Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
1999-12-22
2003-12-30
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
active
06670351
ABSTRACT:
TECHNICAL FIELD
The invention relates to the use of oxandrolone to attenuate myopathy and muscle weakness/wasting associated with infection by human immunodeficiency virus-Type 1.
BACKGROUND OF THE INVENTION
Human immunodeficiency virus (HIV) associated myopathy and/or muscle weakness/wasting is a relatively common clinical manifestation of acquired immunodeficiency syndrome (AIDS). This is one of a number of neuromuscular disorders associated with the disease. There is some evidence to indicate that direct HIV infection of muscle may be at least partly responsible, occasionally resulting in a polymyositis-like disorder. In addition, zidovudine (AZT), an antiviral agent that is used widely in the clinical management of AIDS, has been associated with a toxic myopathy, presumably related to an inhibition of mitochondrial metabolism. In any event, the loss of muscle mass commonly observed in AIDS victims negatively impacts muscle function, however caused.
Individuals with HIV-associated myopathy or muscle weakness or wasting typically experience significant weight loss, generalized or proximal muscle weakness, tenderness, and muscle atrophy. Laboratory tests of samples from such individuals often reveal elevated levels of enzymes associated with muscle degeneration and necrosis, such as creatine kinase, aldolase, and aspartate amino transferase. Electromyographic test results for individuals with HIV-associated myopathy are typically consistent with myopathic changes. Histopathologic tests may reveal muscle fiber necrosis associated with lymphocytic inflammatory infiltrates. In AZT myotoxicity, ragged red fibers are often observed.
Clinical management of HIV-associated myopathy and muscle weakness/muscle wasting varies. In individuals with AZT myopathy, withdrawal of this anti-retroviral agent may be associated with temporary improvement in strength and muscle bulk. Corticosteroid therapy, such as the administration of prednisone, has been occasionally successful when inflammatory infiltrates have been detected in muscle. However, a potential drawback to this approach is that corticosteroids, because of their immunosuppressant activity, may be harmful to individuals with AIDS who are already dangerously immunosuppressed as a consequence of the HIV infection.
Furthermore, corticosteroid use itself is associated with myopathies and an increased susceptibility to infections. Plasmapheresis has also been used with some success, although at least one patient has experienced, despite an increase in muscle strength, substantial weakness over a period of several weeks.
SUMMARY OF THE INVENTION
The present invention provides a method which employs oxandrolone (an anabolic steroid with weak androgenic activity) as an alternative approach to the clinical management of HIV-associated myopathy/muscle weakness/muscle wasting. Loss in muscle mass (wasting) is attenuated, and body weight can be more readily maintained in this manner. Such an approach has been applied successfully to improve strength, reverse weight loss, and provide an improved sense of well-being. Importantly, no evidence of liver injury or other untoward side effects have been observed.
Oxandrolone preferably is administered orally; however, other routes or administration can be utilized as well.
The present method of ameliorating muscle weakness or muscle wasting in a patient infected with HIV-1 comprises administering to the patient daily a sufficient amount of oxandrolone to attenuate the patient's rate of muscle mass loss. To this end, oxandrolone may be administered, orally or otherwise, in a daily dose in the range of about 2.5 to about 20 milligrams. However, the response of individual patients may vary and in some instances a daily dose greater than 20 mg may be required to achieve the desired response. The daily dose may be divided into unit doses of about 1 to about 5 milligrams each, administered to the patient three times per day at about eight-hour intervals.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
Oxandrolone (17-hydroxy-17-methyl-2-oxaandrostan-3-one) is a known compound that is commercially available. The preparation of oxandrolone is described, inter alia, in U.S. Pat. No. 3,128,283 to Pappo, which description is incorporated herein by reference.
Pharmacologically, oxandrolone is a synthetic anabolic steroid similar in structure to testosterone, but having a different, lesser androgenic/anabolic activity ratio. In addition, oxandrolone is unique among all other testosterone analogues in that it contains an oxygen atom instead of a methylene group at the 2-position of the phenanthrene nucleus. In addition, oxandrolone lacks a 4-ene function in its A-ring. The anabolic potency of oxandrolone, estimated as approximately 3 to 13 times that of testosterone, 's believed to result form this unique structure.
Oxandrolone disposition and metabolism in man has been studied following oral administration of a 10 milligram dose. The study indicated that oxandrolone was rapidly and completely absorbed, yielding a mean peak plasma concentration of 417 micrograms of oxandrolone per milliliter at 66 minutes The plasma concentration of oxandrolone declined in a biphasic manner with a distribution half-life of approximately 30 minutes and an elimination half-life of 9.4 hours. Protein binding of oxandrolone was observed to be extensive.
In distinct contrast to other anabolic androgenic steroids such as methyltestosterone, fluoxymesterone, and micronized testosterone, oxandrolone taken orally is excreted mainly unchanged and unconjugated in urine. Urinary excretion of approximately 35 percent of an oral oxandrolone dose has been observed within 72 hours after ingestion. After 96 hours, approximately 65 percent of the administered oxandrolone dose was excreted in urine. Fecal excretion accounts for less than about 3 percent over the same time period.
Oxandrolone compositions, upon administration in accordance with this invention, ameliorate myopathy and muscle weakness in patients suffering from infections by human immunodeficiency virus-Type 1. Anabolic steroids, as a class, are known to stimulate appetite. Improved nutrition is important to individuals with AIDS who have experienced loss of lean body mass. Further, as a consequence of direct interaction with androgen and/or glucocorticoid receptors in muscle, anabolic steroids promote muscle anabolism through both anabolic pathways and anticatabolic pathways.
Anabolic steroids, such as oxandrolone, also increase protein synthesis. For example, oxandrolone increased muscle protein synthesis in a study of acute uremic rats. Similarly, administration of oxandrolone preceded clinical improvement in appetite, cell mass, linear growth, and weight for height in sovs with chronic renal failure. These observations are consistent with anabolic activity. Oxandrolone may also stimulate the secretion of growth hormone and insulin-like growth factors.
In addition to producing beneficial direct anabolic action, oxandrolone is also believed to act as a delayed immunostimulant. In contrast, other appetite stimulants, such as dronabinol, that are currently under evaluation as appetite stimulants for AIDS patients can act as immunosuppressants in animals.
For purposes of administration in accordance with this invention, the active ingredient oxandrolone is combined with solid or liquid pharmaceutical carriers and formulated in unit dosage form using pharmacologically acceptable excipients, or dissolved or suspended in physiologically acceptable solvents or liquid vehicles for oral, percutaneous, or topical administration.
The overall daily dose of oxandrolone to provide a therapeutically effective amount in accordance with the method of this invention can be as low as about 2.5 milligrams and as high as about 20 milligrams, depending upon the patient's response and the mode of administration.
The amount of the active ingredient within the aforementioned ranges that is to be administered depends upon the age, weight and condition of the patient, as well as on factors such a
Bio-Technology General Corporation
Travers Russell
White John P.
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