US20120135960A2 - Use of anti-connexin agents for modulating the therapeutic effect of psychotropic drugs - Google Patents

Use of anti-connexin agents for modulating the therapeutic effect of psychotropic drugs Download PDF

Info

Publication number
US20120135960A2
US20120135960A2 US13/063,409 US200913063409A US2012135960A2 US 20120135960 A2 US20120135960 A2 US 20120135960A2 US 200913063409 A US200913063409 A US 200913063409A US 2012135960 A2 US2012135960 A2 US 2012135960A2
Authority
US
United States
Prior art keywords
connexin
psychotropic drug
dose
effect
product according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US13/063,409
Other languages
English (en)
Other versions
US20110172188A1 (en
Inventor
Franck Mouthon
Mathieu Charveriat
Jean-Philippe Deslys
Francois Iris
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bio Modeling Systems Ou Bmsystems
Commissariat a lEnergie Atomique et aux Energies Alternatives CEA
Original Assignee
Bio Modeling Systems Ou Bmsystems
Commissariat a lEnergie Atomique et aux Energies Alternatives CEA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bio Modeling Systems Ou Bmsystems, Commissariat a lEnergie Atomique et aux Energies Alternatives CEA filed Critical Bio Modeling Systems Ou Bmsystems
Assigned to COMMISSARIAT A L'ENERGIE ATOMIQUE ET AUX ENERGIES ALTERNATIVES, BIO MODELING SYSTEMS OU BMSYSTEMS reassignment COMMISSARIAT A L'ENERGIE ATOMIQUE ET AUX ENERGIES ALTERNATIVES ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CHARVERIAT, MATHIEU, DESLYS, JEAN-PHILIPPE, MOUTHON, FRANCK, IRIS, FRANCOIS
Publication of US20110172188A1 publication Critical patent/US20110172188A1/en
Publication of US20120135960A2 publication Critical patent/US20120135960A2/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • 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
    • A61K31/13—Amines
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61K31/40—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
    • 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
    • A61K31/40—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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4458—Non condensed piperidines, e.g. piperocaine only substituted in position 2, e.g. methylphenidate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and 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
    • A61K31/435—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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with 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
    • A61K31/535—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
    • 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
    • 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
    • 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
    • A61K31/551—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
    • 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
    • A61K31/551—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
    • 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
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • 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
    • A61K31/69—Boron compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/45—Transferases (2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/51—Lyases (4)
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y201/00—Transferases transferring one-carbon groups (2.1)
    • C12Y201/01—Methyltransferases (2.1.1)
    • C12Y201/01006—Catechol O-methyltransferase (2.1.1.6)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y401/00—Carbon-carbon lyases (4.1)
    • C12Y401/01—Carboxy-lyases (4.1.1)
    • C12Y401/01084—D-Dopachrome decarboxylase (4.1.1.84)

Definitions

  • This invention relates to improvements in therapeutic neurological and neuropsychic treatments using psychotropic molecules. More specifically, the invention enables the effects of psychotropic drugs to be modulated and/or potentiated by certain molecules, referred to here as anti-connexin agents.
  • FIG. 1 shows the spectral analysis of the electrical activity of the prefrontal cortex by quantitative EEG of the effect of submeningeal injection of Meclofenamic acid (MFA, black squares) or 18- ⁇ -Glycyrrhetinic acid (Beta GA, white circles).
  • MFA Meclofenamic acid
  • Beta GA 18- ⁇ -Glycyrrhetinic acid
  • the x-axis shows the frequencies analyzed and the y-axis shows the relative powers obtained from the FFT analysis.
  • the spectral analysis is shown as an average for the first hour and for the second hour of recording.
  • FIG. 2 shows the spectral analysis of the electrical activity of the prefrontal cortex by quantitative EEG of the effect of Clozapine alone (0.2 mg/kg intraperitoneally), the connexin inhibitor alone (Meclofenamic acid, 80 ng/kg per submeningeal injection), or the combination [Clozapine and connexin inhibitor].
  • the x-axis shows the frequencies analyzed and the y-axis shows the relative powers obtained from the Fourier transform analysis (FFT).
  • FFT Fourier transform analysis
  • FIG. 3 shows an analysis of the change minute-by-minute in the prefrontal cortex with an average frequency of 8 Hz by quantitative EEG of the effect of Clozapine alone (0.2 mg/kg intraperitoneally), the connexin inhibitor alone (Meclofenamic acid, 80 ng/kg per submeningeal injection) or the combination [Clozapine and connexin inhibitor].
  • the x-axis shows the time in minutes and the y-axis shows the relative powers obtained in the FFT analysis.
  • FIG. 4 shows the spectral analysis of the electrical activity of the prefrontal cortex by quantitative EEG of the effect of the connexin inhibitor by submeningeal injection (Meclofenamic acid, 80 ng/kg), or by intraperitoneal injection (Meclofenamic acid, 2.45 mg/kg).
  • the x-axis shows the frequencies analyzed and the y-axis shows the relative powers obtained from the FFT analysis.
  • the spectral analysis is shown as an average for 6 animals for the first hour and for the second hour of recording.
  • FIG. 5 shows the spectral analysis of the electrical activity of the prefrontal cortex by quantitative EEG of the effect of different doses of the connexin inhibitor by intraperitoneal injection (Meclofenamic acid, 2 mg/kg, 1 mg/kg, 0.5 mg/kg, 0.4 mg/kg).
  • the x-axis shows the frequencies analyzed and the y-axis shows the relative powers obtained from the FFT analysis.
  • the spectral analysis is shown as an average for the first hour and for the second hour of recording.
  • FIG. 6 shows the spectral analysis of the electrical activity of the prefrontal cortex by quantitative EEG of the effect of Paroxetine (0.5 mg/kg intraperitoneally) alone, the connexin inhibitor (Meclofenamic acid, 0.4 mg/kg by intraperitoneal injection) alone, or the combination of Paroxetine and connexin inhibitor.
  • the x-axis shows the frequencies analyzed and the y-axis shows the relative powers obtained from the FFT analysis.
  • the spectral analysis is shown as an average for 6 animals for the first hour and for the second hour.
  • FIG. 7 shows the spectral analysis of the electrical activity of the prefrontal cortex by quantitative EEG of the effect of Modafinil (125 mg/kg and 250 mg/kg intraperitoneally) alone, the connexin inhibitor (Meclofenamic acid 0.4 mg/kg by intraperitoneal injection) alone, or the combination of Modafinil (125 mg/kg intraperitoneally) and connexin inhibitor.
  • the x-axis shows the frequencies analyzed and the y-axis shows the relative powers obtained from the FFT analysis.
  • the spectral analysis is shown as an average for the 6 animals for the first hour and for the second hour.
  • FIG. 8 shows the spectral analysis of the electrical activity of the prefrontal cortex by quantitative EEG of the effect of Diazepam (1 mg/kg intraperitoneally) alone, or the combination of Diazepam (1 mg/kg intraperitoneally) with the connexin inhibitor (Meclofenamic acid, 0.4 mg/kg intraperitoneally).
  • the x-axis shows the frequencies analyzed and the y-axis shows the relative powers obtained from the FFT analysis.
  • the spectral analysis is shown as an average for the 6 animals for the first hour and for the second hour.
  • FIG. 9 shows the spectral analysis of the electrical activity of the prefrontal cortex by quantitative EEG of the effect of Venlafaxine (0.16 mg/kg and 4 mg/kg intraperitoneally) alone, or the combination of Venlafaxine (0.16 mg/kg intraperitoneally) with the connexin inhibitor (Meclofenamic acid, 0.4 mg/kg intraperitoneally).
  • the x-axis shows the frequencies analyzed and the y-axis shows the relative powers obtained from the FFT analysis.
  • the spectral analysis is shown as an average for the 6 animals for the first hour and for the second hour.
  • FIG. 10 shows the spectral analysis of the electrical activity of the prefrontal cortex by quantitative EEG of the effect of Escitalopram (0.8 mg/kg and 4 mg/kg intraperitoneally) alone, or the combination of Escitalopram (0.8 mg/kg intraperitoneally) with the connexin inhibitor (Meclofenamic acid, 0.4 mg/kg intraperitoneally).
  • the x-axis shows the frequencies analyzed and the y-axis shows the relative powers obtained from the FFT analysis.
  • the spectral analysis is shown as an average for the 6 animals for the first hour and for the second hour.
  • FIG. 11 shows the spectral analysis of the electrical activity of the prefrontal cortex by quantitative EEG of the effect of Bupropion (0.16 mg/kg, 0.8 mg/kg and 4 mg/kg intraperitoneally) alone, or the combination of Bupropion (0.16 mg/kg intraperitoneally) with the connexin inhibitor (Meclofenamic acid, 0.4 mg/kg intraperitoneally).
  • the x-axis shows the frequencies analyzed and the y-axis shows the relative powers obtained from the FFT analysis.
  • the spectral analysis is shown as an average for the 6 animals for the first hour and for the second hour.
  • FIG. 12 shows the spectral analysis of the electrical activity of the prefrontal cortex by quantitative EEG of the effect of Sertraline (0.16 mg/kg, 0.8 mg/kg and 4 mg/kg intraperitoneally) alone, or the combination of Sertraline (0.16 mg/kg intraperitoneally) with the connexin inhibitor (Meclofenamic acid, 0.4 mg/kg intraperitoneally).
  • the x-axis shows the frequencies analyzed and the y-axis shows the relative powers obtained from the FFT analysis.
  • the spectral analysis is shown as an average for the 6 animals for the first hour and for the second hour.
  • FIG. 13 shows a diagrammatic representation of the EEG effect in the form of an inverted “U” for sertraline alone according to the dose administered over the two recording hours (0.16 mg/kg, 0.8 mg/kg and 4 mg/kg intraperitoneally) alone, or the combination of Sertraline (0.16 mg/kg intraperitoneally) with the connexin inhibitor (Meclofenamic acid, 0.4 mg/kg intraperitoneally).
  • gap junctions connect the cell cytoplasm, enabling the exchange of ions (Ca + and K + ), second messengers (AMPc, GMPc, IP3), several small metabolites (glucose) and ensuring electrical and metabolic coupling between the cells.
  • the gap junctions are junctions with a selective permeability, formed by protein channels contained in the plasma membrane, and formed by connexin hexamers (Meda P, Médecine/Sciences 1996; 12: 909-920).
  • Connexins are integral proteins of the plasma membrane, which are synthesized by practically every cell type, regardless of the position of a multicellular organism in the phylogenesis of the animal world. In vertebrates, occasional cells not producing connexins are adult striated muscle cells, spermatozoids and circulating blood cells. Unlike numerous membrane proteins, connexins have a short half-life (between 3 and 6 hours), are not glycosylated and do not have an enzymatic activity. At present, at least thirteen distinct connexins have been identified in mammals; corresponding, in humans, to 21 isoforms.
  • connexin In practice, various types of connexin can be present in a plurality of tissues, and most of the cells synthesize a plurality of connexins (Meda P, Médecine/Sciences 1996; 12: 909-920). Before reaching the cell membrane, the connexins assembly in groups of six molecules to form hollow tubular structures called connexons, which join the plasma membrane by means of Golgi vesicles. When cell contact is established, the connexons of a cell align end-to-end with those of the neighboring cell, establishing a continuous hydrophilic channel around 10 nm long. This junctional channel establishes direct contact between the cytoplasms of the two cells in contact, over the intercellular space.
  • connexin 36 connexin 36
  • Mice deficient in connexin 36 do not have any inter-neuron coupling, which helps to confirm the leading role of these particular connexins in at least one type of electrical synapse (Wellershaus K, Exp Cell Res. 2008).
  • the electrical synapses do not transmit information faster than chemical synapses, but have a particular characteristic, that of reciprocity: neither inhibiting nor excitatory, they locally synchronize the state of multiple cells, and bilaterally.
  • the gap junctions acting as low pass filters, this process of normalization of the state of the cells is more effective as it involves more or less long-term changes. Electrical couplings between neurons, owing to their characteristics, would play a role in oscillation phenomena and rhythmic discharges in the neocortex and the hippocampus.
  • connexins are present everywhere in the different brain structures and are involved locally in the oscillations of electrical activities.
  • connexins also play an important role in the general regulation of the electrical activity of the brain. Surprisingly, when they are physiologically present, these proteins indeed have a general desynchronizing role on the electrical activity of the CNS, damping and potentially neutralizing burst phenomena. Conversely, the inhibition of these molecules by means of so-called “anti-connexin” agents makes it possible to synchronize and therefore increase the electrophysiological activity measured.
  • this invention proposes a method for evaluating the effective psychotropic drug equivalent dose that may be combined with the connexin blocking agent in the treatment of a patient suffering from psychiatric and/or neurodegenerative disorders. This combination is intended to obtain the same therapeutic effect as that of the psychotropic drug alone administered at a stronger dose, but with fewer adverse effects.
  • the “effective equivalent dose” of a psychotropic drug refers to the psychotropic drug dose that, when administered in combination with the connexin blocking agent, induces a physiological effect or a pharmacological signature similar or identical to that of the psychotropic drug alone administered at the active pharmacological dose.
  • the “pharmacologically active dose” of a psychotropic drug refers to the psychotropic drug dose classically administered to laboratory animals such as rats, mice, rabbits and so on. Such doses are provided, for example, in Animal models in psychopharmacology . Olivier B, S GmbH J, Mos J, eds. Birkhauser Verlag, Basel; 1991. If this dose is not known, it is possible to determine the pharmacologically active dose of the psychotropic drug by transposing, in the animal, the pharmacologically active doses classically prescribed in humans and that can be consulted in “Médicaments psychotropes: Why etrise en France modiapolitaine. I.
  • the pharmacologically active dose is the maximum psychotropic drug dose that can be administered to an animal without the adverse effects becoming more pronounced than the therapeutic effect.
  • the pharmacologically active dose can be determined cumulatively by administering a plurality of psychotropic drug doses at increasing doses and by measuring, each time, the effect produced by said drug.
  • a “connexin-blocking” agent is a chemical molecule, a protein, a protein fragment or a nucleic acid (RNAi) capable of inhibiting the functional activity of connexins, directly and/or indirectly, and more generally any type of intercellular junctions, and/or capable of functionally inhibiting, directly and/or indirectly any cellular activity involving a connexin-type protein.
  • RNAi nucleic acid
  • Such an agent can also be referred to as an “anti-connexin molecule”.
  • the method for evaluating the effective equivalent dose of a psychotropic drug is based on the quantification of the potentiation of the effect of the psychotropic drug by the agent blocking the connexins.
  • This evaluation is performed in several steps: a step of characterization of the effects specific to the psychotropic agent and a step of measuring the dose benefit of the combination product.
  • the first step consists of determining and quantifying the effects of the psychotropic drug alone at different doses (pharmacologically active dose and doses decreasing from the pharmacologically active dose), and thus having signatures specific to the psychotropic molecule—or standard signatures—at the different doses.
  • the second step consists of determining the psychotropic drug dose, which, administered in combination with the connexin-blocking agent, has the same pharmacological signature as the psychotropic drug alone.
  • the dose of connexin-blocking agent used in combination with the psychotropic drug is first determined by experimental tests.
  • This dose indeed corresponds to the maximum dose of connexin-blocking agent that can be administered without producing a significant specific pharmacological effect.
  • This dose can be adjusted when implementing the method according to the invention so as to optimize the effect of the combination.
  • the effective equivalent dose of the psychotropic drug i.e. the dose of psychotropic drug that, when administered in combination with the connexin-blocking agent, produces the same effect as that of the psychotropic drug alone administered at said pharmacologically active dose.
  • This method for evaluating the effective equivalent dose of a psychotropic drug also makes it possible to evaluate the dose benefit between a combination product combining said psychotropic drug at the effective equivalent dose and a connexin-blocking agent and the psychotropic drug administered at the pharmacologically active dose.
  • dose benefit refers, in this application, to the ratio between the pharmacological dose of the psychotropic drug alone and the effective equivalent dose of the psychotropic drug.
  • dose benefit explains by how much the pharmacological dose of a prescribed psychotropic drug can be reduced in view of its combination with the anti-connexin agent. This reduction in the psychotropic drug dose administered (in combination with the anti-connexin molecules) will not have any consequence in terms of efficacy of the treatment, but will reduce adverse effects.
  • BD Pharmacologically ⁇ ⁇ active ⁇ ⁇ dose ⁇ ⁇ of ⁇ ⁇ the ⁇ ⁇ psychotropic ⁇ ⁇ drug Effective ⁇ ⁇ equivalent ⁇ ⁇ dose ⁇ ⁇ of ⁇ ⁇ the ⁇ ⁇ psychotropic ⁇ ⁇ drug
  • said animal groups are of the same species. Moreover, each animal group receives exclusively either a dose of psychotropic drug alone, or a combination product containing a certain dose of psychotropic drug and an anti-connexin agent, so as to measure, in the animals of the same group, only the effect of said drug or of said combination product alone.
  • said animal groups are the same age and same sex. These animals are preferably laboratory animals, for example rats, mice, rabbits and so on.
  • the number of doses to be tested is determined according to the pharmacological effect of the psychotropic drug or of the combination product combining the psychotropic drug and the connexin-blocking agent; when the pharmacological effect produced by a certain dose is non-existent or insignificant, it is no longer necessary to use lower doses.
  • the administration of the drug or of the combination product can be performed intracerebrally, but is preferably performed intraperitoneally.
  • the effect produced by the psychotropic drug and/or the combination product can be determined by different types of analysis, in particular an electrophysiological or behavioral analysis or blood markers or LCR markers, or by medical imaging.
  • this effect is determined by reference to an electrophysiological response resulting from a given stimulation, in particular in reference to the electroencephalographic activity (EEG) of the animal.
  • EEG electroencephalographic activity
  • This evaluation method also makes it possible to make a selection with regard to the nature of the connexin-blocking agent, to the psychotropic drug, as well as to the doses used.
  • this invention relates to a new combination product containing at least one connexin-blocking agent and a psychotropic drug, and the use thereof in patients with psychiatric and/or neurodegenerative disorders.
  • the family of fenamates includes the following compounds: meclofenamic acid, flufenamic acid, niflumic acid and tolfenamic acid. These compounds all have a non-steroidal anti-inflammatory activity, but this activity is not responsible for their capacity to block the gap junctions. It has indeed been suggested that the fenamates instead establish a direct interaction with the connexins or with the protein membrane interfaces that may influence the conformation of the connexins and therefore the functional role thereof (Harks E G, The Journal of Pharmacology and Experimental Therapeutics 2001 September, 298 (3): 1033-41).
  • Benzoic 2-[(2,6-di-chloro-3-phenyl)amino] acid is a non-steroidal anti-inflammatory agent and a peripheral analgesic of the fenamate class, a prostaglandin inhibitor, described among the water-soluble blockers as being the most effective for reversibly blocking the gap junctions.
  • meclofenamic acid is not specific to a type of connexin and is therefore effective for blocking a large number of cerebral connexins (Pan F, Vis Neurosciences 2007, July-August; 24 (4): 609-18).
  • Glycyrrhetinic acid derivatives refer to 18- ⁇ -glycyrrhetinic acid (BGA) also known as “enoxolone”, 18- ⁇ -glycyrrhetinic acid and carbenoxolone acid, which are triterpinoid saponins known for inhibiting the 11-hydroxysteroid dehydrogenase enzyme. Moreover, these compounds are capable of very effectively inhibiting the gap junctions (Pan F, Vis Neurosciences 2007, July-August; 24 (4): 609-18).
  • Mefloquine of the quinine family, also has a strong antagonist power on the gap junctions (Srinivas M, PNAS 2001, 98: 10942-10947; Pan F, Vis Neurosciences 2007, July-August; 24 (4):609-18).
  • Some anesthetic agents such as halothane and isoflurane, have a rapid and reversible gap junction blocking effect (Burt J M, et al, Circ Research. 1989; 65: 829-37).
  • oleamide(cis-9-octadecenamide), the first amide of oleic acid also has an inhibiting action on the connexin molecules 43 and 32 (Guan X. et al, J. Cell Biol 1997; 139: 1785-92).
  • cyclodextrins ( ⁇ -cyclodextrin ( ⁇ -CD), ⁇ -cyclodextrin ( ⁇ -CD) and ⁇ -cyclodextrin ( ⁇ -CD)), which are natural cyclical oligosaccharides of ⁇ -D-glucopyranose, have proven anti-connexin properties (Locke D. et al, J. Biol Chem 2004; 279: 22883-92).
  • 2-aminoethyldiphenyl borate (2-APB) is a compound recently identified as a gap junction-blocking agent (Bai D, J Pharmacol Exp Ther, 2006 December; 319 (3): 1452-8).
  • This modulator of the inositol 1,4,5-triphosphate receptor however fairly specifically targets certain connexins, such as connexins 26, 30, 36, 40, 45 and 50 (Bai D, J Pharmacol Exp Ther, 2006 December; 319 (3): 1452-8).
  • the peptides corresponding to the extracellular sequences include the conserved patterns QPG and SHVR of E1 (Gap26) and the conserved pattern SRPTEK of E2 (Gap27) of the connexins are more effective for blocking the gap junctions (Chaytor A T et al, J. Physiol 1997; 503: 99-110).
  • the connexin-blocking agents are advantageously chosen from: long-chain alcohols (for example, heptanol and octanol), fenamates (for example, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid), arylaminobenzoates, aminosulfonates (for example taurine), glycyrrhetinic acid derivatives (for example, 18- ⁇ -glycyrrhetinic acid, 18- ⁇ -glycyrrhetinic acid and carbenoxolone), oleamides (for example, cis-9-octadecenamide), or tetraalkylammonium ions and polyamines (such as spermine and spermidine), quinine derivatives (such as mefloquine), 2-ABP, anesthetic agents (halothane or isoflurane), cyclod
  • the connexin-blocking agent is included in the group including melofenamic acid, 18- ⁇ -glycyrrhetinic acid, carbenoxolone, mefloquine and 2-APB, and more preferably in the group including meclofenamic acid, 18- ⁇ -glycyrrhetinic acid and carbenoxolone.
  • Some molecules with a recognized anti-connexin function have also been described for their anti-inflammatory effect, their anesthetic effect or their effect on prostaglandin homeostasis, and therefore, by themselves have effects on the central nervous system.
  • the activities other than anti-connexin activities are not involved in these effects.
  • the use of low doses allows for better tissue specificity depending on the connexin composition of the tissue, because the CNS is especially rich in connexin.
  • the anti-inflammatory molecules can indirectly produce, by their action on the prostaglandin synthase, a structural modification of the connexins (the regulation of the connexin expression levels or of the phosphorylation thereof occurs in particular via PI3K and PKA, themselves dependent on the activity levels of Cox, NO and PG synthetase, targets of anti-inflammatories).
  • This modification in the sense of a reduction in the presence of the connexins in the junctions, indirectly causes a reduction in the functional activity of the connexins similar to a direct blocking of the connexins.
  • the formation of functional gap junctions can be regulated by means of connexin phosphorylation.
  • phosphorylation of certain protein domains of the hexamer sub-units leads to an inhibition in the functionality of the gap junctions, according to the phosphorylation site, by closing the channels or by reducing the presence at the membrane (modification of traffic and half-life of sub-units) (Scemes E, Glia 2008 Jan. 15, 56 (2): 145-53; Postma F R, J Cell Biol 1998 Mar. 9, 140 (5): 1199-209; Shaw R M, Cell 2007, Feb. 9, 128 (3): 547-60; Fabrizi G M, Brain 2007 February, 130 (Pt2): 394-403).
  • molecules can have an indirect gap junction-blocking effect, via the phosphorylation levels of the connexins. They are in particular: lysophosphatidic acid, thrombin and neuropeptides, such as endothelin (Postma F R, J Cell Biol 1998 Mar. 9, 140 (5): 1199-209).
  • the connexin-blocking agent has an indirect effect on the connexins and the gap junctions, and it is chosen from the group consisting of: lysophosphatidic acid, thrombin and neuropeptides, such as endothelin.
  • the connexin-blocking agent is neither an anesthetic agent nor an anti-inflammatory agent, nor a prostaglandin synthesis inhibitor.
  • the connexin-blocking agent is 2-amino ethoxy diphenyl borate (2-APB).
  • the connexin-blocking agent can advantageously improve the therapeutic effect of psychotropic drugs prescribed by a physician for treating a patient suffering from a psychiatric and/or neurodegenerative disorder. In animals, this improvement can be measured by the method for evaluating the effective equivalent dose, which is the first objective of the invention.
  • Psychotropic agent refers to any substance that acts primarily on the state of the central nervous system by modifying certain cerebral biochemical and physiological processes.
  • This invention differs from the prior art in that, in the combination product, therapeutic benefits produced by the connexin-blocking agent are not specific to the use of a psychotropic drug in particular, but apply similarly to numerous molecules having psychotropic effects.
  • the psychotropic drugs are chosen from the dopaminergic, GABAergic, adrenergic, acetylcholinergic, serotoninergic, opioidergic, adenosinergic, ionotropic, histaminergic, IMAO, Catechol-O-methyl transferase, DOPA decarboxylase and noradrenergic psychotropic effectors.
  • effector refers to any substance activating or inhibiting one or more neuroreceptors, and can therefore be an agonist or an antagonist of said receptors.
  • the psychotropic drug is a dopaminergic effector such as loxapine, acepromazine, methylphenidate, amantadine, pergolide, lisuride, bromocriptine, ropinirole, apomorphine, aripiprazole, sulpiride, amisulpride, sultopride, tiapride, pimozide, lisperidone, haloperidol, penfluridol, zuclopenthixol or bupropion.
  • a dopaminergic effector such as loxapine, acepromazine, methylphenidate, amantadine, pergolide, lisuride, bromocriptine, ropinirole, apomorphine, aripiprazole, sulpiride, amis
  • the psychotropic drug is a GABAergic effector such as tiagabine, topiramate, clorazepate, diazepam, clonazepam, oxazepam, lorazepam, bromazepam, lormetazepam, nitrazepam, clotiazepam, alprozolam, estazolam, triazolam, loprazolam, etifoxin, meprobamate, zopiclone, zolpidem, phenobarbital, felbamate or vigabatrine.
  • GABAergic effector such as tiagabine, topiramate, clorazepate, diazepam, clonazepam, oxazepam, lorazepam, bromazepam, lormetazepam, nitrazepam, clotiazepam, alprozolam, estazolam
  • the psychotropic drug is an adrenergic effector such as dihydroergotamine, modafinil, adrafinil, mirtazapine and oxetorone.
  • the psychotropic drug is an acetylcholinergic effector such as sulbutiamine, tropatepin or trihexyphenidyl.
  • the psychotropic drug is a serotoninergic effector such as chlorpromazine, trimipramine, clozapine, olanzapine, cyamemazine, flupentixol, nefopam, fluvoxamine, clomipramine, sertraline, fluoxetine, citalopram, escitalopram, paroxetine, amitriptyline, duloxetine, venlafaxine, buspirone, carpipramine, zolmitriptan, sumatriptan, naratriptan, indoramine, ergotamine, ergotamine tartrate, pizotifene, pipamperone, methysergide, pizotyline, tianeptine, milnacipran, amitriptyline, trimipramine, viloxazine, tianeptine, hypericum and lithium.
  • a serotoninergic effector such as chlorpromazine, trimipramine
  • the psychotropic drug is an opioidergic effector such as nalbuphine, buprenorphine, pethidine, codeine, tramadol, morphine, hydromorphone, oxycodone, methadone, dextropropoxyphene, meperidine, fentanyl, naltrexone or morphine hydrochloride.
  • opioidergic effector such as nalbuphine, buprenorphine, pethidine, codeine, tramadol, morphine, hydromorphone, oxycodone, methadone, dextropropoxyphene, meperidine, fentanyl, naltrexone or morphine hydrochloride.
  • the psychotropic drug is an adenosinergic effector such as carbamazepine or oxcarbazepine.
  • the psychotropic drug is an ionotropic effector such as flunarizine, ethosuximide, levetiracetam, lamotrigine, fosphenytoin or phenyloin.
  • the psychotropic drug is a histaminergic effector such as niaprazine, hydroxyzine or doxylamine.
  • the psychotropic drug is a monoamine oxidase effector such as moclobemide, selegiline or iproniazid.
  • the psychotropic drug is a catechol-O-methyl transferase effector such as entacapone or tolcapone.
  • the psychotropic drug is a DOPA decarboxylase effector such as benserazide or carbidopa.
  • the psychotropic drug is a noradrenergic effector such as mianserine, desipramine, moclobemide or bupropion.
  • the psychotropic drug is an effector acting on the limbic system, such as gabapentin or captodiamine.
  • the psychotropic molecule chosen is clozapine, a dibenzodiazepine derivative, or paroxetine, escitalopram, sertraline or venlafaxine, which are serotoninergic effectors or any other serotoninergic effector such as chlorpromazine, trimipramine, olanzapine, cyamemazine, flupentixol, nefopam, fluvoxamine, clomipramine, fluoxetine, citalopram, amitriptyline, duloxetine, buspirone, carpipramine, zolmitriptan, sumatriptan, naratriptan, indoramine, ergotamine tartrate, pizotifene, pipamperone, methysergide, pizotyline or tianeptine.
  • serotoninergic effectors or any other serotoninergic effector such as chlorpromazine, trimipramine, olanzapine
  • the psychotropic molecule chosen is modafinil, a diphenylmethane derivative, which is an adrenergic effector or any other adrenergic psychotropic effector such as dihydroergotamine, adrafinil, mirtazapine or oxetorone.
  • the psychotropic molecule is chosen from: modafinil, clozapine, paroxetine, diazepam, venlafaxine, escitalopram, bupropion or sertraline.
  • the psychotropic molecule is an antidepressant chosen from: moclobemide (MOCLAMINE), amitriptyline (LAROXYL), clomipramine (ANAFRANIL), milnacipran (IXEL), escitalopram (SEROPLEX), citalopram (SEROPRAM), fluoxetine (PROZAC), paroxetine (DEROXAT), fluvoxamine (FLOXYFRAL), sertraline (ZOLOFT), mitrapazine (NORSET), duloxetine (Cymbalta) or venlafaxine (EFFEXOR) and bupropion (ZYBAN).
  • MOCLAMINE moclobemide
  • LAROXYL amitriptyline
  • ANAFRANIL milnacipran
  • IXEL escitalopram
  • SEROPRAM citalopram
  • fluoxetine PROZAC
  • paroxetine DEOXAT
  • fluvoxamine FLOXYFRAL
  • sertraline Z
  • the psychotropic molecule is an antidepressant chosen from the group including: paroxetine, venlafaxine, escitalopram, bupropion and sertraline.
  • this invention also relates to the use of this product in combination, simultaneously, separately or sequentially, in patients with psychiatric and/or neurodegenerative disorders.
  • Patients needing this treatment may have psychiatric and/or neurodegenerative disorders included in the group consisting of: depression, bipolar disorder, epilepsy, schizophrenia, generalized anxiety, depression, conditions due to stress, panic, phobias, obsessive compulsive disorders, behavioral disorders, immune system depression, fatigue and symptoms associated with pain, chronic fatigue, fibromyalgia, and other disorders such as autism, attention deficit, hyperactivity, eating disorders such as bulimia, anorexia, obesity, psychic disorders such as apathy, migraine, pain, cardiovascular diseases, neurodegenerative disorders and disorders associated with depressive anxiety (Alzheimer's disease, Huntington's disease, Parkinson's disease), drug dependence and drug addiction.
  • psychiatric and/or neurodegenerative disorders included in the group consisting of: depression, bipolar disorder, epilepsy, schizophrenia, generalized anxiety, depression, conditions due to stress, panic, phobias, obsessive compulsive disorders, behavioral disorders, immune system depression, fatigue and symptoms associated with pain, chronic fatigue,
  • the two components of the treatment are administered to the patient simultaneously.
  • the two components can be packaged together, in the form of a mixture, or separately, then mixed spontaneously before being administered together to the patient. More commonly, the two components are administered simultaneously, but separately.
  • the routes of administration of the two components may be different.
  • the administration can also be performed at different sites.
  • the two components are administered sequentially or spaced apart over time, for example in the same day or at an interval ranging from several hours to several weeks, or even several months.
  • this invention involves the use of at least one connexin-blocking agent for preparing a drug intended to be administered before, at the same time, or after a psychotropic drug, in order to treat a patient suffering from psychiatric and/or neurodegenerative disorders.
  • the invention includes the use of at least one connexin-blocking agent, for modulating and/or potentiating the effect of a psychotropic drug in patients with psychiatric and/or neurodegenerative disorders.
  • modulate in this case means intervening, by potentiation or antagonism, on the direct or indirect effects of the psychotropic drug administered before, simultaneously or after the anti-connexin agent, in particular on the adverse effects.
  • the term “potentiate” in this case means significantly increasing the effects of the psychotropic drug administered before, simultaneously or after the anti-connexin agent.
  • the combination of the psychotropic drug with the anti-connexin agent makes it possible to reduce the doses of said psychotropic drug and therefore to limit the adverse effects of said psychotropic drug, and/or to reduce the effects of failure and withdrawal.
  • the invention therefore also relates to the use of at least one connexin-blocking agent, for reducing the doses of said psychotropic drug and/or limiting the adverse effects of said psychotropic drug, and/or reducing the effects of failure and withdrawal.
  • the invention describes a method for treating a patient with psychiatric and/or neurodegenerative disorders, including the administration to said patient of:
  • Electroencephalography is the measurement of the electrical activity of the brain by means of electrodes placed on the scalp, often represented in the form of a line called the electroencephalogram. Comparable to the electrocardiogram, which makes it possible to study the functioning of the heart, the EEG is a painless and noninvasive examination that provides information on the neurophysiologic activity of the brain over time and in particular of the cerebral cortex, either for a diagnostic neurological purpose or for cognitive neuroscience research purposes.
  • the electric signal at the basis of the EEG is the resultant, for each frequency, of the summation of the synchronous post-synaptic action potentials produced by a large number of neurons.
  • the electrical power associated with each frequency can vary independently of that of the others as a function of the individual's behavior or the drug administered (Dimpfel W, Neuropsychobiology. 1986: 15 (2): 101-8).
  • the electroencephalogram of the patient changes, and the distribution of the potentials associated with each frequency constitutes the electropharmacogram of said drug.
  • the electropharmacograms are different for drugs prescribed for different diseases, and are similar when they are intended to treat the same pathologies (Dimpfel W, British Journal of Pharmacology, 2007, 152, 538-548).
  • Electrophalmacograms corresponding to more than 150 drugs have been determined (for example, analgesics, antidepressants, neuroleptics, stimulants, tranquilizers, sedatives and narcotics).
  • analgesics for example, analgesics, antidepressants, neuroleptics, stimulants, tranquilizers, sedatives and narcotics.
  • the parameters of the EEG make it possible to obtain quantitative information on the development in the clinical phase of numerous compounds (Mandema & Danhof, Clin. Pharmacokinet. 1992, 23, 191-215).
  • the measurement of the EEG potential can also be used to identify the cell receptors of the drugs administered (Parker T J, British Journal of Pharmacology 2001, 132, 151-158).
  • the EEG is a measurement of the electrical activity of the brain and there are different modes for representing electroencephalographic data.
  • the first is the representation of the lines and the identification of characteristic undulation phenomena. This qualitative data is informative for clearly determined episodes of electrical activity, but does not provide information on the quantitative aspect of the electrical activity.
  • the experimenter uses the quantitative EEG based on the analysis of the Fourier transform signal making it possible to obtain power values for a given frequency over time.
  • This power value is associated with a control value that makes it possible to determine the power modification for a given frequency over time. This value may be averaged by time periods variable according to the experiments.
  • the EEG potential is very high for very low frequencies (between 0.8 and 4.5 Hz) (delta rhythm) and between 7 and 9.5 Hz (alpha rhythm I), and low intensity at frequencies between 4.75 and 6.75 Hz (theta rhythm) and greater than 18.5 Hz (beta rhythm), which is the sign of a positive clinical response (Galderisi S, Methods Find Exp Clin Pharmacol, 2002, 24, 85-89).
  • the EEG potential is at average intensity on frequencies ranging from 8 to 15 Hz, which can involve extrapyramidal side effects.
  • an EEG potential of average intensity in the second hour for frequencies of 7-9.5 Hz and 12.75-18.50 Hz means that adverse effects will be present (Dimpfel W, British Journal of Pharmacology 2007, 152, 538-548).
  • a group of 6 conscious Wistar rats was pre-implanted with 6 bipolar bilateral electrodes (2 frontal, 2 anterior hippocampic, 2 posterior hippocampic).
  • meclofenamic acid (Sigma) is performed by slow submeningeal injection (80 mg/kg, 4.5 pg/second) or intraperitoneally at different doses.
  • the injection of glycyrrhetinic acid (Sigma) is performed by submeningeal injection (80 mg/kg).
  • the injection of clozapine (Sigma) is performed intraperitoneally (0.2 mg/kg).
  • the injection of paroxetine (Sigma) is performed intraperitoneally (0.5 mg/kg).
  • modafinil (Cephalon) is performed intrapelitoneally (125 mg/kg and 250 mg/kg).
  • the EEG measurements were performed on the different groups of conscious rats (previously implanted and habituated) by 2-hour recordings after injection.
  • the spectral analysis performed by Fourier transform (FFT) makes it possible to obtain relative powers, Hertz-by-Hertz and second-by-second.
  • the FFT data is then averaged minute-by-minute and associated with the solvent control produced the day prior to the recording under strictly identical experimental conditions.
  • the relative spectral powers of the left and right prefrontal cortices are then averaged by 5-minute periods, averaged by groups of 12 5-minute repetitions and represented hour-by-hour.
  • the significance threshold of the relative power modifications for a given frequency for a psychotropic drug alone with respect to the control (solvent of the psychotropic agent) or a psychotropic drug in combination with an anti-connexin with respect to the psychotropic agent administered alone (in favor of a relative power increase or a decrease) was chosen at a value of P ⁇ 0.05.
  • Clozapine is an atypical antipsychotic indicated for schizophrenia, a serotoninergic and dopaminergic receptor antagonist, alternatively an adrenergic, cholinergic and histaminergic antagonist having a typical complex EEG activation spectrum (Parker T J, British Journal of Pharmacology 2001, 132, 151-158) and a considerable list of adverse effects at therapeutic doses (weight gain, decrease in bone marrow and number of leukocytes in the blood).
  • the spectral analysis of the EEGs shows a significant increase in the EEG potential, and therefore in the synchronization of the prefrontal cerebral activity (200%) for frequencies of 8-10 Hz and to a lesser extent for frequencies of 16-20 Hz during the treatment with the antipsychotic alone, from the first hour and extending to the second hour ( FIG. 2 ).
  • the spectral analysis of the EEGs shows a significant increase in the synchronization of the prefrontal cerebral activity (260%) for frequencies of 8-10 Hz and to a lesser extent for frequencies of 16-20 Hz at the first hour.
  • This significant increase in synchronization corresponds to the clozapine spectrum and therefore corresponds to a potentiation of the effect of clozapine by blocking of the connexin junction system.
  • This mechanism of reinforcement of the effect of clozapine by the anti-connexin is controlled over time. Indeed, at the second hour, only the anti-connexin effect persists ( FIG. 2 ).
  • the damping of the fluctuations caused by clocking of the connexin junction system means that the connexins may play a role in the establishment of these brief fluctuations in electrophysiological activity. These fluctuations would correspond to quick activity kindling mechanisms produced the clozapine and controlled by the connexins.
  • the spectral analysis of the EEGs shows a significant increase comparable to the synchronization of the prefrontal cerebral activity at the first hour and for similar frequency ranges. However, the significant increase in synchronization continues at the second hour for peripheral administration, whereas it decreases for central administration. This difference at the second hour is associated with the pharmacokinetics of the administration routes ( FIG. 4 ).
  • These important synchronizations according to the dose may be due to the quantitative representation (number of variable gap junctions according to the central nervous system network, ex: cholinergic, noradrenergic, serotoninergic, etc.) and/or qualitative representation (affinity of the different connexin isoforms for the inhibitor at the given dose) of connexins.
  • Paroxetine is an antidepressant, indicated for acute or chronic depressive episodes, derived from phenylpiperidine of the selective serotonin reuptake inhibitor group and having a considerable list of adverse effects at the therapeutic doses (apathy, pupil dilation, nausea, teratogenicity, somnolence, headaches, weight and appetite changes, changes in sexual behavior, increase in feelings of depression and anxiety, dry mouth, aggressive behavior (in particular in children), possible congenital deformations, erythema, psychomotor instability, itching, depletion (sodium), sweating, suicidal ideation, muscle weakness, muscle pain, unusual levels of aggression, serotonin syndrome).
  • MFA meclofenamic acid
  • the spectral analysis of the EEGs shows a significant increase in the relative powers in the prefrontal cortex, and therefore in the synchronization of the prefrontal cerebral activity (around 200%) at 8-10 Hz and to a lesser extent for frequencies of 2-3 Hz and 18-19 Hz in the treatment with the antidepressant alone, at the first hour and increasing (around 300%) at the second hour for frequencies of 8-10 Hz and to a lesser extent for frequencies of 2-3 Hz and 18-19 Hz ( FIG. 6 ).
  • the spectral analysis of the EEGs shows a significant increase in the synchronization of the prefrontal cerebral activity (600%) for frequencies of 8-10 Hz and to a lesser extent for frequencies of 2-3 Hz and 18-19 Hz at the second hour.
  • This significant increase in synchronization corresponds perfectly to the spectrum for paroxetine alone and therefore corresponds to a considerable potentiation of the effect of paroxetine by blocking the connexin junction system.
  • this mechanism of reinforcement of the effect of paroxetine by the anti-connexin follows the same time course as the paroxetine alone. Indeed, paroxetine alone or in combination with the anti-connexin causes EEG effects that increase at the second hour and that must wear off several hours after administration ( FIG. 6 ).
  • paroxetine produces effects that are more prolonged over time and that take more time to develop.
  • the potentiation by the anti-connexin therefore retains the time course properties of the psychotropic molecules studied (of different chemical natures, targeting different systems and with very different indications) and reinforces the notion of a system of modulation by connexins that is not limited to a single neurotransmission system.
  • Modafinil is a psychostimulant, indicated for the treatment of narcolepsy and idiopathic hypersomnia, a noradrenaline reuptake inhibitor with a list of adverse effects at therapeutic doses (excitation, aggressiveness, insomnia, anorexia, headaches, nausea, stomach ache, allergic skin eruptions).
  • the experimental model was evaluated with the published data providing in particular the pharmacological doses of modafinil in an acute treatment, which are generally 100 to 350 mg/kg (Sebban C, British Journal of Pharmacology (1999) 128, 1045-1054, De saint Hilaire Z., Neuroreport. 2001 Nov. 16; 12 (16): 3533-7). Recordings of the effect of modafinil alone at two doses (125 and 250 mg/kg) were therefore produced.
  • the spectral analysis of the EEGs shows a significant increase in the EEG potential, and therefore in the synchronization of the prefrontal cerebral activity (300% the 250 mg/kg dose and 120% for the 125 mg/kg dose) for frequencies of 2-5 Hz and a significant decrease in the EEG potential, and therefore a desynchronization in the prefrontal cerebral activity (10 to 30%) for frequencies of 10-25 Hz for the 125 mg/kg dose and to a lesser extent for the 250 mg/kg dose for the treatment with the psychostimulant alone, at the first hour and increasing at the second hour ( FIG. 7 ).
  • Diazepam is an anxiolytic, indicated for excessive anxiety episodes, sleeping difficulties, neurotic states, psychosomatic manifestations, alcohol detoxification and epilepsy. Diazepam is a benzodiazepine facilitating GABAergic transmission, with a considerable list of adverse effects at therapeutic doses (somnolence, hypotonia, feeling of intoxication, difficulty concentrating, irritability, aggressiveness, excitation, confusion, hepatitis, allergic skin reactions, dysphagia) and can lead to tolerance and dependence requiring a dosage adjustment during the various phases of the treatment.
  • MFA meclofenamic acid
  • the experimental model was evaluated in order to compare it with the bibliographic data on the EEG effect of diazepam administered intraperitoneally in the conscious rat (Robledo P., Alcohol Clin Exp Res. 1994 April; 18 (2)-363-8). Recordings of the effect of diazepam alone were therefore produced at the 1 mg/kg dose administered intraperitoneally (1.5 to 5 times less than the dose normally used in an acute treatment in the rat).
  • the spectral analysis of the EEGs shows, at the first hour, the characteristic effects of diazepam, namely a slight decrease in power of the 4-7 Hz components (around 25% decrease) and a significant increase in the power of the 11-30 Hz components (around 120%). At the second hour, these effects on the 4-7 Hz and the 11-30 Hz components persist while reducing in intensity and a significant increase in the power of the 1-3 Hz components appears (cf. FIG. 8 ).
  • the spectral analysis of the EEGs shows, at the first hour, a significant increase in the power for the 11-30 Hz components (around 150%) and the 1-3 Hz components (around 120%). This increase in power continues at the second hour with a higher amplitude for the 11-30 Hz components (up to 200%) (cf. FIG. 8 ).
  • this potentiation of the GABAergic system confirms the hypothesis of a modulating role (likely qualitatively and quantitatively dependent on the organization in the chemical neurotransmission systems) on the electrophysiological activities by the connexin junction system.
  • Venlafaxine is an antidepressant, indicated for major depressive episodes in adults, the prevention of recurrent depression in patients with a unipolar disorder, and generalized anxiety for at least 6 months in adults.
  • Venlafaxine is a serotonin and noradrenaline reuptake inhibitor, with an intermediate profile, and with an efficacy comparable to that of the imipramines, and has a considerable list of adverse effects at therapeutic doses (nausea, somnolence, dry mouth, insomnia, vertigo, constipation, sweating, hyponatremia, difficulty ejaculating, diarrhea, vomiting, weight gain, headaches, agitation, shaking, paresthesia, palpitations, accommodation disorder, skin eruptions) and can cause a withdrawal syndrome when the treatment is stopped.
  • venlafaxine In a first phase, the experimental model was evaluated with venlafaxine alone, because no bibliographic data on the EEG effect of venlafaxine in the conscious rat IS available; however, various studies on the effects of venlafaxine, in particular on sleep modifications, provide the pharmacological doses of venlafaxine in acute treatment, which are generally from 1 to 10 mg/kg administered intraperitoneally (Salin-Pascual R J., Psychopharmacology. 1997 February; 129 (3): 295-6).
  • the spectral analysis of the prefrontal EEGs shows a significant increase in power, according to the venlafaxine dose, of the 8-10 Hz components (around 120% for the 0.16 mg/kg dose and 200% for the 4 mg/kg dose) and 16-18 Hz components and to a lesser extent the 24-26 Hz components at the first hour and increasing at the second hour with the appearance of an increase in the power of 1-3 Hz components at 4 mg/kg ( FIG. 9 ).
  • the spectral analysis of the EEGs shows, at the first hour, a significant increase in the power for the 8-10 Hz components (around 350%), 16-18 Hz components (around 200%) and 24-26 Hz components (around 180%).
  • This increase in power continues at the second hour with a decrease in amplitude for the different components (primarily for the 8-10 Hz components) except for the 1-3 Hz components, for which a significant increase in power is observed (cf. FIG. 9 ).
  • Escitalopram is an antidepressant, indicated for major depressive states and the prevention of panic attacks with or without agoraphobia.
  • Escitalopram is a serotonin reuptake inhibitor, with an intermediate profile, and with an efficacy comparable to that of the imipramines, and has a considerable list of adverse effects at therapeutic doses (nausea, headaches, insomnia, constipation, somnolence, sweating, difficulty ejaculating, diarrhea, vomiting, vertigo, trembling, paresthesia, palpitations, orthostatic hypotension and pruritis).
  • the spectral analysis of the prefrontal EEGs shows a significant increase in power, according to the escitalopram dose, of the 6-8 Hz components (around 150% for the 0.8 mg/kg dose and 200% for the 4 mg/kg dose) and 14-16 Hz components and to a lesser extent the 22-24 Hz components at the first hour and decreasing at the second hour (cf. FIG. 10 ).
  • the spectral analysis of the EEGs shows, at the first hour, a significant increase in the power for the 6-8 Hz components (around 450%), 14-16 Hz components (around 230%) and 22-24 Hz components (around 14%). This increase in power continues at the second hour with a decrease in amplitude for the different components (primarily for the 8-10 Hz components) (cf. FIG. 10 ).
  • bupropion in combination with a connexin inhibitor, meclofenamic acid (MFA) were studied.
  • MFA meclofenamic acid
  • Bupropion is an antidepressant, indicated to help in smoking cessation in nicotine-dependent subjects.
  • Bupropion is a noradrenaline and dopamine reuptake inhibitor, with a considerable list of adverse effects at therapeutic doses (skin eruption, pruritis, fever, nausea, headaches, insomnia, vertigo, constipation, vomiting, ataxia, tinnitus, mental confusion, visual disturbances).
  • the experimental model was evaluated because no bibliographic data on the EEG effect of bupropion in the conscious rat is available; however, various studies on the effects of bupropion, in particular on sleep EEG modifications, provide the pharmacological doses of bupropion in acute treatment, which are generally from 5 to 150 mg/kg administered intraperitoneally (Henshall D C, Neuropsychiatr Dis Trat. 2009; 5: 189-206).
  • the spectral analysis of the prefrontal EEGs shows a significant increase in power, according to the bupropion dose, of the 8-10 Hz components from 8-10 Hz (around 180% for the 0.16 mg/kg dose, 450% for the 0.8 mg/kg dose and 280% for the 4 mg/kg dose) and 15-18 Hz components and to a lesser extent the 23-25 Hz components at the first hour.
  • a significant increase with respect to the first hour is observed for the same components for the doses 0.16 mg/kg and 4 mg/kg, while the effect wears off at the 0.8 mg/kg dose ( FIG. 11 ).
  • the spectral analysis of the EEGs shows, at the first hour, a significant increase in the power for the 8-10 Hz components (around 400%), components 15-18 Hz (around 230%) and 23-25 Hz components (around 140%). This increase in power continues at the second hour with a decrease in amplitude for the different components primarily for the 8-10 Hz and 15-18 Hz components) (cf. FIG. 11 ).
  • Sertraline is an antidepressant, indicated for major depressive states in adults, obsessive compulsive disorders in adults and children, and the prevention of recurrent depression in patients with a unipolar disorder.
  • Sertraline is a selective serotonin reuptake inhibitor, with a considerable list of adverse effects at therapeutic doses (skin rashes, pruritis, nausea, headaches, insomnia, vertigo, vomiting, extrapyramidal effect, difficulty ejaculating, constipation, visual disturbances, tachycardia).
  • the spectral analysis of the prefrontal EEGs shows a significant increase in power, according to the sertraline dose, of the 7-9 Hz components (around 260% for the 0.16 mg/kg dose and the 0.8 mg/kg dose and 200% for the 4 mg/kg dose) and 14-17 Hz components and to a lesser extent the 23-25 Hz components at the first hour.
  • a significant increase with respect to the first hour is observed for the same components for the 0.8 mg/kg (900%) and 4 mg/kg (450%) doses, while the effect wears off slightly at the 0.16 mg/kg dose ( FIG. 12 ).
  • the spectral analysis of the EEGs shows, at the first hour, a significant increase in power for the 7-9 Hz components (around 400%), 14-17 Hz components (around 300%) and 23-25 Hz components (around 160%). This increase in power continues at the second hour with a considerable increase in amplitude for the different components, primarily for the 7-9 Hz components (around 1000%) and 14-17 Hz components (around 700%) ( FIG. 12 ).
  • this potentiation of the serotoninergic system confirms the hypothesis of a modulating role on the electrophysiological activities by the connexin junction system.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Emergency Medicine (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biochemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US13/063,409 2008-09-10 2009-09-10 Use of anti-connexin agents for modulating the therapeutic effect of psychotropic drugs Abandoned US20120135960A2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR0856090 2008-09-10
FR0856090A FR2935611B1 (fr) 2008-09-10 2008-09-10 Utilisation d'agents anti-connexines pour moduler l'effet therapeutique de molecules psychotropes
PCT/EP2009/061765 WO2010029131A1 (fr) 2008-09-10 2009-09-10 Utilisation d'agents anti-connexines pour moduler l'effet therapeutique de molecules psychotropes

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2009/061765 A-371-Of-International WO2010029131A1 (fr) 2008-09-10 2009-09-10 Utilisation d'agents anti-connexines pour moduler l'effet therapeutique de molecules psychotropes

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US14/736,004 Division US11077080B2 (en) 2008-09-10 2015-06-10 Use of anti-connexin agents for modulating the therapeutic effect of psychotropic drugs

Publications (2)

Publication Number Publication Date
US20110172188A1 US20110172188A1 (en) 2011-07-14
US20120135960A2 true US20120135960A2 (en) 2012-05-31

Family

ID=40552073

Family Applications (2)

Application Number Title Priority Date Filing Date
US13/063,409 Abandoned US20120135960A2 (en) 2008-09-10 2009-09-10 Use of anti-connexin agents for modulating the therapeutic effect of psychotropic drugs
US14/736,004 Active US11077080B2 (en) 2008-09-10 2015-06-10 Use of anti-connexin agents for modulating the therapeutic effect of psychotropic drugs

Family Applications After (1)

Application Number Title Priority Date Filing Date
US14/736,004 Active US11077080B2 (en) 2008-09-10 2015-06-10 Use of anti-connexin agents for modulating the therapeutic effect of psychotropic drugs

Country Status (12)

Country Link
US (2) US20120135960A2 (fr)
EP (1) EP2344146B1 (fr)
JP (2) JP5809976B2 (fr)
CN (2) CN107519157A (fr)
AU (1) AU2009290861B2 (fr)
CA (1) CA2736623C (fr)
DK (1) DK2344146T3 (fr)
ES (1) ES2420120T3 (fr)
FR (1) FR2935611B1 (fr)
HK (1) HK1160015A1 (fr)
IL (1) IL211694A (fr)
WO (1) WO2010029131A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190351008A1 (en) * 2016-06-13 2019-11-21 Uti Limited Partnership Methods and compositions for modulating opioid withdrawal symptoms
US10519175B2 (en) 2017-10-09 2019-12-31 Compass Pathways Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US11564935B2 (en) 2019-04-17 2023-01-31 Compass Pathfinder Limited Method for treating anxiety disorders, headache disorders, and eating disorders with psilocybin

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2586436A1 (fr) 2011-10-31 2013-05-01 Commissariat à l'Énergie Atomique et aux Énergies Alternatives Utilisation d'agents anti-connexine pour améliorer l'effet thérapeutique d'un inhibiteur de l'acétylcholinestérase
WO2013179264A2 (fr) 2012-05-30 2013-12-05 Universidad Andres Bello Utilisation de composés qui modulent sélectivement la libération astrocytaire de substances par les hémicanaux de connexine et de pannexine, sans influencer les jonctions communicantes, pour le traitement des troubles psychiatriques
PL3024458T3 (pl) * 2013-07-24 2018-08-31 Commissariat à l'énergie atomique et aux énergies alternatives Zastosowanie flekainidu jako środka anty-koneksynowego oraz sposób wzmacniania efektów działania leku psychotropowego
EP3041577B1 (fr) * 2013-09-06 2021-07-21 Knut M. Wittkowski Traitement et prévention de l'autisme et des troubles du spectre autistique
JP2016535006A (ja) * 2013-10-15 2016-11-10 プレジデント アンド フェローズ オブ ハーバード カレッジ 白血病細胞の根絶のための方法および組成物
JP6898848B2 (ja) 2014-09-19 2021-07-07 メモリアル スローン ケタリング キャンサー センター 脳転移を治療するための方法
US20160317477A1 (en) 2015-04-30 2016-11-03 Ovid Therapeutics Inc. Methods of treating prader-willi syndrome
CA2992162A1 (fr) * 2015-07-15 2017-01-19 Theranexus Utilisation de l'amitriptyline pour le blocage des connexons du cerveau et procede d'amplification de son effet in vivo
US9351968B1 (en) 2015-09-09 2016-05-31 Ovid Therapeutics Inc Methods of treating developmental disorders using pipradrol
JP6694289B2 (ja) * 2016-02-12 2020-05-13 株式会社日立製作所 薬効評価補助システム、及び薬効評価補助情報提示方法
JP2019517469A (ja) 2016-05-26 2019-06-24 オービッド・セラピューティクス・インコーポレイテッドＯｖｉｄ Ｔｈｅｒａｐｅｕｔｉｃｓ， Ｉｎｃ． ピプラドロールを用いる行動症候群の治療方法
EP3481387A4 (fr) 2016-08-11 2020-04-08 Ovid Therapeutics Inc Methodes et compositions pour le traitement de troubles épileptiques
KR20200107927A (ko) 2017-09-28 2020-09-16 아스데라 엘엘씨 인지질 조절장애를 수반하는 질환 및 장애에서의 시클로덱스트린의 용도
EP3593822A1 (fr) 2018-07-13 2020-01-15 Theranexus Applications thérapeutiques et diagnostiques d'un nouveau procédé de surveillance d'une interaction neurogliale (memri)
FR3110393B1 (fr) 2020-05-20 2022-05-06 Grn Consulting Compose et composition pour induire une neuroprotection

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007002139A2 (fr) * 2005-06-22 2007-01-04 The Trustees Of The University Of Pennsylvania Neuroprotection de cellules ganglionnaires de la retine

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050107349A1 (en) * 2003-07-24 2005-05-19 Pharmacia Corporation Method for the treatment or prevention of respiratory disorders with a cyclooxygenase-2 inhibitor in combination with a muscarinic receptor antagonist and compositions therewith
EP1516625A1 (fr) * 2003-09-16 2005-03-23 Institut Pasteur Utilisation des pannexines formant des canaux neuronaux dans la thérapie et la diagnose chez les mammifères
WO2005046667A2 (fr) * 2003-11-07 2005-05-26 Research Foundation For Mental Hygiene, Inc. Inhibiteurs du transport par le systeme a permettant de traiter ou de prevenir des troubles neuropsychiatriques
CA2556380A1 (fr) * 2004-03-02 2005-09-15 Pharmacia Corporation Procedes et compositions pour le traitement ou la prevention de troubles psychiatriques avec des inhibiteurs de cox-2 seuls et en combinaison avec des antidepresseurs
JP2009516751A (ja) * 2005-11-21 2009-04-23 ザ・ボード・オブ・トラスティーズ・オブ・ザ・ユニバーシティー・オブ・アラバマ・フォー・アンド・オン・ビハーフ・オブ・ザ・ユニバーシティー・オブ・アラバマ 神経保護のための小分子化合物を使用する方法
CN101062039B (zh) * 2006-04-30 2010-05-12 北京华安佛医药研究中心有限公司 治疗神经系统疾病的药物组合物
US20100015105A1 (en) * 2006-12-27 2010-01-21 Shimon Marom Method of treating schizophrenia
US8637080B2 (en) * 2007-06-28 2014-01-28 Osmotica Kereskedelmi és Szolgáltató, KFT Rupturing controlled release device comprising a subcoat

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007002139A2 (fr) * 2005-06-22 2007-01-04 The Trustees Of The University Of Pennsylvania Neuroprotection de cellules ganglionnaires de la retine

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Turner et al. (Modafinil improves cognition and response inhibition in adult attention-deficit/hyperactivity disorder. Biological psychiatry 55.10 (2004): 1031-1040) *
Urbano et al. (Modafinil enhances thalamocortical activity by increasing neuronal electrotonic coupling. Proc Natl Acad Sci U S A. Jul 24, 2007; 104(30): 12554-12559 *

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2017285725B2 (en) * 2016-06-13 2021-08-19 Uti Limited Partnership Methods and compositions for modulating opioid withdrawal symptoms
US20190351008A1 (en) * 2016-06-13 2019-11-21 Uti Limited Partnership Methods and compositions for modulating opioid withdrawal symptoms
US11298569B2 (en) * 2016-06-13 2022-04-12 Uti Limited Partnership Methods and compositions for modulating opioid withdrawal symptoms
US11447510B2 (en) 2017-10-09 2022-09-20 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US10954259B1 (en) 2017-10-09 2021-03-23 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US11149044B2 (en) 2017-10-09 2021-10-19 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US11180517B2 (en) 2017-10-09 2021-11-23 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US10947257B2 (en) 2017-10-09 2021-03-16 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US10519175B2 (en) 2017-10-09 2019-12-31 Compass Pathways Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US11505564B2 (en) 2017-10-09 2022-11-22 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US11629159B2 (en) 2017-10-09 2023-04-18 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US11851451B2 (en) 2017-10-09 2023-12-26 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US11939346B2 (en) 2017-10-09 2024-03-26 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US11564935B2 (en) 2019-04-17 2023-01-31 Compass Pathfinder Limited Method for treating anxiety disorders, headache disorders, and eating disorders with psilocybin
US11738035B2 (en) 2019-04-17 2023-08-29 Compass Pathfinder Limited Method for treating anxiety disorders, headache disorders, and eating disorders with psilocybin
US11865126B2 (en) 2019-04-17 2024-01-09 Compass Pathfinder Limited Method for treating anxiety disorders, headache disorders, and eating disorders with psilocybin

Also Published As

Publication number Publication date
EP2344146A1 (fr) 2011-07-20
EP2344146B1 (fr) 2013-04-17
CN107519157A (zh) 2017-12-29
US20110172188A1 (en) 2011-07-14
FR2935611A1 (fr) 2010-03-12
CN102164594A (zh) 2011-08-24
DK2344146T3 (da) 2013-07-08
AU2009290861A1 (en) 2010-03-18
CA2736623A1 (fr) 2010-03-18
WO2010029131A1 (fr) 2010-03-18
CN102164594B (zh) 2021-09-28
WO2010029131A9 (fr) 2010-06-10
HK1160015A1 (en) 2012-08-10
ES2420120T3 (es) 2013-08-22
IL211694A0 (en) 2011-06-30
JP5809976B2 (ja) 2015-11-11
JP2012502082A (ja) 2012-01-26
US11077080B2 (en) 2021-08-03
AU2009290861B2 (en) 2015-08-06
IL211694A (en) 2015-05-31
FR2935611B1 (fr) 2010-10-15
JP2015172067A (ja) 2015-10-01
CA2736623C (fr) 2018-05-15
US20150272915A1 (en) 2015-10-01

Similar Documents

Publication Publication Date Title
US11077080B2 (en) Use of anti-connexin agents for modulating the therapeutic effect of psychotropic drugs
Ziemann TMS and drugs
Miyamoto Pharmacology of ramelteon, a selective MT1/MT2 receptor agonist: a novel therapeutic drug for sleep disorders
Addolorato et al. Novel therapeutic strategies for alcohol and drug addiction: focus on GABA, ion channels and transcranial magnetic stimulation
Reilly et al. Pharmacological treatment effects on eye movement control
Somers et al. Transcutaneous electrical nerve stimulation for the management of neuropathic pain: the effects of frequency and electrode position on prevention of allodynia in a rat model of complex regional pain syndrome type II
Müller et al. The in vivo neurochemistry of the brain during general anesthesia
Schwartz et al. Dosing regimen effects of modafinil for improving daytime wakefulness in patients with narcolepsy
Termine et al. Emerging treatment strategies in Tourette syndrome: what’s in the pipeline?
Ahnaou et al. Modulation of group II metabotropic glutamate receptor (mGlu2) elicits common changes in rat and mice sleep–wake architecture
John et al. Caffeine promotes glutamate and histamine release in the posterior hypothalamus
CN107949379A (zh) L‑4‑氯代犬尿氨酸的治疗用途
Bhattacharya et al. NMDA receptor blockade ameliorates abnormalities of spike firing of subthalamic nucleus neurons in a parkinsonian nonhuman primate
Ramage et al. NMDA receptor expression and activity in osteoarthritic human articular chondrocytes
Marcus et al. Effects of competitive and non-competitive NMDA receptor antagonists on dopamine output in the shell and core subdivisions of the nucleus accumbens
Schaffler et al. Comparison of the analgesic effects of a fixed-dose combination of orphenadrine and diclofenac (Neodolpasse®) with its single active ingredients diclofenac and orphenadrine: A Placebo-controlled study using laser-induced somatosensory-evoked potentials from capsaicin-induced hyperalgesic human skin
Fisher et al. Differential effects of NMDA and non-NMDA antagonists on the activity of aromatic L-amino acid decarboxylase activity in the nigrostriatal dopamine pathway of the rat
Sun et al. Altered glutamate metabolism contributes to antiepileptogenic effects in the progression from focal seizure to generalized seizure by low-frequency stimulation in the ventral hippocampus
Turgeon et al. The delayed effects of DTG and MK-801 on latent inhibition in a conditioned taste-aversion paradigm
US20090143450A1 (en) Method for treating central pain syndrom or for inducing centrally generated pain in an animal model
Cairns et al. Intramuscular ketorolac inhibits activation of rat peripheral NMDA receptors
Wohlfarth et al. Acamprosate reduces motor cortex excitability determined by transcranial magnetic stimulation
Onat et al. Experimental absence versus amygdaloid kindling
Zarindast et al. Morphine-induced place preference: interactions with neurotransmitter systems
van Balken et al. Current and future therapeutic approaches in progressive supranuclear palsy

Legal Events

Date Code Title Description
AS Assignment

Owner name: COMMISSARIAT A L'ENERGIE ATOMIQUE ET AUX ENERGIES

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:MOUTHON, FRANCK;CHARVERIAT, MATHIEU;DESLYS, JEAN-PHILIPPE;AND OTHERS;SIGNING DATES FROM 20110316 TO 20110318;REEL/FRAME:026245/0963

Owner name: BIO MODELING SYSTEMS OU BMSYSTEMS, FRANCE

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:MOUTHON, FRANCK;CHARVERIAT, MATHIEU;DESLYS, JEAN-PHILIPPE;AND OTHERS;SIGNING DATES FROM 20110316 TO 20110318;REEL/FRAME:026245/0963

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION