Use of oxandrolone in the treatment of burns an other wounds

Details Use of oxandrolone in the treatment of burns an other wounds Use of oxandrolone in the treatment of burns an other wounds

1997-12-05

2003-06-10

Goldberg, Jerome D. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

Reexamination Certificate

active

06576659

ABSTRACT:

Throughout this specification, various publications are referenced by Arabic numerals within parentheses. Full citations for these references may be found at the end of the specification immediately preceding the claims. The disclosure of these publications in their entireties are hereby incorporated by reference into this specification in order to more fully describe the state of the art to which this invention pertains.
BACKGROUND OF THE INVENTION
Burns
Over one million people are involved in burn accidents in the United States each year. Approximately 150,000 of these patients are hospitalized and over 6000 of these die each year (1).
Following thermal injury, severe protein and fat wasting occurs (1). Loss of as much as 20% of body protein may occur in the first two weeks following major burn injury (2). Increased oxygen consumption, metabolic rate, urinary nitrogen excretion, fat breakdown and steady erosion of body mass are all directly related to burn size and return to normal as the burn wound heals or is covered (1). The metabolic rate in patients with burns covering more than 40% of total body surface is twice as high as the metabolic rate in people without burns (1).
Although the danger associated with acute burn-induced weight loss, especially lean body mass has well been defined, the impact of this process on patient outcome continues to be severely underestimated. The focus of management of critical illness post-burn remains that of cardiopulmonary support and infection control while stress induced catabolism may proceed unchecked leading to a rapid loss of lean tissue (fat-free), mainly muscle which is followed by protein loss in diaphragm, heart, then liver, kidney and splanchnic bed. The loss of visceral proteins may actually begin very early after injury and the muscle protein is used to replace organ losses. It is clear that the response to severe injury or post-surgical infection will become auto-destructive if not contained. Complications will occur including multiple organ dysfunction, the leading cause of death in the post-burn period. A loss of lean body mass exceeding 40% of total is usually fatal. This muscle loss corresponds to a comparable loss of total body protein which affects all organ functions.
Although major advances in surgical nutrition have also been made, attempt at controlling the protein loss often come too little and too late to prevent the catabolism induced complications. The degree of lean tissue loss corresponds very precisely with not only profound weakness, including chest wall and diaphragm impairment, but also decreased immune function, leading to infection, usually pneumonia.
Both lymphocyte and neutrophil immune defenses are impaired. Loss of myocardial muscle leads to decreased contractility. Wound healing becomes markedly impaired and an open wound soon becomes an infected wound. Cell metabolic abnormalities occur including decreased cell energy charge and impaired calcium kinetics.
Despite this well defined concept, a routine assessment of body weight and body protein loss and an aggressive attempt at preventing early protein depletion by controlling the host response to injury and optimizing anabolism is not performed.
The current therapy of burn injury, namely high protein nutrition and early wound closure attenuates the process but patients with large burns enter the recovery phase with a significant deficit in muscle mass. Since the peak rate of restoration of muscle mass, using endogenous stimuli alone, including good nutrition approximates 1 to 1.5 pounds a week, restoration of lean body mass usually requires months.
Use of the anabolic agent, human growth hormone, can increase anabolic activity in the burns, but high expense and complications such as hyperglycemia have prevented widespread use of this agent (3). This agent also has to be administered by injection.
Since the rate of recovery of lean body mass dictates disability time, an increased rate would be of tremendous functional and economic value in burn patients.
The subject invention provides therapies that increase the rate of recovery of lean body mass, thereby reducing the length of stay in a hospital and reducing rehabilitation time. Moreover, the subject invention provides therapies that increase the rate of wound healing. This is of great importance in burn-patients, especially in those patients that receive skin grafts. This is also important in burn-patients which have wounds at donor sites.
Oxandrolone
Oxandrolone(17-methyl-17-hydroxy-2-oxa-5-androstan-3-one) is a known compound which is commercially available. The preparation of oxandrolone is described, inter alia, in U.S. Pat. No. 3,128,283. Oxandrolone is an anabolic steroid synthetically derived from testosterone. Oxandrolone has a unique chemical structure compared with other testosterone analogs. Oxandrolone contains an oxygen rather than a carbon atom at the 2-position within the phenanthrene nucleus (4) and lacks a 4-ene function in the A-ring. The anabolic activity of oxandrolone is approximately 6 times greater than its androgenic activity and has been found to be 6.3 times greater than that of methyltestosterone (4).
Anabolic activity refers to the ability to cause nitrogen retention, promoting weight gain and increasing muscle strength. Androgenic activity refers to the ability to enhance male characteristics (i.e. secondary sex characteristics such as facial hairs and voice changes). Because of the high ratio of anabolic to androgenic activity, oxandrolone is less likely to cause adverse cosmetic consequences in women than many testosterone analogs.
Furthermore, in contrast to the majority of oral androgenic anabolic steroids (e.g. micronized testosterone, methyltestosterone, fluoxymesterone), oxandrolone undergoes relatively little hepatic metabolism (5, 6).
Oxandrolone has been administered to malnourished patients with alcoholic hepatitis (7, 8). Oxandrolone has been shown to be safe even in dosages of up to 80 mg/day in patients with alcoholic hepatitis (7).
The subject invention discloses the use of an oxandrolone for the treatment of cachexia, muscle wasting and involuntary weight loss associated with wounds, especially burns.


REFERENCES:
patent: 5461030 (1995-10-01), Lindenbaum
Selye, Exp. Med. Surg., 28(2), 169-78, Abstract Only 1970.*
Solymoss et al., Toxicol. Appl. Pharmacol., 18(3), 586-92 Abstract Only, 1971.*
Hernon et al., Treatment of Burns, Curr. Probl. Surg., 1987, vol. 2, pp. 347-397 (Exhibit 2).
Wolfe R.R., Nutrition and Metabolism in Burns, In Chernow B. and Shoemaker W.C., eds., Critical Care, State of the Art, Fullerton, California, Society of Crtitical Care Medicine, 1986, vol. 7, pp. 19-61 (Exhibit 3).
Fox et al., (1962), J. Clin. Endocrinol. Metab. 22: 921-924 (Exhibit 4).
Karim et al., (1973), Clin. Pharmacol. Ther. 14: 862-869 (Exhibit 5).
Roubenoff et al., (1991), Nutrition Reviews 49(6): 163-175 (Exhibit 6).
Kopera H. (1985), Acta Endocrinologica, Supplementum 271: 11-18 (Exhibit 7).
Garlick et al. in Ballier's Clinical Gastroenterology, Burns ed., vol. 2, No. 4, 1988, pp. 915-940 (Exhibit 8).
Haupt et al. (1984), The American Journal of Sports Medicine 12 (6): 469-484 (Exhibit 9).
Wilson, J.D. in Goodman and Gilman's, The Pharmacological Basis of Therapeutics, Eight Editon, Pergamon Press, 1990, pp. 1413-1430 (Exhibit 10).
Demling et al., Current Opinion in Critical Care (1996) 2: 482-491 (Exhibit 11).
Kowalewski et al., Acta Endocrinologica (1970) 64:541-547 (1974) (Exhibit 12).
Marmo et al., Gazzetta Medica Italiana (in Italian) (1974) 133: 47-56 —Exhibit 13a English Translation (Exhibit 13/13A).
Albanese et al., Nutritition Report International (1970) 1(4): 231-242 (Exhibit 14).
O'Shea et al., Nutrition Report International (1970) 2(6): 351-362 (Exhibit 15).

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