Therapies for treating pulmonary diseases

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...

Reexamination Certificate

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Details

C514S653000

Reexamination Certificate

active

06288118

ABSTRACT:

AREA OF THE INVENTION
This invention relates compositions and methods for preventing or reducing the onset of symptoms of pulmonary diseases, or treating or reducing the severity of pulmonary diseases. In particular it relates to compositions and methods for treating pulmonary diseases mediated by phosphodiesterase 4 (PDE4) by administering a PDE4 inhibitor with other pharmaceutically active agents which affect pulmonary function.
BACKGROUND OF THE INVENTION
Identification of novel therapeutic agents for treating pulmonary diseases is made difficult by the fact that multiple mediators are responsible for the development of the disease. Thus, it seems unlikely that eliminating the effects of a single mediator could have a substantial effect on all three components of chronic asthma. An alternative to the “mediator approach” is to regulate the activity of the cells responsible for the pathophysiology of the disease.
One such way is by elevating levels of cAMP (adenosine cyclic 3′,5′-monophosphate). Cyclic AMP has been shown to be a second messenger mediating the biologic responses to a wide range of hormones, neurotransmitters and drugs; [Krebs Endocrinology Proceedings of the 4th International Congress Excerpta Medica, 17-29, 1973]. When the appropriate agonist binds to specific cell surface receptors, adenylate cyclase is activated, which converts Mg
+2
-ATP to cAMP at an accelerated rate.
Cyclic AMP modulates the activity of most, if not all, of the cells that contribute to the pathophysiology of extrinsic (allergic) asthma. As such, an elevation of cAMP would produce beneficial effects including: 1) airway smooth muscle relaxation, 2) inhibition of mast cell mediator release, 3) suppression of neutrophil degranulation, 4) inhibition of basophil degranulation, and 5) inhibition of monocyte and macrophage activation. Hence, compounds that activate adenylate cyclase or inhibit phosphodiesterase should be effective in suppressing the inappropriate activation of airway smooth muscle and a wide variety of inflammatory cells. The principal cellular mechanism for the inactivation of cAMP is hydrolysis of the 3′-phosphodiester bond by one or more of a family of isozymes referred to as cyclic nucleotide phosphodiesterases (PDEs).
It has been shown that a distinct cyclic nucleotide phosphodiesterase (PDE) isozyme, PDE IV, is responsible for cAMP breakdown in airway smooth muscle and inflammatory cells. [Torphy, “Phosphodiesterase Isozymes: Potential Targets for Novel Anti-asthmatic Agents” in New Drugs for Asthma, Barnes, ed. IBC Technical Services Ltd., 1989]. Research indicates that inhibition of this enzyme not only produces airway smooth muscle relaxation, but also suppresses degranulation of mast cells, basophils and neutrophils along with inhibiting the activation of monocytes and neutrophils. Moreover, the beneficial effects of PDE IV inhibitors are markedly potentiated when adenylate cyclase activity of target cells is elevated by appropriate hormones or autocoids, as would be the case in vivo. Thus PDE IV inhibitors would be effective in the lung, where levels of prostaglandin E
2
and prostacyclin (activators of adenylate cyclase) are elevated. Such compounds would offer a unique approach toward the pharmacotherapy of bronchial asthma and possess significant therapeutic advantages over agents currently on the market.
In addition, it could be useful to combine therapies in light of the fact that the etiology of many pulmonary diseases involves multiple mediators. In this invention there is presented the combination of a PDE 4 inhibitor and an inhaled long-acting beta agonist for treating pulmonary diseases, particularly COPD or asthma.
SUMMARY OF THE INVENTION
In a first aspect this invention relates to a method for treating a pulmonary disease by administering to a patient in need thereof an effective amount of a PDE 4 inhibitor and a long-acting beta adrenergic bronchodilator either in a single combined form, separately, or separately and sequentially where the sequential administration is close in time, or remote in time.
In a second aspect this invention relates to a composition for treating a pulmonary disease comprising an effective amount of a PDE4 inhibitor, an effective amount of a long-acting beta adrenergic bronchodilator and a pharmaceutically acceptable excipient.
In a third aspect this invention relates to a method for preparing a composition which is effective for preventing the symptoms of treating a pulmonary disease which method comprises mixing an effective amount of a PDE4 inhibitor and a long-acting beta adrenergic bronchodilator with a pharmaceutically acceptable excipient.
DETAILED DESCRIPTION OF THE INVENTION


REFERENCES:
patent: 5858694 (1999-01-01), Plazza et al.
patent: 5889003 (1999-03-01), Dhainaut et al.
patent: 5919801 (1999-07-01), Dhalnaut et al.

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