BG107093A - A use of galantamine for the treatment of neuropsychiatric behaviour associated with alzheimer's disease - Google Patents

Abstract

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 reducing or stabilizing the incidence of neuropsychiatric behaviour seen in Alzheimer's patients. 11 claims, 5 figures

Description

Technical field

The present invention relates to the use of an effective amount of Galanthamine for the manufacture of a medicament for the treatment of neuropsychiatric disorders in Alzheimer's disease-related behavior.

BACKGROUND OF THE INVENTION

Galantamine is a reversible cholinesterase inhibitor that can be isolated from many different plant sources, including yellow daffodil bulbs. Galantamine interacts competitively with the acetylcholinesterase enzyme and demonstrates 10- to 50-fold selectivity for acetyl-butyrylcholinesterase.

Galantamine has been used to treat many chronic conditions that require lifelong treatment. Galantamine has been shown to be effective in treating arthritic disorders (Canada patent application 2,251,114); fatigue syndromes (Canada patent application 2,108,880); delusions (Canada patent application 2,062,094); schizophrenia (Canada patent application 2,108,880); memory impairment, including Alzheimer's disease (US patent 4,663,318); alcoholism (patent application of

Canada 2,039,197); nicotine dependence (Canada patent application 2,153,570); attention disorders (PCT Publication WO 99/21561) and time zone misalignment (Canada patent 2,193,473).

However, none of the studies has demonstrated the applicability of Galantamine to the treatment of neuropsychiatric disorders in Alzheimer's disease-related behavior.

SUMMARY OF THE INVENTION

According to the present invention, it is possible to administer Galantamine in the manufacture of a medicament for the treatment of neuropsychiatric disorders in behavior associated with Alzheimer's disease.

In another embodiment of the invention there is provided a method of treating neuropsychiatric behavioral disorders associated with Alzheimer's disease by administering to a patient in need of such treatment a safe and effective dose of Galantamine or a pharmaceutically acceptable salt thereof.

Short description of the drawings

These and other features of the invention will become more apparent from the following description in connection with the accompanying drawings:

Figure 1 shows the average change in baseline time for ADAS / cog-11 by treatment group (observation)

Figure 2 shows the average change in baseline time for ClBlC-plus by treatment group (observation)

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Figure 3 shows the cumulative percentage of patients with a specific change from baseline according to ADAS / cog11 assessment at month 5

Figure 4 shows the change in ADL performance (performance) for mA.

time from baseline to 5th month

Figure 5 shows the change in NP1 score over time from baseline to month 5.

DESCRIPTION OF THE PREFERRED EMBODIMENT

The present invention relates to the administration of an effective amount of Galantamine for the treatment of neuropsychiatric disorders in Alzheimer's disease-related behavior.

Galantamine, a tertiary alkaloid, was isolated from the bulbs of the Caucasian snowdrop Galantanus woronowi (Proskurina, NF and Yakoleva, AP 1952, Alkaloids of Galantanus woronowi. II. Isolation of a new alkaloid. (In Russian). Zh.Obschchei Khim. (In Russian). Gen. Chem. 22, 18991902). It is also isolated from the common snowdrop Galantanus nivalis (Boit, 1954). Galantamine is a well-known cholinesterase inhibitor that is active at nicotinic receptor sites but not at muscarinic receptor sites. It can cross the blood-brain barrier in humans and has no severe side effects at therapeutically effective dosages.

Galantamine has been widely used as a reversible curative effect in anesthetic practice in the Eastern Bloc countries (review by Paskov, 1986) and experimentally in the West (Bretagne and Valetta, 1965; Wislocki, 1967; Consanitis, 1971).

Galantamine has been marketed by Waldheim (Sanochemia Gruppe) as Nivalin ™ in Germany and Austria since the 1970s for indications of facial neuralgia.

In the present invention, when referring to Galanthamine, the term Gallantamine itself, its derivatives and salts such as halides, for example, Galantamine hydrobromide, are included in the term.

For the purposes of the present invention, galantamine and its derivatives and salts may be prepared according to conventional pharmaceutical methods, optionally together with one or more pharmaceutically acceptable vehicles, excipients or diluents, as is known in the art. Such compositions may be in the form of tablets, capsules, solutions or tablets with sugar glaze, pessaries, creams, suppositories or transdermal forms, depending on the route of administration.

Galantamine has been used to treat many chronic conditions that require lifelong treatment. Galantamine has been shown to be effective in treating arthritic disorders (Canada patent application 2,251,114); fatigue syndromes (Canada patent application 2,108,880); delusions (Canada patent application 2,062,094); schizophrenia (Canada patent application 2,108,880); memory impairment, including Alzheimer's disease (US patent 4,663,318); alcoholism (Canada patent application 2,039,197); nicotine dependence (Canada patent application 2,153,570); attention disorders (PCT Publication WO 99/21561) and time zone misalignment (Canada patent 2,193,473).

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According to the present invention, an effective and safe amount of Galanthamine can be administered for the treatment of neuropsychiatric behavioral disorders associated with Alzheimer's disease.

The exact dosage ranges and modes of administration can be determined empirically by the practitioner depending on individual conditions. For example, if 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 daily. In the following example, the compound may be administered from about 16 mg to about 32 mg daily. The precise daily dosages can be selected from 16 mg, 18 mg, 24 mg or 32 mg daily. Preferably the daily dosage is divided into two or three equal doses.

In one embodiment of the present invention, it has been found that the tolerability or safety of the drug can be improved if the drug is slowly incorporated into the patient within a few weeks.

In one embodiment of the present invention, galanthamine is slowly incorporated into the patient for about 2 to about 10 weeks, with the dose increased over this period.

In one embodiment of the present invention, 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.

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In one embodiment of the present invention, 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 1 week, followed by a maintenance dose from about'32 mg / day.

In one embodiment of the present invention, the patient is receiving a dose of about 8 mg / day for about 2 to about 4 weeks, followed by a dose of about 16 mg / day for about 2 to about 4 weeks, followed by a maintenance dose of about 24 mg / day.

In one embodiment of the present invention, the patient is receiving 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.

In another embodiment of the present invention, the patient receives a dose of about 8 mg / day for about 2 to about 4 weeks, followed by a maintenance dose of about 16 mg / day. In one embodiment of the present invention, the patient is receiving a dose of about 8 mg / day for about 4 weeks, followed by a maintenance dose of about 16 mg / day.

According to the present invention, neuropsychiatric behavioral disorders associated with Alzheimer's disease include, for example: delusions, hallucinations, agitation / aggression, dysphoria, anxiety, euphoria, apathy, disinhibition, irritability / lability and aberrant motor behavior.

Examples of carrying out the invention

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

Patients diagnosed with Alzheimer's disease (approximately 910) were randomized to one of four treatment stream types: placebo; 8 weeks titration of Galantamine 24 mg / day; 4 weeks titration of Galantamine 16 mg / day; or Galantamine 8 mg / day, without titration, for five months. Patients included in the study should have been diagnosed with Alzheimer's disease, according to the Alzheimer's Disease Assessment Scale (ADAS) (Rosen, WG et al., Amer. J. Psychiatry, 141: 1356 -1364, 1984) cognitive grade (ADAS-cog-11) with a score of at least 18 points, as well as a history of cognitive decline that was gradual and progressive over a period of at least six months.

The titration schemes for the different treatment streams were as follows:

Patients in the placebo group received 21 weeks (5 months) of placebo. Patients in the Gal 24 group received 4 weeks 8 mg / day of Galantamine (4 mg, twice daily = bid), 4 weeks of 16 mg / day (8 mg, bid) and 13 weeks of 24 mg / day of Galantamine (12 mg, bid ). Patients in the Gal 16 group received 4 weeks 8 mg / day of Galantamine (4 mg, bid) and 17 weeks of 16 mg / day of Galantamine (8 mg, bid). Patients in the Gal 8 group received 8 mg / day (4 mg, bid) immediately after randomization and continued at this dose for 21 weeks.

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All patients were monitored throughout the study with follow-up and cognitive evaluation at the fourth week, third month and fifth month from the start of the study.

The main performance indicators for the change were ADAS-cog / 11 baseline and CIBIC-plus (Clinician's Interview Based Impression of Change Plus Family Input = Clinician's Impression for Interview Change, plus Family Participation) the fifth month. These two tests together with the * minimum mental state test (Mini-Mental State w

Examination = MMSE) conducted during the screening phase are discussed below:

The ADAS consists of two parts - the cognitive subscale and the behavioral subscale. The behavioral subscale was not applied in this study. The cognitive subscale, ADAS-cog-11, consisted of the following tests: memory tests for word repetition and word recognition, for naming objects and fingers, for commands, for constructive praxis, for ideational praxis, for orientation, for memory test instruction, spoken speech, w speech comprehension, and difficulty finding words, this subscale being the main variable in this study.

In addition to the questions identified above, two additional questions were evaluated by ADAS-cog11: concentration and distraction - the original part of the behavioral subscale, and a late word repetition test (a late repetition of the word repetition questions), which is added for additional information regarding cognitive status. The 13-item advanced ADAS (ADAS-cog 13) was a secondary variable.

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To reduce the variability in circadian fluctuations in the cognitive state, ADAS is always performed at the same time of day, preferably before noon. Only trained evaluators in conducting ADAS have performed the testing. Ideally, the evaluating ADAS was not involved in the treatment of the patient and should not have access to adverse events (AE) reports.

ADAS was performed at 1, 2, 3, 4, and 5 visits (screening, baseline, C4 weeks, 13 weeks, and 5 months or with early discontinuation of the study drug). For word and word recognition tests, two parallel word lists were used, List A and List B. List A was used for visits 1 and 3, and List B was used for visits 2, 4 and 5, or early termination of visits. taking the study medication. From a practical point of view, the words in the word recognition test were presented only once. The total score of the 11 cognitive questions from the original ADAS cognitive scale was reported (ADAScode / 11, range: 0-70 points).

The CIBIC-plus score was the second major variable. An independent, experienced and appropriately trained clinician provided a general impression of the patient's deterioration or improvement during the course of the study, based on separate interviews with the patient and caregivers. If helpful, the CIBIC assessor recorded the original interview for audio and video tapes for future reference.

The change from baseline was evaluated on a 7-point scale, with 1 indicating significant improvement, 4 indicating no change and 7 indicating deterioration. The CIBIC-plus test was performed on visits 2, 3, 4 and 5 (baseline, week 4, week 13 and month 5 or before discontinuation of study medication). Only a trained CIBIC assessor conducted the test.

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MMSE is a very short test of cognitive functions, including time and place orientation, immediate repetition, short-term memory, and the ability to perform sequential letter extraction or re-typing, constructive capabilities, and speech use. The MMSE score is derived from the sum of the points scored for each task completed. The total positive sum is 50. MMSE was performed at visit 1 (screening).

Secondary performance variables were ADAS-cog / 11 and ADCS / ADL scale. The ADCS / ADL scale is discussed below:

The ADCS / ADL scale is a rating scale based on 23-item information evaluating widely applicable daily activities that is appropriate for patients with mild to moderate Alzheimer's disease. The 23 questions were selected for evaluation by the larger 45-item set studied by Galasko et al. (Alzheimer Disease and Associated Disorders, Vol. 11, Suppl. 2, 1997). These individual questions were scored from 0-3 to 07, depending on the question, with a possible positive score of 78. A higher score means a better functioning patient.

The questions and points were as follows:

Feeding (0-3)

Walking (0-3)

Toilet (0-3)

Bathing (0-3)

Good looks (0-3)

Dress Up

Clothing Selection (0-3)

Physical Performance (0-3)

Telephone (0-5)

Television (0-3)

Conversation (0-3)

Serving Food (0-3)

Keeping Your Own Things (0-3)

Making Drinks (0-3)

Making Food or Breakfast (0-4)

Garbage Disposal (0-3)

Traveling Outside the Home (0-3)

Shopping (0-4)

Meeting appointments (0-3)

Ability to stay alone (0-3)

Current activities (0-3)

Reading (0-2)

Writing (0-3)

Hobby (0-3)

Home Auxiliaries (0-4)

Behavioral neuropsychiatric disorder has been monitored by a test known as The Neuropsychiatric Inventory (NPI) (Cummings, J. L. et al., Neurology, 44: 2308-2314, 1994). NPI covers 10 behavioral areas reported in Alzheimer's patients: delusions, hallucinations, agitation / aggression, dysphoria, anxiety, euphoria,

apathy, disinhibition, irritability / lability and aberrant motor behavior. Abnormal behavior (0 points) may be missing for each area or may be present. If present, the frequency and severity of abnormal behavior is evaluated on the basis of answers to a set of sub-questions relating to behavioral events relevant to the field. Severity was rated 1 to 3 as mild, moderate or severe. The frequency was rated 1 to 4 as random, frequent, multiple and very common. Frequency and severity score (maximum points = 12) was calculated for each area. The total NPI score was calculated as the sum of the results for frequency and severity (maximum points = 120). NPI was performed at visits 2, 3, 4 and 5 (baseline, week 4, week 13 and month 5 or with early discontinuation of the study drug).

All data were compared within groups - placebo, galanthamine 8 mg / day, 16 mg / day and 24 mg / day.

Comparisons between groups (with particular attention to placebo differences) were made at each time interval according to the scheme and for each indicator of the scheme. These comparisons are based on the change from baseline points for baseline performance parameters (eg ADAS-cog / 11) and actual points for baseline performance parameters (eg CIBIC-plus).

For comparison of treatment groups with respect to change from baseline, the two-way analysis of variance (ANOVA) model used with treatment and researcher as factors was applied in the continuous data. The interaction between the treatment and the researcher has been studied. The impact of the initial • · · · · · · · · and l · · · · · · · • ·! <> ···· · · · · · · ····· · 9 • ν · · · · ··

9 ·· ···· · «« · ······ Score on the change from the baseline. If baseline assessment was confirmed as significantly determinant (p <10), an analysis of covariance model (ANCOVA) was applied to evaluate the treatment effects and the interaction between treatment and baseline score. If parametric methods were considered inappropriate (the assumption of normal distribution was violated), nonparametric methods were applied, such as a two-way ANOVA of a data category, the Van Elteren test to control the researcher. Following the ANOVA, Fischer's LSD procedure was applied for pairwise comparisons between each galantamine group and the placebo group. The linear contrast for the main effect of treatment was applied to test the dose-response relationship (dose effect).

For consecutive category variables such as CIBIC-plus, the Van Elteren test was used to control the researcher when comparing between groups. For nominal data (eg degree of expression), the Cochran-Mantel-Haenszel general bond test controlling the researcher was applied. To test for increasing effect at increasing dose, linear contrast was applied to the proportion of patients without change or improvement.

If a significant number of patients discontinued treatment prematurely, additional analyzes were performed to evaluate the impact on the results. In addition to the visit analysis, a method for analyzing continuous repeated measurements in assessing the healing effect over time was applied.

The safety of the medicine was also monitored throughout the study. Blood samples for biochemistry and hematology, as well as samples from total urine for urinalysis were taken at each visit and at the completion of the full efficacy test. Systolic and diastolic blood pressure in the sitting position were measured, heart rate and vital signs were recorded at each visit.

Patient demographics and baseline characteristics had to be well balanced across treatment groups (Table 1). The baseline cognitive level of these patients with Alzheimer's disease was mild to average as assessed by MMSE and ADAS-cog / 11 with scores of approximately 18 and 28 to 20.

Table 1: Demographic and baseline characteristics

Study layout and patient characteristics Placebo GAL 8 mg GAL16 mg GAL 24 mg Total number of patients 286 140 279 273 Graduates: number (%) 240 (84%) 108 (77%) 219 (79%) 212 (78%) Paul Men 108 (38%) 50 (36%) 105 (38%) 90 (33%) Women 178 (62%) 90 (64%) 174 (62%) 183 (67%) Age (years) Average (SE) 77.1 (0.46) 76.0 (0.61) 76.3 (0.49) 77.7 (0.43) Average (min-max) 78 (53-100) 77 (52-91) 77 (51-94) 78 (57-95) Race black 13 5 12 14 Caucasian 267 (93%) 132 (94%) 260 (93%) 249 (91%) Spanish 3 3 5 4 Oriental 3 0 1 3 Others 0 0 1 3 Amount at MMSE Average (SE) 17.7 (0.21) 18.0 (0.30) 17.8 (0.21) 17.7 (0.23) Average (min-max) 19 (10-22) 19.0 (10-22) 19 (10-22) 19.0 (10-22) Output ADAS-cog / 11 Average (SE) 29.4 (0.63) 27.8 (0.94) 29.4 (0.66) 29.0 (0.67) Average (min-max) 27 (10-61) 26 (11-62) 28 (10-62) 27 (10-54)

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The number of patients randomized to the four treatment groups was 978. The total number of patients who completed the study was large (approximately 80%) q with a relatively equal proportion of discontinued due to side effects that were relatively rare and correctly distributed across all treatment groups. groups (see Table 2).

Table 2: Discontinuation of study treatment

Reasons for discontinuation of the study Placebo GAL 8 mg / day GAL 16 mg / day GAL 24 mg / day Total patients 286 140 279 273 Total graduates: number (%) 240 (84%) 108 (77%) 219 (79%) 212 (78%) Total Suspended (DC): Number (%) 46 (16%) 32 (23%) 60 (22%) 61 (22%) DC due to side effects 20 (7%) 9 (6%) 19 (7%) 27 (10%) DC due to inefficiency 0 1 (1%) 0 2 (1%) For other reasons ³ 23 (8%) 18 (13%) 29 (10%) 20 (7%) DC due to unfitness for continuation 0 0 4 (1%) 2 (1%) DC for not cooperating 3 (1%) 4 (3%) 7 (3%) 10 (4%) DC for refusing consent 0 0 2 (0.4%) 0

w ^a : Most suspended for other reasons were for refusing consent.

In this study, there were two main performance indicators according to widely applied international standards: change in ADAS-cog / 11 assessment at month 5 compared to baseline and CIBIC-plus assessment at month 5.

As shown in Table 3 and Figure 1, there was a statistically significant curative effect for the treatment groups of 16 and 24 mg / day galanthamine compared to placebo with respect to ADAS-cog / 11. The results of the analysis, based on preliminary data at the last observation, · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · (Last Observation Carried-Forward = LOCF) confirm the result of the observed data. The 8 mg / day group of Galantamine differed significantly from the placebo group in terms of observation but not in LOCF. Galantamine at a dose of 24 mg / day was not significantly more effective than 16 mg / day. However, the duration of administration of the target dose varied by 1 month between the two treatment groups (2 months versus 3 months, respectively).

Table 3: Change from baseline in ADAS-cog / 11 to month 5

Placebo GAL 8 mg GAL16 mg GAL 24 mg 5th month: (observation) 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: (LOCF) N = 255 N = 126 N = 253 N = 253 Average (SE) 1.7 (0.39) 0.4 (0.52) ¼ -1.4 (0.35) *** -1.4 (0.39) ***

A lower rating means a better condition. The p-values are from the two-way ANOVA model.

• Significantly more effective than placebo: *: p ^ 0.05; **: p <0.01; ***: p <0.001; Approximate significance: ♦: 0.05 <p-value <0.10.

• Significantly more effective than 8 mg / day: +: p <0.05; ++: p <0.01.

At the 5-month assessment of ClBIC-plus, the percentage of patients with improved or unchanged assessment was significantly higher with Galantamine 16 or 24 mg / day compared with placebo or Galantamine 8 mg / day (Table 4). After 5 months of treatment, 64% to 68% of patients with 24 or 16 mg / day of galanthamine showed improvement or were unchanged from baseline compared with 47% to 51% with placebo or 8 mg / day of galantamine. The analysis of the LOCF data produced similar results. There was a clear dose-related increase in the percentage of patients with improvement or no change in the ClBIC-plus test (Figure 2).

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

Placebo GAL 8 mg GAL16MT GAL 24 mg 5th month: (observation) N = 237 N = 106 N = 212 N = 212 Improvement / No Change: N (%) 112 (47%) 54 (51% ( 143 (68%) *** ⁺ 136 (64%) *** ⁺⁺ Month 5: (LOCF) N = 263 N = 128 N = 255 N = 253 Improvement / No Change: N (%) 128 (49%) 68 (53%) 169 (66%) *** ⁺ 162 (64%) *** ⁺⁺

P-value from the Van Elteren 7-point scale test

Significantly more effective than placebo: *: p <0.05; **: p <0.01; ***: p <o.001.

Significantly more effective than 8 mg / day: ⁺ : p <0.05; ⁺⁺ : p <0.01.

At month 5, there were significantly more patients without change or with improved grade at 16 and 24 mg / day galanthamine compared to placebo or 8 mg / day galantamine. Patients with baseline ADAS change / 11 with 7 points or more were 15.9% and 22.3% of patients in the 16 and 24 mg / day groups, respectively, compared with the placebo group (7.6%). Overall, there was a higher cumulative percentage of patients with galantamine treatment who showed minimal improvement in each magnitude compared to placebo (Figure 3).

Table 5: Analysis of responding patients at month 5 according to change in ADAS-cog / 11 baseline assessment

Definition of an affected patient Placebo GAL 8 mg GAL16MT GAL 24 mg N = 225 N = 101 N = 208 N = 211 Change <0 points η (%) 94 (41.8) 47 (46.5) 136 (65.4) *** ⁺⁺ 137 (64.9) *** ⁺⁺ Change <4 points η (%) 44 (19.6) 26 (25.7) 74 (35.6) *** ♦ 78 (37.0) *** ⁺ Change <7 points η (%) 17 (7.6) 14 (13.9) 33 (15.9) ** 47 (22.3) *** ♦ ♦ Change <10 points η (%) 8 (3.6) 6 (5.9) 15 (7.2) 22 (10.4) **

P-value from the CMH test • Significantly higher percentages responded than placebo: *: p <0.05; **: p <0.01;

***: p <0.001;

• Significantly higher percentages responded than at 8 mg / day: ⁺ : p <0.05; ⁺⁺ : p <0.01. Approximate significance: ♦: 0.05 <p-value <0.10.

• The difference between 16 and 24 mg / day approaches a significance of ♦: 0.05 <value <0.10.

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Additional secondary indication captures overall changes in the performance of Daily Living Activities (ADL) as measured by the Alzheimer's Disease Cooperative Study Activities of Daily Living (ACDS) Scale As noted above, this scale consists of 23 questions that have been tested and confirmed in patients with mild to moderate Alzheimer's disease.

Galantamine treatment with 16 or 24 mg / day for 5 months was statistically more effective in maintaining overall ADL at baseline than treatment with placebo or 8 mg / day Galantamine (Table 6). The dose-related effect of galantamine treatment is evident in Figure 4, which shows the change in overall ADL score over time.

Table 6: Change in overall ADL score from baseline at month 5

Placebo GAL 8 mg GAL16 mg GAL 24 mg 5th month: (observation) N = 235 N = 106 N = 212 N = 212 Average (SE) -4.0 (0.59) -3.1 (0.91) -0.5 (0.55) *** ⁺ -1.6 (0.61) ** Month 5: (LOCF) N = 262 N = 129 N = 255 N = 253 Average (SE) -3.8 (0.55) -3.2 (0.79) -0.7 (0.050) *** ⁺ -1.5 (0.56) *** ⁺⁺

Higher value means better condition. P-value according to the ANOVA model.

• Significantly more effective than placebo: **: p <0.01; ***: p <o.001.

• Significantly more effective than 8 mg / day: ⁺ : p <0.05; ⁺⁺ : p <0.01.

There was a statistically significant (p <0.05) improvement observed according to the change in the overall NPI score at month 5 from baseline for 16 and 24 mg / day of Galanthamine compared to the worsening of placebo or 8 mg / day of Galantamine (Table 7 and Figure 5). Increasing the number of points means a worsening of the situation. Therefore, maintaining neuropsychiatric deviation in one-level behavior was observed with Galantamine 16 and 24 mg / day.

Table 7: Change in the overall NPI estimate from baseline at month 5

Placebo GAL 8 mg GAL16mt GAL 24 mg 5th month: (observation) N = 234 N = 106 N = 212 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) 2.0 (0.68) 2.3 (1.00) -0.1 (0.71) * -0.0 (0.76) *

Higher value means deterioration. P-value according to the ANOVA model. • Significantly more effective than placebo: *: p <0.05.

The most common adverse events were evenly distributed among treatment groups except for those associated with cholinomimetic agents (Table 8). From these manifestations nausea, vomiting and anorexia showed a mildly pronounced dose-dependent manifestation at a relatively low frequency.

Table 8: Frequency of most common (> 5%) adverse events: number (%) of patients

Side event (preferred term) Placebo GAL 8 mg GAL 16 mg GAL 24 mg Total number of patients 286 140 279 273 Nausea 13 (4.5%) 8 (5.7%) 37 (13.3%) 45 (16.5%) Vomiting 4 (1.4%) 5 (3.6%) 17 (6.1%) 27 (9.9%) Anorexia 9 (3.1%) 8 (5.7%) 18 (6.5%) 24 (8.8%) Excitement 27 (9.4%) 21 (15.0%) 28 (10.0%) 22 (8.1%) Depression 15 (5.2%) 4 (2.9%) 24 (8.6%) 22 (8.1%) Urinary tract infection 19 (6.6%) 11 (7.9%) 23 (8.2%) 22 (8.1%) Dizziness 10 (3.5%) 7 (5.0%) 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%) 12 (4.8%) Weight loss 4 (1.4%) 2 (1.4%) 15 (5.4%) 12 (4.8%) Fall 14 (4.9%) 11 (7.9%) 14 (5.05%) 12 (4.4%) Rhinitis 6 (2.1%) 9 (6.4%) 9 (3.2%) 11 (4.0%) Peripheral edema 7 (2.4%) 9 (6.4%) 8 (2.9%) 7 (2.6%)

For most clinical manifestations of clinical interest, as shown in Table 9, there were no differences or there were slight dose-dependent differences between the treatment groups. Bradycardia was higher in patients treated with Galantamine than placebo, but no dose-related dependence was reported. Syncope had a slight dose-dependent increase in frequency at 24 mg / day galanthamine, but 3 of these cases occurred at a lower dose during titration and were therefore associated with a lower galantamine dose. Consequently, the frequencies shown in Table 6 are likely to be overestimated for the manifestation of syncope at high doses. In addition, 10 of 18 patients with syncopal episode received concomitant cardiovascular treatment including beta-blockers, calcium channel antagonists, ACE inhibitors (ACE = angiotensin-converting enzyme) and / or diuretics. Of these 18 patients, 11 had active cardiovascular disease indicated in their medical history. Therefore, most patients who have survived syncope have either had cardiovascular disease or have been taking cardiovascular medication.

Table 9: Side effects of clinical interest

Side event (preferred term) Placebo GAL 8 mg GAL16 mg GAL 24 mg Total number of patients 286 140 279 273 Bradycardia 1 (0.3%) 5 (3.6%) 7 (2.5%) 8 (2.9%) Γ convulsions 2 (0.7%) 0 0 2 (0.4%) Fatigue 6 (2.1%) 3 (2.1%) 10 (3.6%) 12 (4.8%) Muscle weakness 3 (1.0%) 1 (0.7%) 3 (1.1%) 2 (0.4%) Syncope 2 (0.7%) 2 (1.4%) 5 (1.8%) 9 (3.3%)

The incidence of serious adverse events (SAS) was comparable between the groups and (except for syncope) did not show

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dose-dependent trend (Table 10). The four most common serious adverse events with Galantamine, which are at least 1% of patients in each group, were trauma, syncope, falls and myocardial infarction. There were no dose-dependent increases in gynecologically related serious adverse events. The only serious side effect that showed a dose-dependent relationship was syncope, but for the reasons already indicated, the values may have been overestimated.

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

Side manifestation-. (preferred term) Placebo GAL 8 mg GAL 16 mg GAL 24 mg Total number of patients 286 140 279 273 Total number of patients with some SBS 31 (10.8%) 14 (10.0%) 28 (10.0%) 35 (12.8%) Injury 4 (1.4%) 1 (0.7%) 2 (0.4%) 5 (1.8%) Syncope 2 (0.7%) 1 (0.7%) 2 (0.4%) 5 (1.8%) Asthenia 1 (0.3%) 1 (0.0%) 2 (0.7%) 3 (1.1%) Dyspnea 1 (0.3%) 1 (0.0%) 2 (0.7%) 3 (1.1%) Pneumonia 4 (1.4%) 1 (0.7%) 2 (0.7%) 2 (0.7%) Gynecological haemorrhage 1 (0.0%) 1 (0.0%) 1 (0.0%) 2 (0.4%) Vomiting 1 (0.3%) 1 (0.0%) 2 (0.7%) 2 (0.4%) Stomach ache 1 (0.3%) 1 (0.0%) 2 (0.7%) 1 (0.0%) Diarrhea 1 (0.3%) 1 (0.0%) 3 (1.1%) 1 (0.0%) Mr. Aden 1 (0.3%) 1 (0.0%) 2 (0.7%) 2 (0.7%) Basal cell carcinoma 1 (0.0%) 1 (0.0%) 1 (0.0%) 2 (0.7%) Mammary gland neoplasm in women 2 (0.7%) 1 (0.0%) 1 (0.0%) 1 (0.0%) Fall 3 (1.0%) 4 (2.9%) 2 (0.4%) 3 (1.1%) Surgical intervention 1 (0.3%) 1 (0.0%) 3 (1.1%) 1 (0.0%) Deep thrombophlebitis 1 (0.3%) 1 (0.0%) 1 (0.0%) 2 (0.7%) Transient ischemic incident 1 (0.3%) 1 (0.7%) 2 (0.7%) 1 (0.0%) Myocardial infarction 2 (0.7%) 3 (2.1%) 2 (0.4%) 2 (0.4%) Excitement 1 (0.3%) 2 (1.4%) 2 (0.4%) 1 (0.0%)

• · ·

• · • · · ·: -2?

• · · ·

Side event (preferred term) Placebo GAL 8 mg GAL 16 mg GAL 24 mg Urinary tract infection 1 (0.0%) 1 (0.7%) 2 (0.7%) 1 (0.0%) Heart failure 2 (0.7%) 1 (0.0%) 3 (1.1%) 1 (0.0%) Dehydration 1 (0.0%) 1 (0.0%) 3 (1.1%) 1 (0.0%) Sepsis' ~ 2 (0.7%) 1 (0.0%) 1 (0.0%) 1 (0.0%)

There were 11 deaths during the study. No apparent dose-dependent relationship was observed upon death. None of the deaths were considered by the investigator to be related to the treatment under study.

The results of this example confirm that treatment with 16 or 24 mg / day of Galantamine leads to a statistically significant improvement in neuropsychiatric disorders in behavior, as determined by NPI assessment at month 5 at baseline at 16 and 24 mg / day at compared with worsening with placebo or 8 mg / day galantamine.

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

The present invention is described with reference to a preferred embodiment. However, it will be apparent to one skilled in the art that many variations and modifications can be made without departing from the scope of the invention described in the following claims.

Claims (11)

Patent Claims 1. Administration of an effective amount of Galantamine or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of neuropsychiatric disorders in Alzheimer's disease-related behavior. The use according to claim 1, wherein galanthamine is administered from about 1 mg to about 100 mg / day. The use according to claim 2, wherein galanthamine is administered from about 5 mg to about 50 mg / day. The use according to claim 3, wherein galanthamine is administered from about 16 mg to about 32 mg / day. The use according to claim 4, wherein galanthamine is administered at a dosage of about 24 mg / day, said dosage being achieved after titrating 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 daily dosage of about 24 mg / day. The use according to claim 4, wherein galanthamine is administered at a dosage of about 32 mg / day, said dosage being achieved after titrating 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 daily dosage of about 24 mg / day for one week, followed by a daily dosage of about 24 mg / day. · · · · · · · · · · · · · · · 7. The use according to claim 4, for the cream of Galanthamine is administered at a dosage of from about 16 mg to about 24 mg, said dosage being reached after titration for about 2 to about 10 weeks at a starting dose of about 8 mg, increasing to the final dose from about 16 mg to about 24 mg. The use of claim 7, wherein galanthamine is administered at a dosage of about 24 mg / day, said dosage being achieved after titrating a dose of about 8 mg / day for. about 2 to about 4 weeks, followed by a dose of about 16 mg / day for about 2 to about 4 weeks, followed by a daily dosage of about 24 mg / day. The use of claim 7, wherein galanthamine is administered at a dosage of about 24 mg / day, said dosage being achieved after titrating a dose of about 8 mg / day for about 4 weeks, followed by a dose of about 16 mg / day for for about 4 weeks, followed by a daily dosage of about 24 mg / day. The use according to claim 4, wherein galanthamine is administered at a dosage of about 16 mg / day, said dosage being achieved after titrating a dose of about 8 mg / day for about 2 to about 4 weeks, followed by a daily dosage of about 16 mg / day. The use of claim 9, wherein galantamine is administered at a dosage of about 16 mg / day, said dosage being achieved after titrating a dose of about 8 mg / day for about 4 weeks, followed by a daily dosage of about 16 mg / daily. WO 01/74339