Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2002-07-25
2004-10-26
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S575000, C514S557000, C514S559000, C424S059000, C424S060000, C424S811000, C424S811000, C424S900000, C424S900000
Reexamination Certificate
active
06809118
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a pharmaceutical composition and method for the treatment of radiation cutaneous syndrome. More particularly, the present invention relates to a pharmaceutical composition and method for the treatment of skin reaction involving swelling, desquamation, ulceration, fistula and fibrosis due to radiation exposure or radiotherapy.
2. Description of the Related Art
Radiotherapy is an effective modality for head and neck, skin, anogenital and breast cancers. However, the radiation-induced skin damage collectively termed radiation cutaneous syndrome including acute skin reactions involving swelling, desquamation and ulceration, and late cutaneous fibrosis and fistual limit the therapeutic ration. In addition, the skin is affected in every form of external radiotherapy of internal organs. Application of steroidal or nonsteroidal anti-inflammatories has unsatisfactory results and toxicities. An approach to selectively reduce skin morbidity without compromising tumor mortality by radiotherapy is needed.
The course of radiation cutaneous syndrome follows a distinct pattern. The manifestation stage is characterized by erythema and discrete scaling within hours to days followed by subepidermal swelling and blistering within days to weeks, and then progressing to epidermal atrophy, teleangiectasia and fibrosis within months to years, or even ulceration and fistula formation in severe cases. In chronic forms, cutaneous fibrosis is commonly seen. It is caused by an increased production of collagen fibers in the cutaneous and subcutaneous tissues, which can lead to functional impairment of the affected area, and result in contractures, damage of lymph vessels, and the secondary ulceration. Moreover, a variety of cytokines are locally upregulated following radiation to the skin. Induction of cytokines may be responsible for the early and longer-term side effects on skin after irradiation. Inhibition of TNF-&agr; has been shown to ameliorate the acute inflammation and skin ulcer. The critical role of the TGF-&bgr; in late radiation fibrosis has been proposed as a major target of antifibrotic agents. Thus, simultaneously stimulating the growth of epithelial cells, inhibiting the proliferation of cutaneous fibroblasts, and modulating the fibrogenic growth factors may provide an effective method to reduce skin toxicity in acute and late radiation damage.
SUMMARY OF THE INVENTION
According to the present invention it was surprisingly found that histone deacetylase inhibitors and in particular valproic acid, trichostatin A and phenylbutyrate strongly inhibit the main features of radiation cutaneous syndrome, resulting in decrease of skin swelling, promotion of desquamation healing, and prevention of cutaneous fibrosis. That simultaneously epithelium regrowth is stimulated, cutaneous fibroblast proliferation is inhibited, collagen deposit is decreased, and fibrogenic growth factor (TGF-beta) and the proinflammatory cytokine (TNF-alpha) are suppressed all indicate that valproic acid, trichostatin A and phenylbutyrate are potent agents for the treatment of radiation cutaneous syndrome.
The present invention is directed to the use of a histone deacetylase inhibitor and a pharmaceutically acceptable carrier or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for the treatment of radiation cutaneous syndrome.
Histone deacetylase inhibitors are substances causing an inhibition of the activity of histone deacetylases, resulting in hyperacetylation. Currently compounds shown to inhibit the activity of histone deacetylase fall into six structurally diverse classes, comprising: phenylbutyrate of the short chain fatty acid class, depudecin of the epoxide class, trapoxin A of the cyclic tetrapeptide class containing a 2-amino-8-oxo-9,10-epoxy-decanoyl moiety, depsipeptide of the cyclic tetrapeptide class lacking a 2-amino-8-oxo-9,10-epoxy-decanoyl moiety, trichostatin A of the hydroxamic acid class, and the benzamide class.
Phenylbutyrate inhibits histone deacetylases by a noncompetitive mechanism at millimolar concentrations. Trichostatin A is a specific inhibitor of histone deacetylase, and effective in the submicromolar range.
REFERENCES:
patent: 6538030 (2003-03-01), Chung et al.
patent: 2002/0055542 (2002-05-01), Chung et al.
patent: 2002/0183388 (2002-12-01), Gudas et al.
ADR news, Phenytoin. Stevens-Johnson syndrome: case report, Serious Reactions (ADR news), Feb. 22, 1996, ADISNEWS. See: abstract.*
Merck Index, Ninth Edition, 1976, pp. 137 and 1273.*
U.S. patent application Ser. No. 09/938,926, Chung et al.
Fish & Richardson P.C.
Krass Frederick
Ostrup Clinton
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