WO2001074339A2 - Utilisation de la galantamine dans le traitement du comportement neuropsychiatrique associe a la maladie d'alzheimer - Google Patents

Utilisation de la galantamine dans le traitement du comportement neuropsychiatrique associe a la maladie d'alzheimer Download PDF

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Publication number
WO2001074339A2
WO2001074339A2 PCT/EP2001/003553 EP0103553W WO0174339A2 WO 2001074339 A2 WO2001074339 A2 WO 2001074339A2 EP 0103553 W EP0103553 W EP 0103553W WO 0174339 A2 WO0174339 A2 WO 0174339A2
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Prior art keywords
day
galantamine
dose
dosage
weeks
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Application number
PCT/EP2001/003553
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English (en)
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WO2001074339A3 (fr
Inventor
Wim Louis Julien Parys
Michael Pontecorvo
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Janssen Pharmaceutica N.V.
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
Priority to IL15206101A priority Critical patent/IL152061A0/xx
Priority to AU6584401A priority patent/AU6584401A/xx
Priority to EEP200200554A priority patent/EE200200554A/xx
Priority to KR1020027011063A priority patent/KR20020086911A/ko
Priority to SK1542-2002A priority patent/SK15422002A3/sk
Priority to AU2001265844A priority patent/AU2001265844B2/en
Priority to EP01943200A priority patent/EP1272192A2/fr
Priority to MXPA02009777A priority patent/MXPA02009777A/es
Application filed by Janssen Pharmaceutica N.V. filed Critical Janssen Pharmaceutica N.V.
Priority to PL36127201A priority patent/PL361272A1/xx
Priority to BR0109770-9A priority patent/BR0109770A/pt
Priority to JP2001572084A priority patent/JP2003528913A/ja
Priority to HU0300566A priority patent/HUP0300566A3/hu
Publication of WO2001074339A2 publication Critical patent/WO2001074339A2/fr
Priority to BG107093A priority patent/BG107093A/bg
Publication of WO2001074339A3 publication Critical patent/WO2001074339A3/fr
Priority to HR20020778A priority patent/HRP20020778A2/xx
Priority to NO20024746A priority patent/NO20024746L/no

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • 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

Definitions

  • the present invention relates to the use of an effective amount of galantamine for the production of a medicament for the treatment of neuropsychiatric behaviour associated with Alzheimer's disease.
  • Galantamine is a reversible cholinesterase inhibitor that can be isolated from a number of different plant sources, including daffodil bulbs. Galantamine interacts competitively with the enzyme, acetylcholinesterase, and demonstrates a 10 to 50 fold selectivity for acetyl vs. butyryl cholinesterase.
  • Galantamine has been used for the treatment of a number of chronic diseases, where lifelong treatment may be necessary. Galantamine has been shown to be effective in the treatment of arthritic disorders (Canadian Patent application 2,251,114); fatigue syndromes (Canadian Patent application 2,108,880); mania (Canadian Patent application 2,062,094);schizophrenia (Canadian Patent application 2,108,880); memory dysfunction, including Alzheimer's Disease (United States Patent 4,663,318); alcoholism (Canadian Patent 2,039,197); nicotine dependence (Canadian Patent application 2,153,570); disorders of attention (PCT publication WO 99/21561) and jet lag (Canadian Patent application 2,193,473).
  • arthritic disorders Canadian Patent application 2,251,114
  • fatigue syndromes Canadian Patent application 2,108,880
  • mania Canadian Patent application 2,062,094
  • schizophrenia Canadian Patent application 2,108,880
  • memory dysfunction including Alzheimer's Disease (United States Patent 4,
  • a use of of galantamine for the production of a medicament for the treatment of neuropsychiatric behaviour associated with Alzheimer's disease.
  • a method of treating neuropsychiatric behaviour associated with Alzheimer's disease by administering to a patient in need thereof a safe and effective dose of galanatamine or a pharmaceutically acceptable salt thereof.
  • FIGURE 1 shows the mean change from baseline by treatment group over time
  • FIGURE 2 shows the mean change from baseline by treatment group over time in
  • FIGURE 3 shows the cumulative percentage of patients with specified changed from baseline at Month 5 in ADAS-cog/11 scores.
  • FIGURE 4 shows the change in ADL performance from baseline over time at Month
  • FIGURE 5 shows the change in NPI score from baseline over time to Month 5.
  • the present invention relates to the use of an effective amount of galantamine for the treatment of neuropsychiatric behaviour associated with Alzheimer's disease.
  • Galantamine a tertiary alkaloid
  • Galantanus woronowi Proskurnina, N. F. and Yakoleva, A. P. 1952, Alkaloids of Galanthus woronowi. II. Isolation of a new alkaloid. (In Russian.) Zh.Obschchei Khim. (J. Gen. Chem.) 22, 1899-1902). It has also been isolated from the common snowdrop Galanthus nivalis (Boit, 1954). Galantamine is a well-known acetylcholinesterase inhibitor which is active at nicotinic receptor sites but not on muscarinic receptor sites.
  • Galantamine has been used extensively as a curare reversal agent in anaesthetic practice in Eastern bloc countries (cf. review by Paskow, 1986) and also experimentally in the
  • Galantamine has been marketed by the company Waldheim (Sanochemia protagonist) as ⁇ ivalinTM in Germany and Austria since the 1970s for indications such as facial neuralgia.
  • galantamine we include within this term galantamine itself, derivatives and salts thereof, such as halides, for example galantamine hydrobromide.
  • galantamine and derivates and salts thereof may be formulated according to convention methods of pharmacy, together where appropriate with one or more pharmaceutically acceptable carriers, excipients or diluents, as is known in the art.
  • Such formulations can take the form of tablets, capsules, solutions, or lozenges, pessaries, creams, suppositories or transdermal formulations, depending on the route of administration.
  • Galantamine has been used for the treatment of a number of chronic diseases, where lifelong treatment may be necessary. Galantamine has been shown to be effective in the treatment of arthritic disorders (Canadian Patent application 2,251,114); fatigue syndromes (Canadian Patent application 2,108,880); mania (Canadian Patent application 2,062,094); schizophrenia (Canadian Patent application 2,108,880); memory dysfunction, including Alzheimer's Disease (United States Patent 4,663,318); alcoholism (Canadian Patent 2,039,197); nicotine dependence (Canadian Patent application 2,153,570); disorders of attention (PCT publication WO 99/21561) and jet lag (Canadian Patent application 2,193,473).
  • arthritic disorders Canadian Patent application 2,251,114
  • fatigue syndromes Canadian Patent application 2,108,880
  • mania Canadian Patent application 2,062,094
  • schizophrenia Canadian Patent application 2,108,880
  • memory dysfunction including Alzheimer's Disease (United States Patent 4,663,318); alcoholism
  • a safe and effective amount of galantamine can be used for the treatment of neuropsychiatric behaviour associated with Alzheimer's disease.
  • Precise dosage rates and regimes can be determined empirically by the medical practitioner, depending on individual circumstances. For example, if the compound is delivered orally, a daily dose of about 1 mg to about 100 mg. In a further example the compound can be delivered at about 5 mg to about 50 mg per day. In yet a further example the compound can be delivered at about 16 mg to about 32 mg per day. Precise daily dosages can be selected from 16 mg, 18 mg, 24 mg or 32 mg per day. It is preferred that the daily dosage be divided into two or three equal dosages.
  • the tolerability or safety of the drug can be improved if the patient is introduced to the drug slowly over a number of weeks.
  • the patient is introduced to galantamine slowly from about 2 weeks to about 10 weeks, wherein the dose is increased over this period.
  • the patient receives a dose of about 8 mg/day for about 1 week, followed by a dose of about 16 mg/day for about 1 week, followed by a maintenance dose of about 24 mg/day thereafter.
  • the patient receives a dose of about 8 mg/day for about 1 week, followed by a dose of about 16 mg/day for about 1 week, followed by a dose of about 24 mg/day for about a week, followed by a maintenance dose of about 32 mg/day thereafter.
  • the patient receives a dose of about 8 mg day for from about 2 weeks to about 4 weeks, followed by a dose of about 16 mg/day for from about 2 weeks to about 4 weeks, followed by a maintenance dose of about 24 mg/day thereafter.
  • the patient receives a dose of about 8 mg/day for about 4 weeks, followed by a dose of about 16 mg/day for about 4 weeks, followed by a maintenance dose of about 24 mg/day thereafter.
  • the patient receives a dose of about 8 mg/day for from about 2 weeks to about 4 weeks, followed by a maintenance dose of about 16 mg/day thereafter. In one example of this embodiment the patient receives a dose of about 8 mg/day for about 4 weeks, followed by a maintenance dose of about 16 mg/day thereafter.
  • the neuropsychiatric behaviour associated with Alzheimer's Disease includes for example: delusions, hallucinations, agitation/aggression, dysphoria, anxiety, euphoria, apathy, disinhibition, irritability/lability and aberrant motor behavior.
  • Alzheimer's Disease Patients diagnosed with Alzheimer's Disease (approximately 910) were randomized to one of four treatment arms: placebo; 8 weeks titration to galantamine 24 mg/day; 4 weeks titration to galantamine 16 mg/day, or galantamine 8 mg/day, no titration needed, for five months. Patients included in this study must have been diagnosed with Alzheimer's Disease, had an Alzheimer's Disease Assessment Scale (Rosen, W.G. et al., Amer. J. Psychiatry, 141: 1356- 1364, 1984) cognitive portion (ADAS-cog-11) score of at least 18 and had a history of cognitive decline that was gradual at the onset and progressive over a period of at least six months.
  • Alzheimer's Disease Assessment Scale Rosen, W.G. et al., Amer. J. Psychiatry, 141: 1356- 1364, 1984
  • cognitive portion ADAS-cog-11
  • Subjects in the Placebo group received 21 weeks (5 months) of placebo medication.
  • Subjects in group Gal 24 received 4 weeks of 8 mg/day galantamine (4 mg, twice daily (bid)), 4 weeks of 16-mg/day galantamine (8 mg, bid) and 13 weeks of 24 mg/day galantamine (12 mg, bid).
  • Subjects in group Gal 16 received 4 weeks of 8 mg/day galantamine (4 mg, bid) and 17 weeks of 16-mg/day galantamine (8 mg, bid).
  • Subjects in group Gal 8 received 8 mg/day (4 mg, bid) immediately upon randomization and continued on that dose for 21 weeks.
  • MMSE Mini-Mental State Examination
  • the ADAS consists of two parts — a cognitive subscale and a behavioral subscale.
  • the behavioral subscale was not be used in this study.
  • ADAS-cog-13 The Concentration and Distractibility item, originally part of the behavioral subscale, was performed and a Delayed Word Recall test (delayed recall of the word recall items) was added to give additional information regarding cognitive status.
  • the expanded 13 item ADAS (ADAS-cog 13) was a secondary variable.
  • ADAS advanced cognitive system
  • ADAS rater was not involved in the treatment of the subject and should have no access to AE (adverse event) reporting.
  • the ADAS was performed at visits 1, 2, 3, 4 and 5 (screening, baseline, week 4, week
  • the CIBIC-plus score was a second primary variable.
  • An independent, experienced and properly trained clinician provided a global impression of the subject's deterioration or improvement over the course of the trial, based on separate interviews with the subject and caregivers. If helpful, the CIBIC rater audiotaped or videotaped the baseline interview for future reference.
  • Change from baseline was rated on an 7 point scale, where 1 indicates markedly improved, 4 indicates no change and 7 indicates markedly worse.
  • the CIBIC-plus was performed at visit 2, 3, 4, and 5 (baseline, week 4, week 13, and month 5 or upon early discontinuation of trial medication intake). Only a trained CIBIC rater performed the test.
  • the MMSE is a very brief test of cognitive functions including orientation to time and place, instantaneous recall, short-term memory, and ability to perform serial subtractions or reverse spelling, constructional capacities and the use of language.
  • the MMSE score was derived from the sum of the points assigned to each completed task. A total possible score is 30. The MMSE will be performed at visit 1 (screening).
  • the ADCS/ADL scale is a 23-item informant-based assessment scale measuring widely applicable daily activities appropriate for patients in the mild to moderate category of Alzheimer's Disease.
  • the 23 items were selected for measurement from the larger set of 45 items studied by Galasko et al (Alzheimer Disease and Associated Disorders, Nol
  • NPI Neuronal Inventory
  • the NPI 120). The NPI was performed at visits 2, 3, 4 and 5 (baseline, week 4, week 13, and month 5 or upon early discontinuation of trial medication).
  • ANON A a two-way analysis of variance model with treatment and investigator as factors were used to compare the treatment groups for the change from baseline data. The interaction between treatment and investigator was examined. The impact of the baseline score on change from baseline was evaluated. If the baseline score was found tojbe a relevant predictor (p ⁇ 10), an analysis of co variance model (A ⁇ CONA) was used to assess the treatment effects and the interaction between treatment and baseline score was examined. If the parametric methods were deemed inappropriate (normality assumption violated), nonparametric methods such as two-way A ⁇ ONA on ranked data, Nan Elteren test, controlling for investigator, was used. Following ANONA, Fisher's LSD procedure was used for pairwise comparisons between each galanthamine group and the placebo group. A linear contrast on the main effect for treatment was used to test the dose response relationship.
  • Nan Elteren test controlling for investigator was used for the between group comparison.
  • nominal data e.g., events rates
  • Cochran-Mantel-Haenszel test for general association controlling for investigator was used.
  • a linear contrast on the proportion of patients that stay the same or improve was used to test for increasing response with increasing dose.
  • the number of patients randomized among the four treatment groups was 978.
  • the total number of patients completing this trail was high (approximately 80%) with a relatively even rate of discontinuation due to adverse events was relatively infrequent and evenly distributed among all treatment groups (see Table 2).
  • An additional secondary indication captures overall changes in Activities of daily Living (ADL) performances as measured by the Alzheimer's Disease Cooperative Study Activities of Daily Living (ACDS/ADL) scale. As mentioned above this scale is comprised of 23 items that have been tested and validated in patients with mild to moderately severe Alzheimer's disease.
  • Galantamine treatment with 16 or 24 mg/day for 5 months was statistically more effective in maintaining the ADL total score at baseline levels than treatment with placebo or 8 mg/day of galantamine (Table 6).
  • the dose-related effect of galantamine treatment is apparent in Figure 4 that shows change of total ADL score over time.

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Abstract

Selon cette invention, la galantamine a été utilisée dans le traitement d'un certain nombre de maladies chroniques. Il s'est avéré que la galantamine est sûre et efficace dans le traitement de la maladie d'Alzheimer. Les troubles neuropsychiatriques sont souvent associés à la maladie d'Alzheimer. Selon l'invention, il est démontré que la galantamine est aussi efficace pour réduire ou pour stabiliser l'incidence du comportement neuropsychiatrique observé chez les patients souffrant de cette maladie.
PCT/EP2001/003553 2000-04-03 2001-03-28 Utilisation de la galantamine dans le traitement du comportement neuropsychiatrique associe a la maladie d'alzheimer WO2001074339A2 (fr)

Priority Applications (15)

Application Number Priority Date Filing Date Title
PL36127201A PL361272A1 (en) 2000-04-03 2001-03-28 A use of galantamine for the treatment of neuropsychiatric behaviour associated with alzheimer's disease
AU6584401A AU6584401A (en) 2000-04-03 2001-03-28 A use of galantamine for the treatment of neuropsychiatric behaviour associated with alzheimer's disease
BR0109770-9A BR0109770A (pt) 2000-04-03 2001-03-28 Uso de galantamina para o tratamento do comportamento neuropsiquiátrico associado com a doença de alzheimer
SK1542-2002A SK15422002A3 (sk) 2000-04-03 2001-03-28 Použitie galantamínu na liečenie neuropsychických porúch spojených s Alzheimerovou chorobou
AU2001265844A AU2001265844B2 (en) 2000-04-03 2001-03-28 A use of galantamine for the treatment of neuropsychiatric behaviour associated with alzheimer's disease
EP01943200A EP1272192A2 (fr) 2000-04-03 2001-03-28 Utilisation de la galantamine dans le traitement du comportement neuropsychiatrique associe a la maladie d'alzheimer
MXPA02009777A MXPA02009777A (es) 2000-04-03 2001-03-28 Uso de galantamina para el tratamiento de la conducta neurosiquiatrica asociada con el padecimiento de alzheimer.
IL15206101A IL152061A0 (en) 2000-04-03 2001-03-28 A use of galantamine for the treatment of neuropsychiatric behaviour associated with alzheimer's disease
EEP200200554A EE200200554A (et) 2000-04-03 2001-03-28 Galantamiini või selle farmatseutiliselt sobiva soola kasutamine
KR1020027011063A KR20020086911A (ko) 2000-04-03 2001-03-28 알츠하이머 질환과 관련된 신경정신적 행동의 치료를 위한갈란타민의 용도
JP2001572084A JP2003528913A (ja) 2000-04-03 2001-03-28 アルツハイマー病に伴う神経精神的行動の処置のためのガランタミンの使用
HU0300566A HUP0300566A3 (en) 2000-04-03 2001-03-28 A use of galantamine for the treatment of neuropsychiatric behaviour associated with alzheimer's disease
BG107093A BG107093A (bg) 2000-04-03 2002-09-12 Приложение на галантамин за лечение на невропсихиатрични разстройства в поведението, свързани с болестта на алцхаймер
HR20020778A HRP20020778A2 (en) 2000-04-03 2002-09-26 A use of galantamine for the treatment of neuropsychiatric behaviour associated with alzheimer's disease
NO20024746A NO20024746L (no) 2000-04-03 2002-10-02 Anvendelse av galantamin ved behandling av nevropsykiatrisk oppförsel assosiert med Alzheimers sykdom

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US19425900P 2000-04-03 2000-04-03
US60/194,259 2000-04-03

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WO2001074339A2 true WO2001074339A2 (fr) 2001-10-11
WO2001074339A3 WO2001074339A3 (fr) 2002-09-12

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EP (1) EP1272192A2 (fr)
JP (1) JP2003528913A (fr)
KR (1) KR20020086911A (fr)
CN (1) CN1430514A (fr)
AU (2) AU2001265844B2 (fr)
BG (1) BG107093A (fr)
BR (1) BR0109770A (fr)
CA (1) CA2310926C (fr)
CZ (1) CZ20023543A3 (fr)
EE (1) EE200200554A (fr)
HR (1) HRP20020778A2 (fr)
HU (1) HUP0300566A3 (fr)
IL (1) IL152061A0 (fr)
MX (1) MXPA02009777A (fr)
NO (1) NO20024746L (fr)
PL (1) PL361272A1 (fr)
RU (1) RU2002129298A (fr)
SK (1) SK15422002A3 (fr)
WO (1) WO2001074339A2 (fr)
ZA (1) ZA200207935B (fr)

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EP1453510A2 (fr) * 2001-11-13 2004-09-08 Be Able, LLC Chimiotherapie d'equilibrage des neurotransmetteurs
WO2005014002A1 (fr) * 2003-07-25 2005-02-17 F. Hoffmann-La Roche Ag Combinaison d'antagoniste mglur2 et d'inhibiteur ache destinee au traitement de troubles neurologiques aigus et/ou chroniques
JP2007509031A (ja) * 2003-08-19 2007-04-12 ヤンセン ファーマスーティカ エヌ．ファウ． ガランタミンの口腔用製剤およびその使用
WO2013160728A1 (fr) 2012-04-26 2013-10-31 Alma Mater Studiorum - Universita' Di Bologna Composés à double ciblage pour le traitement de la maladie d'alzheimer
EP2271218B1 (fr) 2008-03-27 2017-05-24 Chase Pharmaceuticals Corporation Utilisation et composition permettant de traiter la démence

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BG66818B1 (bg) * 2013-03-07 2019-01-31 Berbee Beheer B. V. Състав на екстракт от hippeastrum papilio за производство на лекарствени средства и хранителни добавки
WO2016187339A1 (fr) * 2015-05-18 2016-11-24 Synaptec Development Llc Clairance de galantamine d'amyloides
WO2023036105A1 (fr) * 2021-09-09 2023-03-16 上海日馨医药科技股份有限公司 Méthode de traitement d'une maladie neurodégénérative

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EP1453510A4 (fr) * 2001-11-13 2005-03-16 Be Able Llc Chimiotherapie d'equilibrage des neurotransmetteurs
JP2005511615A (ja) * 2001-11-13 2005-04-28 ビー エイブル エルエルシー 神経伝達物質均衡の化学療法
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JP2007509031A (ja) * 2003-08-19 2007-04-12 ヤンセン ファーマスーティカ エヌ．ファウ． ガランタミンの口腔用製剤およびその使用
EP2271218B1 (fr) 2008-03-27 2017-05-24 Chase Pharmaceuticals Corporation Utilisation et composition permettant de traiter la démence
WO2013160728A1 (fr) 2012-04-26 2013-10-31 Alma Mater Studiorum - Universita' Di Bologna Composés à double ciblage pour le traitement de la maladie d'alzheimer

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ZA200207935B (en) 2004-01-30
EP1272192A2 (fr) 2003-01-08
NO20024746L (no) 2002-11-28
MXPA02009777A (es) 2003-03-27
KR20020086911A (ko) 2002-11-20
WO2001074339A3 (fr) 2002-09-12
RU2002129298A (ru) 2004-03-27
AU2001265844B2 (en) 2005-04-14
CN1430514A (zh) 2003-07-16
HRP20020778A2 (en) 2004-04-30
PL361272A1 (en) 2004-10-04
NO20024746D0 (no) 2002-10-02
SK15422002A3 (sk) 2003-04-01
HUP0300566A3 (en) 2004-10-28
BR0109770A (pt) 2003-02-04
BG107093A (bg) 2003-06-30
JP2003528913A (ja) 2003-09-30
CA2310926C (fr) 2002-10-15
IL152061A0 (en) 2003-05-29
EE200200554A (et) 2004-04-15
CZ20023543A3 (cs) 2003-03-12
CA2310926A1 (fr) 2000-10-04
AU6584401A (en) 2001-10-15
HUP0300566A2 (hu) 2003-06-28

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