Methods of medical treatment with sur1-TRPM4 channel inhibitors

Abstract

To provide medical treatment methods with SUR1-TRPM4 channel inhibitors.SOLUTION: Disclosed is a method for treating or preventing adverse outcomes associated with tissue plasminogen activator (tPA) administration, cerebral edema-related side effects, cerebral edema associated with radiation therapy, or migraine headaches, comprising administration of an effective amount of a SUR1-TRPM4 channel inhibitor, such as glyburide, and optionally co-administration of a second therapeutically active agent, to a subject in need thereof. Adverse outcomes associated with tPA administration include cerebral hemorrhage, cerebral edema, physical impairment or death. The SUR1-TRPM4 channel inhibitor is administered prior to the radiation therapy, during the radiation therapy, after the radiation therapy, or combinations thereof. The SUR1-TRPM4 channel inhibitor is administered prior to surgical excision of a brain tumor, CAR-T therapy, or flutarabine administration.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. 35(e) of the filing dates of Provisional Patent Application Serial No. 62 / 368,386, filed July 29, 2016, Provisional Patent Application Serial No. 62 / 368,411, filed July 29, 2016, Provisional Patent Application Serial No. 62 / 368,422, filed July 29, 2016, and Provisional Patent Application Serial No. 62 / 368,436, filed July 29, 2016, the disclosures of which are incorporated herein by reference in their entireties.

[0002] The present invention relates to the field of medical treatment methods, including methods for intravenous administration of drugs to a subject. [Background technology]

[0003] There is a need in the art for new methods of treating or preventing one or more adverse outcomes associated with tissue plasminogen activator (tPA) administration.

[0004] There is a need in the art for new methods of treating or preventing cerebral edema associated with radiation therapy.

[0005] There is a need in the art for new methods of treating or preventing migraines.

[0006] There is a need in the art for new methods of treating or preventing one or more cerebral edema-related side effects associated with patient treatment. Summary of the Invention

[0007] The present disclosure relates to methods of treating or preventing one or more adverse outcomes associated with tissue plasminogen activator (tPA), such as cerebral hemorrhage, cerebral edema, disability, death, or related outcomes. The methods include treating or preventing the adverse outcomes when tPA is administered within an established treatment window of 4.5 hours from stroke onset, and administering at least one SUR1-TRPM4 channel inhibitor.

[0008] In some embodiments, the administration of an effective amount of a SUR1-TRPM4 channel inhibitor, such as glyburide, in a subject in need of tPA administration is performed before administration of tPA. In some other embodiments, the administration of a SUR1-TRPM4 channel inhibitor is performed during administration of tPA. In some other embodiments, the administration of a SUR1-TRPM4 channel inhibitor is performed following administration of tPA. In further embodiments, the administration of a SUR1-TRPM4 channel inhibitor can be performed at any time before, during, or following administration of tPA, or any combination thereof.

[0009] The present disclosure relates to novel methods of treating or preventing one or more cerebral edema-related side effects associated with treatment of a patient, the methods comprising administering to a patient exhibiting or at risk for cerebral edema-related side effects an effective amount of a SUR1-TRPM4 channel inhibitor.

[0010] In some embodiments, the administration of an effective amount of a SUR1-TRPM4 channel inhibitor, such as glyburide, in a subject who requires or is undergoing a treatment that is prone to cerebral edema-related side effects is performed before the start of the treatment. In some other embodiments, the administration of a SUR1-TRPM4 channel inhibitor is performed after the start of a treatment that is prone to cerebral edema-related side effects. In other embodiments, the SUR1-TRPM4 channel inhibitor is administered before or after the occurrence of cerebral edema-related side effects. In further embodiments, the administration of a SUR1-TRPM4 channel inhibitor can be performed at any time, either before, during, or following the start of the treatment or the occurrence of cerebral edema-related side effects.

[0011] The present disclosure relates to a method of treating or preventing migraine in a patient in need of such treatment, the method involving administration of at least one SUR1-TRPM4 channel inhibitor in an amount effective to reduce migraine symptoms in the subject.

[0012] In some embodiments, an effective amount of a SUR1-TRPM4 channel inhibitor, such as glyburide, is administered before the onset of a migraine headache. In some other embodiments, administration of a SUR1-TRPM4 channel inhibitor is administered after the onset of a migraine headache. In further embodiments, administration of a SUR1-TRPM4 channel inhibitor can be administered at any time before, during, or following the onset of a migraine headache, or any combination thereof. In embodiments, a second therapeutically active agent is co-administered with the SUR1-TRPM4 channel inhibitor. In any embodiment, administration can last from about 1 hour to about 96 hours or longer.

[0013] The present disclosure relates to a method for treating or preventing cerebral edema in a subject undergoing radiation therapy, the method comprising administering an effective amount of a SUR1-TRPM4 channel inhibitor to a patient undergoing or likely to undergo radiation therapy in or around the brain.

[0014] In some embodiments, the administration of an effective amount of a SUR1-TRPM4 channel inhibitor, such as glyburide, in a subject who requires or is undergoing radiation therapy is performed before the start of therapy. In some other embodiments, the administration of a SUR1-TRPM4 channel inhibitor is performed during radiation therapy. In some other embodiments, the administration of a SUR1-TRPM4 channel inhibitor is performed after the start of radiation therapy. In other embodiments, the administration of a SUR1-TRPM4 channel inhibitor is performed before or after the onset of brain edema associated with radiation therapy. In further embodiments, the administration of a SUR1-TRPM4 channel inhibitor can be performed at any time before, during, or following the start of radiation therapy or the onset of brain edema. In certain embodiments, for example, the following are provided: (Item 1) A method for treating or preventing one or more adverse outcomes associated with administration of tissue plasminogen activator (tPA), comprising administering to a subject in need of tPA administration an effective amount of a SUR1-TRPM4 channel inhibitor. (Item 2) 2. The method of claim 1, wherein the SUR1-TRPM4 channel inhibitor comprises at least one of glyburide, 4-trans-hydroxy-glibenclamide, 3-cis-hydroxyglibenclamide, tolbutamide, chlorpropamide, tolazamide, repaglinide, nateglinide, meglitinide, midaglizole, tolazamide, gliquidone, LY397364, LY389382, gliclazide, glimepiride, 9-phenanthrol, flufenamic acid, riluzole, spermine, adenosine, quinine, quinidine, diphenylamine-2-carboxylic acid, 3',5'-dichlorodiphenylamine-2-carboxylic acid, 5-nitro-2-(3-phenylpropyl-amino)-benzoic acid, MPB-104, a metabolite that interacts with SUR1, or a combination thereof. (Item 3) 3. The method of any one of items 1 to 2, wherein the SUR1-TRPM4 channel inhibitor comprises glyburide. (Item 4) The method according to any one of items 1 to 3, wherein the adverse outcome comprises at least one of cerebral hemorrhage, cerebral edema, disability, or death. (Item 5) 5. The method according to any one of items 1 to 4, wherein the subject in need of tPA has an ASPECTS of 7 or less. (Item 6) 6. The method according to any one of items 1 to 5, wherein the SUR1-TRPM4 channel inhibitor is administered for about 1 hour to about 96 hours. (Item 7) 7. The method according to any one of items 1 to 6, wherein at least a portion of the SUR1-TRPM4 channel inhibitor is administered prior to administration of tPA. (Item 8) 8. The method according to any one of items 1 to 7, wherein at least a portion of the SUR1-TRPM4 channel inhibitor is administered simultaneously with administration of tPA. (Item 9) 9. The method according to any one of items 1 to 8, wherein at least a portion of the SUR1-TRPM4 channel inhibitor is administered following administration of tPA. (Item 10) 10. The method of any one of items 1 to 9, wherein the SUR1-TRPM4 channel inhibitor is administered via one or more continuous infusions. (Item 11) 11. The method of any one of items 1 to 10, wherein the SUR1-TRPM4 channel inhibitor is administered via injection. (Item 12) 12. The method according to any one of items 1 to 11, wherein the SUR1-TRPM4 channel inhibitor is administered via a transdermal patch or a transdermal gel. (Item 13) 13. The method according to any one of items 1 to 12, wherein the SUR1-TRPM4 channel inhibitor is administered orally. (Item 14) 14. The method according to any one of items 1 to 13, wherein the amount of the SUR1-TRPM4 channel inhibitor is from about 0.05 mg / day to about 3.0 mg / day. (Item 15) 15. The method of any one of items 1 to 14, wherein the administration of the SUR1-TRPM4 channel inhibitor achieves a plasma concentration of the SUR1-TRPM4 channel inhibitor of about 0.4 ng / mL to about 5 ng / mL. (Item 16) 16. The method of any one of items 1 to 15, wherein the administration of the SUR1-TRPM4 channel inhibitor achieves a steady-state SUR1-TRPM4 channel inhibitor concentration of about 3.0 ng / mL to about 30.0 ng / mL. (Item 17) The administration of the SUR1-TRPM4 channel inhibitor comprises administering a C of the SUR1-TRPM4 channel inhibitor of about 1 ng / mL to about 30 ng / mL. max The method according to any one of items 1 to 16, which achieves the above. (Item 18) 13. A method for treating or preventing side effects associated with treatment-induced cerebral edema in a patient, comprising administering to the patient an effective amount of a SUR1-TRPM4 channel inhibitor. (Item 19) 19. The method of item 18, wherein the SUR1-TRPM4 channel inhibitor comprises at least one of glyburide, 4-trans-hydroxy-glibenclamide, 3-cis-hydroxyglibenclamide, tolbutamide, chlorpropamide, tolazamide, repaglinide, nateglinide, meglitinide, midaglizole, tolazamide, gliquidone, LY397364, LY389382, gliclazide, glimepiride, 9-phenanthrol, flufenamic acid, riluzole, spermine, adenosine, quinine, quinidine, diphenylamine-2-carboxylic acid, 3',5'-dichlorodiphenylamine-2-carboxylic acid, 5-nitro-2-(3-phenylpropyl-amino)-benzoic acid, MPB-104, a metabolite that interacts with SUR1, or a combination thereof. (Item 20) 20. The method of any one of items 18 to 19, wherein the SUR1-TRPM4 channel inhibitor comprises glyburide. (Item 21) 21. The method of any one of items 18 to 20, wherein the treatment is at least one course of CAR-T therapy, surgical resection of a brain tumor, or a combination thereof. (Item 22) 22. The method according to any one of items 18 to 21, wherein the treatment is administration of a therapeutic agent comprising flutarabine. (Item 23) 23. The method according to any one of items 18 to 22, wherein at least a portion of the SUR1-TRPM4 channel inhibitor is administered prior to the onset of side effects associated with cerebral edema. (Item 24) 24. The method of any one of items 18 to 23, wherein at least a portion of the SUR1-TRPM4 channel inhibitor is administered following the onset of side effects associated with cerebral edema. (Item 25) 25. The method according to any one of items 18 to 24, wherein the SUR1-TRPM4 channel inhibitor is administered for about 1 hour to about 96 hours. (Item 26) 26. The method of any one of items 18 to 25, wherein the SUR1-TRPM4 channel inhibitor is administered via one or more continuous infusions. (Item 27) 27. The method according to any one of items 18 to 26, wherein the SUR1-TRPM4 channel inhibitor is administered via a transdermal patch or a transdermal gel. (Item 28) 28. The method of any one of items 18 to 27, wherein the SUR1-TRPM4 channel inhibitor is administered via injection. (Item 29) 29. The method according to any one of items 18 to 28, wherein the SUR1-TRPM4 channel inhibitor is administered orally. (Item 30) 30. The method according to any one of items 18 to 29, wherein the amount of the SUR1-TRPM4 channel inhibitor is from about 0.05 mg / day to about 3.0 mg / day. (Item 31) 31. The method of any one of items 18 to 30, wherein the administration of the SUR1-TRPM4 channel inhibitor achieves a plasma concentration of the SUR1-TRPM4 channel inhibitor of about 0.4 ng / mL to about 5 ng / mL. (Item 32) 32. The method of any one of items 18 to 31, wherein the administration of the SUR1-TRPM4 channel inhibitor achieves a steady-state SUR1-TRPM4 channel inhibitor concentration of about 3.0 ng / mL to about 30.0 ng / mL. (Item 33) The administration of the SUR1-TRPM4 channel inhibitor comprises administering a C of the SUR1-TRPM4 channel inhibitor of about 1 ng / mL to about 30 ng / mL. max The method according to any one of items 18 to 32, which achieves the above. (Item 34) 35. A method for treating or preventing cerebral edema associated with radiation therapy, comprising administering an effective amount of a SUR1-TRPM4 channel inhibitor to a patient undergoing radiation therapy. 35. The method of claim 34, wherein the SUR1-TRPM4 channel inhibitor comprises at least one of glyburide, 4-trans-hydroxy-glibenclamide, 3-cis-hydroxyglibenclamide, tolbutamide, chlorpropamide, tolazamide, repaglinide, nateglinide, meglitinide, midaglizole, tolazamide, gliquidone, LY397364, LY389382, gliclazide, glimepiride, 9-phenanthrol, flufenamic acid, riluzole, spermine, adenosine, quinine, quinidine, diphenylamine-2-carboxylic acid, 3',5'-dichlorodiphenylamine-2-carboxylic acid, 5-nitro-2-(3-phenylpropyl-amino)-benzoic acid, MPB-104, a metabolite that interacts with SUR1, or a combination thereof. (Item 36) 36. The method of any one of items 34 to 35, wherein the SUR1-TRPM4 channel inhibitor comprises glyburide. (Item 37) 37. The method according to any one of items 34 to 36, wherein the radiotherapy is gamma irradiation of a brain tumor. (Item 38) The method according to any one of items 34 to 37, wherein the radiation therapy comprises at least one of a cyberknife or a gamma knife. (Item 39) 39. The method according to any one of items 34 to 38, wherein the SUR1-TRPM4 channel inhibitor is administered for about 1 hour to about 96 hours. (Item 40) 40. The method of any one of items 34 to 39, wherein at least a portion of the SUR1-TRPM4 channel inhibitor is administered prior to the radiation therapy. (Item 41) 41. The method according to any one of items 34 to 40, wherein at least a portion of the SUR1-TRPM4 channel inhibitor is administered during the radiation therapy. (Item 42) 42. The method of any one of items 34 to 41, wherein at least a portion of the SUR1-TRPM4 channel inhibitor is administered after the radiation therapy. (Item 43) 43. The method of any one of items 34 to 42, wherein the SUR1-TRPM4 channel inhibitor is administered via one or more continuous infusions. (Item 44) 44. The method according to any one of items 34 to 43, wherein the SUR1-TRPM4 channel inhibitor is administered via a transdermal patch or a transdermal gel. (Item 45) 45. The method of any one of items 34 to 44, wherein the SUR1-TRPM4 channel inhibitor is administered via injection. (Item 46) 46. ​​The method according to any one of items 34 to 45, wherein the SUR1-TRPM4 channel inhibitor is administered orally. (Item 47) 47. The method according to any one of items 34 to 46, wherein the amount of the SUR1-TRPM4 channel inhibitor is from about 0.05 mg / day to about 3.0 mg / day. (Item 48) 48. The method of any one of items 34 to 47, wherein the administration of the SUR1-TRPM4 channel inhibitor achieves a plasma concentration of the SUR1-TRPM4 channel inhibitor of about 0.4 ng / mL to about 5 ng / mL. (Item 49) 49. The method of any one of items 34 to 48, wherein the administration of the SUR1-TRPM4 channel inhibitor achieves a steady-state SUR1-TRPM4 channel inhibitor concentration of about 3.0 ng / mL to about 30.0 ng / mL. (Item 50) The administration of the SUR1-TRPM4 channel inhibitor comprises administering a C of the SUR1-TRPM4 channel inhibitor of about 1 ng / mL to about 30 ng / mL. max The method according to any one of items 34 to 49, which achieves the above. (Item 51) The method of any one of claims 34 to 50, wherein at least a first portion of the SUR1-TRPM4 channel inhibitor is administered via one or more continuous infusions prior to the radiation therapy, and at least a second portion of the SUR1-TRPM4 channel inhibitor is administered via a transdermal patch or orally after the radiation therapy. (Item 52) 13. A method for treating or preventing migraine in a patient in need of treatment, comprising administering to the patient an effective amount of a SUR1-TRPM4 channel inhibitor. (Item 53) 53. The method of claim 52, wherein the SUR1-TRPM4 channel inhibitor comprises at least one of glyburide, 4-trans-hydroxy-glibenclamide, 3-cis-hydroxyglibenclamide, tolbutamide, chlorpropamide, tolazamide, repaglinide, nateglinide, meglitinide, midaglizole, tolazamide, gliquidone, LY397364, LY389382, gliclazide, glimepiride, 9-phenanthrol, flufenamic acid, riluzole, spermine, adenosine, quinine, quinidine, diphenylamine-2-carboxylic acid, 3',5'-dichlorodiphenylamine-2-carboxylic acid, 5-nitro-2-(3-phenylpropyl-amino)-benzoic acid, MPB-104, a metabolite that interacts with SUR1, or a combination thereof. (Item 54) 54. The method of any one of items 52 to 53, wherein the SUR1-TRPM4 channel inhibitor comprises glyburide. (Item 55) 55. The method of any one of items 52 to 54, wherein the SUR1-TRPM4 channel inhibitor is administered for about 1 hour to about 96 hours. (Item 56) 56. The method of any one of items 52 to 55, wherein at least a portion of the SUR1-TRPM4 channel inhibitor is administered subsequent to the onset of the migraine headache. (Item 57) 57. The method of any one of items 52 to 56, wherein at least a portion of the SUR1-TRPM4 channel inhibitor is administered prior to the onset of the migraine headache. (Item 58) 58. The method of any one of items 52-57, further comprising administering a second therapeutically effective agent. (Item 59) 59. The method of claim 58, wherein the second therapeutically active agent comprises at least one of an analgesic, a triptan, a glucocorticoid, an antidepressant, an anti-seizure drug, Botox, or a combination thereof. (Item 60) 60. The method of any one of items 58-59, wherein at least a portion of the SUR1-TRPM4 channel inhibitor and at least a portion of the second therapeutically effective agent are administered prior to the onset of the migraine headache. (Item 61) 61. The method of any one of items 58 to 60, wherein at least a portion of the SUR1-TRPM4 channel inhibitor and at least a portion of the second therapeutically effective agent are administered subsequent to the onset of the migraine headache. (Item 62) 62. The method of any one of items 58-61, wherein the SUR1-TRPM4 channel inhibitor and the second therapeutically effective agent are administered in a ratio of about 75:25 to about 25:75. (Item 63) 63. The method of any one of items 52 to 62, wherein the SUR1-TPRM4 channel inhibitor is administered via one or more continuous infusions. (Item 64) 64. The method of any one of items 52 to 63, wherein the SUR1-TRPM4 channel inhibitor is administered via injection. (Item 65) 65. The method of any one of items 52 to 64, wherein the SUR1-TRPM4 channel inhibitor is administered via a transdermal patch. (Item 66) 66. The method of any one of items 52 to 65, wherein the SUR1-TRPM4 channel inhibitor is administered orally or nasally. (Item 67) 67. The method of any one of items 52 to 66, wherein the amount of the SUR1-TRPM4 channel inhibitor is about 0.05 mg / day to about 3.0 mg / day. (Item 68) 68. The method of any one of items 52 to 67, wherein the administration of the SUR1-TRPM4 channel inhibitor achieves a plasma concentration of the SUR1-TRPM4 channel inhibitor of about 0.4 ng / mL to about 5 ng / mL. (Item 69) 69. The method of any one of items 52 to 68, wherein the administration of the SUR1-TRPM4 channel inhibitor achieves a steady-state SUR1-TRPM4 channel inhibitor concentration of about 3.0 ng / mL to about 30.0 ng / mL. (Item 70) The administration of the SUR1-TRPM4 channel inhibitor comprises administering a C of the SUR1-TRPM4 channel inhibitor of about 1 ng / mL to about 30 ng / mL. max The method according to any one of items 52 to 69, which achieves the above. (Item 71) 71. The method according to any one of items 52 to 70, wherein the migraine is chronic, subchronic, or acute migraine, or a combination thereof. (Item 72) 72. The method of claim 71, wherein the migraine is a menstrual migraine and at least a portion of the SUR1-TPRM4 channel inhibitor is administered at the end of the follicular phase or the beginning of the ovulatory phase of the patient's menstrual cycle. (Item 73) 73. A pharmaceutical composition comprising an effective amount of a SUR1-TRPM4 channel inhibitor for use in the method according to any one of items 1 to 72. (Item 74) 73. Use of a pharmaceutical composition comprising an effective amount of a SUR1-TRPM4 channel inhibitor in the method according to any one of items 1 to 72.

[0015] Reference will now be made to the illustrated exemplary embodiments, and specific language will be used herein to describe the same, it being understood nevertheless that these drawings merely depict exemplary embodiments and therefore should not be considered limiting of the scope thereof. [Brief description of the drawings]

[0016] [Figure 1] 1 shows the mean plasma glyburide concentration time profiles following a bolus injection and a 72-hour intravenous infusion of glyburide at two dose levels. Data are presented on a linear scale with plasma glyburide concentration in ng / mL on the ordinate and duration in hours on the abscissa. [Diagram 2] 1 shows the mean plasma glyburide concentration time profiles from the same study shown in Figure 1. Data are presented on a semi-log scale with plasma glyburide concentration in ng / mL on the vertical logarithmic axis and duration in hours on the horizontal axis. [Diagram 3] Bar graphs comparing outcomes in the four study groups are shown. Each group received a glyburide-containing drug (Cirara), a placebo, tPA, or a combination of any two. In accordance with current clinical practice guidelines, tPA was administered within 4.5 hours after stroke onset. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] Before specific embodiments of the present invention are disclosed and described, it should be understood that the present invention is not limited to the specific processes and materials disclosed herein, which may vary to some extent. It should also be understood that the terms used herein are used to describe specific embodiments only, and are not intended to be limiting, since the scope of the present invention is defined only by the appended claims and their equivalents. It should further be understood that the embodiments disclosed in the following subsections can be combined with other embodiments from the same or other subsections without limitation.

[0018] SUR1-TRPM4 channel inhibitors The SUR1-TRPM4 channel is a NC CA-ATP Also known as channels, they are ion channels found in the cell membranes of neurons, astrocytes, and other cells in mammals. Ion channels help maintain ion gradients between cells and the extracellular fluid, and are associated with ion and associated fluid flow between the intercellular and extracellular spaces. Ion channels consist of subparts including sulfonylurea receptor 1 (SUR1) and transient receptor potential cation channel subfamily M member 4 (TRPM4).

[0019] SUR1-TRPM4 channel inhibitors are compounds that selectively bind to the SUR1 and / or TRPM4 subparts of the SUR1-TRPM4 channel. When a SUR1-TRPM4 channel inhibitor binds to either part of the ion channel, the ion channel is effectively blocked or "turned off," causing fewer or no ions to enter or leave the cell through the ion channel. Fluid flow into or out of the cell is reduced or stopped due to stabilization of the ion gradient.

[0020] SUR1-TRPM4 channel inhibitors include glyburide, 4-trans-hydroxy-glibenclamide, 3-cis-hydroxyglibenclamide, tolbutamide, chlorpropamide, tolazamide, repaglinide, nateglinide, meglitinide, midaglizole, tolazamide, gliquidone, LY397364, LY389382, gliclazide, glimepiride, 9-phenanthrol, flufenamic acid, riluzole, spermine, adenosine, quinine, quinidine, diphenylamine-2-carboxylic acid, 3',5'-dichlorodiphenylamine-2-carboxylic acid, 5-nitro-2-(3-phenylpropyl-amino)-benzoic acid, 5-butyl-7-chloro-6-hydroxybenzo[c]-quinolizinium chloride (MPB-104), a metabolite that interacts with SUR1, or a combination thereof. As used herein, any reference to SUR1-TRPM4 channel inhibitor or "channel inhibitor" should be understood as referring to one or more of the compounds in the preceding list.Furthermore, as used herein, glyburide is generally referred to as a model SUR1-TRPM4 channel inhibitor.The reference to glyburide in a specific embodiment or example is not intended to limit the scope of the present invention, but is illustrative of all SUR1-TRPM4 channel inhibitors.

[0021] Preparation of SUR1-TRPM4 channel inhibitors SUR1-TRPM4 channel inhibitors can be administered in the form of bulk active chemicals, or preferably as pharmaceutical compositions or formulations for efficient and effective administration. Depending on the route of administration and the desired dosage level, the preparation of SUR1-TRPM4 channel inhibitors can vary for each embodiment.

[0022] For example, SUR1-TRPM4 channel inhibitors can be prepared in lyophilized form as taught in U.S. Patent No. 8,858,997, the entire contents of which are incorporated herein by reference. Channel inhibitors can also be prepared as powder compositions, for example, as disclosed in U.S. Patent No. 8,277,845, the entire contents of which are incorporated herein by reference.

[0023] In some embodiments, the channel inhibitor is prepared in a substantially liquid form suitable for intravenous injection or infusion.For example, the SUR1-TRPM4 channel inhibitor can be included in an intravenous infusion solution that includes sugars, amino acids, electrolytes, or other simple chemicals suitable for injection, suspended in water, Ringer's solution, USP, or isotonic sodium chloride, as taught in US patent application Ser. No. 13 / 779,511, the entire contents of which are incorporated herein by reference.In such an embodiment, the channel inhibitor can be suspended with or without a pharma- ceutically acceptable carrier.

[0024] For oral administration, SUR1-TRPM4 channel inhibitor can be prepared as liquid or solid.For example, liquid form for oral administration can include pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup and elixir, as taught in US patent application Ser. No. 13 / 779,511, the entire contents of which are incorporated herein by reference.In addition, solid form for oral administration can be prepared as tablet, capsule, gel capsule or other known oral delivery system.

[0025] In some embodiments, the channel inhibitor can be prepared as a composition that contains at least one other therapeutically active or inactive compound.For example, the composition that contains the SUR1-TRPM4 channel inhibitor and the substance that is effective for maintaining blood pressure and blood glucose level in an acceptable range can be formulated as taught in US patent application Ser. No. 13 / 779,511, the entire contents of which are incorporated herein by reference.

[0026] In some embodiments, the channel inhibitor can be co-administered with a second therapeutically active agent. For example, a therapeutic agent for treating the side effects of migraine headaches, such as analgesics, triptans, glucocorticoids, antidepressants, anticonvulsants, Botox, combinations thereof, or similar drugs, can be co-administered with the SUR1-TRPM4 channel inhibitor. Co-administration can be in the form of a single compound that contains both the SUR1-TRPM4 channel inhibitor and the second therapeutically active agent, or as two compounds, one containing the SUR1-TRPM4 channel inhibitor and one containing the second therapeutically active agent. In either case, the compound can be prepared in any form, including liquid, emulsion, powder, lyophilized, tablet, combinations thereof, and others disclosed herein.

[0027] In some embodiments, the ratio of the SUR1-TRPM4 channel inhibitor to the second therapeutically active agent is about 75:25. In other embodiments, the ratio of the SUR1-TRPM4 channel inhibitor to the second therapeutically active agent is about 25:75. Thus, it is contemplated that the ratio of the SUR1-TRPM4 channel inhibitor:second therapeutically active agent is about 80:20, or 75:25, or 70:30, or 60:40, or 50:50, or 40:60, or 40:70, or 25:75, or 20:80, or any range between these values. Of course, when the SUR1-TRPM4 channel inhibitor is administered alone, the ratio of the SUR1-TRPM4 channel inhibitor to the second therapeutically active agent is substantially 100:0.

[0028] Tissue plasminogen activator Tissue Plasminogen Activator (tPA) is a type of powerful thrombolytic drug. It has become the "gold standard" in the treatment of stroke and has been shown to be effective in improving the chances of survival for patients suffering from stroke. See, Tissue Plasminogen Activator for Acute Ischemic Stroke, 333 NEW ENG. J. Cardiovascular, 2011, 141: 1111-1115, the entire contents of which are incorporated herein by reference. See MED.1581-88 (Dec.4,1995). There are several adverse outcomes associated with administration of tPA. When blood flow to an area of ​​the brain becomes minimal and is restored by administration of tPA, the area of ​​the brain that was deprived of blood is at risk for cerebral hemorrhage or cerebral edema. Restoration of blood flow can lead to temporary or permanent disability or death.

[0029] Administration of SUR1-TRPM4 channel inhibitors is effective in preventing or treating adverse outcomes associated with tPA. For any route of administration and any duration of administration, glyburide or other such drugs can be administered before, simultaneously with, or after administration of tPA or their combination. Glyburide administration can also be administered before or after the occurrence of side effects associated with tPA.

[0030] Large hemispheric infarction (LHI) is an ischemic stroke affecting the entire or subtotal territory of the middle cerebral artery (MCA) with or without the involvement of adjacent vascular territories such as the anterior cerebral artery (ACA) or posterior cerebral artery (PCA). Patients with LHI also have the potential to suffer from cerebral edema. LHI is often complicated by edema, which can ultimately lead to transtentorial herniation and death. For example, swelling resulting from LHI compresses capillary beds and impairs arterial inflow to surrounding tissues, causing further ischemic injury and infarct expansion, and often resulting in brain herniation and death.

[0031] Current clinical guidelines recommend administering tPA within 4.5 hours of stroke onset. Jauch et al., 2002, the entire contents of which are incorporated herein by reference. al.,Guidelines for the Early Management of Patients With Acute Ischemic Stroke:A Guideline for Healthcare Professionals See From the American Heart Association / American Stroke Association, 44 Stroke 870-947 (2013). Longer treatment window times are confounded by the risk of hemorrhagic transformation. Administration of tPA is used to return blood flow to the affected area in an attempt to reduce infarction, but tPA exacerbates edema in LHI as blood flow returns to the area and the brain expands further. Administration of SUR1-TRPM4 channel inhibitors before and / or during and / or after tPA administration to patients with LHI can prevent further cerebral edema as blood flow returns to the area and / or reduce cerebral edema present in LHI patients. For example, LHI patients who are excluded from mechanical thrombectomy due to large lesion size are likely to benefit from edema-reducing medications such as SUR1-TRPM4 channel inhibitors. Consistently, current clinical guidelines recommend exclusion of infarcts involving more than one-third of the middle cerebral artery territory.

[0032] Preferably, a SUR1-TRPM4 channel inhibitor (e.g., glyburide) is administered before, during, and / or after tPA administration to patients with a lesion volume between 80 and 300 ml as measured by magnetic resonance imaging, diffusion weighted imaging, or CT perfusion, or an Alberta Stroke Program Early CT Score (ASPECTS) of 7 or less, or 6 or less, or 5 or less, or 4 or less, or 3 or less. ASPECTS measurements are performed according to standard procedures, e.g., Powers et al., American Heart Association / American Stroke Association Focused Update of the 2013 Guidelines for the Early Management of Cardiac Myocardial Infarction (AME)-related Myocardial Infarction (MMI ... of Patients With Acute Ischemic Stroke Regarding Endovascular Treatment:A Guideline for Healthcare Professionals From the American Heart Association / American Stroke Association, Stroke46(10):3020-3035(2015);Schroeder et al.,STIR and VISTA Imaging Investigators, Validity of acute Stroke lesion volume estimation by diffusion-weighted imaging-Alberta Stroke Program Early Computed Tomographic Score depends on lesion location in 496 patients with middle cerebral artery stroke, Stroke. 45(12):3583-3588(2014), the entire contents of which are incorporated herein by reference in their entirety.

[0033] Administration of tPA is typically by intravenous infusion, although tPA may be administered by any mode, including, but not limited to, injection, oral, or subcutaneous administration. Examples of tPA include activase, tenectoprase, euryokinase, streptokinase, and desmoteplase.

[0034] SUR1-TRPM4 administration The manner and duration of administration of the SUR1-TRPM4 channel inhibitor may vary. Regardless of the route of administration, embodiments may be administered for a period of about 5 to about 96 hours or more. For example, the duration of administration may be about 1 to 5 hours, about 5 to 10 hours, about 10 to 15 hours, about 15 to 20 hours, about 20 to 25 hours, about 25 to 30 hours, about 30 to 35 hours, about 35 to 40 hours, about 40 to 45 hours, about 45 to 50 hours, about 50 to 55 hours, about 55 to 60 hours, about 60 to 65 hours, about 65 to 70 hours, about 70 to 75 hours, about 75 to 80 hours, about 80 to 85 hours, about 85 to 90 hours, or about 90 to 96 hours. In other embodiments, administration of the SUR1-TRPM4 channel inhibitor extends for a period of more than about 5 hours, or more than about 10 hours, or more than about 20 hours, or more than about 30 hours, or more than about 40 hours, or more than about 50 hours, or more than about 60 hours, or more than about 70 hours, or more than about 80 hours, or more than about 90 hours. In further embodiments, administration of the SUR1-TRPM4 inhibitor continues for about 5 hours to about 90 hours, about 15 hours to about 80 hours, about 25 hours to about 70 hours, about 35 hours to about 60 hours, or about 45 to 50 hours.

[0035] In other embodiments, administration may be for an extended period of time, such as about 1 day, or about 2 days, or about 3 days, or about 4 days, or about 5 days or more. For patients with chronic conditions, administration may continue for several days, or for a week, or for 2 weeks, or for 3 weeks or more, or even longer, until symptoms abate.

[0036] In further embodiments, administration of SUR1-TRPM4 may occur about 6 hours or less prior to administration of tPA. As such, embodiments may begin administration about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, or about 1 hour or less prior to administration of tPA. Such embodiments may administer the SUR1-TRPM4 channel inhibitor intermittently during the above-mentioned time periods, or continuously during the above-mentioned time periods.

[0037] At any given administration period, administration may be continuous or as a series of separate administrations and may also involve more than one SUR1-TRPM4 channel inhibitor and / or more than one route of administration.

[0038] In some embodiments, the SUR1-TRPM4 channel inhibitor is administered by one or more continuous infusions. The continuous infusion is an intravenous administration that can last for any of the periods listed above. In further embodiments, the administration includes at least two continuous infusions, with about one to several minutes, about one to several hours, about one to several days, or about one to several months between the multiple continuous infusions. The at least two continuous infusions can administer the same or different SUR1-TRPM4 channel inhibitors.

[0039] In some embodiments, administration of the SUR1-TRPM4 channel inhibitor is accomplished by injection. The injection is intravenous administration, which can be in the form of continuous or bolus administration. Continuous injection is one that lasts for any of the above-mentioned periods. Bolus injection refers to administration of the SUR1-TRPM4 channel inhibitor in a single injection that lasts for a relatively short period, usually about 3 minutes or less. Several bolus injections can be administered consecutively for any of the above-disclosed periods.

[0040] In a further embodiment, the administration method comprises administering a SUR1-TRPM4 channel inhibitor to a subject in a bolus injection, followed by a continuous infusion of the SUR1-TRPM4 channel inhibitor and a bolus injection of one or more additional SUR1-TRPM4 channel inhibitors. In an embodiment, the second bolus injection is administered substantially immediately after the completion of the continuous infusion. For example, the second bolus administration starts less than 1 hour, or less than 30 minutes, or less than 10 minutes, or less than 5 minutes, or less than 3 minutes, or less than 2 minutes, or less than 1 minute after the completion of the continuous infusion. The third bolus injection can start after the completion of the second continuous infusion, and can either start substantially immediately after the completion of the second continuous infusion, or can start after an extended time after the completion of the second continuous infusion. Similarly, the fourth, fifth, or other additional bolus injection and / or additional continuous infusion can be administered either substantially immediately or after an extended period of time. It is contemplated that the entire sequence of bolus injections and continuous infusions may be given entirely before or after administration of tPA, or the sequence may be split before, during, and after administration of tPA, such that one or more bolus injections and / or one or more continuous infusions are given before tPA administration, one or more bolus injections and / or one or more continuous infusions are given during tPA administration, and one or more bolus injections and / or one or more continuous infusions occur after tPA administration. The intravenous administration methods disclosed in U.S. Patent No. 9,254,259, which is incorporated herein by reference in its entirety, can be used.

[0041] In other embodiments, the SUR1-TRPM4 channel inhibitor is administered transdermally. The advantage of transdermal administration is that it can be less invasive compared to administration by infusion or injection, and can be more effective than oral route. For example, the SUR1-TRPM4 channel inhibitor can be administered using a transdermal patch as taught in Manoj K. Mishra, Microcapsules and Transdermal Patch: A Comparative Approach for Improved Delivery of Antidiabetic Drug, 10 AAPS PHARM. SCI. TECH.3, 928-34 (2009), the entire contents of which are incorporated herein by reference. Optionally, the drug can be administered using a transdermal patch as taught in Srinivas Mutalik & Nayanabhirama, Microcapsules and Transdermal Patch: A Comparative Approach for Improved Delivery of Antidiabetic Drug, 10 AAPS PHARM. SCI. TECH.3, 928-34 (2009), the entire contents of which are incorporated herein by reference. Administration may be via a transdermal gel as taught in Udupa, Pharmacological Evaluation of Membrane-Moderated Transdermal Systems of Glipizide, 33 CLINICAL & EXPERIMENTAL PHARMACOLOGY & PHYSIOLOGY, 17-26 (2006). For example, transdermal administration may be used for subjects with chronic conditions that may benefit from sustained and / or long-term administration of SUR1-TRPM4 channel inhibitors. Transdermal administration may be for any duration disclosed above. Administration via a transdermal patch or transdermal gel may be prior to, concurrent with, and / or after administration of tPA, or any combination thereof. In further embodiments, transdermal administration may be accompanied by oral administration, injection, or infusion administration, or combinations thereof, as disclosed above.

[0042] In further embodiments, the SUR1-TRPM4 channel inhibitor is orally administered. Oral administration can be via capsule, tablet, pill, powder, liquid suspension, or other commonly used oral administration forms. Oral administration can be before, during, or after administration of tPA, or any combination thereof. In further embodiments, oral administration can be combined with injection, infusion, or transdermal administration routes or combinations thereof disclosed herein.

[0043] In all embodiments, the administration of the SUR1-TRPM4 channel inhibitor may be intermittent or may be at a gradual, continuous, constant or controlled rate.Furthermore, the time of day and the number of times per hour, day, week or month that the compound is administered may vary depending on the desired dosage.

[0044] Dosage determination As used herein, the term "dose" and its grammatical derivatives and equivalents refer to the amount of SUR1-TRPM4 channel inhibitor administered to a subject. Dose can be described in terms of weight of SUR1-TRPM4 channel inhibitor administered per day, weight of SUR1-TRPM4 channel inhibitor administered per volume, or equivalent types of measurements. The term "effective amount" or "effective dose" refers to the amount of a compound (e.g., a compound of the present invention) that is sufficient to produce beneficial or desired results. An effective amount can be administered in one or more administrations, applications, or dosages, and is not intended to be limited to a particular formulation or route of administration.

[0045] It is understood that the effective amount of SUR1-TRPM4 channel inhibitor as a treatment can vary depending on several factors, including the specific subject to be administered, the route of administration, the possibility or severity of adverse outcomes, the duration or amount of tPA administration, and other procedure-specific conditions.It is also understood that dosage varies between different SUR1-TRPM4 channel antagonists.

[0046] In one embodiment of the present invention, the effective dosage level is measured in mg of SUR1-TRPM4 channel inhibitor per day and ranges from about 0.05 mg / day to about 3.0 mg / day. For example, a suitable daily dose of SUR1-TRPM4 channel inhibitor may be less than about 3.0 mg per day. For example, a suitable daily dose of glyburide may be about 2.5-3.0 mg / day, or about 2.0-2.5 mg / day, or about 1.5-2.0 mg / day, or about 1.0-1.5 mg / day, or about 0.4-1.0 mg / day, or about 0.05-0.4 mg / day. Further, a suitable daily dose may be about 0.05 mg / day, or about 0.25 mg / day, or about 0.5 mg / day, or about 1.0 mg / day, or about 1.5 mg / day, or about 2.0 mg / day, or about 2.5 mg / day, or about 3.0 mg / day. Effective doses for a given patient may also range from about 0.05 mg / day to about 3.0 mg / day, or from about 0.5 mg / day to 2.5 mg / day, or from about 1.0 mg / day to about 2.0 mg / day. Dosage levels of SUR1-TRPM4 are calculated in mg / day for illustrative purposes, but the recited ranges are intended to include similar dosage amounts calculated in any weight unit per hour, day, week, month, treatment period, or similar period.

[0047] Optionally, the dose range of the SUR1-TRPM4 channel inhibitor is an amount that results in a plasma level of about 0.4ng / mL to about 5ng / mL of SUR1-TRPM4. Suitable plasma concentrations include about 5ng / mL, or about 4.5ng / mL, or about 4ng / mL, or about 3.5ng / mL, or about 3ng / mL, or about 2.5ng / mL, or about 2ng / mL, or about 1.5ng / mL, or about 1ng / mL, or about 0.5ng / mL, or similar plasma concentrations. In some embodiments, the preferred plasma concentration of the SUR1-TRPM4 inhibitor may be about 0.4 to 1.0 ng / mL, or about 1.0 to 1.5 ng / mL, or about 1.5 to 2.0 ng / mL, or about 2.0 to 2.5 ng / mL, or about 2.5 to 3.0 ng / mL, or about 3.0 to 3.5 ng / mL, or about 3.5 to 4.0 ng / mL, or about 4.0 to 4.5 ng / mL, or about 4.5 to 5.0 ng / mL, or a combination thereof. The preferred plasma concentration may also be within the range of about 0.5 ng / mL to about 5.0 ng / mL, or about 1.0 ng / mL to about 4.5 ng / mL, or about 1.5 ng / mL to about 4.0 ng / mL, or about 2.0 ng / mL to about 3.5 ng / mL, or about 2.5 ng / mL to about 3.0 ng / mL. It is understood that the amounts listed are for illustrative purposes and that any dosage level substantially similar to those listed is encompassed by the present invention. The ranges are also intended to encompass similar ranges measured in any weight unit of drug per any unit of plasma volume.

[0048] Optionally, the effective dose level is a maximum SUR1-TRPM4 channel inhibitor plasma concentration level ("C maxPreferred maximum SUR1-TRPM4 channel concentrations include about 30 ng / mL, about 28 ng / mL, about 26 ng / mL, about 24 ng / ML, about 22 ng / mL, about 20 ng / mL, about 18 ng / mL, about 16 ng / mL, about 14 ng / mL, about 12 ng / mL, about 10 ng / mL, about 8 ng / mL, about 6 ng / mL, about 4 ng / mL, about 2 ng / mL, or about 1 ng / mL, or similar concentration levels. Suitable maximum concentration levels may also be included in the ranges of about 1-2 ng / mL, about 2-4 ng / mL, about 4-6 ng / mL, about 6-8 ng / mL, about 8-10 ng / mL, about 10-12 ng / mL, about 12-14 ng / mL, about 14-16 ng / mL, about 16-18 ng / mL, about 18-20 ng / mL, about 20-22 ng / mL, about 22-24 ng / mL, about 24-26 ng / mL, about 26-28 ng / mL, or about 28-30 ng / mL. It is understood that any dosage level substantially similar to those listed is encompassed by the present invention. The ranges are also intended to encompass similar ranges measured in any weight unit of drug per any volume unit.

[0049] Optionally, the effective dose level is one that achieves a steady-state SUR1-TRPM4 concentration of about 3.0 ng / mL to about 30.0 ng / mL. Thus, in embodiments, treatment results in a steady-state plasma concentration of about 30 ng / mL, about 27 ng / mL, about 24 ng / mL, about 21 ng / mL, about 18 ng / mL, about 15 ng / mL, about 12 ng / mL, about 9 ng / mL, about 6 ng / mL, about 3 ng / mL, or any concentration between the recited concentrations. In other embodiments, the desired effective steady state concentration may be about 3.0-5.0 ng / mL, or about 5.0-7.0 ng / mL, or about 7.0-10.0 ng / mL, or about 10.0-12.0 ng / mL, or about 12.0-14.0 ng / mL, or about 14.0-16.0 ng / mL, or about 16.0-18.0 ng / mL, or about 18.0-20.0 ng / mL, or about 20.0-22.0 ng / mL, 22.0-24.0 ng / mL, or about 24.0-26.0 ng / mL, or about 26.0-28.0 ng / mL, or about 28.0-30.0 ng / mL, or a combination thereof. In further embodiments, a steady state concentration of about 3.0 ng / mL to about 30.0 ng / mL, or about 5.0 ng / mL to about 28.0 ng / mL, or about 7.0 ng / mL to about 26.0 ng / mL, or about 9.0 ng / mL to about 24.0 ng / mL, or about 11.0 ng / mL to about 22.0 ng / mL, or about 13.0 ng / mL to about 20.0 ng / mL, or about 15.0 ng / mL to about 18.0 ng / mL, or about 16.0 ng / mL to about 17.0 ng / mL, or combinations thereof, may be desired. The desired steady state concentration may vary depending on several factors, including the likelihood and / or severity of adverse outcomes, and may change over time. The disclosed ranges are exemplary and are intended to encompass similar ranges measured in any weight unit per volume.

[0050] The specific effective dose for any particular patient depends on various factors, including the severity or likelihood of the condition; the activity of the particular compound used; the age, weight, overall health, sex and diet of the patient; the preparation of the particular compound; the time and route of administration; the duration of administration; the therapeutic agent used in combination with or simultaneously with the particular compound used; and similar factors known in the medical field. The effective dose may also change over time as any of the adverse outcomes worsen or improve, but tracking the progression of the adverse outcomes by known methods may help determine the dosage level. For chronic conditions, the subject may be administered the effective dose for multiple days, weeks, or months. The number and frequency of administration may vary depending on the likelihood or severity of the adverse outcome and the patient's specific response to the particular SUR1-TRPM4 channel inhibitor administered.

[0051] For any compound used in the methods described herein, effective dose can be estimated from cell-based assay first.Dosage can be formulated in animal model to achieve desired circulating plasma concentration range.Such information can be used to more accurately determine the useful dose in humans.

[0052] The above description of the preferred embodiment has been presented for purposes of illustration and description only. It is not intended to be exhaustive or to limit the application to the precise form disclosed, but modifications and variations are possible and / or will become apparent in light of the above teachings or may be acquired from the practice of the application. The embodiments have been chosen and described in order to explain the principles of the application and its practical application, to enable those skilled in the art to utilize the application in various embodiments and with various modifications as suited to the particular use contemplated. The scope of the application is defined by the claims appended hereto, and it is intended that the claims cover all embodiments of the application, including the disclosed embodiments and their equivalents.

[0053] Side effects related to cerebral edema Brain edema is the swelling of neurons and other cells in the brain due to excess fluid in the intracellular space. As taught in U.S. Patent No. 8,946,293, the entire contents of which are incorporated herein by reference, swelling may be caused by traumatic brain injury and stroke, or swelling may be a side effect of medical treatment that disrupts the ion gradient between the intracellular space and the extracellular space. The latter can be effectively treated or prevented by administering SUR1-TRPM4 channel inhibitors. The channel inhibitor stops or reduces the flow of ions into the cell, which over time returns the ion gradient to normal. The fluid flow associated with the ion gradient also returns to normal, and the swelling of the cells is reduced or eliminated.

[0054] There are many treatments that can cause cerebral edema. For example, a cancer treatment under development by Juno Therapeutics called Chimeric Antigen Receptor T-cell Therapy (CAR-T) is a treatment that administers genetically engineered T cells and powerful chemicals aimed at attacking the patient's cancerous blood cells. See Herper, Juno Therapeutics Stops Trial of Cancer- Killing Cells After 3 Patient Deaths, FORBES MAG. (July 7, 2016). Following CAR-T therapy, three patients died unexpectedly from cerebral edema. Administration of a SUR1-TRPM4 channel inhibitor before and / or after CAR-T therapy and / or before and / or after the occurrence of side effects related to cerebral edema can treat cerebral edema and improve the outcome of CAR-T therapy.

[0055] Another example of a treatment that is prone to side effects related to cerebral edema is the administration of chemotherapy drugs such as flutarabine. Flutarabine is believed to be the component of CAR-T therapy most likely to cause brain tumors. The administration of SUR1-TRPM4 channel inhibitors can prevent the disruption of ion gradients caused by the chemicals in flutarabine and similar drugs.

[0056] Another example is surgical removal of a brain tumor. The cerebral edema caused by the removal of a brain tumor is the result of trauma associated with the surgery and chemicals administered during surgery and recovery. Administration of SUR1-TRPM4 before and / or after surgery can reduce the risk of cerebral edema and can treat any existing cerebral edema.

[0057] In some embodiments, the SUR1-TRPM4 channel inhibitor may be administered before, during, and / or after the initiation of a treatment that is prone to causing side effects associated with cerebral edema. In further embodiments, the SUR1-TRPM4 channel inhibitor may be administered before and / or after the onset of side effects associated with cerebral edema.

[0058] The preceding examples are illustrative and are not intended to limit the scope of the present application. The underlying treatment or procedure causing the side effects associated with cerebral edema may include any treatment or procedure that exhibits such side effects.

[0059] SUR1-TRPM4 administration The manner and duration of administration of the SUR1-TRPM4 channel inhibitor may vary. Regardless of the route of administration, embodiments may be administered for a period of about 1 to about 96 hours or more. For example, the administration period may be about 1 to 5 hours, about 5 to 10 hours, about 10 to 15 hours, about 15 to 20 hours, about 20 to 25 hours, about 25 to 30 hours, about 30 to 35 hours, about 35 to 40 hours, about 40 to 45 hours, about 45 to 50 hours, about 50 to 55 hours, about 55 to 60 hours, about 60 to 65 hours, about 65 to 70 hours, about 70 to 75 hours, about 75 to 80 hours, about 80 to 85 hours, about 85 to 90 hours, or about 90 to 96 hours. In other embodiments, administration of the SUR1-TRPM4 channel inhibitor extends for a period of more than about 5 hours, or more than about 10 hours, or more than about 20 hours, or more than about 30 hours, or more than about 40 hours, or more than about 50 hours, or more than about 60 hours, or more than about 70 hours, or more than about 80 hours, or more than about 90 hours. In further embodiments, administration of the SUR1-TRPM4 inhibitor continues for about 5 hours to about 90 hours, about 15 hours to about 80 hours, about 25 hours to about 70 hours, about 35 hours to about 60 hours, or about 45 to 50 hours.

[0060] In other embodiments, administration may be for an extended period of time, such as about 1 day, or about 2 days, or about 3 days, or about 4 days, or about 5 days or more. For patients with chronic conditions, administration may continue for several days, or for a week, or for 2 weeks, or for 3 weeks or more, or even longer, until symptoms abate.

[0061] In further embodiments, administration of SUR1-TRPM4 may be done about 6 hours or less before the start of a treatment that tends to cause cerebral edema. In such cases, embodiments may begin administration about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, or about 1 hour or less before the start of treatment. Such embodiments may administer the SUR1-TRPM4 channel inhibitor intermittently during the above period, or continuously during the above period.

[0062] At any given administration period, administration may be continuous or as a series of separate administrations and may also involve more than one SUR1-TRPM4 channel inhibitor and / or more than one route of administration.

[0063] In some embodiments, the SUR1-TRPM4 channel inhibitor is administered by one or more continuous infusions. The continuous infusion is an intravenous administration that can last for any of the periods listed above. In further embodiments, the administration includes at least two continuous infusions, with about one to several minutes, about one to several hours, about one to several days, or about one to several months between the multiple continuous infusions. The at least two continuous infusions can administer the same or different SUR1-TRPM4 channel inhibitors.

[0064] In some embodiments, administration of the SUR1-TRPM4 channel inhibitor is accomplished by injection. The injection is intravenous administration, which can be in the form of continuous or bolus administration. Continuous injection is one that lasts for any of the above-mentioned periods. Bolus injection refers to administration of the SUR1-TRPM4 channel inhibitor in a single injection that lasts for a relatively short period, usually about 3 minutes or less. Several bolus injections can be administered consecutively for any of the above-disclosed periods.

[0065] In a further embodiment, the administration method comprises administering a SUR1-TRPM4 channel inhibitor to a subject in a bolus injection, followed by a continuous infusion of the SUR1-TRPM4 channel inhibitor and a bolus injection of one or more additional SUR1-TRPM4 channel inhibitors. In an embodiment, the second bolus injection is administered substantially immediately after the completion of the continuous infusion. For example, the second bolus administration starts less than 1 hour, or less than 30 minutes, or less than 10 minutes, or less than 5 minutes, or less than 3 minutes, or less than 2 minutes, or less than 1 minute after the completion of the continuous infusion. The third bolus injection can start after the completion of the second continuous infusion, and can either start substantially immediately after the completion of the second continuous infusion, or can start after an extended time after the completion of the second continuous infusion. Similarly, the fourth, fifth, or other additional bolus injection and / or additional continuous infusion can be administered either substantially immediately or after an extended period of time. It is contemplated that the entire sequence of bolus injections and continuous infusions may be given entirely before or after the onset of cerebral edema-related side effects, or the sequence may be split before, during, and after the onset of cerebral edema-related side effects, such that one or more bolus injections and / or one or more continuous infusions are given before the onset of cerebral edema-related side effects, one or more bolus injections and / or one or more continuous infusions are given during the onset of cerebral edema-related side effects, and one or more bolus injections and / or one or more continuous infusions occur after the onset of cerebral edema-related side effects. The intravenous administration methods disclosed in U.S. Patent No. 9,254,259, the entire contents of which are incorporated herein by reference, may be used.

[0066] In other embodiments, the SUR1-TRPM4 channel inhibitor is administered transdermally. The advantage of transdermal administration is that it can be less invasive compared to administration by infusion or injection, and can be more effective than oral route. For example, the SUR1-TRPM4 channel inhibitor can be administered using a transdermal patch as taught in Manoj K. Mishra, Microcapsules and Transdermal Patch: A Comparative Approach for Improved Delivery of Antidiabetic Drug, 10 AAPS PHARM. SCI. TECH.3, 928-34 (2009), the entire contents of which are incorporated herein by reference. Optionally, the drug can be administered using a transdermal patch as taught in Srinivas Mutalik & Nayanabhirama, Microcapsules and Transdermal Patch: A Comparative Approach for Improved Delivery of Antidiabetic Drug, 10 AAPS PHARM. SCI. TECH.3, 928-34 (2009), the entire contents of which are incorporated herein by reference. Administration may be via a transdermal gel as taught in Udupa, Pharmacological Evaluation of Membrane-Moderated Transdermal Systems of Glipizide, 33 CLINICAL & EXPERIMENTAL PHARMACOLOGY & PHYSIOLOGY, 17-26 (2006). For example, transdermal administration may be used for subjects with chronic conditions that may benefit from sustained and / or long-term administration of SUR1-TRPM4 channel inhibitors. Transdermal administration may be for any of the periods disclosed above. Administration via a transdermal patch or transdermal gel may be prior to, concurrently with, and / or after the occurrence of side effects associated with cerebral edema or the initiation of a treatment that tends to cause cerebral edema, or any combination thereof. In further embodiments, transdermal administration may be accompanied by oral administration, injection, or infusion administration, or combinations thereof, as disclosed above.

[0067] In further embodiments, the SUR1-TRPM4 channel inhibitor is orally administered. Oral administration can be via capsule, tablet, pill, powder, liquid suspension, or other commonly used oral administration forms. Oral administration can be before, during, and / or after the occurrence of side effects related to cerebral edema or the beginning of treatments that tend to cause cerebral edema, or any combination thereof. In further embodiments, oral administration can be combined with injection, infusion, or transdermal administration routes or combinations thereof disclosed herein.

[0068] In all embodiments, administration of the SUR1-TRPM4 channel inhibitor may be intermittent or at a gradual, continuous, constant or controlled rate.Furthermore, the time of day and the number of times per hour, day, week or month that the compound is administered may vary depending on the desired dosage.

[0069] Dosage determination As used herein, the term "dosage" and its grammatical derivatives and equivalents refer to the amount of SUR1-TRPM4 channel inhibitor administered to a subject.Dose can be described as the weight of SUR1-TRPM4 channel inhibitor administered per day, the weight of SUR1-TRPM4 channel inhibitor administered per volume, or in equivalent form of measurement.The term "effective amount" or "effective dosage" refers to the amount of compound (e.g., compound of the present invention) that is sufficient to produce beneficial or desired results.An effective amount can be administered in one or more administrations, applications, or dosages, and is not intended to be limited to a particular formulation or route of administration.

[0070] It is understood that the effective amount of SUR1-TRPM4 channel inhibitor as a treatment can vary depending on several factors, including the specific subject to be administered, the route of administration, the possibility or severity of cerebral edema, the duration or amount of treatment that tends to cause cerebral edema, and other procedure-specific conditions.It is also understood that the dosage varies between different SUR1-TRPM4 channel inhibitors.

[0071] In one embodiment of the present invention, the effective dosage level is measured in mg of SUR1-TRPM4 channel inhibitor per day and ranges from about 0.05 mg / day to about 3.0 mg / day. For example, a suitable daily dose of SUR1-TRPM4 channel inhibitor may be less than about 3.0 mg per day. For example, a suitable daily dose of glyburide may be about 2.5-3.0 mg / day, or about 2.0-2.5 mg / day, or about 1.5-2.0 mg / day, or about 1.0-1.5 mg / day, or about 0.4-1.0 mg / day, or about 0.05-0.4 mg / day. Further, a suitable daily dose may be about 0.05 mg / day, or about 0.25 mg / day, or about 0.5 mg / day, or about 1.0 mg / day, or about 1.5 mg / day, or about 2.0 mg / day, or about 2.5 mg / day, or about 3.0 mg / day. Effective doses for a given patient may also range from about 0.05 mg / day to about 3.0 mg / day, or from about 0.5 mg / day to 2.5 mg / day, or from about 1.0 mg / day to about 2.0 mg / day. Dosage levels of SUR1-TRPM4 are calculated in mg / day for illustrative purposes, but the recited ranges are intended to include similar dosage amounts calculated in any weight unit per hour, day, week, month, treatment period, or similar period.

[0072] Optionally, the dose range of the SUR1-TRPM4 channel inhibitor is an amount that results in a plasma level of about 0.4ng / mL to about 5ng / mL of SUR1-TRPM4. Suitable plasma concentrations include about 5ng / mL, or about 4.5ng / mL, or about 4ng / mL, or about 3.5ng / mL, or about 3ng / mL, or about 2.5ng / mL, or about 2ng / mL, or about 1.5ng / mL, or about 1ng / mL, or about 0.5ng / mL, or similar plasma concentrations. In some embodiments, the preferred plasma concentration of the SUR1-TRPM4 inhibitor may be about 0.4-1.0 ng / mL, or about 1.0-1.5 ng / mL, or about 1.5-2.0 ng / mL, or about 2.0-2.5 ng / mL, or about 2.5-3.0 ng / mL, or about 3.0-3.5 ng / mL, or about 3.5-4.0 ng / mL, or about 4.0-4.5 ng / mL, or about 4.5-5.0 ng / mL, or a combination thereof. The preferred plasma concentration may also be within the range of about 0.5 ng / mL to about 5.0 ng / mL, or about 1.0 ng / mL to about 4.5 ng / mL, or about 1.5 ng / mL to about 4.0 ng / mL, or about 2.0 ng / mL to about 3.5 ng / mL, or about 2.5 ng / mL to about 3.0 ng / mL. It is understood that the amounts listed are for illustrative purposes and that any dosage level substantially similar to those listed is encompassed by the present invention. The ranges are also intended to encompass similar ranges measured in any weight unit of drug per any unit of plasma volume.

[0073] Optionally, the effective dose level is a maximum SUR1-TRPM4 channel inhibitor plasma concentration level ("C maxPreferred maximum SUR1-TRPM4 channel concentrations include about 30 ng / mL, about 28 ng / mL, about 26 ng / mL, about 24 ng / ML, about 22 ng / mL, about 20 ng / mL, about 18 ng / mL, about 16 ng / mL, about 14 ng / mL, about 12 ng / mL, about 10 ng / mL, about 8 ng / mL, about 6 ng / mL, about 4 ng / mL, about 2 ng / mL, or about 1 ng / mL, or similar concentration levels. Suitable maximum concentration levels may also be included in the ranges of about 1-2 ng / mL, about 2-4 ng / mL, about 4-6 ng / mL, about 6-8 ng / mL, about 8-10 ng / mL, about 10-12 ng / mL, about 12-14 ng / mL, about 14-16 ng / mL, about 16-18 ng / mL, about 18-20 ng / mL, about 20-22 ng / mL, about 22-24 ng / mL, about 24-26 ng / mL, about 26-28 ng / mL, or about 28-30 ng / mL. It is understood that any dosage level substantially similar to those listed is encompassed by the present invention. The ranges are also intended to encompass similar ranges measured in any weight unit of drug per any volume unit.

[0074] Optionally, the effective dose level is one that achieves a steady-state SUR1-TRPM4 concentration of about 3.0 ng / mL to about 30.0 ng / mL. Thus, in embodiments, treatment results in a steady-state plasma concentration of about 30 ng / mL, about 27 ng / mL, about 24 ng / mL, about 21 ng / mL, about 18 ng / mL, about 15 ng / mL, about 12 ng / mL, about 9 ng / mL, about 6 ng / mL, about 3 ng / mL, or any concentration between the recited concentrations. In other embodiments, the desired effective steady state concentration may be about 3.0-5.0 ng / mL, or about 5.0-7.0 ng / mL, or about 7.0-10.0 ng / mL, or about 10.0-12.0 ng / mL, or about 12.0-14.0 ng / mL, or about 14.0-16.0 ng / mL, or about 16.0-18.0 ng / mL, or about 18.0-20.0 ng / mL, or about 20.0-22.0 ng / mL, 22.0-24.0 ng / mL, or about 24.0-26.0 ng / mL, or about 26.0-28.0 ng / mL, or about 28.0-30.0 ng / mL, or a combination thereof. In further embodiments, a steady state concentration of about 3.0 ng / mL to about 30.0 ng / mL, or about 5.0 ng / mL to about 28.0 ng / mL, or about 7.0 ng / mL to about 26.0 ng / mL, or about 9.0 ng / mL to about 24.0 ng / mL, or about 11.0 ng / mL to about 22.0 ng / mL, or about 13.0 ng / mL to about 20.0 ng / mL, or about 15.0 ng / mL to about 18.0 ng / mL, or about 16.0 ng / mL to about 17.0 ng / mL, or combinations thereof, may be desired. The desired steady state concentration may vary depending on several factors, including the likelihood and / or severity of cerebral edema, and may change over time. The disclosed ranges are exemplary and are intended to encompass any similar range measured on a weight per volume basis.

[0075] The specific effective dose for any particular patient depends on various factors, including the severity or likelihood of the condition; the activity of the particular compound used; the age, weight, overall health, sex and diet of the patient; the preparation of the particular compound; the time and route of administration; the duration of administration; the therapeutic agent used in combination with or simultaneously with the particular compound used; and similar factors known in the medical field.The effective dose may also vary over time as any of the side effects associated with cerebral edema worsen or improve.For chronic conditions, subjects may be administered an effective dose for multiple days, weeks, or months.The number and frequency of administration may vary depending on the likelihood or severity of the side effects associated with cerebral edema and the specific response of the patient to the particular SUR1-TRPM4 channel inhibitor administered.

[0076] For any compound used in the methods described herein, effective dose can be estimated from cell-based assay first.Dosage can be formulated in animal model to achieve desired circulating plasma concentration range.Such information can be used to more accurately determine the useful dosage in humans.

[0077] Radiation therapy associated with cerebral edema Radiation therapy is a useful treatment for cancerous cells throughout the body. Gamma rays are irradiated to cancerous tumors to stop the proliferation of cancerous cells. Radiation therapy works by breaking down the DNA in cells, either directly or by generating free radicals. Radiation affects healthy cells as well as cancerous cells. Healthy cells affected by radiation swell because the free radicals or direct radiation alter the permeability of their cell membranes, thereby allowing ions and excess fluid to enter the cells.

[0078] See AM. BRAIN TUMOR ASS'N, Conventional Radiation Therapy, 1-14 (2016), the entire contents of which are incorporated herein by reference. Cellular swelling can cause cerebral edema and exacerbate brain tumor symptoms.

[0079] Administration of SUR1-TRPM4 channel inhibitors can be effective for brain edema caused by radiation therapy. SUR1-TRPM4 channel inhibitors act to regulate ion channels in cell membranes, thereby normalizing ion gradients and fluid flow between intracellular and extracellular spaces. The normalized gradients and fluid flow are effective in reducing or preventing cell swelling, which treats or prevents brain edema.

[0080] Radiation therapy can be administered by any method known in the medical field. For example, radiation therapy can be administered using a high-performance robotic system such as a Cyberknife or Gamma Knife. Administration of a SUR1-TRPM4 channel inhibitor can enable Gamma Knife or Cyberknife procedures that were previously impossible or would have been prohibitively dangerous due to the risk of cerebral edema. Administration of a SUR1-TRPM4 channel inhibitor to a subject undergoing radiation therapy can reduce or eliminate the need for anti-inflammatory and other therapeutic drugs, many of which have known adverse side effects, currently administered to radiation therapy patients. For example, administration of a SUR1-TRPM4 channel inhibitor can reduce the need for dexamethasone, which is known to cause several adverse side effects, such as seizures, depression, hypoglycemia, pancreatitis, and others.

[0081] Radiation therapy for brain tumors is most likely to cause cerebral edema, but as used herein, radiation therapy refers to therapeutic, preventive, or palliative radiation applied to or in close proximity to the brain. It is expected that long-term radiation therapy for cancers in other locations, such as the lung or breast, may cause cerebral edema due to free radicals introduced into the body. Some cancers may metastasize to the brain, and administration of a SUR1-TRPM4 channel inhibitor prior to or following metastasis can prevent or reduce cerebral edema caused by metastasis. Primary or secondary tumors may repeatedly metastasize to the brain, increasing cerebral edema. Cancers that may result in cerebral edema include, but are not limited to, lung cancer, breast cancer, melanoma, lymphoma, gastrointestinal cancer, genitourinary tract cancer, osteosarcoma, head and neck cancer, combinations thereof, or any other systemic cancer that may metastasize to the brain.

[0082] In some embodiments, the SUR1-TRPM4 channel inhibitor may be administered before, during, and / or after the initiation of radiation therapy. In further embodiments, the SUR1-TRPM4 channel inhibitor may be administered before and / or after the onset of radiation therapy-associated cerebral edema.

[0083] SUR1-TRPM4 administration The manner and duration of administration of the SUR1-TRPM4 channel inhibitor may vary. Regardless of the route of administration, embodiments may be administered for a period of about 1 to about 96 hours or more. For example, the administration period may be about 1 to 5 hours, about 5 to 10 hours, about 10 to 15 hours, about 15 to 20 hours, about 20 to 25 hours, about 25 to 30 hours, about 30 to 35 hours, about 35 to 40 hours, about 40 to 45 hours, about 45 to 50 hours, about 50 to 55 hours, about 55 to 60 hours, about 60 to 65 hours, about 65 to 70 hours, about 70 to 75 hours, about 75 to 80 hours, about 80 to 85 hours, about 85 to 90 hours, or about 90 to 96 hours. In other embodiments, administration of the SUR1-TRPM4 channel inhibitor extends for a period of more than about 5 hours, or more than about 10 hours, or more than about 20 hours, or more than about 30 hours, or more than about 40 hours, or more than about 50 hours, or more than about 60 hours, or more than about 70 hours, or more than about 80 hours, or more than about 90 hours. In further embodiments, administration of the SUR1-TRPM4 inhibitor continues for about 5 hours to about 90 hours, about 15 hours to about 80 hours, about 25 hours to about 70 hours, about 35 hours to about 60 hours, or about 45 to 50 hours.

[0084] In other embodiments, administration may be for an extended period of time, such as about 1 day, or about 2 days, or about 3 days, or about 4 days, or about 5 days or more. For patients with chronic conditions, administration may continue for several days, or for a week, or for 2 weeks, or for 3 weeks or more, or even longer, until symptoms abate.

[0085] In further embodiments, administration of SUR1-TRPM4 may occur about 6 hours or less before the start of radiation therapy. In such cases, embodiments may begin administration about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, or about 1 hour or less before the start of radiation therapy. Such embodiments may administer the SUR1-TRPM4 channel inhibitor intermittently during the above period, or continuously during the above period.

[0086] At any given administration period, administration may be continuous or as a series of separate administrations and may also involve more than one SUR1-TRPM4 channel inhibitor and / or more than one route of administration.

[0087] In some embodiments, the SUR1-TRPM4 channel inhibitor is administered by one or more continuous infusions. The continuous infusion is an intravenous administration that can last for any of the periods listed above. In further embodiments, the administration includes at least two continuous infusions, with about one to several minutes, about one to several hours, about one to several days, or about one to several months between the multiple continuous infusions. The at least two continuous infusions can administer the same or different SUR1-TRPM4 channel inhibitors.

[0088] In some embodiments, administration of the SUR1-TRPM4 channel inhibitor is accomplished by injection. The injection is intravenous administration, which can be in the form of continuous or bolus administration. Continuous injection is one that lasts for any of the above-mentioned periods. Bolus injection refers to administration of the SUR1-TRPM4 channel inhibitor in a single injection that lasts for a relatively short period, usually about 3 minutes or less. Several bolus injections can be administered consecutively for any of the above-disclosed periods.

[0089] In a further embodiment, the administration method comprises administering a SUR1-TRPM4 channel inhibitor to a subject in a bolus injection, followed by a continuous infusion of the SUR1-TRPM4 channel inhibitor and a bolus injection of one or more additional SUR1-TRPM4 channel inhibitors. In an embodiment, the second bolus injection is administered substantially immediately after the completion of the continuous infusion. For example, the second bolus administration starts less than 1 hour, or less than 30 minutes, or less than 10 minutes, or less than 5 minutes, or less than 3 minutes, or less than 2 minutes, or less than 1 minute after the completion of the continuous infusion. The third bolus injection can start after the completion of the second continuous infusion, and can either start substantially immediately after the completion of the second continuous infusion, or can start after an extended time after the completion of the second continuous infusion. Similarly, the fourth, fifth, or other additional bolus injection and / or additional continuous infusion can be administered either substantially immediately or after an extended period of time. The entire sequence of bolus injections and continuous infusions may be given entirely before or after the onset of cerebral edema, or the sequence may be split before, during, and after the onset of cerebral edema, such that one or more bolus injections and / or one or more continuous infusions are given before the onset of cerebral edema, one or more bolus injections and / or one or more continuous infusions are given during the onset of cerebral edema, and one or more bolus injections and / or one or more continuous infusions occur after the onset of cerebral edema. The intravenous administration methods disclosed in U.S. Patent No. 9,254,259, the entire contents of which are incorporated herein by reference, may be used.

[0090] In other embodiments, the SUR1-TRPM4 channel inhibitor is administered transdermally. The advantage of transdermal administration is that it can be less invasive compared to administration by infusion or injection, and can be more effective than oral route. For example, the SUR1-TRPM4 channel inhibitor can be administered using a transdermal patch as taught in Manoj K. Mishra, Microcapsules and Transdermal Patch: A Comparative Approach for Improved Delivery of Antidiabetic Drug, 10 AAPS PHARM. SCI. TECH.3, 928-34 (2009), the entire contents of which are incorporated herein by reference. Optionally, the drug can be administered using a transdermal patch as taught in Srinivas Mutalik & Nayanabhirama, Microcapsules and Transdermal Patch: A Comparative Approach for Improved Delivery of Antidiabetic Drug, 10 AAPS PHARM. SCI. TECH.3, 928-34 (2009), the entire contents of which are incorporated herein by reference. Administration may be via a transdermal gel as taught in Udupa, Pharmacological Evaluation of Membrane-Moderated Transdermal Systems of Glipizide, 33 CLINICAL & EXPERIMENTAL PHARMACOLOGY & PHYSIOLOGY, 17-26 (2006). For example, transdermal administration may be used for subjects with chronic conditions that may benefit from sustained and / or long-term administration of SUR1-TRPM4 channel inhibitors. Transdermal administration may be for any of the periods disclosed above. Administration via a transdermal patch or transdermal gel may be before, simultaneously with, and / or after the onset of cerebral edema or the initiation of radiation therapy, or any combination thereof. In further embodiments, transdermal administration may be accompanied by oral administration, injection, or infusion administration, or combinations thereof, as disclosed above.

[0091] In further embodiments, the SUR1-TRPM4 channel inhibitor is orally administered. Oral administration can be via capsule, tablet, pill, powder, liquid suspension, or other commonly used oral administration forms. Oral administration can be before, during, or after the onset of cerebral edema or the start of radiation therapy, or any combination thereof. In further embodiments, oral administration can be combined with injection, infusion, or transdermal administration route or combination thereof disclosed herein.

[0092] In further embodiments, the SUR1-TRPM4 channel inhibitor may be administered by any combination of the routes of administration disclosed herein. In one such embodiment, the subject may receive continuous infusion (intravenously) before and / or during administration of radiation, followed by oral and / or transdermal administration after radiation therapy. Oral and / or transdermal administration may be given at the radiation therapy facility and / or sent home with the subject via prescription. Continuous infusion may begin about 6 hours before radiation therapy and may continue for any period of time disclosed herein, during and / or after radiation therapy, and before radiation therapy. In some embodiments, continuous infusion begins 6 hours before radiation therapy and continues for up to 24 hours. It is contemplated that continuous infusion may begin about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, or about 1 hour before the start of radiation therapy. Subsequent oral and / or transdermal administration may continue for any period of time disclosed herein, or until symptoms are alleviated. The dosage level of continuous infusion and oral and / or transdermal administration may be the same, or the oral and / or transdermal dosage may be lower than the dosage level of continuous infusion.In another such embodiment, the subject receives the SUR1-TRPM4 channel inhibitor via bolus injection and continuous infusion administration as disclosed above, followed by oral and / or transdermal administration following radiation therapy.Continuous infusion and / or bolus injection / continuous infusion combination may be completely before radiation therapy, before radiation therapy, and during and / or following radiation therapy, and may continue for any period of time as disclosed herein.

[0093] In all embodiments, the administration of the SUR1-TRPM4 channel inhibitor may be intermittent or may be at a gradual, continuous, constant or controlled rate.Furthermore, the time of day and the number of times per hour, day, week or month that the compound is administered may vary depending on the desired dosage.

[0094] Dosage determination As used herein, the term "dosage" and its grammatical derivatives and equivalents refer to the amount of SUR1-TRPM4 channel inhibitor administered to a subject. Dosage can be described in terms of the weight of SUR1-TRPM4 channel inhibitor administered per day, the weight of SUR1-TRPM4 channel inhibitor administered per volume, or in equivalent form of measurement. The term "effective amount" or "effective dose" refers to the amount of a compound (e.g., a compound of the present invention) that is sufficient to produce beneficial or desired results. An effective amount can be administered in one or more administrations, applications, or dosages, and is not intended to be limited to a particular formulation or route of administration.

[0095] It is understood that the effective amount of SUR1-TRPM4 channel inhibitor as treatment may vary depending on several factors, including the specific subject to be administered, the route of administration, the possibility or severity of cerebral edema, the duration or amount of radiation therapy, and other procedure-specific conditions.It is also understood that dosage varies between different SUR1-TRPM4 channel inhibitors.

[0096] In one embodiment of the present invention, the effective dosage level is measured in mg of SUR1-TRPM4 channel inhibitor per day and ranges from about 0.05 mg / day to about 3.0 mg / day. For example, a suitable daily dose of SUR1-TRPM4 channel inhibitor may be less than about 3.0 mg per day. For example, a suitable daily dose of glyburide may be about 2.5-3.0 mg / day, or about 2.0-2.5 mg / day, or about 1.5-2.0 mg / day, or about 1.0-1.5 mg / day, or about 0.4-1.0 mg / day, or about 0.05-0.4 mg / day. Further, a suitable daily dose may be about 0.05 mg / day, or about 0.25 mg / day, or about 0.5 mg / day, or about 1.0 mg / day, or about 1.5 mg / day, or about 2.0 mg / day, or about 2.5 mg / day, or about 3.0 mg / day. Effective doses for a given patient may also range from about 0.05 mg / day to about 3.0 mg / day, or from about 0.5 mg / day to 2.5 mg / day, or from about 1.0 mg / day to about 2.0 mg / day. Dosage levels of SUR1-TRPM4 are calculated in mg / day for illustrative purposes, but the recited ranges are intended to include similar dosage amounts calculated in any weight unit per hour, day, week, month, treatment period, or similar period.

[0097] Optionally, the dose range of the SUR1-TRPM4 channel inhibitor is an amount that results in a plasma level of about 0.4ng / mL to about 5ng / mL of SUR1-TRPM4. Suitable plasma concentrations include about 5ng / mL, or about 4.5ng / mL, or about 4ng / mL, or about 3.5ng / mL, or about 3ng / mL, or about 2.5ng / mL, or about 2ng / mL, or about 1.5ng / mL, or about 1ng / mL, or about 0.5ng / mL, or similar plasma concentrations. In some embodiments, the preferred plasma concentration of the SUR1-TRPM4 inhibitor may be about 0.4 to 1.0 ng / mL, or about 1.0 to 1.5 ng / mL, or about 1.5 to 2.0 ng / mL, or about 2.0 to 2.5 ng / mL, or about 2.5 to 3.0 ng / mL, or about 3.0 to 3.5 ng / mL, or about 3.5 to 4.0 ng / mL, or about 4.0 to 4.5 ng / mL, or about 4.5 to 5.0 ng / mL, or a combination thereof. The preferred plasma concentration may also be within the range of about 0.5 ng / mL to about 5.0 ng / mL, or about 1.0 ng / mL to about 4.5 ng / mL, or about 1.5 ng / mL to about 4.0 ng / mL, or about 2.0 ng / mL to about 3.5 ng / mL, or about 2.5 ng / mL to about 3.0 ng / mL. It is understood that the amounts listed are for illustrative purposes and that any dosage level substantially similar to those listed is encompassed by the present invention. The ranges are also intended to encompass similar ranges measured in any weight unit of drug per any unit of plasma volume.

[0098] Optionally, the effective dosage level is a maximum SUR1-TRPM4 channel inhibitor plasma concentration level ("C maxPreferred maximum SUR1-TRPM4 channel concentrations include about 30 ng / mL, about 28 ng / mL, about 26 ng / mL, about 24 ng / ML, about 22 ng / mL, about 20 ng / mL, about 18 ng / mL, about 16 ng / mL, about 14 ng / mL, about 12 ng / mL, about 10 ng / mL, about 8 ng / mL, about 6 ng / mL, about 4 ng / mL, about 2 ng / mL, or about 1 ng / mL, or similar concentration levels. Suitable maximum concentration levels may also be included in the ranges of about 1-2 ng / mL, about 2-4 ng / mL, about 4-6 ng / mL, about 6-8 ng / mL, about 8-10 ng / mL, about 10-12 ng / mL, about 12-14 ng / mL, about 14-16 ng / mL, about 16-18 ng / mL, about 18-20 ng / mL, about 20-22 ng / mL, about 22-24 ng / mL, about 24-26 ng / mL, about 26-28 ng / mL, or about 28-30 ng / mL. It is understood that any dosage level substantially similar to those listed is encompassed by the present invention. The ranges are also intended to encompass similar ranges measured in any weight unit of drug per any volume unit.

[0099] Optionally, the effective dose level is one that achieves a steady-state SUR1-TRPM4 concentration of about 3.0 ng / mL to about 30.0 ng / mL. Thus, in embodiments, treatment results in a steady-state plasma concentration of about 30 ng / mL, about 27 ng / mL, about 24 ng / mL, about 21 ng / mL, about 18 ng / mL, about 15 ng / mL, about 12 ng / mL, about 9 ng / mL, about 6 ng / mL, about 3 ng / mL, or any concentration between the recited concentrations. In other embodiments, the desired effective steady state concentration may be about 3.0-5.0 ng / mL, or about 5.0-7.0 ng / mL, or about 7.0-10.0 ng / mL, or about 10.0-12.0 ng / mL, or about 12.0-14.0 ng / mL, or about 14.0-16.0 ng / mL, or about 16.0-18.0 ng / mL, or about 18.0-20.0 ng / mL, or about 20.0-22.0 ng / mL, 22.0-24.0 ng / mL, or about 24.0-26.0 ng / mL, or about 26.0-28.0 ng / mL, or about 28.0-30.0 ng / mL, or a combination thereof. In further embodiments, a steady state concentration of about 3.0 ng / mL to about 30.0 ng / mL, or about 5.0 ng / mL to about 28.0 ng / mL, or about 7.0 ng / mL to about 26.0 ng / mL, or about 9.0 ng / mL to about 24.0 ng / mL, or about 11.0 ng / mL to about 22.0 ng / mL, or about 13.0 ng / mL to about 20.0 ng / mL, or about 15.0 ng / mL to about 18.0 ng / mL, or about 16.0 ng / mL to about 17.0 ng / mL, or combinations thereof, may be desired. The desired steady state concentration may vary depending on several factors, including the likelihood and / or severity of edema, and may change over time. The disclosed ranges are exemplary and are intended to encompass any similar range measured on a weight per volume basis.

[0100] In embodiments where more than one route of administration is used, the dosage level may be the same for each route of administration, or each may use a different dosage level. In certain embodiments where the patient is sent home with an oral and / or transdermal formulation, the dosage may be lower than the dosage used before, during, or immediately after radiation therapy. It is also contemplated that the prescribed dosage level may be gradually decreased over time as cerebral edema subsides, and / or gradually increased leading up to a radiation therapy session or if cerebral edema persists.

[0101] The specific effective dose for any particular patient depends on various factors, including the severity or possibility of the condition; the activity of the specific compound used; the age, weight, overall health, sex and diet of the patient; the preparation of the specific compound; the time and route of administration; the duration of administration; the therapeutic agent used in combination with or simultaneously with the specific compound used; and similar factors known in the medical field.As cerebral edema worsens or the amount of radiation administered changes, the effective dose may also vary over time.For chronic conditions, the subject may be administered an effective dose for multiple days, weeks, months.The number and frequency of administration may vary depending on the possibility or severity of cerebral edema and the specific response of the patient to the specific SUR1-TRPM4 channel inhibitor administered.

[0102] For any compound used in the methods described herein, effective dose can be estimated from cell-based assay first.Dosage can be formulated in animal model to achieve desired circulating plasma concentration range.Such information can be used to more accurately determine the useful dosage in humans.

[0103] Migraine Migraine is a severe episodic headache that may last for a long time, and is often accompanied by severe gastrointestinal disturbances such as nausea or vomiting, and hypersensitivity to light and / or sound. It is believed that migraine is caused by abnormal activity in the dura, such as swelling, which interferes with the trigeminal nerve and sends strong nerve signals throughout the body. See Bogduk, Anatomy and Physiology of Headache, 49 BIOMED. & PHARAMCO. THERAPY, 435-445 (1995), the entire contents of which are incorporated herein by reference. Less severe headaches are also believed to be the result of swelling of the dura or other areas of the brain. Migraine may be sporadic or familial hemiplegic migraine, menstrual migraine, or other acute or subchronic migraine.

[0104] Administration of SUR1-TRPM4 channel inhibitors can reduce swelling in the dura or other areas of the brain by blocking the SUR1-TRPM4 channel that is associated with the flow of ions and fluids between the intracellular space and the extracellular space, thereby reducing swelling in those areas. Co-administration of a second therapeutically active agent with a SUR1-TRPM4 channel inhibitor can enhance the effectiveness of migraine treatment or help reduce the side effects of migraine, such as severe pain. Examples of second therapeutically active agents that can be co-administered with a SUR1-TRPM4 channel inhibitor include analgesics, triptans, glucocorticoids, antidepressants, antiseizure drugs, Botox, combinations thereof, or similar compounds.

[0105] Administration of the SUR1-TRPM4 channel inhibitor, or co-administration of the SUR1-TRPM4 channel inhibitor with a second therapeutically active compound, may occur before the onset of a migraine headache, or after the onset of a migraine headache. In embodiments, administration or co-administration may last from about 1 to 96 hours, and may be continuous or intermittent during this period.

[0106] SUR1-TRPM4 Administration and Coadministration The manner and duration of administration of the SUR1-TRPM4 channel inhibitor may vary. Regardless of the route of administration, embodiments may be administered for a period of about 1 to about 96 hours or more. For example, the administration period may be about 1 to 5 hours, about 5 to 10 hours, about 10 to 15 hours, about 15 to 20 hours, about 20 to 25 hours, about 25 to 30 hours, about 30 to 35 hours, about 35 to 40 hours, about 40 to 45 hours, about 45 to 50 hours, about 50 to 55 hours, about 55 to 60 hours, about 60 to 65 hours, about 65 to 70 hours, about 70 to 75 hours, about 75 to 80 hours, about 80 to 85 hours, about 85 to 90 hours, or about 90 to 96 hours. In other embodiments, administration of the SUR1-TRPM4 channel inhibitor extends for a period of more than about 5 hours, or more than about 10 hours, or more than about 20 hours, or more than about 30 hours, or more than about 40 hours, or more than about 50 hours, or more than about 60 hours, or more than about 70 hours, or more than about 80 hours, or more than about 90 hours. In further embodiments, SUR1-TRPM4 inhibitor administration lasts for about 5 hours to about 90 hours, about 15 hours to about 80 hours, about 25 hours to about 70 hours, about 35 hours to about 60 hours, or about 45 hours to about 50 hours. Co-administration of SUR1-TRPM4 and a second therapeutically active compound may similarly last for a period of about 1 to about 96 hours or more.

[0107] In other embodiments, administration or co-administration may be for an extended period of time, such as about 1 day, or about 2 days, or about 3 days, or about 4 days, or about 5 days, or more. For patients with chronic conditions, administration or co-administration may continue for several days, or for a week, or for 2 weeks, or for 3 weeks, or more, or even longer, until symptoms are alleviated.

[0108] In some embodiments, administration of the SUR1-TRPM4 channel inhibitor and / or the second therapeutically active agent can be timed to begin with a known cause of migraine or pre-migraine symptoms. For example, for menstrual migraine, administration can begin at the beginning of the follicular phase, the beginning of the ovulation phase, any time between these two phases, or any time that coincides with the decline in estrogen levels. The decline in estrogen associated with these phases typically occurs between about days 10 and 18 of the menstrual cycle. For example, the SUR1-TRPM4 channel inhibitor and / or the second therapeutically active agent is preferably administered orally, intranasally, transdermally, by bolus injection, or a combination thereof, beginning on about days 10-18, or about days 12-16, or about days 13-15 of the menstrual cycle, for up to two weeks of treatment per month. Menstrual migraine is exemplary, and similar administration cycles can be utilized for other subchronic migraines, at doses of about 0.5-1.5 mg per day.

[0109] In some embodiments, administration of the SUR1-TRPM4 channel inhibitor and / or second therapeutically active agent can be done for a relatively short period of time and is effective for treating acute migraine headaches, such as hemiplegic (including sporadic or familial) migraine headaches. In such embodiments, administration can be done for any period disclosed herein, but more preferably for about 24 hours, 22 hours, 20 hours, 18 hours, 16 hours, 14 hours, 12 hours, 10 hours, 8 hours, 6 hours, 4 hours, 2 hours, or 1 hour. Relief of symptoms can occur, for example, about 6 to 8 hours after treatment begins. Treatment of these acute migraine headaches can be done by injection, oral, transdermal, and / or intranasal administration. Hemiplegic migraine headaches are exemplary, and similar dosing schedules can be used for other acute migraine headaches, at a dosage of about 2 to 3 mg per day.

[0110] In any given administration or co-administration period, the administration or co-administration may be continuous or as a series of separate administrations and may also involve more than one SUR1-TRPM4 channel inhibitor, and / or more than one route of administration.

[0111] In some embodiments, the SUR1-TRPM4 channel inhibitor and / or the second therapeutically active agent are administered by one or more continuous infusions. The continuous infusion is an intravenous administration that can last for any of the periods listed above. In further embodiments, the administration or co-administration includes at least two continuous infusions, with about one to several minutes, about one to several hours, about one to several days, or about one to several months between the multiple continuous infusions. The at least two continuous infusions may administer the same or different SUR1-TRPM4 channel inhibitor. The at least two continuous infusions may administer the same or different second therapeutically active agent. The at least two continuous infusions may administer the SUR1-TRPM4 channel inhibitor and / or the second therapeutically active agent.

[0112] In some embodiments, administration of the SUR1-TRPM4 channel inhibitor and / or administration of the second therapeutically active agent is accomplished by injection. The injection is an intravenous administration that can be in the form of continuous or bolus administration. A continuous injection is one that lasts for any of the above-mentioned periods. A bolus injection refers to administration of the SUR1-TRPM4 channel inhibitor and / or the second therapeutically active agent in a single injection that lasts for a relatively short period of time, usually about 3 minutes or less. Several bolus injections can be administered consecutively for any of the above-disclosed periods. In some embodiments, several bolus injections can administer one or both of the SUR1-TRPM4 channel inhibitor and the second therapeutically active agent. In some embodiments, several bolus injections can alternate between injections of the SUR1-TRPM4 and the second therapeutically active agent, and the alternating injections can be performed in any order.

[0113] In further embodiments, the method of administration or co-administration comprises administering a bolus injection to a subject, followed by a continuous infusion and one or more additional bolus injections. In embodiments, the second bolus injection is administered substantially immediately after the completion of the continuous infusion. For example, the second bolus injection starts less than 1 hour, or less than 30 minutes, or less than 10 minutes, or less than 5 minutes, or less than 3 minutes, or less than 2 minutes, or less than 1 minute after the completion of the continuous infusion. The third bolus injection can start after the completion of the second continuous infusion, and can either start substantially immediately after the completion of the second continuous infusion, or can start after an extended period of time after the completion of the second continuous infusion. Similarly, the fourth, fifth, or other additional bolus injection and / or additional continuous infusion can be administered either substantially immediately or after an extended period of time. It is contemplated that the entire sequence of bolus injections and continuous infusions may be given completely before or after the onset of a migraine headache, or the sequence may be split before, during, and after the onset of a migraine headache, such that one or more bolus injections and / or one or more continuous infusions are given before the onset of a migraine headache, one or more bolus injections and / or one or more continuous infusions are given during the onset of a migraine headache, and one or more bolus injections and / or one or more continuous infusions occur after the onset of a migraine headache. The intravenous administration method disclosed in U.S. Pat. No. 9,254,259, the entirety of which is incorporated herein by reference, may be used. In the preceding embodiment, any of the bolus injections or continuous infusions may be, without limitation, either a SUR1-TRPM4 channel inhibitor or a second therapeutically active agent. In the preceding embodiment, any of the bolus injections or continuous infusions may be, without limitation, both a SUR1-TRPM4 channel inhibitor and a second therapeutically active agent.

[0114] In another embodiment, the SUR1-TRPM4 channel inhibitor and / or the second therapeutically active agent are administered transdermally. The advantage of transdermal administration is that it can be less invasive compared to administration by infusion or injection, and can be more effective than the oral route. For example, the SUR1-TRPM4 channel inhibitor and / or the second therapeutically active agent can be administered transdermally, as described in Manoj K. Mishra, Microcapsules and Transdermal Patch: A Comparative Approach for Improved Delivery, the entire contents of which are incorporated herein by reference. The drug may be administered using a transdermal patch as taught in Srinivas Mutalik & Nayanabhirama Udupa, Pharmacological Evaluation of Membrane-Moderated Transdermal Systems of Glipizide, 33 CLINICAL & EXPERIMENTAL PHARMACOLOGY & PHYSIOLOGY, 17-26(2006), the entire contents of which are incorporated herein by reference. For example, transdermal administration may be used for subjects with chronic conditions that may benefit from sustained and / or long-term administration of the SUR1-TRPM4 channel inhibitor and / or second therapeutically active agent. Transdermal administration may be for any of the periods disclosed above. Administration via a transdermal patch or transdermal gel may occur before, simultaneously with, and / or after the onset of a migraine headache, or any combination thereof. In further embodiments, transdermal administration may be accompanied by oral, nasal, injection, or infusion administration as disclosed above, or a combination thereof.

[0115] In further embodiments, the SUR1-TRPM4 channel inhibitor and / or the second therapeutically active agent are orally administered. Oral administration can be via capsule, tablet, pill, powder, liquid suspension, or other commonly used oral administration forms. Oral administration can be before, during, or after the onset of a migraine headache, or any combination thereof. In further embodiments, oral administration can be combined with injection, infusion, nasal, or transdermal administration routes or combinations thereof disclosed herein.

[0116] In further embodiments, the SUR1-TRPM4 channel inhibitor and / or the second therapeutically active agent are administered intranasally. Intranasal administration may be particularly effective in treating acute migraine, such as hemiplegic migraine, or subchronic migraine, such as menstrual migraine. Intranasal administration may be before, during, or after the onset of a migraine, or any combination thereof. In further embodiments, intranasal administration may be combined with injection, infusion, transdermal, oral, or other administration routes or combinations thereof disclosed herein.

[0117] In all embodiments, administration of the SUR1-TRPM4 channel inhibitor and / or the second therapeutically active agent may be intermittent, or at a gradual, continuous, constant or controlled rate. Additionally, the time of day and number of times per hour, day, week or month that the compound is administered may vary depending on the desired dosage.

[0118] In some co-administration embodiments, the SUR1-TRPM4 channel inhibitor and the second therapeutically active agent are administered substantially simultaneously. In other co-administration embodiments, one of the SUR1-TRPM4 channel inhibitor or the second therapeutically active agent is administered completely before the other of the SUR1-TRPM4 channel inhibitor and the second therapeutically active agent. The period between administration of the SUR1-TRPM4 channel inhibitor and administration of the second therapeutically active agent, and / or the period between administration of the second therapeutically active agent and administration of the SUR1-TRPM4 channel inhibitor can be any of the above-listed periods or shorter, such as about 2 minutes, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, etc. In some embodiments, administration of either the SUR1-TRPM4 channel inhibitor or the second therapeutically active agent can begin first, and the other can begin second, and the period of time between the start of the first administration and the start of the second administration can be any period such that there is a period during which both the SUR1-TRPM4 channel inhibitor and the second therapeutically active agent are administered simultaneously. The period of simultaneous administration can be the full length of either, both, or neither of the administration of the SUR1-TRPM4 channel inhibitor and the administration of the second therapeutically active agent.

[0119] In all co-administration embodiments, the SUR1-TRPM4 channel inhibitor can be administered by any administration route disclosed herein, and the second therapeutically active agent can also be administered by any administration route disclosed herein.In all co-administration embodiments, the SUR1-TRPM4 channel inhibitor can be administered for any administration period disclosed herein, and the second therapeutically active agent can also be administered for any administration period disclosed herein.The administration of the SUR1-TRPM4 channel inhibitor and the second therapeutically active agent does not have to be the same administration route or form, or the same administration period, but may be.

[0120] Dosage determination As used herein, the term "dosage" and its grammatical derivatives and equivalents refer to the amount of SUR1-TRPM4 channel inhibitor administered to a subject. Dosage can be described in terms of weight of drug administered per day, weight of drug administered per volume, or equivalent types of measurements. The term "effective amount" or "effective dose" refers to the amount of a compound (e.g., a compound of the present invention) that is sufficient to produce beneficial or desired results. An effective amount can be administered in one or more administrations, applications, or dosages, and is not intended to be limited to a particular formulation or route of administration.

[0121] It is understood that the effective amount of a SUR1-TRPM4 channel inhibitor and / or second therapeutically active agent as a treatment may vary depending on several factors, including the particular subject receiving the treatment, the route of administration, the likelihood or severity of migraine headaches, and other procedure-specific conditions. It is also understood that dosages vary between different SUR1-TRPM4 channel inhibitors and / or second therapeutically active agents.

[0122] In one embodiment of the present invention, the effective dosage level is measured in mg of SUR1-TRPM4 channel inhibitor per day and ranges from about 0.05 mg / day to about 3.0 mg / day. For example, a suitable daily dose of SUR1-TRPM4 channel inhibitor may be less than about 3.0 mg per day. For example, a suitable daily dose of glyburide may be about 2.5-3.0 mg / day, or about 2.0-2.5 mg / day, or about 1.5-2.0 mg / day, or about 1.0-1.5 mg / day, or about 0.4-1.0 mg / day, or about 0.05-0.4 mg / day. Further, a suitable daily dose may be about 0.05 mg / day, or about 0.25 mg / day, or about 0.5 mg / day, or about 1.0 mg / day, or about 1.5 mg / day, or about 2.0 mg / day, or about 2.5 mg / day, or about 3.0 mg / day. Effective doses for a given patient may also range from about 0.05 mg / day to about 3.0 mg / day, or from about 0.5 mg / day to 2.5 mg / day, or from about 1.0 mg / day to about 2.0 mg / day. Dosage levels of SUR1-TRPM4 are calculated in mg / day for illustrative purposes, but the recited ranges are intended to include similar dosage amounts calculated in any weight unit per hour, day, week, month, treatment period, or similar period. Suitable daily doses of the second therapeutically active agent are in the same range as those of the SUR1-TRPM4 channel inhibitor. The daily doses of the SUR1-TRPM4 channel inhibitor and the second therapeutically active agent may be substantially the same or may vary.

[0123] Optionally, the dose range of the SUR1-TRPM4 channel inhibitor is an amount that results in a plasma level of about 0.4ng / mL to about 5ng / mL of SUR1-TRPM4. Suitable plasma concentrations include about 5ng / mL, or about 4.5ng / mL, or about 4ng / mL, or about 3.5ng / mL, or about 3ng / mL, or about 2.5ng / mL, or about 2ng / mL, or about 1.5ng / mL, or about 1ng / mL, or about 0.5ng / mL, or similar plasma concentrations. In some embodiments, the preferred plasma concentration of the SUR1-TRPM4 inhibitor may be about 0.4 to 1.0 ng / mL, or about 1.0 to 1.5 ng / mL, or about 1.5 to 2.0 ng / mL, or about 2.0 to 2.5 ng / mL, or about 2.5 to 3.0 ng / mL, or about 3.0 to 3.5 ng / mL, or about 3.5 to 4.0 ng / mL, or about 4.0 to 4.5 ng / mL, or about 4.5 to 5.0 ng / mL, or a combination thereof. The preferred plasma concentration may also be within the range of about 0.5 ng / mL to about 5.0 ng / mL, or about 1.0 ng / mL to about 4.5 ng / mL, or about 1.5 ng / mL to about 4.0 ng / mL, or about 2.0 ng / mL to about 3.5 ng / mL, or about 2.5 ng / mL to about 3.0 ng / mL. The amounts listed are for illustrative purposes, and it is understood that any dosage level substantially similar to those listed is encompassed by the present invention.This range is also intended to encompass a similar range measured by any weight unit of drug per any plasma volume unit.The preferred plasma concentration of the second therapeutically active agent is in the same range as that of the SUR1-TRPM4 channel inhibitor.The plasma concentrations of the SUR1-TRPM4 channel inhibitor and the second therapeutically active agent may be substantially the same or may vary.

[0124] Optionally, the effective dose level is a maximum SUR1-TRPM4 channel inhibitor plasma concentration level ("C maxPreferred maximum SUR1-TRPM4 channel concentrations include about 30 ng / mL, about 28 ng / mL, about 26 ng / mL, about 24 ng / ML, about 22 ng / mL, about 20 ng / mL, about 18 ng / mL, about 16 ng / mL, about 14 ng / mL, about 12 ng / mL, about 10 ng / mL, about 8 ng / mL, about 6 ng / mL, about 4 ng / mL, about 2 ng / mL, or about 1 ng / mL, or similar concentration levels. Suitable maximum concentration levels may also be included in the ranges of about 1-2 ng / mL, about 2-4 ng / mL, about 4-6 ng / mL, about 6-8 ng / mL, about 8-10 ng / mL, about 10-12 ng / mL, about 12-14 ng / mL, about 14-16 ng / mL, about 16-18 ng / mL, about 18-20 ng / mL, about 20-22 ng / mL, about 22-24 ng / mL, about 24-26 ng / mL, about 26-28 ng / mL, or about 28-30 ng / mL. It is understood that any dosage level substantially similar to those listed is encompassed by the present invention. This range is also intended to encompass a similar range measured in any weight unit of drug per any volume unit. Suitable maximum plasma concentrations of the second therapeutically active agent are in the same range as those of the SUR1-TRPM4 channel inhibitor. The maximum concentrations of the SUR1-TRPM4 channel inhibitor and the second therapeutically active agent may be substantially the same or may vary.

[0125] Optionally, the effective dose level is one that achieves a steady-state SUR1-TRPM4 concentration of about 3.0 ng / mL to about 30.0 ng / mL. Thus, in embodiments, treatment results in a steady-state plasma concentration of about 30 ng / mL, about 27 ng / mL, about 24 ng / mL, about 21 ng / mL, about 18 ng / mL, about 15 ng / mL, about 12 ng / mL, about 9 ng / mL, about 6 ng / mL, about 3 ng / mL, or any concentration between the recited concentrations. In other embodiments, the desired effective steady state concentration may be about 3.0-5.0 ng / mL, or about 5.0-7.0 ng / mL, or about 7.0-10.0 ng / mL, or about 10.0-12.0 ng / mL, or about 12.0-14.0 ng / mL, or about 14.0-16.0 ng / mL, or about 16.0-18.0 ng / mL, or about 18.0-20.0 ng / mL, or about 20.0-22.0 ng / mL, 22.0-24.0 ng / mL, or about 24.0-26.0 ng / mL, or about 26.0-28.0 ng / mL, or about 28.0-30.0 ng / mL, or a combination thereof. In further embodiments, a steady state concentration of about 3.0 ng / mL to about 30.0 ng / mL, or about 5.0 ng / mL to about 28.0 ng / mL, or about 7.0 ng / mL to about 26.0 ng / mL, or about 9.0 ng / mL to about 24.0 ng / mL, or about 11.0 ng / mL to about 22.0 ng / mL, or about 13.0 ng / mL to about 20.0 ng / mL, or about 15.0 ng / mL to about 18.0 ng / mL, or about 16.0 ng / mL to about 17.0 ng / mL, or combinations thereof, may be desired. The desired steady state concentration may vary depending on several factors, including migraine likelihood and / or severity, and may change over time. The disclosed ranges are exemplary and are intended to encompass any similar range measured on a weight per volume basis. The steady state concentration of the second therapeutically active agent may be in the same range as that of the SUR1-TRPM4 channel inhibitor. The steady state concentrations of the SUR1-TRPM4 channel inhibitor and the second therapeutically active agent may be substantially the same or may vary.

[0126] The specific effective dose for any particular patient depends on various factors, including the severity or likelihood of migraine headache; the activity of the specific compound used; the age, weight, overall health, sex and diet of the patient; the preparation of the specific compound; the time and route of administration; the duration of administration; the therapeutic agent used in combination with or simultaneously with the specific compound used; and similar factors known in the medical field. As the migraine headache worsens or improves, the effective dose may also vary over time. For chronic conditions, the subject may be administered an effective dose for multiple days, weeks, months. The number of administrations or co-administrations and the frequency of administration or co-administration may vary depending on the likelihood or severity of migraine headache and the specific response of the patient to the specific SUR1-TRPM4 channel inhibitor administered and / or the second therapeutically active agent administered.

[0127] For any compound used in the methods described herein, effective dosage can be estimated from cell-based assay first.Dosage can be formulated in animal model to achieve desired circulating plasma concentration range.Such information can be used to more accurately determine the useful dosage in humans. EXAMPLES

[0128] Embodiments are further described with reference to the following examples, which are provided for illustrative purposes only and should not be used to limit or interpret the scope of the invention.

[0129] Example 1 Appropriate Dosage Levels of Glyburide To determine the appropriate dosing level of SUR1-TRPM4, glyburide was administered to 24 healthy adult subjects by bolus injection followed by a 72-hour continuous infusion to determine the plasma concentration levels of glyburide throughout the study and to determine the pharmacokinetic profile of the drug. Eight subjects received a bolus injection of 17.3 ng of glyburide followed by a 0.4 mg / day glyburide infusion for 72 hours. The remaining 16 subjects received a bolus injection of 130 ng of glyburide followed by a 3.0 mg / day glyburide infusion for 72 hours. The two groups were referred to as the 0.4 mg / day group and the 3.0 mg / day group, respectively.

[0130] Figure 1 shows the plasma glyburide concentration time profile in subjects. The table shows glyburide concentration in ng / mL on the ordinate and time period on the abscissa. It is shown on a linear scale and includes standard deviations for both the 0.4 mg / day and 3.0 mg / day groups.

[0131] FIG. 2 shows the same glyburide concentration time profile on a semi-logarithmic scale.

[0132] [Table 1]

[0133] The mean steady-state glyburide concentrations (Css) were 3.7 ng / mL for the 0.4 mg / day group and 24.4 ng / mL for the 3.0 mg / day group. There was no evidence of glyburide accumulation, and steady state was reached according to the terminal half-life of the drug. The mean beta half-life (beta-HL), dose-corrected steady-state concentrations (Css / D), and weight-corrected volumes of the central compartment (V1,w), steady-state volume of distribution (Vss,w) and clearance (CL,w) values ​​were similar between dose levels, consistent with dose-independent pharmacokinetics.

[0134] After the first bolus RP-1127 IV injection, plasma M1 levels were detected at 1 hour for the 0.4 mg / day dose group and at 10 minutes for the 3.0 mg / day dose group. Plasma M2 levels were detected at 2 hours for the 0.4 mg / day dose group and at 20 minutes for the 3.0 mg / day dose group. Over a 72.5 hour period after the first bolus injection, plasma M1 concentrations averaged ≦0.56 ng / mL in the 0.4 mg / day dose group and ≦4.4 ng / mL in the 3.0 mg / day dose group. Over a 72.5 hour period after the first bolus injection, plasma concentrations of M2 were significantly lower than those of M1, averaging ≦0.19 ng / mL in the 0.4 mg / day dose group and ≦1.4 ng / mL in the 3.0 mg / day dose group. Levels of the glyburide metabolites, M1 and M2, were significantly lower than those of glyburide, representing, on average, 18% and 6% of the steady-state concentration of glyburide. Metabolite exposure was approximately proportional to RP-1127 dose.

[0135] Example 2 tPA followed by glyburide A study was conducted involving 77 subjects with LHI to demonstrate the efficacy of glyburide and similar compounds in preventing or treating adverse outcomes associated with tPA. The subjects were divided into four groups. Group 1 received tPA and placebo; Group 2 received tPA and Cirara, a commercially available glyburide formulation; Group 3 received placebo only without tPA; Group 4 received Cirara without tPA. As used herein, the term "placebo" refers to a nominal pharmaceutical formulation that does not contain a pharmacologic active agent or lacks the specific pharmaceutical agent of interest in a given study. In the examples disclosed herein, the placebo lacks the SUR1-TRPM4 channel inhibitor. As used herein, the term "Cirara" refers to the commercially available intravenous formulation of glyburide. In this example, tPA was administered according to current clinical guidelines for managing ischemic stroke within 4.5 hours after stroke onset (Jauch et al. 2013). It is used as an illustrative reference to demonstrate the efficacy of glyburide and other SUR1-TRPM4 channel inhibitors in reducing adverse outcomes associated with tPA and is not intended to be limiting.

[0136] [Table 2]

[0137] The adverse outcome examined in this study was death. This is for illustrative purposes only and is not intended to be limiting. At the end of the study, group 2, who received both a glyburide-containing drug and tPA, had the lowest mortality rate of only 16%. In contrast, group 1, who received tPA and a placebo, had the highest mortality rate of 41%. The baseline group, group 3, received neither tPA nor a glyburide-containing drug, and had a mortality rate of 29%. Group 4 had a mortality rate of 19%.

[0138] The fact that group 1 had a higher mortality rate than the baseline group, group 3, indicates that the deaths were related to the administration of tPA. The reduction in mortality seen in group 4 indicates that glyburide alone is effective in reducing death and other adverse outcomes, but the best explanation for the prevention of death emerged when both glyburide and tPA were administered. This indicates that administration of glyburide can reduce the adverse outcomes associated with administration of tPA.

[0139] Figure 3 shows a bar graph comparing the outcomes of the four study arms described in this study. As is evident from the graph, the best outcomes following tPA administration are achieved by administering a glyburide-containing compound.

[0140] Example 3 A clinical trial will be conducted to compare the effects of the SUR1-TRPM4 channel inhibitor glyburide administered to patients undergoing CAR-T therapy, surgical resection of brain tumors, and / or diagnosed with cerebral edema with matched control patients.

[0141] This is a randomized, open-label, parallel-group study investigating the effects of glyburide administered beginning on the first day after surgery or on the first day after the onset or diagnosis of an adverse event related to cerebral edema.

[0142] In one treatment group, glyburide is administered as a bolus followed by a continuous infusion.

[0143] In the second treatment group, glyburide is administered via a transdermal patch or transdermal gel.

[0144] In a third treatment group, glyburide is administered via injection, for example, intravenous infusion.

[0145] In the fourth treatment group, glyburide is administered orally.

[0146] Glyburide is administered at 0.5, 1, 1.5, 2, 2.5, or 3.0 mg / day.

[0147] The trial period lasts from a few days to a few weeks.

[0148] Plasma levels of glyburide are determined daily.

[0149] The control group will be matched with respect to age, sex, and preoperative stage. The control group will not receive any treatment, but will receive postoperative adjuvant therapy according to local standard practice.

[0150] Each patient will be monitored via blood sampling and MRI. A diagnostic contrast MRI of the brain will be performed prior to inclusion in the study.

[0151] The following comparisons were made: Occurrence of one or more side effects related to cerebral edema: headache Neck pain or stiffness Nausea or vomiting Dizziness Irregular breathing Vision loss or change memory loss Inability to walk Difficulty speaking Impaired consciousness Seizures loss of consciousness Incidence of dose-limiting toxicity (DLT) Development of increased edema and initiation of dexamethasone (or administration of any corticosteroid intended to treat cerebral edema) Change in ktrans Changes in the ratio of water-suppressed inversion recovery (FLAIR) Incidence of Common Terminology Criteria for Adverse Events (CTCAE) Increased cerebral edema as measured by FLAIR volumetric imaging Incidence of postoperative infection Postoperative pain management

[0152] Results: Compared to the control group, the patient group receiving glyburide was found to have a significant reduction or inhibition of side effects related to cerebral edema.

[0153] Example 4 A clinical trial will be conducted to compare the effects of the SUR1-TRPM4 channel inhibitor glyburide administered to patients diagnosed with brain tumors or metastases and undergoing radiation therapy, eg, gamma irradiation, with matched control patients.

[0154] This is a randomized, open-label, parallel-group study investigating the effect of glyburide administered starting on day 1 after radiation therapy.

[0155] In one treatment group, glyburide is administered as a bolus followed by a continuous infusion.

[0156] In the second treatment group, glyburide is administered via a transdermal patch or transdermal gel.

[0157] In a third treatment group, glyburide is administered via injection, for example, intravenous infusion.

[0158] In the fourth treatment group, glyburide is administered orally.

[0159] Glyburide is administered at 0.5, 1, 1.5, 2, 2.5, or 3.0 mg / day.

[0160] The trial period lasts from a few weeks to a few months.

[0161] Plasma levels of glyburide are determined weekly.

[0162] The control group will be matched with respect to age, sex, and pre-radiotherapy stage. The control group will not receive glyburide treatment, but will receive a placebo or a corticosteroid, such as dexamethasone, for the purpose of treating cerebral edema.

[0163] Each patient will be monitored via blood sampling and MRI. A diagnostic contrast MRI of the brain will be performed prior to inclusion in the study.

[0164] The following comparisons were made: Occurrence of one or more side effects related to cerebral edema: headache Neck pain or stiffness Nausea or vomiting Dizziness Irregular breathing Vision loss or change memory loss Inability to walk Difficulty speaking Impaired consciousness Seizures loss of consciousness Incidence of dose-limiting toxicity (DLT) Development of increased edema and initiation of dexamethasone (or administration of any corticosteroid intended to treat cerebral edema) Change in ktrans Changes in the ratio of water-suppressed inversion recovery (FLAIR) Incidence of Common Terminology Criteria for Adverse Events (CTCAE) Increased cerebral edema as measured by FLAIR volumetric imaging Incidence of postoperative infection Postoperative pain management

[0165] Results: Compared to the control group, the patient group receiving glyburide was found to have a significant reduction or inhibition of side effects related to cerebral edema.

[0166] Example 5 The clinical trial will be conducted to compare the effects of the SUR1-TRPM4 channel inhibitor glyburide administered to patients with a history of migraine headaches.

[0167] This is a randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study to investigate the efficacy, safety, and tolerability of glyburide for migraine prophylaxis.

[0168] In one treatment group, glyburide is administered as a bolus followed by a continuous infusion.

[0169] In the second treatment group, glyburide is administered via a transdermal patch or transdermal gel.

[0170] In a third treatment group, glyburide is administered via injection, for example, intravenous infusion.

[0171] In the fourth treatment group, glyburide is administered orally.

[0172] Glyburide is administered at 0.5, 1, 1.5, 2, 2.5, or 3.0 mg / day.

[0173] The test period lasts from a few days to a week.

[0174] Outcome measures: Number of migraine days during weeks 9–12 of the treatment period. Change in scores from the Completeness of Response Survey (CORS) (Timeframe: Visit 1 (screening) and Visit 2 (end of study after 2-month treatment period)). CORS scores for pain (0–4), associated pathology (0–4), limbic / emotional symptoms (0–5), and speed of return to functionality (1–5) represent measures of patient-relevant outcome. Higher scores represent better treatment effects. The analysis will compare CORS scores for usual care (pre-study) and glyburide (study drug). Frequency of migraines Migraine Severity Duration of migraine headache The occurrence of precursors Severity of impairment Rescue medication use Percentage of Responders Comprehensive evaluation of the test drug

[0175] Results: Compared with the placebo group, patients receiving glyburide showed greater improvements in migraine outcome measures after 12 weeks of treatment.

[0176] Incorporation by Reference The entire disclosures of each of the patent documents and scientific articles mentioned herein are incorporated by reference for all purposes.

[0177] Equivalent The invention disclosed herein may be embodied in other specific forms without departing from its spirit or essential characteristics. Therefore, the preceding embodiments should be considered as illustrative rather than limiting the present invention in all respects. Therefore, the scope of the present invention is indicated not by the preceding description but rather by the appended claims, and all modifications within the meaning and scope of the claims are intended to be embraced therein.

Claims

[Claim 1] The invention as depicted in the drawings.

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