NZ621474B2 - Levomilnacipran drug for functional rehabilitation after an acute neurological stroke - Google Patents
Levomilnacipran drug for functional rehabilitation after an acute neurological stroke Download PDFInfo
- Publication number
- NZ621474B2 NZ621474B2 NZ621474A NZ62147412A NZ621474B2 NZ 621474 B2 NZ621474 B2 NZ 621474B2 NZ 621474 A NZ621474 A NZ 621474A NZ 62147412 A NZ62147412 A NZ 62147412A NZ 621474 B2 NZ621474 B2 NZ 621474B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- dextromilnacipran
- levomilnacipran
- mixture
- brain
- pharmaceutical composition
- Prior art date
Links
- GJJFMKBJSRMPLA-DZGCQCFKSA-N Levomilnacipran Chemical compound C=1C=CC=CC=1[C@]1(C(=O)N(CC)CC)C[C@H]1CN GJJFMKBJSRMPLA-DZGCQCFKSA-N 0.000 title claims abstract description 36
- 229960000685 Levomilnacipran Drugs 0.000 title claims abstract description 35
- 230000000926 neurological Effects 0.000 title claims description 16
- 230000001154 acute Effects 0.000 title claims description 14
- 239000003814 drug Substances 0.000 title abstract description 12
- 229940079593 drugs Drugs 0.000 title abstract description 10
- GJJFMKBJSRMPLA-HIFRSBDPSA-N Milnacipran Chemical compound C=1C=CC=CC=1[C@@]1(C(=O)N(CC)CC)C[C@@H]1CN GJJFMKBJSRMPLA-HIFRSBDPSA-N 0.000 claims abstract description 72
- 239000000203 mixture Substances 0.000 claims abstract description 42
- 208000006011 Stroke Diseases 0.000 claims abstract description 30
- 238000011084 recovery Methods 0.000 claims abstract description 28
- 206010008190 Cerebrovascular accident Diseases 0.000 claims abstract description 26
- 201000001084 cerebrovascular disease Diseases 0.000 claims abstract description 25
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- 210000004556 Brain Anatomy 0.000 claims description 20
- 206010070976 Craniocerebral injury Diseases 0.000 claims description 12
- 208000005765 Traumatic Brain Injury Diseases 0.000 claims description 12
- 239000004480 active ingredient Substances 0.000 claims description 7
- 230000002490 cerebral Effects 0.000 claims description 6
- 230000002792 vascular Effects 0.000 claims description 6
- 230000000472 traumatic Effects 0.000 claims description 5
- 230000002008 hemorrhagic Effects 0.000 claims description 4
- 230000002354 daily Effects 0.000 claims description 3
- 230000000302 ischemic Effects 0.000 claims description 3
- 230000031891 intestinal absorption Effects 0.000 claims description 2
- 239000000546 pharmaceutic aid Substances 0.000 claims description 2
- 208000008208 Craniocerebral Trauma Diseases 0.000 abstract 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 32
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 27
- 230000002401 inhibitory effect Effects 0.000 description 21
- 229960002748 Norepinephrine Drugs 0.000 description 20
- 102000005962 receptors Human genes 0.000 description 20
- 108020003175 receptors Proteins 0.000 description 20
- 229960000600 Milnacipran Drugs 0.000 description 18
- 241000282414 Homo sapiens Species 0.000 description 17
- 230000000694 effects Effects 0.000 description 17
- 229940076279 Serotonin Drugs 0.000 description 16
- 201000010099 disease Diseases 0.000 description 15
- 210000004027 cells Anatomy 0.000 description 12
- 239000003112 inhibitor Substances 0.000 description 12
- 102000019208 Serotonin Plasma Membrane Transport Proteins Human genes 0.000 description 10
- 108010012996 Serotonin Plasma Membrane Transport Proteins Proteins 0.000 description 10
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 10
- 230000003902 lesions Effects 0.000 description 10
- 239000011780 sodium chloride Substances 0.000 description 9
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 229960002464 Fluoxetine Drugs 0.000 description 6
- RTHCYVBBDHJXIQ-UHFFFAOYSA-N N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propan-1-amine Chemical compound C=1C=CC=CC=1C(CCNC)OC1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-UHFFFAOYSA-N 0.000 description 6
- IENZQIKPVFGBNW-UHFFFAOYSA-N Prazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1=CC=CO1 IENZQIKPVFGBNW-UHFFFAOYSA-N 0.000 description 6
- 229960001289 Prazosin Drugs 0.000 description 6
- 102000030014 alpha-1 adrenergic receptor family Human genes 0.000 description 6
- 108020004102 alpha-1 adrenergic receptor family Proteins 0.000 description 6
- 230000001965 increased Effects 0.000 description 6
- 239000002287 radioligand Substances 0.000 description 6
- UCTWMZQNUQWSLP-VIFPVBQESA-N Epinephrine Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 230000034994 death Effects 0.000 description 5
- 229960003638 dopamine Drugs 0.000 description 5
- 229960005139 epinephrine Drugs 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 208000001183 Brain Injury Diseases 0.000 description 4
- 206010048962 Brain oedema Diseases 0.000 description 4
- 206010010071 Coma Diseases 0.000 description 4
- 206010018987 Haemorrhage Diseases 0.000 description 4
- 206010033799 Paralysis Diseases 0.000 description 4
- 239000000951 adrenergic alpha-1 receptor antagonist Substances 0.000 description 4
- 230000003042 antagnostic Effects 0.000 description 4
- 230000001684 chronic Effects 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 230000001537 neural Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000000159 protein binding assay Methods 0.000 description 4
- 230000035945 sensitivity Effects 0.000 description 4
- 229940025084 Amphetamine Drugs 0.000 description 3
- 206010003210 Arteriosclerosis Diseases 0.000 description 3
- 208000006752 Brain Edema Diseases 0.000 description 3
- 206010018852 Haematoma Diseases 0.000 description 3
- 206010019468 Hemiplegia Diseases 0.000 description 3
- 206010061216 Infarction Diseases 0.000 description 3
- SFLSHLFXELFNJZ-MRVPVSSYSA-N L-Noradrenaline Natural products NC[C@@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-MRVPVSSYSA-N 0.000 description 3
- 102000008092 Norepinephrine Plasma Membrane Transport Proteins Human genes 0.000 description 3
- 108010049586 Norepinephrine Plasma Membrane Transport Proteins Proteins 0.000 description 3
- 208000002193 Pain Diseases 0.000 description 3
- 239000007983 Tris buffer Substances 0.000 description 3
- 239000000556 agonist Substances 0.000 description 3
- 229960002734 amfetamine Drugs 0.000 description 3
- 239000005557 antagonist Substances 0.000 description 3
- 238000004166 bioassay Methods 0.000 description 3
- 238000003745 diagnosis Methods 0.000 description 3
- 239000002270 dispersing agent Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 238000007918 intramuscular administration Methods 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 230000000051 modifying Effects 0.000 description 3
- 238000002610 neuroimaging Methods 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 230000035939 shock Effects 0.000 description 3
- 238000004088 simulation Methods 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 230000001225 therapeutic Effects 0.000 description 3
- 210000001519 tissues Anatomy 0.000 description 3
- 230000000007 visual effect Effects 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- BRZYSWJRSDMWLG-DJWUNRQOSA-N (2R,3R,4R,5R)-2-[(1S,2S,3R,4S,6R)-4,6-diamino-3-[(2S,3R,4R,5S,6R)-3-amino-4,5-dihydroxy-6-[(1R)-1-hydroxyethyl]oxan-2-yl]oxy-2-hydroxycyclohexyl]oxy-5-methyl-4-(methylamino)oxane-3,5-diol Chemical compound O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H]([C@@H](C)O)O2)N)[C@@H](N)C[C@H]1N BRZYSWJRSDMWLG-DJWUNRQOSA-N 0.000 description 2
- QXWYKJLNLSIPIN-YUMQZZPRSA-N (2S,3S)-2-azaniumyl-3-(3,4-dihydroxyphenyl)-3-hydroxypropanoate Chemical compound [O-]C(=O)[C@@H]([NH3+])[C@@H](O)C1=CC=C(O)C(O)=C1 QXWYKJLNLSIPIN-YUMQZZPRSA-N 0.000 description 2
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 2
- -1 (±)aminomethyl Chemical group 0.000 description 2
- DUGOZIWVEXMGBE-UHFFFAOYSA-N Adhd patch Chemical compound C=1C=CC=CC=1C(C(=O)OC)C1CCCCN1 DUGOZIWVEXMGBE-UHFFFAOYSA-N 0.000 description 2
- 208000007415 Anhedonia Diseases 0.000 description 2
- 206010002855 Anxiety Diseases 0.000 description 2
- 206010057666 Anxiety disease Diseases 0.000 description 2
- 206010003178 Arterial thrombosis Diseases 0.000 description 2
- 210000001367 Arteries Anatomy 0.000 description 2
- 210000004369 Blood Anatomy 0.000 description 2
- 206010052346 Brain contusion Diseases 0.000 description 2
- 208000000094 Chronic Pain Diseases 0.000 description 2
- 206010010254 Concussion Diseases 0.000 description 2
- HCYAFALTSJYZDH-UHFFFAOYSA-N Desimpramine Chemical compound C1CC2=CC=CC=C2N(CCCNC)C2=CC=CC=C21 HCYAFALTSJYZDH-UHFFFAOYSA-N 0.000 description 2
- 208000001640 Fibromyalgia Diseases 0.000 description 2
- 101700048515 LEC1 Proteins 0.000 description 2
- 101700046135 LEC2 Proteins 0.000 description 2
- 208000001652 Memory Disorders Diseases 0.000 description 2
- 229960001344 Methylphenidate Drugs 0.000 description 2
- DPWPWRLQFGFJFI-UHFFFAOYSA-N Pargyline Chemical compound C#CCN(C)CC1=CC=CC=C1 DPWPWRLQFGFJFI-UHFFFAOYSA-N 0.000 description 2
- 229960001779 Pargyline Drugs 0.000 description 2
- CBQGYUDMJHNJBX-RTBURBONSA-N Reboxetine Chemical compound CCOC1=CC=CC=C1O[C@H](C=1C=CC=CC=1)[C@@H]1OCCNC1 CBQGYUDMJHNJBX-RTBURBONSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000000674 adrenergic antagonist Substances 0.000 description 2
- 230000036506 anxiety Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 230000001149 cognitive Effects 0.000 description 2
- 230000001054 cortical Effects 0.000 description 2
- 230000002939 deleterious Effects 0.000 description 2
- 229960003914 desipramine Drugs 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 229960001104 droxidopa Drugs 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 230000003278 mimic Effects 0.000 description 2
- 210000002569 neurons Anatomy 0.000 description 2
- 230000000414 obstructive Effects 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 239000000902 placebo Substances 0.000 description 2
- 229940068196 placebo Drugs 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 229960003770 reboxetine Drugs 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-M stearate Chemical compound CCCCCCCCCCCCCCCCCC([O-])=O QIQXTHQIDYTFRH-UHFFFAOYSA-M 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- XNCDYJFPRPDERF-NQQJLSKUSA-N (1S,2R)-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropane-1-carboxamide;hydrochloride Chemical compound Cl.C=1C=CC=CC=1[C@]1(C(=O)N(CC)CC)C[C@H]1CN XNCDYJFPRPDERF-NQQJLSKUSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K 2qpq Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 108060003346 ADRA1A Proteins 0.000 description 1
- 102100020221 ADRA1A Human genes 0.000 description 1
- 108060003347 ADRA1B Proteins 0.000 description 1
- 102100020207 ADRA1B Human genes 0.000 description 1
- 108060003348 ADRA1D Proteins 0.000 description 1
- 101700084127 AVP Proteins 0.000 description 1
- 102100017238 AVP Human genes 0.000 description 1
- 206010000370 Accident at home Diseases 0.000 description 1
- 229940022663 Acetate Drugs 0.000 description 1
- 206010001497 Agitation Diseases 0.000 description 1
- 208000006888 Agnosia Diseases 0.000 description 1
- 241001047040 Agnosia Species 0.000 description 1
- 206010002329 Aneurysm Diseases 0.000 description 1
- 206010003119 Arrhythmia Diseases 0.000 description 1
- 229940072107 Ascorbate Drugs 0.000 description 1
- 206010003591 Ataxia Diseases 0.000 description 1
- 206010003658 Atrial fibrillation Diseases 0.000 description 1
- 208000008035 Back Pain Diseases 0.000 description 1
- 206010049848 Balance disease Diseases 0.000 description 1
- 208000007204 Brain Death Diseases 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 206010007521 Cardiac arrhythmias Diseases 0.000 description 1
- 206010008132 Cerebral thrombosis Diseases 0.000 description 1
- 210000004720 Cerebrum Anatomy 0.000 description 1
- 210000003737 Chromaffin Cells Anatomy 0.000 description 1
- 206010008874 Chronic fatigue syndrome Diseases 0.000 description 1
- WSEQXVZVJXJVFP-UHFFFAOYSA-N Citalopram Chemical compound O1CC2=CC(C#N)=CC=C2C1(CCCN(C)C)C1=CC=C(F)C=C1 WSEQXVZVJXJVFP-UHFFFAOYSA-N 0.000 description 1
- 206010057668 Cognitive disease Diseases 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 208000008313 Contusions Diseases 0.000 description 1
- 208000004981 Coronary Disease Diseases 0.000 description 1
- 210000003792 Cranial Nerves Anatomy 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229940030606 DIURETICS Drugs 0.000 description 1
- 206010049095 Decerebration Diseases 0.000 description 1
- 208000000264 Deglutition Disorders Diseases 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 206010054089 Depressive symptom Diseases 0.000 description 1
- 208000002173 Dizziness Diseases 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- 241000083551 Ena Species 0.000 description 1
- 206010015769 Extradural haematoma Diseases 0.000 description 1
- 210000003414 Extremities Anatomy 0.000 description 1
- 206010061129 Eye movement disease Diseases 0.000 description 1
- 206010016059 Facial pain Diseases 0.000 description 1
- 206010016256 Fatigue Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010019233 Headache Diseases 0.000 description 1
- 102000003839 Human Proteins Human genes 0.000 description 1
- 108090000144 Human Proteins Proteins 0.000 description 1
- 241000282619 Hylobates lar Species 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010022114 Injury Diseases 0.000 description 1
- 208000005615 Interstitial Cystitis Diseases 0.000 description 1
- 208000002551 Irritable Bowel Syndrome Diseases 0.000 description 1
- 206010061256 Ischaemic stroke Diseases 0.000 description 1
- 241000229754 Iva xanthiifolia Species 0.000 description 1
- TYQCGQRIZGCHNB-JLAZNSOCSA-N L-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 1
- 206010024855 Loss of consciousness Diseases 0.000 description 1
- 206010024870 Loss of libido Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 206010061284 Mental disease Diseases 0.000 description 1
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 210000003657 Middle Cerebral Artery Anatomy 0.000 description 1
- 208000008433 Motor Disorders Diseases 0.000 description 1
- 208000002430 Multiple Chemical Sensitivity Diseases 0.000 description 1
- 206010052904 Musculoskeletal stiffness Diseases 0.000 description 1
- 208000010125 Myocardial Infarction Diseases 0.000 description 1
- 102000004868 N-methyl-D-aspartate receptors Human genes 0.000 description 1
- 108090001041 N-methyl-D-aspartate receptors Proteins 0.000 description 1
- 208000004296 Neuralgia Diseases 0.000 description 1
- 208000009668 Neurobehavioral Manifestations Diseases 0.000 description 1
- 206010062501 Non-cardiac chest pain Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 229940049964 Oleate Drugs 0.000 description 1
- 206010073261 Ovarian theca cell tumour Diseases 0.000 description 1
- 210000001672 Ovary Anatomy 0.000 description 1
- 206010033775 Paraesthesia Diseases 0.000 description 1
- 208000000450 Pelvic Pain Diseases 0.000 description 1
- 229960001999 Phentolamine Drugs 0.000 description 1
- 206010036312 Post-traumatic epilepsy Diseases 0.000 description 1
- 206010037180 Psychiatric symptom Diseases 0.000 description 1
- 206010037211 Psychomotor hyperactivity Diseases 0.000 description 1
- 210000001747 Pupil Anatomy 0.000 description 1
- 206010037714 Quadriplegia Diseases 0.000 description 1
- 206010040984 Sleep disease Diseases 0.000 description 1
- 206010041466 Speech disease Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000002667 Subdural Hematoma Diseases 0.000 description 1
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 description 1
- 208000007839 Temporomandibular Joint Disorders Diseases 0.000 description 1
- 206010043220 Temporomandibular joint syndrome Diseases 0.000 description 1
- 206010043269 Tension headache Diseases 0.000 description 1
- 208000008548 Tension-Type Headache Diseases 0.000 description 1
- 208000001644 Thecoma Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 102000003978 Tissue plasminogen activator Human genes 0.000 description 1
- 108090000373 Tissue plasminogen activator Proteins 0.000 description 1
- 206010044390 Transient ischaemic attack Diseases 0.000 description 1
- 208000003443 Unconsciousness Diseases 0.000 description 1
- 241000958541 Vulpes zerda Species 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000003213 activating Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive Effects 0.000 description 1
- 230000000240 adjuvant Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000001800 adrenalinergic Effects 0.000 description 1
- 230000001058 adult Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000036626 alertness Effects 0.000 description 1
- 230000000172 allergic Effects 0.000 description 1
- 230000003109 amnesic Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001396 anti-anti-diuretic Effects 0.000 description 1
- 230000003501 anti-edematous Effects 0.000 description 1
- 230000002421 anti-septic Effects 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 201000007201 aphasia Diseases 0.000 description 1
- 230000001174 ascending Effects 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 230000003376 axonal Effects 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-M benzoate Chemical compound [O-]C(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-M 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking Effects 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 231100000874 brain damage Toxicity 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000000271 cardiovascular Effects 0.000 description 1
- 150000003943 catecholamines Chemical class 0.000 description 1
- 230000022534 cell killing Effects 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 108091006028 chimera Proteins 0.000 description 1
- 229960001653 citalopram Drugs 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000000875 corresponding Effects 0.000 description 1
- 230000001808 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- AIMMVWOEOZMVMS-UHFFFAOYSA-N cyclopropanecarboxamide Chemical compound NC(=O)C1CC1 AIMMVWOEOZMVMS-UHFFFAOYSA-N 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 230000003111 delayed Effects 0.000 description 1
- 201000010064 diabetes insipidus Diseases 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 230000001079 digestive Effects 0.000 description 1
- 201000009910 diseases by infectious agent Diseases 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002708 enhancing Effects 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 230000003480 fibrinolytic Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 229940050411 fumarate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000005714 functional activity Effects 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000036449 good health Effects 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229920000591 gum Polymers 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000000004 hemodynamic Effects 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000000968 intestinal Effects 0.000 description 1
- 230000003834 intracellular Effects 0.000 description 1
- 201000001429 intracranial thrombosis Diseases 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 230000002045 lasting Effects 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-M laurate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 1
- 229940070765 laurate Drugs 0.000 description 1
- 229960001926 levomilnacipran hydrochloride Drugs 0.000 description 1
- 230000007787 long-term memory Effects 0.000 description 1
- 238000002595 magnetic resonance imaging Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-L maleate(2-) Chemical compound [O-]C(=O)\C=C/C([O-])=O VZCYOOQTPOCHFL-UPHRSURJSA-L 0.000 description 1
- 230000036244 malformation Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000015654 memory Effects 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000005487 naphthalate group Chemical group 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 230000000955 neuroendocrine Effects 0.000 description 1
- 210000004255 neuroglia Anatomy 0.000 description 1
- 239000003176 neuroleptic agent Substances 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 230000003000 nontoxic Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000002474 noradrenergic Effects 0.000 description 1
- 201000005016 ocular motility disease Diseases 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-M oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC([O-])=O ZQPPMHVWECSIRJ-KTKRTIGZSA-M 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-L oxalate Chemical compound [O-]C(=O)C([O-])=O MUBZPKHOEPUJKR-UHFFFAOYSA-L 0.000 description 1
- 229940039748 oxalate Drugs 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M palmitate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000002085 persistent Effects 0.000 description 1
- MRBDMNSDAVCSSF-UHFFFAOYSA-N phentolamine Chemical compound C1=CC(C)=CC=C1N(C=1C=C(O)C=CC=1)CC1=NCCN1 MRBDMNSDAVCSSF-UHFFFAOYSA-N 0.000 description 1
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000001144 postural Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000000750 progressive Effects 0.000 description 1
- 230000002685 pulmonary Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 235000019615 sensations Nutrition 0.000 description 1
- 230000036362 sensorimotor function Effects 0.000 description 1
- 230000001953 sensory Effects 0.000 description 1
- 230000006403 short-term memory Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 230000000392 somatic Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000004083 survival Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002459 sustained Effects 0.000 description 1
- 201000010874 syndrome Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 229960000187 tissue plasminogen activator Drugs 0.000 description 1
- 231100000730 tolerability Toxicity 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 230000000699 topical Effects 0.000 description 1
- 230000001052 transient Effects 0.000 description 1
- 201000010875 transient cerebral ischemia Diseases 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-M valerate Chemical compound CCCCC([O-])=O NQPDZGIKBAWPEJ-UHFFFAOYSA-M 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- 239000004562 water dispersible granule Substances 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- 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
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Abstract
Disclosed herein are pharmaceutical compositions and mixtures containing levomilnacipran/dextromilnacipran in which the mixture does not contain more than 5 wt % of dextromilnacipran. Also disclosed is the use of the mixtures and compositions as a drug in functional recovery after a cerebrovascular accident or head trauma. accident or head trauma.
Description
LEVOMILNACIPRAN-BASED DRUG FOR FUNCTIONAL RECOVERY
AFTER ACUTE OGICAL EVENTS
DESCRIPTION
There are two types of acute neurological events
leading to motor and cognitive deficit: one is of
vascular origin i.e. a Cerebrovascular Accident
(stroke) and the other is of traumatic origin i.e.
tic Brain Injury.
According to WHO, a Cerebrovascular Accident (CVA)
is “rapidly developing clinical signs of focal (at
times global) disturbance of cerebral on, g
more than 24 hours or leading to death with no apparent
cause other than that of vascular origin”. The term
brain attack is also used or apoplexy. CVA is to be
distinguished from a transient ischemic attack (TIA)
defined as “sudden loss of cerebral or ocular function
lasting less than 24 hours assumed to be due to an
embolism or vascular thrombosis”. CVA is the most
frequent type of ogical disease: in Western
countries it represents the third cause of death (after
coronary diseases and cancers) and the leading cause of
handicap acquired at adult age and the second cause of
dementia (Murray CJ, Lopez AD, Mortality by cause for
eight regions of the world: Global Burden of Disease
Study, Lancet, 1997; 349:1269-1276).
With CVA the vascular problem concerned is either
o-embolic (80% of CVAs) due to interrupted blood
supply through obstruction of an , or hemorrhagic
(20% of CVAs) h rupture of an artery. Cerebral
thrombosis is most often caused by arteriosclerosis
(hardening and inflammation of the vascular wall).
Interrupted circulation secondary to arterial
thrombosis (obstruction by a blood clot) is the cause
of infarction (death, necrosis of the region concerned)
accompanied by softening of the corresponding ory
which is no longer irrigated. Gradually the dead tissue
is replaced by conjunctive tissue formed of glial
cells. Another cause of infarction is a brain sm
in which an atheroma plaque (fat) may detach itself
from a large vessel, or when a blood clot is formed for
example in c cardiopathy (myocardial infarction,
valvulopathy, arrhythmia through atrial fibrillation)
and comes to obstruct a al artery causing an
infarction. Brain hemorrhage may also be due to
arteriosclerosis, most often accompanied by arterial
hypertension. Brain hemorrhages may also be caused by
congenital al malformation, infection, brain
tumor, or even an upsetting event, an emotion or
strenuous effort. Hemorrhage is the origin of hematoma
formation which gradually resolves.
CVA diagnosis is firstly clinical. Examination of
motor capacities and sensitivity of all or part of the
body directs diagnosis towards the site of the lesions
which is med by brain imaging. Diagnosis may give
rise to problems in comatose, aphasic or amnesic
patients. The seriousness of clinical signs varies from
the lack of any notable sign to death within a period
of a few days and may include motor, coordination and
walking disorders, and disorders of sensitivity,
, visual field, memory and psyche.
Treatment of CVA is started immediately after the
event and takes into account the ischemic or
hagic origin, determined by brain imaging using
CT brain scans with or without st agent, and
magnetic resonance imaging (MRI). To treat ischemic CVA
the goal is to regulate hydroelectrolytic balance and
arterial re and to obtain reperfusion of the
injured territory using olytic agents such as
anti-platelet agents (aspirin) and fibrinolytics (e.g.
rt-PA (recombinant tissue plasminogen activator)) when
the CVA is taken in charge less than 4h30 after the
first signs. For hemorrhagic CVA, surgery is indicated
if it is possible taking into account the topography
and volume of the hematoma, the t’s level of
consciousness and general condition. Recovery, after
the acute phase, is very progressive and may take
several months or years. It often requires
rehabilitation to treat speech and/or walking
disorders. While motor disorders (movements) and
sensory disorders (sensation) can generally be ed
intellectual sequels may be rsible.
Traumatic brain injury (TBI) is the main cause of
death and severe handicap before the age of 45. The
main causes are: road accidents (about 50%), sports
accidents, occupational accidents, domestic accidents,
attacks, natural disasters and acts of war. There are
ent types of TBI:
- concussion: jarring of the brain subsequent to
a violet blow to the brain, whether or not accompanied
by initial or temporary loss of consciousness, with no
visible radiological lesion to the brain. Return to
consciousness spontaneously occurs after a few seconds,
minutes or hours after the traumatic event in relation
to the extent of the shock and may leave ent
memory disorders, even ary complications: extradural
hematoma, sub-dural hematoma, cerebral edema.
- brain contusion: in this case, there are
anatomical lesions of the brain (hemorrhagic is
with edema), not necessarily at the site of impact,
which may become complicated with brain edema.
- immediate deep coma: this is the most serious
form of concussion. The patient is in a deep,
persistent coma after the shock since the dysfunction
of the ascending reticular activating system lies at
deeper depth. Signs of decerebration are possible
indicating the ce of e mesencephalic and
axonal lesions related to concentric propagation and
the concentration of the shock waves towards the centre
of the brain (stereotaxic ena).
The management of TBI includes the search by brain
imaging for surgically curable lesions (hematoma),
surgery on operable lesions or if not intensive care
medical treatment in a specialized unit (anti-edema,
pulmonary resuscitation etc.). Diuretics are used to
reduce brain edema, and mannitol to dehydrate the brain
tissue. At times brain edema is extensive enough to
initiate brain tion (engaging of the lower part
of the brain underneath the falx cerebri towards the
contralateral cerebral hemisphere, engaging of the
lower part of the brain into the foramen ).
Meningeal hemorrhage may also be associated with brain
contusion, translating as headaches, stiff neck and
alertness disorders. Clinical and radiological
monitoring is set up after emergency treatment.
Prognosis depends on the extent of the initial lesions,
patient age and general condition before the event. The
more the coma is superficial and the younger the
t in good health before the event the greater the
s of recovery. However coma may lead to brain
death in some cases.
After the critical period following after the
traumatic event and return to consciousness, as is the
case with CVA, there is a period of functional recovery
which may leave neurological sequels: signs of plegia
or paralysis, balance disorders, symbol disorders of
aphasia or agnosia type, signs of lesions to the
cranial nerves; neuroendocrine disorders: diabetes
insipidus, weight loss, fatigue, dizziness, loss of
libido and impotency; mental disorders: anxiety after
awareness of potentially rsible sequels,
anhedonia. Other consequences are less frequent:
uent post-traumatic epilepsy, ar ers
such as aneurysm rupture or brain arterial thrombosis.
The field of the invention concerns medical action
with the goal of improving recovery and functional
rehabilitation after an acute neurological event
whether a CVA or TBI. Within the context of the
invention, improving recovery and functional
litation means accelerating and amplifying the
resolving of motor, neurophysiological, cognitive or
psychiatric ms whose onset occurred at the time
of the neurological event, or one or more of these
symptoms. ing to the ion, the motor,
neurophysiological, cognitive and psychiatric symptoms
include but are not limited to:
- paralysis and plegia, including hemiplegia and
tetraplegia;
- paresthesia or sensitivity disorders;
- coordination disorders, ataxia of the limbs and
walking;
- eye movement disorders;
- swallowing disorders;
- speech disorders whether concerning perception
and tanding or expression;
- a and disrupted spatial orientation;
- sight disorders and disorders of the visual
field;
- pupil anomalies;
- attention disorders;
- memory disorders affecting short-term memory
(recent events) or long-term memory (past
events;
- perception ers, essentially visual
concerning recognition of objects, images
writing or physiognomies;
- disorders of executory functions such as action
planning;
- anxiety;
- anhedonia and depressive symptoms;
- perseverance;
- iveness.
The invention also concerns recovery and
functional rehabilitation after a ent
neurological event occurring after an initial
neurological event, caused by the consequence thereof
on postural e, loss of sight or visuospatial
neglect.
Studies in animal and man have shown that it is
possible to rate or amplify functional recovery
after an acute neurological event, via the
administration of medical treatment immediately or even
after a period of a few days to a few months following
after the event. In animal models of unilateral
occlusion of the middle cerebral artery, which mimic
CVA, and models of focal cortical lesions, which mimic
TBI (Goldstein LB. Basic and clinical studies of
pharmacological effects on recovery from brain injury,
J. Neural Transplant & Plasticity, 1993, 4:175-192;
Feeney DM, de Smet AM, Rai S, energic modulation
of hemiplegia: facilitation and maintenance of
recovery. Restor Neurol & Neurosci, 2004, 22:175-190),
medical treatments which proved to be active in the rat
and cat are:
- amphetamine, a product which increases
ellular levels of noradrenaline, serotonin
and dopamine,
- transplantation of chromaffin cells, which
secrete noradrenaline;
- intracerebral infusion of noradrenaline, but not
serotonin or dopamine;
- administration of a noradrenaline precursor;
- administration of alpha-adrenergic ts.
al studies, in small groups of ts,
have shown the possibility of improving motor recovery
after CVA by treatment with amphetamine (Sonde L,
Nordström M, Nilsson CG, Lökk J, Viitanen M, A double-
blind placebo-controlled study of the effects of
amphetamine and therapy after stroke. Cerebrovasc
Dis, 2001,12:253-257); L-DOPS, a noradrenaline
precursor (Nishino K, Sasaki T, Takahashi K, Chiba M,
Ito T, The norepinephrine precursor L-threo-3,4-
dihydroxyphenylserine facilitates motor recovery in
chronic stroke patients. J. Clin Neurosci, 2001, 8:547-
550), methylphenidate, an agent that also increases the
extracellular rates of noradrenaline, nin and
dopamine (Tardy J, Pariente J, Leger A, Dechamont-
Palacin S, at A, Guiraud V, Conchou F, Albucher
JF, Marque P, Franceries X, Cognard C, Rascol O,
t F, Loubinoux I, Methylphenidate modulates
cerebral post-stroke reorganization, Neuroimage, 2006,
33 :913-922), reboxetine, a selective inhibitor for the
reuptake of noradrenaline (Zitel S, Weiller C, Liepert
J, Reboxetine improves motor function in chronic
. A pilot study, J. Neurol, 2007, 254:197-201),
fluoxetine, a selective inhibitor for the reuptake of
serotonin (Pariente J, Loubinoux I, Carel C, Albucher
JF, Leger A, Manelfe C, Rascol O, Chollet F, tine
modulates motor performance and cerebral activation of
patients ring from stroke, Ann Neurol, 2001,
50:718-729). The effect of fluoxetine administered for
3 months was confirmed in a larger double-blind,
o-controlled al study (Chollet F, Tardy J,
Albucher JF, Thalamas C, Berard E, Lamy C, Bejot Y,
Deltour S, Jaillard A, Niclot P, Guillon B, Moulin T,
Marque P, Pariente J, Arnaud C, Loubinoux I, Fluoxetine
for motor recovery after acute ischaemic stroke
(FLAME): a randomized placebo-controlled trial. Lancet
Neurol, 2011, 10:123-30).
It is important to point out that these
therapeutic approaches are not intended to restore or
protect the injured brain area but to enable the brain
which has some plasticity to reorganize its circuits to
allow non-injured regions to ensure the ons
normally carried out by the injured region, whether
motor, neurophysiological or cognitive functions. This
was med by onal imagery after CVA and TBI.
The ability of the monoamines (noradrenaline,
serotonin, dopamine) to promote the functional
reorganization of the brain tallies with their known
rophic role for developing neurons to ensure the
differentiation and survival of neurons.
From these data showing the crucial role of
serotonin and noradrenaline in functional recovery, it
is concluded that a nal product which produces a
rise in extracellular levels of both noradrenaline and
serotonin would have an advantage over medicinal
products which only increase serotonin levels, such as
fluoxetine, for treatment after an acute neurological
event.
lnacipran is the (1S, 2R) omer of
milnacipran (Z (±)aminomethyl)-N,N’-diethylphenyl
cyclopropane carboxamide) described in patents
and WO 2009/127737. Milnacipran is an
inhibitor of the reuptake of enaline and
serotonin having a balanced effect on these two
neurotransmitters (Briley M, Prost JF, Moret C,
Preclinical pharmacology of milnacipran. Int Clin
Psychopharmacol, 1996 Suppl 4:9-14; Preskorn SH,
Milnacipran: a dual norepinephrine and serotonin
ke pump inhibitor, J Psychiatr Pract, 2004,
:119-26). Milnacipran is a drug used in depression
(Spencer CM and Wilde MI, Milnacipran: a review of its
use in depression. Drugs, 1998, -427) and in
fibromyalgia (Owen RT, Milnacipran hloride: its
efficacy, safety and tolerability e in
fibromyalgia syndrome. Drugs Today (Barc) 2008, 44:653-
60). Patent applications WO2003/039598, WO2003/068211,
WO2003/077897, /090743, WO2004/009069,
WO2004/030633, WO2004/045718, WO/2007/038620,
WO2008/019388, WO2008/021932 and WO2008/147843 also
describe the use of milnacipran and its enantiomers in
chronic fatigue syndrome, attention deficit with
hyperactivity, al pain syndromes, functional
somatic syndromes, cognitive and sleep disorders,
irritable bowel syndrome, chronic lumbar pain, chronic
pelvic pain, interstitial cystitis, non-cardiac chest
pain, neuropathic pain, temporomandibular joint
disorder, atypical facial pain, tension headache,
multiple chemical sensitivities, chronic pain
associated with medical treatment or radiotherapy or
other indications of chronic pain; in particular these
patent applications do not describe the use of
milnacipran for the treatment of CVA and TBI.
Levomilnacipran is the isomer deemed to be the
active isomer of milnacipran; it has the highest
affinity for noradrenaline and serotonin transporters
compared with that of the other enantiomer,
dextromilnacipran, and blocks the reuptake of
noradrenaline and serotonin at lower concentrations
than those required by milnacipran (Example 1).
Surprisingly however dextromilnacipran is the most
powerful isomer on the alpha1-adrenergic receptor in
rat or man (Example 1). In addition, dextromilnacipran
has alpha1-antagonist behavior: it does not activate
the recombinant human alpha1 receptor and antagonizes
the effect of line le 2).
Preclinical and clinical data indicate that the
alpha1-adrenergic receptor plays a crucial role in
functional recovery after a neurological event. Indeed
a single administration of prazosin, a ive
nist of the alpha1 receptor (Hoffman and
Lefkowitz, Catecholamines, homimetic drugs and
adrenergic receptor antagonists, in Goodman and
Gilman’s, The Pharmacological Basis of Therapeutics,
Hardman JG, d LE, Molinoff P B, Ruddon RW
publishers, 9th n, 1995, McGraw-Hill, New York,
pp. 229) delays functional recovery after eral
focal traumatic contusion of the sensorimotor cortex in
the rat (Feeney DM and Westerberg VS, Norepinephrine
and brain damage: alpha noradrenergic pharmacology
alters functional recovery after cortical trauma. Can J
Psychology, 1990, 44: 233-252) and precipitates the reonset
of motor symptoms in the rat up to 6 months after
a unilateral frontal lesion in the rat when motor
functional recovery has been effective (Stibick DL and
Fennec DM, Enduring vulnerability to transient
reinstatement of hemiplegia by prazosin after tic
brain injury, J. Neurotrauma, 2001, 18:303-312). In
healthy volunteers, the administration of prazosin
ses the efficacy of motor training in inducing
cerebral plasticity in the cortex, in the absence of
any change in cortical-motor excitability (Sawaki L,
Werhahn KJ, Barco R, Kopylev L, Cohen LG, Effect of an
-adrenergic blocker on plasticity ed by
motor training, Exp Brain Res, 2003, 148:504-508).
Training-induced plasticity is assumed to contribute
towards motor functional recovery after an acute
neurological event. Goldstein et al (The influence of
drugs on the recovery of sensorimotor function after
stroke, J Neuro Rehab, 1990, 4:137-144) conducted a
study in CVA patients and found that those who were
prescribed drugs having deleterious effects on
functional recovery in experimental animals, which
notably ed prazosin, had lower motor scores on
the Fugl-Meyer scale than those not given these drugs
with deleterious s, over a 30-day prospective
study following after inclusion. All these preclinical
and clinical data show that an alpha1-adrenergic
antagonist must not be administered to a patient in
functional recovery phase after an acute neurological
event.
It has therefore surprisingly been discovered that
it would be contra-indicated to administer
milnacipran, which was found to be an alpha1-
adrenergic antagonist when developing the invention, to
a patient in functional recovery after an acute
neurological event whether a CVA or TBI. Therefore
contrary to the ion made in application
WO2006/006617, the milnacipran te which contains
an equal proportion of lnacipran and
dextromilnacipran, must not be prescribed in the above-
mentioned clinical ions. On the contrary,
substantially pure levomilnacipran or a
lnacipran/dextromilnacipran mixture containing
dextromilnacipran in a proportion not exceeding 5% by
weight of the said mixture (see Example 3) should be
used during functional recovery after an acute
neurological event whether a CVA or TBI.
Patent WO2004/075886 claims the use of
levomilnacipran to prepare a medication for a variety
of pathologies in patients presenting with
cardiovascular risk, on the basis of the observation
that levomilnacipran induces fewer hemodynamic
phenomena than the milnacipran racemate in dogs.
However, this patent does not disclose the ular
activity of dextromilnacipran on the alpha1-adrenergic
receptor and even less so the use of levomilnacipran
for functional recovery after CVA or TBI.
Further, according to the invention,
levomilnacipran is used in the form of a
pharmaceutically acceptable salt chosen from among the
inorganic acid addition salts non-toxic for patients in
whom they are administered. The term “pharmaceutically
able” refers to molecular entities and
compositions which do not e any adverse or
allergic effect or other undesirable reaction when
administered to man or animal. Examples of
pharmaceutically acceptable acid addition salts include
the hydrobromide, hydrochloride, e, bisulfate,
phosphate, nitrate, acetate, oxalate, valerate, oleate,
palmitate, stearate, laurate, , benzoate,
lactate, phosphate, tosylate, citrate, maleate,
fumarate, succinate, tartrate, naphthylate salts and
the like (see for example Berge SM, Bighley LD,
use DC, ceutical salts, 1977, 66:1-19). The
preferred salt r in the present invention is
levomilnacipran hydrochloride.
The invention also concerns a pharmaceutical
composition characterized in that it contains
levomilnacipran as active ingredient and at least one
pharmaceutically able excipient. When used
herein, the term pharmaceutically acceptable excipient
includes any diluent, adjuvant or excipient such as
preserving agents, filler agents, disintegrating,
wetting, emulsifying, dispersing, antibacterial or
antifungal agents, or agents which can delay intestinal
and digestive tion and tion. The use of
these media or vectors is well known to the person
skilled in the art.
The pharmaceutical compositions may contain
substantially pure levomilnacipran or mixtures of
levomilnacipran and dextromilnacipran, provided that
the proportion of dextromilnacipran is insufficient for
the alpha1-adrenergic antagonist activity to be
significant and for the patient to be exposed to
blocking of the alpha1-adrenergic receptor. A
simulation of the activity of the
lnacipran/dextromilnacipran mixtures, confirmed
by experimental data, shows that the anti-alpha1
activity becomes significant with mixtures containing
more than 5% of dextromilnacipran (Example 3). The
proportion of dextromilnacipran in a
lnacipran/dextromilnacipran mixture must not
ore exceed 5% by weight of the said mixture.
The pharmaceutical compositions according to the
t invention can be formulated for administration
to mammals, including man. The compositions of the
invention can be administered via oral, sublingual,
sub-cutaneous, intramuscular, enous, transdermal,
local or rectal route. In this case, the active
ingredient can be administered in unit administration
forms, in a mixture with conventional pharmaceutical
rs, to animal or human beings. The suitable unit
administration forms comprise the forms via oral route
such as s, capsules, powders, granules, each
containing a predetermined quantity of levomilnacipran,
they also include oral solutions or sions in an
aqueous liquid or non-aqueous liquid, or an oil/water
or water/oil liquid emulsion, gual and mouth
administration forms, sub-cutaneous or transdermal,
topical, intramuscular, intravenous, intra-nasal or
intraocular administration forms and rectal
administration forms. When a solid composition is
prepared in tablet form, the levomilnacipran is mixed
with a pharmaceutical vehicle such as gelatin, starch,
lactose, ium stearate, talc, gum Arabica, silica
or the like. It is possible to coat the s with
sucrose or other suitable materials.
The release of the said active ient can be
delayed to obtain sustained release so as to allow the
administration of a single daily dose. Said galenic
formulation can be obtained following the method
described in patent EP 939 626 or any other method.
A capsule preparation is obtained by mixing the
active ingredient with a diluent and pouring the
mixture ed into soft or hard capsules.
A preparation in syrup or elixir form can contain
the active ingredient combined with a sweetener, an
antiseptic, and a suitable flavoring agent and coloring
agent.
s or water-dispersible granules can contain
the active ingredient in a mixture with dispersing or
wetting agents, or suspending agents, and also with
flavor enhancing or sweetening agents.
For rectal administration, recourse is had to
suppositories prepared with s melting at rectal
temperature e.g. cocoa butter or polyethylene glycols.
For parenteral administration (intravenous,
intramuscular, intradermal, sub-cutaneous), intra-nasal
or intra-ocular stration, aqueous sions are
used, isotonic saline solutions or sterile solutions
for injection which contain pharmaceutically compatible
dispersing and/or wetting agents.
The active ingredient may also be formulated in
the form of microcapsules optionally with one or more
additive rs.
Advantageously the ceutical composition
according to the present invention is intended for
administration via oral route.
The dosages of the pharmaceutical compositions
containing lnacipran in the itions of the
invention are adjusted to obtain a quantity of active
substance which is efficient to obtain the desired
therapeutic response for a composition particular to
the administration route. The chosen dosage level
therefore depends on the desired therapeutic effect,
the chosen route of administration, the desired length
of treatment, the weight, age and gender of the
t, the sensitivity of the individual to be
treated. As a result, the optimal dosage must be
determined in relation to parameters deemed to be
nt by specialists in the field.
Preferably the levomilnacipran is administered in
pharmaceutically acceptable compositions in which the
daily dose of levomilnacipran, expressed as base
amount, is between 25 and 200 mg taken in a single
administration or several times per day. Further
preferably, the pharmaceutical composition allows
modified intestinal absorption so that a single
administration per day is sufficient.
Reference to any prior art in the specification is
not, and should not be taken as, an acknowledgment, or
any form of suggestion, that this prior art forms part
of the common general knowledge stralia or any
other jurisdiction or that this prior art could
reasonably be expected t1) be ained, understood
and regarded as relevant Inf a person skilled ill the
art.
As used herein, except where the context es
otherwise, the term "comprise" and variations of the
term, such as "comprising", "comprises" and
ised”, are not intended to exclude other
ves, components, integers or steps.
Example 1
Measurement of the affinity of the two isomers of
milnacipran for the enaline and serotonin
transporters and for the alphal—adrenergic receptor.
The affinities of levomilnacipran and
dextromilnacipran were measured on the binding to the
recombinant human transporters of noradrenaline and
serotonin, and on the binding to the human recombinant
alphal receptor. The inhibition by these two products
of the ke of noradrenaline PH] and serotonin
PH] was also measured.
Methods:
— Binding to the noradrenaline transporter: binding
was measured on membranes of MDCK cells expressing
3O this transporter, purchased from Perkin—Elmer (batch
N° 4lB—l65-A), d in 50 mM TRIS—HCl buffer
containing 120 mM NaCL and 5 mM KCl at a
concentration of 5 pg proteins, in the presence of
2 mM N—methyl—nisoxetine [3H] and increasing
concentrations of levomilnacipran or
16 A
dextromilnacipran (10'11 to 10‘5 M). The bound
on was separated by filtration and washing in
cooled TRIS + NaCl + KCl buffer. Non—specific
binding was ed in the presence of 10 pM
desipramine.
Binding to the serotonin transporter: binding was
ed on membranes of MDCK cells expressing this
transporter, purchased from Perkin—Elmer (Batch
N° 316—199-A) diluted in 50 mM TRIS-HCl buffer
containing 120 mM NaCl and 5 mM KCl at a
concentration of 5 pg of proteins, in the presence
of 2 nM citalopram [3H] and increasing
trations of levomilnacipran or
dextromilnacipran (10-11 to 10-5 M). The bound
fraction was separated by filtration and washing in
cooled TRIS + NaCl + KCl buffer. Non-specific
binding was ed in the presence of 10 µM
fluoxetine.
- g to the recombinant human alpha1 receptor:
binding was measured on membranes of CHO cells
(Chinese Hamster Ovary) expressing the human alpha1B
receptor (Wurch T, Boutet-Robinet EA, Palmier C,
Colpaert FC, s PJ, Constitutive coupling of
chimeric dopamine ha1B or to the
olipase C pathway: inverse agonism to silent
antagonism of neuroleptic drugs, J Pharmacol Exp
Ther, 2003, 304:380-390) diluted in 50 mM TRIS-HCl
buffer at a concentration of 7.8 µg of proteins, in
the presence of 0.1 nM prazosin [3H] and increasing
concentrations of levomilnacipran or
dextromilnacipran (10-11 to 10-5 M). The bound
fraction was separated by filtration and washing in
cooled TRIS buffer. Non-specific binding was
measured in the presence of 10 µM phentolamine.
- Reuptake of noradrenaline [3H]: CHO-K1 cells were
permanently transfected with the gene of the human
transporter of enaline by electric pulsing
(Biorad gene pulser) and the transfected clones were
then selected by incubation in geneticin. To measure
reuptake, the transfected cells were cultured in 24-
well plates then incubated in the presence of
pargyline and ate (100 µM) and noradrenaline
[3H] (specific activity = 40.7 Ci/mole) at a
concentration of 10 nM. Reuptake was halted by
aspiration and rinsing the medium and the
radioactivity captured by the cells was counted by
liquid scintillation. The non-specific signal was
determined in the presence of 10 µM desipramine.
- Reuptake of serotonin [3H]: CHO-K1 cells were
transfected permanently with the gene of the human
transporter of serotonin by electric pulsing (Biorad
gene pulser) and the transfected clones were
selected by incubation in geneticin. To measure
reuptake, the transfected cells were cultured in 24-
well plates then incubated in the presence of
pargyline and ascorbate (100 µM) and serotonin[3H]
(specific activity = 32.7 e) at a
tration of 10 nM. Reuptake was halted by
aspiration and rinsing of the medium and the
ed ctivity by the cells was counted by
liquid scintillation. The ecific signal was
determined in the presence of 10 µM fluoxetine.
Results:
Table 1 gives the values of inhibition constants
(Ki) of levomilnacipran and dextromilnacipran for the
serotonin and noradrenaline transporters, and of the
alpha1-adrenergic receptor.
Table 1
Value of Ki for binding or of IC50
for reuptake (µM)
Target lnacipran dextromilnacipran
Binding to the
noradrenaline 0.091 10.5
transporter (NET)
Binding to the
serotonin 0.011 0.32
transporter
(SERT)
Inhibition of
noradrenaline 0.010 0.15
reuptake[3H]
Inhibition of
nin 0.018 0.28
reuptake[3H]
α1A adrenergic 110 3.4
receptor
Example 2
Measurement of the intrinsic activity of
milnacipran on recombinant human alpha1A and
alpha1B receptors.
The intrinsic functional activity of
dextromilnacipran was measured on cells expressing the
human alpha1A and alpha1B receptors to determine the
agonist/antagonist property thereof.
Methods:
CHO-K1 cells having stable expression of the human
alpha1A receptor or human alpha1B receptor were
obtained using the bed method (Vicentic et al.
Biochemistry and pharmacology of epitope-tagged
alpha1a-adrenergic or subtype, J Pharm Exp Ther,
2002, 30265). The agonist activity was evaluated by
metry measurement of the intracellular
concentration of calcium following a conventional
technique using a fluorescent calcium chelator and
signal recording with a Fluorometric Imaging Plate
Reader (FLIPR, lar Devices, Saint-Grégoire,
). As positive nce (-)adrenaline was used,
and responses were then normalized to the response of
(-)adrenaline at a concentration of 10 µM.
Results:
Over a concentration range of 3.10-7 M to 10-3 M,
dextromilnacipran did not show any agonist activity
higher than 10% of the activity of the (-)adrenaline,
whether on the alpha1A receptor or alpha1B receptor.
The (-)adrenaline was then incubated in increasing
concentrations (3.10-10 to 3.10-5 M) in the presence of
levomilnacipran or dextromilnacipran at a concentration
of 300 µM. Figure 1 shows that the concentration-
response curve of the (-)adrenaline is shifted towards
the right by dextromilnacipran by a factor of about 100
for the alpha1A sub-type and by about 10 for the
B sub-type. For levomilnacipran, the shift is
only about 3 for the alpha1A sub-type and 2 for the
alpha1B sub-type. It is concluded that
dextromilnacipran is an antagonist for these two subtypes
of alpha1-adrenergic receptors. Levomilnacipran
is also an antagonist of the alpha1A and alpha1B
receptors but to a much less powerful extent than
dextromilnacipran.
Example 3
cological characteristics of mixtures of
levomilnacipran and dextromilnacipran, with varying
proportions of the enantiomers.
Objectives
Levomilnacipran (enantiomer, 1S, 2R) has a
distinct pharmacological profile compared with racemic
ipran (2207) and the other 1R, 2S enantiomer
(dextromilnacipran). Levomilnacipran is the most active
enantiomer on the desired targets: binding with the
enaline transporter (NET), binding with the
serotonin transporter (SERT) and the PCP site (NMDA
receptor, glutamate ), but is the least active on
non-desired targets i.e. on α1A and α1B adrenergic
receptors. We ted the cological properties
of different es (containing varied tages of
dextromilnacipran). First, binding assays were
simulated and the apparent inhibition constants of the
mixtures for NET, SERT and the α1A receptors were
calculated. Next, the simulation was experimentally
validated for the α1A receptors for which the
variations in levomilnacipran had the most impact.
Methods
tion
The inhibition constants (value of Ki) of
levomilnacipran and dextromilnacipran on the main
targets were experimentally determined using
conventional binding assays with specific radioligands
and recombinant human proteins (see Example 1).
For each target, the total of bound radioligand
was ated taking into t the inhibitor effect
of each tor. The total of each occupied target is
described using the conventional law of mass action:
(1) R.S. = Kd
(2) R.I1 = Ki1
(3) R.I2 = Ki2
(4) Bmax = B + RI1 + RI2 + R
where R is the concentration of free binding sites;
Bmax is the total concentration of sites; B is the
concentration of sites bound to the radioligand; S is
the radioligand concentration; Kd is the iation
constant of the radioligand; i1 is the concentration of
inhibitor 1; Ki1 is the inhibition constant of
inhibitor 1; RI1 is the concentration of sites occupied
by inhibitor 1; i2 is the concentration of inhibitor 2;
Ki2 is the inhibition constant of inhibitor 2 and RI2 is
the concentration of sites occupied by inhibitor 2.
On the basis of equations (1) to (4):
Bmax.S
B = -------------------------
S + Kd (1 + i1/Ki1 + I2/Ki2)
The values of B were calculated taking into
account the real values of Ki1 and Ki2 (see Table above)
g the proportion of dextromilnacipran to vary by
0.01% to 30% in the mixture, and varying the
concentration of the mixture from 0.01 to 52.0 µM. The
values of Kd and S which were used were similar to the
values of the binding assays. A theoretical inhibition
curve was ore plotted with each combination of
values of the different parameters. Then the apparent
IC50 value for each curve was calculated by non-linear
regression as per the ic equation:
Y = 100/1 + 10(i-LogIC50)
where i is the concentration of the inhibitor (mixture)
and the apparent value of Ki was derived using the
Cheng-Prussoff equation: IC50 = Ki (1 + S/Kd).
2.2 Binding assays
A series of levomilnacipran and milnacipran
mixtures with varying proportions of dextromilnacipran
was prepared, and each mixture was incubated at varying
concentrations with membranes of cells expressing the
recombinant human α1A receptor and using prazosin[3H]
as radioligand. The apparent IC50 value for each curve
was calculated by non-linear regression as per the
logistic equation:
Y = 100/1 + 10(i-LogIC50)
where i is the tration of the tor (mixture)
and the apparent value of Ki was derived using the
Cheng-Prussoff equation: IC50 = Ki (1 + S/Kd).
Results
The results are expressed as apparent Ki value as
a on of dextromilnacipran percentage (Figure 1).
Figure 2 shows: the apparent Ki values of
simulated assays (A, B and C) and measured values (D)
of mixtures of levomilnacipran (F2695) and
dextromilnacipran (F2696) with increasing proportions
of dextromilnacipran for NET, SERT or α1A receptor
targets.
The values of Ki for NET and SERT were not too
affected by different proportions of dextromilnacipran.
On the contrary, the apparent value of Ki for the α1A
receptors, whether for simulation assays or for real
assays, was dramatically affected when the tage
of milnacipran was increased, which indicates
that the impact on the α1 ors is non-negligible.
If it is considered that the impact becomes nonnegligible
when the value of Ki drops by half, the
maximum percentage of milnacipran is about 5%.
Conclusion
A mixture with a proportion of dextromilnacipran
higher than this 5% may not be bioequivalent to
antially pure” levomilnacipran, or to a mixture
with smaller proportions of dextromilnacipran. The
impact on the α1A receptors of mixtures with
proportions of dextromilnacipran higher than 5% is not
negligible and such mixtures should not be used in the
treatment of functional recovery after a stroke.
Claims (10)
1. A levomilnacipran/dextromilnacipran mixture containing dextromilnacipran in a proportion not ing 5% by weight of the said mixture for use thereof as medicinal product for ry and functional rehabilitation after an acute neurological event and recurrences thereof.
2. The mixture according to claim 1 for use 10 thereof in patients diagnosed with cerebral vascular accident of ischemic or hemorrhagic origin.
3. The mixture according to claim 1 for use thereof in patients diagnosed with traumatic brain 15
4. A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and a levomilnacipran/dextromilnacipran. mixture containing dextromilnacipran in a proportion not ing 5% by weight of the said mixture as active ingredient for use 20 thereof as medicinal product for recovery and functional rehabilitation after an acute neurological event and recurrences thereof.
5. A pharmaceutical composition according to claim 4 for use in patients sed with 25 cerebrovascular accident.
6. A pharmaceutical composition according to claim 4 for use in patients diagnosed with traumatic brain injury.
7. A pharmaceutical ition according to any 3O one of claims 4 to 6 wherein the daily dosage of levomilnacipran is n 50 and 200 mg.
8. A pharmaceutical ition according to any one of claims 4 to 7 wherein the composition is in a modified intestinal absorption form allowing the 35 administration of a single dose per day.
9. A levomilnacipran/dextromilnacipran mixture according to claim 1, substantially as herein bed.
10. A pharmaceutical composition according to claim 4, substantially as herein described.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR1156917A FR2978350B1 (en) | 2011-07-28 | 2011-07-28 | LEVOMILNACIPRAN-BASED MEDICINAL PRODUCT FOR FUNCTIONAL REHABILITATION AFTER ACUTE NEUROLOGICAL ACCIDENT |
FR1156917 | 2011-07-28 | ||
PCT/EP2012/064764 WO2013014263A1 (en) | 2011-07-28 | 2012-07-27 | Levomilnacipran drug for functional rehabilitation after an acute neurological stroke |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ621474A NZ621474A (en) | 2015-02-27 |
NZ621474B2 true NZ621474B2 (en) | 2015-05-28 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2018250214B2 (en) | Methods and compositions for treating aging-associated impairments using CCR3-inhibitors | |
Lauterbach | An extension of hypotheses regarding rapid-acting, treatment-refractory, and conventional antidepressant activity of dextromethorphan and dextrorphan | |
ES2646363T3 (en) | Tapentadol for the prevention and treatment of depression and anxiety | |
JP2010531879A (en) | Drug showing anxiolytic action based on hydrogenated pyrido [4,3-b] indole, pharmacological compound thereof and method of application | |
US20060122127A1 (en) | Methods for reducing the side effects associated with mirtzapine treatment | |
JP2019123748A (en) | Galantamine clearance of amyloid beta | |
US20200054622A1 (en) | Methods and Compositions for Treating Aging-Associated Impairments Using CCR3-Inhibitors | |
KR101903713B1 (en) | Method for Preventing and/or Treating Chronic Traumatic Encephalopathy-II | |
NZ621474B2 (en) | Levomilnacipran drug for functional rehabilitation after an acute neurological stroke | |
US20140179794A1 (en) | Levomilnacipran-based drug for functional recovery after acute neurological events | |
OA16854A (en) | Levomilnacipran drug for functional rehabilitation after an acute neurological stroke | |
AU2015258814B2 (en) | Clearance of amyloid ss | |
CN111032048B (en) | Use of buspirone for the treatment of functional dizziness | |
JP7528065B2 (en) | Methods and compositions for treating age-related dysfunction using CCR3 inhibitors | |
EA041007B1 (en) | USE OF BUSPIRONE FOR THE TREATMENT OF FUNCTIONAL VERTIGO | |
KR20060072126A (en) | The combination of a serotonin reuptake inhibitor and amoxapine |