Methods and materials for treating hyperoxalemia and / or hyperoxaluria

Abstract

This document provides methods and materials for treating hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e.g., kidney stone disease). For example, methods and materials for using one or more compounds that can activate oxalate transport to treat a mammal (e.g., a human) having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e.g., kidney stone disease) are provided. In some cases, one or more of atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib can be administered to a mammal (e.g., a human) having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e.g., kidney stone disease) to treat the mammal.

Description

[0001] METHODS AND MATERIALS FOR TREATING HYPEROXALEMIA AND / OR HYPEROXALURIA

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Patent Application Serial No. 63 / 542,582, filed on October 5, 2023. The disclosure of the prior application is considered part of, and is incorporated by reference in, the disclosure of this application.

[0004] STATEMENT REGARDING FEDERAL FUNDING

[0005] This invention was made with government support under DK114857 awarded by the National Institutes of Health. The government has certain rights in the invention.

[0006] TECHNICAL FIELD

[0007] This document relates to methods and materials for treating hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e.g., kidney stone disease). For example, this document provides methods and materials for using one or more compounds that can activate oxalate transport to treat a mammal (e.g., a human) having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e.g., kidney stone disease). In some cases, a compound such as atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, erlotinib, or any combination thereof can be administered to a mammal (e.g., a human) having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e.g., kidney stone disease)to treat the mammal. BACKGROUND

[0008] Kidney stone disease is the second most prevalent kidney disease in the U.S. after hypertension. It is a key source of patient discomfort and disability, lost working days, and over $10 billion in annual healthcare expenditures including >$1.3 million in annual emergency room visits (with 20% of emergency room visits leading to hospitalization). The lifetime risk of kidney stone disease is 10-20%. Ahistory of even a single kidney stone occurrence is associated with a significantly increased risk of poor renal outcome, including chronic kidney disease (CKD) and end-stage renal disease (ESRD). Significantly, kidney stones have a recurrence rate of up to 50% in 5 years and up to 80% in 10-20 years.

[0009] SUMMARY

[0010] This document provides methods and materials for treating hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e.g., kidney stone disease). In some cases, one or more compounds that can activate oxalate transport can be administered to a mammal having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e.g., kidney stone disease) to treat the hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria. For example, a compound such as atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, erlotinib, or a combination thereof can be administered to a mammal (e.g., a human) having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e.g., kidney stone disease) to treat the mammal.

[0011] In some cases, one or more compounds that can activate oxalate transport can be used to reduce the level of oxalate in a mammal’s (e.g., a human’s) body. For example, one or more compounds that can activate oxalate transport can be administered to a mammal (e g., a human) to reduce the level of oxalate in the blood of the mammal having hyperoxalemia (e.g., to treat the mammal). In another example, one or more compounds that can activate oxalate transport can be administered to a mammal (e.g., a human) to reduce the level of oxalate in the urine of the mammal having hyperoxaluria (e.g., to treat the mammal).

[0012] As demonstrated herein, certain compounds approved for other conditions (e.g., atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, erlotinib, or combinations thereof) can activate oxalate transport and can be used to treat hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e.g., kidney stone disease).

[0013] In general, one aspect of this document features methods for treating hyperoxalemia in a mammal. The methods can include, or consist essentially of, administering a compound to a mammal having hyperoxalemia, where the compound is selected from the group consisting of atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib, thereby activating oxalate transport within the mammal. The mammal can be a human. The compound can be a tyrosine kinase inhibitor. The method can be effective to reduce a level of oxalate in the mammal’s blood to less than 5 pM. The method can include identifying the mammal as having hyperoxalemia. The method can include identifying the mammal as being in need of the administration of the compound. The method can include administering 2 or more or the compounds.

[0014] In another aspect, this document features methods for treating hyperoxaluria in a mammal. The methods can include, or consist essentially of, administering a compound to a mammal having hyperoxaluria, where the compound is selected from the group consisting of atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib, thereby activating oxalate transport within the mammal. The mammal can be a human. The compound can be a tyrosine kinase inhibitor. The method can be effective to reduce a level of oxalate in the mammal’s urine to less than 30 mg / day. The method can include identifying the mammal as having hyperoxaluria. The method can include identifying the mammal as being in need of the administration of the compound. The method can include administering 2 or more or the compounds.

[0015] In another aspect, this document features methods for treating kidney stone disease in a mammal. The methods can include, or consist essentially of, administering a compound to a mammal having kidney stone disease, where the compound is selected from the group consisting of atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib, thereby activating oxalate transport within the mammal. The mammal can be a human. The compound can be a tyrosine kinase inhibitor. The size of a kidney stone present in the mammal can be reduced. The number of kidney stones present in the mammal can be reduced. The method can include identifying the mammal as having kidney stone disease. The method can include identifying the mammal as being in need of the administration of the compound. The method can include administering 2 or more or the compounds.

[0016] In another aspect, this document features methods for reducing a level of oxalate within a mammal. The methods can include, or consist essentially of, administering a compound to a mammal, where the compound is selected from the group consisting of atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib, thereby activating oxalate transport within the mammal. The mammal can be a human. The compound can be a tyrosine kinase inhibitor. The level of oxalate can be reduced in blood of the mammal. The level of oxalate can be reduced in urine of the mammal.

[0017] In another aspect, this document features methods for stimulating oxalate transport in a cell within a mammal. The methods can include, or consist essentially of, administering a compound to a mammal, where the compound is selected from the group consisting of atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib, thereby activating oxalate transport within the mammal. The mammal can be a human. The compound can be a tyrosine kinase inhibitor. The cell can be an epithelial cell. The cell can be an intestinal tissue. The cell can be an intestinal epithelial cell.

[0018] In another aspect, this document features compositions including one or more atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib for use in the preparation of a medicament to treat hyperoxalemia or hyperoxaluria.

[0019] In another aspect, this document features compositions including one or more of atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib for use in the treatment of hyperoxalemia or hyperoxaluria. In another aspect, this document features compositions including one or more atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib for use in the preparation of a medicament to treat kidney stone disease.

[0020] In another aspect, this document features compositions including one or more of atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib for use in the treatment of kidney stone disease.

[0021] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although methods and materials similar or equivalent to those described herein can be used to practice the invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0022] The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.

[0023] BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1. A schematic showing oxalate sources and homeostasis.

[0025] Figure 2. A schematic of an exemplary cell-based high-throughput assay (HTS) using fisher rat thyroid cells to detect chloride / oxalate (Cl / Ox) exchange. Figure 3. Human intestinal Caco2-BBE cells treated with ponatinib exhibited increased oxalate transport as compared to control cells.

[0026] Figure 4. Human intestinal Caco2-BBE cells treated with dasatinib exhibited increased oxalate transport as compared to control cells.

[0027] Figure 5. Human intestinal Caco2-BBE cells treated with gefitinib did not exhibit increased oxalate transport as compared to control cells.

[0028] Figure 6. Activators of oxalate transport stimulated oxalate transport in C2 cells. Activators shown include atorvastatin (At), cinacalcet (Cin), cyproheptadine (Cyp), vortioxetine (Vor), pizotifen (Piz), ritonavir (Rit), dronedarone (Dr), thioridazine (Thio), nilotinib (Nil), bexarotene (Bex), mebendazole (Meb), racecadotril (Rac), pefloxacin (Pef), cabazitaxel (Cab), oxibendazole (Oxi), pyridostigmine (Pyr), olanzapine (Ola), trifluoperazine (Tri), AZ-5104 (AZ), centrimonium (Cen), and cladribine (Clad).

[0029] Figure 7. C2 cells treated with phentolamine (Phe), bifonazole (Bif), regorafenib (Reg), or dabrafenib (Dab) exhibited decreased oxalate transport. C2 cells treated with candesartan (Can) or ruxolitinib (Rux) exhibited no change in oxalate transport.

[0030] DETAILED DESCRIPTION

[0031] This document provides methods and materials for treating hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e.g., kidney stone disease). In some cases, one or more compounds that can activate oxalate transport (e.g., one or more of atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib) can be administered to a mammal (e.g., a human) having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e.g., kidney stone disease) to treat that mammal. In some cases, one or more compounds that can activate oxalate transport can be used to reduce the level of oxalate in the blood of a mammal (e g., a human) having hyperoxalemia (e.g., to treat the mammal). In some cases, one or more compounds that can activate oxalate transport can be used to reduce the level of oxalate in the urine of a mammal (e.g., a human) having hyperoxaluria (e.g., to treat the mammal).

[0032] In some cases, one or more compounds that can activate oxalate transport (e.g., one or more of atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib) can be used to treat one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria. Examples of diseases, disorders, and conditions associated with hyperoxalemia and / or hyperoxaluria include, without limitation, kidney stone disease, chronic kidney disease (CKD), progression of cyst growth in autosomal dominant polycystic kidney disease (ADPKD), end-stage renal disease (ESRD), primary hyperoxaluria, poor renal allograft (e.g., transplanted kidney) survival, CKD-associated cardiovascular diseases, ESRD-associated cardiovascular diseases, inflammatory bowel disease (IBD), obesity, intestinal resection, post bariatric surgery, malabsorption syndromes, and diabetes.

[0033] In some cases, administering one or more compounds that can activate oxalate transport (e.g., one or more of atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib) to a mammal (e.g., a human) having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e.g., kidney stone disease) can be effective to reduce the level of oxalate in the blood of the mammal (e.g., a human). For example, one or more compounds that can activate oxalate transport can be administered to a mammal (e.g., a human) in need thereof (e.g., a human having hyperoxalemia) to reduce the level of oxalate in the blood of the mammal. In some cases, administering one or more compounds that can activate oxalate transport to a mammal (e.g., a human) having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e.g., kidney stone disease) can be effective to reduce the level of oxalate in the blood of the mammal (e.g., a human) to less than 5 pM (e.g., less than 4.5 pM, less than 4 uM, less than 3.5 M, less than 3 pM, less than 2.5 M, less than 2 uM, less than 1.5 pM, or less than 1 pM).

[0034] In some cases, administering one or more compounds that can activate oxalate transport (e.g., one or more of atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib) to a mammal (e.g., a human) having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e.g., kidney stone disease) can be effective to reduce the level of oxalate in the urine of the mammal (e.g., a human). For example, one or more compounds that can activate oxalate transport can be administered to a mammal (e.g., a human) in need thereof (e.g., a human having hyperoxaluria) to reduce the level of oxalate in the urine of the mammal. In some cases, administering one or more compounds that can activate oxalate transport to a mammal (e.g., a human) having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e g., kidney stone disease) can be effective to reduce the level of oxalate in the urine of the mammal (e.g., a human) to less than 30 mg of oxalate excreted in the urine in a 24-hour period (mg / day) (e.g., less than 29 mg / day, less than 28 mg / day, less than 27 mg / day, less than 26 mg / day, or less than 25 mg / day).

[0035] In some cases, administering one or more compounds that can activate oxalate transport (e.g., one or more of atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib) to a mammal (e.g., a human) having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e.g., kidney stone disease) can be effective to reduce the severity of one or more symptoms of hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e.g., kidney stone disease). For example, one or more compounds that can activate oxalate transport can be administered to a mammal (e.g., a human) in need thereof (e.g., a human having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria such as kidney stone disease) to reduce the severity of one or more symptoms of hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e.g., kidney stone disease). For example, examples of symptoms of kidney stone disease include, without limitation, sharp pain (e.g., in the back, side, lower stomach area, and / or groin), discolored urine (e.g., urine that looks pink, red, or brown due to the presence of blood in the urine), frequent urge to urinate, pain when urinating, not being able to urinate or producing only a small amount during urination, chills, fever, upset stomach, and vomiting. In some cases, the methods and materials described herein can be effective to reduce the severity of one or more symptoms of hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e.g., kidney stone disease) in a mammal by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent.

[0036] In some cases, administering one or more compounds that can activate oxalate transport (e.g., one or more of atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib) to a mammal (e.g., a human) having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e.g., kidney stone disease) can be effective to reduce the size of one or more kidney stones present within the mammal. For example, one or more compounds that can activate oxalate transport can be administered to a mammal (e.g., a human) in need thereof (e.g., a human having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria such as kidney stone disease) to reduce the size of one or more kidney stones present within the mammal. In some cases, the methods and materials provided herein can be used as described herein to reduce the size of one or more kidney stones in the mammal by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent.

[0037] In some cases, administering one or more compounds that can activate oxalate transport (e.g., one or more of atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib) to a mammal (e.g., a human) having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e.g., kidney stone disease) can be effective to reduce the number of kidney stones present within the mammal. For example, one or more compounds that can activate oxalate transport can be administered to a mammal (e g., a human) in need thereof (e.g., a human having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria such as kidney stone disease) to reduce the number kidney stones present within the mammal. In some cases, the methods and materials provided herein can be used as described herein to reduce the number of kidney stones in the mammal by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent.

[0038] In some cases, administering one or more compounds that can activate oxalate transport (e.g., one or more of atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib) to a mammal (e.g., a human) having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e.g., kidney stone disease) can be effective to stimulate oxalate transport within the mammal. For example, one or more compounds that can activate oxalate transport can be administered to a mammal (e.g., a human) in need thereof (e.g., a human having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria such as kidney stone disease) to stimulate oxalate transport across a cell membrane of a cell within a mammal. One or more compounds that can activate oxalate transport can be used to stimulate oxalate transport across a membrane of any appropriate cell type. In some cases, one or more compounds that can activate oxalate transport can be used to stimulate oxalate transport across a cell membrane of an epithelial cell. One or more compounds that can activate oxalate transport can be used to stimulate oxalate transport across a cell membrane of a cell in any appropriate location within a mammal (e.g., a human). In some cases, one or more compounds that can activate oxalate transport can be used to stimulate oxalate transport across a cell membrane of a cell in an intestinal tissue within a mammal (e.g., a human). In some cases, one or more compounds that can activate oxalate transport can be used to stimulate oxalate transport across a cell membrane of an intestinal epithelial cell within a mammal (e.g., a human). For example, one or more compounds that can activate oxalate transport can be used to stimulate oxalate transport from blood within a mammal (e.g., a human) into the intestinal lumen (a process known as transcellular oxalate secretion), such that the oxalate is excreted into feces of the mammal.

[0039] When one or more compounds that can activate oxalate transport (e.g., one or more of atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib) are used to stimulate oxalate transport within a mammal (e.g., a human), the one or more compounds can stimulate oxalate transport by activating any appropriate oxalate transporter. Examples of oxalate transporters that can be stimulated using one or more compounds that can activate oxalate transport as described herein include, without limitation A6 oxalate transporters, A2 oxalate transporters, and Al oxalate transporters.

[0040] When one or more compounds that can activate oxalate transport (e.g., one or more of atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib) are used to stimulate oxalate transport within a mammal (e.g., a human), the one or more compounds can be effective to increase the level of oxalate transport within a mammal (e.g., a human). The term “increased level” as used herein with respect to a level of oxalate transport refers to any level after treatment that is higher than a level of oxalate transport before treatment. In some cases, an increased level of oxalate transport can be a post-treatment level that is at least 1 (e.g., about 1.1, about 1.2, about 1.3 about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, or more) fold higher than a pre-treatment level of oxalate transport. In some cases, an increased level of oxalate transport can be a post-treatment level that is at least 2% (e.g., about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, or more) higher than a pre-treatment level of oxalate transport. The term “pre-treatment level” as used herein with respect to a level of oxalate transport refers to the level of oxalate transport typically observed any time before treatment (e g., before administration of one or more of atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib). The term “post-treatment level” as used herein with respect to a level of oxalate transport refers to the level of oxalate transport typically observed from about 3 hours to about 6 weeks (e.g., from about 3 hours to about 4 weeks, from about 3 hours to about 2 weeks, from about 3 hours to about 1 week, from about 3 hours to about 5 days, from about 3 hours to about 72 hours, from about 3 hours to about 48 hours, from about 3 hours to about 36 hours, from about 3 hours to about 24 hours, from about 24 hours to about 6 weeks, from about 36 hours to about 6 weeks, from about 48 hours to about 6 weeks, from about 72 hours to about 6 weeks, from about 5 day to about 6 weeks, from about 1 week to about 6 weeks, from about 2 weeks to about 6 weeks, from about 4 weeks to about 6 weeks, from about 12 hours to about 4 weeks, from about 24 hours to about 2 weeks, from about 36 hours to about 1 week, from about 48 hours to about 72 hours, from about 12 hours to about 36 hours, from about 24 hours to about 48 hours, from about 36 hours to about 72 hours, from about 48 hours to about 1 week, from about 72 hours to about 2 weeks, from about 1 week to about 3 weeks, or from about 2 weeks to about 4 weeks) after treatment (e.g., after administration of one or more of atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib). It will be appreciated that levels of oxalate transport from comparable samples are used when determining whether or not a particular level is an increased level of oxalate transport.

[0041] Any appropriate mammal having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e g., kidney stone disease) can be treated as described herein (e g., by administering one or more compounds that can activate oxalate transport). Examples of mammals that can have hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e.g., kidney stone disease) and can be treated as described herein include, without limitation, humans, non-human primates (e.g., monkeys), horses, bovine species, porcine species, dogs, cats, mice, and rats. In some cases, a human having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e g., kidney stone disease) can be treated by administering one or more compounds that can activate oxalate transport (e.g., one or more of atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib).

[0042] In some cases, the methods described herein also can include identifying a mammal as being in need of treatment with one or more compounds that can activate oxalate transport (e.g., one or more of atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib) and / or as having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e.g., kidney stone disease). Examples of methods for identifying a mammal as having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e.g., kidney stone disease) include, without limitation, urine tests (e.g., to measure oxalate in the urine), blood tests (e.g., to measure oxalate levels in the blood), stone analysis (e.g., to determine the composition of kidney stones after they passed through urine or were removed with surgery), imaging techniques (e.g., kidney X-rays, ultrasounds, and / or computerized tomography (CT) scans), and / or genetic testing (e.g., for different forms of primary hyperoxaluria (types 1-3) and / or for mutations in one or more oxalate transporters).

[0043] Once identified as being in need of treatment with one or more compounds that can activate oxalate transport (e.g., one or more of atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib) and / or as having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e.g., kidney stone disease), a mammal can be treated as described herein (e.g., by administering one or more compounds that can activate oxalate transport). For example, a mammal identified as having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e.g., kidney stone disease) can be administered or instructed to self-administer one or more compounds that can activate oxalate transport (e.g., one or more of atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib).

[0044] A compound that can activate oxalate transport and can be used as described herein (e.g., to treat a mammal (e.g., a human) having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria such as kidney stone disease) can be any appropriate compound. In some cases, a compound that can activate oxalate transport and can be used as described herein (e.g., to treat a mammal (e.g., a human) having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria such as kidney stone disease) can be an anti-cancer agent (e.g., a chemotherapeutic agent). In some cases, a compound that can activate oxalate transport and can be used as described herein (e.g., to treat a mammal (e.g., a human) having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria such as kidney stone disease) can be an antibacterial agent. In some cases, a compound that can activate oxalate transport and can be used as described herein (e.g., to treat a mammal (e.g., a human) having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria such as kidney stone disease) can be an antiinflammatory agent. In some cases, a compound that can activate oxalate transport and can be used as described herein (e.g., to treat a mammal (e.g., a human) having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria such as kidney stone disease) can be an anti-diarrheal agent. In some cases, a compound that can activate oxalate transport and can be used as described herein (e.g., to treat a mammal (e.g., a human) having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria such as kidney stone disease) can be an anti-angiogenic agent. In some cases, a compound that can activate oxalate transport and can be used as described herein (e.g., to treat a mammal (e.g., a human) having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria such as kidney stone disease) can be an agent that can inhibit one or more ion currents (e.g., Na+, K+, and / or Ca2+currents). In some cases, a compound that can activate oxalate transport and can be used as described herein (e.g., to treat a mammal (e.g., a human) having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria such as kidney stone disease) can be a non-peptide compound.

[0045] In some cases, a compound that can activate oxalate transport and can be used as described herein (e.g., to treat a mammal (e.g., a human) having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria such as kidney stone disease) can be a tyrosine kinase inhibitor (e.g., a BCR-ABL tyrosine kinase inhibitor).

[0046] In some cases, a compound that can activate oxalate transport and can be used as described herein (e.g., to treat a mammal (e.g., a human) having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria such as kidney stone disease) can be a PI3K inhibitor.

[0047] In some cases, a compound that can activate oxalate transport and can be used as described herein (e.g., to treat a mammal (e.g., a human) having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria such as kidney stone disease) can be a Akt inhibitor. In some cases, a compound that can activate oxalate transport and can be used as described herein (e.g., to treat a mammal (e.g., a human) having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria such as kidney stone disease) can be a mTOR inhibitor. In some cases, a compound that can activate oxalate transport and can be used as described herein (e.g., to treat a mammal (e.g., a human) having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria such as kidney stone disease) can inhibit (e.g., can interact with and inhibit) a G protein-coupled receptor (GPCR; e g., a M3 muscarinic receptor, a Ca receptor, or a 5HT2 receptor).

[0048] Examples of compounds that can activate oxalate transport and can be used as described herein (e.g., to treat a mammal (e.g., a human) having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria such as kidney stone disease) include, without limitation, those compounds shown in Table 1.

[0049] Table 1. Exemplary compounds that can activate oxalate transport.

[0050] In some cases, one or more compounds that can activate oxalate transport (e.g., one or more of atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib) can be formulated into a composition (e.g., a pharmaceutical composition) for administration to a mammal (e.g., a human). For example, one or more compounds that can activate oxalate transport can be formulated into a pharmaceutically acceptable composition for administration to a mammal (e.g., a human) having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e.g., kidney stone disease). In some cases, one or more compounds that can activate oxalate transport can be formulated together with one or more pharmaceutically acceptable carriers (additives), excipients, and / or diluents. Examples of pharmaceutically acceptable carriers, excipients, and diluents that can be used in a composition described herein include, without limitation, sucrose, lactose, starch (e.g., starch glycolate), cellulose, cellulose derivatives (e.g., modified celluloses such as microcrystalline cellulose and cellulose ethers like hydroxypropyl cellulose (HPC) and cellulose ether hydroxypropyl methyl cellulose (HPMC)), xylitol, sorbitol, mannitol, gelatin, polymers (e.g., polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), crosslinked polyvinylpyrrolidone (crospovidone), carboxymethyl cellulose, polyethylene-polyoxypropylene-block polymers, and crosslinked sodium carboxymethyl cellulose (croscarmellose sodium)), titanium oxide, azo dyes, silica gel, fumed silica, talc, magnesium carbonate, vegetable stearin, magnesium stearate, aluminum stearate, stearic acid, antioxidants (e.g., vitamin A, vitamin E, vitamin C, retinyl palmitate, and selenium), citric acid, sodium citrate, parabens (e.g., methyl paraben and propyl paraben), petrolatum, dimethyl sulfoxide, mineral oil, serum proteins (e.g., human serum albumin), glycine, sorbic acid, potassium sorbate, water, salts or electrolytes (e.g., saline, protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyacrylates, waxes, wool fat, and lecithin.

[0051] A composition (e.g., a pharmaceutical composition) containing one or more compounds that can activate oxalate transport (e.g., one or more of atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib) can be formulated into any appropriate dosage form. Examples of dosage forms include solid or liquid forms including, without limitation, gels, liquids, suspensions, solutions (e.g., sterile solutions), sustained-release formulations, and delay ed- release formulations.

[0052] A composition (e.g., a pharmaceutical composition) containing one or more compounds that can activate oxalate transport (e.g., one or more of atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib) can be designed for parenteral (e.g., intramuscular, subcutaneous, intravenous, rectal, and inhalation) administration. Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions that can contain anti-oxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations can be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.

[0053] A composition (e.g., a pharmaceutical composition) containing one or more compounds that can activate oxalate transport (e g., one or more of atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib) can be administered locally or systemically. For example, a composition containing one or more compounds that can activate oxalate transport can be administered systemically by intramuscular, subcutaneous, intravenous, rectal, or inhalation administration to a mammal (e.g., a human).

[0054] An effective amount of a composition (e.g., a pharmaceutical composition) containing one or more compounds that can activate oxalate transport (e.g., one or more of atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib) can be any amount that can treat a mammal (e.g., a human) having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e.g., kidney stone disease) without producing significant toxicity to the mammal. For example, an effective amount of atorvastatin can be from about 40 milligrams of polypeptide(s) per 24-hour period (mg / day) to about 80 mg / day. For example, an effective amount of cinacalcet can be from about 60 mg / day to about 360 mg / day. For example, an effective amount of cyproheptadine can be from about 16 mg / day to about 32 mg / day. For example, an effective amount of vortioxetine can be from about 5 mg / day to about 20 mg / day. For example, an effective amount of pizotifen can be from about 1.5 mg / day to about 6 mg / day. For example, an effective amount of ritonavir can be from about 600 mg / day to about 1200 mg / day. For example, an effective amount of dronedarone can be about 400 mg / day. For example, an effective amount of thioridazine can be from about 200 mg / day to about 800 mg / day. For example, an effective amount of nilotinib can be about 800 mg / day (e.g., about 400 mg twice daily). For example, an effective amount of bexarotene can be from about 300 mg per body surface area (mg / m2) to about 400 mg / m2. For example, an effective amount of mebendazole can be from about 40 mg per kilogram body weight of the mammal being treated per 24-hour period (mg / kg / day) to about 50 mg / kg / day. For example, an effective amount of racecadotril can be about 100 mg every 8 hours for up to 7 days. For example, an effective amount of pefloxacin can be about 800 mg / day (e.g., about 400 mg twice daily). For example, an effective amount of cabazitaxel can be from about 20 mg / m2 every three weeks to about 25 mg / kg mg / m2 every three weeks. For example, an effective amount of pyridostigmine can be less than 960 mg / day give at from about 60 mg every 3-4 hours to about 120 mg every 3-4 hours. For example, an effective amount of olanzapine can be from about 5 mg / day to about 50 mg / day. For example, an effective amount of trifluoperazine can be from about 15 mg / day to about 40 mg / day. For example, an effective amount of cladribine can be from about 0.09 mg / kg / day to about 0.15 mg / kg / day or about 5.6 mg / m2. For example, an effective amount of ponatinib can be about 45 mg / day. For example, an effective amount of dasatinib can be about 40 mg / day. For example, an effective amount of erlotinib can be about 150 mg / day. The effective amount can remain constant or can be adjusted as a sliding scale or variable dose depending on the mammal’s response to treatment. Various factors can influence the actual effective amount used for a particular application. For example, the frequency of administration, duration of treatment, use of multiple treatment agents, route of administration, and severity of the condition may require an increase or decrease in the actual effective amount administered. The frequency of administration of a composition (e.g., a pharmaceutical composition) containing one or more compounds that can activate oxalate transport (e.g., one or more of atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib) can be any frequency that can treat a mammal (e.g., a human) having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e.g., kidney stone disease) without producing significant toxicity to the mammal. For example, the frequency of administration can be from about once a day to about once a month, from about twice a day to about once a week, from about three times a day to about once a month, from about twice a week to about twice a month, or from about once a month to about twice a year. The frequency of administration can remain constant or can be variable during the duration of treatment. A course of treatment with a composition containing one or more compounds that can activate oxalate transport can include rest periods. As with the effective amount, various factors can influence the actual frequency of administration used for a particular application. For example, the effective amount, duration of treatment, use of multiple treatment agents, route of administration, and severity of the condition may require an increase or decrease in administration frequency.

[0055] An effective duration for administering a composition (e.g., a pharmaceutical composition) containing one or more compounds that can activate oxalate transport (e.g., one or more of atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib) can be any duration that treat a mammal (e.g., a human) having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e.g., kidney stone disease) without producing significant toxicity to the mammal. For example, the effective duration can vary from several days to several weeks, months, or years. In some cases, an effective duration can be for the lifetime of a mammal (e.g., a human). Multiple factors can influence the actual effective duration used for a particular treatment. For example, an effective duration can vary with the frequency of administration, effective amount, use of multiple treatment agents, route of administration, and severity of the condition being treated.

[0056] In some cases, methods for treating a mammal (e.g., a human) as described herein (e g., by administering one or more compounds that can activate oxalate transport) can include administering to the mammal the one or more compounds that can activate oxalate transport (e.g., one or more of atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib) as the sole active ingredient(s). For example, a composition containing one or more compounds that can activate oxalate transport can include the one or more compounds that can activate oxalate transport as the sole active ingredient(s) in the composition for treating a mammal (e.g., a human) having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e.g., kidney stone disease).

[0057] In some cases, methods for treating a mammal (e.g., a human) as described herein (e g., by administering one or more compounds that can activate oxalate transport) also can include administering to the mammal one or more (e.g., one, two, three, or more) additional agents used to treat hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e g., kidney stone disease) and / or performing one or more (e.g., one, two, three, or more) therapies used to treat hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e.g., kidney stone disease). For example, a combination therapy used to treat a mammal (e.g., a human) having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e.g., kidney stone disease) can include administering to the mammal one or more compounds that can activate oxalate transport (e.g., one or more of atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib), and administering to the mammal one or more (e.g., one, two, three, or more) additional agents used to treat hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e.g., kidney stone disease). In some cases, an additional agent that can be administered to a mammal to treat hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e.g., kidney stone disease) can be a diuretic. In some cases, an additional agent that can be administered to a mammal to treat hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e.g., kidney stone disease) can be an anti-hypertensive agent. Examples of additional agents that can be administered to a mammal (e.g., a human) having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e.g., kidney stone disease) to treat the mammal include, without limitation, lumasiran (e.g., OXLUMO®), vitamin B-6 (also referred to as pyridoxine), and combinations thereof. In cases where one or more compounds that can activate oxalate transport are used in combination with additional agents used to treat a mammal (e.g., a human) having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e.g., kidney stone disease), the one or more additional agents can be administered at the same time (e.g., in a single composition containing one or more compounds that can activate oxalate transport and containing the one or more additional agents) or independently. For example, a composition including one or more compounds that can activate oxalate transport can be administered first, and the one or more additional agents administered second, or vice versa.

[0058] In some cases, a combination therapy used to treat a mammal (e.g., a human) having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e.g., kidney stone disease) can include administering to the mammal one or more compounds that can activate oxalate transport (e.g., one or more of atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib), and can include performing one or more (e.g., one, two, three, or more) therapies used to treat hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e.g., kidney stone disease). Examples of additional therapies that can be used to treat a mammal (e.g., a human) having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e.g., kidney stone disease) include, without limitation, dialysis, extracorporeal shock wave lithotripsy (ESWL), surgery to remove one or more kidney stones (e.g., percutaneous nephrolithotomy), kidney transplant, and / or kidney and liver transplant. In cases where one or more compounds that can activate oxalate transport are used in combination with one or more therapies used to treat a mammal (e.g., a human) having hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e.g., kidney stone disease), the one or more additional therapies can be performed at the same time or independently of the administration of the one or more compounds that can activate oxalate transport. For example, one or more compounds that can activate oxalate transport can be administered before, during, or after the one or more additional therapies are performed.

[0059] In some cases, the level of oxalate present within a mammal (e.g., within urine of a mammal and / or within blood of a mammal) can be monitored. Any appropriate method can be used to determine whether or not the level of oxalate within a mammal is reduced following treatment. For example, urine tests (e.g., to measure oxalate in the urine) and / or blood tests (e.g., to measure oxalate levels in the blood), can be used to determine whether or not the level of oxalate within a mammal is reduced after treatment as compared to a level determined before treatment.

[0060] The invention will be further described in the following examples, which do not limit the scope of the invention described in the claims.

[0061] EXAMPLES

[0062] Example 1: In Vitro Screen for Oxalate Transport

[0063] Oxalate is an unavoidable toxic metabolic end-product that can combine with calcium to form kidney stones, which impair kidney function. Approximately 50% of oxalate comes from dietary sources and the other 50% is produced by the liver (Figure 1). The majority of plasma oxalate passes through the kidneys to be eliminated in the urine, but the risk for stone formation can be affected by small increases in urine oxalate, even within the normal urine oxalate range of 25-30 mg / day. Lowering serum oxalate levels and / or urine oxalate levels can have a therapeutic implication for hyperoxalemia and / or hyperoxaluria as well as diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e.g., kidney stone disease). However, there are currently no small molecule drugs that can directly address hyperoxalemia or hyperoxaluria.

[0064] This Example describes the discovery that a number of small molecules approved for other conditions can activate oxalate transport and can be used to treat hyperoxalemia, hyperoxaluria, and / or one or more diseases, disorders, and / or conditions associated with hyperoxalemia and / or hyperoxaluria (e.g., kidney stone disease).

[0065] Methods

[0066] A highly sensitive cell-based high-throughput assay (HTS) was developed to identify and validate small molecule activators and / or positive allosteric modulators (PAMs) for the key intestinal luminal oxalate transporters SLC26A6 (A6) and / or SLC26A2 (A2). A fluorogenic 96-well assay was established using fisher rat thyroid cells (FRT) that have a stably expressed chloride sensor protein (YFP; allowing non-invasive monitoring of intracellular Cl’ fluctuations) that have been further engineered to stably express either the human A6 (hA6) or human A2 (hA2) transporters. The parental transporter null FRT / EFYP chloride sensor cell line provided a control for transporter specific effects. The YFP was an enhanced FYP (EYFP) that was further engineered to contain mutations that enhanced its sensitivity and selectivity for C1‘ anions. FRT cells were used because of their low intrinsic permeability to anions that are transported by A6 and A2 and their good adherence and rapid growth on uncoated plastic. This cell-based HTS assay demonstrated that extracellular addition of high oxalate containing buffer derived hA6 - or hA2 -mediated oxalate / Cl exchange led to decreased intracellular Cl and associated increased (dequenched) EYFP fluorescence that was measured on a plate reader (or imager) in both kinetic and endpoint modes (Figure 2). The HTS assay was used to look for small molecule compounds that enhanced this rate of EYFP dequench only in hA6 or hA2 expressing FRT / EFYP cells, presumably acting as transporter activators or PAMs.

[0067] Results

[0068] A number of small molecules approved for other conditions were screened, and several drugs which are already in clinical use were identified as small molecules activators for A6 and / or A2. Four tyrosine kinases inhibitors (e.g., dasatinib, ponatinib, gefitinib, and erlotinib) were tested for their effects on oxalate transport by the human intestinal epithelial Caco2-BBE cells (C2). A6 mediates > 49% of oxalate transport in C2 cells, with -80% of oxalate transport in C2 cells mediated by A6+A2. Ponatinib stimulated oxalate transport by C2 cells following treatment for 15 minutes (1.54-fold and 1.75-fold for the 10 and 20 pM concentrations, respectively; Figure 3). Dasatinib stimulated oxalate transport by C2 cells following treatment for 15 minutes (1.58-fold) for the 20 pM concentration (Figure 4). 10 pM concentration of dasatinib led to -15% stimulation. Erlotinib stimulated oxalate transport by C2 cells following treatment for 15 minutes at 10 pM. No effect was seen from gefitinib (treatment for 15 minutes at 10 pM; Figure 5).

[0069] Additional compounds were screened, and 21 drugs tested (at 10-20 pM concentrations x 15 minutes) stimulated oxalate transport in C2 cells to different levels (Figure 6). Atorvastatin (At), cinacalcet (Cin), cyproheptadine (Cyp), vortioxetine (Vor), pizotifen (Piz), ritonavir (Rit), dronedarone (Dr), thioridazine (Thio), nilotinib (Nil), bexarotene (Bex), mebendazole (Meb), racecadotril (Rac), pefloxacin (Pef), cabazitaxel (Cab), oxibendazole (Oxi), pyridostigmine (Pyr), olanzapine (Ola), trifluoperazine (Tri), AZ- 5104 (AZ), centrimonium (Cen), and cladribine (Clad) significantly stimulated oxalate transport in C2 cells by about 1.36-fold, 1.51-fold, 1.60-fold, 2.07-fold, 1.42-fold, 1.55-fold, 1.27-fold, 1.82-fold, 1.45-fold, 1.22-fold, 1.29-fold, 1.24-fold, 1.39-fold, 1.56-fold, 1.40-fold, 1.44-fold, 1.17-fold, 1.56-fold, 1.18-fold, 1.69-fold, and 1.47-fold, respectively, compared with control (treated with vehicle).

[0070] Example 2: Small molecule drugs as inhibitors of oxalate transporters

[0071] The HTS described in Example 1 also identified several small molecule drugs as potential inhibitors for A6 and / or A2. To assess whether one or more of these potential inhibitors could reduce A6- and / or A2-mediated oxalate transport by C2 cells, seven of them were tested. It was observed that four drugs inhibited oxalate transport by C2 cells (Figure 7). Phentolamine (Phe) inhibited oxalate transport by -29%, bifonazole (Bif) inhibited oxalate transport by -20%, regorafenib (Reg) inhibited oxalate transport by -16%, and dabrafenib (Dab) inhibited oxalate transport by -20.5. On the other hand, candesartan (Can) and ruxolitinib (Rux) had no significant effects. Rotigotine also significantly reduced (-37%) oxalate transport by C2 cells. Collectively, these results strongly support that the observed stimulatory or inhibitory effects on oxalate transport by C2 cells were specific and not due to general nonspecific drug effects on oxalate transport.

[0072] C2 cells resemble the native intestinal epithelium and therefore one or more small molecule drug(s) with biologic activity in C2 cells stimulate intestinal oxalate secretion in vivo, to reduce urinary and plasma oxalate levels as observed with the Oxalobacter-denved factors stimulating oxalate transport by C2 cells and reducing urinary oxalate excretion in hyperoxaluric mice (Arvans et al., J. Am. Soc. Nephrol., 28:876-887 (2017)).

[0073] It has been shown that Oxalobacter-denved conditioned medium significantly reduced urinary oxalate excretion in PHI mice (a mouse model of primary hyperoxaluria type 1 (PHI)) (Arvans et al., J. Am. Soc. Nephrol., 28:876-887 (2017); and Salido et al., Proc. Natl. Acad. Sci. USA 103:18249-18254 (2006)). Therefore, these mice were used to evaluate the therapeutic potential of small molecule drugs. The in vivo therapeutic effects of vortioxetine, thioridazine, and cyproheptadine were tested. Following baseline urine and blood samples collection, PHI mice received the above drugs by oral gavage once daily (20 pM daily for 8 days). Control mice received vehicle (DMSO). The urine and blood samples were acidified and stored at -80 °C. Urine and plasma oxalate levels are measured by an ion chromatograph mass spectrometry (IC-MS).

[0074] Although transformed C2 cells resemble the native intestinal epithelium, they do not fully recapitulate the in vivo physiological responses. Primary stem-cell derived intestinal organoids (Org) were established as an ex vivo model of the intestinal epithelium, and they mimic the full spectrum of physiological responses in vivo (Zachos et al., J. Biol. Chem. 291 :3759-3766 (2016)). Thioridazine, vortioxetine, and cyproheptadine (all at 10 pM x 25 minutes) stimulated oxalate transport by a sigmoid colon organoid by 26.6%, 25.3%, and 10%, respectively. In addition, thioridazine and vortioxetine (both at 10 pM x 25 minutes) stimulated oxalate transport by a distal colonic organoid by 10.8% and 15%, respectively.

[0075] These results demonstrate that these drugs work in human tissues in vivo, and can be used for the prevention and / or treatment of hyperoxalemia, hyperoxaluria, and related disorders (including kidney stones).

[0076] Example 3: Treating hyperoxalemia

[0077] A human identified as having hyperoxalemia is administered one or more compounds that can activate oxalate transport selected from the group consisting of atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib. The administered compound(s) can reduce the level of oxalate in the blood of the human.

[0078] Example 4: Treating hyperoxaluria

[0079] A human identified as having hyperoxaluria is administered one or more compounds that can activate oxalate transport selected from the group consisting of atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib. The administered compound(s) can reduce the level of oxalate in the urine of the human.

[0080] Example 5: Treating Kidney Stone Disease

[0081] A human identified as having kidney stone disease is administered one or more compounds that can activate oxalate transport selected from the group consisting of atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib. In some cases, the administered compound(s) can reduce the size of one or more kidney stones present within the human. In some cases, the administered compound(s) can reduce the number of kidney stones present within the human.

[0082] OTHER EMBODIMENTS

[0083] It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

WHAT IS CLAIMED IS:

1. A method for treating hyperoxalemia in a mammal in need thereof, wherein said method comprises administering a compound to said mammal, wherein said compound is selected from the group consisting of atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib, thereby activating oxalate transport within said mammal.

2. The method of claim 1, wherein said mammal is a human.

3. The method of any one of claims 1-2, wherein said compound is a tyrosine kinase inhibitor.

4. The method of any one of claims 1-3, wherein said method is effective to reduce a level of oxalate in the mammal’s blood to less than 5 pM.

5. The method of any one of claims 1-4, wherein said method comprises identifying said mammal as having said hyperoxalemia.

6. The method of any one of claims 1-5, wherein said method comprises identifying said mammal as being in need of said administration of said compound.

7. The method of any one of claims 1-6, wherein said method comprises administering 2 or more of said compounds.

8. A method for treating hyperoxaluria in a mammal in need thereof, wherein said method comprises administering a compound to said mammal, wherein said compound is selected from the group consisting of atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib, thereby activating oxalate transport within said mammal.

9. The method of claim 8, wherein said mammal is a human.

10. The method of any one of claims 8-9, wherein said compound is a tyrosine kinase inhibitor.

11. The method of any one of claims 8-10, wherein said method is effective to reduce a level of oxalate in the mammal’s urine to less than 30 mg / day.

12. The method of any one of claims 8-11, wherein said method comprises identifying said mammal as having said hyperoxaluria.

13. The method of any one of claims 8-12, wherein said method comprises identifying said mammal as being in need of said administration of said compound.

14. The method of any one of claims 8-13, wherein said method comprises administering 2 or more of said compounds.

15. A method for treating kidney stone disease in a mammal in need thereof, wherein said method comprises administering a compound to said mammal, wherein said compound is selected from the group consisting of atorvastatin, cinacalcet, cyproheptadine, vortioxetine,pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib, thereby activating oxalate transport within said mammal.

16. The method of claim 15, wherein said mammal is a human.

17. The method of any one of claims 15-16, wherein said compound is a tyrosine kinase inhibitor.

18. The method of claim 17, wherein the size of a kidney stone present in said mammal is reduced.

19. The method of claim 17, wherein the number of kidney stones present in said mammal is reduced.

20. The method of any one of claims 15-19, wherein said method comprises identifying said mammal as having said kidney stone disease.

21. The method of any one of claims 15-20, wherein said method comprises identifying said mammal as being in need of said administration of said compound.

22. The method of any one of claims 15-21, wherein said method comprises administering 2 or more of said compounds.

23. A method for reducing a level of oxalate within a mammal in need thereof, wherein said method comprises administering a compound to said mammal, wherein said compound is selected from the group consisting of atorvastatin, cinacalcet, cyproheptadine, vortioxetine,pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib, thereby activating oxalate transport within said mammal.

24. The method of claim 23, wherein said mammal is a human.

25. The method of any one of claims 23-24, wherein said compound is a tyrosine kinase inhibitor.

26. The method of any one of claims 23-25, wherein said level of oxalate is reduced in blood of said mammal.

27. The method of any one of claims 23-26, wherein said level of oxalate is reduced in urine of said mammal.

28. A method for stimulating oxalate transport in a cell within a mammal in need thereof, wherein said method comprises administering a compound to said mammal, wherein said compound is selected from the group consisting of atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib, thereby activating oxalate transport within said mammal.

29. The method of claim 28, wherein said mammal is a human.

30. The method of any one of claims 28-29, wherein said compound is a tyrosine kinase inhibitor.

31. The method of any one of claims 28-30, wherein said cell is an epithelial cell.

32. The method of any one of claims 28-30, wherein said cell is an intestinal tissue.

33. The method of any one of claims 28-30, wherein said cell is an intestinal epithelial cell.

34. The use of a composition comprising one or more of atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib to treat hyperoxalemia or hyperoxaluria.

35. A composition comprising one or more atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib for use in the preparation of a medicament to treat hyperoxalemia or hyperoxaluria.

36. A composition comprising one or more of atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib for use in the treatment of hyperoxalemia or hyperoxaluria.

37. The use of a composition comprising one or more of atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib,bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib to treat kidney stone disease.

38. A composition comprising one or more atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib for use in the preparation of a medicament to treat kidney stone disease.

39. A composition comprising one or more of atorvastatin, cinacalcet, cyproheptadine, vortioxetine, pizotifen, ritonavir, dronedarone, thioridazine, nilotinib, bexarotene, mebendazole, racecadotril, pefloxacin, cabazitaxel, oxibendazole, pyridostigmine, olanzapine, trifluoperazine, AZ-5104, centrimonium, cladribine, ponatinib, dasatinib, and erlotinib for use in the treatment of kidney stone disease.

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