CA2209735C - Treatment of attention-deficit/hyperactivity disorder - Google Patents
Treatment of attention-deficit/hyperactivity disorder Download PDFInfo
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- CA2209735C CA2209735C CA002209735A CA2209735A CA2209735C CA 2209735 C CA2209735 C CA 2209735C CA 002209735 A CA002209735 A CA 002209735A CA 2209735 A CA2209735 A CA 2209735A CA 2209735 C CA2209735 C CA 2209735C
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- hyperactivity disorder
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- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 title claims abstract description 38
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 title claims abstract description 38
- VHGCDTVCOLNTBX-QGZVFWFLSA-N atomoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=CC=C1C VHGCDTVCOLNTBX-QGZVFWFLSA-N 0.000 claims abstract description 16
- 229960002430 atomoxetine Drugs 0.000 claims abstract description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 16
- 208000035475 disorder Diseases 0.000 claims description 15
- 239000002767 noradrenalin uptake inhibitor Substances 0.000 abstract description 2
- 230000000694 effects Effects 0.000 description 12
- 239000003814 drug Substances 0.000 description 9
- 229940079593 drug Drugs 0.000 description 7
- 208000024891 symptom Diseases 0.000 description 7
- 230000006735 deficit Effects 0.000 description 4
- 208000013403 hyperactivity Diseases 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 208000020016 psychiatric disease Diseases 0.000 description 4
- DUGOZIWVEXMGBE-UHFFFAOYSA-N Methylphenidate Chemical compound C=1C=CC=CC=1C(C(=O)OC)C1CCCCN1 DUGOZIWVEXMGBE-UHFFFAOYSA-N 0.000 description 3
- 229960001344 methylphenidate Drugs 0.000 description 3
- 239000002775 capsule Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 208000019901 Anxiety disease Diseases 0.000 description 1
- GDLIGKIOYRNHDA-UHFFFAOYSA-N Clomipramine Chemical compound C1CC2=CC=C(Cl)C=C2N(CCCN(C)C)C2=CC=CC=C21 GDLIGKIOYRNHDA-UHFFFAOYSA-N 0.000 description 1
- HCYAFALTSJYZDH-UHFFFAOYSA-N Desimpramine Chemical compound C1CC2=CC=CC=C2N(CCCNC)C2=CC=CC=C21 HCYAFALTSJYZDH-UHFFFAOYSA-N 0.000 description 1
- 241001508558 Hypera Species 0.000 description 1
- 208000019022 Mood disease Diseases 0.000 description 1
- PHVGLTMQBUFIQQ-UHFFFAOYSA-N Nortryptiline Chemical compound C1CC2=CC=CC=C2C(=CCCNC)C2=CC=CC=C21 PHVGLTMQBUFIQQ-UHFFFAOYSA-N 0.000 description 1
- 208000012202 Pervasive developmental disease Diseases 0.000 description 1
- 208000001431 Psychomotor Agitation Diseases 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- 206010038743 Restlessness Diseases 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- 229960000836 amitriptyline Drugs 0.000 description 1
- KRMDCWKBEZIMAB-UHFFFAOYSA-N amitriptyline Chemical compound C1CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 KRMDCWKBEZIMAB-UHFFFAOYSA-N 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 208000029560 autism spectrum disease Diseases 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 229960004606 clomipramine Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229960003914 desipramine Drugs 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000018459 dissociative disease Diseases 0.000 description 1
- 230000003291 dopaminomimetic effect Effects 0.000 description 1
- 229960004801 imipramine Drugs 0.000 description 1
- BCGWQEUPMDMJNV-UHFFFAOYSA-N imipramine Chemical compound C1CC2=CC=CC=C2N(CCCN(C)C)C2=CC=CC=C21 BCGWQEUPMDMJNV-UHFFFAOYSA-N 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- VHGCDTVCOLNTBX-UHFFFAOYSA-N n-methyl-3-(2-methylphenoxy)-3-phenylpropan-1-amine Chemical compound C=1C=CC=CC=1C(CCNC)OC1=CC=CC=C1C VHGCDTVCOLNTBX-UHFFFAOYSA-N 0.000 description 1
- 230000002474 noradrenergic effect Effects 0.000 description 1
- 230000000966 norepinephrine reuptake Effects 0.000 description 1
- 229940127221 norepinephrine reuptake inhibitor Drugs 0.000 description 1
- 229960001158 nortriptyline Drugs 0.000 description 1
- 208000022821 personality disease Diseases 0.000 description 1
- 230000001739 rebound effect Effects 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
-
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- 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
- A61P25/20—Hypnotics; Sedatives
-
- 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
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- 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)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Psychiatry (AREA)
- Anesthesiology (AREA)
- Psychology (AREA)
- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Medicinal Preparation (AREA)
- Steroid Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Crystals, And After-Treatments Of Crystals (AREA)
- Plural Heterocyclic Compounds (AREA)
- Superconductors And Manufacturing Methods Therefor (AREA)
Abstract
Tomoxetine, a norepinephrine uptake inhibitor, is used to treat attention- deficit/hyperactivity disorder.
Description
CA 0220973~ 1997-07-07 WO96/21430 PCT~S96/00091 TREATMENT OF ATTENTION-DEFICIT/HYPERACTIVITY DISORDER
The invention belongs to the fields of pharmaceutical chemistry and psychiatric medicine, and provides a method of treatment of the psychiatric disorder known as attention-deficit/hyperactivity disorder.
Backaround of the Invention For some decades it has been recognized that a significant number of children are persistently hyperactive and have an attention span so short as to be disabling in school and in many personal relationships. Such children in earlier times would no doubt have been dismissed as incorrigible and punished or even confined in an institution.
Some long time ago, however, it was realized that these children cannot control their hyperactivity and inattention, and the medical professions began to try to help them.
Methylphenidate (RitalinTM)has been used for some time to treat such children and it often significantly improves their ability to function and coexist with other people at school and at home. However, the drug has the disadvantages of re~uiring several doses per day, and producing a rebound effect as the effect of each dose fades awa~. Further, the drug causes sleeplessness and lack of appetite in some patients. Methylphenidate has both noradrenergic and dopaminergic activities.
Imipramine, desipramine, nortriptyline, amitriptyline and clomipramine are also used in some cases of attention-deficit/hyperactivity disorder (ADHD). Those tricyclic drugs, however, have a number of physiological t mechanisms and, as a class, tend to produce a number of side effects and require careful supervision and dose titration.
l In the last decade, psychiatrists have realized that ADHD is not only a disorder of childhood, but often continues in the adult. It is obvious that hyperactivity and short attention span cause grave disruption in an adult's CA 0220973~ 1997-07-07 WO96/21430 PCT~S96/00091 life, but it is only recently that such patients have been able to obtain any treatment.
The need for a safe and convenient treatment for ADHD, applicable to both children an-d adults and without the $, disadvantages possessed by methylphenidate continues to be a concern of the psychiatric profession.
The present invention provides a method of treating attention-deficit/hyperactivity disorder comprising the administration to a patient in need of such treatment of an effective amount of tomoxetine.
The invention also provides the use of tomoxetine for the manufacture of a medicament for treating attention-deficit/hyperactivity disorder; and the use of tomoxetine for treating attention-deficit/hyperactivity disorder.
Tomoxetine is a well-known drug, the chemical name of which is ~ N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine. It is regularly used as a salt, and salts are included in the term tomoxetine as used here. See, for example, Gehlert, et al., Meuroscience Letters 157, 203-06 (1993), for a discussion of the mechanism of tomoxetine~s activity as a norepinephrine reuptake inhibitor. Tomoxetine is quite active in that function, and moreover is substantiallv free of other central nervous system activities at the concen~rations or doses at which it effectively inhibits norepinephrine reuptake. Thus, it is quite free of side effects and is properly considered to be a selective drug.
Tomoxetine is a notably safe drug, and its use in ADHD, in both adults and children, is a superior treatment for that disorder because of its improved safety. Further, tomoxetine is effective at relatively low doses, as discussed below, and may safely and effectively be administered once per day. Thus, difficulties created by the multiple dosing of patients, particularly children and disorganized adults, are completely avoided.
CA 0220973~ 1997-07-07 WO96/21430 PCT~S96/00091 The effective dose of tomoxetine for ADHD is in the range from about 5 mg/day to about lO0 mg/day. The preferred adult dose is in the range from about lO to about 80 mg/day, and a more highly preferred adult dose is from about 20 to about 60 mg/day. The childrenls dose of course is smaller, in the range from about 5 to about 70 mg/day, more preferably from about lO to about 60 mg/day and still more preferably from about lO to about 50 mg/day. The optimum dose for each patient, as always, must be set by the physician in charge of the case, taking into account the patient's size, other medications which the patient requires, severity of the disorder and all of the other circumstances of the patient.
Since tomoxetine is readily orally absorbed and requires only once/day administration, there is little or no reason to administer it in any other way than orally. It may be produced in the form of a clean, stable crystal, and thus is easily formulated in the usual oral pharmaceutical forms, such as tablets, capsules, suspensions, and the like. The usual methods of pharmaceutical scientists are applicable.
It may usefully be administered, if there is any reason to do so in a particular circumstance, in other pharmaceutical forms, such as injectable solutions, depot injections, suppositories and the like, which are well known to and understood by pharmaceutical scientists. It will substantially always be preferred, however, to administer tomoxetine as a tablet or capsule and such pharmaceutical forms are recommended.
The ADHD patient is rather readily recognized, and most people have been in contact with children, if not adults, who exhibit some or all of the symptoms of the disorder. The best description of the disorder is the diagnostic criteria for ADHD, published by the American l Psychiatric Association in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Version (1994), as follows.
CA 0220973~ 1997-07-07 WO96121430 PCT~S96/00091 Diagnostic criteria for Attention-Deficit/
Hyperactivity Disorder A. Either (1) or (2):
(1) six (or more) of the following symptoms of inattention have persisted for at least 6 months to a degree that is maladaptive and inconsistent with developmental level:
Ina t t en t i on (a) often fails to give close attention to details or makes careless mistakes in schoolwork, work, or other activities (b) often has difficulty sustaining attention in tasks or play activities (c) often does not seem to listen when spoken to directly (d) often does not follow through on instructions and fails to finish schoolwork, chores, or duties in the workplace (not due to oppositional behavior or failure to understand instructions) (e) often has difficulty organizing tasks and activities (f! often avoids, dislikes, or is reluctant to engage in tasks that require sustained mental effort (such as schoolwork or homework) (g) often loses things necessar for tasks or activities (e.g., toys, school assignments, pencils, books, or tools) (h) is often easily distracted by extraneous stimuli CA 0220973~ 1997-07-07 W O 96121430 PCTrUS96/00091 (i) is often forgetful in daily activities (2) six (or more) of the following symptoms of hyperactivity-impulsi~rity have persisted for at least 6 months to a degree that is maladaptive and inconsistent with developmental level:
Hyp era ct i vi ty (a) often fidgets with hands or feet or squirms in seat (h! often leaves seat in classroom or in other situations in which remaining seated is expected (c) often runs about or climbs excessively in situations in which it is inappropriate (in adolescents or adults, may be limited to subjective feelings of restlessness) (d) often has difficulty playing or engaging in leisure activities quietly (e) is often "on the go" or often acts as if "driven by a motor~
(f) often talks excessively Impulsivity (g) often blurts out answers before questions have been completed (h) often has difficulty awaiting turn (i) often interrupts or intrudes on ~ others (e.g., butts into 7 conversations or games) B. Some hyperactive-impulsive or inattentive symptoms that caused impairment were present before age 7 years.
C. Some impairment from the symptoms is present in two or more settings (e.g., at school [or wor~ and at home).
CA 0220973~ 1997-07-07 WO96/21430 PCT~S96/00091 D. There must be clear evidence of clinically significant impairment in social, academic, or occupational functioning.
E. The symptoms do not occur exclusively during the course of a Pervasive Developmental Disorder, Schizophrenia, or other Psychotic Disorder and are not better accounted for by another mental disorder (e.g., Mood Disorder, Anxiety Disorder, Dissociative Disorder, or a Personality Disorder).
It will be seen that ADHD is a disorder made up of two components, the attention deficit component and the hyperactivity component, which are to a degree independent.
Treatment with tomoxetine is effective in patients who are primarily suffering from either com~onent or from the combined disorder.
While ADHD is still primarily regarded as a disorder of children, it is now understood that many ADHD
patients, as many as 50%, continue to suffer from the disorder as they grow through adolescence into adulthood.
Biederman and associates have extensively studied the adult ADHD patient, and have found numerous cases. See, for example, Biederman, et al., Am. J. Psvchiatr~ 150, 1792-98 (1993). They found that cases of adult ADHD were frequently found among the parents and adult siblings of childhood ADHD
patients. Thus, it appears that the disease is not only carried forward into adulthood, but is inheritable.
The Biederman, et al. article cited immediately above, as well as another article by the same authors, Am. J.
Psvchiatrv 14~, 564-77 (1991), reports studies of ADHD
patients who also have one or more other psychiatric disorders. The authors indicate that such psychiatric co- t morbidity is quite common among ADHD patients and, naturally, cloud the diagnosis and treatment of such patients.
Tomoxetine is effective in the treatment of ADHD, even though CA 0220973~ 1997-07-07 W O96/21430 PCTrUS9G/00091 the situation of the trea~ed patientSmay~be complicated by co-morbidity with one or more additional disorders.
The mere listing of the above diagnostic criteria indicates the seriousness of ADHD and the damage which it does to the patient. A person having a moderately severe case of ADHD is substantially entirely unable to concentrate and hence unable to do meaningful work or study; is a continuing distraction and nuisance to those around her or him, because of the uselessly impulsive activity which the disorder causes; and consumes his or her family in cleaning up and repairing the damage and disruption which he or she causes. Such a patient of school age may substantially damage the teacher's ability to accomplish the class~ goals, because the ADHD child will continually disrupt the class, distract the other childre=n and consume the teacheris effort.
Thus, it is readily apparent that an improved treatment of ADHD is needed, and that the present invention is accordingly important to many people.
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. In general terms, however, for purposes of the present invention, 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, and an adult is considered to be a patient of 1~ years or older.
The invention belongs to the fields of pharmaceutical chemistry and psychiatric medicine, and provides a method of treatment of the psychiatric disorder known as attention-deficit/hyperactivity disorder.
Backaround of the Invention For some decades it has been recognized that a significant number of children are persistently hyperactive and have an attention span so short as to be disabling in school and in many personal relationships. Such children in earlier times would no doubt have been dismissed as incorrigible and punished or even confined in an institution.
Some long time ago, however, it was realized that these children cannot control their hyperactivity and inattention, and the medical professions began to try to help them.
Methylphenidate (RitalinTM)has been used for some time to treat such children and it often significantly improves their ability to function and coexist with other people at school and at home. However, the drug has the disadvantages of re~uiring several doses per day, and producing a rebound effect as the effect of each dose fades awa~. Further, the drug causes sleeplessness and lack of appetite in some patients. Methylphenidate has both noradrenergic and dopaminergic activities.
Imipramine, desipramine, nortriptyline, amitriptyline and clomipramine are also used in some cases of attention-deficit/hyperactivity disorder (ADHD). Those tricyclic drugs, however, have a number of physiological t mechanisms and, as a class, tend to produce a number of side effects and require careful supervision and dose titration.
l In the last decade, psychiatrists have realized that ADHD is not only a disorder of childhood, but often continues in the adult. It is obvious that hyperactivity and short attention span cause grave disruption in an adult's CA 0220973~ 1997-07-07 WO96/21430 PCT~S96/00091 life, but it is only recently that such patients have been able to obtain any treatment.
The need for a safe and convenient treatment for ADHD, applicable to both children an-d adults and without the $, disadvantages possessed by methylphenidate continues to be a concern of the psychiatric profession.
The present invention provides a method of treating attention-deficit/hyperactivity disorder comprising the administration to a patient in need of such treatment of an effective amount of tomoxetine.
The invention also provides the use of tomoxetine for the manufacture of a medicament for treating attention-deficit/hyperactivity disorder; and the use of tomoxetine for treating attention-deficit/hyperactivity disorder.
Tomoxetine is a well-known drug, the chemical name of which is ~ N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine. It is regularly used as a salt, and salts are included in the term tomoxetine as used here. See, for example, Gehlert, et al., Meuroscience Letters 157, 203-06 (1993), for a discussion of the mechanism of tomoxetine~s activity as a norepinephrine reuptake inhibitor. Tomoxetine is quite active in that function, and moreover is substantiallv free of other central nervous system activities at the concen~rations or doses at which it effectively inhibits norepinephrine reuptake. Thus, it is quite free of side effects and is properly considered to be a selective drug.
Tomoxetine is a notably safe drug, and its use in ADHD, in both adults and children, is a superior treatment for that disorder because of its improved safety. Further, tomoxetine is effective at relatively low doses, as discussed below, and may safely and effectively be administered once per day. Thus, difficulties created by the multiple dosing of patients, particularly children and disorganized adults, are completely avoided.
CA 0220973~ 1997-07-07 WO96/21430 PCT~S96/00091 The effective dose of tomoxetine for ADHD is in the range from about 5 mg/day to about lO0 mg/day. The preferred adult dose is in the range from about lO to about 80 mg/day, and a more highly preferred adult dose is from about 20 to about 60 mg/day. The childrenls dose of course is smaller, in the range from about 5 to about 70 mg/day, more preferably from about lO to about 60 mg/day and still more preferably from about lO to about 50 mg/day. The optimum dose for each patient, as always, must be set by the physician in charge of the case, taking into account the patient's size, other medications which the patient requires, severity of the disorder and all of the other circumstances of the patient.
Since tomoxetine is readily orally absorbed and requires only once/day administration, there is little or no reason to administer it in any other way than orally. It may be produced in the form of a clean, stable crystal, and thus is easily formulated in the usual oral pharmaceutical forms, such as tablets, capsules, suspensions, and the like. The usual methods of pharmaceutical scientists are applicable.
It may usefully be administered, if there is any reason to do so in a particular circumstance, in other pharmaceutical forms, such as injectable solutions, depot injections, suppositories and the like, which are well known to and understood by pharmaceutical scientists. It will substantially always be preferred, however, to administer tomoxetine as a tablet or capsule and such pharmaceutical forms are recommended.
The ADHD patient is rather readily recognized, and most people have been in contact with children, if not adults, who exhibit some or all of the symptoms of the disorder. The best description of the disorder is the diagnostic criteria for ADHD, published by the American l Psychiatric Association in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Version (1994), as follows.
CA 0220973~ 1997-07-07 WO96121430 PCT~S96/00091 Diagnostic criteria for Attention-Deficit/
Hyperactivity Disorder A. Either (1) or (2):
(1) six (or more) of the following symptoms of inattention have persisted for at least 6 months to a degree that is maladaptive and inconsistent with developmental level:
Ina t t en t i on (a) often fails to give close attention to details or makes careless mistakes in schoolwork, work, or other activities (b) often has difficulty sustaining attention in tasks or play activities (c) often does not seem to listen when spoken to directly (d) often does not follow through on instructions and fails to finish schoolwork, chores, or duties in the workplace (not due to oppositional behavior or failure to understand instructions) (e) often has difficulty organizing tasks and activities (f! often avoids, dislikes, or is reluctant to engage in tasks that require sustained mental effort (such as schoolwork or homework) (g) often loses things necessar for tasks or activities (e.g., toys, school assignments, pencils, books, or tools) (h) is often easily distracted by extraneous stimuli CA 0220973~ 1997-07-07 W O 96121430 PCTrUS96/00091 (i) is often forgetful in daily activities (2) six (or more) of the following symptoms of hyperactivity-impulsi~rity have persisted for at least 6 months to a degree that is maladaptive and inconsistent with developmental level:
Hyp era ct i vi ty (a) often fidgets with hands or feet or squirms in seat (h! often leaves seat in classroom or in other situations in which remaining seated is expected (c) often runs about or climbs excessively in situations in which it is inappropriate (in adolescents or adults, may be limited to subjective feelings of restlessness) (d) often has difficulty playing or engaging in leisure activities quietly (e) is often "on the go" or often acts as if "driven by a motor~
(f) often talks excessively Impulsivity (g) often blurts out answers before questions have been completed (h) often has difficulty awaiting turn (i) often interrupts or intrudes on ~ others (e.g., butts into 7 conversations or games) B. Some hyperactive-impulsive or inattentive symptoms that caused impairment were present before age 7 years.
C. Some impairment from the symptoms is present in two or more settings (e.g., at school [or wor~ and at home).
CA 0220973~ 1997-07-07 WO96/21430 PCT~S96/00091 D. There must be clear evidence of clinically significant impairment in social, academic, or occupational functioning.
E. The symptoms do not occur exclusively during the course of a Pervasive Developmental Disorder, Schizophrenia, or other Psychotic Disorder and are not better accounted for by another mental disorder (e.g., Mood Disorder, Anxiety Disorder, Dissociative Disorder, or a Personality Disorder).
It will be seen that ADHD is a disorder made up of two components, the attention deficit component and the hyperactivity component, which are to a degree independent.
Treatment with tomoxetine is effective in patients who are primarily suffering from either com~onent or from the combined disorder.
While ADHD is still primarily regarded as a disorder of children, it is now understood that many ADHD
patients, as many as 50%, continue to suffer from the disorder as they grow through adolescence into adulthood.
Biederman and associates have extensively studied the adult ADHD patient, and have found numerous cases. See, for example, Biederman, et al., Am. J. Psvchiatr~ 150, 1792-98 (1993). They found that cases of adult ADHD were frequently found among the parents and adult siblings of childhood ADHD
patients. Thus, it appears that the disease is not only carried forward into adulthood, but is inheritable.
The Biederman, et al. article cited immediately above, as well as another article by the same authors, Am. J.
Psvchiatrv 14~, 564-77 (1991), reports studies of ADHD
patients who also have one or more other psychiatric disorders. The authors indicate that such psychiatric co- t morbidity is quite common among ADHD patients and, naturally, cloud the diagnosis and treatment of such patients.
Tomoxetine is effective in the treatment of ADHD, even though CA 0220973~ 1997-07-07 W O96/21430 PCTrUS9G/00091 the situation of the trea~ed patientSmay~be complicated by co-morbidity with one or more additional disorders.
The mere listing of the above diagnostic criteria indicates the seriousness of ADHD and the damage which it does to the patient. A person having a moderately severe case of ADHD is substantially entirely unable to concentrate and hence unable to do meaningful work or study; is a continuing distraction and nuisance to those around her or him, because of the uselessly impulsive activity which the disorder causes; and consumes his or her family in cleaning up and repairing the damage and disruption which he or she causes. Such a patient of school age may substantially damage the teacher's ability to accomplish the class~ goals, because the ADHD child will continually disrupt the class, distract the other childre=n and consume the teacheris effort.
Thus, it is readily apparent that an improved treatment of ADHD is needed, and that the present invention is accordingly important to many people.
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. In general terms, however, for purposes of the present invention, 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, and an adult is considered to be a patient of 1~ years or older.
Claims (16)
1. The use of tomoxetine for treating attention-deficit/hyperactivity disorder in a patient in need thereof.
2. The use of Claim 1 wherein the predominantly inattentive type of attention-deficit/hyperactivity disorder is treated.
3. The use of Claim 1 wherein the predominantly hyperactive-impulsive type of attention-deficit/hyperactive disorder is treated.
4. The use of Claim 1 wherein the combined type of attention-deficit/hyperactivity disorder is treated.
5. The use of Claim 1 wherein the patient is an adult.
6. The use of Claim 5 wherein the predominantly inattentive type of attention-deficit/hyperactivity disorder is treated.
7. The use of Claim 5 wherein the predominantly hyperactive-impulsive type of attention-deficit/hyperactive disorder is treated.
8. The use of Claim 5 wherein the combined type of attention-deficit/hyperactivity disorder is treated.
9. The use of Claim 1 wherein the patient is an adolescent.
10. The use of Claim 9 wherein the predominantly inattentive type of attention-deficit/hyperactivity disorder is treated.
11. The use of Claim 9 wherein the predominantly hyperactive-impulsive type of attention-deficit/hyperactive disorder is treated.
12. The use of Claim 9 wherein the combined type of attention-deficit/hyperactivity disorder is treated.
13. The use of Claim 1 wherein the patient is a child.
14. The use of Claim 13 wherein the predominantly inattentive type of attention-deficit/hyperactivity disorder is treated.
15. The use of Claim 13 wherein the predominantly hyperactive-impulsive type of attention-deficit/hyperactive disorder is treated.
16. The use of Claim 13 wherein the combined type of attention-deficit/hyperactivity disorder is treated.
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| US08/371,341 | 1995-01-11 | ||
| US08/371,341 US5658590A (en) | 1995-01-11 | 1995-01-11 | Treatment of attention-deficit/hyperactivity disorder |
| PCT/US1996/000091 WO1996021430A1 (en) | 1995-01-11 | 1996-01-04 | Treatment of attention-deficit/hyperactivity disorder |
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| CA2209735A1 CA2209735A1 (en) | 1996-07-18 |
| CA2209735C true CA2209735C (en) | 2002-10-01 |
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1995
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1996
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