Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2000-04-07
2003-07-08
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S861000
Reexamination Certificate
active
06589989
ABSTRACT:
This application is a 371 of PCT/EP/98/05236 filed Aug. 18, 1998.
The present invention relates to the use of 9-cis retinoic acid and derivatives or precursors thereof for the manufacture of a medicament for the treatment of T-helper cell type 1 mediated immune diseases as well as to the use of said active substances for the treatment of such diseases.
Despite intensive clinical research with retinoids in the last 27 years, retinoids have not been reported to be clinically useful in the therapy of immunologically mediated diseases. Neither diseases caused by T-helper type-1 cell (Th1) dependent cellular immunity, nor diseases caused by T-helper type-2 cell (Th2) dependent humoral immunity, have been reported to respond to retinoids. As to the classification into Th1 dependent diseases—such as autoimmune and other cell-mediated immune diseases, e.g. rheumatoid arthritis, multiple sclerosis, uveoretinitis, thyreoiditis, Crohn's disease, insulin dependent diabetes mellitus, eczema and systemic lupus erytheematosus, as well as rejection of allogeneic organ transplants—and Th2 dependent diseases—i.e. diseases with dominant humoral or antibody-mediated diseases such as allergic disorders, e.g. atopic dermatitis, allergic rhinitis, hay fever and allergic bronchial asthma—reference is made to Romragnani, ed, Th 1 and Th 2 Cells in Health and Disease. Chem. Immunol., Karger, Basel, 63, pp. 158-170 and 187-203 (1996).
For the first time, quite unexpectedly, it has now been found that a retinoid—namely 9-cis retinoic acid as well as its salts, its esters and its metabolic precursors or prodrugs as well as metabolites of 9-cis retinoic acid, such as 4-oxo-9-cis retinoic acid—is clinically efficacious in the therapy of Th1 dependent diseases.
In the scope of the present invention the term “metabolic precursors and prodrugs as well as metabolites of 9-cis retinoic acid” encompasses compounds that are converted metabolically into 9-cis retinoic acid, and it includes, in particular, 9-cis retinal and 9-cis retinol as well as pharmaceutically acceptable acetals of 9-cis retinal and pharmaceutically acceptable hydrolyzable esters of 9-cis retinol as well as metabolites of 9-cis retinoic acid such as 4-oxo-9-cis retinoic acid or their glucuronides.
In accordance with this invention, it has thus been found that that administration of 9-cis retinoic acid, its pharmaceutically acceptable salts, its pharmaceutically acceptable hydrolyzable esters, 9-cis retinal, its pharmaceutically acceptable acetals, 9-cis retinol and its pharmaceutically acceptable hydrolyzable esters, as well as metabolites of 9-cis retinoic acid, are efficacious in treating patients with T-helper cell type 1 (Th1) mediated diseases.
The invention therefore relates to the use of 9-cis retinoic acid, a pharmaceutically acceptable salt or a pharmaceutically acceptable hydrolyzable ester thereof, 9-cis retinal or a pharmaceutically acceptable acetal thereo: or 9-cis retinol or a pharmaceutically acceptable hydrolyzable ester thereof as well as metabolites of 9-cis retinoic acid for the manufacture of a medicament for the treatment of T-helper cell type 1 (Th1) mediated immune diseases.
The invention also relates to a method for treating patients having T-helper cell type 1 (Th1) mediated immune diseases comprising administering to said human patient a compound selected from the group consisting of 9-cis retinoic acid, pharmaceutically acceptable salts and pharmaceutically acceptable hydrolyzable esters thereof, 9-cis retinal and pharmaceutically acceptable acetals thereof as well as 9-cis retinol and pharmaceutically acceptable hydrolyzable esters thereof as well as metabolites of 9-cis retinoic acid said compound being administered in an amount effective to treat said disease.
In the scope of the present invention, the term “T-helper cell type 1 mediated immune diseases” relates to diseases with dominant cellular immune response, and it encompasses, in particular, autoimmune and other cell-mediated immune diseases, such as rheumatoid arthritis, multiple sclerosis, uveoretinitis, thyreoiditis, Crohn's disease, insulin dependent diabetes mellitus, eczema, systemic lupus erythematosus and allogeneic graft rejection (e.g. rejection of allogeneic skin, kidney, heart, liver or lung transplants). The term “eczema” relates, in particular, to eczema due to delayed type hypersensitivity. The term “treatment” or “treating” includes preventive and/or therapeutic treatments.
9-cis retinoic acid and its derivatives and metabolic precursors and prodrugs as well as metabolites of 9-cis retinoic acid when administered to patients are effective, in particular in the therapy of the following T-helper cell type 1 (Th1) mediated diseases: rheumatoid arthritis, multiple sclerosis, uveoretinitis, thyreoiditis, Crohn's disease, insulin dependent diabetes mellitus, systemic lupus erythematosus as well as eczema with its various classes of exogenous eczema, such as irritant dermatitis, allergic contact dermatitis, tylotic eczema or pompholyx, endogenous eczema, such as seborrheic eczema (also called seborrhoic dermatitis or seborrheic dermatitis), asteatotic eczema and discoid eczema, and eczemas localised at various sites of the body. 9-cis retinoic acid and its derivatives and metabolic precursors and prodrugs are effective in all those immune diseases which might be somehow linked with an increase of Th1 cell activity and an increased secretion of the related cytokines interleukin-12, interleukin-2, interferon &ggr; and tumor necrosis factor &agr;, &bgr;.
For the treatment of Th1 mediated diseases other than eczema, the active compound, i.e. 9-cis retinoic acid, a pharmaceutically acceptable salt or a pharmaceutically acceptable hydrolyzable ester thereof, 9-cis retinal or a pharmaceutically acceptable acetal thereof or 9-cis retinol or a pharmaceutically acceptable hydrolyzable ester thereof or metabolites of 9-cis retinoic acid, is administered orally. For the treatment of eczema the active compound is administered either orally or topically. Preferably, said compound is administered as a composition containing said active compound and a pharmaceutically acceptable carrier or diluent compatible with said active compound. In preparing such composition, any conventional pharmaceutically acceptable carrier can be utilized. When the drug is administered orally, it is generally administered at regular intervals, conveniently at mealtimes or once daily. It has been established that this compound is effective in doses which show no or only mild side effects when given orally or when given topically. Therefore, oral administration of the active compound is generally preferred. For treating eczema however topical administration may also be used advantageously.
In the treatment of T-helper cell type 1 mediated immune diseases, 9-cis retinoic acid and its derivatives and metabolic precursors and prodrugs as well as its metabolites, when administered orally, are therapeutically efficacious in doses which induce no adverse events or only such mild side effect as dry lips and transient headache. At present, all retinoids exerting therapeutic effects in dermatological and oncological indications have to be administered orally in doses which induce more or less marked side effects, belonging to the toxic syndrome of hypervitaminosis A, such as mucocutaneous, musculoskeletal and neurologic manifestations, particularly headache. In addition, they produce laboratory abnormalities such as elevated transaminases (ALAT, ASAT), elevated alkaline phosphatase, as well as elevated triglycerides and cholesterol. In contrast, the daily doses of 9-cis retinoic acid and its derivatives and metabolic precursors and prodrugs and metabolites of 9-cis retinoic acid (typically 20 to 60 mg) therapeutically efficacious in T-helper cell type 1 mediated immune diseases produce only very slight side effects, such as dry lips and transient headache, whereas all the other toxic signs and symptoms of the hypervitaminosis A syndrome, including the laboratory abnormalities, were
Bollag Werner
Ott Fritz
Basilea Pharmaceutica AG
Ebel Eileen M.
Jarvis William R. A.
Johnston George W.
Kim Vickie
LandOfFree
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