TNF receptor and steroid hormone in a combined therapy

Details TNF receptor and steroid hormone in a combined therapy TNF receptor and steroid hormone in a combined therapy

1998-02-27

2001-05-01

Moezie, F. T. (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Cyclopentanohydrophenanthrene ring system doai

C514S002600, C514S012200, C514S169000, C514S170000

Reexamination Certificate

active

06225300

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to the use of a TNF Receptor together with a steroid hormone to produce a pharmaceutical composition for the treatment of lethal bacterial and viral infections as well as autoimmune and inflammatory diseases. It also relates to said pharmaceutical compositions for the simultaneous, separate or sequential use of its active ingredients for the above specified treatment.
In particular, it relates to the use of TBP-1 together with dehydroepiandrosterone (DHEA) or its metabolites to produce a pharmaceutical composition for the treatment of septic shock.
BACKGROUND OF THE INVENTION
Septic shock as a consequence of Gram-negative bacteremia or endotoxemia remains a critical clinical condition in spite of adequate antibiotic therapy.
It is now known that the lethal consequences of septic shock results from an exaggerated host response, mediated by protein factors such as TNF and interleuldn 1 (IL-1), rather than from the pathogen directly.
Tumour necrosis factor (TNF) is a cytokine produced mainly by activated macrophages, which elicits a wide range of biological effects. These include an important role in endotoxic shock and in inflammatory, immunoregulatory, proliferative, cytotoxic and antiviral activities.
The induction of the various cellular responses mediated by TNF is initiated by its interaction with two distinct cell surface receptors of approximately 55 kDa (also called TNF-R1) and 75 kDa (also called TNF-R2). The extracellular soluble portions of these receptors, called respectively TBP-1 (TNF Binding Protein-1) and TBP-2 (TNF Binding Protein-2), have been isolated and cloned (see EP Patents 308 378, 398 327 and EP patent Application 433 900).
Several studies in animal models of TNF-mediated endotoxic shock indicated that both anti-TNF antibodies and soluble TNF-receptor are able to counteract the lethal effects induced (see for example: Bentler, B et al., Science, 229:869 (1985), Lesslauer, W. et al., Eur. J. Immunol., 21:2883 (1991), Evans, T. J. et al. J. Exp. Med., 180:2173 (1994) and Mohler K. M. et al., J. Immunol. 151:1548 (1993)).
The in vivo protective effects of urinary as well as recombinant TBP-1 (derived from both CHO and
E. Coli
cells) in experimental models of septic shock have already been demonstrated (see Bertini. R. et al., Eur. Cytokine Netw. 4(1):39 (1993) and Ythier A., et al., Cytokines. 5:459 (1993)).
DHEA (INN: Prasterone) is an adrenocortical steroid hormone which is an intermediate in the biosynthesis of other hormones including testosterone and estradiol-17&bgr;.
The precise biological functions of DHEA are still unclear. Experimental and epidemiological data suggest an inverse relationship between low levels of DHEA in serum and morbidity from atherosclerotic cardiovascular disease (see Barret-Connor, D. et al., N. Engl. J. Med. 315:1519 (1986)), cancer (see Gordon, G.B., et al., Cancer Res. 51:1366 (1991)) and immunodeficiency virus (HIV) infection (Villette. J. M. et al. J. Clin. Endocrinol. Metab. 70:572 (1990)).
An immunomodulating activity of this drug has also been reported; in particular. DHEA has been shown to prevent the development of systemic lupus erythematosus in a mouse model (Lucas, J. et al. J. Clin. Invest. 75:2091 (1985)).
It has been demonstrated that DHEA regulates the systemic resistance against lethal viral infections induced by different viruses: coxsackievirus B4 (as reported in Loria. R. M. et al., Ann. N.Y. Acad. Sci. 293), herpes virus type 2 (see Loria, R. M. et al., J. Med. Virol., 26:301 (1988)), West Nile virus (a neurovirulent Sindbis virus) and Semliki Forest virus (as reported in Ben-Nathan, D. et al. Arch. Virol. 20:263 (1989)).
It has also been reported that DHEA has similar protective effects against a lethal bacterial infection induced by
Enterococciis faecalis
(see Loria. R. M. et al. in Symposium Pharmaco-Clinique, Roussel-Uclaf 9:24 (1989)).
Danenberg. H. D. et at. (Antimicrob. Agents Chemother. 36:2275 (1992)) reported that DHEA has the capability of protecting mice from septic shock induced by lipopolvsaccharides (LPS) alone or by Tumor Necrosis Factor alpha (TNF-&agr;) in combination with D-Galactosamine. LPS administration resulted in high levels of TNF-&agr;, a response that was significantly blocked by DHEA, both in vivo and in vitro.
DISCLOSURE OF THE INVENTION
The main object of the present invention is the use of a TNF Receptor in combination with a steroid hormone to produce a pharmaceutical composition for the treatment of lethal bacterial and viral infections as well as autoimmune and inflammatory diseases. The TNF Receptor and the steroid hormone can be administered simultaneously, separately or sequentially.
The Applicants have, in fact, found that in such treatment there is a synergic effect between the two active ingredients.
Another object of the present invention is, therefore, the method for treating lethal bacterial and viral infections as well as autoimmune and inflammatory diseases by administering simultaneously, separately or sequentially an effective amount of TNF Receptor and an effective amount of a steroid hormone, together with a pharmaceutically acceptable excipient.
A further object of the present invention are the pharmaceutical compositions containing a TNF Receptor and a steroid hormone, in the presence of one or more pharmaceutically acceptable excipients, for the simultaneous, separate or sequential administration of its active ingredients in the treatment of lethal bacterial and viral infections as well as autoimmune and inflammatory diseases.
In case of separate or sequential use of the two active ingredients, the pharmaceutical compositions of the invention will consist of two different formulations, each comprising one of the two active ingredients together with one or more pharmaceutically acceptable excipients.
The administration of such active ingredients may be by intravenous, intramuscular or subcutaneous route. Other routes of administration, which may establish the desired blood levels of the respective ingredients, are comprised by the present invention.
Non-limitative examples of pathologies, in which the above active ingredients are indicated, are the following: septic shock, AIDS, rheumatoid arthritis, lupus erythematosus and multiple sclerosis. Particularly preferred is the treatment of septic shock.
The TNF Receptor is preferably selected between the extracellular soluble domain of TNF-R1, i.e. TBP-1, and the extracellular soluble domain of TNF-R2, i.e. TBP-2. TBP-1 is particularly preferred. Recombinant human TBP-1 (r-hTBP-1) is advantageously used according to the invention.
The steroid hormone can be both a corticosteroid or an androgen. Preferably, it is an androgen. More preferably, it is DHEA or one of its metabolites, dispersed in a suitable medium, for example a phospholipid emulsion or carboxyinethyl cellulose or polyvinylpirrolidone.
Therefore, a preferred embodiment of the invention consists in the combined use of r-hTBP-1 and DHEA in the treatment of septic shock. In this case, the Applicant has found that it is possible to reduce at least four times the effective dose of r-hTBP-1.
The above effect has been showed with in in vivo experiments in mice.
In particular, a murine model has been used in the present invention, according to which septic shock is induced by administering lipopolysaccharides (LPS) in combination with D-Galactosarmine.
For the human therapy, the preferred doses of the active ingredient are 20 mg of r-hTBP-1 and 80 mg of DHEA, preferably divided into four administrations in a 24-hours period.
The invention will now be described by means of the following Examples, which should not be construed as in any way limiting the present invention. The Examples will refer to the Figures specified here below.


REFERENCES:
patent: 92512528 (1992-11-01), None
patent: 92 13095 (1992-08-01), None
patent: 94 06476 (1994-03-01), None
patent: 95 03827 (1995-02-01), None
Stedman's Medical Dictionary, 26 Ed. Williams & Wilkins, Baltimore, pp 1608-1609, 1995.*
H.D. Danenberg, et

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