Method of treating side effects induced by therapeutic agents

Abstract

The invention relates to agents for the prevention of organ damage, in particular of the kidneys and the inner ear, induced by the administration of aminoglycosides. Agents according to the invention are all substances which are megalin and/or cubilin antagonists (inhibitors). In particular, these are molecules (compounds) having polybasic structures which bind to megalin and inhibit the binding of aminoglycosides and related substances.

1 . A method for reducing the accumulation of cisplatin in kidney or inner ear cells of a human subject in need of such reduction, and thereby reducing kidney or inner ear damage attributable to said accumulation, said method comprising administering to said individual, before, during or after administration of cisplatin, a cisplatin accumulation-reducing effective amount of a substance, which substance is not itself cisplatin, said substance being basic and having an amino group, and being capable of binding to a megalin and/or a cubilin receptor in kidney or inner ear cells and inhibiting binding of said cisplatin to said receptor, said administration of the substance being at a time such that the substance competes with the cisplatin for said receptor, said method resulting in less kidney or inner ear damage to the subject, as a result of administration of the cisplatin and the substance together, as compared to the administration of the same amount of the cisplatin alone. 
     
     
         2 . The method of  claim 1 , wherein said substance is capable of binding to a kidney cell megalin and/or cubilin receptor and inhibiting the binding of cisplatin to said receptor, whereby the accumulation of cisplatin in kidney cells is reduced, and thereby kidney damage attributable to such accumulation is reduced, said method resulting in less kidney damage to the subject, as a result of administration of the cisplatin and the substance together, as compared to the administration of the same amount of the cisplatin alone. 
     
     
         3 . The method according to  claim 2 , wherein said substance has a polybasic charge distribution. 
     
     
         4 . The method according to  claim 2 , wherein said substance in solution has at least  3  positive charges. 
     
     
         5 . The method according to  claim 2 , wherein said substance is selected from the group consisting of a peptide and a protein. 
     
     
         6 . The method according to  claim 5 , wherein said substance is said peptide, and wherein said peptide is a fragment of naturally occurring RAP (receptor-associated protein). 
     
     
         7 . The method according to  claim 6 , wherein said substance is capable of binding at least 25% of the binding sites for said cisplatin on said receptor megalin. 
     
     
         8 . The method according to  claim 6 , wherein said substance is capable of binding at least 25% of the binding sites for said cisplatin on said receptor cubilin. 
     
     
         9 . The method according to  claim 5  wherein said peptide has at most 104 amino acids. 
     
     
         10 . The method according to  claim 1 , wherein said substance has at least 2 times greater affinity for said receptor megalin than said cisplatin has for said receptor megalin. 
     
     
         11 . The method according to  claim 1 , wherein said substance has at least 2 times greater affinity for said receptor cubilin than said cisplatin has for said receptor cubilin. 
     
     
         12 . The method according to  claim 1 , wherein said accumulation of said cisplatin is reduced by at least 25%. 
     
     
         13 . The method according to  claim 1 , wherein the ratio of said substance administered to said cisplatin administered is at least 200:1 mol:mol to 1:200 mol:mol. 
     
     
         14 . The method of  claim 1  wherein said substance is capable of binding to an inner ear cell megalin and/or cubilin receptor and inhibiting the binding of cisplatin to said receptor, whereby the accumulation of cisplatin in inner ear cells is reduced, and thereby inner ear damage attributable to such accumulation is reduced, said method resulting in less inner ear damage to the subject, as a result of administration of the cisplatin and the substance together, as compared to the administration of the same amount of the aminoglycoside alone. 
     
     
         15 . The method according to  claim 14 , wherein said substance has a polybasic charge distribution. 
     
     
         16 . The method according to  claim 14 , wherein said substance in solution has at least 3 positive charges. 
     
     
         17 . The method according to  claim 14 , wherein said substance is selected from the group consisting of a peptide and a protein. 
     
     
         18 . The method according to  claim 17 , wherein said substance is said peptide, and wherein said peptide is a fragment of naturally occurring RAP (receptor-associated protein). 
     
     
         19 . The method according to  claim 18 , wherein said substance is capable of binding at least 25% of the binding sites for said cisplatin on said receptor megalin. 
     
     
         20 . The method according to  claim 18 , wherein said substance is capable of binding at least 25% of the binding sites for said cisplatin on said receptor cubilin. 
     
     
         21 . The method according to  claim 18  wherein said peptide has at most 104 amino acids. 
     
     
         22 . The method according to  claim 14 , wherein said substance has at least 2 times greater affinity for said receptor megalin than said cisplatin has for said receptor megalin. 
     
     
         23 . The method according to  claim 14 , wherein said substance has at least 2 times greater affinity for said receptor cubilin than said cisplatin has for said receptor cubilin. 
     
     
         24 . The method according to  claim 14 , wherein said accumulation of said cisplatin is reduced by at least 25%. 
     
     
         25 . The method according to  claim 14 , wherein the ratio of said substance administered to said cisplatin administered is at least 200:1 mol:mol to 1:200 mol:mol.