Treatment of kidney diseases associated with elevated avp

Abstract

Disclosed are the methods for treating kidney disease including autosomal dominant polycystic kidney disease (ADPKD) in a subject, comprising the step of administering to the subject a composition comprising a therapeutically effective amount of ticagrelor or a derivative thereof, treating ADPKD. Disclosed are methods of decreasing arginine vasopressin (AVP) production in a subject comprising the step of administering to the subject a composition comprising an effective amount of ticagrelor, thereby decreasing AVP production. Disclosed are methods for treating dilutional hyponatremia in a subject comprising the step of administering to the subject a composition comprising an effective amount of ticagrelor, thereby decreasing AVP production.

What is claimed is: 
     
         1 . A method for inhibiting arginine vasopressin (AVP) production in hypothalamus comprising administering to hypothalamic cells or contacting hypothalamic cells with an effective amount of ticagrelor or a derivative thereof, thereby inhibiting arginine vasopressin (AVP) production in hypothalamic cells. 
     
     
         2 . A method for inhibiting arginine vasopressin (AVP) production in a subject in need thereof, comprising administering to the subject a composition comprising an effective amount of ticagrelor or a derivative thereof, thereby decreasing AVP production in the subject. 
     
     
         3 . A method for inhibiting cyst growth in a kidney of a subject suffering from a kidney disease associated with elevated AVP, comprising administering to the subject a composition comprising an effective amount of ticagrelor or a derivative thereof, thereby inhibiting cyst growth in a kidney of the subject. 
     
     
         4 . A method for treating a kidney disease associated with elevated AVP in a subject suffering therefrom, comprising the step of administering to the subject a composition comprising a therapeutically effective amount of ticagrelor or a derivative thereof, thereby treating the kidney disease in the subject. 
     
     
         5 . A method for treating a disease associated with elevated AVP in a subject suffering therefrom, comprising the step of administering to the subject a composition comprising a therapeutically effective amount of ticagrelor or a derivative thereof, thereby treating the disease in the subject. 
     
     
         6 . A method for lowering circulating levels of AVP in a subject, comprising administering to the subject an effective amount of a composition comprising an effective amount of ticagrelor or a derivative thereof, thereby lowering circulating levels of AVP in the subject. 
     
     
         7 . The method of  claim 3  or  4 , wherein the kidney disease is an autosomal dominant polycystic kidney disease (ADPKD). 
     
     
         8 . The method of  claim 7 , wherein ADPKD is associated with mutation of PKD1 gene and/or PKD2 gene. 
     
     
         9 . The method of  claim 7 , wherein ADPKD is associated with altered expression of PKD1 gene and/or PKD2 gene. 
     
     
         10 . The method of  claim 9 , wherein altered expression is reduced expression. 
     
     
         11 . The method of  claim 7 , wherein ADPKD is associated with reduced or altered activity of PKD1 protein and/or PKD2 protein. 
     
     
         12 . The method of  claim 7 , wherein ADPKD is associated with increased renal epithelial cell proliferation. 
     
     
         13 . The method of  claim 7 , wherein ADPKD is associated with bilateral renal enlargement and cyst. 
     
     
         14 . The method of  claim 4 , wherein treating kidney disease comprises inhibiting AVP production in the subject. 
     
     
         15 . The method of  claim 14 , wherein inhibiting AVP production lowers AVP plasma level in the subject. 
     
     
         16 . The method of  claim 15 , wherein lowered AVP plasma level in the subject may be detected as a lower urinary AVP concentration or excretion by the subject. 
     
     
         17 . The method of  claim 4 , wherein treating kidney disease comprises slowing down the progression of the disease. 
     
     
         18 . The method of  claim 4 , wherein treating kidney disease comprises slowing down progression of a cystic disease. 
     
     
         19 . The method of  claim 18  or  19 , wherein slowing down progression of the disease or of the cystic disease comprises reducing risk of developing kidney failure and/or end-stage renal disease. 
     
     
         20 . The method of  claim 4 , wherein treating kidney disease comprises reducing cAMP production in renal collecting duct cells of the subject. 
     
     
         21 . The method of  claim 20 , wherein the renal collecting duct cell is or comprises a principal cell. 
     
     
         22 . The method of  claim 4 , wherein treating kidney disease increases urine output and/or decreases urine osmolality. 
     
     
         23 . The method of  claim 5 , wherein the disease is selected from the group consisting of hypertension, preeclampsia, congestive heart failure, cardiorenal syndrome, cirrhosis of liver, diabetic ketoacidosis, post-traumatic stress disorder (PTSD), countering effect of loop diuretics, high altitude pulmonary edema, autism, syndrome of inappropriate antidiuretic hormone (SIADH), autosomal dominant polycystic kidney disease (ADPKD), dilutional hyponatremia and disease associated with elevated activity of AVP-V2 receptor-cAMP axis. 
     
     
         24 . The method of  claim 23 , wherein autism is autism spectrum disorder (ASD). 
     
     
         25 . The method of  claim 23 , wherein elevated activity of AVP-V2 receptor-cAMP axis comprises elevated circulating AVP and/or elevated V2 receptor signaling in the subject. 
     
     
         26 . The method of  claim 25 , wherein elevated V2 receptor signaling comprises elevated cAMP level in a V2 receptor positive cell of the subject. 
     
     
         27 . The method of  claim 26 , wherein the V2 receptor positive cell is a renal collecting duct cell. 
     
     
         28 . The method of  claim 27 , wherein the renal collecting duct cell is or comprises a principal cell. 
     
     
         29 . The method of  claim 28 , wherein the principal cell translocates aquaporin protein to apical plasma membrane. 
     
     
         30 . The method of  claim 29 , wherein the aquaporin protein is in a subapical vesicle prior to transport to apical plasma membrane. 
     
     
         31 . The method of  claim 28 , wherein the principal cell increases expression of aquaporin gene. 
     
     
         32 . The method of  claim 29  or  31 , wherein the aquaporin is selected from the group consisting of aquaporin protein 2 (AQP2) and aquaporin protein 3 (AQP3). 
     
     
         33 . The method of  claim 29  or  31 , wherein translocation of aquaporin and/or increased expression of aquaporin gene alters transepithelial water transport. 
     
     
         34 . The method of  claim 33 , alteration of transepithelial water transport comprises increased re-absorption of water by the principal cell or renal collecting duct cell, decreased urine output, increased urine osmolality, and/or increased urinary AVP excretion. 
     
     
         35 . The method of  claim 34 , wherein the increased urinary AVP excretion positively correlates with an increased plasma AVP level. 
     
     
         36 . The method of  claim 5 , wherein treating the disease in the subject comprises inhibiting AVP production in hypothalamus. 
     
     
         37 . The method of  claim 5 , wherein treating the disease in the subject comprises lowering circulating level of AVP in the subject. 
     
     
         38 . The method of  claim 37 , wherein lowering circulating level of AVP reduces signaling by AVP-dependent V2 receptor in a cell of the subject. 
     
     
         39 . The method of  claim 37 , wherein lowering circulating level of AVP reduces signaling by AVP-dependent V1 receptor in a cell of the subject. 
     
     
         40 . The method of  claim 39 , wherein the V1 receptor is selected from the set of V1a receptor and V1b receptor. 
     
     
         41 . The method of  claim 38  or  39 , wherein reduced signaling by AVP-dependent V1 or V2 receptor slows or reverses a disease associated with elevated AVP in the subject. 
     
     
         42 . The method of  claim 38 , wherein the cell is a renal collecting duct cell. 
     
     
         43 . The method of  claim 42 , wherein the renal collecting duct cell is or comprises a principal cell. 
     
     
         44 . The method of  claim 43 , wherein the principal cell has a lower cAMP level. 
     
     
         45 . The method of  claim 44 , wherein lowering of cAMP level results in a decrease number of aquaporin proteins on apical surface of the principal cell. 
     
     
         46 . The method of  claim 45 , wherein lowering of cAMP level results in a decreased expression of aquaporin genes. 
     
     
         47 . The method of  claim 45 , wherein the aquaporin proteins are selected from the group consisting of aquaporin protein 2 (AQP2) and aquaporin protein 3 (AQP3). 
     
     
         48 . The method of  claim 45 , wherein the aquaporin protein is aquaporin protein 2 (AQP2). 
     
     
         49 . The method of  claim 45 , wherein the decreased number of aquaporin proteins on apical surface of the principal cell result in a decreased re-absorption of water by the principal cell or renal collecting duct cell, increased urine output, decreased urine osmolality, and/or decreased urinary AVP excretion. 
     
     
         50 . The method of  claim 49 , wherein decreased urinary AVP excretion positively correlates with a decreased plasma AVP level. 
     
     
         51 . The method of  claim 4  or  5 , wherein treating a disease or a kidney disease associated with elevated AVP in a subject comprises lowering level of circulating AVP in the subject. 
     
     
         52 . The method of  claim 2 ,  3 ,  4 ,  5  or  6 , wherein the subject is a human, non-human primate, rabbit, sheep, rat, dog, cat, pig, or mouse. 
     
     
         53 . The method of  claim 2 ,  3 ,  4 ,  5  or  6 , wherein the subject has been diagnosed with a need for treatment of ADPKD prior to the administering step. 
     
     
         54 . The method of  claim 2 ,  3 ,  4 ,  5  or  6 , wherein the subject is in need of treatment of a kidney disease 
     
     
         55 . The method of  claim 2 ,  3 ,  4 ,  5  or  6 , wherein the subject is free of a coagulation disorder. 
     
     
         56 . The method of  claim 55 , wherein the coagulation disorder is a hypercoagulation disorder or thrombophilia. 
     
     
         57 . The method of  claim 56 , wherein the hypercoagulation disorder or thrombophilia is inherited hypercoagulable condition. 
     
     
         58 . The method of  claim 57 , wherein the inherited hypercoagulable condition is associated with and selected from the group consisting of factor V Leiden mutation, prothrombin gene mutation, antithrombin III deficiency, protein C deficiency, protein S deficiency, elevated homocysteine level, elevated fibrinogen level, dysfibrinogenemia, elevated factor VIII level, factor XIII mutation, elevated factor IX level, elevated factor XI level, fibrinolysis disorder, plasminogen deficiency and elevated plasminogen activator inhibitor (PAI-1). 
     
     
         59 . The method of  claim 55 , wherein the coagulation disorder is a bleeding disorder. 
     
     
         60 . The method of  claim 59 , wherein the bleeding disorder is congenital. 
     
     
         61 . The method of  claim 60 , wherein the congenital bleeding disorder is selected from the group consisting of hemophilia, factor II deficiency, factor V deficiency, factor VII deficiency, factor X deficiency, factor XI deficiency, factor XII deficiency, factor XIII deficiency, von Willebrand's disease, Bernard-Soulier syndrome, complete plasminogen activator inhibitor 1 (PAI-1) deficiency, congenital afrinogenemia, glycoprotein VI deficiency, gray platelet syndrome, Noonan syndrome, prekallikrein deficiency, prothrombin deficiency, Stormorken syndrome, thrombocytopenia-absent radius (TAR) syndrome and Wiskott-Aldrich syndrome. 
     
     
         62 . The method of  claim 7 , wherein diagnosis of ADPKD comprises one or more of large echogenic kidneys without distinct macroscopic cysts at 50% risk for ADPKD, presence of bilateral renal enlargement and cysts, PKD1 gene mutation, PKD2 gene mutation, and mutation in modifiers of PKD1 expression or PKD2 expression. 
     
     
         63 . The method of  claim 7 , wherein treating ADPKD comprises reducing cyst number or size or decreasing kidney size. 
     
     
         64 . The method of  claim 7 , further comprising ameliorating one or more symptoms associated with ADPKD. 
     
     
         65 . The method of  claim 64 , wherein one or more symptoms associated with ADPKD is selected from the group consisting of acute loin pain, haematuria, ballotable kidneys, sub arachnoid hemorrhage (berry aneurysm), hypertension, associated liver cyst, uremia due to renal failure, anemia due to CKD, increase RBC or erythropoeitin secretion. 
     
     
         66 . The method of  claim 3 ,  4  or  5 , further comprising administering one or more additional therapeutic. 
     
     
         67 . The method of  claim 66 , wherein the one or more additional therapeutic is a mTOR inhibitor. 
     
     
         68 . The method of  claim 67 , wherein the mTOR inhibitor is selected from the group consisting of Sirolimus, Everolimus (RAD001), Temsirolimus (CCI-779), Ridaforolimus (AP23573, MK-8669), Deforolimus, Dactolisib, BGT226, SF1126, PKI-587, Sapanisertib (INK128), AZD8055 and AZD2014. 
     
     
         69 . The method of  claim 67 , wherein the mTOR inhibitor is selected from the group consisting of Sirolimus and Everolimus (RAD001). 
     
     
         70 . The method of  claim 66 , wherein the one or more additional therapeutic is a somatostatin analogue. 
     
     
         71 . The method of  claim 70 , wherein the somatostatin analogue is selected from the group consisting of Octreotide, Pasireotide (SOM230), dopastatin BIM-23A387, dopastatin BIM-23A760, somatostatin octapeptide-doxorubicin RC-121, somatostatin octapeptide-doxorubicin RC-160, somatostatin octapeptide-2-pyrrolino-DOX conjugate AN-201, AN-238 (AN-201 linked to RC-121), JF-10-81,  90 Y-DOTATOC, 177Lu DOTATATE [177Lu]DOTA-Tyr(3)-octreotate and Lanreotide. 
     
     
         72 . The method of  claim 70 , wherein the somatostatin analogue is selected from the group consisting of Octreotide and Lanreotide. 
     
     
         73 . The method of  claim 66 , wherein the one or more additional therapeutic is a vasopressin V2 receptor antagonist. 
     
     
         74 . The method of  claim 73 , wherein the vasopressin V2 receptor antagonist is selected from the group consisting of OPC-31260, Lixivaptan, Mozavaptan, Satavaptan, Lixivaptan, Conivaptan (YM-087), SR-121463A, VPA-985 and Tolvaptan (OPC-41061). 
     
     
         75 . The method of  claim 73 , wherein the vasopressin V2 receptor antagonist is selected from the group consisting of OPC-31260 and Tolvaptan. 
     
     
         76 . The method of  claim 66 , wherein the one or more additional therapeutic is an epidermal growth factor receptor inhibitor. 
     
     
         77 . The method of  claim 76 , wherein the epidermal growth factor receptor inhibitor is selected from the group consisting of bosutinib, gefitinib, lapatinib, cetuximab, panitumumab, vandetanib, neratinib, necitumumab, osimertnib and erlotinib. 
     
     
         78 . The method of  claim 76 , wherein the epidermal growth factor receptor inhibitor is selected from the group consisting of bosutinib, gefitinib and erlotinib. 
     
     
         79 . The method of  claim 66 , wherein the one or more additional therapeutic is administered before, after or taken with a composition comprising ticagrelor or its derivative. 
     
     
         80 . The method of  claim 3 ,  4  or  5 , wherein the composition comprising ticagrelor or its derivative is administered orally, intravenously, subcutaneously or intramuscularly, as an implant or patch, or via a needle or microneedles. 
     
     
         81 . The method of  claim 66 , wherein the one or more additional therapeutic is administered orally, intravenously, subcutaneously or intramuscularly, or as an implant or patch, or via a needle or microneedles. 
     
     
         82 . The method of  claim 66 , wherein one or more additional therapeutic is administered by the same route as a composition comprising ticagrelor or its derivative. 
     
     
         83 . The method of  claim 66 , wherein one or more additional therapeutic is administered by a different route as a composition comprising ticagrelor or its derivative. 
     
     
         84 . The method of  claim 2 ,  3 ,  4 ,  5  or  6 , wherein the step of administering to the subject a composition comprising an effective amount of ticagrelor is a long-term treatment regimen. 
     
     
         85 . The method of  claim 84 , wherein the long-term treatment regimen is at least 2 weeks. 
     
     
         86 . The method of  claim 84 , wherein the long-term treatment regimen is at least 1 month. 
     
     
         87 . The method of  claim 84 , wherein the long-term treatment regimen is at least 1 year. 
     
     
         88 . The method of  claim 84 , wherein the long-term treatment regimen is at least 5 years. 
     
     
         89 . The method of  claim 84 , wherein the long-term treatment regimen is a lifetime from a diagnosis of need to treat. 
     
     
         90 . The method of  claim 84 , wherein the long-term treatment is continuous. 
     
     
         91 . The method of  claim 84 , wherein the long-term treatment is discontinuous, wherein the treatment is interrupted by one or more period in which administration of the composition comprising an effective amount of ticagrelor or its derivative is withheld. 
     
     
         92 . The method of  claim 84 , wherein withholding a composition comprising an effective amount of ticagrelor or its derivative is for a sufficient amount of time or for a specified amount of time. 
     
     
         93 . The method of  claim 92 , wherein withholding a composition comprising an effective amount of ticagrelor or its derivative is for a sufficient amount of time in which withholding inhibits or reverses uncontrolled bleeding from the wound or internal ulcer. 
     
     
         94 . The method of  claim 92 , wherein withholding a composition comprising an effective amount of ticagrelor or its derivative for a specified amount of time reduces risk of uncontrolled bleeding associated with a procedure or therapy. 
     
     
         95 . The method of  claim 94 , wherein the procedure is surgery or intervention radiology. 
     
     
         96 . The method of  claim 94 , wherein the therapy increases bleeding time or decreases clotting time so as to place the subject at risk for uncontrolled bleeding. 
     
     
         97 . The method of  claim 1 , wherein the decrease in AVP production is determined by comparing AVP levels detected in the blood or urine of the subject before administering ticagrelor or its derivative to AVP levels detected in the blood or urine of the subject after administering ticagrelor or its derivative. 
     
     
         98 . The method of  claim 97 , wherein AVP levels detected in the blood or urine of the subject after administering ticagrelor are detected at least one week after administering ticagrelor. 
     
     
         99 . A method for treating dilutional hyponatremia in a subject, comprising the step of administering to the subject a composition comprising an effective amount of ticagrelor or a derivative thereof, thereby decreasing arginine vasopressin (AVP) production. 
     
     
         100 . The method of  claim 99 , further comprising ameliorating one or more symptoms associated with dilutional hyponatremia. 
     
     
         101 . The method of  claim 99 , further comprising administering an additional therapeutic. 
     
     
         102 . The method of  claim 101 , wherein the additional therapeutic is a vasopressin V2 receptor antagonist. 
     
     
         103 . The method of  claim 101 , wherein the vasopressin V2 receptor antagonist is selected from the group consisting of OPC-31260, Lixivaptan, Mozavaptan, Satavaptan, Lixivaptan, Conivaptan (YM-087), SR-121463A, VPA-985 and Tolvaptan (OPC-41061). 
     
     
         104 . The method of  claim 101 , wherein the additional therapeutic is tolvaptan. 
     
     
         105 . The method of  claim 99 , wherein the subject is a human, non-human primate, rabbit, sheep, rat, dog, cat, pig, or mouse. 
     
     
         106 . A method for reducing one or more symptoms associated with ADPKD in a subject, comprising the step of administering to the subject a composition comprising an effective amount of ticagrelor or a derivative thereof, so as to reduce circulating levels of AVP, thereby reducing one or more symptoms associated with ADPKD in the subject. 
     
     
         107 . The method of  claim 106 , wherein one or more symptoms associated with ADPKD is selected from the group consisting of acute loin pain, haematuria, ballotable kidneys, sub arachnoid hemorrhage (berry aneurysm), hypertension, associated liver cyst, uremia due to renal failure, anemia due to CKD, increase RBC or erythropoeitin secretion. 
     
     
         108 . The method of  claim 99  or  106 , further comprising administering one or more additional therapeutic. 
     
     
         109 . The method of  claim 108 , wherein the additional therapeutic is selected from the group consisting of a mTOR inhibitor, a somastostatin analogue, a vasopressin V2 receptor antagonist and an epidermal growth factor receptor inhibitor. 
     
     
         110 . The method of  claim 108 , wherein the additional therapeutic is selected from the group consisting of Sirolimus, Everolimus (RAD001), Temsirolimus (CCI-779), Ridaforolimus (AP23573, MK-8669), Deforolimus, Dactolisib, BGT226, SF1126, PKI-587, Sapanisertib (INK128), AZD8055, AZD2014, Octreotide, Pasireotide (SOM230), dopastatin BIM-23A387, dopastatin BIM-23A760, somatostatin octapeptide-doxorubicin RC-121, somatostatin octapeptide-doxorubicin RC-160, somatostatin octapeptide-2-pyrrolino-DOX conjugate AN-201, AN-238 (AN-201 linked to RC-121), JF-10-81,  90 Y-DOTATOC, 177Lu DOTATATE [177Lu]DOTA-Tyr(3)-octreotate, Lanreotide, OPC-31260, Lixivaptan, Mozavaptan, Satavaptan, Lixivaptan, Conivaptan (YM-087), SR-121463A, VPA-985 and Tolvaptan (OPC-41061), bosutinib, gefitinib, lapatinib, cetuximab, panitumumab, vandetanib, neratinib, necitumumab, osimertnib and erlotinib. 
     
     
         111 . The method of  claim 108 , wherein the additional therapeutic is selected from the group consisting of Sirolimus, Everolimus (RAD001), Octreotide, Lanreotide, OPC-31260, Tolvaptan, bosutinib, gefitinib and erlotinib. 
     
     
         112 . The method of  claim 108 , wherein the additional therapeutic is tolvaptan. 
     
     
         113 . The method of  claim 106 , wherein the subject is a mammal. 
     
     
         114 . The method of  claim 113 , wherein the mammal is a human, non-human primate, rabbit, sheep, rat, dog, cat, pig, or mouse. 
     
     
         115 . The method of  claim 1 ,  2 ,  3 ,  4 ,  5 ,  6 ,  99  or  106 , wherein the effective amount of the ticagrelor or derivative thereof is in a plasma range of about 1.0 to 6.0 μM. 
     
     
         116 . The method of  claim 1 ,  2 ,  3 ,  4 ,  5 ,  6 ,  99  or  106 , wherein the effective amount of the ticagrelor is in a plasma range of about 1.0 to 6.0 μM. 
     
     
         117 . The method of  claim 1 ,  2 ,  3 ,  4 ,  5 ,  6 ,  99  or  106 , wherein the effective amount of the derivative thereof is in a plasma range equivalent to the effective inhibition of AVP production or lowering circulating AVP level by a trigrelor plasma concentration of about 1.0 to 6.0 μM in the subject. 
     
     
         118 . The method of  claim 1 ,  2 ,  3 ,  4 ,  5 ,  6 ,  99  or  106 , wherein the method is free of or not dependent on P2Y12 receptor activity in the hypothalamus. 
     
     
         119 . A method for treating ADPKD in a subject suffering therefrom, comprising the step of administering to the subject a composition comprising a therapeutically effective amount of ticagrelor or a derivative thereof, thereby treating ADPKD in the subject. 
     
     
         120 . The method of  claim 119 , wherein the subject is free of an elevated level of plasma AVP and/or elevated level of urinary AVP. 
     
     
         121 . The method of  claim 119 , wherein administering to the subject a composition comprising a therapeutically effective amount of ticagrelor or a derivative thereof comprises reducing cyst number and/or size or decreasing or preventing the increase of kidney size. 
     
     
         122 . The method of  claim 119 , wherein administering to the subject a composition comprising a therapeutically effective amount of ticagrelor or a derivative thereof alleviates or reduces one or more symptoms associated with ADPKD. 
     
     
         123 . The method of  claim 122 , wherein the one or more symptoms associated with ADPKD is selected from the group consisting of acute loin pain, haematuria, ballotable kidneys, sub arachnoid hemorrhage (berry aneurysm), hypertension, associated liver cyst, uremia due to renal failure, anemia due to CKD, increase RBC or erythropoeitin secretion. 
     
     
         124 . The method of  claim 119 , further comprising administering one or more additional therapeutic. 
     
     
         125 . The method of  claim 124 , wherein the additional therapeutic is selected from the group consisting of a mTOR inhibitor, a somastostatin analogue, a vasopressin V2 receptor antagonist and an epidermal growth factor receptor inhibitor. 
     
     
         126 . The method of  claim 124 , wherein the additional therapeutic is selected from the group consisting of Sirolimus, Everolimus (RAD001), Temsirolimus (CCI-779), Ridaforolimus (AP23573, MK-8669), Deforolimus, Dactolisib, BGT226, SF1126, PKI-587, Sapanisertib (INK128), AZD8055, AZD2014, Octreotide, Pasireotide (SOM230), dopastatin BIM-23A387, dopastatin BIM-23A760, somatostatin octapeptide-doxorubicin RC-121, somatostatin octapeptide-doxorubicin RC-160, somatostatin octapeptide-2-pyrrolino-DOX conjugate AN-201, AN-238 (AN-201 linked to RC-121), JF-10-81,  90 Y-DOTATOC, 177Lu DOTATATE [177Lu]DOTA-Tyr(3)-octreotate, Lanreotide, OPC-31260, Lixivaptan, Mozavaptan, Satavaptan, Lixivaptan, Conivaptan (YM-087), SR-121463A, VPA-985 and Tolvaptan (OPC-41061), bosutinib, gefitinib, lapatinib, cetuximab, panitumumab, vandetanib, neratinib, necitumumab, osimertnib and erlotinib. 
     
     
         127 . The method of  claim 124 , wherein the additional therapeutic is selected from the group consisting of Sirolimus, Everolimus (RAD001), Octreotide, Lanreotide, OPC-31260, Tolvaptan, bosutinib, gefitinib and erlotinib. 
     
     
         128 . The method of  claim 124 , wherein the additional therapeutic is tolvaptan. 
     
     
         129 . The method of  claim 119 , wherein the subject is a human, non-human primate, rabbit, sheep, rat, dog, cat, pig, or mouse.