Methods of reducing the severity of mucositis

Abstract

The invention provides methods of reducing the severity of mucositis, involving administration of a toll-like receptor 4 antagonist.

1 . A method of reducing the severity of mucositis in a patient, the method comprising the step of administering to the patient a composition comprising a compound that blocks activation of toll-like receptor 4. 
     
     
         2 . The method of  claim 1 , wherein the compound is a lipid A analog. 
     
     
         3 . The method of  claim 2 , wherein the lipid A analog is within the formula: 
       
         
           
           
               
               
           
         
         where R 1  is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         where each J, K, and Q, independently, is straight or branched C1 to C15 alkyl; L is O, NH, or CH 2 ; M is O or NH; and G is NH, O, S, SO, or SO 2 ; 
         R 2  is straight or branched C5 to C15 alkyl; 
         R 3  is selected from the group consisting of straight or branched C5 to C18 alkyl, 
       
       
         
           
           
               
               
           
         
         where E is NH, O, S, SO, or SO 2 ; each A, B, and D, independently, is straight or branched C1 to C15 alkyl; 
         R 4  is selected from the group consisting of straight or branched C4 to C20 alkyl, and 
       
       
         
           
           
               
               
           
         
         where each U and V, independently, is straight or branched C2 to C15 alkyl and W is hydrogen or straight or branched C1 to C5 alkyl; 
         R A  is R 5  or R 5 —O—CH 2 —, R 5  being selected from the group consisting of hydrogen, J′, -J′-OH, -J′-O—K′, -J′-O—K′—OH, and -J′-O—PO(OH) 2 , where each J′ and K′, independently, is straight or branched C1 to C5 alkyl; 
         R 6  is selected from the group consisting of hydroxy, halogen, C1 to C5 alkoxy and C1 to C5 acyloxy; 
         A 1  and A 2 , independently, are selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         where Z is straight or branched C1 to C10 alkyl; or a pharmaceutically acceptable salt or phosphate ester thereof. 
       
     
     
         4 . The method of  claim 3 , wherein the lipid A analog is of the structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or phosphate ester thereof. 
       
     
     
         5 . The method of  claim 4 , wherein the lipid A analog is of the structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or phosphate ester thereof. 
       
     
     
         6 . The method of  claim 1 , wherein the mucositis is oral mucositis. 
     
     
         7 . The method of  claim 1 , wherein the mucositis is of the gastrointestinal tract. 
     
     
         8 . The method of  claim 1 , wherein the patient has mucositis. 
     
     
         9 . The method of  claim 1 , wherein the patient does not have, but is at risk of developing, mucositis. 
     
     
         10 . The method of  claim 9 , wherein development of mucositis is inhibited in the patient by administration of the composition. 
     
     
         11 . The method of  claim 10 , wherein development of mucositis is prevented in the patient by administration of the composition. 
     
     
         12 . The method of  claim 1 , wherein the patient is a cancer patient. 
     
     
         13 . The method of  claim 1 , wherein the patient has recently been, will shortly be, or is currently subject to treatment with head or neck irradiation, or stem cell or bone marrow transplantation. 
     
     
         14 . The method of  claim 1 , wherein said administration step occurs prior to, concurrently with, or after a treatment that places the patient at risk of developing mucositis, or a combination thereof. 
     
     
         15 . The method of  claim 14 , wherein said administration step occurs prior to a treatment that places the patient at risk of developing mucositis. 
     
     
         16 . The method of  claim 14 , wherein said administration step occurs concurrently with a treatment that places the patient at risk of developing mucositis. 
     
     
         17 . The method of  claim 14 , wherein said administration step occurs after treatment that places the patient at risk of developing mucositis. 
     
     
         18 . The method of  claim 14 , wherein said administration step occurs concurrently with a treatment that places the patient at risk of developing mucositis, further comprising a step of administering the composition at least once during days 0-3 after the treatment that places the patient at risk of developing mucositis. 
     
     
         19 . The method of  claim 14 , wherein the treatment that places the patient at risk of developing mucositis comprises radiation therapy. 
     
     
         20 . The method of  claim 14 , wherein the treatment that places the patient at risk of developing mucositis comprises chemotherapy. 
     
     
         21 . The method of  claim 1 , wherein the composition is administered to the patient topically. 
     
     
         22 . The method of  claim 1 , wherein the composition is administered to the patient by intravenous infusion. 
     
     
         23 . The method of  claim 1 , further comprising the step of administering antimicrobial therapy to the patient. 
     
     
         24 . The method of  claim 23 , wherein the antimicrobial therapy is antibiotic therapy.