WO2008048194A1 - Utilisation du tamoxifène inhibiteur de la protéine kinase c pour le traitement d'un trouble bipolaire - Google Patents

Utilisation du tamoxifène inhibiteur de la protéine kinase c pour le traitement d'un trouble bipolaire Download PDF

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Publication number
WO2008048194A1
WO2008048194A1 PCT/TR2007/000063 TR2007000063W WO2008048194A1 WO 2008048194 A1 WO2008048194 A1 WO 2008048194A1 TR 2007000063 W TR2007000063 W TR 2007000063W WO 2008048194 A1 WO2008048194 A1 WO 2008048194A1
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Prior art keywords
tamoxifen
bipolar
treatment
placebo
mania
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PCT/TR2007/000063
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English (en)
Inventor
Aysegul Yildiz Yesilogluj.
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Yesilogluj Aysegul Yildiz
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Publication of WO2008048194A1 publication Critical patent/WO2008048194A1/fr

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    • 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
    • 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

  • Tamoxifen citrate has been compared to placebo for treatment of acute mania.
  • Tamoxifen Gador® OR Nolvadex®
  • Tamoxifen is widely used for prophylaxis and treatment of breast cancer, and it's mechanism of action has similarities to the mechanism of action of Lithium and Valproate, which are the standard
  • Bipolar disorder is a chronic mental illness that affects 1-2% of the adult population 1 2 and is associated with a substantial risk of suicide among those affected 1 ' 3 .
  • Tamoxifen citrate is the only relatively selective PKC inhibitor available for human use. It is a synthetic nonsteroidal antiestrogen, has been widely used in the treatment of breast cancer. 18 Many of its effects are clearly due to estrogen receptor antagonism 18 but it is also a potent protein kinase C inhibitor 19"21 that crosses the blood-brain barrier 19 . Other than Bebchuk and colleague's study, there have been no previous published studies designed to specifically investigate the potential mood altering effects of tamoxifen, although mild to moderate depression has been described in patients receiving long term tamoxifen for breast cancer. 22
  • Placebo-controlled, double-blind, randomized clinical trials have been recognized as the standard by which to establish a drug's safety, efficacy, and dose- relationships in most major psychiatric illnesses.
  • the justifications for using placebo control groups in such trials are the fluctuating natural course of most psychiatric illnesses, the wide variability in placebo response across patient groups, and the influence of psychosocial factors on treatment response.
  • 24 ' 25 There have been four potential alternatives to use of placebo control group proposed in studies of acute mania. 2627 These are add-on studies, variable dose designs, establishing a priori threshold effect size with active comparison control, and comparisons with historical controls.
  • Subjects are 50 adults diagnosed with bipolar affective disorder by using DSM-IV criteria, most recent episode manic or mixed, with or without psychotic features. All the diagnosis is based on the Structured Clinical Interview for the DSM-IV, administered by a trained investigator (Pl).
  • a minimum total score of at least 20 on the Young-Mania Rating Scale (Y- MRS) 28 are required at the screening visit and on the day of randomization (baseline).
  • Subject screening includes medical and psychiatric history, physical examination, and laboratory screen including LFT's, TSH, HCG, BUN, Cr, and serum toxicology. Blood samples are collected from the patients included in the study for the measurements of the PKC activity and PKC translocation in response to serotonin under the influence of tamoxifen at baseline and after the first week of treatment.
  • magnetic resonance imaging/spectroscopy are applied to the study patients under the influence of midazolam/fentanil sedation both in the manic state at baseline and study end point as well as after eutyhmia has been achieved. All psychotropic medication therapy (except benzodiazepines) are tapered during the screening period and discontinued at least 1 day before randomization.
  • Subjects successfully screened who meet inclusion and exclusion criteria are randomly assigned to receive the protein kinase C inhibitor, tamoxifen or identical placebo tablets in a 1 :1 ratio and a double blind fashion for 3 weeks.
  • Computer- generated codes are used to create randomized blocks of clinical trial material kits before study startup (randomization blocks are prepared by the ARGEFAR, a contract research organization). Each kit contains all clinical trial material to be used by a patient throughout the 3-week study.
  • the starting dose of tamoxifen is 20 mg bid. After the first day of therapy, daily dose is adjusted upward, by 10 mg increments per day up to 80 mg/d in divided doses. Similar daily dose adjustments are applied for the placebo group.
  • lorazepam Concomitant use of lorazepam is allowed during double blind therapy as clinically indicated. Lorazepam use is avoided after the initial 12 days after randomization, whenever possible. Subjects are monitored weekly during the 3 week double blind trial. Young Mania Rating Scale (YMRS), Clinical Global Impressions-Biopolar Version of Severity of llness (CGI-BP) 29 mania score, Hamilton Depression Rating Scale (HAM-D) 30 and Positive and Negative Syndrome Scale (PANSS) 31 , and side effect questionnaire (SEs) are administered by semi-structured interviews at each week. Inclusion Criteria:
  • Assessment tools include Y-MRS, HAM-D, CGI-BP, and PANSS.
  • Responders are defined as those subjects who demonstrate a 50 % or greater improvement over baseline in the Y-MRS score in the 3 week trial.
  • the principle investigator who is trained in the rating instruments and blind to treatment, performed all study assessments on a weekly basis by using all available clinical information.
  • the primary efficacy variable is defined as the reduction from baseline of the Y- MRS total score after 3 weeks of therapy.
  • Response is defined as at least 50 % improvement from baseline to the endpoint in the Y-MRS total score. Following hypotheses are proposed to be tested;
  • Tola scores from rating scales are derived from the individual items; if any single item is missing, the total score is treated as missing. All statistical evaluations are made by using SPSS 13.0. Mean baseline scores for each group are compared using the independent samples Student's t test. Lorazepam use in each group is compared on a weekly basis using the independent samples Student's t test. Response rates as defined by ⁇ 50% improvement in the Y-MRS scores are compared by using the Chi-Square test. Statistical significance in the change scores of the Y-MRS, HAM-D, CGI-BP, and PANSS within and in between the groups are assessed by using the paired and unpaired samples Student's t test as appropriate. Drug effects are analyzed using repeated measures analysis of variance (ANOVA). Since in this study, most patients could complete the trial, analysis on an 'intent to treat basis' is not required.
  • ANOVA repeated measures analysis of variance
  • FIG. 1 Change in YMRS scores in tamoxifen & placebo groups: The primary efficacy variable is defined as the reduction from baseline of the Young Mania Rating Scale (YMRS) total score after 3 weeks of therapy. This figure shows that there is greater reduction the YMRS total score measuring manic or mixed mood symptoms in the tamoxifen citrate group as compared to the placebo group.
  • YMRS Young Mania Rating Scale
  • FIG. 1 Change in CGl Mania scores in tamoxifen & placebo groups: This figure shows that there is greater reduction in the Clinical Global Impressions-Bipolar Version of Severity of Illness (CGI-BP) mania score in the tamoxifen citrate group as compared to the placebo group.
  • CGI-BP Clinical Global Impressions-Bipolar Version of Severity of Illness
  • FIG. 3 Change in PANSS scores in tamoxifen & placebo groups: This figure shows that there is greater reduction in the Positive and Negative Syndrome Scale (PANSS) score in the tamoxifen citrate group as compared to the placebo group.
  • PANSS Positive and Negative Syndrome Scale
  • Jope RS Anti-bipolar therapy: mechanism of action of lithium.
  • Jope RS A bimodal model of the mechanism of action of lithium. MoI psychiatry 1999; 4:21-25
  • Hahn CG Friedman E: Abnormalities in protein kinase C signaling and the pathophysiology of bipolar disease. Bipolar Disorders 1999; 1 :81-86 17.
  • Bebchuk JM Arfken CL, Dolan-Manji S, Murphy J, Hasanat K, Manji HK: A preliminary investigation of a protein kinase C inhibitor in the treatment of acute mania.
  • Jordon VC A current view of tamoxifen for the treatment of breast cancer.
  • Horgan K Cooke E, hallet MB, Mansel RE: Inhibition of protein kinase C mediated signal transduction by tamoxifen: importance for antitumor activity.
  • Leber P The future controlled trials. Is there an alternative to randomized controlled trial. Psychopharmacol Bull 1991; 27:3-8 27. Leber P: Challenges to the ethicality of clinical research. Psychopharmacol Bull 1996; 32: 11-13

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (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)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Psychiatry (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)

Abstract

Selon l'invention, des sujets bipolaires avec des épisodes maniaques/mixtes ont été choisis de manière aléatoire pour recevoir soit du tamoxifène (80 mg/jour), soit des comprimés de placebo identiques dans un rapport 1/1 pendant trois semaines. A la fin de l'essai de trois semaines, le traitement au tamoxifène s'est avéré avoir de fortes propriétés anti-maniaques. L'inhibition de la protéine kinase C semble être une des cibles directes du lithium et du valproate, traitements existants efficaces du trouble bipolaire et de la manie. Ces observations peuvent conduire à la description de la physiopathologie qui sous-tend le trouble bipolaire et à la mise au point de thérapies innovantes.
PCT/TR2007/000063 2006-10-20 2007-07-09 Utilisation du tamoxifène inhibiteur de la protéine kinase c pour le traitement d'un trouble bipolaire WO2008048194A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2006/05898 2006-10-20
TR200605898 2006-10-20

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WO2008048194A1 true WO2008048194A1 (fr) 2008-04-24

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010135703A3 (fr) * 2009-05-21 2011-01-13 Jina Pharmaceuticals, Inc. Procédés et compositions d'endoxifène pour traiter des maladies de mammifères
US20120201908A1 (en) * 2009-08-19 2012-08-09 Lunera Equities, Lllp Method of treating bipolar disorder or depression using an antiestrogen
US9333190B2 (en) 2006-11-21 2016-05-10 Jina Pharmaceuticals, Inc. Endoxifen compositions and methods
WO2021205405A1 (fr) * 2020-04-10 2021-10-14 Jina Pharmaceuticals, Inc. Endoxifène pour le traitement d'un trouble bipolaire i
WO2021205404A1 (fr) * 2020-04-10 2021-10-14 Jina Pharmaceuticals, Inc. Endoxifen pour le traitement du trouble bipolaire de type i

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005030143A2 (fr) * 2003-09-26 2005-04-07 Yale University Chelerythrine, analogues de celle-ci et leur utilisation pour traiter un trouble et d'autres troubles cognitifs

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005030143A2 (fr) * 2003-09-26 2005-04-07 Yale University Chelerythrine, analogues de celle-ci et leur utilisation pour traiter un trouble et d'autres troubles cognitifs

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
BEBCHUK J M ET AL: "A preliminary investigation of a protein kinase C inhibitor in the treatment of acute mania.", ARCHIVES OF GENERAL PSYCHIATRY JAN 2000, vol. 57, no. 1, January 2000 (2000-01-01), pages 95 - 97, XP008084309, ISSN: 0003-990X *
KULKARNI JAYASHRI ET AL: "A pilot study of hormone modulation as a new treatment for mania in women with bipolar affective disorder", PSYCHONEUROENDOCRINOLOGY, vol. 31, no. 4, May 2006 (2006-05-01), pages 543 - 547, XP005334313, ISSN: 0306-4530 *
MANJI HUSSEINI K ET AL: "Modulation of CNS signal transduction pathways and gene expression by mood-stabilizing agents: Therapeutic implications", JOURNAL OF CLINICAL PSYCHIATRY, vol. 60, no. SUPPL. 2, 1999, pages 27 - 39, XP008084310, ISSN: 0160-6689 *
MANJI HUSSEINI K ET AL: "Protein kinase C signaling in the brain: Molecular transduction of mood stabilization in the treatment of manic-depressive illness", BIOLOGICAL PSYCHIATRY, vol. 46, no. 10, 15 November 1999 (1999-11-15), pages 1328 - 1351, XP002453972, ISSN: 0006-3223 *
YILDIZ-YESILOGLU AYSEGUL: "Targeted treatment strategies in mania: Anti-manic effects of a PKC inhibitor-tamoxifen", BIOLOGICAL PSYCHIATRY, vol. 61, no. 8, Suppl. S, April 2007 (2007-04-01), & 62ND ANNUAL SCIENTIFIC MEETING OF THE SOCIETY-OF-BIOLOGICAL-PSYCHIAT RY; SAN DIEGO, CA, USA; MAY 17 -20, 2007, pages 23S, XP008084313, ISSN: 0006-3223 *
ZARATE CARLOS A JR ET AL: "Efficacy of a protein kinase C inhibitor (tamoxifen) in the treatment of acute mania: a pilot study.", BIPOLAR DISORDERS SEP 2007, vol. 9, no. 6, September 2007 (2007-09-01), pages 561 - 570, XP002453973, ISSN: 1398-5647 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9333190B2 (en) 2006-11-21 2016-05-10 Jina Pharmaceuticals, Inc. Endoxifen compositions and methods
US10376479B2 (en) 2006-11-21 2019-08-13 Jina Pharmaceuticals, Inc. Endoxifen compositions and methods
WO2010135703A3 (fr) * 2009-05-21 2011-01-13 Jina Pharmaceuticals, Inc. Procédés et compositions d'endoxifène pour traiter des maladies de mammifères
JP2012527484A (ja) * 2009-05-21 2012-11-08 ジャイナ ファーマシューティカルズ，インコーポレーテッド 哺乳動物疾患の治療におけるエンドキシフェンの方法および組成物
US20120201908A1 (en) * 2009-08-19 2012-08-09 Lunera Equities, Lllp Method of treating bipolar disorder or depression using an antiestrogen
WO2021205405A1 (fr) * 2020-04-10 2021-10-14 Jina Pharmaceuticals, Inc. Endoxifène pour le traitement d'un trouble bipolaire i
WO2021205404A1 (fr) * 2020-04-10 2021-10-14 Jina Pharmaceuticals, Inc. Endoxifen pour le traitement du trouble bipolaire de type i

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