Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-12-04
2002-03-19
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S232000, C546S241000
Reexamination Certificate
active
06358977
ABSTRACT:
This application is a 371 of PCT SE99/00683 Apr. 26, 1999.
FIELD OF THE INVENTION
The present invention relates to the use of 4-piperidinemethanol derivatives for the production of a pharmaceutical composition for treatment of neurodevelopmental disorders. The invention also relates to a method for treatment of such disorders.
BACKGROUND
Neurodevelopmental disorders, such as autism, ADHD (Attention Deficit Hyperactivity Disorder) and DAMP (Deficits in Attention, Motor Control and Perception) are quite common and they lead both to suffering for the patient and to high treatment costs for society.
Childhood autism is a chronic condition leading to a life-long handicap of varying severity. Very few individuals with this diagnosis lead an independent life as adults. Cardinal symptoms of autism are impaired sociability, communication and imagination (Wing's triad). Examples of other symptoms are insistence on sameness, reluctance to switch behavioral program, rigidity, stereotypies, defective habituation and a very meagre behavioral repertoire [Kanner L. (1943) Autistic disturbances of affective contact. Nervous Child 2: 217-250]. Asperger's syndrome [Wing L. (1981) Asperger's syndrome: a clinical account. Psychol Med 11: 115-129] is another autism spectrum disorder characterized by pronounced social impairments but with a higher level of cognitive functioning than in autism. The prevalence of autism is 1 to 2 per 1,000 children, if less severely affected cases are included [Gillberg C. (1993) Autism and related behaviours. J Intellectual Disability Research 37: 343-372; Gillberg C., Coleman M. (1992) The biology of the autistic syndromes. 2nd edition, Clinics in Developmental Medicine no 126. Mac Keith Press, London]. Asperger's syndrome is more common, with a prevalence of about 0.5% [Ehlers S., Gillberg C. (1993) The epidemiology of Asperger's syndrome. A total population study. J Child Psychol Psychiat 34: 1327-1350]. Hitherto, pharmacological interventions aimed at alleviating symptoms of autism have been at most partly successful.
There are striking similarities between symptoms seen in autism and those produced by glutamate antagonists in healthy subjects [Carroll M. E. (1990) PCP and hallucinogens. Adv Alcohol Subst Abuse 9: 167-190; Garey R. E., Weisberg L. A., Heath R. G. (1977) Phencyclidine: An overview. J Psychedelic Drugs 9: 280-285; Gerland G. (1996) En riktig människa. Bokförlaget Cura AB, Stockholm; Grandin T. (1992) An inside view of autism. In Schopler E., Mesibov G. B. (eds) High-functioning Individuals with Autism. Plenum Press, New York, pp 105-126; Grandin T. (1996) My experiences with visual thinking sensory problems and communication difficulties. http://www.autism.org/temple/visual.html; Hansen G., Jensen S. B., Chandresh L., Hilden T. (1988) The psychotropic effect of ketamine. J Psychoactive Drugs 20: 419-425; Kootz J. P., Cohen D. J. (1981) Modulation of sensory intake in autistic children. J Am Acad Child Psychiat 20: 692-701; Krystal J. H., Karper L. P., Seibyl J. P., Freeman G. K., Delaney R., Bremner J. D., Heninger G. R., Bowers M. B., Charney D. S. (1994) Subanesthetic effects of the noncompetitive NMDA antagonist ketamine, in humans: Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Pshychiatry 51: 199-214; Muir K. W., Lees K. R. (1995) Clinical experience with excitatory amino acid antagonist drugs. Stroke 26: 503-515; Sacks O. (1993/1994) An anthropologist on mars. The New Yorker December 27-January 3: 106-125; Schäfer S. (1996) Stjärnor, linser och äpplen—att leva med autism. Bokförlaget Cura AB, Stockholm; Wing L. (1997) Syndromes of autism and atypical development. In Cohen D. J., Volkmar F. R. (eds) Handbook of Autism and Pervasive Developmental Disorders, 2nd edition. John Wiley & Sons, Inc, New York, pp 148-170]. Examples of such symptoms are: distorted perception of all modalities, defective habituation (manifested i.a. as an obsession with trivial matters), perseverant behavior, defective proprioception/misinterpretation of body position in space, difficulties estimating time/time distortion, concrete thinking, rapid mood fluctuations, anxiety, inappropriate/blunted affect, stereotypies, assaultive behavior, apathy/passivity, social withdrawal, catatonia, and dystonia. These similarities are logical, in view of the neuroanatomical and neuroimaging studies showing aberrations in brain regions that are rich in glutamate neurons, such as medial temporal structures like the amygdala and the hippocampus [see e.g. Bauman M., Kemper T. L. (1985) Histoanatomic observations of the brain in early infantile autism. Neurology 35: 866-874; Bauman M. L. (1991) Microscopic neuroanatomic abnormalities in autism. Pediatrics 87: 791-796; Hoon Jr. A. H., et al. (1992) The mesial-temporal lobe and autism: Case report and review. Develop Med Child Neurol 34: 252-265; Raymond G. V., et al. (1996) Hippocampus in autism: a Golgi analysis. Acta Neuropathol 91: 117-119; Chugani H. T., et al. (1996) Infantile spasms: III. Prognostic implications of bitemporal hypometabolism on positron emission tomography. Ann Neurol 39: 643-649], and cortical areas such as the frontal, prefrontal [see e.g. Minshew N. J. (1991) Indices of neural function in autism: Clinical and biological implications. Pediatrics 87: 774-780; Zilbovicius M., et al. (1995) Delayed maturation of the frontal cortex in childhood autism. Am J Psychiatry 152: 248-252] and parietal cortex [see e.g. Courchesne E., et al. (1993) Parietal lobe abnormalities detected on magnetic resonance images of patients with infantile autism. Am J Roentgenology 160: 387-393], indicating deficient glutamate transmission in autism.
ADHD (Attention Deficit Hyperactivity Disorder) and DAMP (Deficits in Attention, Motor Control and Perception) are neurodevelopmental disorders with prevalence rates of about 5% in a child population. DAMP is the term used in Scandinavia and is virtually synonymous to ADHD but describes, apart from the difficulties with attention, the deficits in motor control and the perceptual aberrations.
ADHD/DAMP is 2-3 times more common in boys than in girls. In half of the ADHD/DAMP cases, the symptoms have disappeared or been greatly reduced by 20 years of age. 20-25% of the children with an ADHD/DAMP diagnosis have developed an antisocial personality disorder with criminality and substance abuse by the time they reach 20 years of age.
It is estimated that about a million children in the US with an ADHD diagnosis are treated with psychostimulants like d-amphetamine and methylphenidate, which improve attention, ability to focus, hyperactivity and impulsivity in about 70%. In Europe, the use of psychostimulants to treat ADHD/DAMP is much less frequent than in the US.
Due to the reluctance in many countries to use psychostimulant, potentially addictive, drugs in children, there is a great need to develop effective and safe drugs to treat ADHD/DAMP.
Brain imaging studies indicate hypofunctioning frontal lobes and defect corticostriatal functioning in ADHD/DAMPtsee Lou H. C., et al. (1984) Focal cerebral hypoperfusion in children with dysphasia and/or in attention deficit disorder. Arch Neurol. 41: 825-829; Lou H. C., et al. (1989) Striatal dysfunction in attention deficit and hyperkinetic disorder. Arch Neurol. 46: 48-52; Zametkin A. J., et al. (1990) Cerebral glucose metabolism in adults with hyperactivity of childhood onset. New Engl J Med 323: 1361-1366; Giedd J. N., et al. (1994) Quantitative morphology of the corpus callosum in attention deficit hyperactivity disorder. Am J Psychiatry 151: 665-9; Casey B. J. et al. (1997) Implication of right frontostriatal circuitry in response inhibition and attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 36: 374-831. Since corticostriatal neurons are glutamatergic, it is reasonable to assume that glutamatergic transmission is deficient in ADHD/DAMP. Whereas autism probably involves a global deficiency in
A. Carlsson Research AB
Covington Raymond
Rotman Alan L.
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