Synergistic effect of a sulfonylurea and/or non-sulfonylurea Kchannel blocker, and a phosphodiesterase 3 type inhibitor

Abstract

The present invention provides methods of treating non-insulin dependent diabetes mellitus, insulin resistance, Syndrome X, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, polycystic ovary syndrome, cataracts, hyperglycemia, or impaired glucose tolerance, the methods comprising the step of administering to a patient having or at risk of having non-insulin dependent diabetes mellitus, insulin resistance, Syndrome X, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, polycystic ovary syndrome, cataracts, hyperglycemia, or impaired glucose tolerance a synergistic amount of: 1) a sulfonylurea, a non-sulfonylurea K + ATP channel blocker, or a sulfonylurea and a non-sulfonylurea K + ATP channel blocker; and 2) a cAMP phosphodiesterase type 3 inhibitor. The present invention also provides kits and pharmaceutical compositions that comprise: 1) a sulfonylurea, a non-sulfonylurea K + ATP channel blocker, or a sulfonylurea and a non-sulfonylurea K + ATP channel blocker; and 2) a cAMP phosphodiesterase type 3 inhibitor. The present invention also relates to kits and pharmaceutical compositions that comprise 1) a sulfonylurea, a non-sulfonylurea K + ATP channel blocker, or a sulfonylurea and a non-sulfonylurea K + ATP channel blocker; 2) a cAMP phosphodiesterase type 3 inhibitor; and 3) an additional compound useful for the treatment of non-insulin dependent diabetes mellitus, insulin resistance, Syndrome X, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, polycystic ovary syndrome, cataracts, hyperglycemia, or impaired glucose tolerance.

What is claimed is:  
     
         1 . A method of treating non-insulin dependent diabetes mellitus, the method comprising the step of administering to a patient having or at risk of having non-insulin dependent diabetes a synergistic amount of: 1) a sulfonylurea, a non-sulfonylurea K +  ATP channel blocker, or a sulfonylurea and a non-sulfonylurea K +  ATP channel blocker; and 2) a cAMP phosphodiesterase type 3 inhibitor.  
     
     
         2 . The method of  claim 1  wherein the cAMP phosphodiesterase type 3 inhibitor is a selective cAMP phosphodiesterase type 3B inhibitor.  
     
     
         3 . The method of  claim 1  wherein the sulfonylurea is glyburide, chlorpropamide, glibenclamide, glipizide, gliclazide, glimepiride, tolbutamide, acetohexamide, or tolazamide.  
     
     
         4 . The method of  claim 1  wherein the sulfonylurea is glipizide or glyburide.  
     
     
         5 . The method of  claim 1  wherein the sulfonylurea is glyburide.  
     
     
         6 . The method of  claim 1  wherein the cAMP phosphodiesterase type 3 inhibitor is milrinone, amrinone, enoximone, indolidan, cilostamide, lixazinone, imazodan, cilostazol, bemorandan, siguazodan, adibendan, pimobendan, saterinone, sulmazol, or vesnarinone.  
     
     
         7 . The method of  claim 1  wherein the cAMP phosphodiesterase type 3 inhibitor is milrinone.  
     
     
         8 . The method of  claim 1  wherein the cAMP phosphodiesterase type 3 inhibitor is milrinone and the sulfonylurea is glyburide.  
     
     
         9 . The method of  claim 1  wherein the non-sulfonylurea K +  ATP channel blocker is repaglinide or nateglinide.  
     
     
         10 . A method of treating insulin resistance, the method comprising the step of administering to a patient having or at risk of having insulin resistance a synergistic amount of: 1) a sulfonylurea, a non-sulfonylurea K +  ATP channel blocker, or a sulfonylurea and a non-sulfonylurea K +  ATP channel blocker; and 2) a cAMP phosphodiesterase type 3 inhibitor.  
     
     
         11 . A method of treating Syndrome X, the method comprising the step of administering to a patient having or at risk of having Syndrome X a synergistic amount of: 1) a sulfonylurea, a non-sulfonylurea K +  ATP channel blocker, or a sulfonylurea and a non-sulfonylurea K +  ATP channel blocker; and 2) a cAMP phosphodiesterase type 3 inhibitor.  
     
     
         12 . A method of treating diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, polycystic ovary syndrome, or cataracts, the method comprising the step of administering to a patient having or at risk of having diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, polycystic ovary syndrome, or cataracts a synergistic amount of: 1) a sulfonylurea, a non-sulfonylurea K +  ATP channel blocker, or a sulfonylurea and a non-sulfonylurea K +  ATP channel blocker; and 2) a cAMP phosphodiesterase type 3 inhibitor.  
     
     
         13 . A method of treating hyperglycemia, the method comprising the step of administering to a patient having or at risk of having hyperglycemia a synergistic amount of: 1) a sulfonylurea, a non-sulfonylurea K +  ATP channel blocker, or a sulfonylurea and a non-sulfonylurea K +  ATP channel blocker; and 2) a cAMP phosphodiesterase type 3 inhibitor.  
     
     
         14 . A method of treating impaired glucose tolerance, the method comprising the step of administering to a patient having or at risk of having impaired glucose tolerance a synergistic amount of: 1) a sulfonylurea, a non-sulfonylurea K +  ATP channel blocker, or a sulfonylurea and a non-sulfonylurea K +  ATP channel blocker; and 2) a cAMP phosphodiesterase type 3 inhibitor.  
     
     
         15 . A pharmaceutical composition comprising a sulfonylurea or non-sulfonylurea K +  ATP channel blocker and a cAMP phosphodiesterase type 3 inhibitor.  
     
     
         16 . A pharmaceutical composition according to  claim 15  comprising a sulfonylurea and a cAMP phosphodiesterase type 3 inhibitor.  
     
     
         17 . A pharmaceutical composition according to  claim 15  comprising a non-sulfonylurea K +  ATP channel blocker and a cAMP phosphodiesterase type 3 inhibitor.  
     
     
         18 . A pharmaceutical composition comprising a sulfonylurea, a non-sulfonylurea K +  ATP channel blocker, and a cAMP phosphodiesterase type 3 inhibitor.  
     
     
         19 . A kit for the treatment of non-insulin dependent diabetes mellitus, the kit comprising: 
 a) a first pharmaceutical composition comprising: 1) a sulfonylurea, a non-sulfonylurea K +  ATP channel blocker, or a sulfonylurea and a non-sulfonylurea K +  ATP channel blocker; and 2) a cAMP phosphodiesterase type 3 inhibitor;    b) a second pharmaceutical composition comprising a second compound useful for the treatment of non-insulin dependent diabetes mellitus; and    c) a container for containing the first and second compositions.    
     
     
         20 . A kit in accordance with  claim 19  wherein the second compound is selected from: 
 insulin and insulin analogs;  
 GLP-1 (7-37) (insulinotropin) and GLP-1 (7-36)-NH 2 ;  
 biguanides;  
 glycogen phosphorylase inhibitors;  
 aldose reductase inhibitors;  
 α2-antagonists;  
 imidazolines;  
 glitazones (thiazolidinediones);  
 PPAR-gamma agonists;  
 fatty acid oxidation inhibitors;  
 α-glucosidase inhibitors;  
 β-agonists;  
 lipid-lowering agents;  
 antiobesity agents;  
 vanadate, vanadium complexes and peroxovanadium complexes;  
 amylin antagonists;  
 glucagon antagonists;  
 gluconeogenesis inhibitors;  
 somatostatin agonists and antagonists; or  
 antilipolytic agents.  
 
     
     
         21 . A kit in accordance with  claim 19  wherein the second compound is selected from LysPro insulin, GLP-1 (7-37) (insulinotropin), GLP-1 (7-36)-NH 2 , metformin, phenformin, buformin, midaglizole, isaglidole, deriglidole, idazoxan, efaroxan, fluparoxan, linogliride, ciglitazone, pioglitazone, englitazone, troglitazone, darglitazone, rosiglitazone, clomoxir, etomoxir, acarbose, miglitol, emiglitate, voglibose, MDL-25,637, camiglibose, MDL-73,945, BRL 35135, BRL 37344, Ro 16-8714, ICI D7114, CL 316,243, benfluorex, fenfluramine, Naglivan®, acipimox, WAG 994, Symlin™, or AC2993.  
     
     
         22 . A kit in accordance with  claim 19  wherein the second compound is selected from insulin, biguanides, or thiazolidinediones.  
     
     
         23 . A kit for the treatment of non-insulin dependent diabetes mellitus, insulin resistance, Syndrome X, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, polycystic ovary syndrome, cataracts, hyperglycemia, or impaired glucose tolerance, the kit comprising: 
 a) a first pharmaceutical composition comprising: 1) a sulfonylurea, a non-sulfonylurea K +  ATP channel blocker, or a sulfonylurea and a non-sulfonylurea K +  ATP channel blocker; and 2) a cAMP phosphodiesterase type 3 inhibitor;    b) a second pharmaceutical composition comprising a second compound useful for the treatment of non-insulin dependent diabetes mellitus, insulin resistance, Syndrome X, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, polycystic ovary syndrome, cataracts, hyperglycemia, or impaired glucose tolerance; and    c) a container for containing the first and second compositions.    
     
     
         24 . A kit for the treatment of non-insulin dependent diabetes mellitus, insulin resistance, Syndrome X, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, polycystic ovary syndrome, cataracts, hyperglycemia, or impaired glucose tolerance, the kit comprising: 
 a) a first pharmaceutical composition comprising a sulfonylurea or a non-sulfonylurea K +  ATP channel blocker, or a sulfonylurea and a non-sulfonylurea K +  ATP channel blocker    b) a second pharmaceutical composition comprising a cAMP phosphodiesterase type 3 inhibitor; and    c) a container for containing the first and second compositions.    
     
     
         25 . A kit in accordance with  claim 24  wherein the sulfonylurea is glyburide and the cAMP phosphodiesterase type 3 inhibitor is milrinone.