SK15422002A3 - A use of galantamine for the treatment of neuropsychiatric behaviour associated with Alzheimer's disease - Google Patents

Abstract

Galantamine has been used in the treatment of a number of chronic diseases. Galantamine has been found to be safe and effective in the treatment of Alzheimer's disease. Neuropsychiatric disorders are often associated with Alzheimer's disease. It is demonstrated that galantamine is also effective in reducing or stabilizing the incidence of neuropsychiatric behaviour seen in Alzheimer's patients.

Description

USE OF GALANTAMINE IN THE TREATMENT OF NEUROPSYCHIATRIC BEHAVIOR OF ALZHEIMER DISEASE

The present invention relates to the use of an effective amount of galantamine for the manufacture of a medicament for the treatment of neuropsychiatric behavior associated with Alzheimer's disease.

BACKGROUND OF THE INVENTION

Galantamine is a reversible cholinesterase inhibitor that can be isolated from a variety of plant sources, including narcissus bulbs. Galantamine interacts competitively with the enzyme acetylcholine esterase, and exhibits 10 to 50 times higher selectivity for acetyl than for butyrylcholine esterase.

Galantamine has been used to treat a number of chronic diseases where lifelong treatment may be required. 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 disorders, including Alzheimer's disease (U.S. Patent 4,663,318); Alcoholism (Canadian Patent 2,039,197); nicotine dependence (Canadian patent application 2,153,570); Attention Deficit Disorders (PCT Publication WO 99/21561) and Desynchronisers (Canadian Patent Application 2,193,473).

However, none of these studies has shown utility

01-2218-02-Ce Galantamine for the treatment of neuropsychiatric behavior associated with Alzheimer's disease.

DESCRIPTION OF THE INVENTION

Accordingly, according to the present invention there is provided the use of galantamine for the manufacture of a medicament for the treatment of neuropsychiatric behavior associated with Alzheimer's disease.

In another embodiment, provided herein is a method of treating neuropsychiatric behavior associated with Alzheimer's disease by administering a safe and effective dose of galantamine or a pharmaceutically acceptable salt thereof to a patient in need thereof.

BRIEF DESCRIPTION OF THE CHART

These and other features of the invention will be much clearer from the following description, in which a reference is made by the accompanying drawings, wherein:

FIGURE 1 shows the mean change from baseline for treatment group over time in ADAS-cog / 11 (observed case)

FIGURE 2 shows the mean change from baseline for treatment group over time in CIBIS-plus (observed case)

FIGURE 3 shows the increasing percentage of patients with this change from baseline at month 5 in the ADAS-cog / 11 score

FIGURE 4 shows changes in ADL from baseline over month 5

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FIGURE 5 shows the change in NPI score from baseline in month 5.

DESCRIPTION OF THE PREFERRED FORM

The present invention relates to the use of an effective amount of galantamine for the treatment of neuropsychiatric behavior associated with Alzheimer's disease.

Galantamine is a tertiary alkaloid that has been isolated from Galantanus woronowi snowdrop bulbs (Proskurnina, N.F. and Yakoleva, A.P. 1952, Alkaloids of Galantanus woronowi II.

Isolation of a new alkaloid: (In Russian.) Zh.Obschchei.Khim.

(J. Gen. Chem.) 22, 1899-1902. It was also isolated from the common snowdrop Galanthus nivalis (Boit, 1954). Galantamine is a well-known acetylcholine esterase inhibitor that is active at nicotinic receptor sites but not at muscarinic receptor sites. It is able to cross the human blood-brain barrier and exhibits no serious side effects at therapeutically effective doses.

Galantamine has been frequently used as an anti-curate antidote in anesthesia methods in Eastern Bloc countries (review article Paskow, 1986) and experimentally also in the West (Bretagne and Valetta, 1965; Wislicki, 1967; Consanitis 1971).

Galantamine was marketed by Waldheim (Sanochemia Gruppe) in Germany and Austria as Nivalin ™ in 1970 for indications such as renal neuralgia.

In the present invention, where galantamine is mentioned, we include galantamine itself, derivatives and salts thereof such as halides such as galantamine hydrobromide.

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For the purposes of the present invention, galantamine and its derivatives may be prepared by conventional methods in pharmacy, together with one or more appropriate pharmaceutically acceptable carriers, excipients or diluents known in the art.

Thus prepared may be in the form of tablets, capsules, solution or lozenges, pessaries, creams, suppositories or transdermal preparations, depending on the route of administration.

Galantamine has been used to treat a number of chronic diseases where lifelong treatment may be required. 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 disorders, including Alzheimer's disease (U.S. Patent 4,663,318); Alcoholism (Canadian Patent 2,039,197); nicotine dependence (Canadian patent application 2,153,570); attention deficit disorders (PCT publication WO 99/21561) and desynchronism (Canadian patent application 2,193,473).

According to the present invention, a safe and effective amount of galantamine can be used in the treatment of neuropsychiatric behavior associated with Alzheimer's disease.

The frequency and dosage regimen must be determined empirically by the practitioner, depending on the individual situation. For example, when the compound is administered orally, the daily dose is from about 1 mg to about 100 mg. In another example, the compound may be administered from about 5 mg to about 50 mg per

01-2218-02-Ce day. And in yet another example, the compound may be administered from about 16 mg to about 32 mg per day. The exact daily doses may be selected from 16 mg, 18 mg, 24 mg or 32 mg per day. It is preferred that the daily dose be divided into two or three equal doses.

In one embodiment of the present invention, it has been found that tolerance or safety of a drug can be improved if the patient is exposed to the drug slowly over a number of weeks.

In one embodiment of the present invention, the patient is exposed to galantamine slowly from about two weeks to about ten weeks, where the dose is increased during this period.

In one embodiment of the present invention, the patient receives a dose of about 8 mg / day for about one week, followed by a dose of about 16 mg / day for one week, followed by a sustained dose of about 24 mg / day.

In one embodiment of the present invention, the patient receives a dose of about 8 mg / day for about one week followed by a dose of about 16 mg / day for about one week, followed by a dose of about 24 mg / day for about one week, followed by a sustained dose. about 32 mg / day.

In one embodiment of the present invention, the patient receives a dose of about 8 mg / day for about two weeks to about 4 weeks, followed by a dose of about 16 mg / day for about two weeks to about 4 weeks, followed by a sustained dose of about 24 mg / day. day.

In one example of this form, the patient receives a dose of about 8 mg / day for about 4 weeks, followed by

01-2218-02-Ce dose of about 16 mg / day for about 4 weeks, followed by a maintenance dose of about 24 mg / day.

In another embodiment of the present invention, the patient receives a dose of about 8 mg / day for about two weeks to about 4 weeks, followed by a sustained dose of about 16 mg / day. In one example of this form, the patient receives a dose of about 8 mg / day for about 4 weeks, followed by a sustained dose of about 16 mg / day.

According to the present invention, the neuropsychiatric behavior associated with Alzheimer's disease includes, for example: nausea, hallucinations, outrage / aggression, annoyance, anxiety, euphoria, apathy, disinhibition, irritability / lability, motor behavior disorders.

The present invention is illustrated by the following example, which should not be construed as limiting.

EXAMPLES

Patients diagnosed with Alzheimer's disease (approximately 910) were randomly assigned to one of four treatment groups: placebo; 8 weeks of galantamine 24 mg / day; 4 weeks of galantamine 16 mg / day or galantamine 8 mg / day, and no use for five months. Patients involved in this study had to be diagnosed for Alzheimer's disease, had an Alzheimer's disease rating scale (Rosen, WG et al., Amer. J. Psychiatry, 141: 13561364, 1984) with a cognitive dose score (ADAS-cog-11) of at least 18 and had a history of cognitive decline that was initially gradual and progressive for at least six months.

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The titration programs for the different treatment groups are as follows:

Subjects in the placebo group received placebo for 21 weeks (5 months). Subjects in the Gal 24 group received 4 weeks 8 mg / day, galantamine (4 mg, twice daily, (fraction)), 4 weeks 16 mg / day galantamine (8 mg fraction), and 13 weeks of 24 mg / day galantamine (12- mg share). Subjects in the Gal 16 group were taken 4 weeks 8 mg / day of galantamine. (4 mg fraction), and 17 weeks 16 mg / day galantamine (8 mg fraction). Subjects in the Gal 8 group received 8 mg / day (4 mg fraction) immediately after randomization, and continued at this dose for 21 weeks.

All patients were monitored, closely monitored and evaluated during the study, four weeks, three months and five months after the start of the study.

The primary effect was changes from baseline ADAScog / 11 and CIBIC-plus score (Clinician's Interview Based Impression of Change Plus Family Input) at the fifth month. These two tests together with MMSE (Mini-Mental State Examination), which was conducted in the investigative phase, are discussed below.

ADAS consists of two parts - cognitive function and behavioral function. Behavioral function was not used in this study. The cognitive function, ADAS-cogll, consists of memory tests of word recall and word recognition, object and finger naming, control, design practice, conceptual practice, orientation, memorizing test instructions, spoken language proficiency, spoken language comprehension and difficulty finding words was the primary variable in this study.

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In addition to the above-mentioned deletion of the ADAS-cog11 items, two additional ADAS items were evaluated: the focus and distracted item, which was originally the behavioral function part, was added, and a delayed word recall test was added (the delayed item entry).

I recall the word) for further information regarding the cognitive state. The extended 13 ADAS item (ADAS-cog13) was a secondary variable.

To reduce variability due to daily fluctuations in the cognitive situation, ADAS was always performed at the same time of day, preferably before noon. The test was performed only by an experienced ADAS appraiser. Ideally, the assessor's ADAS has not been involved in the subject's treatment and should not have access to the AE (adverse event) report.

ADAS was performed during visits 1, 2, 3, 4 and 5 (examination, baseline, week 4, week 13 and 5 months, or after the early drug test). Two parallel word lists, list A and list B, were used to recall and recognize word. List A was used at visits 1 and 3, and list B at visits 2, 4, and 5 or after the drug administration test was terminated early. For practical reasons, words for word recognition have been shown only once. A total score of 11 cognitive items of the original cognitive ADAS function (ADAS-cog / 11, range: -0-70) was recorded.

The CIBIC-plus score was the second primary variable. An independent, experienced and appropriately trained clinician provided a comprehensive assessment of the subject's deterioration or improvement over the course of treatment, based on separate interviews with the subject and caregivers. If this can help for future use, the CIBIC appraiser records the baseline interview to audio or video cassettes.

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The change from baseline was assessed by a 7 point scale where 1 indicates a significant improvement, 4 indicates no change and 7 indicates a significant deterioration. CIBIC-plus was performed at visits 2, 3, 4, and 5 (baseline; week 4, week 13, and 5 months, or after the drug administration test was terminated early). The test was performed only by a trained CIBIC appraiser.

MMSE is a very short test of cognitive functions, including orientation in time and space, immediate recall, short-term memory, and the ability to convert multiple counts or spelling backwards, constructive ability and language use. The MMSE score was derived from the total number of points assigned to each complete task. The total possible score is 30. MMSE will be transferred at Visit 1 (Examination).

Secondary efficacy variables include the ADAS-cog / 11 and ADCS / ADL scale. The ADCS / ADL test is discussed below:

The ADCS / ADL scale is a 23-item, resource-dependent assessment scale that extensively measures relevant daily activities in patients in the light to moderate Alzheimer's category. 23 items were selected for measurement from a large set of 45 items that were studied by Galask et al. (Alzheimer Disease and Associated Disorders, Vol 11, Supp. 2, 1997). These individual items were rated from 0-3 to 07, depending on the question, with a possible overall score of 78. A higher score indicates a higher patient performance.

The items and ratings were as follows:

Dining (0-3)

Walking (0-3)

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WC Visit (0-3)

Swimming (0-3)

Appearance care (0-3)

Dressing up

Choice of clothing (0-3)

Physical Design (0-4)

Phone (0-5)

Television (0-3)

Conversation (0-3)

Dishwashing (0-3)

Procurement of personal belongings (0-3)

Beverage Procurement (0-3)

Food preparation or snack (0-4)

Garbage collection (0-3)

Traveling Away (0-4)

Shopping (0-4)

Meeting Appointments (0-3)

Ability to Stay Alone (0-3)

Current Events (0-3)

Reading (0-2)

Writing (0-3)

Hobbies (0-3)

Home Appliances (0-4)

Neuropsychiatric behavior was followed by a test known as NPI (The Neuropsychiatric Inventory (Cummings, JL et al., Neurology, 94: 2308-2314, 1994). NPI includes 10 areas of behavior described in Alzheimer's patients: mischief, hallucinations, indignation). aggression, anxiety, anxiety, euphoria, apathy, disinhibition, irritability / lability, motor behavior disorders Abnormal behavior may be present or not for each area (score 0). seriousness based on responses to a set of subqueries concerning

01-2218-02-Ce is behavior related to that area. The severity was rated one to three as easy, moderate and pronounced.

The frequency was rated one to four as occasional, repeated, frequent, and very common. Frequency and severity scores (maximum score = 12) were calculated for each region. Total NPI was calculated as the sum of frequency and severity results (maximum score = 120). NPIs were performed at visits 2, 3, 4, and 5 (baseline, week 4, week 13, and month 5, or after the early drug test).

All data were compared between the placebo, galantamine 8 mg / day, 16 mg / day, and 24 mg / day treatment groups.

The treatment groups were compared with each other (with a particular focus on placebo differences) at each scheduled time interval and for each endpoint addition schedule. These comparisons will be based on a change in the scores of efficacy parameters compared to baseline (e.g. ADAS-cog / 11) and initially evaluated for efficacy parameters without baseline (e.g. CIBIC-plus).

For continuous data, a two-way treatment difference analysis (ANOVA) model was used and researchers were used as agents to compare the change in baseline values in treatment groups. The relationship between treatment and researcher was investigated. The effect of baseline scores on the change from baseline was evaluated. If baseline scores were found to be a serious indication (p <10), a covariance model analysis (ANCOVA) was used to achieve a therapeutic effect and the relationship between treatment and baseline scores was investigated. If the parametric methods seemed to be inappropriate (breach of the presumption of normality) were used as a control for the nonparametric method investigator; as two way ANOVA on

01-2218-02-Če Associated Data, Van Elteren Test. Subsequently, ANOVA, Fisher's LSD procedure was used for pairwise comparisons between each galantamine group and placebo group. A linear difference in the main treatment effect was used to test the dose-response relationship.

For rank categorical variables such as the CIBIC-plus score, the researcher used the Van Elteren test for cross-group comparisons. For nominal values (eg occurrence of cases), the Cochran-Mantel-Haenszel test was used for the general association for the investigator. A linear difference in the proportion of patients who remained the same or improved was used to test for increasing response with increasing dose.

If a significant proportion of subjects were terminated prematurely, further analyzes were performed to assess the impact on results. In addition, a visit analysis method was used to evaluate the impact of treatment over time.

The safety of the drug was also monitored during treatment. During each visit and at the end of all efficacy tests, blood samples were taken for biochemical and haematological examinations and urine samples were taken at random for urine examination. Systolic and diastolic blood pressure were measured at the sitting position, heart rate and vital signs were recorded at each visit.

The patient's demographic and baseline characteristics were well balanced across all treatment groups (Table 1). The underlying cognitive behavior of these Alzheimer's patients was from mild to moderate, as measured by MMSE and ADAScog / 11 scores of approximately 18 and 28 to 20, respectively.

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Table 1: Demographic and basic characteristics

characteristic test and patients placebo GAL 8 mg GAL 16 mg GAL 24 mg Total number patients 286 140 279 273 Finished: N (%) 240 (84%) 108 (77%) 219 (78%) 212 (78%) sex Man A woman 107 (38%) 178 (63%) 49 (36%) 90 (64%) 105 (38%) 174 (62%) 90 (33%) 183 (67%) Age: (years) Average (SE) Median (min-max) 77.1 (0, 46) 77 (53-100) 76.0 (0, 61) 76 (52-91) 76.3 (0.49) 77 (51-94) 77.7 (0, 43) 77 (57-95) race Black White Hispanic oriental other 13 267 (93%) 3 3 0 5 132 (94%) 3 0 0 12 260 (93%) 5 1 1 14 249 (91%) 4 3 3 Total MMSE: Average (SE) Median (min-max) 17.7 (0.21) 19 (10-22) 18.0 (0.30) 19 (10-22) 17.8 (0.21) 19 (10-22) 17.7 (0.23) 19 (10-22) Default value ADAS-cog / 11 Average (SE) Median (min-max) 29.4 (0, 63) 27 (11-61) 27.8 (0, 94) 26 (11-62) 29.4 (0, 66) 28 (11-62) 29.0 (0.67) 27 (10-54)

The number of patients randomized to four treatment groups was 978. The total number of patients who completed this test was high (approximately 80%), with a relatively low incidence of discontinuation due to adverse events that were uncommon and

01-2218-02-Ce evenly distributed among all treatment groups (see Table 2).

Table 2: Discontinuation of experimental treatment

Reasons for interruption treatment placebo GAL 8mg / day GAL 16mg / day GAL 24mg / day Total number of patients 286 140 279 273 are alternatively completed: N (%) 240 (83%) 107 (77%) 219 (78%) 213 (78%) Total number interruptions (DC- discontinued): N 46 (16%) 32 (24%) 60 (21%) 62 (21%) DC due to undesirable effect 20 (6%) 9 (6%) 19 (7%) 27 (10%) DC due to ineffectiveness 0 1 (1%) 0 2 (1%) DC for other reasons ^a 23 (8%) 18 (14%) 29 (10%) 20 (6%) DC due to inability continue 0 0 4 (1%) 2 (1%) DC for reasons poor compliance 3 (1%) 4 (3%) 7 (4%) 10 (4%) DC due to cancellation approval 0 0 1 (0.4%) 0

/ ^a ; Most interruptions for other reasons were due to withdrawal of consent.

In this study, two primary efficacy targets were broadly used international standards; change in ADAS-cog / II score at month 5 compared to baseline and CIBIC-plus score at month 5.

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Table 3 and Figure 1 show a statistically significant treatment effect for the galantamine treatment group at doses of 16 and 24 mg / day compared to placebo for ADAS-cog / 11. The results of the LOCF data analysis (the last observation carried-forward) corresponded to the results based on the recorded data. The group treated with galantamine at 8 mg / day was significantly different from placebo for the reported cases but not for LOCF. Galantamine at 24 mg / day was not shown to be significantly more effective than 16 mg / day. However, the duration of exposure to the target dose was 1 month (two months for 24 mg / day versus three months for 16 mg / day) between the two groups.

Table 3: Changes from baseline in ADAS-cog / 11 at month 5

placebo GAL 8 mg GAL 16 mg GAL 24 mg Month 5: (seen cases) n = 225 n = 101 n = 208 n = 211 Average (SE) 1.8 (0.43) 0.1 (0.58) * -1.5 (0.40) ★ ★ ★ ★ -1.8 (0.44) * * * + Month 5: n = 225 n = 126 n = 253 n = 253 Average (SE) 1.7 (0.39) 0.4 (0.52) 4 -1.4 (0.35) * * -1.4 (0.39)

Lower scores mean better. P-values based on two-way ANOVA model.

Significantly more effective than placebo: *: p 0.05; **: p <

0.01; ***: p 0.001;

near: 4: 0.05 <p -values <0.10.

Significantly more effective than 8 mg / day: ⁺ : p £ 0.05: p: p

0, 01.

To estimate CIBIC-plus at month 5, there were percentages of patients

01-2218-02-Ce with improved or unchanged score significantly higher for galantamine treatment at 16 or 24 mg / day compared to placebo or galantamine at 8 mg / day (Table 4). After 5 months of treatment, 64% -68% of galantamine patients at 24 or 16 mg / day showed improvement or unchanged from baseline compared to 47% to 51% of placebo or galantamine patients by similar results. A noticeable increase in the percentage of patients who showed improvement or no change in CIBIC-plus (Figure 2). 16 mg / day. Dose-dependency analysis of LOCF data was here

Table 4: CIBIC-plus at month 5 for improved or unchanged scores

placebo GAL 8 mg GAL 16 mg GAL 24 mg Month 5: (seen cases) n = 237 n = 10 6 n = 212 n = 212 Improvement / no change 112 (47%) 54 (51%) 143 (68%) *** ⁺ 136 (64%) *** Month 5: (LOCF) n = 263 n = 128 n = 255 n = 253 Improvement / no change n (%) 128 (50%) 68 (53%) 169 (66%) *** ⁺ 162 (64%) *** = ¥

P - value from Van Elteren test on 7 point scale.

Significantly more effective than placebo: * p ≥ 0.05; **: p

0, 01; ***: p 0.001;

• Significantly more effective than 8 mg / day: ⁺ : p 0.05: / =: p

0.01.

At month 5, significantly more patients responded with unchanged or improved scores with galantamine 16 and 24 mg / day compared to placebo or galantamine 8 mg / day. Patients responding in ADAS-cog / 11 changes since

01-2218-02-Ce baseline of 7 or more points was 15.9% in the 16 mg / day group and 22.3% in the 24 mg / day group compared to the placebo group (7.6%). Overall, there was a higher cumulative percentage of galantamine-treated patients who responded with minimal improvement of any significance compared to placebo (Figure 3).

Table 5: Analysis of respondents based on change in ADAS-cog / 11 score from baseline in month 5

Definition of respondent placebo GAL 8 mg GAL 16 mg GAL 24 mg n = 225 n = 101 n = 2 08 n = 211 Change £ 0 points n (%) 94 (41.8) 47 (45, 5) 136 (66, 4) • Jc · Ά · 137 (64.9) * Change £ -4 points n (%) 44 (18, 6) 26 (25, 7) 74 (36, 6) * * * 4 78 (37.0) *** + £ -7 points change n (%) 17 (7.6) 14 (13, 9) 33 (15.9) Jr Jr 47 (22) * * * φφ Change £ -10 points n (%) 8 (3.6) 6 (5.9) 15 (7.2) 22 (10.4) Jr Jr

P-values on the CMH test • Significantly higher percentage of respondents than placebo: *: p £ 0.05; **: p ≥ 0.01; ***: p £ 0.001;

near: 4: 0.05 <p -values <0.10.

Significantly higher percentage of respondents than 8 mg / day: ⁺ : p £ 0.05; # =: p £ 0.01;

near: 4: 0.05 <p -values <0.10.

• The difference between 16 and 24 mg / day approaches 4: 0.05 <p -values <0.10.

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Other secondary grades captured overall changes in ADL (Activities of Daily Living) performance as measured by the Alzheimer's Disease Cooperatiye Study Activities of Daily Living (ADL) scale. As noted above, this scale includes 23 items that have been tested and confirmed in patients with Alzheimer's disease from mild to moderate disability.

Treatment with galantamine 16 or 24 mg / day for 5 months was statistically more effective at keeping the overall ADL score at baseline than placebo or galantamine 8 mg / day (Table 6). The effect in relation to the dose of galantamine is apparent from Figure 4, which shows the change in total ADL score over time.

Table 6: Change in total ADL score from baseline in month 5

placebo GAL 8 mg GAL 16 mg GAL 24 mg Month 5: (seen cases) n = 235 n = 10 6 n = 212 n = 212 Average (SE) -4.0 - -0, 5 (0.55) -1.6 (0.61) (0.59) 3.1 (0.91) *** + Jr Jr Month 5: (LOCF) n = 262 n = 129 n = 255 n = 253 Average (SE) -3, 8 -3.2 -0.7 (0.05) -1.5 (0.56) (0.55) (0.79) Jr Jr Je -yA Jr Jr

Higher scores mean better. P-values based on a two-way ANOVA model.

• Significantly more effective than placebo: **: p 0,01 0.01; ***: p 0,01

0,001;

01-2218-02-Ce • Significantly more effective than 8 mg / day: ⁺ : p £ 0.05: p

0, 01.

A statistically significant (p <0.05) benefit was observed in the change in total NPI score at month 5 relative to baseline values for 16 and 24 mg / day galantamine compared to worsening with placebo or 8 mg / day galanatamine (Table 7 and Figure 5). ). The increase in scores indicated a worsening of the condition.

Thus, maintenance of neuropsychiatric behavior was observed with galantamine 16 and 24 mg / day.

Table 7: Change in overall NPI score from baseline in month 5

placebo GAL 8 mg GAL 16 mg GAL 24 mg Month 5: (seen cases) n = 234 n = 106 n = 211 n = 212 Average (SE) -2.3 (0.74) -2.3 (1.121) -0.1 (0.76) * -0.1 (0, 86) * Month 5 (LOCF) n = 262 n = 129 n = 255 n = 253 Average (SE) -2.5 (0.68) -2.3 (1.00) -0.1 (1.00) * -0.0 (0.56) ★

Higher scores mean better. P two way ANOVA model.

• Significantly more effective than placebo:

values are based on *: p 0.05;

The most common side effects were evenly distributed

01-2218-02-Če in treatment groups except for cases associated with cholinomimetic agents (Table 8). Of these coherent cases, nausea, vomiting and anorexia have occurred with a relatively low incidence.

Table 8: Occurrence of the most frequent (^ 5%) side effects: number (%) of patients

side symptoms (priority title) placebo GAL 8 mg GAL 16 mg GAL 24 mg are alternatively all patients 286 140 279 273 nausea 13 (4.5%) 8 (5.7%) 37 (13.3%) 45 (16.5%) sickness 4 (1.4%) 5 (3.6%) 17 (6.1%) 27 (9.9%) Loss of appetite 9 (3.1%) 8 (5.7%) 18 (6.5%) 24 (8.8%) excitability 27 (9.4%) 21 (15.0%) 28 (11, 0%) 22 (8.1%) depression 15 (5.2%) 4 (2.9%) 24 (8.6%) 22 (8%) infection urinary tract 19 (6.6%) 11 (7.9%) 23 (8.2%) 22 (8.1%) Dizziness 10 (3.5%) 7 (4.9, 0%) 15 (5/4%) 19 (7.0%) Injury 12 (4.2%) 5 (3.6%) 12 (4.3%) 16 (5.9%) diarrhea 17 (5.9%) 7 (5.0%) 34 (12.2%) 15 (5.5%) dyspepsia 7 (2.4%) 4 (2.9%) 13 (4.7%) 15 (5.5%) Headache 13 (4.5%) 5 (3.6%) 19 (6.8%) 13 (4.8%) reduction scales 4 (1.4%) 2 (1.4%) 15 (5.4%) 13 (4.8%) crashes 14 (4.9%) 11 (7.9%) 14 (5.05%) 12 (4.4%)

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Inflammation of the nose mucous membrane 6 (2.1%) 9 (6.4%) 9 (3.2%) 11 (4.0%) Peripherals bypasses 7 (2.4%) 9 (6.4%) 8 (2.9%) 7 (2.6%)

For most of the clinical signs of clinical concern, as listed in Table 9, there were no or small dose-related differences between treatment groups. There was a higher incidence of bradycardia in patients treated with galantamine compared to placebo, but there was no dose-related relationship. In cases of transient unconsciousness, dose escalation to galantamine 24 mg / day was readily apparent, but 3 of these cases occurred during titration at a lower dose and can therefore be attributed to a lower dose of galantamine. Thus, the occurrences in Table 6 are very likely to be overestimated due to transient unconsciousness at higher doses. In addition, 10 of the 18 patients who experienced transient unconsciousness were taking concomitant medications for cardiovascular disease containing beta blockers, calcium channel antagonists; ACE inhibitors or diuretics. Of these 18 patients, 11 had a history of active cardiovascular disease. Therefore, most patients who experienced transient unconsciousness were either in a cardiovascular state or were taking medications for cardiovascular disease.

Table 9: Clinically interesting side effects

side symptoms (priority title) placebo GAL 8 mg GAL 16 mg GAL 24 mg Half of all patients 286 140 279 273

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bradycardia 1 (0.3%) 5 (3.6%) 7 (2.5%) 8 (2.9%) convulsions 2 (0.7%) 0 0 1 (0.4%) fatigue 6 (2.1%) 3 (2.1%) 10 (3.6%) 13 (4.8%) Muscle weakness 3 (1.0, 0%) 1 (0.7%) 3 (1.1%) 1 (0.4%) transitional unconsciousness 2 (0.7%) 2 (1.4%) 5 (1.8%) 9 (3.3%)

The incidence of serious side effects was comparable across treatment groups and (except transient unconsciousness) was not dose related (Table 10). The four most frequent serious side effects with galantamine and occurring in at least 1% of patients in any group were injuries, transient unconsciousness, falling, and myocardial infarction. No dose-related increase in GI-related side effects was observed. The only serious side effect that was related to dosing was transient unconsciousness, but for the reasons already presented, these figures are overestimated.

Table 10: Serious adverse events (with 2 patients in any group)

side symptoms (priority title) placebo GAL 8 mg GAL 16 mg GAL 2 4 mg are alternatively all patients 286 140 279 273 are alternatively patients

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with any SAE 31 (10.8%) 14 (10.0%) 28 (11, 0%) 35 (12.8%) Injury 4 (1.4%) 1 (0.7%) 1 (0.4%) 5 (1.8%) transitional unconsciousness 2 (0.7%) 1 (0.7%) 4 (1.4%) 5 (1.8%) body weakness 1 (0.3%) 0 (0.0%) 2 (0.7%) 1 (0.4%) asthma 1 (0.3%) 0 (0.1%) 2 (0.7%) 3 (1.1%) Pneumonia 4 (1.4%) 1 (0.7%) 2 (0.7%) 3 (1.1%) hemorrhage 0 (0.1%) ' 0 (0.0%) 0 (0.0%) 2 (0.7%) sickness 1 (0.3%) 0 (0.1%) 2 (0.7%) 1 (0.4%) pain abdominal 1 (0.3%) 0 (0.1%) 2 (0.7%) 0 (0.0%) diarrhea 1 (0.3%) 0 (0.0%) 3 (1.1%) 0 (0.1%) nausea 1 (0.3%) 0 (0.0%) 2 (0.7%) 0 (0.0%) cancer basal cell 0 (0.0%) 0 (0.0%) 0 (0.0%) 2 (0.7%) tumor breast u women 2 (0.7%) 0 (0.0%) 0 (0.0%) 0 (0.1%) crashes 3 (1.0%) 4 (2.9%) 1 (0.4%) 3 (1.1%) surgical intervention 1 (0.3%) 0 (0.0%) 3 (1.1%) 0 (0.0%) Deep inflammation veins 1 (0.3%) " 0 (0.0%) 0 (0.0%) 2 (0.7%). ' temporary ischemic attack 1 (0.3%) 1 (0.7%) 2 (0.7%) 0 (0.0%) heart attack myocardial 2 (0.7%) 3 (2.1%) 1 (0.4%) 1 (0.4%) excitability 1 (0.3%) 2 (1.4%) 1 (0.4%) 0 (0.0%) infection

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urinary tract 0 (0.0%) 1 (0.7%) 2 (0.7%) 0 (0.1%) Failure heart 2 (0.7%) 0 (0.0%) 3 (1.1%) 0 (0.1%) dehydration 0 (0.0%) 0 (0.0%) 3 (1.1%) 0 (0.1%) sepsis 2 (0.7%) 0 (0.0%) 0 (0.0%) 0 (0.1%)

There were 11 deaths during the experiment. There was no apparent association between dosing and death. None of the deaths was associated with the investigator by the investigator.

The results of this example confirmed that treatment with either galantamine of either 16 mg / day or 24 mg / day resulted in a statistically significant improvement in neuropsychiatric behavior as determined by NPI score at month 5 relative to baseline at 16 mg / day and 24 mg / day at compared to a worsening of placebo or galantamine 8 mg / day.

All scientific publications and patent documents are incorporated herein by reference.

The present invention has been described with respect to preferred forms. However, it will be apparent to those skilled in the art that numerous modifications and modifications can be made without departing from the scope of the invention as described in the following claims.

Claims (11)

PATENT Use of an effective amount of galantamine or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of neuropsychiatric behavior associated with Alzheimer's disease. The use of claim 1, wherein galantamine is administered from about 1 mg to about 100 mg per day. The use of claim 2, wherein galantamine is administered from about 5 mg to about 50 mg per day. The use of claim 3, wherein galantamine is administered from about 16 mg to about 32 mg per day. Use according to claim 4, wherein galantamine is administered as a dose of about 24 mg per day, wherein said dose is reached after a dose titration of about 8 mg / day for about 1 week, followed by a dose of about 16 mg / day after for about 1 week, followed by a daily dose of about 24 mg / day. ,, I The use of claim 4, wherein, galantamine is administered as a dose of about 32 mg per day, wherein said dose is achieved after a dose titration of about 8 mg / day for about 1 week, followed by a dose of about 16 mg / day after for about 1 week, followed by a dose of about 24 mg / day for about 1 week, followed by a daily dose of about 32 mg / day. The use of claim 4, wherein the galantamine is 01-2218-02-Ce administered as a dose of from about 16 mg to about 24 mg of galantamine, wherein said dose is achieved after titration from about 2 to about 10 weeks, with an initial dose of about 8 mg, which is increased to a final dose of about 16 mg to about 24 mg. The use of claim 7, wherein galantamine is administered as a dose of about 24 mg / day, wherein said dose is achieved after a dose titration of about 8 mg / day for a period of about 2 weeks to about 4 weeks, followed by a dose of about 16 mg / day. mg / day for from about 2 weeks to about 4 weeks, followed by a daily dose of about 24 mg / day. The use of claim 7, wherein galantamine is administered as a dose of about 24 mg / day, wherein said dose is achieved after titrating 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 daily dose of about 24 mg / day. The use of claim 4, wherein it is administered as a dose of about 16 mg / day, where it is achieved after titrating the dose by mg / day for a period of about 2 weeks to weeks, followed by a daily dose of 16 mg / day. galantamine is said dose of about 8 to about 4 ° about The use of claim 9, wherein galantamine is administered as a dose of about 16 mg / day, wherein said dose is achieved after titrating a dose of about 8 mg / day for about 4 weeks, followed by a daily dose of about 16 mg / day. day. WO 01/74335) RCT / 01/0153 1/5 Figure 1 Mean ± SE change in ADAS-Cog / 11 Value Week 4 cl S