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WO2007039123A2 - Traitement combine - Google Patents

Traitement combine Download PDF

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Publication number
WO2007039123A2
WO2007039123A2 PCT/EP2006/009182 EP2006009182W WO2007039123A2 WO 2007039123 A2 WO2007039123 A2 WO 2007039123A2 EP 2006009182 W EP2006009182 W EP 2006009182W WO 2007039123 A2 WO2007039123 A2 WO 2007039123A2
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WO
WIPO (PCT)
Prior art keywords
therapeutic administration
treatment
pharmaceutically acceptable
acceptable salt
psychotic disorder
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Application number
PCT/EP2006/009182
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English (en)
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WO2007039123A3 (fr
Inventor
Lee Anthony Dawson
Martin Lowy
David Graeme Walker
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Smithkline Beecham Corporation
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Publication of WO2007039123A2 publication Critical patent/WO2007039123A2/fr
Publication of WO2007039123A3 publication Critical patent/WO2007039123A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • This invention relates to combination therapy for treating psychotic and other mood disorders, to therapeutic combinations and compositions comprising them, and to methods of treatment of psychotic and other mood disorders.
  • NK3 receptor antagonist talnetant ((S)-(-)-N-( ⁇ -ethylbenzyl)-3-hydroxy-2- phenylquinoline-4-carboxamide), its preparation and its use in the treatment of pulmonary disorders, disorders of the central nervous system and neurodegenerative disorders are disclosed in published International Patent application WO 95/32948. Published International Patent applications WO 97/19927, WO 97/19928, WO 99/14196 and WO 02/094187 disclose additional therapeutic utilities for talnetant, pharmaceutically acceptable salts and processes for its preparation.
  • the above-mentioned patent applications are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.
  • the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of an NK3 antagonist or a pharmaceutically acceptable salt thereof to a patient receiving therapeutic administration of an antipsychotic agent.
  • the invention provides the use of an NK3 antagonist or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of an antipsychotic agent.
  • the invention also provides the use of an NK3 antagonist or a pharmaceutically acceptable salt thereof in adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of an antipsychotic agent.
  • the invention further provides an NK3 antagonist or a pharmaceutically acceptable salt thereof for use for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of an antipsychotic agent.
  • the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of an antipsychotic agent to a patient receiving therapeutic administration of an NK3 antagonist or a pharmaceutically acceptable salt thereof.
  • the invention provides the use of an antipsychotic agent in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of an NK3 antagonist or a pharmaceutically acceptable salt thereof.
  • the invention also provides the use of an antipsychotic agent for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of an NK3 antagonist or a pharmaceutically acceptable salt thereof.
  • the invention provides a method of treatment of a psychotic disorder by simultaneous therapeutic administration of an NK3 antagonist or a pharmaceutically acceptable salt thereof in combination with an antipsychotic agent.
  • the invention further provides the use of a combination of an NK3 antagonist or a pharmaceutically acceptable salt thereof and an antipsychotic agent in the manufacture of a medicament for simultaneous therapeutic administration in the treatment of a psychotic disorder.
  • the invention further provides the use of a combination of an NK3 antagonist or a pharmaceutically acceptable salt thereof and an antipsychotic agent for simultaneous therapeutic administration in the treatment of a psychotic disorder.
  • the invention further provides the use of an NK3 antagonist or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for simultaneous therapeutic administration with an antipsychotic agent in the treatment of a psychotic disorder.
  • the invention further provides the use of an NK3 antagonist or a pharmaceutically acceptable salt thereof for simultaneous therapeutic administration with an antipsychotic agent in the treatment of a psychotic disorder.
  • the invention further provides an NK3 antagonist or a pharmaceutically acceptable salt thereof for use for simultaneous therapeutic administration with an antipsychotic agent in the treatment of a psychotic disorder.
  • the invention further provides the use of an antipsychotic agent in the manufacture of a medicament for simultaneous therapeutic administration with an NK3 antagonist or a pharmaceutically acceptable salt thereof in the treatment of a psychotic disorder.
  • the invention further provides the use of an antipsychotic agent for simultaneous therapeutic administration with an NK3 antagonist or a pharmaceutically acceptable salt thereof in the treatment of a psychotic disorder.
  • the invention provides a kit-of-parts for use in the treatment of a psychotic disorder comprising a first dosage form comprising an NK3 antagonist or a pharmaceutically acceptable salt thereof and one or more further dosage forms each comprising an antipsychotic agent for simultaneous therapeutic administration.
  • the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of talnetant or a pharmaceutically acceptable salt thereof to a patient receiving therapeutic administration of an antipsychotic agent.
  • the invention provides the use of talnetant or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of an antipsychotic agent.
  • the invention also provides the use of talnetant or a pharmaceutically acceptable salt thereof in adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of an antipsychotic agent.
  • the invention further provides talnetant or a pharmaceutically acceptable salt thereof for use for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of an antipsychotic agent.
  • the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of an antipsychotic agent to a patient receiving therapeutic administration of talnetant or a pharmaceutically acceptable salt thereof.
  • the invention provides the use of an antipsychotic agent in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of talnetant or a pharmaceutically acceptable salt thereof.
  • the invention also provides the use of an antipsychotic agent for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of talnetant or a pharmaceutically acceptable salt thereof.
  • the invention provides a method of treatment of a psychotic disorder by simultaneous therapeutic administration of talnetant or a pharmaceutically acceptable salt thereof in combination with an antipsychotic agent.
  • the invention further provides the use of a combination of talnetant or a pharmaceutically acceptable salt thereof and an antipsychotic agent in the manufacture of a medicament for simultaneous therapeutic administration in the treatment of a psychotic disorder.
  • the invention further provides the use of a combination of talnetant or a pharmaceutically acceptable salt thereof and an antipsychotic agent for simultaneous therapeutic administration in the treatment of a psychotic disorder.
  • the invention further provides the use of talnetant or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for simultaneous therapeutic administration with an antipsychotic agent in the treatment of a psychotic disorder.
  • the invention further provides the use of talnetant or a pharmaceutically acceptable salt thereof for simultaneous therapeutic administration with an antipsychotic agent in the treatment of a psychotic disorder.
  • the invention further provides talnetant or a pharmaceutically acceptable salt thereof for use for simultaneous therapeutic administration with an antipsychotic agent in the treatment of a psychotic disorder.
  • the invention further provides the use of an antipsychotic agent in the manufacture of a medicament for simultaneous therapeutic administration with talnetant or a pharmaceutically acceptable salt thereof in the treatment of a psychotic disorder.
  • the invention further provides the use of an antipsychotic agent for simultaneous therapeutic administration with talnetant or a pharmaceutically acceptable salt thereof in the treatment of a psychotic disorder.
  • the invention provides a kit-of-parts for use in the treatment of a psychotic disorder comprising a first dosage form comprising talnetant or a pharmaceutically acceptable salt thereof and one or more further dosage forms each comprising an antipsychotic agent for simultaneous therapeutic administration.
  • the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of talnetant or a pharmaceutically acceptable salt thereof to a patient receiving therapeutic administration of an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer.
  • the invention provides the use of talnetant or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer.
  • the invention also provides the use of talnetant or a pharmaceutically acceptable salt thereof in adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer.
  • the invention further provides talnetant or a pharmaceutically acceptable salt thereof for use for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer.
  • an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer.
  • the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer to a patient receiving therapeutic administration of talnetant or a pharmaceutically acceptable salt thereof.
  • an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer to a patient receiving therapeutic administration of talnetant or a pharmaceutically acceptable salt thereof.
  • the invention provides the use of an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of talnetant or a pharmaceutically acceptable salt thereof.
  • the invention also provides the use of an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of talnetant or a pharmaceutically acceptable salt thereof.
  • the invention provides a method of treatment of a psychotic disorder by simultaneous therapeutic administration of talnetant or a pharmaceutically acceptable salt thereof in combination with an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer.
  • the invention further provides the use of a combination of talnetant or a pharmaceutically acceptable salt thereof and an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer in the manufacture of a medicament for simultaneous therapeutic administration in the treatment of a psychotic disorder.
  • the invention further provides the use of a combination of talnetant or a pharmaceutically acceptable salt thereof and an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer for simultaneous therapeutic administration in the treatment of a psychotic disorder.
  • the invention further provides the use of talnetant or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for simultaneous therapeutic administration with an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer in the treatment of a psychotic disorder.
  • the invention further provides the use of talnetant or a pharmaceutically acceptable salt thereof for simultaneous therapeutic administration with an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer in the treatment of a psychotic disorder.
  • the invention further provides talnetant or a pharmaceutically acceptable salt thereof for use for simultaneous therapeutic administration with an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer in the treatment of a psychotic disorder.
  • the invention further provides the use of an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer in the manufacture of a medicament for simultaneous therapeutic administration with talnetant or a pharmaceutically acceptable salt thereof in the treatment of a psychotic disorder.
  • the invention further provides the use of an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer for simultaneous therapeutic administration with talnetant or a pharmaceutically acceptable salt thereof in the treatment of a psychotic disorder.
  • the invention provides a kit-of-parts for use in the treatment of a psychotic disorder comprising a first dosage form comprising talnetant or a pharmaceutically acceptable salt thereof and one or more further dosage forms each comprising an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer for simultaneous therapeutic administration.
  • a mood stabiliser an antidepressant
  • an anxiolytic a drug for extrapyrimidal side effects
  • a cognitive enhancer for simultaneous therapeutic administration.
  • Particular advantages associated with the combinations, uses and methods of treatment of the invention include equivalent or improved efficacy at doses of administration which are lower than those commonly used for the individual components. Improved treatments of positive symptoms and/or negative symptoms and/or cognitive symptoms of the psychotic disorders may also be observed.
  • the combinations, uses and methods of treatment of the invention may also provide advantages in treatment of patients who fail to respond adequately and show residual disease symptoms or who are resistant to treatment resistant with certain active ingredients.
  • the combinations, uses and methods of treatment of the invention may also provide advantages in terms of tolerablity and safety as the dose of the drugs may be lowered while retaining comparable efficacy.
  • the combination therapies of the invention are administered adjunctively.
  • adjunctive administration is meant the coterminous or overlapping administration of each of the components in the form of separate pharmaceutical compositions or devices. This regime of therapeutic administration of two or more therapeutic agents is referred to generally by those skilled in the art and herein as adjunctive therapeutic administration; it is also known as add-on therapeutic administration.
  • a patient receives separate but coterminous or overlapping therapeutic administration of an NK3 antagonist, such as talnetant or a pharmaceutically acceptable salt thereof, and an antipsychotic agent, a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects or a cognitive enhancer are within the scope of the current invention.
  • an NK3 antagonist such as talnetant or a pharmaceutically acceptable salt thereof
  • an antipsychotic agent such as talnetant or a pharmaceutically acceptable salt thereof
  • an antipsychotic agent such as talnetant or a pharmaceutically acceptable salt thereof
  • an antipsychotic agent such as talnetant or a pharmaceutically acceptable salt thereof
  • an antipsychotic agent such as talnetant or a pharmaceutically acceptable salt thereof
  • an antipsychotic agent such as talnetant or a pharmaceutically acceptable salt thereof
  • an antipsychotic agent such as talnetant or a pharmaceutically acceptable salt thereof
  • an antipsychotic agent such as talnetant or a pharmaceutically
  • an NK3 antagonist such as talnetant or a pharmaceutically acceptable salt thereof, is administered as adjunctive therapeutic treatment to patients who are receiving administration of an antipsychotic agent, a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects or a cognitive enhancer, but the scope of the invention also includes the adjunctive therapeutic administration of an antipsychotic agent, a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects or a cognitive enhancer to patients who are receiving administration of an NK3 antagonist such as talnetant or a pharmaceutically acceptable salt thereof.
  • the combination therapies of the invention may also be administered simultaneously.
  • simultaneous administration is meant a treatment regime wherein the individual components are administered together, either in the form of a single pharmaceutical composition or device comprising or containing both components, or as separate compositions or devices, each comprising one of the components, administered simultaneously.
  • Such combinations of the separate individual components for simultaneous combination may be provided in the form of a kit-of-parts.
  • psychotic disorder includes :-
  • Schizophrenia including the subtypes Paranoid Type (295.30), Disorganised Type (295.10), Catatonic Type (295.20), Undifferentiated Type (295.90) and Residual Type (295.60); Schizophreniform Disorder (295.40); Schizoaffective Disorder (295.70) including the subtypes Bipolar Type and Depressive Type; Delusional Disorder (297.1 ) including the subtypes Erotomanic Type, Grandiose Type, Jealous Type, Persecutory Type, Somatic Type, Mixed Type and Unspecified Type; Brief Psychotic Disorder (298.8); Shared Psychotic Disorder (297.3); Psychotic Disorder Due to a General Medical Condition including the subtypes With Delusions and With Hallucinations; Substance- Induced Psychotic Disorder including the subtypes With Delusions (293.81 ) and With Hallucinations (293.82); and Psychotic Disorder Not Otherwise Specified (298.9).
  • adjunctive or simultaneous administration of an antipsychotic agent and talnetant as described herein may also be useful in:
  • Depression and mood disorders other than bipolar disorder
  • Major Depressive Episode including Major Depressive Episode, Manic Episode, Mixed Episode and Hypomanic Episode
  • Depressive Disorders including Major Depressive Disorder, Dysthymic Disorder (300.4), Depressive Disorder Not Otherwise Specified (311 )
  • Other Mood Disorders including Mood Disorder Due to a General Medical Condition (293.83) which includes the subtypes With Depressive Features, With Major Depressive-like Episode, With Manic Features and With Mixed Features), Substance-Induced Mood Disorder (including the subtypes With Depressive Features, With Manic Features and With Mixed Features) and Mood Disorder Not Otherwise Specified (296.90);
  • Anxiety disorders including Panic Attack; Panic Disorder including Panic Disorder without Agoraphobia (300.01 ) and Panic Disorder with Agoraphobia (300.21); Agoraphobia; Agoraphobia Without History of Panic Disorder (300.22), Specific Phobia (300.29, formerly Simple Phobia) including the subtypes Animal Type, Natural Environment Type, Blood-Injection-Injury Type, Situational Type and Other Type), Social Phobia (Social Anxiety Disorder, 300.23), Obsessive-Compulsive Disorder (300.3), Posttraumatic Stress Disorder (309.81 ), Acute Stress Disorder (308.3), Generalized Anxiety Disorder (300.02), Anxiety Disorder Due to a General Medical Condition (293.84), Substance-Induced Anxiety Disorder, Separation Anxiety Disorder (309.21 ), Adjustment Disorders with Anxiety (309.24) and Anxiety Disorder Not Otherwise Specified (300.00); c) Substance-related disorders including Substance Use Disorders such as Substance Dependence, Substance Craving
  • Sleep disorders including primary sleep disorders such as Dyssomnias such as Primary Insomnia (307.42), Primary Hypersomnia (307.44), Narcolepsy (347), Breathing- Related Sleep Disorders (780.59), Circadian Rhythm Sleep Disorder (307.45) and Dyssomnia Not Otherwise Specified (307.47); primary sleep disorders such as Parasomnias such as Nightmare Disorder (307.47), Sleep Terror Disorder (307.46), Sleepwalking Disorder (307.46) and Parasomnia Not Otherwise Specified (307.47); Sleep Disorders Related to Another Mental Disorder such as Insomnia Related to Another Mental Disorder (307.42) and Hypersomnia Related to Another Mental Disorder (307.44); Sleep Disorder Due to a General Medical Condition, in particular sleep disturbances associated with such diseases as neurological disorders, neuropathic pain, restless leg syndrome, heart and lung diseases; and Substance-Induced Sleep Disorder including the subtypes Insomnia Type, Hypersomnia Type, Parasomnia Type and Mixed Type; sleep apnea and jet-lag
  • Eating disorders such as Anorexia Nervosa (307.1 ) including the subtypes Restricting Type and Binge-Eating/Purging Type; Bulimia Nervosa (307.51 ) including the subtypes Purging Type and Nonpurging Type; Obesity; Compulsive Eating Disorder; Binge Eating Disorder; and Eating Disorder Not Otherwise Specified (307.50); f) Autism Spectrum Disorders including Autistic Disorder (299.00), Asperger's Disorder (299.80), Rett's Disorder (299.80), Childhood Disintegrative Disorder (299.10) and Pervasive Disorder Not Otherwise Specified (299.80, including Atypical Autism);
  • Attention-Deficit/Hyperactivity Disorder including the subtypes Attention-Deficit /Hyperactivity Disorder Combined Type (314.01 ), Attention-Deficit /Hyperactivity Disorder Predominantly Inattentive Type (314.00), Attention-Deficit /Hyperactivity Disorder Hyperactive-Impulse Type (314.01 ) and Attention-Deficit /Hyperactivity Disorder Not Otherwise Specified (314.9); Hyperkinetic Disorder; Disruptive Behaviour Disorders such as Conduct Disorder including the subtypes childhood-onset type (321.81 ), Adolescent- Onset Type (312.82) and Unspecified Onset (312.89), Oppositional Defiant Disorder (313.81 ) and Disruptive Behaviour Disorder Not Otherwise Specified; and Tic Disorders such as Tourette's Disorder (307.23);
  • Personality Disorders including the subtypes Paranoid Personality Disorder (301.0), Schizoid Personality Disorder (301.20), Schizotypal Personality Disorder (301 ,22), Antisocial Personality Disorder (301.7), Borderline Personality Disorder (301 ,83), Histrionic Personality Disorder (301.50), Narcissistic Personality Disorder (301 ,81), Avoidant Personality Disorder (301.82), Dependent Personality Disorder (301.6), Obsessive-Compulsive Personality Disorder (301.4) and Personality Disorder Not Otherwise Specified (301.9);
  • Enhancement of cognition including mild cognitive impairment and the treatment of cognition impairment in other diseases such as schizophrenia, bipolar disorder, depression, other psychiatric disorders and psychotic conditions associated with cognitive impairment, e.g. Alzheimer's disease; and
  • Sexual dysfunctions including sexual Desire Disorders such as Hypoactive Sexual Desire Disorder (302.71 ), and sexual Aversion Disorder (302.79); sexual arousal disorders such as Female sexual Arousal Disorder (302.72) and Male Erectile Disorder (302.72); orgasmic disorders such as Female Orgasmic Disorder (302.73), Male Orgasmic Disorder (302.74) and Premature Ejaculation (302.75); sexual pain disorder such as Dyspareunia (302.76) and Vaginismus (306.51); sexual Dysfunction Not Otherwise Specified (302.70); paraphilias such as Exhibitionism (302.4), Fetishism (302.81 ), Frotteurism (302.89), Pedophilia (302.2), Sexual Masochism (302.83), sexual Sadism (302.84), Transvestic Fetishism (302.3), Voyeurism (302.82) and Paraphilia Not Otherwise Specified (302.9); gender identity disorders such as Gender Identity Disorder in Children (302.6) and Gender Identity Disorder in Adolescents or Adults (302.85);
  • the therapy of the present invention may be used for the treatment of cognitive impairment when not associated with a psychotic disorder, for example the treatment of impairment of cognitive functions including attention, executive function, orientation, learning disorders, memory (i.e. memory disorders, amnesia, amnesic disorders, transient global amnesia syndrome and age-associated memory impairment) and language function; cognitive impairment as a result of stroke, Alzheimer's disease, Huntington's disease, Pick disease, AIDS-related dementia or other dementia states such as Multiinfarct dementia, alcoholic dementia, hypothyroidism-related dementia, and dementia associated to other degenerative disorders such as cerebellar atrophy and amyotropic lateral sclerosis; other acute or sub-acute conditions that may cause cognitive decline such as delirium or depression (pseudodementia states) trauma, head trauma, age related cognitive decline, stroke, neurodegeneration, drug-induced states, neurotoxic agents, mild cognitive impairment, age related cognitive impairment, autism related cognitive impairment, Down's syndrome, cognitive deficit related to psychosis, and post- electroconvul
  • the therapy of the present invention may also be used as a memory and/or cognition enhancer in healthy humans with no cognitive and/or memory deficit.
  • the therapy of the present invention may also be used the treatment of traumatic pain such as postoperative pain; traumatic avulsion pain such as brachial plexus; chronic pain such as arthritic pain such as occurring in osteo-, rheumatoid or psoriatic arthritis; neuropathic pain such as post-herpetic neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia, fibromyalgia, causalgia, peripheral neuropathy, diabetic neuropathy, chemotherapy-induced neuropathy, AIDS related neuropathy, occipital neuralgia, geniculate neuralgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy, phantom limb pain; various forms of headache such as migraine, acute or chronic tension headache, temporomandibular pain, maxillary sinus pain, cluster headache; odontalgia; cancer pain; pain of visceral origin; gastrointestinal pain; nerve entrapment pain; sport's injury pain; dysmenn
  • the therapy of the present invention may also for inflammation.
  • it may be used in the treatment of inflammation in asthma, influenza, chronic bronchitis and rheumatoid arthritis; in the treatment of inflammatory diseases of the gastrointestinal tract such as Crohn's disease, postoperative gastric ileus (POI), ulcerative colitis, inflammatory bowel disease (IBD) and non-steroidal anti-inflammatory drug induced damage; inflammatory diseases of the skin such as herpes and eczema; inflammatory diseases of the bladder such as cystitis and urge incontinence; and eye and dental inflammation.
  • the therapy of the present invention may also be used for the treatment of allergic disorders, in particular allergic disorders of the skin such as urticaria, and allergic disorders of the airways such as rhinitis.
  • the therapy of the present invention may be used for the treatment of emesis, i.e. nausea, retching and vomiting.
  • Emesis includes acute emesis, delayed emesis and anticipatory emesis.
  • Emesis may be induced by drugs such as cancer chemotherapeutic agents such as alkylating agents, e.g. cyclophosphamide, carmustine, lomustine and chlorambucil; cytotoxic antibiotics, e.g. dactinomycin, doxorubicin, mitomycin-C and bleomycin; anti- metabolites, e.g. cytarabine, methotrexate and 5- fluorouracil; vinca alkaloids, e.g.
  • etoposide, vinblastine and vincristine etoposide, vinblastine and vincristine; and others such as cisplatin, dacarbazine, procarbazine and hydroxyurea; and combinations thereof; radiation sickness; radiation therapy, e.g. irradiation of the thorax or abdomen, such as in the treatment of cancer; poisons; toxins such as toxins caused by metabolic disorders or by infection, e.g. gastritis, or released during bacterial or viral gastrointestinal infection; pregnancy; vestibular disorders, such as motion sickness, vertigo, dizziness and Meniere's disease; postoperative sickness; gastrointestinal obstruction; reduced gastrointestinal motility; visceral pain, e.g.
  • myocardial infarction or peritonitis migraine; increased intercranial pressure; decreased intercranial pressure (e.g. altitude sickness); opioid analgesics, such as morphine; and gastro-oesophageal reflux disease, acid indigestion, over-indulgence of food or drink, acid stomach, sour stomach, waterbrash/regurgitation, heartburn, such as episodic heartburn, nocturnal heartburn, and meal-induced heartburn and dyspepsia.
  • the therapy of the present invention may also be used for the treatment of gastrointestinal disorders such as irritable bowel syndrome (IBS); skin disorders such as psoriasis, pruritis and sunburn; vasospastic diseases such as angina, vascular headache and Reynaud's disease; cerebral ischeamia such as cerebral vasospasm following subarachnoid haemorrhage; fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis; disorders related to immune enhancement or suppression such as systemic lupus erythematosus and rheumatic diseases such as fibrositis; and cough.
  • IBS irritable bowel syndrome
  • skin disorders such as psoriasis, pruritis and sunburn
  • vasospastic diseases such as angina, vascular headache and Reynaud's disease
  • cerebral ischeamia such as cerebral vasospasm following subarachnoid haemorrh
  • the therapy of the present invention may also be used for the treatment of neurotoxic injury which follows cerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospam, hypoglycemia, hypoxia, anoxia or perinatal asphyxia cardiac arrest.
  • Antipsychotic drugs which may be used in the therapy of the present invention include typical antipsychotics (for example chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine, thiothixine, haloperidol, thiflurpromazine, pimozide, droperidol, chlorprothixene, molindone, amisulpride and loxapine); and atypical antipsychotics (for example clozapine, olanzapine, risperidone, quetiapine, aripirazole, ziprasidone, asenapine, bifeprunox, paliperidone, ocaperidone, blonanserin, lurasidone and SB773812).
  • typical antipsychotics for example chlorpromazine, thioridazine, mesoridazine, fluphenazine
  • Alternative antipsychotic drugs which may be used in the therapy of the present invention include pizotifen, iloperidone, ritanserin, ketanserin, cyproheptadine, benperidol, flupentixol, levipromazine, pericyazine, promazine, remoxipride, sertindole, sulpiride, zotepine and zupenthixolclozapine.
  • Mood stabilisers which may be used in the therapy of the present invention include lithium, sodium valproate/valproic acid/divalproex, carbamazepine, lamotrigine, gabapentin, topiramate, oxcarbazepine and tiagabine.
  • Cognitive enhancers which may be used in the therapy of the present invention include example cholinesterase inhibitors (such as tacrine, donepezil, rivastigmine and galantamine), H3 antagonists and muscarinic M1 agonists (such as cevimeline).
  • cholinesterase inhibitors such as tacrine, donepezil, rivastigmine and galantamine
  • H3 antagonists such as muscarinic M1 agonists (such as cevimeline).
  • Antidepressant drugs which may be used in the therapy of the present invention include NK-1 antagonists; NK1 and NK2 dual antagonists; NK2 antagonists; serotonin agonists (such as rauwolscine, yohimbine and metoclopramide); serotonin reuptake inhibitors (such as citalopram, escitalopram, fluvoxamine, femoxetine, indalpine, zimeldine, paroxetine and sertraline); dual serotonin/noradrenaline reuptake inhibitors (such as venlafaxine, reboxetine, duloxetine and milnacipran); Noradrenaline reuptake inhibitors (such as reboxetine); tricyclic antidepressants (such as amitriptyline, clomipramine, imipramine, maprotiline, nortriptyline and trimipramine); monoamine oxidase inhibitors (such as isocarboxa
  • Anxiolytics which may be used in the therapy of the present invention include benzodiazepines such as alprazolam and lorazepam.
  • Drugs for extrapyramidal side effects which may be used in the therapy of the present invention include anticholinergics (such as benztropine, biperiden, procyclidine and trihexyphenidyl), antihistamines (such as diphenhydramine) and dopaminergics (such as amantadine).
  • anticholinergics such as benztropine, biperiden, procyclidine and trihexyphenidyl
  • antihistamines such as diphenhydramine
  • dopaminergics such as amantadine
  • drugs which may be used in the therapy of the present invention include sumatriptan.
  • tradenames and suppliers of selected active ingredients are as follows: clozapine (available under the tradename CLOZARIL®, from Mylan, Zenith Goldline, UDL, Novartis); olanzapine (available under the tradename ZYPREXA®, from Lilly; ziprasidone (available under the tradename GEODON®, from Pfizer); risperidone (available under the tradename RISPERDAL®, from Janssen); quetiapine fumarate (available under the tradename SEROQUEL®, from AstraZeneca); haloperidol (available under the tradename HALDOL®, from Ortho-McNeil); chlorpromazine (available under the tradename THORAZINE®, from GlaxoSmithKline; fluphenazine (available under the tradename PROLIXIN®, from Apothecon, Copley, Schering, Teva, and American Pharmaceutical Partners, Pasadena); thiothixene (available under the tradename NAVA
  • the NK3 antagonist is talnetant or a pharmaceutically acceptable salt thereof.
  • talnetant with pharmaceutically acceptable acids
  • Suitable pharmaceutically acceptable salts of talnetant include basic salts with the appropriate acid for example organic carboxylic acids such as acetic, lactic, tartaric, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p- toluenesulfonic acids and inorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamic acids and the like.
  • talnetant is the free base.
  • Talnetant may be crystallised or recrystallised from solvents such as aqueous and organic solvents. In such cases solvates may be formed.
  • the invention includes within its scope stoichiometric solvates including hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation. All solvates and all alternative physical forms of talnetant or its pharmaceutically acceptable derivatives as described herein, including but not limited to alternative crystalline forms, amorphous forms and polymorphs are also within the scope of this invention, and all references to "talnetant” herein include all pharmaceutically acceptable salts, and all solvates and alternative physical forms thereof.
  • the active ingredient for use in combination with the NK3 antagonist, or talnetant is an atypical antipsychotic, for example clozapine, olanzapine, risperidone, quetiapine, aripirazole, ziprasidone, asenapine, bifeprunox, paliperidone, ocaperidone, blonanserin, lurasidone and SB773812.
  • atypical antipsychotic for example clozapine, olanzapine, risperidone, quetiapine, aripirazole, ziprasidone, asenapine, bifeprunox, paliperidone, ocaperidone, blonanserin, lurasidone and SB773812.
  • the active ingredient for use in combination with the NK3 antagonist, or talnetant is a typical antipsychotic, for example chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine, thiothixine, haloperidol, thiflurpromazine, pimozide, droperidol, chlorprothixene, molindone, amisulpride and loxapine.
  • a typical antipsychotic for example chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine, thiothixine, haloperidol, thiflurpromazine, pimozide, droperidol, chlorprothixene, molindone, amisulpride and loxapine.
  • the active ingredient for use in combination with the NK3 antagonist, or talnetant is a mood stabiliser, for example lithium, sodium valproate/valproic acid/divalproex, carbamazepine, lamotrigine, gabapentin, topiramate, oxcarbazepine or tiagabine.
  • a mood stabiliser for example lithium, sodium valproate/valproic acid/divalproex, carbamazepine, lamotrigine, gabapentin, topiramate, oxcarbazepine or tiagabine.
  • the active ingredient for use in combination with the NK3 antagonist, or talnetant is an antidepressant, for example a serotonin agonist (such as rauwolscine, yohimbine or metoclopramide); a serotonin reuptake inhibitor (such as citalopram, escitalopram, fluvoxamine, femoxetine, indalpine, zimeldine, paroxetine or sertraline); a dual serotonin/noradrenaline reuptake inhibitor (such as venlafaxine, reboxetine, duloxetine or milnacipran); a noradrenaline reuptake inhibitors (such as reboxetine); a tricyclic antidepressants (such as amitriptyline, clomipramine, imipramine, maprotiline, nortriptyline or trimipramine); a monoamine oxidase inhibitor (such as isocarboxa
  • the active ingredient for use in combination with the NK3 antagonist, or talnetant is an anxiolytic, for example a benzodiazepine such as alprazolam or lorazepam.
  • the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of talnetant or a pharmaceutically acceptable salt thereof to a patient receiving administration of olanzapine.
  • the invention provides the use of talnetant or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving administration of olanzapine.
  • the invention provides the use of talnetant or a pharmaceutically acceptable salt thereof for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving administration of olanzapine.
  • the invention provides talnetant or a pharmaceutically acceptable salt thereof for use for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving administration of olanzapine.
  • the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of talnetant or a pharmaceutically acceptable salt thereof to a patient receiving administration of risperidone.
  • the invention provides the use of talnetant or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving administration of risperidone.
  • the invention provides the use of talnetant or a pharmaceutically acceptable salt thereof for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving administration of risperidone.
  • the invention provides talnetant or a pharmaceutically acceptable salt thereof for use for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving administration of risperidone.
  • the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of talnetant or a pharmaceutically acceptable salt thereof to a patient receiving administration of aripiprazole.
  • the invention provides the use of talnetant or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving administration of aripiprazole. In one embodiment, the invention provides the use of talnetant or a pharmaceutically acceptable salt thereof for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving administration of aripiprazole.
  • the invention provides talnetant or a pharmaceutically acceptable salt thereof for use for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving administration of aripiprazole.
  • the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of talnetant or a pharmaceutically acceptable salt thereof to a patient receiving administration of quetiapine.
  • the invention provides the use of talnetant or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving administration of quetiapine.
  • the invention provides the use of talnetant or a pharmaceutically acceptable salt thereof for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving administration of quetiapine.
  • the invention provides talnetant or a pharmaceutically acceptable salt thereof for use for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving administration of quetiapine.
  • the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of talnetant or a pharmaceutically acceptable salt thereof to a patient receiving administration of ziprasidone.
  • the invention provides the use of talnetant or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving administration of ziprasidone. In one embodiment, the invention provides the use of talnetant or a pharmaceutically acceptable salt thereof for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving administration of ziprasidone.
  • the invention provides talnetant or a pharmaceutically acceptable salt thereof for use for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving administration of ziprasidone.
  • the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of talnetant or a pharmaceutically acceptable salt thereof to a patient receiving administration of haloperidol.
  • the invention provides the use of talnetant or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving administration of haloperidol.
  • the invention provides the use of talnetant or a pharmaceutically acceptable salt thereof for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving administration of haloperidol.
  • the invention provides talnetant or a pharmaceutically acceptable salt thereof for use for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving administration of haloperidol.
  • the active ingredient component or components may also be administered in their basic or acidic forms as appropriate or, where appropriate, in the form of a pharmaceutically acceptable salt or other derivative. All solvates and all alternative physical forms of the active ingredient or agents or their pharmaceutically acceptable salts or derivatives as described herein, including but not limited to alternative crystalline forms, amorphous forms and polymorphs, are also within the scope of this invention.
  • the forms and derivatives used are those which are approved for therapeutic administration as monotherapies, including those mentioned in Table 1 , but all references to active ingredients herein include all pharmaceutically acceptable salts or other derivatives thereof, and all solvates and alternative physical forms thereof.
  • the NK3 antagonist such as talnetant or its pharmaceutically acceptable salts or solvates and the other active ingredient or their pharmaceutically acceptable salts, derivatives or solvates may each be administered in pure form, but each of the components may be formulated into any suitable pharmaceutically acceptable and effective composition which provides effective levels of the respective component in the body.
  • suitable pharmaceutical compositions include, but are not limited to tablets, capsules, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations such as oral or sterile parenteral solutions or suspensions.
  • the NK3 antagonist such as talnetant or its pharmaceutically acceptable salts or solvates and the other active ingredient and their pharmaceutically acceptable salts, derivatives or solvates may be administered together in pure form, but the combined components may be formulated into any suitable pharmaceutically acceptable and effective composition which provides effective levels of each of the components in the body.
  • the choice of the most appropriate pharmaceutical compositions for the combined components is within the skill of the art.
  • Suitable formulations include, but are not limited to tablets, sub-lingual tablets, buccal compositions, capsules, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations such as oral or sterile parenteral solutions or suspensions.
  • compositions of each of the components, or of the combination of the components is in the form of a unit dose.
  • Unit dose presentation forms of the components, or of the combination of the components, for oral administration may be tablets and capsules and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize- starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulphate.
  • binding agents for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone
  • fillers for example lactose, sugar, maize- starch, calcium phosphate, sorbitol or glycine
  • tabletting lubricants for example magnesium
  • the solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are of course conventional in the art.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
  • Oral liquid preparations for the components, or for the combination of the components may be in the form of, for example, emulsions, syrups, suspensions or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, or hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, or hydrogenated edible fats
  • emulsifying agents for example lecithin, sorbitan monooleate,
  • fluid unit dosage forms are prepared utilizing the component or the combination of the components and a sterile vehicle, and, depending on the concentration used, can be either suspended or dissolved in the vehicle.
  • the components or the combination of the components can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, a preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner, except that the component is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration.
  • the components, or the combination of the components can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the component or the combination of the components.
  • the components or the combination of the components may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the components or the combination of the components of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • compositions of each of the components or of the combination or of the components may contain from 0.1% to 99% by weight, such as from 10-60% by weight, of the active material, depending on the method of administration.
  • the unit dose of the talnetant component is in the range of 10-600 milligrammes, each unit dose being administered up to four times daily. In one embodiment, the unit dose of the talnetant component is in the range 100-600 milligrammes, each unit dose being administered up to four times daily.
  • the daily and unit doses of the active ingredient will depend upon which active ingredient is employed, but will typically be the recommended or approved dosage for the specific active ingredient when administered as monotherapy.
  • adjunctive administration of talnetant may permit lower doses of the active ingredient than those normally recommended when the active ingredient is prescribed as monotherapy. Typical daily doses of the active ingredients suitable for use in adjunctive or simultaneous administration according to the invention are shown in Table 1.
  • talnetant 600mg BID plus risperidone (2mg BID) will be compared to risperidone (2mg BID) plus placebo and placebo plus placebo in subjects with an acute exacerbation of schizophrenia. This will be an international multicenter, double-blind, randomized study.
  • the Screening Phase begins with the Screen Visit and can last from 1 to 7 days. At the Baseline visit, evaluations will be conducted to determine eligibility for randomization into the Treatment Phase of the study for all subjects. Subjects who have a PANSS score that has not changed by more than 20% since the initial Screen Visit remain eligible for study participation. Subjects not meeting these criteria are withdrawn from the study. The Treatment Phase will begin the day after the Baseline Visit. Eligible subjects will be randomized (1:1:1) to treatment with risperidone (2mg BID) plus talnetant (600mg BID), risperidone (2mg BID) plus placebo or placebo plus placebo for a 6-week, double-blind treatment period. No dose adjustments will be permitted with risperidone. Subjects with significant tolerability issues will be dropped from the study. No other antipsychotic medications will be permitted during the screening or treatment phase of the study, although certain rescue medications will be specified and permitted.
  • Subjects will remain in-patient for the duration of the treatment period.
  • the primary efficacy measure the PANSS total, will be administered at Screen, Baseline, and weekly through the 6-week treatment period. Secondary efficacy measures will be assessed at specific visits.

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Abstract

L'invention concerne une méthode permettant de traiter un trouble psychotique par l'administration d'un traitement complémentaire comprenant un antagoniste de NK3 ou un sel pharmaceutiquement acceptable de celui-ci, à un patient traité avec un agent antipsychotique.
PCT/EP2006/009182 2005-09-22 2006-09-20 Traitement combine WO2007039123A2 (fr)

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US11351154B2 (en) 2011-09-09 2022-06-07 University Of Virginia Patent Foundation Molecular genetic approach to treatment and diagnosis of alcohol and drug dependence
US11491136B2 (en) * 2017-02-14 2022-11-08 Research Triangle Institute Proline-based neuropeptide FF receptor modulators
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WO2009029308A1 (fr) * 2007-08-27 2009-03-05 University Of Virginia Patent Foundation Combinaisons de médicaments pour le traitement de l'alcoolisme et de la pharmacodépendance
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US8697361B2 (en) 2008-02-28 2014-04-15 University Of Virginia Patent Foundation Serotonin transporter gene and treatment of alcoholism
US12221654B2 (en) 2008-02-28 2025-02-11 University Of Virginia Patent Foundation Serotonin transporter gene and treatment of opioid-related disorders
US11905562B2 (en) 2008-02-28 2024-02-20 University Of Virginia Patent Foundation Serotonin transporter gene and treatment of opioid-related disorders
US10533226B2 (en) 2008-02-28 2020-01-14 University Of Virginia Patent Foundation Serotonin transporter gene and treatment of alcoholism
US10619209B2 (en) 2008-02-28 2020-04-14 University Of Virginia Patent Foundation Serotonin transporter gene and treatment of opioid-related disorders
US11116753B2 (en) 2010-07-02 2021-09-14 University Of Virginia Patent Foundation Molecular genetic approach to treatment and diagnosis of alcohol and drug dependence
US11957664B2 (en) 2010-07-02 2024-04-16 University Of Virginia Patent Foundation Molecular genetic approach to treatment and diagnosis of alcohol and drug dependence
US10603307B2 (en) 2010-07-02 2020-03-31 University Of Virginia Patent Foundation Molecular genetic approach to treatment and diagnosis of alcohol and drug dependence
US11324723B2 (en) 2010-07-02 2022-05-10 University Of Virginia Patent Foundation Molecular genetic approach to treatment and diagnosis of alcohol and drug dependence
US12274692B2 (en) 2010-07-02 2025-04-15 University Of Virginia Patent Foundation Molecular genetic approach to treatment and diagnosis of alcohol and drug dependence
US12226401B2 (en) 2010-07-02 2025-02-18 University Of Virginia Patent Foundation Molecular genetic approach to treatment and diagnosis of alcohol and drug dependence
US8753815B2 (en) 2010-07-02 2014-06-17 University Of Virginia Patent Foundation Molecular genetic approach to treatment and diagnosis of alcohol and drug dependence
US12150931B2 (en) 2010-07-02 2024-11-26 University Of Virginia Patent Foundation Molecular genetic approach to treatment and diagnosis of alcohol and drug dependence
US9539242B2 (en) 2010-07-02 2017-01-10 University Of Virginia Patent Foundation Molecular genetic approach to treatment and diagnosis of alcohol and drug dependence
US11351154B2 (en) 2011-09-09 2022-06-07 University Of Virginia Patent Foundation Molecular genetic approach to treatment and diagnosis of alcohol and drug dependence
US11826350B2 (en) 2017-02-14 2023-11-28 Research Triangle Institute Proline-based neuropeptide FF receptor modulators
US11491136B2 (en) * 2017-02-14 2022-11-08 Research Triangle Institute Proline-based neuropeptide FF receptor modulators
WO2021154631A1 (fr) * 2020-01-30 2021-08-05 Javed Mohammad Polythérapies pour le traitement de troubles du système nerveux central
WO2023211779A1 (fr) * 2022-04-25 2023-11-02 Kallyope, Inc. Traitement de troubles de la céphalée par des modulateurs nk3
US12281114B2 (en) 2023-04-18 2025-04-22 Kallyope, Inc. NK3 modulators and uses thereof

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