CA2949545C - Methods of treating and preventing vascular instability diseases - Google Patents

Methods of treating and preventing vascular instability diseases Download PDF

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CA2949545C
CA2949545C CA2949545A CA2949545A CA2949545C CA 2949545 C CA2949545 C CA 2949545C CA 2949545 A CA2949545 A CA 2949545A CA 2949545 A CA2949545 A CA 2949545A CA 2949545 C CA2949545 C CA 2949545C
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CA2949545A1 (en
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Christopher C. GIBSON
Dean Y. Li
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University of Utah Research Foundation Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/0033—Features or image-related aspects of imaging apparatus, e.g. for MRI, optical tomography or impedance tomography apparatus; Arrangements of imaging apparatus in a room
    • A61B5/004—Features or image-related aspects of imaging apparatus, e.g. for MRI, optical tomography or impedance tomography apparatus; Arrangements of imaging apparatus in a room adapted for image acquisition of a particular organ or body part
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/05—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves
    • A61B5/055—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves involving electronic [EMR] or nuclear [NMR] magnetic resonance, e.g. magnetic resonance imaging
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/45—Non condensed piperidines, e.g. piperocaine having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

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Abstract

Methods are disclosed for treating and preventing vascular instability diseases, such as cerebral cavernous malformation, by the administration of tempol, cholecalciferol, derivatives thereof, pharmaceutically-acceptable salts thereof, or combinations thereof. Methods are disclosed for reducing the number of cerebral cavernous malformation (CCM) lesions in a patient having, or at risk of developing, at least one CCM lesion. Methods are disclosed for reducing the growth rate of the number of cerebral cavernous malformation (CCM) lesions in a patient having, or at risk of developing, at least one CCM lesion. Method are disclosed for preventing or treating a sign or symptom of cerebral cavernous malformation (CCM) in a patient with at least one CCM lesion. Methods are disclosed for decreasing cerebrovascular inflammation, reducing cerebrovascular permeability, or both, in a patient having, or at risk of developing, a cerebral cavernous malformation (CCM) lesion. Methods are disclosed for improving cerebrovascular health in a patient having, or at risk of developing, a cerebral cavernous malformation (CCM) lesion.

Description

METHODS OF TREATING AND PREVENTING
VASCULAR INSTABILITY DISEASES
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Patent Application No.
14/728,800, filed June 2, 2015, titled METHODS OF TREATING AND PREVENTING
VASCULAR INSTABILITY DISEASES, and U.S. Provisional Patent Application No.
62/014,540, filed June 19, 2014, titled METHODS OF TREATING AND

Claims (54)

Claims:
1. A composition comprising tempo!, cholecalciferol, calcidiol or calcitriol, or tempo or 4-arnino tempo, a pharmaceutically-acceptable salt of the foregoing, or combinations thereof for use in reducing a number of, a growth rate of, or both, of cerebral cavernous malformation (CCM) lesions.
2. The composition for use of claim 1, wherein said composition is for administration to a patient in which a number, a size, or both, of the at least one CCM lesion has been determined in the patient.
3. The composition for use of claim 2, wherein said composition is for administration to a patient in which the number and the size of the at least one CCM lesion has been determined in the patient prior to the use of the composition.
4. The composition for use of claim 2 or 3, wherein said composition is for administration to a patient in which the number and the size of the at least one CCM lesion has been determined in the patient after the use of the composition.
5. The composition for use of any one of claims 2-4, wherein said composition is for administration to a patient in which the number, the size, or both, of the at least one CCM
lesion has been determined in the patient using magnetic resonance imaging (MRI).
6. The composition for use of any one of claims 1-5, wherein the patient has one CCM lesion.
7. The composition for use of any one of claims 1-5, wherein the patient has two or more CCM
lesions.
8. The composition for use of any one of claims 1-7, wherein said composition is for administration to a patient in which a mutation in at least one gene associated with CCM has been identified in the patient.
9. The composition for use of claim 8, wherein the at least one gene associated with CCM is selected from at least one of CCM2, KRIT1, or PDCD10.
10. The composition for use of claim 8, wherein the mutation comprises a heterozygous germline mutation in the CCM2 gene in the patient.
11. The composition for use of any one of claims 1-10, further comprising aloin, apomorphine hydrochloride, dimercaprol, gedunin, or pindolol; or a pharmaceutically-acceptable salt thereof.
12. The composition for use of any one of claims 1-11, wherein the patient is human.
13. A composition comprising tempol, cholecalciferol, calcidiol or calcitriol, or tempo or 4-amino tempo, a pharmaceutically-acceptable salt of the foregoing, or combinations thereof for use in preventing or treating a sign or symptom of cerebral cavernous malformation (CCM) in a patient with at least one CCM lesion.
14. The composition for use of claim 13, wherein the sign or symptom of CCM is selected from at least one of intracerebral hemorrhage, increased permeability of cerebral vasculature, epilepsy, or focal neurological deficit.
15. The composition for use of claim 14, wherein said composition is for administration a patient having at least one CCM lesion who has experienced an intracerebral hemorrhage within a predetermined time period prior to administration.
16. The composition for use of claim 15, wherein the predetermined time period is at least one year.
17. The composition for use of claim 15, wherein the predetermined time period is at least two years.
18. A composition comprising tempo!, cholecalciferol, calcidiol or calcitriol, tempo or 4-amino tempo, a pharmaceutically-acceptable salt of the foregoing, or combinations thereof for use in decreasing cerebrovascular inflammation, reducing cerebrovascular permeability, or both, in a patient having, or at risk of developing, a cerebral cavernous malformation (CCM) lesion.
19. A use of a composition comprising tempol, cholecalciferol, calcidiol or calcitriol, or tempo or 4-amino tempo, a pharmaceutically-acceptable salt of the foregoing, or combinations thereof for reducing a number of, a growth rate of, or both, of cerebral cavernous malformation (CCM) lesions.
20. The use of claim 19, wherein said composition is for administration to a patient in which a number, a size, or both, of the at least one CCM lesion has been determined in the patient.
21. The use of claim 20, wherein said composition is for administration to a patient in which the number and the size of the at least one CCM lesion has been determined in the patient prior to the use of the composition.
22. The use of claim 20 or 21, wherein said composition is for administration to a patient in which the number and the size of the at least one CCM lesion has been determined in the patient after the use of the composition.
23. The use of any one of claims 20-22, wherein said composition is for administration to a patient in which the number, the size, or both, of the at least one CCM lesion has been determined in the patient using magnetic resonance imaging (MRI).
24. The use of any one of claims 19-23, wherein the patient has one CCM
lesion.
25. The use of any one of claims 19-23, wherein the patient has two or more CCM lesions.
26. The use of any one of claims 19-25, wherein said composition is for administration to a patient in which a mutation in at least one gene associated with CCM has been identified in the patient.
27. The use of claim 26, wherein the at least one gene associated with CCM is selected from at least one of CCM2, KRITI, or PDCD10.
28. The use of claim 26, wherein the mutation comprises a heterozygous germline mutation in the CCM2 gene in the patient.
29. The use of any one of claims 19-28, wherein the composition further comprises aloin, apomorphine hydrochloride, dimercaprol, gedunin, or pindolol; or a pharmaceutically-acceptable salt thereof.
30. The use of any one of claims 19-29, wherein the patient is human.
31. A use of a composition comprising tempol, cholecalciferol, calcidiol or calcitriol, or tempo or 4-amino tempo, a pharmaceutically-acceptable salt of the foregoing, or combinations thereof for preventing or treating a sign or symptom of cerebral cavernous malformation (CCM) in a patient with at least one CCM lesion.
32. The use of claim 31, wherein the sign or symptorn of CCM is selected from at least one of intracerebral hemorrhage, increased permeability of cerebral vasculature, epilepsy, or focal neurological deficit.
33. The use of claim 32, wherein said composition is for administration a patient having at least one CCM lesion who has experienced an intracerebral hemorrhage within a predetermined time period prior to administration.
34. The use of claim 33, wherein the predetermined time period is at least one year.
35. The use of claim 33, wherein the predetermined time period is at least two years.
36. A use of a composition comprising tempol, cholecalciferol, calcidiol or calcitriol, tempo or 4-amino tempo, a pharmaceutically-acceptable salt of the foregoing, or combinations thereof for decreasing cerebrovascular inflammation, reducing cerebrovascular permeability, or both, in a patient having, or at risk of developing, a cerebral cavernous malformation (CCM) lesion.
37. A use of a composition comprising tempo!, cholecalciferol, calcidiol or calcitriol, or tempo or 4-amino tempo, a pharmaceutically-acceptable salt of the foregoing, or combinations thereof for preparation of a medicament for reducing a number of, a growth rate of, or both, of cerebral cavernous malformation (CCM) lesions.
38. The use of claim 37, wherein said composition is for administration to a patient in which a number, a size, or both, of the at least one CCM lesion has been determined in the patient.
39. The use of claim 38, wherein said composition is for administration to a patient in which the number and the size of the at least one CCM lesion has been determined in the patient prior to the use of the composition.
40. The use of claim 38 or 39, wherein said composition is for administration to a patient in which the number and the size of the at least one CCM lesion has been determined in the patient after the use of the composition.
41. The use of any one of claims 38-40, wherein said composition is for administration to a patient in which the number, the size, or both, of the at least one CCM lesion has been determined in the patient using magnetic resonance imaging (MRI).
42. The use of any one of claims 37-41, wherein the patient has one CCM
lesion.
43. The use of any one of claims 37-41, wherein the patient has two or more CCM lesions.
44. The use of any one of claims 37-43, wherein said composition is for administration to a patient in which a mutation in at least one gene associated with CCM has been identified in the patient.
45. The use of claim 44, wherein the at least one gene associated with CCM is selected from at least one of CCM2, KRIT1, or PDCD10.
46. The use of claim 44, wherein the mutation comprises a heterozygous germline mutation in the CCM2 gene in the patient.
47. The use of any one of claims 37-46, wherein the composition further comprises aloin, apomorphine hydrochloride, dimercaprol, gedunin, or pindolol; or a pharmaceutically-acceptable salt thereof.
48. The use of any one of claims 37-47, wherein the patient is human.
49. A use of a composition comprising tempol, cholecalciferol, calcidiol or calcitriol, or tempo or 4-amino tempo, a pharmaceutically-acceptable salt of the foregoing, or combinations thereof for preparation of a medicament for preventing or treating a sign or symptom of cerebral cavernous malformation (CCM) in a patient with at least one CCM lesion.
50. The use of claim 49, wherein the sign or symptorn of CCM is selected from at least one of intracerebral hemorrhage, increased permeability of cerebral vasculature, epilepsy, or focal neurological deficit.
51. The use of claim 50, wherein said composition is for administration a patient having at least one CCM lesion who has experienced an intracerebral hemorrhage within a predetermined time period prior to administration.
52. The use of claim 51, wherein the predetermined time period is at least one year.
53. The use of claim 51, wherein the predetermined time period is at least two years.
54. A use of a composition comprising tempol, cholecalciferol, calcidiol or calcitriol, tempo or 4-amino tempo, a pharmaceutically-acceptable salt of the foregoing, or combinations thereof for preparation of a medicament for decreasing cerebrovascular inflammation, reducing cerebrovascular permeability, or both, in a patient having, or at risk of developing, a cerebral cavernous malformation (CCM) lesion.
CA2949545A 2014-06-19 2015-06-16 Methods of treating and preventing vascular instability diseases Active CA2949545C (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US201462014540P 2014-06-19 2014-06-19
US62/014,540 2014-06-19
US14/728,800 US9314457B2 (en) 2014-06-19 2015-06-02 Methods of treating and preventing vascular instability diseases
US14/728,800 2015-06-02
PCT/US2015/036062 WO2015195685A1 (en) 2014-06-19 2015-06-16 Methods of treating and preventing vascular instability diseases

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CA2949545A1 CA2949545A1 (en) 2015-12-23
CA2949545C true CA2949545C (en) 2022-07-19

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EP3157532A1 (en) 2017-04-26
AU2015277341B2 (en) 2020-06-25
IL249599B (en) 2021-06-30
IL249599A0 (en) 2017-02-28
CN106659727A (en) 2017-05-10
EP3157532A4 (en) 2017-12-20
RU2712170C2 (en) 2020-01-24
MX378931B (en) 2025-03-11
EP3157532B1 (en) 2021-03-24
US9937162B2 (en) 2018-04-10
KR102419504B1 (en) 2022-07-12
CA2949545A1 (en) 2015-12-23
AU2015277341A1 (en) 2016-12-01
JP6621424B2 (en) 2019-12-18
ES2879331T3 (en) 2021-11-22
US9314457B2 (en) 2016-04-19
WO2015195685A1 (en) 2015-12-23
US20150366848A1 (en) 2015-12-24
RU2016145265A (en) 2018-07-19
JP2017518340A (en) 2017-07-06
KR20170021249A (en) 2017-02-27
BR112016029437B1 (en) 2022-11-29
DK3157532T3 (en) 2021-06-28
US20160220546A1 (en) 2016-08-04
MX2016015695A (en) 2017-05-30
BR112016029437A2 (en) 2017-08-22
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