NZ755661A - Novel combinations of a h3 antagonist and a noradrenaline reuptake inhibitor, and the therapeutical uses thereof - Google Patents
Novel combinations of a h3 antagonist and a noradrenaline reuptake inhibitor, and the therapeutical uses thereofInfo
- Publication number
- NZ755661A NZ755661A NZ755661A NZ75566119A NZ755661A NZ 755661 A NZ755661 A NZ 755661A NZ 755661 A NZ755661 A NZ 755661A NZ 75566119 A NZ75566119 A NZ 75566119A NZ 755661 A NZ755661 A NZ 755661A
- Authority
- NZ
- New Zealand
- Prior art keywords
- combination
- chosen
- anyone
- duloxetine
- antagonist
- Prior art date
Links
- 239000003395 histamine H3 receptor antagonist Substances 0.000 title claims abstract description 16
- 239000002767 noradrenalin uptake inhibitor Substances 0.000 title claims description 12
- 230000001225 therapeutic Effects 0.000 title description 4
- 230000001430 anti-depressive Effects 0.000 claims abstract description 11
- 239000000935 antidepressant agent Substances 0.000 claims abstract description 11
- 239000000203 mixture Substances 0.000 claims description 42
- 201000010099 disease Diseases 0.000 claims description 31
- ZEUITGRIYCTCEM-KRWDZBQOSA-N Duloxetine Chemical compound C1([C@@H](OC=2C3=CC=CC=C3C=CC=2)CCNC)=CC=CS1 ZEUITGRIYCTCEM-KRWDZBQOSA-N 0.000 claims description 24
- 150000001875 compounds Chemical class 0.000 claims description 24
- 229960002866 duloxetine Drugs 0.000 claims description 24
- 239000003814 drug Substances 0.000 claims description 16
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 claims description 13
- 229960002748 Norepinephrine Drugs 0.000 claims description 13
- VHGCDTVCOLNTBX-QGZVFWFLSA-N Atomoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=CC=C1C VHGCDTVCOLNTBX-QGZVFWFLSA-N 0.000 claims description 11
- 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 claims description 11
- 239000000556 agonist Substances 0.000 claims description 11
- 229960002430 atomoxetine Drugs 0.000 claims description 11
- 229960003770 reboxetine Drugs 0.000 claims description 11
- 239000011780 sodium chloride Substances 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 10
- 206010041349 Somnolence Diseases 0.000 claims description 8
- 230000003935 attention Effects 0.000 claims description 8
- HCYAFALTSJYZDH-UHFFFAOYSA-N Desimpramine Chemical compound C1CC2=CC=CC=C2N(CCCNC)C2=CC=CC=C21 HCYAFALTSJYZDH-UHFFFAOYSA-N 0.000 claims description 6
- 230000001149 cognitive Effects 0.000 claims description 6
- 229960003914 desipramine Drugs 0.000 claims description 6
- 239000012453 solvate Substances 0.000 claims description 6
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical group C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 claims description 6
- 229960004688 venlafaxine Drugs 0.000 claims description 6
- KYYIDSXMWOZKMP-UHFFFAOYSA-N Desvenlafaxine Chemical compound C1CCCCC1(O)C(CN(C)C)C1=CC=C(O)C=C1 KYYIDSXMWOZKMP-UHFFFAOYSA-N 0.000 claims description 4
- 229960001623 desvenlafaxine Drugs 0.000 claims description 4
- 201000003631 narcolepsy Diseases 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 208000001573 Cataplexy Diseases 0.000 claims description 3
- 230000002950 deficient Effects 0.000 claims description 3
- 239000004615 ingredient Substances 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 206010001584 Alcohol abuse Diseases 0.000 claims description 2
- 208000006068 Idiopathic Hypersomnolence Diseases 0.000 claims description 2
- 208000001797 Obstructive Sleep Apnea Diseases 0.000 claims description 2
- 206010061536 Parkinson's disease Diseases 0.000 claims description 2
- 201000010769 Prader-Willi syndrome Diseases 0.000 claims description 2
- 206010037211 Psychomotor hyperactivity Diseases 0.000 claims description 2
- 208000003615 Sleep Wake Disorders Diseases 0.000 claims description 2
- 206010048010 Withdrawal syndrome Diseases 0.000 claims description 2
- 201000003082 alcohol use disease Diseases 0.000 claims description 2
- 230000027288 circadian rhythm Effects 0.000 claims description 2
- 230000035591 circadian rhythms Effects 0.000 claims description 2
- 150000003840 hydrochlorides Chemical class 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 201000009032 substance abuse Diseases 0.000 claims description 2
- 231100000736 substance abuse Toxicity 0.000 claims description 2
- 230000002195 synergetic Effects 0.000 abstract description 3
- 230000001737 promoting Effects 0.000 abstract 1
- NNACHAUCXXVJSP-UHFFFAOYSA-N Pitolisant Chemical compound C1=CC(Cl)=CC=C1CCCOCCCN1CCCCC1 NNACHAUCXXVJSP-UHFFFAOYSA-N 0.000 description 17
- 229960003651 pitolisant Drugs 0.000 description 16
- 229940079593 drugs Drugs 0.000 description 13
- 241000700159 Rattus Species 0.000 description 11
- 230000007958 sleep Effects 0.000 description 11
- 230000000694 effects Effects 0.000 description 7
- -1 (3S){4-[3-(3-methylpiperidin yl)propoxy]phenyl}pyridine 1-oxide Chemical compound 0.000 description 6
- 210000002442 Prefrontal Cortex Anatomy 0.000 description 6
- 206010062519 Poor quality sleep Diseases 0.000 description 5
- 238000009472 formulation Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 230000004617 sleep duration Effects 0.000 description 4
- 210000001175 Cerebrospinal Fluid Anatomy 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 238000001690 micro-dialysis Methods 0.000 description 3
- 230000002474 noradrenergic Effects 0.000 description 3
- 239000000546 pharmaceutic aid Substances 0.000 description 3
- 230000000699 topical Effects 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- YFGHCGITMMYXAQ-UHFFFAOYSA-N Modafinil Chemical compound C=1C=CC=CC=1C(S(=O)CC(=O)N)C1=CC=CC=C1 YFGHCGITMMYXAQ-UHFFFAOYSA-N 0.000 description 2
- 241000700157 Rattus norvegicus Species 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 230000003042 antagnostic Effects 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-M caproate Chemical compound CCCCCC([O-])=O FUZZWVXGSFPDMH-UHFFFAOYSA-M 0.000 description 2
- 239000000890 drug combination Substances 0.000 description 2
- 238000003304 gavage Methods 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 229960001165 modafinil Drugs 0.000 description 2
- 239000002469 receptor inverse agonist Substances 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000005062 synaptic transmission Effects 0.000 description 2
- WXTMDXOMEHJXQO-UHFFFAOYSA-M 2,5-dihydroxybenzoate Chemical compound OC1=CC=C(O)C(C([O-])=O)=C1 WXTMDXOMEHJXQO-UHFFFAOYSA-M 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- KPGXRSRHYNQIFN-UHFFFAOYSA-L 2-oxoglutarate(2-) Chemical compound [O-]C(=O)CCC(=O)C([O-])=O KPGXRSRHYNQIFN-UHFFFAOYSA-L 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
- WTDRDQBEARUVNC-LURJTMIESA-N 3-hydroxy-L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 1
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-Aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 1
- QCXJEYYXVJIFCE-UHFFFAOYSA-M 4-acetamidobenzoate Chemical compound CC(=O)NC1=CC=C(C([O-])=O)C=C1 QCXJEYYXVJIFCE-UHFFFAOYSA-M 0.000 description 1
- ODHCTXKNWHHXJC-VKHMYHEASA-M 5-oxo-L-prolinate Chemical compound [O-]C(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-M 0.000 description 1
- ILYBMUDLGFMEMU-UHFFFAOYSA-N 7-$l^{1}-oxidanyl-2,3,4,5,6,7-hexaoxoheptan-1-olate Chemical compound [O]C(=O)C(=O)C(=O)C(=O)C(=O)C(=O)C[O-] ILYBMUDLGFMEMU-UHFFFAOYSA-N 0.000 description 1
- 229940035678 ANTI-PARKINSON DRUGS Drugs 0.000 description 1
- 229940005513 ANTIDEPRESSANTS Drugs 0.000 description 1
- 230000035533 AUC Effects 0.000 description 1
- 229940072107 Ascorbate Drugs 0.000 description 1
- 229940009098 Aspartate Drugs 0.000 description 1
- 229940050390 Benzoate Drugs 0.000 description 1
- 230000036912 Bioavailability Effects 0.000 description 1
- 210000004369 Blood Anatomy 0.000 description 1
- 210000004556 Brain Anatomy 0.000 description 1
- 229960002802 Bromocriptine Drugs 0.000 description 1
- OZVBMTJYIDMWIL-AYFBDAFISA-N Bromocriptine Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)CC(C)C)C(C)C)C2)=C3C2=C(Br)NC3=C1 OZVBMTJYIDMWIL-AYFBDAFISA-N 0.000 description 1
- POTBKLVBOJZRNG-UHFFFAOYSA-M C1=CC=C2C(O)(C([O-])=O)CC=CC2=C1 Chemical compound C1=CC=C2C(O)(C([O-])=O)CC=CC2=C1 POTBKLVBOJZRNG-UHFFFAOYSA-M 0.000 description 1
- DSSYKIVIOFKYAU-UHFFFAOYSA-N Camphor Chemical compound C1CC2(C)C(=O)CC1C2(C)C DSSYKIVIOFKYAU-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate dianion Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229940001468 Citrate Drugs 0.000 description 1
- 229940109275 Cyclamate Drugs 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 1
- CKLJMWTZIZZHCS-UHFFFAOYSA-N DL-aspartic acid Chemical compound OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 description 1
- 229940120124 Dichloroacetate Drugs 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N Glycerol 3-phosphate Chemical compound OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 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
- 229940001447 Lactate Drugs 0.000 description 1
- JYTUSYBCFIZPBE-AMTLMPIISA-N Lactobionic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-N 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
- QIAFMBKCNZACKA-UHFFFAOYSA-M N-benzoylglycinate Chemical compound [O-]C(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-M 0.000 description 1
- 229940049964 Oleate Drugs 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N Pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 229940043131 Pyroglutamate Drugs 0.000 description 1
- BKRGVLQUQGGVSM-KBXCAEBGSA-N Revanil Chemical compound C1=CC(C=2[C@H](N(C)C[C@H](C=2)NC(=O)N(CC)CC)C2)=C3C2=CNC3=C1 BKRGVLQUQGGVSM-KBXCAEBGSA-N 0.000 description 1
- UHSKFQJFRQCDBE-UHFFFAOYSA-N Ropinirole Chemical compound CCCN(CCC)CCC1=CC=CC2=C1CC(=O)N2 UHSKFQJFRQCDBE-UHFFFAOYSA-N 0.000 description 1
- UDIPTWFVPPPURJ-UHFFFAOYSA-M Sodium cyclamate Chemical compound [Na+].[O-]S(=O)(=O)NC1CCCCC1 UDIPTWFVPPPURJ-UHFFFAOYSA-M 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000000240 adjuvant Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 230000000172 allergic Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000111 anti-oxidant Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000000939 antiparkinson agent Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-M benzoate Chemical compound [O-]C(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-M 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- 230000035514 bioavailability Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-M camphorsulfonate anion Chemical compound C1CC2(CS([O-])(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-M 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 229940114081 cinnamate Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000001054 cortical Effects 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000001955 cumulated Effects 0.000 description 1
- NXMUXTAGFPJGTQ-UHFFFAOYSA-N decanoic acid;octanoic acid Chemical compound CCCCCCCC(O)=O.CCCCCCCCCC(O)=O NXMUXTAGFPJGTQ-UHFFFAOYSA-N 0.000 description 1
- JXTHNDFMNIQAHM-UHFFFAOYSA-M dichloroacetate Chemical compound [O-]C(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-M 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 230000003292 diminished Effects 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-M dodecyl sulfate Chemical compound CCCCCCCCCCCCOS([O-])(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-M 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 230000000517 effect on sleep Effects 0.000 description 1
- 238000000835 electrochemical detection Methods 0.000 description 1
- 230000000534 elicitor Effects 0.000 description 1
- 230000002708 enhancing Effects 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-L ethane-1,2-disulfonate Chemical compound [O-]S(=O)(=O)CCS([O-])(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-L 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 description 1
- 229940044170 formate Drugs 0.000 description 1
- 239000012458 free base Substances 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
- DSLZVSRJTYRBFB-DUHBMQHGSA-L galactarate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C([O-])=O DSLZVSRJTYRBFB-DUHBMQHGSA-L 0.000 description 1
- 230000002496 gastric Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 230000002068 genetic Effects 0.000 description 1
- 229940114119 gentisate Drugs 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 229940097042 glucuronate Drugs 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-L glutarate(2-) Chemical compound [O-]C(=O)CCCC([O-])=O JFCQEDHGNNZCLN-UHFFFAOYSA-L 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 230000000742 histaminergic Effects 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-M isethionate Chemical compound OCCS([O-])(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-M 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-M isobutyrate Chemical compound CC(C)C([O-])=O KQNPFQTWMSNSAP-UHFFFAOYSA-M 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M isothiocyanate Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 229940099584 lactobionate Drugs 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
- 229960004502 levodopa Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 229960003587 lisuride Drugs 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-L malate(2-) Chemical compound [O-]C(=O)C(O)CC([O-])=O BJEPYKJPYRNKOW-UHFFFAOYSA-L 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
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M methanoate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 230000000051 modifying Effects 0.000 description 1
- 230000001730 monoaminergic Effects 0.000 description 1
- 230000037023 motor activity Effects 0.000 description 1
- XTEGVFVZDVNBPF-UHFFFAOYSA-L naphthalene-1,5-disulfonate(2-) Chemical compound C1=CC=C2C(S(=O)(=O)[O-])=CC=CC2=C1S([O-])(=O)=O XTEGVFVZDVNBPF-UHFFFAOYSA-L 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-M naphthalene-1-sulfonate Chemical compound C1=CC=C2C(S(=O)(=O)[O-])=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-M 0.000 description 1
- 230000001537 neural Effects 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N nicotinic acid Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-M oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC([O-])=O ZQPPMHVWECSIRJ-KTKRTIGZSA-M 0.000 description 1
- PXQPEWDEAKTCGB-UHFFFAOYSA-M orotate Chemical compound [O-]C(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-M 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-L oxalate Chemical compound [O-]C(=O)C([O-])=O MUBZPKHOEPUJKR-UHFFFAOYSA-L 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M palmitate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 230000000803 paradoxical Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000001050 pharmacotherapy Methods 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L propanedioate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229960001879 ropinirole Drugs 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 230000037322 slow-wave sleep Effects 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 241000894007 species Species 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-M stearate Chemical compound CCCCCCCCCCCCCCCCCC([O-])=O QIQXTHQIDYTFRH-UHFFFAOYSA-M 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
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 150000004685 tetrahydrates Chemical class 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 239000002562 thickening agent Substances 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
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 230000001131 transforming Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Abstract
The present invention relates to combinations of a H3 antagonist and an antidepressant, which exhibit a synergistic wake promoting activity.
Description
NOVEL COMBINATIONS OF A H3 ANTAGONIST AND A NORADRENALINE
REUPTAKE INHIBITOR, AND THE THERAPEUTICAL USES THEREOF
The present invention concerns novel combinations and their uses for treating
wakefulness disorders in patients suffering from deficient noradrenaline release.
Wakefulness is controlled by several monoaminergic neuronal systems in brain, mainly
the histaminergic and noradrenergic systems which are active during wake and silent
during sleep. Hence, increase in histamine or noradrenaline release results in wake
promotion at the expense of sleep states.
Histamine H3 receptor antagonist/inverse agonists (X. Ligneau et al. J. Pharmacol. Exp
Ther. 2007, 320, 365, J.S. Lin et al. Neurobiology of Disease 2008, 30, 74, RX Guo et al.
Brit. J. Pharmacol. 2009, 157, 104) are known to modulate sleep/wake increasing
wakefulness.
discloses H3 ligands such as (3S){4-[3-(3-methylpiperidin
yl)propoxy]phenyl}pyridine 1-oxide of formula:
herein referred as “compound (A)”, and their pharmaceutically acceptable salts, hydrates,
or hydrated salts.
Pitolisant (Wakix®) (ie) the monohydrochloride salt of 1-{3-[3-(4-
chlorophenyl)propoxy]propyl}piperidine has been one of the first H3 antagonists / inverse
agonists on the market and is currently authorized in Europe for the treatment of
narcolepsy with or without cataplexy.
The effect of H3 antagonists on noradrenaline has been disclosed in AD Medhurst et al.
(J. Pharmacol. Exp. Ther. 2007, 321, 1032-1045), G. Flik et al. (J. Mol. Neurosci. 2015,
56, 320-328) and J.S. Lin et al. (Neurobiology of Disease 2008, 30,74–83).
Antidepressants with noradrenaline reuptake inhibitor properties such as duloxetine,
reboxetine, atomoxetine, venlafaxine… (C. Sanchez et al. Pharmacol. Biochem. Behav.
2007, 86, 468) increase wake at the expense of deep sleep and/or REM sleep.
Kallweit ET AL (EXPERT OPINION ON PHARMACOTHERAPY vol. 18, no.8, 2017,
pages 809-817) reports the pharmacological management of narcolepsy with depression,
and suggests e.g. venlafaxine.
Lin ET AL (Neurobiology of Disease, vol.30, no. 1, 2008, pages 74-83) discloses the use
of tiprolisant combined with modafinil.
It has now been discovered that the combination of a H3 antagonist with an
antidepressant chosen from the noradrenaline reuptake inhibitors, unexpectedly leads to
tremendous increase in the quiet wake and decrease in the REM sleep, which are
respectively enhanced/diminished in a supra-additive, synergistic manner as compared to
the effect of each compound given alone.
According to a first object, the present invention thus concerns a combination of:
● a H3 antagonist or inverse agonist of formula:
(I)
Where in formula (I):
R is H or Methyl,
R is Cl or where * represents the position of attachment to the
phenyl ring,
n is 0 or 1,
● an antidepressant chosen from the noradrenaline reuptake inhibitors.
According to an embodiment, said H3 antagonist/inverse agonist is chosen from one of
the following compounds:
And any of their pharmaceutically acceptable salts, or solvates thereof.
More particularly, said H3 antagonist/inverse agonist is the hydrochloride salt of
More particularly said H3 antagonist/inverse agonist is the dihydrochloride, tetrahydrate of
(herein called BP1.3656B).
According to an embodiment, the compounds may be in the form of their free base, or
alternatively, in the form of pharmaceutically acceptable salts such as hydrochloride,
oxalate, dihydrochloride, hydrobromide, dihydrobromide, naphthalene-1,5-disulfonate,
sulfate, ethane-1,2-disulfonate, cyclamate, toluenesulfonate, paratoluenesulfonate,
thiocyanate, nitrate, methanesulfonate, dodecylsulfate, naphthalenesulfonate,
benzenesulfonate, dichloroacetate, glycerophosphate, 2-hydroxyethanesulfonate,
aspartate, maleate, phosphate, ethanesulfonate, camphorsulfonate, glutamate,
alginate, pamoate, 2-oxo-glutarate, 1-hydroxynaphthoate, malonate, gentisate,
salicylate, tartrate, fumarate, galactarate, citrate, glucuronate, lactobionate, 4-
aminosalicylate, glycolate, sesquiglycolate, glucoheptonate, pyroglutamate, mandelate,
malate, hippurate, formate, gluconate, lactate, oleate, ascorbate, benzoate, succinate, 4-
acetamidobenzoate, glutarate, cinnamate, adipate, sebacate, camphorate, acetate,
caproate, nicotinate, isobutyrate, propionate, caprate caprylate, caproate, laurate,
palmitate, stearate, undecenoate, caprylate, orotate, carbonate, 5-sulfocalicylate, 1-
hydroxynaphtoate, 3-hydroxynaphtoate; and/or solvates such as hydrates,
ethanolate, hemiethanolate.
Accordingly, the expression “compound” as used herein also refers to the
pharmaceutically acceptable salts thereof and/or the solvates of said unless specified
otherwise.
According to an embodiment, the antidepressant is chosen from from duloxetine,
reboxetine, atomoxetine, desipramine, venlafaxine, desvenlafaxine, more particularly
duloxetine.According to an embodiment, said antidepressant is not venlafaxine.
According to an embodiment, said antidepressant is a noradrenaline reuptake inhibitor
chosen from duloxetine, reboxetine, atomoxetine, desipramine, desvenlafaxine, in
particular duloxetine, reboxetine, atomoxetine, desipramine.
According to an embodiment,
said H3 antagonist/inverse agonist is chosen from one of the following
compounds:
and any of their pharmaceutically acceptable salts, or solvates; and
said noradrenaline reuptake inhibitor is chosen from duloxetine, reboxetine, and
atomoxetine.
According to an embodiment, the combination is the combination of
, HCl (pitolisant) with duloxetine.
According to another object, the present invention also concerns a pharmaceutical
composition comprising a combination according to the invention, wherein both
ingredients are administered simultaneously, separately, or staggered over time.
According to another object, the present invention also concerns the combination of the
invention for use for treating and/or preventing a disorder chosen from excessive daytime
sleepiness, substance such as alcohol abuse disorders, and/or with attention and
cognitive deficit, in a patient suffering from deficient noradrenaline release.
The identification of those subjects who are in need of treatment of herein-described diseases
and conditions is well within the ability and knowledge of one skilled in the art. A clinician
skilled in the art can readily identify, by the use of clinical tests, physical examination, genetic
tests and medical/family history, those subjects who are in need of such treatment.
According to an embodiment, said disorder is excessive daytime sleepiness and occurs in
a patient suffering from:
- Narcolepsy with and without cataplexy,
- Idiopathic hypersomnia,
- Daytime sleepiness disorders,
- Obstructive sleep apnea,
- Circadian rhythm sleep-wake disorders,
- Parkinson’s disease, or
- Prader-Willi Syndrome.
According to an alternative embodiment, said disorder is attention and cognitive deficit
and occurs in a patient suffering from attention deficit and hyperactivity disorder (ADHD).
According to a further alternative embodiment, said disorder is excessive daytime
sleepiness, attention and cognitive deficit and occurs in a patient suffering from
depression.
According to a still further alternative embodiment, said disorder is chosen from substance
abuse withdrawal syndromes.
It should be noted that the alternative embodiment are not mutually exclusive and may be
considered in addition to each other.
Actual dosage levels of the compounds may be varied so as to obtain an amount of active
ingredient that is effective to obtain a desired therapeutic response for a particular
composition and method of administration. The selected dosage level therefore depends
upon the desired therapeutic effect, on the route of administration, on the desired duration
of treatment and other factors, e.g. the condition of the patient.
A therapeutically effective amount can be readily determined by the attending diagnostician,
as one skilled in the art, by the use of conventional techniques and by observing results
obtained under analogous circumstances. In determining the therapeutically effective amount,
a number of factors are considered by the attending diagnostician, including, but not limited to:
the species of subject; its size, age, and general health; the specific disease involved; the
degree of involvement or the severity of the disease; the response of the individual subject;
the particular compound administered; the mode of administration; the bioavailability
characteristic of the preparation administered; the dose regimen selected; the use of
concomitant medication; and other relevant circumstances.
The amount of the compounds which is required to achieve the desired biological effect will
vary depending upon a number of factors, including the type of formulation of the drug to be
administered, the type of disease, the disease state of the patient and the route of
administration.
In general terms, the preferred dosage of a drug to be administered is likely to depend on
such variables as the type and extent of progression of the disease or disorder, the overall
health status of the particular patient, the relative biological efficacy of the compound selected,
and formulation of the compound excipient, and its route of administration.
The daily dose of the H3 antagonist/inverse agonist (I) may generally be comprised between
1 μg and 50mg a day per patient. As an illustration, the preferred doses for pitolisant are 5-
40 mg/day, more preferably 10-30 mg/day, and for BP1.3656B 1-100 μg/day, preferably 5-
30 μg/day
The daily dose of the antidepressant may generally be comprised between 2 mg and 250 mg
a day per patient. Illustrated doses are detailed below:
Desipramine : 10-300 mg/day, preferably 25-200 mg/day; Duloxetine : 20-120 mg/day,
preferably 30-60 mg/day; Venlafaxine : 35-375 mg/day, preferably 35-225 mg/day;
Desvenlafaxine : 50-400 mg/day, preferably 50-100 mg/day; Atomoxetine : 10-100
mg/day, preferably 10-60 mg/day; Reboxetine : 2-12 mg/day, preferably 2-8 mg/day.
According to a further embodiment, the method of the invention also comprises the
administration of one or more further active ingredient, selected from anti-Parkinson drugs
such as levodopa, ropinirole, lisuride, bromocriptine, pramixepole or selected from anti-
narcoleptic or purported anti-narcoleptic drugs from another class including modafinil.
The compounds can be formulated into the same or distinct pharmaceutical compositions by
admixture with one or more pharmaceutically acceptable excipients.
The compositions may conveniently be administered in unit dosage form and may be
prepared by any of the methods well known in the pharmaceutical art, for example, as
described in Remington: The Science and Practice of Pharmacy, 20 ed.; Gennaro, A. R.,
Ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2000.
The compounds may be administered by various administration routes such as oral;
parenteral including sub-cutaneous, intramuscular, intra-venous; sublingual, topical; local;
intratracheal; intranasal; transdermal or rectal, the active ingredients being combined with
a pharmaceutically acceptable excipient or vehicle in one or two pharmaceutical
compositions.
In particular, the formulations suitable for parenteral administration are sterile and include
emulsions, suspensions, aqueous and non-aqueous injection solutions, which may
contain suspending agents and thickening agents and anti-oxidants, buffers, bacteriostats
and solutes which render the formulation isotonic, and have a suitably adjusted pH, with
the blood of the intended recipient. For the topical application, the compositions of the
invention may be used as creams, gels, ointments or lotions.
According to the invention, oral administration of the compound (I) or composition in an
appropriate formulation is advantageously used. Formulations which are suitable to be
administered orally to a patient include discrete units such as capsules, such as soft or
hard gelatine, tablets, each containing a predetermined amount of the compound of
formula (I). They also include powder; granules; solutions or suspensions in an aqueous
liquid or a non-aqueous liquid, or oil-in-water liquid emulsion or water-in-oil liquid
emulsion. Gastrointestinal resistant formulations are also contemplated for oral
formulations, in particular for duloxetine.
“Pharmaceutically” or “pharmaceutically acceptable” refer to molecular entities and
compositions that do not produce an adverse, allergic or other untoward reaction when
administered to an animal, or a human, as appropriate.
As used herein, “pharmaceutically acceptable excipient, vehicle or carrier” includes in
particular diluents, adjuvants, excipients, or vehicles. The use of such ingredients for
pharmaceutical active substances is well known in the art.
In the context of the invention, the term “treating” or “treatment”, as used herein, means
reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to
which such term applies, or one or more symptoms of such disorder or condition.
“Therapeutically effective amount” means an amount of a compound/ medicament
according to the present invention effective in producing the desired therapeutic effect.
According to the invention, the term “patient”, or “patient in need thereof”, is intended for a
human or non-human mammal affected or likely to be affected with the above disorders.
Preferably, the patient is a human.
The compounds may be administered in unit dosage forms, wherein the term “unit dose”
means a single dose which is capable of being administered to a patient, and which can be
readily handled and packaged, remaining as a physically and chemically stable unit dose
comprising either the active compound itself, or as one or two pharmaceutically acceptable
compositions.
The appropriate unitary dosage forms comprise the oral forms; the sublingual, buccal,
intratracheal, intraocular, intranasal forms, by inhalation, the topical, transdermal, sub-
cutaneous, intramuscular or intra-venous, and the rectal forms and the implants.
FIGURES:
• Figure 1 represents the drug-induced changes in sleep-wake balance over 12
hours post dosing in rats (Mean ± SEM of 15 to 16 individual values) in quiet wake
duration (Figure 1A) and REM sleep duration (Figure 1B) following administration
of pitolisant and duloxetine
• Figure 2 represents the drug-induced changes in sleep-wake balance over 12
hours post dosing in rats (Mean ± SEM of 15 to 16 individual values) in quiet wake
duration (Figure 2A) and REM sleep duration (Figure 2B) following administration
of compound BP1.3656B and duloxetine.
• Figure 3 represents the drug-induced changes in sleep-wake balance over 12
hours post dosing in rats (Mean ± SEM of 15 to 16 individual values) in quiet wake
duration (Figure 3A) and REM sleep duration (Figure 3B) following administration
of pitolisant and reboxetine.
• Figure 4 represents the drug-induced changes in sleep-wake balance over 12
hours post dosing in rats (Mean ± SEM of 15 to 16 individual values) in quiet wake
duration (Figure 4A) and REM sleep duration (Figure 4B) following administration
of pitolisant and atomoxetine.
• Figure 5 represents the drug-induced increase in noradrenaline release in rat
prefrontal cortex over basal release (AUC over 150 min post dosing) following
administration of pitolisant and duloxetine (Mean ± SEM of 6 to 9 individual
values).
Examples
Example 1 : Effect on sleep/wake
Effects on sleep/wake parameters were investigated in male Wistar rats. Briefly, rats were
stereotaxically implanted with cortical electrodes for electroencephalogram (EEG)
recording using a telemetric system (Data Sciences Int., Saint Paul, MN, USA) for the
acquisition, transfer and storage of motor activity and EEG signals. EEG signals were
analysed according to a procedure adapted from the algorithm proposed by R.P. Louis et
al. (J. Neurosci. Methods, 2004, 133, 71-80) and the analysis of vigilance stages
according to H. Kleinlogel (Neuropsychobiol. 1990-91, 23, 197-204) after a fast Fourier
transformation of 8-second duration EEG epochs. This allows the determination for each
epoch of its vigilance stage (i.e. active wakefulness, quiet wakefulness, light or deep slow
wave sleeps and REM sleep also named paradoxical sleep). Rats received orally
(gavage) vehicle, drug or drug combination around 30 minutes before the light onset.
Then, EEG signals were continuously recorded and further integrated over the 12-hour
diurnal phase.
Effects on sleep/wake recorded in rats of drugs alone or combined are presented in the
Figure 1 (Pitolisant/duloxetine), Figure 2 (BP1.3656B/duloxetine), Figure 3
(pitolisant/reboxetine) and Figure 4 (pitolisant/atomoxetine):
In the case of the pitolisant/duloxetine combination, the combination was shown to lead to
an increase in the quite wake of +35% as compared to a cumulated increase of +19%. In
addition, when the two compounds are combined, the decrease in the REM sleep elicited
by duloxetine is potentiated compared to the effect of duloxetine alone (-35% vs. -23%)
whereas pitolisant itself over 12 hours does not have any significant effect.
Example 2 : Noradrenaline release in the prefrontal cortex
Both histamine H3 receptor antagonist/inverse agonists (J.S. Lin et al. Neurobiology of
Disease 2008, 30, 74, G. Flik et al. J. Mol. Neurosci. 2015, 56, 320) and noradrenaline
reuptake inhibitors (F.P. Bymaster et al. Current Pharmaceutical Design, 2005, 11, 1475,
F.P. Bymaster et al. Neuropsychopharmacol. 2002, 27, 699) are known to enhance the
extracellular noradrenaline in the prefrontal cortex and reflecting an activation of the
noradrenergic neurotransmission. However, in both cases, the enhancement is limited.
Effects on noradrenaline release in the prefrontal cortex were investigated in vivo by
microdialysis in vigil male Wistar rats as described by AD Medhurst et al. (J. Pharmacol.
Exp. Ther. 2007, 321, 1032-1045) and G. Flik et al. (J. Mol. Neurosci. 2015, 56, 320-328).
Briefly, anaesthetized rats were implanted with a guide cannulae for sampling in the
prefrontal cortex. After at least one week of recovery post-surgery, the microdialysis probe
was inserted in the guide cannulae and perfused continuously with artificial cerebrospinal
fluid (CSF). The rat was habituated to the microdialysis cage for ~3 hours. Then, rats
received orally (gavage) vehicle, drug or drug combination. CSF samples collected every
30 minutes were analysed for their noradrenaline content by HPLC coupled to a
electrochemical detection. Noradrenaline sample levels were expressed in percentage of
basal noradrenaline release recorded over 1.5 hour before vehicle or drug treatment.
Unexpectedly, when the two types of compounds are combined, the activation of the
noradrenergic neurotransmission in the prefrontal cortex is enhanced in a synergistic
manner as shown by the following data and illustrated in Figure 5:
Maximal
Maximal increase statistics p value versus
drug (% of basal noradrenaline release) saline pitolisant duloxetine
increase
recorded
pitolisant +148 ± 49% >0.05
duloxetine +113 ± 31% <0.05
over 150
combination +385 ± 115% <0.05 <0.05 <0.05
min post
dosing
Hence, the association of the two classes of compounds may allow a decrease in the
dosage of each component and, thereby, enhanced tolerance.
Claims (15)
1. A combination of: ● a H3 antagonist or inverse agonist of formula: Where in formula (I): R is H or Methyl, R is Cl or where * represents the position of attachment to the 10 phenyl ring, n is 0 or 1, ● an antidepressant chosen from the noradrenaline reuptake inhibitors. 15
2. The combination according to claim 1 wherein said antidepressant is not venlafaxine.
3. The combination according to claim 1 or 2 wherein said antidepressant is a noradrenaline reuptake inhibitor chosen from duloxetine, reboxetine, atomoxetine, desipramine, desvenlafaxine. 20
4. The combination according to anyone of claims 1 to 3 wherein said H3 antagonist/inverse agonist is chosen from one of the following compounds: And any of their pharmaceutically acceptable salts, or solvates thereof.
5. The combination according to anyone of the preceding claims wherein said H3 antagonist/inverse agonist is the hydrochloride salt of 5
6. The combination according to anyone of the preceding claims wherein said noradrenaline reuptake inhibitors are chosen from duloxetine, reboxetine, atomoxetine, desipramine.
7. The combination according to anyone of the preceding claims wherein : 10 said H3 antagonist/inverse agonist is chosen from one of the following compounds: and any of their pharmaceutically acceptable salts, or solvates; and said noradrenaline reuptake inhibitor is chosen from duloxetine, reboxetine, and 15 atomoxetine.
8. The combination according to anyone of the preceding claims which is the combination of or a pharmaceutically acceptable salt thereof, with duloxetine.
9. The combination according to anyone of claims 1 to 7 which is the combination of or a pharmaceutically acceptable salt thereof, with duloxetine.
10. A pharmaceutical composition comprising a combination according to anyone of the preceding claims, wherein both ingredients are administered simultaneously, separately, or staggered over time. 5
11. The use of the combination according to anyone of claims 1 to 9 for preparing a medicament use for treating and/or preventing a disorder chosen from excessive daytime sleepiness, substance such as alcohol abuse disorders, and/or with attention and cognitive deficit, in a patient suffering from deficient noradrenaline release.
12. The use combination for use according to claim 11, wherein said disorder is excessive daytime sleepiness and occurs in a patient suffering from: - Narcolepsy with and without cataplexy, - Idiopathic hypersomnia, 15 - Daytime sleepiness disorders, - Obstructive sleep apnea, - Circadian rhythm sleep-wake disorders, - Parkinson’s disease, or - Prader-Willi Syndrome.
13. The combination for use according to claim 11 wherein said disorder is attention and cognitive deficit and occurs in a patient suffering from attention deficit and hyperactivity disorder (ADHD). 25
14. The combination for use according to claim 11 wherein said disorder is excessive daytime sleepiness, attention and cognitive deficit and occurs in a patient suffering from depression.
15. The combination for use according to claim 11 wherein said disorder is chosen 30 from substance abuse withdrawal syndromes.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP18306017.7 | 2018-07-27 |
Publications (1)
Publication Number | Publication Date |
---|---|
NZ755661A true NZ755661A (en) |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US12059416B2 (en) | Combinations of a H3 antagonist and a noradrenaline reuptake inhibitor, and the therapeutical uses thereof | |
EA012176B1 (en) | Novel use of peptide compounds for treating pain in painful diabetic neuropathy | |
EP1682152A2 (en) | Compositions and methods for treatment of nervous system disorders | |
EA025421B1 (en) | Treatment for lipodystrophy | |
RU2563821C2 (en) | Application of 4-aminopyridine for improving condition in case of neurocognitive and/or neuropsychiatric disorder in patients with demyelinating and other diseases of nervous system | |
US9987279B2 (en) | Pharmaceutical composition for prevention and/or treatment of urinary incontinence | |
CA3238102A1 (en) | Treating liver disorders with an ssao inhibitor | |
JP2007500230A (en) | Methods and materials for treating, detecting and reducing the risk of developing Alzheimer's disease | |
NZ755661A (en) | Novel combinations of a h3 antagonist and a noradrenaline reuptake inhibitor, and the therapeutical uses thereof | |
EP3378477A1 (en) | New therapeutical use of h3-ligands | |
RU2809163C2 (en) | New combinations of h3 receptor antagonists and norepinephrine reuptake inhibitors and their therapeutic use | |
KR102172351B1 (en) | Use of phenoxypropylamine compounds to treat depression | |
US20240269133A1 (en) | Methods of treating interstitial cystitis/bladder pain syndrome | |
CN112822997A (en) | Compositions and methods for treating autism | |
CN112789045A (en) | Compositions and methods for treating autism | |
US11974992B2 (en) | Use of serotonin 5-HT1A receptor agonists to treat diseases associated with sudden unexpected death in epilepsy | |
JP2023523862A (en) | Use of Dopamine D3 Partial Agonists to Treat Central Nervous System Disorders | |
CN111773204A (en) | Application of sodium dichloroacetate in preparing medicine for treating vascular dementia |