Compositions and methods for treatment

Abstract

The present invention provides compounds and methods for the treatment of LFA-1 mediated diseases. In particular, LFA-1 antagonists are described herein and these antagonists are used in the treatment of LFA-1 mediated diseases. One aspect of the invention provides for diagnosis of an LFA-1 mediated disease and administration of a LFA-1 antagonist, after the patient is diagnosed with a LFA-1 mediated disease. In some embodiments, the LFA-1 mediated diseases treated are dry eye disorders. Also provided herein are methods for identifying compounds which are LFA-1 antagonists.

1 .- 101 . (canceled) 
     
     
         102 . A method of modulating the interaction between (i) a member selected from the group consisting of CD11a, CD18, or a combination thereof and (ii) an intercellular adhesion molecule selected from the group consisting of ICAM-1, ICAM-2, and ICAM-3, or any combination of any of the foregoing, in a patient in need of such modulation, said method comprising administering to said patient a modulation effective amount of the compound 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         103 . A method as defined in  claim 102 , wherein the patient does not have Sjogren's syndrome. 
     
     
         104 . A method as defined in  claim 102 , wherein the patient has Sjogren's syndrome. 
     
     
         105 . A method as defined in  claim 102 , wherein said administration comprises topical administration of said compound via a carrier vehicle selected from a group consisting of liquid drops, liquid wash, gel, ointment, spray, liposome, and any combination of any of the foregoing. 
     
     
         106 . A method as defined in  claim 105 , wherein said topical administration comprises infusion of said compound or salt to an eye of said patient via a device selected from the group consisting of a pump-catheter system, a continuous or selective release device, a contact lens, or any combination of any of the foregoing. 
     
     
         107 . A method as defined in  claim 102 , wherein said administration comprises systemically administering a liquid or liquid suspension of said compound or salt via nose drops, nasal spray, nebulized liquid, or any combination of any of the foregoing to oral or nasopharyngeal airways of said patient, such that said modulation effective amount of said compound or salt contacts one or more of the lacrimal gland, conjunctival tissue, tears, or ocular surface of the eye of said patient. 
     
     
         108 . A method as defined in  claim 102 , wherein said administration comprises administering an oral form of said compound or salt, such that said modulation effective amount of said compound or salt contacts one or more of the lacrimal gland, conjunctival tissue, tears, or ocular surface of the eye of said patient via systemic absorption and circulation. 
     
     
         109 . A method as defined in  claim 102 , wherein said administration comprises administering an injectable form of said compound or salt, such that said modulation effective amount of said compound or salt contacts one or more of the lacrimal tissues, conjunctival tissue, tears, or ocular surface of the eye of said patient via systemic absorption and circulation. 
     
     
         110 . A method as defined in  claim 102 , wherein said administration comprises administering a suppository dosage form of said compound or salt, such that said modulation effective amount of said compound or salt contacts one or more of the lacrimal tissues, conjunctival tissue, tears, or ocular surface of the eye of said patient via systemic absorption and circulation. 
     
     
         111 . A method as defined in  claim 102 , wherein said administration comprises administering an intraocular instillation of a gel, cream, powder, foam, crystals, liposomes, spray, liquid suspension form, or any combination of any of the foregoing of said compound or salt. 
     
     
         112 . A method as defined in  claim 102 , wherein said compound or salt is administered to the ocular surfaces of said patient in a modulation effective amount sufficient to achieve concentrations thereof of from about 1×10 −7  to about 1×10 −1  moles/liter. 
     
     
         113 . A method of modulating the interaction between (i) a member selected from the group consisting of CD11a, CD18, or a combination thereof and (ii) an intercellular adhesion molecule selected from the group consisting of ICAM-1, ICAM-2, and ICAM-3, or any combination of any of the foregoing, in a patient in need of such modulation, said method comprising administering to said patient a modulation effective amount of the compound 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, whereby said administration is effective in promoting tear secretion or mucin production in said eye in said patient, and wherein said patient does not have Sjogren's syndrome. 
       
     
     
         114 . A method of modulating the interaction between (i) a member selected from the group consisting of CD11a, CD18, or a combination thereof and (ii) an intercellular adhesion molecule selected from the group consisting of ICAM-1, ICAM-2, and ICAM-3, or any combination of any of the foregoing, in a patient in need of such modulation, said method comprising administering to said patient a modulation effective amount of the compound 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, whereby said administration is effective in promoting tear secretion or mucin production in said eye in said patient, and wherein said patient has Sjogren's syndrome. 
       
     
     
         115 . A method of modulating the interaction between (i) a member selected from the group consisting of CD11a, CD18, or a combination thereof and (ii) an intercellular adhesion molecule selected from the group consisting of ICAM-1, ICAM-2, and ICAM-3, or any combination of any of the foregoing, in a patient in need of such modulation, said method comprising performing a dry eye diagnostic test on said patient; determining whether said patient suffers from a dry eye disease based on the results of said diagnostic step; and upon diagnosis of said dry eye disease, administering to said patient a modulation effective amount of the compound 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, and wherein said patient does not have Sjogren's syndrome. 
       
     
     
         116 . A method of modulating the interaction between (i) a member selected from the group consisting of CD11a, CD18, or a combination thereof and (ii) an intercellular adhesion molecule selected from the group consisting of ICAM-1, ICAM-2, and ICAM-3, or any combination of any of the foregoing, in a patient in need of such modulation, said method comprising performing a dry eye diagnostic test on said patient; determining whether said patient suffers from a dry eye disease based on the results of said diagnostic step; and upon diagnosis of said dry eye disease, administering to said patient a modulation effective amount of the compound 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, and wherein said patient has Sjogren's syndrome. 
       
     
     
         117 . A method as defined in  claim 115 , wherein said diagnostic step comprises imaging an eye of said patient, analysis of a biological sample of an eye of said patient, or a combination of the foregoing. 
     
     
         118 . A method as defined in  claim 116 , wherein said diagnostic step comprises imaging an eye of said patient, analysis of a biological sample of an eye of said patient, or a combination of the foregoing. 
     
     
         119 . A method as defined in  claim 102 , wherein said administration is via a sustained release insert or implant, subconjunctival injection, intraocular injection, periocular injection, retrobulbar injection, intracameral injection, or any combination of any of the foregoing. 
     
     
         120 . A method as defined in  claim 102 , wherein said administration comprises delivery of a liquid or liquid suspension of said compound or salt via nose drops, nasal spray, nebulized liquid, or any combination of any of the foregoing to oral or nasopharyngeal airways of said patient, such that said modulation effective amount of said compound or salt contacts one or more of the lacrimal gland, conjunctival tissue, tears, or ocular surface of the eye of said patient via nasolacrimal ducts. 
     
     
         121 . A method as defined in  claim 102 , wherein said administration comprises administering an injectable form of said compound or salt, such that said modulation effective amount of said compound or salt contacts one or more of the lacrimal tissues, conjunctival tissue, tears, or ocular surface of the eye of said patient via local delivery. 
     
     
         122 . A method as defined in  claim 106 , wherein said continuous or selective release device comprises an ocular insert or implant. 
     
     
         123 . A method as defined in  claim 106 , wherein said modulation effective amount of said compound or salt is distributed regionally to one or more of the nose, nasal passages, and nasal cavity. 
     
     
         124 . A method as defined in  claim 122 , wherein said continuous or selective release device comprises a biocompatible polymer. 
     
     
         125 . A method as defined in  claim 111 , wherein said gel, cream, powder, foam, crystals, liposomes, spray, or liquid suspension administers said compound or salt via controlled release of said compound or salt from a biocompatible polymer.