Compositions and methods for treating COPD and other inflammatory conditions
The present invention features, inter alia, pharmaceutical compositions and their use in the preparation of a medicament (e.g., a medicament for inflammation, such as an inflammatory lung disease) or in a therapeutic regimen. The compositions can include at least two active agents: a first agent that inhibits PDE4 (e.g., roflumilast) and a second active agent that inhibits the expression or activity of one or more PDE4B variants (e.g., PDE4B2). The compositions and methods will attenuate an unwanted up-regulation of a PDE4B (e.g., PDE4B2) and may thereby improve treatment with the first agent (e.g., roflumilast). For example, the second agent may improve the efficacy of the first agent, decrease the effective dose of the first agent, ameliorate the tolerance to the first agent that would otherwise develop (e.g., in patients with COPD exacerbation), reduce unwanted side effects caused by the first agent, or otherwise improve treatment regimes including a PDE4 inhibitor.
1. A method of treating chronic obstructive pulmonary disease (COPD), the method comprising administering an effective amount of roflumilast and an effective amount of a second agent to a patient having COPD,
wherein the patient is infected with Haemophilus influenzae,
wherein the second agent inhibits the upregulated activity or upregulated expression of phosphodiesterase 4B2 (PDE4B2) associated with roflumilast treatment and Haemophilus influenzae infection, and
wherein the second agent is selected from the group consisting of a glucocorticoid; a hypoxia-inducible factor 1α (HIF-1α) inhibitor selected from the group consisting of chrysin, chetomin, 2-methoxyestradiol, cryptotanshinone, and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG); curcumin; an alkenyldiarylmethane; a 2-arylpyrimidine; a triazine; a pyridazino[4,5-b]indolizine; a nucleic acid molecule that selectively inhibits the expression of PDE4B2; and combinations thereof.
2. The method of claim 1 , wherein the roflumilast and the second agent are combined in single dosage form.
3. The method of claim 1 , wherein the roflumilast and the second agent are administered concurrently or sequentially by the same or different routes of administration.
4. The method of claim 3 , wherein the roflumilast is administered orally and the second agent is administered directly to the lungs.
5. The method of claim 3 , wherein the second agent is formulated as a dry powder for administration directly to the lungs by inhalation.
6. The method of claim 1 , wherein the glucocorticoid is selected from the group consisting of dexamethasone, cortisol, cortisone, prednisone, prednisolone, methylprednisolone, betamethasone, triamcinolone, beclometasone, fludrocortisone acetate, deoxycorticosterone acetate, and aldosterone.
7. The method of claim 1 , wherein the HIF-1α inhibitor is 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG).
8. The method of claim 1 , wherein the alkenyldiarylmethane is:
or a pharmaceutically acceptable salt thereof.
9. The method of claim 1 , wherein the 2-arylpyrimidine is:
or a pharmaceutically acceptable salt thereof.
10. The method of claim 1 , wherein the triazine is a compound according to the formula:
wherein each of R 4 , R 5 , and R 6 is selected from the group consisting of hydrogen, halogen, cyano, carboxyl, alkyl, aryl, or heterocycle and can be optionally substituted with one or more of halogen, cyano, carboxyl, alkyl, aryl, or heterocycle.
11. The method of claim 1 , wherein the pyridazino[4,5-b]indolizine is a compound according the formula:
wherein R 1 is H or —NO 2 ,
or a pharmaceutically acceptable salt thereof.