Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2000-01-31
2003-04-29
Qazi, Sabiha (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C552S548000, C552S551000, C552S553000, C552S542000, C552S541000, C514S169000
Reexamination Certificate
active
06555530
ABSTRACT:
FIELD OF THIS INVENTION
The present invention relates to the use of a combination of estrogens or SERMs with delta-gonadien-21-ol-3,20-diones for treating diabetes, particularly type II diabetes. The present invention also embraces pharmaceutical compositions and kits comprising these compounds and methods of using the compounds and their pharmaceutical compositions.
BACKGROUND OF THIS INVENTION
Diabetes mellitus is a systemic disease characterized by disorders in the actions of insulin and other regulatory hormones in the metabolism of carbohydrates, fats and proteins, and in the structure and function of blood vessels. The primary symptom of diabetes is hyperglycemia, often accompanied by glucosuria, the presence in urine of large amounts of glucose, and polyuria, the excretion of large volumes of urine. Additional symptoms arise in chronic or long standing diabetes. These symptoms include degeneration of the walls of blood vessels. Although many different organs are affected by these vascular changes, the nerves, eyes and kidneys appear to be the most susceptible. As such, long-standing diabetes mellitus, even when treated with insulin, is a leading cause of blindness.
There are two recognized types of diabetes. Type I diabetes is of juvenile onset, ketosisprone, develops early in life with much more severe symptoms and has a near-certain prospect of later vascular involvement. Control of this type of diabetes is difficult and requires exogenous insulin administration. Type II diabetes mellitus is of adult onset, ketosis-resistant, develops later in life, is milder and has a more gradual onset.
One of the most significant advancements in the history of medical science came in 1922 when Banting and Best demonstrated the therapeutic effects of insulin in diabetic dogs. However, even today, a clear picture of the basic biochemical defects of the disease is not known, and diabetes remains a serious health problem. It is believed that two percent of the United States' population is afflicted with some form of diabetes. The introduction of orally effective hypoglycemic agents was an important development in the treatment of hyperglycemia. Oral hypoglycemic agents are normally used in the treatment of adult onset diabetes.
Observations in animal models on glucose metabolism for type II diabetes and in humans suggest that sex steroids play a permissive role in the phenotypic expression of hyperglycemia. These observations have prompted studies on the effects of androgens and estrogens on blood glucose levels. Testosterone administration to intact or ovarectomized female rats resulted in marked insulin resistance which correlated to morphological changes in muscle, Holmang, et al.,
Am.J.Physiol
., 259, E555-560 (1990); Holmang, et al.,
Am.J.Physiol
., 262, E851-855 (1992). In streptozotocin diabetic rats, implanted testosterone antagonized the ability of residual insulin to maintain glycemic control, Le et al.,
Endocrinology
, 116, 2450-2455 (1985). In contrast, glucosuria disappeared in castrated diabetic KK mice and reappeared when androgens were replaced in these mice, Nonaka, et al.,
Jpn.J.Vet.Sci
., 50, 1121-1123 (1988); Higuichi, et al.,
Exp.Anim
., 38, 25-29 (1989).
Results from estrogen administrations also support the hypothesis that the balance between androgens and estrogens is critical to the development of hyperglycemia. Daily estradiol administrations to diabetic KK mice normalized the blood glucose levels and eliminated glucosuria, Toshiro, et al.,
Jpn.J.Vet.Sci
., 51, 823-826 (1989). Estradiol also lowered the blood glucose levels of C57BL6J-ob/ob mice, Dubuc,
Proc.Soc.Exp.Biol.Med
., 180, 468-473 (1985) and C57BL/KsJ-db/db mice, Garris,
Anatomical Record
, 225, 310-317 (1989).
In Biochemical and Biophysical Research Communications, (Dec. 24, 1996) 229 (3) 752-7, Diabetic Medicine, (September 1996) 13 (9 Suppl 6) s148-50 and Journal of Clinical endocrinology and metabolism, (September 1996) 81 (9) 3299-306, and several other journals, are disclosed insulin sensitizers, in particular thiazolidinediones, and their use in treating diabetes mellitus, in particular NIDDM. Insulin sensitizers lowers blood glucose without stimulating insulin secretion, and in some instances even lowers insulin levels in mammals.
There remains a need in the art for combined compositions and methods that are useful to reduce blood glucose concentrations. There is a further need for such compositions that lack or has decreased undesirable side effects of estrogen(s) and/or progesterone(s).
One object of the present invention is to provide compositions in one dosage form which can effectively be used to treat type II diabetes.
Another object of the present invention is to provide compositions, method of treatment or kits exhibiting a synergistic effect.
A further object of the present invention is to provide compositions, method of treatment or kits exhibiting no substantial side effects, such as high level of coronary heart disease events.
Other objects of the present invention will become apparent upon reading the present description.
DESCRIPTION OF THIS INVENTION
The present invention is based in part on the discovery that a representative combination of an estrogen or estrogen receptor modulator and a compound of formula I
wherein R
1
, R
2
and R
3
independently of each other are C
1-12
alkyl, in the form of 21R or 21S epimers or mixtures thereof, or a pharmaceutically acceptable salt thereof, is effective for reducing blood glucose concentrations, and for treating type I and II diabetes in mammals, such as humans.
The present invention is based in part on the discovery that a representative combination of an estrogen or estrogen receptor modulator and a compound of formula I are also useful for treating conditions associated with insulin resistance. Conditions associated with insulin resistance can result from disorders such as diabetes mellitus and its chronic complications, obesity, hyperlipidemias and dyslipidemias, atherosclerosis, hypertension, cardiovascular disease, AIDS, cancer, wasting/cachexia, sepsis, trauma associated with burns, malnutrition and stress; aging, lupus and other autoimmune diseases, endocrine disease, hyperuricemia, polycystic ovary syndrome and complications arising from athletic activity or inactivity.
The combination of an estrogen or estrogen receptor modulator and a compound of formula I shows a synergistic effect in treatment of type I and 11 diabetes and/or in reducing blood glucose concentrations and/or a synergistic effect on side-effects, such as cardiovascular disorders, eg. lowering lipids.
In a first aspect the invention relates to a method of reducing blood glucose concentrations which method comprises administering to a subject an effective amount of an estrogen or estrogen receptor modulator in combination with an effective amount of a compound of formula I
wherein R
1
, R
2
and R
3
independently of each other are C
1-12
alkyl, in the form of 21R or 21S epimers or mixtures thereof, or a pharmaceutically acceptable salt thereof, in an amount sufficient to reduce blood glucose concentrations.
In a second aspect the invention relates to a method of treating type I and II diabetes, preferably type II diabetes which method comprises administering to a subject an effective amount of an estrogen or estrogen receptor modulator in combination with an effective amount of a compound of formula I
wherein R
1
, R
2
and R
3
independently of each other are C
1-12
alkyl, in the form of 21R or 21S epimers or mixtures thereof, or a pharmaceutically acceptable salt thereof, in an amount sufficient to treat type I and II diabetes, preferably type II diabetes.
In a third aspect the invention relates to a kit containing a treatment for type I and II diabetes, preferably type II diabetes comprising a) an effective amount of an estrogen or estrogen receptor modulator and a pharmaceutically acceptable carrier in a first unit dosage form; b) an effective amount of a compound of formula I
wherein R
1
, R
2
and R
3
independently of each other are C
Began, Esq. Marc A.
Bork, Esq. Richard W.
Green, Esq. Reza
Novo Nordisk A S
Qazi Sabiha
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