Combination of an hmg-coa reductase inhibitor and a farnesyl-pyrophosphatase synthase inhibitor for the treatment of diseases related to the persistence and/or accumulation of prenylated proteins

Abstract

The invention relates to the use of a hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor and of a farnesyl-pyrophosphate synthase inhibitor, or of one of their associated physiologically acceptable salts, in the preparation of a composition, particularly a pharmaceutical composition, for use in the treatment of human or animal, pathological or nonpathological situations related to the accumulation and/or the persistence of prenylated proteins in cells, such as during progeria (Hutchinson-Gilford syndrome), restrictive dermopathy or physiological ageing.

1 - 15 . (canceled) 
     
     
         16 . A method of treating a condition selected from the group consisting of skin aging, premature skin aging, progeria, lipodystrophy, and restrictive dermopathy, the method comprising administering to a subject in need thereof an effective amount of a combination comprising:
 at least one inhibitor of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, and   at least one inhibitor of farnesyl pyrophosphate synthase.   
     
     
         17 . The method of  claim 16 , wherein the HMG-CoA reductase inhibitor is a statin or a physiologically-acceptable salt thereof. 
     
     
         18 . The method of  claim 17 , wherein the HMG-CoA reductase inhibitor is a water-soluble statin. 
     
     
         19 . The method of  claim 17 , wherein the HMG-CoA reductase inhibitor is selected from the group consisting of atorvastatin, simvastatin, pravastatin, rivastatin, mevastatin (or compactin), fluindostatin, velostatin, fluvastatin, dalvastatin, cerivastatin, pentostatin, rosuvastatin, lovastatin, pitavastatin, and physiologically-acceptable salts thereof. 
     
     
         20 . The method of  claim 16 , wherein the farnesylpyrophosphate synthase inhibitor is an aminobiphosphonate (NBP) or a physiologically-acceptable salt thereof. 
     
     
         21 . The method of  claim 20 , wherein the aminobiphosphonate is selected from the group consisting of:
 alendronic acid or the ionic form thereof, alendronate;   clodronic acid or the ionic form thereof, clodronate;   etidronic acid or the ionic form thereof, etidronate;   ibandronic acid or the ionic form thereof, ibandronate;   medronic acid or the ionic form thereof, medronate;   neridronic acid or the ionic form thereof, neridronate;   olpadronic acid or the ionic form thereof, olpadronate;   pamidronic acid or the ionic form thereof, pamidronate;   risedronic acid or the ionic form thereof, risedronate;   tiludronic acid or the ionic form thereof, tiludronate;   zoledronic acid or the ionic form thereof, zoledronate;   4-N,N-dimethylaminomethane diphosphonic acid or the ionic form thereof, dimethylaminomethanediphosphonate; and   α-amino-(4-hydroxybenzylidene)diphosphonate.   
     
     
         22 . The method of  claim 21 , wherein the farnesylpyrophosphate synthase inhibitor is zoledronic acid or the ionic form thereof, zoledronate. 
     
     
         23 . The method of  claim 16 , wherein the premature skin ageing is not related to a genetic mutation in an LMNA gene. 
     
     
         24 . A composition comprising a synergistically-effective amount of a combination of:
 at least one inhibitor of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, and   at least one inhibitor of farnesyl pyrophosphate synthase,   wherein the composition is used in the treatment of conditions selected from the group consisting of skin aging, premature skin aging, premature myolipocutaneous aging, progeria, lipodystrophy, and restrictive dermopathy.   
     
     
         25 . The composition of  claim 24 , wherein the HMG-CoA reductase inhibitor is a statin or a physiologically-acceptable salt thereof. 
     
     
         26 . The composition of  claim 25 , wherein the HMG-CoA reductase inhibitor is a water-soluble statin. 
     
     
         27 . The composition of  claim 25 , wherein the HMG-CoA reductase inhibitor is selected from the group consisting of atorvastatin, simvastatin, pravastatin, rivastatin, mevastatin (or compactin), fluindostatin, velostatin, fluvastatin, dalvastatin, cerivastatin, pentostatin, rosuvastatin, lovastatin, pitavastatin, and physiologically-acceptable salts thereof. 
     
     
         28 . The composition of  claim 24 , wherein the farnesylpyrophosphate synthase inhibitor is an aminobiphosphonate (NBP) or a physiologically-acceptable salt thereof. 
     
     
         29 . The composition of  claim 28 , wherein the aminobiphosphonate is selected from the group consisting of:
 alendronic acid or the ionic form thereof, alendronate;   clodronic acid or the ionic form thereof, clodronate;   etidronic acid or the ionic form thereof, etidronate;   ibandronic acid or the ionic form thereof, ibandronate;   medronic acid or the ionic form thereof, medronate;   neridronic acid or the ionic form thereof, neridronate;   olpadronic acid or the ionic form thereof, olpadronate;   pamidronic acid or the ionic form thereof, pamidronate;   risedronic acid or the ionic form thereof, risedronate;   tiludronic acid or the ionic form thereof, tiludronate;   zoledronic acid or the ionic form thereof, zoledronate;   4-N,N-dimethylaminomethane diphosphonic acid or the ionic form thereof, dimethylaminomethanediphosphonate; and   α-amino-(4-hydroxybenzylidene)diphosphonate.   
     
     
         30 . The composition of  claim 29 , wherein the farnesylpyrophosphate synthase inhibitor is zoledronic acid or the ionic form thereof, zoledronate. 
     
     
         31 . The composition of  claim 24 , wherein the premature skin aging is not related to a genetic mutation in an LMNA gene. 
     
     
         32 . A method for the treatment of a skin disorder related to the accumulation of farnesylated and/or geranylgeranylated protein in skin cells, wherein the skin disorder is selected from the group consisting of natural skin aging, premature skin aging not related to a genetic mutation, and lipodystrophy, the method comprising the step of administering to an individual in need thereof an effective amount of at least one inhibitor of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, and at least one aminobisphosphonate,
 wherein the HMG-CoA reductase inhibitor is selected from the group consisting of atorvastatin, simvastatin, pravastatin, rivastatin, mevastatin, fluindostatin, velostatin, fluvastatin, dalvastatin, cerivastatin, pentostatin, rosuvastatin, lovastatin, pitavastatin, and physiologically-acceptable salts thereof;   wherein the aminobiphosphonate is selected from the group consisting of alendronic acid or the ionic form thereof, ibandronic acid or the ionic form thereof, neridronic acid or the ionic form thereof, olpadronic acid or the ionic form thereof, risedronic acid or the ionic form thereof, zoledronic acid or the ionic form thereof, icandronic acid or the ionic form thereof, minodronic acid or the ionic form thereof, 4-N,N-dimethylaminomethane diphosphonic acid or the ionic form thereof, and α-amino-(4-hydroxybenzylidene)diphosphonate;   wherein the amount of the HMG-CoA reductase inhibitor and amount of aminobisphosphonate have a synergistic effect on reducing the accumulation of farnesylated and/or geranylgeranylated protein in skin cells; and   wherein the HMG-CoA reductase inhibitor and aminobisphosphonate are formulated for administration on the skin.   
     
     
         33 . The method of  claim 32 , wherein the aminobisphosphonate is zoledronic acid or the ionic form thereof. 
     
     
         34 . The method of  claim 32 , wherein the premature skin aging is not related to a genetic mutation in an LMNA gene. 
     
     
         35 . The method of  claim 32 , wherein the HMG-CoA reductase inhibitor is a statin or a physiologically-acceptable salt thereof. 
     
     
         36 . The method of  claim 35 , wherein the HMG-CoA reductase inhibitor is a water-soluble statin. 
     
     
         37 . The method of  claim 35 , wherein the HMG-CoA reductase inhibitor is selected from the group consisting of atorvastatin, simvastatin, pravastatin, rivastatin, mevastatin (or compactin), fluindostatin, velostatin, fluvastatin, dalvastatin, cerivastatin, pentostatin, rosuvastatin, lovastatin, pitavastatin, and physiologically-acceptable salts thereof. 
     
     
         38 . The method of  claim 32 , wherein the farnesylpyrophosphate synthase inhibitor is an aminobiphosphonate (NBP) or a physiologically-acceptable salt thereof. 
     
     
         39 . The method of  claim 38 , wherein the aminobiphosphonate is selected from the group consisting of:
 alendronic acid or the ionic form thereof, alendronate;   clodronic acid or the ionic form thereof, clodronate;   etidronic acid or the ionic form thereof, etidronate;   ibandronic acid or the ionic form thereof, ibandronate;   medronic acid or the ionic form thereof, medronate;   neridronic acid or the ionic form thereof, neridronate;   olpadronic acid or the ionic form thereof, olpadronate;   pamidronic acid or the ionic form thereof, pamidronate;   risedronic acid or the ionic form thereof, risedronate;   tiludronic acid or the ionic form thereof, tiludronate;   zoledronic acid or the ionic form thereof, zoledronate;   4-N,N-dimethylaminomethane diphosphonic acid or the ionic form thereof, dimethylaminomethanediphosphonate; and   α-amino-(4-hydroxybenzylidene)diphosphonate.   
     
     
         40 . A composition comprising a synergistically-effective amount of a combination of:
 at least one HMG-CoA reductase inhibitor selected from the group consisting of atorvastatin, simvastatin, pravastatin, rivastatin, mevastatin, fluindostatin, velostatin, fluvastatin, dalvastatin, cerivastatin, pentostatin, rosuvastatin, lovastatin, pitavastatin, and one of the physiologically-acceptable salts thereof;   at least one aminobiphosphonate selected from the group consisting of alendronic acid or the ionic form thereof, ibandronic acid or the ionic form thereof, neridronic acid or the ionic form thereof, olpadronic acid or the ionic form thereof, risedronic acid or the ionic form thereof, zoledronic acid or the ionic form thereof, icandronic acid or the ionic form thereof, minodronic acid or the ionic form thereof, 4-N,N-dimethylaminomethane diphosphonic acid or the ionic form thereof, and α-amino-(4-hydroxybenzylidene)diphosphonate;   said composition formulated for administration on the skin,   wherein the amount of the HMG-CoA reductase inhibitor and amount of aminobisphosphonate have a synergistic effect on reducing the accumulation of farnesylated and/or geranylgeranylated protein in skin cells; and   wherein the composition is administered for the treatment of a skin disorder related to the accumulation of farnesylated and/or geranylgeranylated protein in skin cells, selected from the group consisting of natural skin aging, premature skin ageing not related to a genetic mutation and lipodystrophy.