EP1395253A2 - Traitement de troubles anxieux - Google Patents

Traitement de troubles anxieux

Info

Publication number
EP1395253A2
EP1395253A2 EP01996376A EP01996376A EP1395253A2 EP 1395253 A2 EP1395253 A2 EP 1395253A2 EP 01996376 A EP01996376 A EP 01996376A EP 01996376 A EP01996376 A EP 01996376A EP 1395253 A2 EP1395253 A2 EP 1395253A2
Authority
EP
European Patent Office
Prior art keywords
norepinephrine reuptake
reuptake inhibitor
dsm
tomoxetine
disorder
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.)
Withdrawn
Application number
EP01996376A
Other languages
German (de)
English (en)
Inventor
Holly Ann Read
David Michelson
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.)
Eli Lilly and Co
Original Assignee
Eli Lilly and Co
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 Eli Lilly and Co filed Critical Eli Lilly and Co
Publication of EP1395253A2 publication Critical patent/EP1395253A2/fr
Withdrawn legal-status Critical Current

Links

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
    • 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
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • 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
    • 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
    • A61P25/22—Anxiolytics

Definitions

  • the invention belongs to the fields of pharmaceutical chemistry and central nervous system medicine, and provides a method of treatment for anxiety disorders .
  • Anxiety disorders represent the most prevalent type of psychiatric disorders in the United States.
  • Anxiety disorders include panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, specific phobia, social phobia, and generalized anxiety disorder. All are characterized by uneasiness, a sense of fearfulness, and distress for no apparent reason. These disorders, if left untreated, reduce the quality of life and productivity of patients suffering from them. In the United States alone, more than 23 million people suffer from anxiety disorders. The cost to society from these disorders is staggering, estimated in 1990 at $46.6 billion in the United States alone in direct and indirect costs .
  • Currently available methods for treating anxiety disorders include behavioral therapy, cognitive therapy, and relaxation techniques. These methods typically take a considerable amount of time to achieve their desired effect .
  • these methods may be used in combination with one of a number of medications.
  • Currently used medications include benzodiazepines, beta-blockers, buspirone, monoamine oxidase inhibitors, serotonin reuptake inhibitors, and tricyclic antidepressants, all of which have liabilities associated with their use.
  • the benzodiazepines are potentially habit forming and can cause drowsiness; beta- blockers cannot be used if the patient has certain preexisting medical conditions such as asthma, congestive heart failure, diabetes, vascular disease, hyperthyroidism, or angina pectoris; buspirone has a long induction period before its beneficial effects are realized; patients taking monoamine oxidase inhibitors are under strict dietary constraints and there is the potential for drug interactions, low blood pressure, moderate weight gain, reduced sexual response, and insomnia; the serotonin reuptake inhibitors can cause nausea, nervousness, and delayed ejaculation; and the tricyclic antidepressants can cause dry mouth, constipation, blurry vision, difficulty in urination, dizziness, low blood pressure, and moderate weight gain. New methods for treating anxiety disorders are needed which avoid or diminish the liabilities of current therapies.
  • the present invention provides a method for the treatment of anxiety disorders which comprises administering to a mammal in need of such treatment an effective amount of a selective norepinephrine reuptake inhibitor.
  • the present invention also provides a method for the prevention of anxiety disorders which comprises administering to a mammal susceptible to said disorders an effective amount of a selective norepinephrine reuptake inhibitor.
  • the present invention provides a method for the treatment or prevention of anxiety disorders that relies on a novel mechanism of action.
  • This method comprises treating a mammal suffering from or susceptible to anxiety disorders with a compound that is a selective norepinephrine reuptake inhibitor.
  • This mechanism is operative in mammals and the preferred mammal is a human.
  • a further embodiment of this invention comprises the administration of a composition that exhibits selective norepinephrine reuptake inhibitor activity.
  • the composition may be composed of one or more agents that, individually or together, are selective inhibitors of norepinephrine reuptake .
  • the present invention also provides the use of a selective norepinephrine reuptake inhibitor for the preparation of a medicament useful for the treatment or prevention of anxiety disorders.
  • the present invention further provides the use of a selective norepinephrine reuptake inhibitor for the preparation of a medicament useful for the treatment of anxiety disorders with comorbid Attention-deficit Hyperactivity Disorder.
  • norepinephrine reuptake inhibitors which show 50% effective concentrations of about 1000 nM or less, in the protocol described by Wong et al . , Drug Development Research, ⁇ _, 397 (1985) .
  • the norepinephrine reuptake inhibitors useful for the method of the present invention are characterized in being selective for the inhibition of neurotransmitter reuptake relative to their ability to act as direct agonists or antagonists at other receptors.
  • Norepinephrine reuptake inhibitors useful for the method of the present invention include, but are not limited to:
  • Tomoxetine (R) - (-) -N-methyl-3- (2-methylphenoxy) - 3-phenylpropylamine, is usually administered as the hydrochloride salt.
  • Tomoxetine was first disclosed in U.S. Patent #4,314,081.
  • the word "tomoxetine” will be used here to refer to any acid addition salt or the free . base of the molecule. See, for example, Gehlert, et al . , Neuroscience Letters, 157, 203-206 (1993), for a discussion of tomoxetine' s activity as a norepinephrine reuptake inhibitor;
  • the compounds of formula I The compounds of formula I :
  • X is C ⁇ C alkylthio
  • Y is C ⁇ -C 2 alkyl or a pharmaceutically acceptable salt thereof.
  • the compounds of formula I were described in U.S. Patent 5,281,624, of Gehlert, Robertson, and Wong, and in Gehlert, et al . , Life Sciences, 55/(22) , 1915-1920, (1995). The compounds are there taught to be inhibitors of norepinephrine reuptake in the brain. It is also explained that the compounds exist as stereoisomers, and that they accordingly include not only the racemates, but also the isolated individual isomers as well as mixtures of the individual isomers.
  • the compounds of formula I include the following exemplary species :
  • Reboxetine (R) -N-methyl-3- (2-methylthiophenoxy) -3-phenyl- propylamine; and Reboxetine (EdronaxTM) , 2- [ ⁇ - (2-ethoxy)phenoxy- benzyl]morpholine, is usually administered as the racemate. It was first taught by U.S. Patent 4,229,449, which describes its utility for the treatment of depression. Reboxetine is a selective norepinephrine reuptake inhibitor. The term "reboxetine" will be used here to refer to any acid addition salt or the free base of the molecule existing as the racemate or either enantio er.
  • norepinephrine reuptake inhibitor is selective for norepinephrine over other neurotransmitters . It is especially preferred that the norepinephrine reuptake inhibitor be selected from tomoxetine, reboxetine, or (R)-N- methyl-3- (2-methylthiophenoxy) -3-phenylpropylamine.
  • tomoxetine hydrochloride for the methods of the present invention is the most preferred embodiment of the present invention.
  • acids commonly employed to form such salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids, such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like
  • organic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid and the like.
  • salts thus are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1, 4-dioate, hexyne-1, 6-dioate, benzoate, chlorobenzoate, me.thylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phen
  • the dosages of the drugs used in the present invention must, in the final analysis, be set by the physician in charge of the case using knowledge of the drugs, the properties of the drugs in combination as determined in clinical trials, and the characteristics of the patient including diseases other than that for which the physician is treating the patient.
  • General outlines of the dosages, and some preferred dosages, can and will be provided here .
  • Tomoxetine from about 5 mg/day to about 200 mg/day; preferably in the range from about 60 to about 150 mg/day; more preferably from about 60 to about 130 mg/day; and still more preferably from about 60 to about 120 mg/day; Compounds of formula I: from about 0.01 mg/kg to about 20 mg/kg; preferred daily doses will be from about 0.05 mg/kg to 10 mg/kg; ideally from about 0.1 mg/kg to about 5 mg/kg;
  • Reboxetine from about 1 to about 30 mg, once to four times/day; preferred, from about 5 to about 30 mg once/day.
  • oral administration is not the only route or even the only preferred route .
  • transdermal administration may be very desirable for patients who are forgetful or petulant about taking oral medicine.
  • Compounds of Formula I may also be administered by the percutaneous, intravenous, intramuscular, intranasal or intrarectal route, in particular circumstances.
  • the route of administration may be varied in any way, limited by the physical properties of the drugs, the convenience of the patient and the caregiver, and other relevant circumstances (Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Co. (1990)).
  • the pharmaceutical compositions are prepared in a manner well known in the pharmaceutical art .
  • the carrier or excipient may be a solid, semi-solid, or liquid material that can serve as a vehicle or medium for the active ingredient. Suitable carriers or excipients are well known in the art.
  • the pharmaceutical composition may be adapted for oral, inhalation, parenteral, or topical use and may be administered to the patient in the form of tablets, capsules, aerosols, inhalants, suppositories, solutions, suspensions, or the like.
  • the compounds of the present invention may be administered orally, for example, with an inert diluent or capsules or compressed into tablets .
  • the compounds may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like.
  • These preparations should contain at least 4% of the compound of the present invention, the active ingredient, but may be varied depending upon the particular form and may conveniently be between 4% to about 70% of the weight of the unit.
  • the amount of the compound, present in compositions is such that a suitable dosage will be obtained.
  • Preferred compositions and preparations according to the present invention may be determined by a person skilled in the art.
  • the tablets, pills, capsules, troches, and the like may also contain one or more of the following adjuvants: binders such as microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch or lactose, disintegrating agents such as alginic acid, Primogel, corn starch and the like; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; and sweetening agents such as sucrose or saccharin may be added or a flavoring agent such as peppermint, methyl salicylate or orange flavoring.
  • a liquid carrier such as polyethylene glycol or a fatty oil.
  • dosage unit forms may contain other various materials that modify the physical form of the dosage unit, for example, as coatings.
  • tablets or pills may be coated with sugar, shellac, or other coating agents.
  • a syrup may contain, in addition to the present compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used.
  • a formulation useful for the administration of R-(- ) -N-methyl 3- ( (2-methylphenyl) oxy) -3-phenyl-l-aminopropane hydrochloride comprises a dry mixture of R-(-)-N- ethyl 3- ( (2-methylphenyl) oxy) -3-phenyl-l-aminopropane hydrochloride with a diluent and lubricant.
  • a starch such as pregelatinized corn starch, is a suitable diluent and a silicone oil, such as dimethicone, a suitable lubricant for use in hard gelatin capsules .
  • Suitable formulations are prepared containing about 0.4 to 26% R- (-) -N-methyl 3-((2- methylphen-yl) oxy) -3-phenyl-l-aminopropane hydrochloride, about 73 to 99% starch, and about 0.2 to 1.0% silicone oil.
  • the following tables illustrate particularly preferred formulations :
  • the compounds of the present invention may be incorporated into a solution or suspension.
  • These preparations typically contain at least 0.1% of a compound of the invention, but may be varied to be between 0.1 and about 90% of the weight thereof .
  • the amount of the compound of formula I present in such compositions is such that a suitable dosage will be obtained.
  • the solutions or suspensions may also include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylene diaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose .
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Preferred compositions and preparations are able to be determined by one skilled in the art.
  • the compounds of the present invention may also be administered topically, and when done so the carrier may suitably comprise a solution, ointment, or gel base.
  • the base for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, bees wax, mineral oil, diluents such as water and alcohol, and emulsifiers, and stabilizers.
  • Topical formulations may contain a concentration of the formula I, or its pharmaceutical salt, from about 0.1 to about 10% w/v (weight per unit volume) .
  • Cerebral cortices are homogenized in 9 volumes of a medium containing 0.32 M sucrose and 10 mM glucose. Crude synaptosomal preparations are isolated after differential centrifugation at 1000 x g for 10 minutes and 17,000 x g for 28 minutes. The final pellets are suspended in the same medium and kept in ice until use within the same day.
  • Synaptosomal uptake of 3 H ⁇ norepinephrine is determined as follows. Cortical synaptos ⁇ mes (equvalent to 1 mg of protein) are incubated at 37°C for 5 minutes in 1 mL Krebs-bicarbonate medium containing also 10 mM glucose, 0.1 mM iproniazide, 1 mM ascorbic acid, 0.17 mM EDTA and 50 nM 3 H-norepinephrine . The reaction mixture is immediately diluted with 2 mL of ice-chilled Krebs-bicarbonate buffer and filtered under vacuum with a cell harvester (Brandel, Gaithersburg, MD) .
  • Anxiety disorders are a heterogeneous class of diseases .
  • the most common types of anxiety disorders are described in the following paragraphs.
  • Panic disorder is characterized by the sudden onset of intense apprehension, tearfulness, or terror. An attack of panic disorder is unprovoked and may last for a discrete period of time. During these attacks, it is not uncommon for the victim to experience shortness of breath, palpitations, chest pain or discomfort, choking or a smothering sensation, and fear of losing control .
  • Generalized Anxiety Disorder
  • Generalized anxiety disorder is characterized by at least 6 months of persistent and excessive anxiety and worry. It is associated with physical anxiety symptoms such as muscle aches, fatigue, difficulty sleeping, sweating, dizziness, and nausea.
  • Phobia Specific phobia is a persistent, intense, and irrational fear associated with a particular object or situation that leads to avoidance of that object or situation.
  • Social Phobia is a persistent fear of one or more situations in which the person is exposed to possible scutiny by others and the person fears that he or she may do something or act in a way that will be humiliating. Social phobias can include extreme shyness .
  • Obsessive-compulsive disorder is characterized by obsessions that cause anxiety and compulsions which serve to neutralize the anxiety. Common obsessions include fear of dirt, germs, or contamination or fear of harming someone; common compulsions are excessive cleaning, counting, double- checking, and hoarding.
  • Post-Traumatic Stress Disorder is characterized by the re-experiencing of an extremely traumatic event accompanied by symptoms of increased arousal and by avoidance of the stimuli associated with the trauma. Individuals can become so preoccupied with the experience that they are unable to lead a normal life.
  • DSM 292.89 Sedative, Hypnotic, or Anxiolytic DSM 292.89 Other [Unknown] Substance DSM 292.89
  • Obsessive-Compulsive Disorder is a preferred embodiment of the present invention.
  • a further embodiment of the present invention is a method of treating anxiety disorders with comorbid Attention-deficit Hyperactivity Disorder comprising administering to a patient in need of treatment of both anxiety disorders and
  • Attention-deficit Hyperactivity Disorder an effective amount of a selective norepinephrine reuptake inhibitor.
  • the method of the present invention is effective in the treatment of patients who are children, adolescents or adults, and there is no significant difference in the symptoms or the details of the manner of treatment among patients of different ages.
  • a child is considered to be a patient below the age of puberty
  • an adolescent is considered to be a patient from the age of puberty up to about 18 years of age
  • an adult is considered to be a patient of 18 years or older.
  • a female subject presented with chronic fingernail biting The subject was treated with 60 mg of tomoxetine hydrochloride, twice daily for 13 consecutive days. At the time of final assessment the subject demonstrated significant improvement, with healthy appearing fingernails except for one finger. The patient's chronic fingernail biting behavior resumed upon termination of treatment with tomoxetine hydrochloride.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Investigating Or Analysing Biological Materials (AREA)

Abstract

Selon la présente invention, des inhibiteurs spécifiques de recaptage de la noradrénaline sont utilisés dans le traitement de troubles anxieux, notamment du trouble obsessionnel-compulsif.
EP01996376A 2000-11-15 2001-11-06 Traitement de troubles anxieux Withdrawn EP1395253A2 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US24901000P 2000-11-15 2000-11-15
US249010P 2000-11-15
US26536201P 2001-01-31 2001-01-31
US265362P 2001-01-31
PCT/US2001/027801 WO2002040006A2 (fr) 2000-11-15 2001-11-06 Traitement de troubles anxieux

Publications (1)

Publication Number Publication Date
EP1395253A2 true EP1395253A2 (fr) 2004-03-10

Family

ID=26939750

Family Applications (1)

Application Number Title Priority Date Filing Date
EP01996376A Withdrawn EP1395253A2 (fr) 2000-11-15 2001-11-06 Traitement de troubles anxieux

Country Status (16)

Country Link
EP (1) EP1395253A2 (fr)
JP (1) JP2004529073A (fr)
KR (1) KR20030051812A (fr)
CN (1) CN1822825A (fr)
AU (1) AU2002217757A1 (fr)
BR (1) BR0115301A (fr)
CA (1) CA2426069A1 (fr)
CZ (1) CZ20031339A3 (fr)
EA (1) EA200300567A1 (fr)
HR (1) HRP20030384A2 (fr)
IL (1) IL155874A0 (fr)
MX (1) MXPA03004190A (fr)
NO (1) NO20032156L (fr)
PL (1) PL366119A1 (fr)
SK (1) SK5422003A3 (fr)
WO (1) WO2002040006A2 (fr)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE60226715D1 (de) * 2001-03-06 2008-07-03 Lilly Co Eli Monoamin-aufnahme-inhibitor
NZ537521A (en) * 2002-08-14 2007-05-31 Pharmacia & Upjohn Co Llc Use of reboxetine for the treatment of hot flashes
GB0309440D0 (en) * 2003-04-25 2003-06-04 Lilly Co Eli Quinolone derivatives
WO2004103356A2 (fr) * 2003-05-15 2004-12-02 Eli Lilly And Company Traitement du dysfonctionnement emotionnel
CN1889940A (zh) * 2003-12-12 2007-01-03 伊莱利利公司 热潮红、冲动控制障碍和全身性医学病症引起的人格变化的治疗
EP2234960A2 (fr) 2008-01-09 2010-10-06 Mayo Foundation for Medical Education and Research Inhibition du recaptage de neurotransmetteurs
WO2011056788A2 (fr) * 2009-11-03 2011-05-12 Mayo Foundation For Medical Education And Research Inhibition du recaptage de neurotransmetteur
WO2011056773A2 (fr) * 2009-11-03 2011-05-12 Mayo Foundation For Medical Education And Research Inhibition du recaptage de neurotransmetteur
WO2014159251A2 (fr) 2013-03-14 2014-10-02 Mayo Foundation For Medical Education And Research Inhibition du recaptage de neurotransmetteurs
CN113710319B (zh) * 2019-02-01 2024-10-11 霍夫曼技术有限责任公司 用于治疗焦虑相关病症的组合物和方法

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997041878A1 (fr) * 1996-05-07 1997-11-13 Merck & Co., Inc. Traitement de troubles de l'humeur, a l'aide d'un secretagogue d'hormone de croissance
IT1305322B1 (it) * 1998-04-23 2001-05-04 Pharmacia & Upjohn Spa Uso di reboxetina per il trattamento di disturbi nervosi
ES2246488T3 (es) * 1999-07-01 2006-02-16 PHARMACIA & UPJOHN COMPANY LLC Reboxetina para tratar la migraña.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0240006A2 *

Also Published As

Publication number Publication date
JP2004529073A (ja) 2004-09-24
CA2426069A1 (fr) 2002-05-23
AU2002217757A1 (en) 2002-05-27
NO20032156D0 (no) 2003-05-13
KR20030051812A (ko) 2003-06-25
CZ20031339A3 (cs) 2003-10-15
WO2002040006A2 (fr) 2002-05-23
BR0115301A (pt) 2004-12-14
PL366119A1 (en) 2005-01-24
SK5422003A3 (en) 2003-12-02
WO2002040006A3 (fr) 2003-12-24
HRP20030384A2 (en) 2003-08-31
NO20032156L (no) 2003-05-13
CN1822825A (zh) 2006-08-23
EA200300567A1 (ru) 2004-10-28
IL155874A0 (en) 2003-12-23
MXPA03004190A (es) 2003-09-22

Similar Documents

Publication Publication Date Title
US6184222B1 (en) Treatment of conduct disorder
US6028070A (en) Treatment of oppositional defiant disorder
CN1379672A (zh) 高度选择性去甲肾上腺素再摄取抑制剂及其使用方法
AU2002217757A1 (en) Treatment of anxiety disorders
US20080200555A1 (en) Use of norepinephrine reuptake inhibitors for the treatment of tic disorders
US6683114B2 (en) Treatment of psoriasis
TW200300672A (en) Treatment of cognitive failure
US20040034106A1 (en) Treatment of anxiety disorders
ZA200303738B (en) Treatment of anxiety disorders.
US4443479A (en) Pharmaceutical methods and compositions using parabenzoquinone
HUP0301863A2 (hu) Szorongásos megbetegedések gyógyítása szelektív norepinefrin visszavétel gátló hatású vegyületekkel
US4522830A (en) Pharmaceutical methods using parabenzoquinone to treat muscle spasms
MXPA00002837A (en) Treatment of oppositional defiant disorder
MXPA00002829A (en) Treatment of conduct disorder

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO SI

17P Request for examination filed

Effective date: 20040624

17Q First examination report despatched

Effective date: 20040923

REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1063438

Country of ref document: HK

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20050204

REG Reference to a national code

Ref country code: HK

Ref legal event code: WD

Ref document number: 1063438

Country of ref document: HK