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WO 2013/043925 Al FIG. 14 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2013/043925 Al 28 March 2013 (28.03.2013) WIPOIPCT (51) International Patent Classification: HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, A61K 31/4196 (2006.01) A61K 45/06 (2006.01) KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, A61K 31/495 (2006.01) A61P 3/10 (2006.01) ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, (21) International Application Number: RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, PCT/US2012/056419 TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, (22) International Filing Date: ZM, ZW. 20 September 2012 (20.09.2012) (84) Designated States (unless otherwise indicated, for every (25) Filing Language: English kind of regional protection available)·. ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, (26) Publication Language: English UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, (30) Priority Data: TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, 61/537,411 21 September 2011 (21.09.2011) US EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, ΓΓ, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, (71) Applicant: GIUEAD SCIENCES, INC. [US/US]; 333 TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, Lakeside Drive, Foster City, California 94404 (US). ML, MR, NE, SN, TD, TG). (72) Inventors: DHALLA, Arvinder; c/o Gilead Sciences, Declarations under Rule 4.17: Inc., 333 Lakeside Drive, Foster City, California 94404 — as to the applicant's entitlement to claim the priority of the (US). BELARDINELLI, Luiz; c/o Gilead Sciences, Inc., earlier application (Rule 4.17(iii)) 333 Lakeside Drive, Foster City, California 94404 (US). Published: (74) Agents: TANNER, Lorna L. et al.; Foley & Fardner FFP, 975 Page Mill Road, Palo Alto, California 94304 (US). — with international search report (Art. 21(3)) (81) Designated States (unless otherwise indicated, for every — before the expiration of the time limit for amending the kind of national protection available)·. AE, AG, AF, AM, claims and to be republished in the event of receipt of AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, amendments (Rule 48.2(h)) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (54) Title: SODIUM CHANNEL BLOCKERS REDUCE GLUCAGON SECRETION σι B c 100η * * * Vehicle c Ranolazine 're Compound A Sitagliptin w re c ω o σι re re o ω 3 ω o ω ο. lllllllllllllllllllllllllllllllllllllllllllllllllllllllllffl c "5 ω c A l ι Insulin Glucagon FIG. 14 (57) Abstract: It is discovered that sodium-channel blockers inhibit the secretion of glucagon from pancreatic alpha cells. The present disclosure, based on such discoveries, provides compositions and methods for the treatment of hyperglycemia and related 2013/043925 diseases and conditions with Na-channel blockers. w o WO 2013/043925 PCT/US2012/056419 SODIUM CHANNEL BLOCKERS REDUCE GLUCAGON SECRETION CROSS REFERENCE TO RELATED APPFICATIONS [0001] This application claims the benefit under 35 U.S. C. § 119(e) of United States Provisional Applications Serial Number 61/537,411 filed September 21, 2011, the content of 5 which is incorporated by reference in its entirety into the present disclosure. FIELD [0002] Methods are provided for treating diabetes, lowering plasma levels of glucose and HbAlc and delaying onset of diabetic complications in a diabetic or pre-diabetic patient. BACKGROUND 10 [0003] Diabetes mellitus is a disease characterized by hyperglycemia; altered metabolism of lipids, carbohydrates and proteins; and an increased risk of complications from vascular disease. Diabetes is an increasing public health problem, as it is associated with both increasing age and obesity. [0004] There are two major types of diabetes mellitus: 1) Type I, also known as insulin 15 dependent diabetes (T1DM), and 2) Type II, also known as insulin independent or non-insulin dependent diabetes (T2DM or NIDDM). T1DM is due to insufficient amounts of circulating insulin whereas type 2 diabetes is due to a decrease in the response of peripheral tissue to insulin. Ultimately, insulin deficiency is present in both types of diabetes. [0005] T1DM results from the body’s failure to produce insulin, the hormone that 20 “unlocks” the cells of the body, allowing glucose to enter and fuel them. The complications of TIDM include heart disease and stroke; retinopathy (eye disease); kidney disease (nephropathy); neuropathy (nerve damage); as well as maintenance of good skin, foot and oral health. [0006] T2DM results from the body’s inability to either produce enough insulin or the 25 cell’s inability to use the insulin that is naturally produced by the body. The condition where the body is not able to optimally use insulin is called insulin resistance. In patients with T2DM, stress, infection, and medications (such as corticosteroids) can also lead to severely elevated blood sugar levels. Accompanied by dehydration, severe blood sugar elevation in -1- WO 2013/043925 PCT/US2012/056419 patients with T2DM can lead to an increase in blood osmolality (hyperosmolar state). This condition can lead to coma. [0007] Insulin lowers the concentration of glucose in the blood by stimulating the uptake and metabolism of glucose by muscle and adipose tissue. Insulin stimulates the storage of 5 glucose in the liver as glycogen, and in adipose tissue as triglycerides. Insulin also promotes the utilization of glucose in muscle for energy. Thus, insufficient insulin levels in the blood, or decreased sensitivity to insulin, gives rise to excessively high levels of glucose in the blood. [0008] The toxic effects of excess plasma levels of glucose include the glycosylation of 10 other proteins. Glycosylated products accumulate in tissues and may eventually form cross-linked proteins, which cross-linked proteins are termed advanced glycosylation end products. It is possible that non-enzymatic glycosylation is directly responsible for expansion of the vascular matrix and vascular complications of diabetes. For example, glycosylation of collagen results in excessive cross-linking, resulting in atherosclerotic vessels. Also, the 15 uptake of glycosylated proteins by macrophages stimulates the secretion of pro-inflammatory cytokines by these cells. The cytokines activate or induce degradative and proliferative cascades in mesenchymal and endothelial cells respectively. [0009] The glycation of hemoglobin provides a convenient method to determine an integrated and long-term index of the glycemic state. The level of glycosylated proteins 20 reflects the level of glucose over a period of time and is the basis of an assay referred to as the hemoglobin Ale (HbAlc) assay. [0010] Thus, controlling blood glucose levels is a desirable therapeutic goal. A number of oral antihyperglycemic agents are known. Medications that increase the insulin output by the pancreas include sulfonylureas (including chlorpropamide (Orinase®), tolbutamide 25 (Tolinase®), glyburide (Micronase®), glipizide (Glucotrol®), and glimepiride (Amaryl®)) and meglitinides (including reparglinide (Prandin®) and nateglinide (Starlix®)). Medications that decrease the amount of glucose produced by the liver include biguanides (including metformin (Glucophage®). Medications that increase the sensitivity of cells to insulin include thazolidinediones (including troglitazone (Resulin®), pioglitazone (Actos®) 30 and rosiglitazone (Avandia®)). Medications that decrease the absorption of carbohydrates from the intestine include alpha glucosidase inhibitors (including acarbose (Precose®) and -2- WO 2013/043925 PCT/US2012/056419 miglitol (Glyset®)). Actos® and Avandia® can change the cholesterol patterns in diabetics. Precose® works on the intestine; its effects are additive to diabetic medications that work at other sites, such as sulfonylureas. ACE inhibitors can be used to control high blood pressure, treat heart failure, and prevent kidney damage in people with hypertension or diabetes. ACE 5 inhibitors or combination products of an ACE inhibitor and a diuretic, such as hydrochlorothazide, are marketed. However, a need still remains for more effective, safer treatments. SUMMARY [0011] It has been discovered that α-cells of certain diabetic mice have increased glucagon 10 content, express larger Na+ current and have increased action potential duration, amplitude and firing frequency as compared to cells from normal mice. These conditions sensitize the cells for increased glucagon secretion. This data suggests that inhibition of abnormal glucagon secretion from α-cells can provide a novel and first-in-class mechanism for the treatment of hyperglycemia and related diseases and conditions, such as diabetes. 15 [0012] The present disclosure further provides data evidencing that various sodium (Na)-channel blockers inhibited the secretion of glucagon from pancreatic islets. Along with the above discovery, the present disclosure provides evidence that sodium-channel blockers can be used to treat hyperglycemia and related diseases and conditions. [0013] In one embodiment, the present disclosure provides a method of reducing the 20 secretion of glucagon from a pancreatic alpha cell, comprising contacting the alpha cell with an agent that suppresses the influx of sodium ions through sodium channels. [0014] In another embodiment the present disclosure provides a method of reducing
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