Treatment of cell-mediated immune diseases

Abstract

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 disease as well as to the use of said active substances for the treatment of such diseases, which diseases are eczematoid conditions in a human patient.

1 . The use of 9-cis retinoic acid and pharmaceutically acceptable salts and pharmaceutically acceptable hydrolyzable esters thereof as well as prodrugs and metabolites thereof and their pharmaceutically acceptable salts and pharmaceutically acceptable hydrolyzable esters for the manufacture of a medicament for the treatment of T-helper cell type 1 mediated immune diseases.  
     
     
         2 . The use of a compound selected from the group consisting of 9-cis retinoic acid and pharmaceutically acceptable salts and pharmaceutically acceptable hydrolyzable esters thereof 9-cis retinal and pharmaceutically acceptable acetals thereof, and 9-cis retinal and pharmaceutically acceptable hydrolyzable esters thereof as active ingredient for the manufacture of a medicament for the treatment of T-helper cell type 1 mediated immune diseases.  
     
     
         3 . The use according to  claim 1  or  2 , wherein the active ingredient is used in combination with a pharmaceutically acceptable carrier.  
     
     
         4 . The use according to  claim 1 ,  2  or  3 , wherein the medicament is manufactured for oral or topical administration.  
     
     
         5 . The use according to any one of  claims 1  to  4 , wherein the medicament is manufactured as a tablet, capsule, pill, sachet, ointment, cream or lotion.  
     
     
         6 . The use according to any one of  claims 1  to  5 , wherein the medicament is manufactured as a tablet, capsule, pill or sachet containing 5 to 50 mg, preferably 10 to 20 mg, of active ingredient.  
     
     
         7 . The use according to any one of  claims 1  to  6 , wherein the medicament is manufactured for oral daily dosage of from 0.05 mg to 1.5 mg, preferably from 0.3 mg to 0.9 mg, per kg of body weight.  
     
     
         8 . The use according to any one of  claims 1  to  5 , wherein the medicament is manufactured as an ointment, cream or lotion containing 0.0005 to 0.05 percent by weight, preferably 0.001 to 0.01 percent by weight, of the active ingredient.  
     
     
         9 . The use according to any one of  claims 1  to  8 , wherein the active ingredient is selected from the group consisting of 9-cis retinoic acid and alkali metal salts, alkaline earth metal salts, benzyl esters, lower alkyl esters and 9-fluorenylmethyl esters thereof, 9-cis retinal and dialkyl acetals and dibenzyl acetal thereof, and 9-cis retinol and esters thereof formed with C 1 -C 20 -carboxylic acids.  
     
     
         10 . The use according to  claims 1  to  9  wherein the active ingredient is 9-cis retinoic acid or a pharmaceutically acceptable salt thereof.  
     
     
         11 . The use according to any one of  claims 1  to  7 ,  9  and  10 , wherein the medicament is manufactured for the treatment of autoimmune diseases, 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 or allogeneic graft rejection.  
     
     
         12 . The use according to any one of  claims 1  to  10 , wherein the medicament is manufactured for the treatment of exogenous eczema, such as irritant dermatitis, allergic contact dermatitis, tylotic eczema, pompholyx or of endogeneous eczema, such as seborrheic eczema, asteatotic eczema and discoid eczema.  
     
     
         13 . A method of treating an eczematoid condition in a human patient afflicted with the condition, comprising orally administering to said patient 9-cis retinoic acid in an amount effective to treat the condition in said patient.  
     
     
         14 . The method of  claim 13 , wherein the condition comprises active eczema lesions.  
     
     
         15 . The method of  claim 14 , wherein the condition comprises active eczema lesions of: irritant dermatitis, allergic contact dermatitis, seborrheic eczema, asteatotic eczema, or discoid eczema.  
     
     
         16 . The method of  claim 13 , wherein the condition comprises preexisting eczema lesions which are in remission.  
     
     
         17 . The method of  claim 16 , wherein the condition comprises preexisting lesions of: irritant dermatitis, allergic contact dermatitis, tylotic eczema or pompholyx, seborrheic dermatitis, asteatotic eczema, or discoid eczema; which lesions are in remission.  
     
     
         18 . The method of  claim 13 , wherein the effective amount of the 9-cis retinoic acid is from about 0.3 to about 0.9 milligrams per kilogram of body weight.  
     
     
         19 . The method of  claim 13 , wherein the 9-cis retinoic acid is administered in a composition comprising 9-cis retinoic acid or a precursor thereof which delivers 9-cis retinoic acid.  
     
     
         20 . The method of  claim 19 , wherein the precursor is selected from the group consisting of pharmaceutically acceptable: salts of 9-cis retinoic acid; hydrolyzable esters of 9-cis retinoic acid; 9-cis retinal; hydrolyzable esters 9-cis retinal; 9-cis retinol; and hydrolyzable esters of 9-cis retinol.  
     
     
         21 . The method of  claim 19 , wherein the composition is present in an oral unit dosage form.  
     
     
         22 . The method of  claim 21 , wherein the oral unit dosage form is a tablet, capsule, pill or sachet containing from twenty to sixty milligrams of 9-cis retinoic acid or a pharmaceutically acceptable salt or hydrolyzable ester thereof.  
     
     
         23 . A method of treating an eczematoid condition of the skin in a human patient in need of such treatment, comprising topically applying to the area of the skin of said patient subject to the condition 9-cis retinoic acid in an amount effective to alleviate the effects of the condition.  
     
     
         24 . The method of  claim 23 , wherein the condition comprises active eczema lesions.  
     
     
         25 . The method of  claim 24 , wherein the condition comprises active eczema lesions of: irritant dermatitis, allergic contact dermatitis, tylotic eczema or pompholyx, seborrheic eczema, asteatotic eczema, or discoid eczema.  
     
     
         26 . The method of  claim 23 , wherein the condition comprises preexisting eczema lesions which are in remission.  
     
     
         27 . The method of  claim 26 , wherein the condition comprises preexisting lesions of: irritant dermatitis, allergic contact dermatitis, tylotic eczema or pompholyx, seborrheic dermatitis, asteatotic eczema, or discoid eczema; which lesions are in remission.  
     
     
         28 . The method of  claim 23 , wherein the 9-cis retinoic acid is applied in a topical composition comprising a compound selected from the group consisting of 9-cis retinoic acid and dermatologically acceptable salts thereof.  
     
     
         29 . The method of  claim 28 , wherein the composition contains the compound in an amount from about 0.001 to about 0.05 percent by weight of the composition.  
     
     
         30 . The method of  claim 29 , wherein the composition contains the compound in an amount from about 0.003 to about 0.03 percent by weight of the composition.  
     
     
         31 . The method of  claim 30 , wherein the composition contains the compound in an amount from about 0.005 to about 0.01 percent by weight of the composition.  
     
     
         32 . The method of  claim 31 , wherein the composition is present in the form of an ointment, cream, gel, lotion, or shampoo.  
     
     
         33 . A method of treating a T-helper cell type 1 mediated immune disease in a human patient, comprising administering to the patient a compound in an amount effective to treat the disease; wherein the compound is selected from the group consisting of 9-cis retinoic acid, pharmaceutically acceptable salts and hydrolyzable esters thereof, precursors and metabolites of 9-cis retinoic acid and pharmaceutically acceptable salts and hydrolyzable esters thereof.  
     
     
         34 . The method of  claim 33 , wherein 9-cis retinoic acid or a pharmaceutically acceptable salt thereof is administered.  
     
     
         35 . The method of  claim 33 , wherein a precursor of 9-cis retinoic acid selected from the group consisting of 9-cis retinal, pharmaceutically acceptable acetals of 9-cis retinal, 9-cis retinol, pharmaceutically acceptable hydrolyzable esters of 9-cis retinol, and pharmaceutically acceptable salts thereof, is administered.  
     
     
         36 . The method of  claim 33 , wherein the compound is administered orally.  
     
     
         37 . The method of  claim 36 , wherein the effective amount of the compound is from 0.05 to 1.5 milligrams per kilograms of body weight per day.  
     
     
         38 . The method of  claim 37 , wherein effective amount of the compound is from 0.3 to 0.9 milligrams per kilograms of body weight per day.  
     
     
         39 . The method of  claim 33 , wherein the disease is an eczematoid condition and the compound is administered topically.  
     
     
         40 . The method of  claim 33 , wherein the compound is administered in a composition comprising the compound and a pharmaceutically acceptable carrier.  
     
     
         41 . The method of  claim 40 , wherein the composition is in the form of a tablet, capsule, pill or sachet.  
     
     
         42 . The method of  claim 41 , each tablet, capsule, pill or sachet contains from five to fifty milligrams of the compound.  
     
     
         43 . The method of  claim 42 , wherein each tablet, capsule, pill or sachet contains from ten to twenty milligrams of the compound.  
     
     
         44 . The method of  claim 40 , wherein the composition is in the form of an ointment, cream or lotion.  
     
     
         45 . The method of  claim 44 , wherein the composition contains the compound in an amount from 0.0005 to 0.05 percent by weight of the composition.  
     
     
         46 . The method of  claim 45 , wherein the composition contains the compound in an amount from 0.001 to 0.01 percent by weight of the composition.  
     
     
         47 . The method of claim 33 , wherein the compound is selected from the group consisting of 9-cis retinoic acid and alkali metal salts, alkaline earth metal salts, benzyl esters, lower alkyl esters and 9-fluorenylmethyl esters thereof, 9-cis retinal and dialkyl acetals and dibenzyl acetal thereof, and 9-cis retinol and esters thereof formed with C 1 -C 20 -carboxylic acids.  
     
     
         48 . The method of  claim 36 , wherein the disease which is treated is rheumatoid arthritis, multiple sclerosis, uveoretinitis, thyreoiditis, Crohn's disease, insulin dependent diabetes mellitus, eczema, systemic lupus erythematosus or allogeneic graft rejection.  
     
     
         49 . The method of  claim 33 ,  36  or  39 , wherein the disease is an exogenous eczema.  
     
     
         50 . The method of  claim 49 , wherein the exogenous eczema is irritant dermatitis, allergic contact dermatitis, tylotic eczema or pompholyx.  
     
     
         51 . The method of  claim 33 ,  36  or  39 , wherein the disease is an endogenous eczema.  
     
     
         52 . The method of  claim 51 , wherein the endogenous eczema is seborrhoic eczema, asteatotic eczema or discoid eczema.