia, while the mechanism of action of roxithromycin is related to inhibition of inflammation. Procellular hormones such as IL-6 and TNF. Thus, the combination of formoterol fumarate and roxithromycin does provide an effective, indeed multi-model therapy for patients with cachexia and anorexia risk or suffering from cachexia and anorexia. Example 4: pH値 and buffer Effect of liquid strength on the solubility of roxithromycin in water The amount of roxithromycin equivalent to 1 〇 mg/ml was added to various solutions and stirred at 25 ° C for 24 hours. The solution was filtered through a syringe and analyzed by HPLC [roxithromycin]. The strength of roxithromycin was analyzed by reverse phase HPLC in accordance with the requirements of the European Pharmacopoeia (EP) Luo-40-200840590 erythromycin monograph. The pH of the solution was measured according to U S P < 7 9 1 >, and the solution osmotic pressure was measured by u S P < 7 8 5 >. The water solubility limit of roxithromycin is determined by the influence of buffer type (phosphate and citrate), buffer concentration, pH 値 and co-solvent (ethanol). Table 6 shows the solubility of roxithromycin in phosphate buffer without ethanol. Table 7, Table 8, and Table 9 show the solubility results of roxithromycin in phosphate buffers (10 mM, 20 mM, and 50 mM, respectively) in which 0, 5, and 10% ethanol co-solvents were added. Taken together these tables show that the solubility of roxithromycin increases with a decrease in pH値, an increase in phosphate concentration, and an increase in ethanol in the range of the study. Table 6 Effect of pH of phosphate buffer without ethanol cosolvent on the solubility of roxithromycin at 25 °C [Roxithromycin] mg/ml pH in [phosphate] = (mM) 10 20 50 5 3.2 5.2 7.2 6 2.8 4.2 6.7 7 1.4 1.3 2.0

Table 7 Effect of Adding Ethanol Cosolvent 1 pH of OmM Phosphate Buffer on Solubility of 2 5 C Lower Roxithromycin [Roxithromycin] mg/ml in 1 OmM Phosphate and Ethanol (%) pH値0 5 10 5 3.2 3.5 3.8 6 2.8 4.1 3.9 1.7 7 1.4 1.8 -41 - 200840590 Table 8 Effect of pH 値 of 20 mM phosphate buffer with ethanol co-solvent on the solubility of roxithromycin at 25 ° C [Roxithromycin] mg/ml in 20 mM phosphate and ethanol (%) pH 値 0 5 10 5 5.2 5.5 6.0 6 4.2 4.6 5.0 7 1.3 1.7 2.1 9 Adding ethanol cosolvent 5〇η Roxithromycin dissolved Effect of the pH of the phosphate buffer on 25 ° C in 50 mM phosphate and ethanol (%) [roxithromycin] mg / ml pH 5 0 5 10 5 7.2 8.3 9.2 6 6.7 8.1 9.3 7 2.0 2.3 3.1

Table 1 shows the data on the solubility of roxithromycin and the solution osmotic pressure in citrate buffer, which are affected by pH 値 and citrate concentration. The table shows that the osmotic pressure increases as the [citrate] increases and the pH increases within the range of the study. In the above-mentioned phosphate buffer solution, the solubility of roxithromycin decreased as the pH 値 increased. In the citrate buffer solution, the solubility of roxithromycin has a complex dependence on citrate concentration. -42- 200840590 Table 1 Effect of 0 p Η値 and [citrate] on the solubility and osmotic pressure of roxithromycin at 25 ° C [Citrate], (mM) pH 値 solution osmotic pressure Phytomycin 200 4 (mOsm/kG) 366 (mg/mL) 2.74 200 5 462 1.90 200 6 521 1.72 200 7 532 1.25 100 4 203 1.89 100 5 243 2.77 100 6 260 2.30 100 7 271 1.23 50 4 110 4.61 50 5 124 3.57 50 6 139 2.76 50 7 138 0.98 20 4 43 4.13 20 5 47 3.54 20 6 57 2.45 20 7 60 0.50

In summary, this example shows a decrease in pH (from 4 to 7), an increase in the concentration of ethanol cosolvent (from 10% to 10%), and a decrease in the concentration of citrate buffer (from 20 to 200 mM). Solubility. Example 5: Effect of pH 値 and buffer strength on the stability of roxithromycin water The stability of roxithromycin was 2 mg at pH 5 and buffer (citrate) at 5, 25 and 40 ° C. The effect of /ml [roximycin] is determined. The erythromycin % purity is determined by the area normalization method of the reverse phase -43-200840590 HPLC method which meets the requirements of the European Pharmacopoeia (EP) monograph. The pH of the solution was determined according to USP <791> 〇 Table 1 1 shows the % purity 値 and storage period (months) of the roxithromycin 2 mg/ml solution stored at 40 °C. Table 1 2 and Table 1 3 show the % purity data of the roxithromycin solution stored at 25 ° C and 5 ° C, respectively.

Table 11 [Citrate] and pH 値 effect of roxithromycin (2 mg / ml) % purity 不同 in different storage periods in 40 ° C citrate buffer. Area normalization method at different times (months) Roxithromycin % Purity Buffer 0 0.3 0.5 0.9 1.5 2.6 5.3 pH 5, 100 mM 90 60 46 31 14 4 pH 6, 100 mM 98 85 77 72 66 58 48 pH 4, 50 mM 78 15 3 1 pH 5, 50 mM 92 66 55 44 28 13 3 pH6, 50mM 98 89 82 77 71 65 61 pH4, 20mM 81 27 10 2 pH5, 20mM 96 74 66 60 50 36 21 pH6, 20mM 98 95 92 89 84 79 76 44- 200840590 Table 12 [Citrate] and pH Effect of 値 on the 25 ° C citrate buffer in different storage periods of roxithromycin (2 mg / ml) % purity 不同 different time (months) area normalization method roxithromycin% purity buffer 0 0.3 0.5 0.9 1.5 2.6 5.3 7.3 pH5, 100 mM 90 79 76 75 73 67 60 50 pH6, 100 mM 98 94 92 89 85 81 78 76 pH4, 50 mM 78 71 65 59 47 33 15 6 pH5, 50 mM 92 82 78 77 74 71 67 59 pH6, 50mM 98 96 94 92 89 85 81 78 pH4?20mM 81 74 70 65 56 48 28 15 pH5?20mM 96 88 84 80 77 75 75 71 pH6?20mM 98 97 96 96 94 92 90 87

Table 13 [Citrate] and pH 値 Effect of Roxithromycin (2 mg/ml) % purity 不同 in different storage periods in 5 ° C citrate buffer. Area normalization method at different times (months) Roxithromycin % Purity Buffer 0 0.3 0.5 0.9 1.5 2.6 5.3 7.3 pH5? 100mM 90 85 83 81 79 78 7.6 76 pH6, 100mM 90 96 95 95 93 90 86 84 pH4, 50mM 98 76 76 75 73 71 64 60 pH5 ?50mM 78 88 85 84 81 79 78 77 pH6, 50mM 92 97 96 96 95 93 90 87 pH4, 20mM 98 78 77 77 75 74 69 67 pH5? 20mM 81 93 91 89 85 82 80 79 pH6520mM 96 98 97 97 97 96 96 94 In summary, this example shows an increase in pH 値 (from 4 to 6) and a decrease in citrate concentration (from 20 mM to 100 mM) to increase the stability of roxithromycin. A water blend containing 2 mg/ml roxithromycin and a pH 6 of 20 mM citrate buffer -45-200840590 solution was not stable enough. Example 6 Effect of pH値 and buffer concentration on the solubility of formoterol fumarate Water A solution of formoterol fumarate in an amount equivalent to 10 mg/ml was added to various solutions. The solution was stirred at 25 ° C for 24 hours, filtered through a syringe and analyzed for the concentration of formoterol fumarate by reverse phase HPLC in the European Pharmacopoeia Formoterol fumarate monograph. Solubility of formoterol fumarate is limited by the effect of citrate buffer concentration (20 to 200 mM) and pH 値 (4 to 7). Table 10 summarizes the solubility and osmolality of fumarate fumarate in citrate buffer, which is affected by pH and citrate concentrations. The table shows that the osmotic pressure increases as the citrate concentration increases and the pH 値 increases within the range of the study. The solubility of formoterol fumarate decreases with increasing pH. In citrate buffer solution, the solubility of formoterol fumarate showed a complex dependence on citrate concentration. These data show that the solubility of formoterol fumarate is relatively insensitive to pH 値 and citrate concentrations in the pH range of 5 to 7. The solubility of formoterol fumarate at pH 4 was slightly higher than at pH 25. -46- 200840590 Dissolution of formoterol fumarate at 25 °C Table 14 Effect of pH 値 and [Citrate and solution osmotic pressure]

[Citrate], (mM) pH値200 4 200 5 200 6 200 7 100 4 100 5 100 6 100 7 50 4 50 5 50 6 50 7 20 4 20 5 20 6 20 7 Formoterol solution Troy (mOsm/kG) (mg/mL)** 392 3.69 473 2.90 527 2.72 543 2.84 205 3.01 249 2.69 275 2.87 278 2.60 113 3.69 130 2.77 140 2.78 146 2.92 49 2.71 56 2.35 60 2.47 66 2.33 Ideally, The oral solution of formoterol fumarate will support a concentration of formoterol fumarate of about 0.001 to 0.005 mg/ml, and thus is between 〇· 8 to 0. 32 mg (the expected dose required for anti-cachexia activity). The dose will require a dose of about 75 ml. The solubility of the method described in this example shows that the solubility of fluticacil fumarate at pH 4 to pH 7 of 20 to 200 m Μ citrate buffer concentration is higher than 1 mg/ml. . -47- 200840590 Example 7: Stability of 0.020 mg/ml formoterol fumarate in 20 mM citrate buffer (pH 5.5) containing 4.5% mannitol and 0.1% potassium sorbate according to Banerjee et al. (U.S. Patent No. 6,667,344), in the range of pH = 3 to pH = 7, the stability of formoterol fumarate is optimal at about pH 5, as mentioned by Banerjee et al. in the reference patent, "at pH 値The 60 °C ratio constants at 3, 4, 5, and 7 are about 0.62, 0.11, 0.04 4, and 0.55/day, respectively. Therefore, an aqueous solution of formoterol at a buffer concentration of 5 mM and an ionic strength of 0.05 at 60 ° C The dissociation is lowest at a pH of about 5.0. The estimated half-life of formoterol in the compositions provided herein is about 6.2 years at 5 °C and about 7.5 months at 25 °C. The stability of formoterol fumarate to a carrier suitable for oral solutions is 0.020 mg/ml in an aqueous solution containing 20 mM citrate buffer (pH 5.5), 4.5% mannitol and 0.1% potassium sorbate. Formoterol fumarate. Samples of this blend were stored at 5, 25, and 40 t:. At predetermined time intervals, a portion of the sample was taken from these samples and determined by reverse phase HPLC as reported in the literature by Akapo et al. (Akapo, et al: J Pharm Biomed Anal 33: 93 5 -4 5, 2003). Strength of "formoterol fumarate". The solution pH was measured according to 113? <791>, and the solution osmotic pressure was measured by 1;8?<7 85>. Table 1 5 shows the osmotic pressure data and confirms that there is no change in osmotic pressure under the conditions of the study. Table 1 6 summarizes the pH値 data and confirms that there is no significant change in the condition of the study. Table 17 summarizes the fumarate fumarate strength data for the solution at a predetermined time interval at 5, 25 and 40 °C. At the 3 month time point, the delay -48-200840590 fumarate strength loss was negligible at 5 °C and about 3 % at 25 °C. At 1.5 months, the strength of formoterol fumarate lost about 15% at 40 °C. Table 15 Osmotic pressure results of 0.020 mg/ml formoterol fumarate in 20 mM citrate buffer at pH 5.5 plus 4.5% mannitol and 0.1% potassium sorbate

Time point (month) 5 °C Osmotic pressure at different temperatures (mOsm) 25〇C 40°C 0.5 N/A 332 331 1.5 331 332 333 3.0 338 336 N/A Table 16 20 mM citrate buffer at pH 5.5 pH 値 result of 0.020 mg/ml fumarate fumarate in liquid plus 4.5% mannitol and 0.1% potassium sorbate

Time point (month) 5 °C Solution pH at different temperatures 値25〇C 40°C 0 5.54 N/AN/A 0.5 N/A 5.53 5.53 1.5 5.59 5.54 5.59 3.0 5.57 5.56 N/A 49- 200840590 Table 17 pH 5.5 containing 4.5% mannitol and oj% potassium sorbate, intensity of formoterol fumarate in a 2OmM citrate solution a, b fumarate fumarate (mg/mL) at different times (months), °c ) 0 0.25 0.5 1.5 3 40 0.0206 0.0189 0.0175 40 0.0207 0.0190 0.0175 25 0.0206 0.0203 0.0196 0.0199 0.0200 25 0.0207 0.0204 0.0198 0.0200 0.0200 5 0.0206 0.0202 0.0208 5 0.0207 0.0203 0.0209 a· The result is the average 値 of the repeated injection of the sample. Spaces indicate unmeasured data This example shows that the intensity loss of formoterol fumarate at a time point of 3 months is negligible at 5 °C and about 3% at 25 °C. After a period of 1.5 months, the loss of strength of formoterol fumarate was about 15% at 40 °C. Example 8: Co-adjustment to pH 6, 20 mM citrate buffer plus 4.5% mannitol and 0.1% potassium sorbate, the stability of formoterol fumarate and roxithromycin to confirm the fumarate fumarate The stability of the combination with roxithromycin in a carrier suitable for oral solutions is prepared in an aqueous solution containing 20 mM citrate buffer (pH 6.0), 4.5% mannitol and 0.1% potassium sorbate. Mg/ml of formoterol fumarate and roxithromycin of 2.0 mg/ml. The samples of this blend were stored at 5, 25, and 40 ° C and tested for the strength of formoterol fumarate and the strength of roxithromycin over 0, 2, and 4 weeks at -50-200840590. The strength of formoterol fumarate is determined by reverse phase HPLC as reported in the literature of Akapo et al. (Akapo, et al.: J Pharm Biomed Anal 3 3:93 5 -45, 2003). The strength of roxithromycin was analyzed by reverse phase HPLC in accordance with the requirements of the European Pharmacopoeia (EP) Roxithromycin monograph. Table 1 8 shows the fumarate fumarate strength data and Table 1 9 shows the roxithromycin strength data. After a four week time point, the stability data confirmed that there was no evidence of increased decomposition of the combined composition compared to similar data using formoterol fumarate alone (Example 7) or roximycin alone (Example 5). Table 18 Formoterol fumarate strength (μg/ml) at 5, 25, and 40 °C at 4 weeks time 値 Time Formoterol strength at different temperatures (°C) (μg/ml)

5 25 40 0 4.73 4.73 4.73 2 Not tested 4.91 4.76 4 4.92 4.73 3.95 Table 19 Roxithromycin strength (mg/ml) at 5, 25, and 40 °C at 4 weeks time 値 Different temperatures (° C) Lower erythromycin intensity (mg/ml) 5 25 40 0 1.92 1.92 1.92 2 1.74 L61 4 1.92 1.71 1.47 Example 9: Solubility of megestrol acetate for various cosolvents and excipients -51 - Effects of 200840590 Examples 4 - 8 show that a carrier containing about 20 m Μ citrate plus 4.5% mannitol and a pH 値 between 5 and 6 may be suitable for 2 mg/ml roxithromycin and about 5 μg/ A liquid oral dosage form of the composition of milliliters to about 50 micrograms per milliliter of formoterol fumarate. Since megestrol acetate may enhance the effectiveness of the combination of roxithromycin and formoterol in the prevention and treatment of cancer cachexia, the development of three drugs including megestrol acetate plus roxithromycin and formoterol Group 0 oral solution blends may have potential price 値 (in terms of patient compliance). Oral dosage forms of megestrol acetate have been marketed including 40 mg tablets, 800 mg / 20 ml suspension and 625 mg / 5 ml oral suspension. The stability data in Examples 5 and 7 shows that pH 値5 to 6, 20 mM citrate buffer solution containing roxithromycin and formoterol fumarate will need to be stored at a refrigerated temperature for long-term storage at room temperature. For short-term patients. A 150 mg dose of roxithromycin can be administered through a 75 ml dosing volume of a 2 mg/ml solution. Therefore, the target boundary strip φ of the 3-drug combination oral solution includes: • Megestrol acetate acetate 〇·5 to 4 mg/ml (= 300 mg twice a day for every 6 to 75 ml of the administration volume, for Luo Hong Required for mycin) • pH 値5 to 6 (required for storage stability of roxithromycin and formoterol) • Refrigerated storage (required for storage stability of roxithromycin and formoterol) Chemical and physical compatibility of fluocetrol due to the inherent water solubility of megestrol acetate is 2 μg/ml (FDA approved Bristol Meyers Squibb megestrol acetate-52 - 200840590 The formulation of a solution of 40 mg of lozenge), development of a solution blend suitable for oral administration will require the use of a cosolvent, a surfactant, a complexing agent and/or a combination of these inactive ingredients. The solvent and cyclodextrin complexing agent were added in various ratios to a pH 5.5, 20 mM citrate buffered aqueous solution containing 4.5% mannitol. Excess (10 mg/ml) megestrol acetate was added to each test solution and undissolved megestrol acetate was stirred at 5 ° C for 24 hours and then removed by filtration. [Megestrol acetate] in each test φ test solution was determined by reverse phase HPLC method as described by Burana-Osot J, et al.: J Pharm Biomed Anal 40:1068-72, 2006 . The results of this water solubility limit of megestrol acetate showed that 12 test solutions increased the solubility of megestrol acetate to > 5 mg / ml. The 12 test solutions (and the corresponding megestrol acetate solubility limit) are: • 80:20 polyethylene glycol (PEG) 600 average molecular weight: buffer (〇·6 mg/ml) • 80 : 20 PEG 400 average molecular weight: buffer (ο』mg/ml) • 10% polyethylene glycol 1 000 vitamin E succinate in 55:20:25 propylene glycol: PEG 400 ··buffer (0.8 mg/ml • 20% β-cyclodextrin (〇·8 mg/ml) • 30% β-cyclodextrin (1.3 mg/ml) • 3% seven (2,6-di-indole-methyl) β-cyclodextrin ( ]L1 mg/ml) • 10% seven (2,6·di-0-methyl) β-cyclodextrin (3.3 mg/ml) • 3% sulfobutyl ether 卩cyclodextrin sodium salt (0.8 mg/ml) • 10% γ-cyclodextrin (〇·6 mg/ml) -53- 200840590 • 3% 2-hydroxypropyl β-cyclodextrin substitution degree 4.3 (0 · 6 mg/ml) • 10% 2-hydroxypropyl Substituted β-cyclodextrin substitution degree 4.3 (1.2 mg/ml), and • 10% carboxymethyl β-cyclodextrin substitution degree 3 (0.7 mg/ml)

In the above table, most of the solutions having high solubility of megestrol acetate contain a cyclodextrin complexing agent. The cyclodextrin increases the solubility of megestrol acetate in water is not unpredictable, as the literature contains many uses of cyclodextrin to increase general drugs (Strickley RG: Pharm Res 21:201-30, 20 04, Albers Ε, and Muller BW) : Crit Rev Ther Drug Carrier Syst 12:311-37,1 995), and steroid hormones (Albers E, and Muller BW: J Pharm Sci 8 1:75 6-6 1, 1 992, Nandi I, et al: AAPS

PharmSciTech 4: E1, 2003, Cserhati T, and Forgacs E: J %

Pharm Biomed Anal 18:179-85, 1998, Albers E, and

Muller BW: J Pharm Sci 8 1:756-6 1,1 992,Pitha,J.,US Patent No 4,727,064,February 1 9 8 8) and especially macrolide antibiotics (Shastri, V., et al· US Patent No. 6,699,505, Mar 2004, Salem: Int J Pharm 250: 403 - 1 4, 2003) Solubility reference. Similarly, the increase in solubility of megestrol acetate by PEG 400 and PEG 600 cosolvents is consistent with literature observations (Millard J, et al.: Int J Pharm 245:1 53 -66, 2002, Li P, et al. : J Pharm Sci 88··1107-11, 1 999). The increase in solubility of megestrol acetate caused by polyethylene glycol vitamin E succinate is also consistent with literature observations (Roy et al, US Patnet No 6, 730, 679, 4 May 2004, Yu, et al., Pharm. Res., 16:1812-1817, 1 999). Surprisingly, however, any of the 12 solutions listed above can also be used to prepare a liquid oral dosage form comprising a combination of megestrol acetate plus fumarate-54-200840590 formoterol and roxithromycin. As shown in Examples 4-8, roxithromycin and formoterol fumarate can be suitably formulated in 20 mM citrate buffer of pH 値 5 to 6 plus 4.5% mannitol. Therefore, any of the 11 solutions listed in the above examples will be suitable for inclusion of 2 mg/ml roxithromycin, 0.005 mg/ml formoterol, and > 〇·5 mg/ml acetate. The ketone 3 combination is in a liquid oral dosage form. This addition of a suitable preservative and flavoring composition will have practical application in the treatment of cachexia patients. Example 1 〇: Rotamycin and fumarate fumarate multiparticulate solid oral dosage form for the treatment and prevention of cachexia and anorexia in humans may require a dose of 300 mg/day of roxithromycin and 160 μg/day of fumaric acid Trot dose. Although the patient can successfully administer roxithromycin and formoterol fumarate in a separate solid oral dosage form twice a day, the combination of the two active pharmaceutical ingredients in a single solid oral dosage form has significant patient compliance. Sexual advantage. Another significant advantage in terms of compliance is the inclusion of two active pharmaceutical ingredients in a single solid oral dosage form with sustained release properties so that the composition can be administered once a day. Factors affecting the design of a suitable combination solid oral dosage form of roxithromycin and formoterol fumarate include: • Wide range of differential doses of the two active ingredients • Very effective fumarate fumarate active pharmaceutical ingredient in the processed dispersion form Environmental Health and Safety Considerations -55 - 200840590 • The clinical development of the elasticity of roxithromycin and formoterol fumarate dosage form • The size of the solid oral dosage form • The masking of roxithromycin • Roxithromycin Possible chemical interactions with formoterol fumarate and • Selective flexibility between immediate release and slow release formulations. Roxithromycin and formoterol fumarate particles have thus been developed for solid oral dosage forms of multiparticulate single drugs and/or pharmaceutical combinations. The high drug armor concentration of roxithromycin granules can be prepared by various methods known to those skilled in the art, but the extrusion/spheronization method is particularly suitable for the preparation of erythromycin granules. Low drug armoured formoterol particles can be prepared by methods known to those skilled in the art, but the method of spraying formoterol fumarate to inactive sugar particles is particularly useful for preparing formoterol fumarate particles. In principle, these roxithromycin and/or formoterol particles can then be sprayed to alter environmental safety, release rate and/or chemical interaction characteristics. The multiparticulates which are filled into hard capsules or compressed into tablets may also provide the elasticity of the strength of the active ingredient in the final dosage form. Four rhodamine particle granules were prepared. Table 2 shows the composition of the blend and the numbered name -56- 200840590 Table 20 Nomenclature of the erythromycin blend formulation Formula No. Target Polymer*

Drug Decoration (%) Per 150 mg Roxithromycin Dose Particles Mg Adhesive Filling 1-A 79.0% 189.9 HPMC E4M MCC 2-B 80.0% 187.5 HPMC E5 MCC 3-C 85.0% 176.5 HPMC E4M MCC 4 -D 90.0% 166.7 HPMC E5 MCC *HPMC is hydroxypropyl methylcellulose, MCC microcrystalline cellulose is used to prepare three fumarate fumarate particles. Table 2 1 shows the composition of the mixture. Table 2 1 Nominal composition of formoterol fumarate formula

Formula number drug packaging (%) Target per 80 micrograms of fumarate fumarate dose particles mg core * type polymer binder * coated 6-F 0.053% 150.0 sugar HPMC E5 HPMC 7-G 0.053% 150.0 MCC HPMC E5 HPMC 8-H 0.053% 150.0 Sugar PVP K29/32 HPMC *HPMC hydroxypropyl methylcellulose, MCC microcrystalline cellulose, PVP system polyvinylpyrrolidone representative preparation method is described below. The procedure used to prepare the roxithromycin blend 2B is as follows: • Roxithromycin, microcrystalline cellulose PH101 and HPMC E5 were weighed and added to a planetary mixer (Hobart) and stirred for 5 minutes. -57- 200840590 • Weigh 95 grams of pure water and add water to the stirring powder within 2 minutes. • Stir the wet powder for 1 minute and scrape the mixing bowl wall. • Pass the wet mass through an LCI Bench-Top centrifugal extruder equipped with a 1.0 mM round sieve. The extrudate was collected for spheronization preparation. • Approximately 100 grams of the extrudate was placed in a Caleva Bench-Top spheronizer and started for 5 to 10 minutes to squash the extrudate into granules. • Continue the rounding step until all extrudates have been processed. • Collect the moist particles and dry them at 45 °C for 1 hour. The procedure for preparing the roxithromycin blend 4D is as follows: • Roxithromycin, microcrystalline cellulose PH101 and HPMC E5 were weighed and added to a planetary mixer (Hobart) and stirred for 5 minutes. • Weigh 60 grams of pure water and add water to the stirring powder in 1 minute. • Stir the moist powder for 1 minute and scrape the mixing bowl wall. • Pass the wet mass through an LCIBench-Top centrifugal extruder equipped with a 1.0 mM round sieve. The extrudate was collected for spheronization preparation. • Place approximately 100 grams of the extrudate in a Caleva Bench-Top rounder. A portion of the Cab-O-Sil was added to the spheronizer and started for 1 to 2 minutes to squash the extrudate into granules. • Continue the rounding step until all extrudates have been processed. • The wet granules were collected and dried under air flow at 45 °C for 12 hours. The procedure for the preparation of formoterol fumarate blend 6F is as follows: • Weighed formoterol, sugar core and HPMC E5 (two parts) and added -58- 200840590 to the fluid bed (bottom spray column). • Prepare two 7.5% HPMC solutions using the two scales of HPMC E5. After the clear solution was formed, formoterol fumarate was added and mixed to a portion of the HPMC solution to prepare a layered solution. • Preheat the sugar core in the liquid to a product temperature of 40 to 45 °C using an inlet temperature of 60 °C. • Start spraying the stratified solution onto the core with an atomization pressure of 1 to 1.5 bar. Adjust the intake air temperature to maintain the product temperature of 3 6 to 4 3 °C. • When all layered solutions have been sprayed, dry the pellets to a product temperature of approximately 45 °C. • Start spraying the second HPMC solution (coating solution) onto the layered core using an atomizing gas pressure of 1 to 1.5 bar. Adjust the intake air temperature to maintain the product temperature between 36 and 43 °C. • When all of the coating solution has been sprayed, dry the layered coated pellets to a product temperature of about 45 to 50 °C. The procedure for preparing the fumarate fumarate blend 7G is as follows: • Weighing fumarate fumarate, microcrystalline cellulose core and HPMC E5 (two parts) and adding the core to the fluid bed (bottom spray column). • Prepare two 7.5% HPMC solutions using the two scales of HPMC E5. After the clear solution was formed, formoterol fumarate was added and mixed to a portion of the HPMC solution to prepare a layered solution. • Use intake air temperature 6 (TCC core in TC preheated liquid to product temperature 40 to 45t. • Start spraying the stratified solution to the core - 59- 200840590 with an atomization pressure of 1 to 1.5 bar. Adjust the intake air Temperature to maintain product temperature 36 to 43 ° C. • When all stratified solutions have been sprayed, dry the granules to a product temperature of approximately 45 ° C. • Start spraying the second HPMC solution with an atomizing pressure of 1 to 1.5 bar (coating solution) onto the layered core. Adjust the inlet air temperature to maintain the product temperature of 3 6 to 4 3 t. • When all the coating solution has been sprayed, dry the layered coated particles _ to the product temperature 45 to 50 ° C. The procedure for preparing the formoterol fumarate blend 8H is as follows: • Weighing fumarate fumarate, sugar core, povidone and HPMC E5, and adding the core to the fluid bed (Bottom spray column) • Prepare 7.5% HPMC solution (coating solution) • Prepare 7.5% povidone solution using a mixture of 50/50 pure water and ethanol. Add and mix fumarate when forming a clear solution Mo% Trot was added to the solution to prepare a layered solution. Preheat the sugar core in the liquid to a product temperature of 4 〇 to 4 5 〇C using an inlet temperature of 60 ° C. • Start spraying the stratified solution onto the core with an atomization pressure of 1 to 1.5 bar. Adjust the intake air temperature to Maintain product temperature 3 6 to 43 ° C. • When all the layered solution has been sprayed, 'dry 1 dry the product to a temperature of about 45 ° C. · Start spraying HPMC with an atomizing pressure of 1 to 1.5 bar. Solution (coating solution) onto the layered core. Adjust the inlet air temperature to maintain the temperature of -60-200840590 product 36 to 43 ° C. • Dry the layered coated particles when all coating solutions have been sprayed The product temperature was about 45 to 50 ° C. The amount of roxithromycin in each of the prepared blends was determined by HPLC. Table 22 shows the results of the strength test to give milligrams of roxithromycin in 1 mg of granules. The number indicates that it is also expressed in milligrams of granules required to provide a dose of 150 mg of roxithromycin. The table shows that roxithromycin granules can be prepared in the range of sputum concentration and produce 150 mg of rosin. The amount of granules required for the dose of mycin is in capsules or ingots that can be added to a reasonable size. The dosage form is within the range of particle mass. Table 22 Strength of Roxithromycin Concentration Test Condensation Roxithromycin mg/1 〇〇mg granules granules mg/150 mg roxithromycin dose-1A 77.6 193 -2B 78.2 192 -3C 82.8 181 -4D 87.9 171 The amount of formoterol fumarate in each of the prepared blends was determined by HPLC. Table 23 shows the results of the strength test to be present in 1 mg of granules of formoterol fumarate. The weight (micrograms) is also expressed as the weight of the granules (mg) required to provide a dose of 80 micrograms of formoterol fumarate. The table shows that the formoterol fumarate granules can be prepared in the range of sputum concentration and the granule content required to produce 80 micrograms of formoterol fumarate dose can be added to a reasonable size capsule or lozenge dosage form. Within the range of particle quality. The table also shows satisfactory consistency of the amount of formoterol fumarate containing -61 - 200840590 between different samples. Table 23 Intensity Test Formulation of Formoterol Fumarate Blends Composition Formoteol Weight per Microgram of Microparticles (micrograms) Change of Formoterol fumarate per 80 micrograms * Sample 1 Sample 2 Average 値%RSD Average particle size Weight (mg) -6F 2.50 2.35 2.43 4% 330 -7G 1.85 2.0 1.93 6% 416 -8H 5.95 5.75 5.85 2% 137 The solubility characteristics of roxithromycin granules are determined by HPLC at 37 ° C using USP I method. The measurement was carried out using a pH 6, 20 mM citrate buffer or pH 2.7 aqueous HCl as a dissolution medium. The pH 6 medium approaches the pH of the intestinal compartment and pH 2.7 is near the upper pH limit of the gastric compartment. It is not practical to determine the solubility characteristics of roxithromycin at pH 値 < 2.7, because the catalyzed decomposition of roxithromycin occurs very rapidly according to Zhang et al. (J Pharm Sci 93: 1 300-9, 2004). Table 24 shows the dissolution test results at pH 2.7 and Table 25 shows the dissolution data for the pH 値6 medium. At pH 2.7, the roxithromycin granule blend released about 50% of the added roxithromycin within 1 hour. After a longer interval, the decreased roxithromycin recovery showed that the decomposition of roxithromycin (about 5% per hour) was consistent with the release. At pH 値6, slightly less than 50% of the added roxithromycin was released in about 2 hours and about 70% was released in 18 hours. These dissolution data show that the roxithromycin granule blend will rapidly release about half of the added roxithromycin in the gastric compartment during a typical 1-hour gastric emptying period, with the rest slowly releasing after entering the intestinal compartment. -62- 200840590 Table 24 Addition of t-erythromycin % at different time points in the pH 値 2.7 dissolution medium. Different blends * Added addition of roxithromycin % Time (hours) -1A -2B -3C - 4D 0.083 28.3% 24.9% 24.6% 26.1% 0.17 33.3% 40.5% 31.0% 36.0% 0.5 44.6% 42.1% 49.6% 1 52.5% 52.7% 49.7% 43.3% 2 59.5% 59.4% 56.3% 63.8% 4 51.8% 54.5% 54.2 % 53.9% 6 43.6% 43.3% 42.1% 42.3%

t% according to the number of milligrams of microparticles added to the dissolution medium in Table 22 and the average micrograms of formoterol per 100 milligrams of microparticles. Table 25 Additions recovered at different time points in the pH 値6 dissolution medium Roxithromycin% Added to the different blends of t added roxithromycin % time (/", hour) -1A -2B -3C -4D 0.08 7 7 8 5 0.17 13 9 14 10 0.25 19 14 18 16 0.33 24 19 24 21 0.50 31 26 19 16 1.0 28 28 28 31 2.0 44 44 51 18 77 73 71 71 i·The number of milligrams of microparticles added to the dissolution medium according to Table 22 and the fumt of each 100 milligrams of microparticles Recovery of the average micrograms of Luo. The dissolution rate of the fumarate fumarate particle granules was determined by the USP I method using pH 6, 20 mM citrate buffer as medium (close to the intestine -63-200840590 pH). The formoterol fumarate concentration was determined by HPLC. Table 26 shows the results of the dissolution test. The table confirms that 275% of the added formoterol fumarate is released in about 5 minutes. This test dosage form is therefore suitable for immediate release, solid oral dosage forms. Table 26 Addition of formoterol fumarate at different time points in the pH 値6 dissolution medium. Different blends were recovered. Added fumotrol% time (hours) -6F -7G -8H 5 79% 79% 85% 10 89% 82% 87% 20 99% 82% 85% 30 98% 85% 90% 60 94% 92% 90% 120 98% 87% 90% 1080 96% 90% 90% Ten according to Table 22 Molecular weight of microparticles to the dissolution medium and recovery of the average micrograms of formoterol per 100 milligrams of microparticles. Conclusion Although various specific embodiments and examples have been described herein, those of ordinary skill in the art It will be appreciated that many different implementations of the invention can be carried out without departing from the spirit or scope of the invention. For example, roxithromycin used in the above examples may be substituted with other macrolides such as, but not limited to, clarithromycin or azithromycin. Other changes will be known to those of ordinary skill in the field. -64- 200840590

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 illustrates the effects of 40 mg/kg and 50 mg/kg roxithromycin (with or without 1 mg/kg formoterol fumarate) on the gastrocnemius muscle of AH-inoculated rats. -65-

Claims (1)

200840590 X. Patent Application Scope 1 - A pharmaceutical composition for the prevention and treatment of a wasting disease in a mammal is a combination of a macrolide and a β2-agonist. 2. If the application of the scope of the patent application is applied, the medicine further includes an appetite stimuli. 3 • The application further includes megestrol acetate as applied in the second application of the patent application. φ 4 . The use of the third aspect of the patent application, wherein the megestrol acetate will be administered at a dose of between about 100 mg/day and about 1,200 mg/day. 5. The use of claim 4, wherein the megestrol acetate is administered at a dose of between about 100 mg/day to about 1,000 mg/day. 6. The use of claim 4, wherein the megestrol acetate is administered at a dose of between about 400 mg/day and about 1,200 mg/day. 7. The use of claim 1 wherein the macrolide and the β2-agonist have no substantial pharmacological interaction. φ 8 The application of claim 1 wherein the difference in serum half-life 値 of the macrolide and the β2-agonist is less than about 70%. 9. The use of claim 8 wherein the difference in serum half-life enthalpy of the macrolide and the beta2-agonist is less than about 50%. 10. The use of claim 9 wherein the difference in serum half-life enthalpy of the macrolide and the beta2-agonist is less than about 30%. 11. The use of claim 8 wherein the macrolide and the beta2-agonist have substantially different clearance mechanisms. 12. The use of claim 1 wherein the macrolide and -66 - 200840590 the beta 2 agonist will be administered as separate pharmaceutically acceptable carriers. 13. The use of claim 1 wherein the macrolide and the beta2-agonist will be administered in the same pharmaceutically acceptable carrier. 14. The use of claim 1 wherein the macrolide is roxithromycin, clarithromycin or azithromycin. 1 5 · The application of claim 14 of the patent application wherein the macrolide lactone 0 is roxithromycin. 16. The use of claim 15 wherein the erythromycin is administered at a dose of between about 25 mg/day and about 75 mg/day. 1 7 • As applied in claim 16 of the patent application, wherein the erythromycin will be administered at a dose of between about 50 mg/day and about 300 mg/day. 18. The application of claim 17 wherein the rosacea will be administered at a dose of between about 50 mg/day and about 200 mg/day. 19. The use of claim 16 wherein the roxithromycin φ will be administered at a dose of between about 150 mg/day and about 75 mg/day. 20. The use of claim 18, wherein the β2_agonist is formoterol fumarate, bambuterol or albuterol. 21. The use of claim 20, wherein the β2_agonist is formoterol fumarate. 22. The application of the second aspect of the patent application, wherein the formoterol fumarate will be administered at a dose of between about 5 micrograms/day and about 500 micrograms/day. -67 - 200840590 23. The use of item 22, wherein the formoterol fumarate will be administered at a dose of between about 5 micrograms/day to about 240 micrograms/day. 24. A medicine for preventing and treating a wasting disease in a mammal. a composition comprising a combination of a macrolide and a β2-agonist in a pharmaceutically acceptable carrier, wherein the macrolide and the β2-agonist are administered as a composition It exists in an amount effective to prevent or at least alleviate the wasting disease. 25. The pharmaceutical composition of claim 24, wherein the macrolide and the β2-agonist have no substantial pharmacological interaction. 26. The pharmaceutical composition of claim 24, wherein the difference in serum half-life 値 of the macrolide and the β2-agonist is less than about 70%. 2 7. The pharmaceutical composition of claim 26, wherein the difference in serum half-life 値 of the macrolide and the β2-agonist is less than about 50%. 2 8 · The pharmaceutical composition of claim 27, wherein the difference between the serum half-life 値 of the macrolide and the β γ agonist is less than about 30% ° 29 as claimed in claim 28 A pharmaceutical composition wherein the macrolide and the beta2-agonist have substantially different clearance mechanisms. The pharmaceutical composition of claim 24, wherein the macrolide is roxithromycin, azithromycin or clarithromycin. 3 1 · The pharmaceutical composition of the third paragraph of the patent application, wherein the macro-68-200840590 cyclic lactone is roxithromycin. 3 2 . The pharmaceutical composition of claim 31, wherein the rosinmycin is in an amount sufficient to deliver a dose of between about 50 mg/day to about 750 mg/day to the mammal. presence. 3 3. The pharmaceutical composition of claim 32, wherein the rosinmycin is in an amount sufficient to deliver a dose of between about 50 mg/day to about 300 mg/day to the mammal. presence. 3. A pharmaceutical composition according to claim 3, wherein the erythromycin is in an amount sufficient to deliver a dose of between about 50 mg/day to about 200 mg/day to the mammal. presence. The pharmaceutical composition of claim 32, wherein the rosinmycin is sufficient to deliver a dose of between about 155 mg/day to about 750 mg/day to the licking animal. The amount exists. The pharmaceutical composition of claim 24, wherein the β 2 -agonist is formoterol fumarate, bambuterol or salbutamol. 3 7. The pharmaceutical composition of claim 36, wherein the β2-agonist is formoterol fumarate. A pharmaceutical composition according to claim 3, wherein the formoterol fumarate is present in an amount sufficient to deliver a dose of from about 5 micrograms/day to about 240 micrograms/day to the mammal. 3. The pharmaceutical composition of claim 38, wherein the formoterol fumarate is present in an amount sufficient to deliver a dose of between about 5 micrograms/day to about 80 micrograms/day to the mammal. 40. The use of a macrolide for the preparation of a medicament for the prevention and treatment of mammals. 69. 200840590 Medical use of a disease. 41. The use of claim 40, wherein the macrolide is roxithromycin or azithromycin. 42. The application of claim 41, wherein the macrolide is roxithromycin. 43. The use of claim 42, wherein the erythromycin is present in an amount sufficient to deliver a dose of between about 50 mg/day to about 750 mg/day to the mammal. 44. The use of claim 43, wherein the erythromycin is present in an amount sufficient to deliver a dose of between about 50 mg/day to about 300 mg/day to the mammal. 4. The use of claim 44, wherein the rosacea is present in an amount sufficient to deliver a dose of between about 50 mg/day to about 200 mg/day to the mammal. 46. The use of claim 45, wherein the erythromycin is present in an amount sufficient to deliver a dose of from about 155 mg/day to about 750 mg/day to the mammal. 47. The use of claim 40, further comprising a non-sterol anti-inflammatory agent. 48. The use of claim 47, wherein the non-steroidal anti-inflammatory agent is a non-selective cyclooxygenase inhibitor. 4 9 . The use of the fourth aspect of the patent application, wherein the non-steroidal anti-inflammatory agent is a selective cyclooxygenase 2 (C〇X 2 ) inhibitor. 5 0. If the application of the scope of claim 1 is applied, the medicine further includes -70- 200840590 Non-sterol anti-inflammatory agents. 5 1. The use of claim 50, wherein the non-steroidal anti-inflammatory agent is a non-selective cyclooxygenase inhibitor. 5 2. The use of claim 51, wherein the non-steroidal anti-inflammatory agent is a selective cyclooxygenase 2 (COX-2) inhibitor. -71 -