NO319421B1 - Terapeutisk bruk av melatonin - Google Patents
Terapeutisk bruk av melatonin Download PDFInfo
- Publication number
- NO319421B1 NO319421B1 NO20015738A NO20015738A NO319421B1 NO 319421 B1 NO319421 B1 NO 319421B1 NO 20015738 A NO20015738 A NO 20015738A NO 20015738 A NO20015738 A NO 20015738A NO 319421 B1 NO319421 B1 NO 319421B1
- Authority
- NO
- Norway
- Prior art keywords
- melatonin
- accordance
- neuroleptic
- pharmaceutical formulation
- neuroleptic compound
- Prior art date
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- YJPIGAIKUZMOQA-UHFFFAOYSA-N Melatonin Natural products COC1=CC=C2N(C(C)=O)C=C(CCN)C2=C1 YJPIGAIKUZMOQA-UHFFFAOYSA-N 0.000 title claims description 30
- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 title claims description 30
- 229960003987 melatonin Drugs 0.000 title claims description 30
- 230000001225 therapeutic effect Effects 0.000 title description 2
- 239000003176 neuroleptic agent Substances 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 14
- 206010043118 Tardive Dyskinesia Diseases 0.000 claims description 13
- 230000000701 neuroleptic effect Effects 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 7
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 6
- 238000013270 controlled release Methods 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- RGCVKNLCSQQDEP-UHFFFAOYSA-N Perphenazine Chemical compound C1CN(CCO)CCN1CCCN1C2=CC(Cl)=CC=C2SC2=CC=CC=C21 RGCVKNLCSQQDEP-UHFFFAOYSA-N 0.000 claims description 5
- 238000009472 formulation Methods 0.000 claims description 5
- 229960000762 perphenazine Drugs 0.000 claims description 5
- KAAZGXDPUNNEFN-UHFFFAOYSA-N Clotiapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2SC2=CC=C(Cl)C=C12 KAAZGXDPUNNEFN-UHFFFAOYSA-N 0.000 claims description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 4
- 239000002671 adjuvant Substances 0.000 claims description 4
- 229960003864 clotiapine Drugs 0.000 claims description 4
- 229960004170 clozapine Drugs 0.000 claims description 4
- QZUDBNBUXVUHMW-UHFFFAOYSA-N clozapine Chemical compound C1CN(C)CCN1C1=NC2=CC(Cl)=CC=C2NC2=CC=CC=C12 QZUDBNBUXVUHMW-UHFFFAOYSA-N 0.000 claims description 4
- 229960005017 olanzapine Drugs 0.000 claims description 4
- KVWDHTXUZHCGIO-UHFFFAOYSA-N olanzapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 KVWDHTXUZHCGIO-UHFFFAOYSA-N 0.000 claims description 4
- -1 pirperazine Chemical compound 0.000 claims description 4
- WSPOMRSOLSGNFJ-AUWJEWJLSA-N (Z)-chlorprothixene Chemical compound C1=C(Cl)C=C2C(=C/CCN(C)C)\C3=CC=CC=C3SC2=C1 WSPOMRSOLSGNFJ-AUWJEWJLSA-N 0.000 claims description 3
- BTFMCMVEUCGQDX-UHFFFAOYSA-N 1-[10-[3-[4-(2-hydroxyethyl)-1-piperidinyl]propyl]-2-phenothiazinyl]ethanone Chemical compound C12=CC(C(=O)C)=CC=C2SC2=CC=CC=C2N1CCCN1CCC(CCO)CC1 BTFMCMVEUCGQDX-UHFFFAOYSA-N 0.000 claims description 3
- PLDUPXSUYLZYBN-UHFFFAOYSA-N Fluphenazine Chemical compound C1CN(CCO)CCN1CCCN1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C21 PLDUPXSUYLZYBN-UHFFFAOYSA-N 0.000 claims description 3
- KLPWJLBORRMFGK-UHFFFAOYSA-N Molindone Chemical compound O=C1C=2C(CC)=C(C)NC=2CCC1CN1CCOCC1 KLPWJLBORRMFGK-UHFFFAOYSA-N 0.000 claims description 3
- KLBQZWRITKRQQV-UHFFFAOYSA-N Thioridazine Chemical compound C12=CC(SC)=CC=C2SC2=CC=CC=C2N1CCC1CCCCN1C KLBQZWRITKRQQV-UHFFFAOYSA-N 0.000 claims description 3
- GFBKORZTTCHDGY-UWVJOHFNSA-N Thiothixene Chemical compound C12=CC(S(=O)(=O)N(C)C)=CC=C2SC2=CC=CC=C2\C1=C\CCN1CCN(C)CC1 GFBKORZTTCHDGY-UWVJOHFNSA-N 0.000 claims description 3
- WNTYBHLDCKXEOT-UHFFFAOYSA-N acetophenazine Chemical compound C12=CC(C(=O)C)=CC=C2SC2=CC=CC=C2N1CCCN1CCN(CCO)CC1 WNTYBHLDCKXEOT-UHFFFAOYSA-N 0.000 claims description 3
- 229960000276 acetophenazine Drugs 0.000 claims description 3
- 229960001552 chlorprothixene Drugs 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- 229960002690 fluphenazine Drugs 0.000 claims description 3
- 229960000423 loxapine Drugs 0.000 claims description 3
- XJGVXQDUIWGIRW-UHFFFAOYSA-N loxapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2OC2=CC=C(Cl)C=C12 XJGVXQDUIWGIRW-UHFFFAOYSA-N 0.000 claims description 3
- SLVMESMUVMCQIY-UHFFFAOYSA-N mesoridazine Chemical compound CN1CCCCC1CCN1C2=CC(S(C)=O)=CC=C2SC2=CC=CC=C21 SLVMESMUVMCQIY-UHFFFAOYSA-N 0.000 claims description 3
- 229960000300 mesoridazine Drugs 0.000 claims description 3
- 229960004938 molindone Drugs 0.000 claims description 3
- 229960004265 piperacetazine Drugs 0.000 claims description 3
- 229960001534 risperidone Drugs 0.000 claims description 3
- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 208000024891 symptom Diseases 0.000 claims description 3
- 229960002784 thioridazine Drugs 0.000 claims description 3
- 229960005013 tiotixene Drugs 0.000 claims description 3
- ZEWQUBUPAILYHI-UHFFFAOYSA-N trifluoperazine Chemical compound C1CN(C)CCN1CCCN1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C21 ZEWQUBUPAILYHI-UHFFFAOYSA-N 0.000 claims description 3
- 229960002324 trifluoperazine Drugs 0.000 claims description 3
- XSCGXQMFQXDFCW-UHFFFAOYSA-N triflupromazine Chemical compound C1=C(C(F)(F)F)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 XSCGXQMFQXDFCW-UHFFFAOYSA-N 0.000 claims description 3
- 229960003904 triflupromazine Drugs 0.000 claims description 3
- OXAUOBQMCDIVPQ-IOXNKQMXSA-N zuclopenthixol acetate Chemical compound C1CN(CCOC(=O)C)CCN1CC\C=C\1C2=CC(Cl)=CC=C2SC2=CC=CC=C2/1 OXAUOBQMCDIVPQ-IOXNKQMXSA-N 0.000 claims description 3
- 229960003939 zuclopenthixol acetate Drugs 0.000 claims description 3
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 229950000688 phenothiazine Drugs 0.000 claims description 2
- 150000005075 thioxanthenes Chemical class 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims 2
- PQJUJGAVDBINPI-UHFFFAOYSA-N 9H-thioxanthene Chemical compound C1=CC=C2CC3=CC=CC=C3SC2=C1 PQJUJGAVDBINPI-UHFFFAOYSA-N 0.000 claims 1
- 239000000654 additive Substances 0.000 claims 1
- 150000002990 phenothiazines Chemical class 0.000 claims 1
- 238000011282 treatment Methods 0.000 description 7
- 239000000902 placebo Substances 0.000 description 5
- 229940068196 placebo Drugs 0.000 description 5
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
- 239000004925 Acrylic resin Substances 0.000 description 2
- 229920000178 Acrylic resin Polymers 0.000 description 2
- 208000012661 Dyskinesia Diseases 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- ZPEIMTDSQAKGNT-UHFFFAOYSA-N chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 description 2
- 229960001076 chlorpromazine Drugs 0.000 description 2
- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000003607 modifier Substances 0.000 description 2
- 229940076279 serotonin Drugs 0.000 description 2
- AKUVRZKNLXYTJX-UHFFFAOYSA-N 3-benzylazetidine Chemical compound C=1C=CC=CC=1CC1CNC1 AKUVRZKNLXYTJX-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-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
- 102000001419 Melatonin receptor Human genes 0.000 description 1
- 108050009605 Melatonin receptor Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 229960001657 chlorpromazine hydrochloride Drugs 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229960003878 haloperidol Drugs 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 230000017311 musculoskeletal movement, spinal reflex action Effects 0.000 description 1
- 210000004560 pineal gland Anatomy 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000000698 schizophrenic effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/382—Heterocyclic compounds having sulfur as a ring hetero atom having six-membered rings, e.g. thioxanthenes
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4515—Non condensed piperidines, e.g. piperocaine having a butyrophenone group in position 1, e.g. haloperidol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Biomedical Technology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Psychology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Indole Compounds (AREA)
Description
Foreliggende oppfinnelse angår en framgangsmåte og en farmasøytisk utforming for anvendelse ved behandling av tardiv dyskinesi.
Tardiv dyskinesi (TD) er en ufrivillig bevegelses-forstyrrelse, som utvikles hos en høy prosentandel av pasienter som har blitt behandlet med neuroleptiske medikamenter. Et antall artikler i litteraturen, foreslår et omvendt forhold mellom melatonin-utskilling og forekomsten av TD symptomer. Så vidt søker kjenner til er det imidlertid bare i ett tilfelle forsøkt administrasjon av eksogent melatonin i denne sammenhengen, hvorved det ble oppdaget at mens behandling av rotter med fjernet pineal kjertel, med haloperidol, ga betydelig hardere adferds-forstyrrelse enn hos uopererte rotter, var påfølgende administrasjon av melatonin (4 mg i.p.) forbundet med en ubetydelig reduksjon i hardheten av bevegelsene i løpet av en time (Sabdyk, R., et al., Int. J. Neurosci., 1989,48 (3-4): 303-8). Mengden melatonin som ble brukt i dette ubetydelige resultatet tilsvarte mer enn 1000 mg for et 70 kg menneske, så det er ikke overraskende at påfølgende forsøk for TD terapi har unngått bruk av eksogent melatonin. I US patent 5,691,324 for Sandyk, R., er for eksempel TD ett av et antall forhold, relatert til mangelfull serotonin transmisjon og svekket melatonin funksjon, som blir behandlet ved administrasjon av en blanding som øker serotonin neurotransmisjonen, hos pasienten, etterfulgt av bruk av et magnetisk felt på hjernen. Hele US 5,691,324 er tatt med her ved referanse.
I sammenheng med tardiv dyskinesi er det overraskende oppdaget at eksogent melatonin gir en betydelig terapeutisk effekt hos mennesker, ved et doserings-forhold som i det minste er en størrelsesorden lavere (med hensyn til gjennomsnittlig vekt av mennesker i forhold til labratorie-dyr) enn det som ble benyttet i rapporten i Int. J. Neurosci., som omtalt ovenfor.
I et aspekt framskaffer foreliggende oppfinnelse en farmasøytisk utforming som, i tillegg til i det minste en bærer, fortynner eller adjuvans, omfatter i det minste en neuroleptisk forbindelse og melatonin.
I et annet aspekt framskaffer oppfinnelsen anvendelse av melatonin i framstillingen av et medikament for å forebygge eller behandle symptomer av tardiv dyskinesi hos en pasient. Medikamentet har fortrinnsvis form som en farmasøytisk utforming, som inkluderer i det minste en av de følgende tilleggs-forbindelsene (a) og (b); (a) i det minste en bærer, fortynner eller adjuvans, (b) i det minste en neuroleptisk forbindelse.
Oppfinnelsen
Medikamentet / den farmasøytiske utformingen kan administreres i enhver beleilig form, så som tilpasset en oral, rektal, parenteral eller transdermal administrasjon. Det kan for eksempel være i enhets-doserings form. I en spesiell utforming er melatoninet i en styrt frigivelses-utforming, idet melatoninet fortrinnsvis frigis ved en forhåndsbestemt styrt hastighet.
Mengden melatonin som nå er forutsatt for anvendelse ved forebygging eller behandling av tardiv dyskinesi, vil være mengden som er funnet å være effektiv for dette formålet, som nå er antatt å være mer enn 0,5 mg men ikke mer enn 100 mg daglig, for eksempel 0,5-50 mg, fortrinnsvis 2,5 - 20 mg for oral administrasjon, og mellom 0,1 og 50 mg for parenteral eller transdermal administrasjon. I samsvar med oppfinnelsen kan en effektiv mengde melatonin utformes for eksempel sammen med en effektiv mengde av et neuroleptisk medikament. Det foreliggende medikamentet / farmasøytiske utformingen kan også omfatte i det minste en melatonin-reseptor modifikator og/eller melatonin profil modifikator.
Straks konseptet for foreliggende oppfinnelse med behandling eller forebygging av TD ved anvendelse av melatonin er kjent i samsvar med foreliggende oppfinnelse, vil det ikke kreves oppfinneriske evner for å fastslå rekken av effektive mengder av melatonin for det foreliggende formål, for ulike administrasjons-ruter. Mens den farmasøytiske utformingen inkluderer i det minste en neuroleptisk forbindelse, kan denne for eksempel velges fra slike forbindelser som inneholder i det minste en av de følgende ring-systemene, nemlig piperidine, piperazine, morpholine, 5,6,7,8-tetrahydroindole, phenothiazine og thioxanthene. Eksempler på neuroleptiske forbindelser er klorpromazine, triflupromazine, mesoridazine, piperacetazine, thioridazine, acetophenazine, fluphenazine, perphenazine, trifluoperazine, klorprothixene, thiothixene, haloperiodol, loxapine, molindone (jfr. tabell 1) og clothiapine, clozapine, olanzapine, risperidone og zuclopenthioxol acetat, samt deres farmasøytisk akseptable salter.
Oppfinnelsen vil illustreres med de følgende eksemplene.
Eksempel 1
De følgende ingrediensene ble blandet sammen, og blandingen ble komprimert i en 7 mm sylindrisk presse (eng. punch), ved 2,5 tonn, for å gi tabletter med styrt frigivelse; klorpromazine-hydroklorid (275 mg/tablett), melatonin (5 mg/tablett), Eudragit™ RS 100 akrylisk resin-bærer (Rohm Pharma) og laktose i et vektforhold på omtrent 1:1. Mens denne utformingen skulle administreres i samsvar med en leges instruksjoner, er det nå forventet at to slike tabletter tatt to timer før sengetid vil være passe.
Eksempel 2
De følgende ingrediensene ble blandet sammen, og blandingen ble komprimert i en 7 mm sylindrisk presse, ved 2,5 tonn, for å gi tabletter med styrt frigivelse; perphenazine (10 mg/
tablett), melatonin (5 mg/tablett), og Eudragit™RSPO akrylisk resin bærer (Rohm Pharma), laktose og kalsiumhydrogen-fosfat i en vekt-mengde tilsvarende omtrent 2:1:2,5. Mens denne utformingen skulle administreres i samsvar med en leges instruksjoner, er det nå antatt at to slike tabletter tatt to timer før sengetid, vil være passe.
Eksempel 3
Effekten av melatonin på tardiv dyskinesi ble bestemt med en forsøkspopulasjon på 22 pasienter, hvorav 6 var shcizoaffective og 16 var paranoide schizofrene. Alle pasientene, som over (ang tid hadde mottatt neuroleptisk behandling, ble diagnostisert i samsvar med DSM IV. Det var 11 menn og 11 kvinner, alder 39 ± 15, fra 17-61 år, hvor 19 fullførte forsøket og ble inkludert i resultatene. På en tilfeldig, dobbelt skjult, kryssløps metode ble subjektene daglig gitt enten 2 x 5 mg melatonin, i en utforming med styrt frigivelse (Circadin™, Neurim Pharmaceuticals, Israel), to timer før sengetid, eller en placebo med identisk utseende, i en periode på seks uker, med en fire-ukers placebo utvasking mellom de to behandlings-periodene. I tillegg til melatoninet eller placeboen mottok hver pasient henholdsvis en av de følgende daglige dosene av neuroleptiske medikamenter, eller i to tilfeller ingen neuroleptiske medikamenter; klorpromazine (250), clothiapine (20, 80 eller 160), clozapine (200,400 eller 550), haloperiodol (5, 15 eller 20), olanzapine (10 eller 15), perphenazine (4, 8,12, 32 eller 32), risperidorie (4) eller zuclopenthixol acetat (4 eller 20). I løpet av den siste uka av hver behandl ings-periode, ble TD hardheten vurdert ved bruk av Abnormal Involuntary Movements Scale (AIMS), og det ble gjort sammenligninger mellom placebo eller melatonin behandlinger, og grunnlinjen. Resultatene er gjengitt i tabell 2 og 3. Konklusjon: Den foreliggende studien avslørte en svært betydelig (p < 0,001, MANOVA) nedgang, dvs. forbedring etter melatonin administrasjon, sammenlignet med placebo (henholdsvis -3 ± 2,1 og -1 ± 1,3).
Claims (7)
1. Farmasøytisk utforming omfattende i det minste en bærer, tynner eller adjuvans, karakterisert ved å ytterligere omfatte i det minste en neuroleptisk forbindelse og melatonin.
2. Farmasøytisk utforming i samsvar med krav 1, karakterisert ved i det minste ett av de følgende trekk (i) den er utformet for oral, rektal, parenteral eller transdermal administrasjon, (ii) den er i en enhetsdoserings-form, hver enhets-dose omfatter en mengde melatonin i området 2,5 - 20 mg, (iii) den er i form av en styrt frigivelses utforming, idet melatonin fortrinnsvis frigis ved en forhåndsbestemt hastighet, (iv) den neuroleptiske forbindelsen er valgt blant forbindelser som inneholder i det minste en av de følgende ring-systemene; piperidine, pirperazine, morpholine, 5,6,7,8-tetrahydroindole, fenothiazine og thioxanthene.
3. Farmasøytisk utforming i samsvar med krav 1 eller 2, karakterisert ved at den neuroleptiske forbindelsen er valgt blant gruppen omfattende klorpormazine, triflupromazine, mesoridazine, piperacetazine, thioridazine, acetophenazine, fluphenazine, perphenazine, trifluoperazine, klorprothixene, thiothixene, haloperiodol, loxapine, molindone, clothiapine, clozapine, olanzapine, risperidone og zuclopenthixol-acetat, samt farmasøytisk akseptable salter av disse.
4. Anvendelse av melatonin i framstilling av et medikament for å forebygge eller behandle symptomer av tardiv dyskinesi hos en pasient
5. Anvendelse i samsvar med krav 4, idet medikamentet har form som en farmasøytisk utforming som inkluderer i det minste en av de følgende tilsetningene (a) og (b): (a) i det minste en bærer, tynner eller adjuvans, og (b) i det minste en neuroleptisk forbindelse.
6. Anvendelse i samsvar med krav 5, idet den farmasøytiske utformingen i tillegg er karakterisert ved ett av de følgende trekk: (i) den er tilpasset for oral, rektal, parenteral eller transdermal administrasjon, (ii) den er en enhets-dose form, hver enhet-dose omfatter en mengde melatonin som ligger i området 2,5 - 20 mg; (iii) den er i form av en styrt frigivelses-utforming, idet melatonin fortrinnsvis frigjøres med en forhåndsbestemt styrt hastighet, (iv) den neuroleptiske forbindelsen er valgt fra gruppen inneholdende en av de følgende ring-systemene, nemlig: piperidine, piperazine, morpholine, 5,6,7,8-tetrahydroindole, phenothiazine og thioxanthene.
7. Anvendelse i samsvar med krav 5 eller 6, idet den neuroleptiske forbindelsen er valgt fra gruppen omfattende klorpormazine, triflupromazine, mesoridazine, piperacetazine, thioridazine, acetophenazine, fluphenazine, perphenazine, trifluoperazine, klorprothixene, thiothixene, haloperiodol, loxapine, molindone, clothiapine, clozapine, olanzapine, risperidone og zuclopentixol-acetat, samt farmasøytisk akseptable salter av disse.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IL13017199A IL130171A (en) | 1999-05-27 | 1999-05-27 | Melatonin for use in preventing and treating tardive dyskinesia, pharmaceutical preparations containing it and its use in the manufacture of medicines |
| PCT/IL2000/000296 WO2000072843A1 (en) | 1999-05-27 | 2000-05-24 | Therapeutic use of melatonin |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO20015738D0 NO20015738D0 (no) | 2001-11-26 |
| NO20015738L NO20015738L (no) | 2002-01-25 |
| NO319421B1 true NO319421B1 (no) | 2005-08-08 |
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| Application Number | Title | Priority Date | Filing Date |
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| NO20015738A NO319421B1 (no) | 1999-05-27 | 2001-11-26 | Terapeutisk bruk av melatonin |
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| KR (1) | KR20020015329A (no) |
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| NZ527142A (en) * | 2003-07-23 | 2006-03-31 | Douglas Pharmaceuticals Ltd | A stable suspension formulation |
| CA2556753C (en) * | 2004-02-20 | 2014-11-25 | Lifescape Biosciences Incorporated | Compositions and methods for sleep regulation |
| CN1299680C (zh) * | 2005-08-29 | 2007-02-14 | 陈彦方 | 一种治疗失眠的黑白制剂 |
| US7494674B2 (en) | 2006-09-22 | 2009-02-24 | Lapointe Andrew T | Nutraceutical with tart cherries and method of treatment therewith |
| WO2008116004A2 (en) | 2007-03-19 | 2008-09-25 | Vita Sciences, Llc | Transdermal patch and method for delivery of vitamin b12 |
| WO2008128166A1 (en) * | 2007-04-13 | 2008-10-23 | Concert Pharmaceuticals Inc. | Deuterated derivatives of 4-(6-fluoro-1, 2-benzisoxazol-3-yl) piperidine compounds |
| US20100256197A1 (en) * | 2009-04-02 | 2010-10-07 | Silver Eagle Labs Nv, Llc | Nicotine Dissolving Film With Or Without Menthol |
| US20100256215A1 (en) * | 2009-04-02 | 2010-10-07 | Silver Eagle Labs Nv, Llc | Menthol-Melatonin Dissolving Film |
| US9532952B2 (en) | 2011-01-28 | 2017-01-03 | Physician's Seal, LLC | Controlled-release compositions of melatonin combined with sedative and/or analgesic ingredients |
| WO2012103411A2 (en) | 2011-01-28 | 2012-08-02 | Zx Pharma, Llc | Controlled-release melatonin composition and related methods |
| FR3000896B1 (fr) | 2013-01-14 | 2016-08-26 | Philippe Perovitch | Forme galenique pour l'administration de principe(s) actif(s) permettant l'induction acceleree du sommeil et/ou le traitement des troubles du sommeil |
| US11071739B1 (en) | 2020-09-29 | 2021-07-27 | Genus Lifesciences Inc. | Oral liquid compositions including chlorpromazine |
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| US5691324A (en) * | 1994-01-14 | 1997-11-25 | Sandyk; Reuven | Methods useful for the treatment of neurological and mental disorders related to deficient serotonin neurotransmission and impaired pineal melatonin functions |
| US6469044B1 (en) * | 1995-02-01 | 2002-10-22 | Neurim Pharmaceuticals (1991) Ltd. | Method for treating patients suffering from drug dependencies which lead to plasma melationin deficiencies |
| AUPO274596A0 (en) * | 1996-10-04 | 1996-10-31 | Armstrong, Stuart Maxwell | Method for the treatment of neurological or neuropsychiatric disorders |
| AUPO588297A0 (en) * | 1997-03-26 | 1997-04-24 | Luminis Pty Limited | Mediation in melatonin production |
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- 2000-05-24 TR TR2001/03418T patent/TR200103418T2/xx unknown
- 2000-05-24 EA EA200101240A patent/EA004057B1/ru not_active IP Right Cessation
- 2000-05-24 CN CNB008081069A patent/CN1176652C/zh not_active Expired - Fee Related
- 2000-05-24 WO PCT/IL2000/000296 patent/WO2000072843A1/en not_active Application Discontinuation
- 2000-05-24 EE EEP200100623A patent/EE200100623A/xx unknown
- 2000-05-24 BR BR0017329-0A patent/BR0017329A/pt not_active IP Right Cessation
- 2000-05-24 JP JP2000620955A patent/JP2003500446A/ja active Pending
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- 2000-05-24 HU HU0201405A patent/HUP0201405A3/hu unknown
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- 2000-05-26 TN TNTNSN00117A patent/TNSN00117A1/fr unknown
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- 2001-12-20 ZA ZA200110436A patent/ZA200110436B/xx unknown
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