WO2013185187A1 - Méthodes de traitement des stéréotypies, des déficits dans le comportement social et des comportements compulsifs associés à la neuropsychiatrie et aux troubles neurologiques du développement utilisant le récepteur peptidique libérant la gastrine et composition pharmaceutique contenant grp - Google Patents

Méthodes de traitement des stéréotypies, des déficits dans le comportement social et des comportements compulsifs associés à la neuropsychiatrie et aux troubles neurologiques du développement utilisant le récepteur peptidique libérant la gastrine et composition pharmaceutique contenant grp Download PDF

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Publication number
WO2013185187A1
WO2013185187A1 PCT/BR2012/000182 BR2012000182W WO2013185187A1 WO 2013185187 A1 WO2013185187 A1 WO 2013185187A1 BR 2012000182 W BR2012000182 W BR 2012000182W WO 2013185187 A1 WO2013185187 A1 WO 2013185187A1
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WO
WIPO (PCT)
Prior art keywords
neuropsychiatric
disorder
gly
neurodevelopmental disorder
neurodevelopmental
Prior art date
Application number
PCT/BR2012/000182
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English (en)
Inventor
Gilberto Schwartsmann
Rafael Roesler
Michele MICHELIN BECKER
Rudimar DOS SANTOS RIESGO
Original Assignee
Gilberto Schwartsmann
Rafael Roesler
Michelin Becker Michele
Dos Santos Riesgo Rudimar
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.)
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Application filed by Gilberto Schwartsmann, Rafael Roesler, Michelin Becker Michele, Dos Santos Riesgo Rudimar filed Critical Gilberto Schwartsmann
Priority to BR112014031123A priority Critical patent/BR112014031123A2/pt
Priority to PCT/BR2012/000182 priority patent/WO2013185187A1/fr
Publication of WO2013185187A1 publication Critical patent/WO2013185187A1/fr

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    • 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
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Definitions

  • the invention is directed towards methods of treating symptoms associated with neuropsychiatric and neurodevelopmental disorders, in particular symptoms related to stereotyped behaviors, social behavior deficits, and obsessive behaviors.
  • Stereotyped and obsessive behaviors and deficits in social behavior and attachment are features of neuropsychiatric and neurodevelopmental disorders including autism spectrum disorders (ASD), schizophrenia, and obsessivecompulsive disorder (OCD). Novel therapeutic targets and treatment strategies for the treatment of symptoms associated to these behavioral alterations are warranted (DiCicco-Bloom et al., 2006).
  • Gastrin-releasing peptide (GRP; Ala-Pro-Val-Ser- Val-Gly-Gly-Gly-Thr-Val-Leu-Ala-Lys-Met-Tyr-Pro-Arg-Gly-Asn-His-Trp-Ala-Val- Gly-His-Leu-Met-NH2), a neuropeptide that is the mammalian analog of the amphibian peptide bombesin (Pyr-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly- His-Leu-Met NH2), acts by binding to the GRP receptor (GRPR, also called BB 2 receptor) on neuronal membranes (Jensen et al. 2008; Roesler e
  • GRPR GRPR gene
  • a translocation breakpoint on the X chromosome in the first intron of the GRPR gene was described in a patient with autism accompanied by mental retardation and epilepsy (Ishikawa-Brush et al. 1997).
  • Another study analyzing mutations of the GRPR gene in Italian autistic patients identified a possible role of mutations of the GRPR gene in ASD in two patients (Seidita et al., 2008).
  • pharmacological GRPR blockade during central nervous system development in rats results in long-lasting and profound deficits in aspects of social behavior including social interaction in adults and maternal odor preference in juvenile rats (Garcia et al. 2010; Presti- Torres et al., 2007; 2012).
  • Unites States Patent Application 20080051315 describes the use of a GRPR agonist for treating fear-related disorders, including phobia, chronic anxiety, panic attack, post-traumatic stress disorder, and autism.
  • United States Patent 7,795,385 (WO 2006/063837 A2; Schwartsmann et al.) describes the use of GRPR antagonists for treating or preventing brain disorders, preferably bipolar disorder, and in particular the different forms and/or subforms of bipolar disorder, such as mania, acute mania, severe mania, hypomania, depression, moderate depression, dysthymia, severe depression, episodes of mania and/or depression, psychosis/psychotic symptoms (e.g. hallucinations, delusions), mixed bipolar state, bipolar I disorder, bipolar II disorder and/or rapid-cycling bipolar disorder.
  • bipolar disorder preferably bipolar disorder
  • the different forms and/or subforms of bipolar disorder such as mania, acute mania, severe mania, hypomania, depression, moderate depression, dysthymia, severe depression, episodes of mania and/or depression, psychosis/psychotic symptoms (e.g. hallucinations, delusions), mixed bipolar state, bipolar I disorder, bipolar II
  • the present invention aims to address this need by providing a therapeutic method to ameliorate those symptoms.
  • the present invention provides a method for treating symptoms associated with stereotyped behaviors, obsessive behaviors, and social behavior deficits, in a subject in need of intervention, by administering to the subject a therapeutically effective amount of a composition containing GRP or a comparable GRPR agonist, including bombesin.
  • neuropsychiatric or neurodevelopmental disorder being Rett syndrome, Angelman syndrome, cerebral palsy, schizophrenia, obsessive-compulsive disorder (OCD), mental retardation, mood disorder, preferentially major depressive disorder, tardive dyskinesia, stereotypic movement disorder and frontotemporal dementia.
  • OCD obsessive-compulsive disorder
  • the invention provides a pharmaceutical composition containing human recombinant GRP dissolved in saline solution (NaCI 0.9%) in an adequate amount that allows a dose of 160 pmol/kg to be administered to the subject subcutaneously (s.c.) or intravenously (i.v.).
  • the composition is preferably administered for a defined period, preferably once a day during 3 days or once a day during 4 days.
  • compositions containing the GRPR agonist can be given to the subject in solid or liquid formulations through any therapeutically adequate administration route, including the oral, sublingual, nasal, ophthalmic, intradermic, anal, subcutaneous, or intravenous routes.
  • Table 1 Symptoms before and after one daily infusion of human recombinant gastrin-releasing peptide (160 pmol/kg, s.c.) over 4 days to a patient diagnosed with classical autism.
  • the inventors have found a consistent amelioration of symptoms including stereotyped and obsessive behaviors and social withdraw after administration over a defined period of GRP to subjects afflicted with autism.
  • the aim of the study was to examine the effects of systemic administration of GRP on symptoms related to social interaction, withdrawn, communication, and stereotyped and obsessive behaviors in three pediatric patients (all males, ages 5 (patient 1), 5 (patient 2), and 4 (patient 3) diagnosed with classical autism.
  • the results presented here were obtained from the clinical assessment of three patients using standardized scales and tests in a pilot study.
  • the assessment of symptoms related to autism was performed one day before GRP administration. On four consecutive days after treatment, subjects were given a daily s.c. injection of GRP at the dose of 160 pmol/kg. After the 4 th GRP injection, the patients were again assessed for the symptoms using the same standardized tests and scales. The patients were evaluated for symptoms and monitored for vital signs and possible drug-related adverse effects by one researcher directly involved in the study.
  • the ADI-R Autism Diagnostic Interview-Revised (ADI-R; version translated and validated in Brazil): The ADI-R is a widely used structured interview conducted with the parents of subjects under evaluation for possible ASD. The instrument measures behaviors related primarily to reciprocal social interaction, communication, and language.
  • SQ Social Communication Questionnaire
  • Childhood Autism Rating Scale This is a standardized behavior rating scale. The child is rated on a scale from one to four, ranging from normal to severe, and quantitative scores ranging from 15 to 60. The items rated are relationship to people, imitation, emotional response, body, object use, adaptation to change, visual response, listening response, taste-smell- touch response and use, fear and nervousness, verbal communication, nonverbal communication, activity level, level and consistency of intellectual response, and general impressions.
  • the scale can be completed by the subject's clinician or parent, based on observations of the child's behavior.
  • Parental report (for patient 1): Behavioral changes reported by the parents as positive during GRP treatment included: 1 ) a reduction in compulsive showering - before treatment the patient took 5-6 showers daily and asked to shower every time he felt anxious, dirty, sweating, or hurt - from the first day of infusion; 2) reduced stereotyped behavior - the patient displayed stereotyped hand movements pointing repeatedly the index finger to the nose; stereotypy ceased after the first day of GRP infusion; and returned, with other previously unobserved movements, after the last day of infusion; 3) a decrease in agitation, with a larger effect on the first day of treatment with GRP; 4) increased tolerance to frustration with reduced argues and shouting at the parents; 5) improved mood at waking time, calm behavior after infusions, and better sleep pattern, without waking up during the night or requiring rituals before sleeping; 6) improvement in interest and pattern of playing; before the treatment, played only with toy cars in a stereotyped and limited way; lost interest for any other toys a few minutes after getting
  • Table 1 summarizes the symptoms assessed before and after the first and second administrations of GRP for patient 1. Improvements after GRP treatment were observed in body and hand stereotypies, use of objects, fear and anxiety, compulsive behaviors, facial expressions, using other person's hand, and social smiling.
  • Neonatal gastrin-releasing peptide receptor blockade reduces maternal odor preference in rats. Behavioural Brain Research, 214, 456-459.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Neurosurgery (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Psychology (AREA)
  • Psychiatry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne des méthodes de traitement de symptômes tels que les stéréotypies, les déficits dans le comportement social et les comportements obsessionnels chez un sujet souffrant d'un trouble neuropsychiatrique ou d'un trouble neurologique du développement. Les méthodes consistent à administrer à un sujet une quantité thérapeutiquement efficace de peptide libérant la gastrine (GRP) ou d'autre agoniste du récepteur de GRP (GRPR).
PCT/BR2012/000182 2012-06-11 2012-06-11 Méthodes de traitement des stéréotypies, des déficits dans le comportement social et des comportements compulsifs associés à la neuropsychiatrie et aux troubles neurologiques du développement utilisant le récepteur peptidique libérant la gastrine et composition pharmaceutique contenant grp WO2013185187A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
BR112014031123A BR112014031123A2 (pt) 2012-06-11 2012-06-11 métodos baseados em receptor do peptídeo liberador de gastrina para o tratamento de estereotipias, déficits de comportamento social e comportamentos compulsivos associados a transtornos neuropsiquiátricos e de desenvolvimento neurológico e composição farmacêutica contendo peptídeo de liberação de gastrina
PCT/BR2012/000182 WO2013185187A1 (fr) 2012-06-11 2012-06-11 Méthodes de traitement des stéréotypies, des déficits dans le comportement social et des comportements compulsifs associés à la neuropsychiatrie et aux troubles neurologiques du développement utilisant le récepteur peptidique libérant la gastrine et composition pharmaceutique contenant grp

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/BR2012/000182 WO2013185187A1 (fr) 2012-06-11 2012-06-11 Méthodes de traitement des stéréotypies, des déficits dans le comportement social et des comportements compulsifs associés à la neuropsychiatrie et aux troubles neurologiques du développement utilisant le récepteur peptidique libérant la gastrine et composition pharmaceutique contenant grp

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WO2013185187A1 true WO2013185187A1 (fr) 2013-12-19

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WO (1) WO2013185187A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060134109A1 (en) * 2002-09-09 2006-06-22 Nura Inc. G protein coupled receptors and uses thereof
US20080051315A1 (en) * 2003-12-11 2008-02-28 Eric Kandel Grp Receptor-Related Methods for the Treating and Preventing Fear-Related Disorders
US20080268032A1 (en) * 2006-06-23 2008-10-30 Aegis Therapeutics Llc Stabilizing Alkylglycoside Compositions and Methods Thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060134109A1 (en) * 2002-09-09 2006-06-22 Nura Inc. G protein coupled receptors and uses thereof
US20080051315A1 (en) * 2003-12-11 2008-02-28 Eric Kandel Grp Receptor-Related Methods for the Treating and Preventing Fear-Related Disorders
US20080268032A1 (en) * 2006-06-23 2008-10-30 Aegis Therapeutics Llc Stabilizing Alkylglycoside Compositions and Methods Thereof

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