Corticoid therapy

Details Corticoid therapy Corticoid therapy

1999-10-06

2001-07-10

Criares, Theodore J. (Department: 1617)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Cyclopentanohydrophenanthrene ring system doai

C514S171000, C514S324000, C514S651000

Reexamination Certificate

active

06258802

ABSTRACT:

BACKGROUND OF THE INVENTION
The use of corticoids for a variety of indications is well known. They are used to treat, for example, asthma, rheumatoid arthritis and auto-immune diseases, including lupus, Scleroderma, Wegener's granulomatiosis, and the like. Some corticoids also exhibit progestational activity. One example is triamcinolone acetonide. The usefulness of such progestational corticoids is often impaired in some women by the side effects of such agents. For instance, those major side effect include menstrual irregularity and/or hot flashes. Such side effects can result in reluctance or even avoidance of the use of the corticoid as well as to restrict the medicinal formulations, such as inhalation therapies versus oral tablets or other systemic delivery systems or routes. Among females and males, reproductive capabilities can be impaired when corticoidal therapies are administered.
It has now been discovered that the side effects of the progestational corticoids can be modulated by the cojoint use of a selective estrogen receptor modulator (also known as an SERM, selective estrogen or anti-estrogen).
The use of an anti-estrogen in medical practice is known. While the anti-estrogen therapy which has been developed has been successful, it is not without problems. One reason is that endogenous hormone production implicates a hyper-activity of the hypothalamic-pituitary-gonadal axis. When estrogen binds to its receptors, there is a feedback mechanism which becomes activated and regulates the endogenous production of pituitary gonadotropins and, in turn, estrogen, so that the hormonal milieu remains within the physiological range. However, when an anti-estrogen binds to the estrogen receptors, altered estrogen feedback mechanisms are implicated in a pharmacological manner compared to what occurs when estrogen binds normally. The anti-estrogens themselves can induce multiple follicular growth which, in turn, causes the production of endogenous ovarian estrogens. One example is the use of clomiphene or tamoxifen for ovulation induction. At the time of the first anti-estrogen dose administration and continuing for some period of time, the endogenous estrogen produced as a consequence of the multiple follicular growth may not appear to pose a problem. However, at some point, which is totally unpredictable and which varies from individual to individual, endogenous estrogen can be produced such that the quantity of estrogen present can elevate blood levels well above 300 pg/ml. Indeed, estradiol concentration in plasma may exceed a few thousand pg/ml in some instances. Therefore, while the use of an anti-estrogen seeks to reduce or modify or eliminate the side effects of estrogen, its use over time may have the reverse effect by inducing an excess concentration of estrogen. Not only may the use of the anti-estrogen exaggerate the estrogen side effects which the therapeutic course seeks to avoid, but the anti-estrogen may also even eliminate the primary benefit of its administration in the first instance. For example, a “run away” endogenous estrogen can induce ovulation in those situations where the administration of the anti-estrogen was designed to provide contraception. This feature of anti-estrogen therapy makes the establishment and maintenance of appropriate dosages of anti-estrogen difficult and in some cases impossible, especially when the therapeutic goal is simultaneously to limit excessive estrogenic impact in one tissue while providing adequate estrogenic stimulation in another tissue.
In light of the characteristics of the anti-estrogen, the discovery that it can be used to modify the side effects of corticoid therapy is surprising and unexpected. By this combination, patients can better tolerate higher corticoid doses, with fewer side effects, as well as a broader array of drug delivery systems.
It is the object of this invention to modify the side effects of the use of progestational corticoids. This and other objects of the invention will become apparent to those of ordinary skill in the art from the following detailed description.
SUMMARY OF THE INVENTION
This invention relates to a method of using a glucocorticoid and modifying the side effects thereof by use of a SERM such as tamoxifen. More particularly, the invention involves superposing the use of a selective estrogen receptor modulator on the administration of a glucocorticoid compound which also exhibits substantial progestin-like activity in an overlapping dose range.
DETAILED DESCRIPTION OF THE INVENTION
Corticoids which exhibit progestin-like activity are employed in the present invention to treat a variety of indications in accordance with their well known activity. They can thus be used to treat, for example, asthma, rheumatoid arthritis and a variety of auto-immune diseases, including lupus, scleroderma, Wegener's granulomatosis, and the like. Examples of such progestational corticoid compounds which can be utilized include triamcinolone acetonide, fluticasone propionate, mometasone furoate, beclomethoasone dipropionate, budesonide, prednisone, and the like. Other examples of such progestational corticoid active compounds arc well known in the art.
The formulation of dosage forms containing the corticoid, as well as the dosage amount and mode of administration are those known in the art. The progestational corticoid active compound can thus be administered by way of any art recognized means as practiced in the pharmaceutical arts. For example, it can be formulated so that it is administered orally, subcutaneously, intramuscularly, buccally, by inhalation, by a skin patch for transdermal absorption, contained within an inert matrix which is implanted within the body and in the depot state or intravaginally in a matrix that releases the material.
In accordance with the present invention, an additional therapy, namely the use of a selective estrogen reception modulator (also known as an SERM, selective estrogen or anti-estrogen) is superposed on the known use of the corticoid.
Any known SERM can be used in the practice of this invention. Examples of known SERMs include, but are not limited to, clomiphene; cycladiene; tamoxifen; nafoxidine; nitromifene citrate (N-55,945-27); 13-ethyl-17&agr;-ethynl-17&bgr;-hydroxygona-4-9-11-trien-3-one (R2323); diphenol hydrochryscne; erythro-MEA; allenolic acid; cyclofenyl; chlorotrianisene; ethamoxytriphetol; triparanol; CI-626; CI-680; MER-25; U-11,555A; U-11,100A; ICI-46,669; ICI-46,474; CN-55,945; compounds of the formula:
where R
1
is hydrogen, an aromatic group or alkyl of preferably no more than nine carbon atoms, R is an aromatic or alkyl group of preferably no more than nine carbon atoms and various of their derivatives; the triphenyl compounds described in U.S. Pat. No. 2,914,563 which are of the formula:
wherein one of the R groups is a basic ether of the formula OC
n
H
2n
A in which n is 2, 3 or 4 and A is a C
1-4
dialkylamino group, N-piperidyl or &bgr;-morpholinyl and the other R and R
1
are hydrogen, halogen or methoxy while X is halogen; as well as benzothiophenes such as those described in U.S. Pat. No. 5,624,940 of the formula:
in which Rand R
3
are independently hydrogen, C
1-4
alkyl, —CO(C
1-6
alkyl) or —COAr in which Ar is optionally substituted phenyl, R
2
is pyrrolidino, hexamethyleneamino or piperidino, or a salt thereof. Example of the benzothiophenes include raloxifene (6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinethoxy)-benzoyl] benzo[b]- thiophene) and LY353381.HCl benzothyphenes. The SERMs can also be employed in the form of their pharmaceutical acceptable non-toxic salt or complexes. Examples include the acid addition salt such as, for instance, citrate, hydrochloride, hydrobromide, sulfate, phosphate, nitrate, oxalate, fumarate, gluconate, tannate, maleate, acetate, benzoate, succinate, alginate, maleate, absorbate, tartrate and the like. The complexes can be with metals or various organic moietics.
The SERM aspect of the present invention is similar to the previous use of such materials for the

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