Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
1998-11-03
2004-02-24
Qazi, Sabiha (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S169000, C514S170000, C514S171000, C514S172000, C514S177000, C514S182000
Reexamination Certificate
active
06696432
ABSTRACT:
The invention relates to a combination of dehydroepiandrosterone and aromatase inhibitors as well as the new use of dehydroepiandrosterone (DHEA) in combination with aromatase inhibitors for the production of a pharmaceutical agent for treating a relative and/or absolute androgen deficiency in men.
In men, increasing age leads to a reduction of testicular androgen production and androgen concentration in the organism, as well as, in men-and women equally, to a reduction of adrenal production of dehydroepiandrosterone, a hormonal precursor for androgens and estrogens. In contrast to the situation in women, in whom estrogen production drops to castration values within a comparatively short period, this takes decades in men and involves an only gradual drop. It can nevertheless be clearly demonstrated that the total concentration of testosterone in the serum in the higher age group is significantly reduced compared to the values in young men. Because of the increase in steroid hormone-binding globulin (SHBG) that coincides with the aging process, moreover, the proportion of free, unbound, and thus biologically active testosterone drops. In addition, it is clear that the serum levels of estrogens, although they are produced from androgens by direct conversion, do not drop in the same way as a function of age. As a result, the hormonal environment is significantly altered.
In men, the hormonal environment of the sexual steroids is characterized by a significant preponderance of androgens over estrogens. While the circulating main component of androgens, testosterone, is detected in the serum in units in the range of nmol/l the estrogen antagonist, estradiol, can be measured only in the range of pmol/l. This considerable preponderance of androgen can be detected basically in the entire late puberty period of life, but there is a clearly different intensity of this androgen dominance as a function of age. With increasing age and particularly so in those over the age of 60, there is a less pronounced emphasis of the androgen preponderance. Table 1 shows published test series in which the ratio of testosterone serum to estradiol serum was determined in a comparison of young to old men (≧60 years).
TABLE 1
Comparison of the T/E
2
Ratio in Serum in Young and Old
Men
Young (<60
Old (<60
% &Dgr;
Reference
years)
years)
(reduction)
Deslypere et
206:1
128:1
−38%
al.
1)
Pirke & Dörr
2)
324:1
174:1
−46%
Baker et al.
3)
372:1
225:1
−31%
Murano et
155:1
98:1
−37%
al.
4)
160:1
84:1
−48%
a.m.
p.m.
1)
Deslypere, J. P. et al., Journal of Clinical Endocrinology and Metabolism, 64, No. 1, 1987
2)
Pirke, K. M. & Doerr, P., Acta Endocrinologica, 74 (1973), 792-800
3)
Baker, H. W. G. et al., Clinical Endocrinology, 5 (1976), 349-372
4)
Murano, E. P. et al., Acta Endocrinologica, 99 (1982), 619-623
Although in the above-mentioned works, the ratio of testosterone to estradiol is indicated to some extent in considerably different orders of magnitudes—which can be attributed to the different measuring methods that are used—in older men there is clear agreement between the relative decreases in the preponderance of testosterone by 30-50% and the previous values found in young men.
The relative testosterone deficiency that occurs can have a disadvantageous effect in many respects. It is assumed that, e.g., an imbalance between androgens and estrogens that accompanies the drop in testosterone, generally at, for example, constant estrogen concentrations, is of decisive importance for the occurrence of benign prostatic hyperplasia (BPH). Regardless of the effects of estrogens, however, the relative testosterone deficiency per se can also be regarded as responsible for a number of age-related disorders. Reduction of muscle mass, accompanied by limitation of physical capacity, reduction of bone density and in individual cases even osteoporosis, reduction of libido and potency, and psycho-vegetative disorders can be mentioned here. All above-mentioned disorders are often generically referred to as
“Kilmakterium virile. [Male Menopause].”
The standard treatment for this syndrome, which is presumably caused by androgen deficiency, has been to supply androgens exogenically. Orally active androgens and long-chain testosterone esters with a depot effect that are to be administered intramuscularly are used. These forms of therapy are suitable for improving the symptoms caused by androgen deficiency, but produce an only inadequate approximation of the physiological state.
As a substance to be administered orally, either a testosterone derivative, i.e., not a natural testosterone, is given (e.g., Proviron
(R)
, or the administration is accompanied by a disproportionately large increase in dihydrotestosterone (DHT) that deviates from the physiological situation (e.g., Andriol
(R)
). Unlike testosterone, DHT seems to be the androgen component that is of great importance for the development of BPH and also of androgenetic alopecia.
In the case of depot formulations, the uneven release from the depot represents a problem that has not yet been satisfactorily resolved; it initially results in an increase in testosterone that extends significantly beyond the normal range, but toward the end of the dosage interval it leads to significantly reduced testosterone values.
It has long been known that, in addition to androgens, estrogens are also involved in the endocrine control circuit that keeps the androgen level in men constant. By administering pharmacological doses of estrogen-active substances, such as, e.g., diethylstilbestrol, it is possible in patients with prostate cancer to largely suppress the hypophyseal LH release and to reduce the testosterone level in the serum to the castration level.
From experience with use of pure antiandrogens in prostate-cancer patients who belong to the same age group as patients with male menopause, the extent of the counterregulatory potential can be assessed. If the central inhibiting action of androgens is suppressed by pure antiandrogens such as flutamide or casodex, in this age group this results in a counterregulatory increase in the serum testosterone concentration by about 50-60% compared to the starting value. In the case of treatment that lasts for months, however, there were indications of a lessening of the activity of counterregulation in the case of the prostate-cancer patients who were treated with pure antiandrogens, i.e., the initially significantly increased androgen levels drop again (Lund and Rasmussen, 1988; Mahler and Denis, 1990: Delaere and Van Thillo, 1991).
It is noteworthy that the reduction in androgens with age is not prevented by activation of the counterregulation mechanism. The reason for this is considered to be that, on the one hand, the testicular function generally diminishes with age, but, on the other hand, the feedback mechanism is also more sensitive to sexual steroids (Deslypere, J. P. et al., Journal of Clinical Endocrinology and Metabolism, 64, No. 1, 1987). Consequently, it has to be assumed that a less pronounced counterregulation is present in older men compared to younger men (see below), and thus for long-term use a serum androgen concentration that is higher than the starting value can be expected.
In contrast, it is known that in younger men, in long-term treatment testosterone values are also effectively increased by daily treatment with antiestrogens (with considerable partial estrogenic action in each case) (Treatment of Male Infertility, Springer-Verlag Berlin, Heidelberg, N.Y. 1982; Fuse, H. et al., Archives of Andrology 31 (1993) 139-145).
Based on theoretical considerations, antiestrogens do not seem well suited for treatment of a relative androgen deficiency in men. Thus, treatment with antiestrogens has no effect on the estrogen level since the antiestrogens block the action of estrogens on their receptor. When antiestrogens are used as receptor blockers, inadequate compliance immediately led to an adverse effect since the higher estrogen concentration can act directly o
Elliesen Jörg
Habenicht Ursula
Neumann Friedmund
Radlmaier Albert
Millen White Zelano & Branigan P.C.
Qazi Sabiha
Schering Aktiengesellschaft
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