MXPA02009777A - 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 FOR THE TREATMENT OF NEUROPSYCHIATRIC BEHAVIOR ASSOCIATED WITH THE DEATH OF ALZHEIMER The present invention describes the use of an effective amount of galantamine for the production of a medicament for the treatment of the neuropsychiatric behavior associated with the Alzheimer's disease.

BACKGROUND OF THE INVENTION Galantamine is a reversible calinester loop inhibitor that can be isolated from a number of different plant sources, including narcissus bulbs. Galantami interacts competitively with the enzyme, acetylcholinesterase, and demonstrates a selectivity of 10 to 50 times for acetyl vs. butyryl cholinesterase. Galantamine "has been used for the treatment of a number of chronic conditions where life-long treatment may be necessary Galantamine has been shown to be effective in the treatment of arthritic disorders (Canadian Patent Application 2,251,114); (Canadian patent application 2,208,880), mania (Canadian patent application 2,062,094), schizophrenia (Canadian patent application 2,108,880), memory dysfunction, including Alzheimer's disease (US 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 interval (Canadian patent application 2,193,473). However, none of the studies demonstrates the usefulness of galantamine for the treatment of neuropsychiatric behavior associated with Alzheimer's disease.

BRIEF DESCRIPTION OF THE INVENTION Thus, according to the present invention there is provided a use of galantamine for the production of a medicament for the treatment of a neuropsychiatric behavior associated with the Alzheimer's disease. In a further embodiment, a method is provided for treating neuropsychiatric behavior associated with Alzheimer's disease by administering to a patient in need thereof, a safe and effective dose of galantamine or a pharmaceutically acceptable salt thereof.

BRIEF DESCRIPTION OF THE DRAWINGS These and other aspects of the invention will become more apparent from the following description in which reference is made to the drawings Annexes, where: Figure 1 shows the average change of a reference line through the treatment group with time in ADAS-cog / 11 (observed case). Figure 2 shows the average change of the reference line through the treatment group with time in CIBIC-plus (observed case). Figure 3 shows the cumulative percentage of patients with specific changes of the baseline at month 5 in ADAS-cog / 11 assessments. Figure 4 shows the change in the ADL performance of the reference line, with time in month 5. Figure 5 shows the change in the NPI valuation of the reference line, with time in month 5.

DESCRIPTION OF THE PREFERRED MODALITY The present invention describes the use of an effective amount of galantamine for the treatment of neuropsychiatric behavior associated with Alzheimer's disease.

Galantamine, a tertiary alkaloid, has been isolated from bulbs of the Caucasus wintergill Galantanus woronowi (Proskumina, NF and Yakoleva, AP 1952, Galanthus woronowi alkaloids, II, Isolation of a new alkaloid. 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 very well-known acetylcholinesterase inhibitor that is active at the sites of the nicotinic receptor but is not active at the moscarinic receptor sites. It is able to pass the blood brain barrier in humans, and does not present severe side effects in therapeutically effective doses. Galantamine has been used extensively as a curative investment agent in anesthetic practice in countries of the Eastern Bloc (see review by Paskow, 1986) and also experimentally in the West (see Bretagne and Valetta, 1965: Wisiicki, 1967; Consanitis. 1971). Galantamine has been marketed through the Waldheim company (Sanochemia Gruppe) as Nivalin ™ in Germany and Austria since 1970 for indications such as facial neuralgia. In the present invention when we refer to galantamine we include within this term the galantamine by itself, the derivatives and salts thereof, such as the halides, for example the galantamine hydrobromide.

For the purposes of the present invention, galantamine and the derivatives and salts thereof can be formulated according to conventional pharmacy methods together with, where appropriate, one or more pharmaceutically acceptable carriers, excipients or diluents, as know in the technique. Such formulations may 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 conditions, where treatment for all life 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 (U.S. 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 interval (Canadian patent application 2,193,473). According to the present invention, a safe and effective amount of galantamine can be used for the treatment of neuropsychiatric behavior associated with Alzheimer's disease. The percentages of precise doses and regimens can be determined empirically by the medical specialist, depending of the individual circumstances. For example, if the compound is administered orally, the daily dose is from about 1 mg to about 100 mg. In a further example the compound can be supplied in about 5 mg to about 50 mg per day. In a further example, the compound can be supplied in about 16 mg to about 32 mg per day. The daily, precise doses can 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 the tolerability or safety of the drug can be improved if the patient is slowly introduced to galantamine, from 2 weeks to about 10 weeks, where the dose is increased during this period. In one embodiment of the present invention the patient receives a dose of 8 mg / day for about 1 week, followed by a dose of 16 mg / day for about 1 week, followed by a sustained dose of about 24 mg / day onwards. In one embodiment of the present invention the patient receives a dose of 8 mg / day for about 1 week, followed by a dose of 16 mg / day for about 1 week, followed by a dose of 24 mg / day for about 1 week followed by a sustained dose of 32 mg / day and up. In one embodiment of the present invention, the patient receives a dose of 8 mg / day for about 2 weeks to about 4 weeks, followed by a dose of 16 mg / day for about 2 weeks to about 4 weeks. weeks, followed by a sustained dose of about 24 mg / day and up. In one example of this modality 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 sustained dose of about 24 weeks. mg / day and up. In a further embodiment of the present invention the patient receives a dose of about 8 mg / day for about 2 weeks to about 4 weeks, followed by a sustained dose of 16 mg / day and up. In one example of this modality the patient receives a dose of about 8 mg / day for about 4 weeks, followed by a sustained dose of about 16 mg / day and up. According to the present invention, the neuropsychiatric behavior associated with the Alzheimer's disease includes, for example: delirium, hallucinations, agitation / aggression, dysphoria, anxiety, euphoria, apathy, disinhibition, irritability / instability and aberrant motor behavior. The present invention is illustrated by the following example, which is not intended to be limiting.

EXAMPLES Patients diagnosed with Alzheimer's disease (approximately 910) are treated at random with one of the four forms of treatment: placebo; 8 weeks of assessment with 24 mg / day of galantamine; 4 weeks of assessment with 16 mg / day of galantamine, or 8 mg / day of galantamine, no evaluation is needed, for five months. The patients included in this study must have been diagnosed with the Alzheimer's disease, have a scale of evaluation of the Alzheimer's disease (Rosen, WG et al., Amer. J. Psychiatry, 141: 1356-1364, 1984) assessment of the cognitive portion (ADAS-cog-11) of at least 18 and have a history of cognitive decline stage that is gradual at the beginning and progressive over a period of at least six months. The assessment program for the various types of treatment arms is as follows: Subjects in the placebo group receive 21 weeks of medical treatment with placebo (5 months). The subjects in the group Ga! 24 receive 4 mg / day of galantamine for 4 weeks (4 mg, twice a day (bid)), 4 weeks of 16 mg / day of galantamine (8 mg, bid) and 13 weeks of 24 mg / day of galantamine ( 12 mg, bid). The subjects in the Gal 16 group received 8 mg / day of galantamine (4 mg, bid) and 17 weeks of 16 mg / day of galantamine (8 mg, bid) for 4 weeks. The subjects in the group Gal 8 received 8 mg / day of galantamine (4 mg, bid) immediately in the randomization and this dose was continued for 21 weeks. All patients are monitored during the study, with a continuous and cognitive evaluation in four weeks, three months and five months after the start of the study. The end points of primary efficacy are the change of the ADAS-cog / 11 baseline and the CIBIC-plus assessment (impression based on the clinician's interview of the family's entry plus the change) in the fifth month . These two tests in conjunction with the mini-mental state examination (MMSE), which is done at the selection stage, are described below: ADAS consists of two parts, a cognitive subscale and a sub-scale of behavior. The sub-scale of behavior is not used in this study. The cognitive sub-scale, the ADAS-cog-11, consists of the memory of words and the memory tests of recognition of words, the naming of objects and fingers, commands, structural practice, practice in relation to The ideas, orientation, memory test instructions, spoken language skills, spoken language comprehension, and difficulty in finding words are the first variables in this study. In addition to the previously specified elements of the ADAS-cog-11, two additional ADAS elements are evaluated: the concentration and distraction element, originally part of the sub-scale of the behavior, is performed and a test of the recall of the words retained (Retained memory of the elements of the memory of the words) are added, to provide additional information regarding the cognitive state. The ADAS expanded element 13 (ADAS-cog 13) is a secondary variable. To reduce the variability due to fluctuations for a period of 24 hours in the cognitive state the ADAS is always done at the same time of the day, preferably before noon. Only an experienced ADAS classifier performs the test. Ideally, the ADAS classifier is not involved in the treatment of the subject and can not access the AE report (adverse case). ADAS is performed on visits 1, 2, 3, 4 and 5 (selection, baseline, week 4, week 13 and month 5 or in the early interruption of the ingestion of the test medication). For word recall and word recognition, two lists of parallel words are used, list A and list B. List A is used in visits 1 and 3, list B in visits 2, 4, and 5 or in the early interruption of the ingestion of the test medication. For practical reasons words for the recognition of words, they are presented only once. The total assessment of the cognitive elements 11 in the original ADAS cognitive sub-scale (ADAS-cog / 11, scale: 0-70), is recorded. The CIBIC-plus assessment is a second primary variable. An experienced clinician, independently and appropriately trained, provides a global impression of the subject's deterioration or improvement with the course of the test, based on separate interviews with the subject and the subjects. care provided. It may be useful, the magnetic band sound record of the CIBIC classifier or the video band record of the baseline interview for future reference. The change of the reference line is classified on a scale of 7 points, where one indicates a marked improvement, 4 indicates that there is no change and 7 indicates a marked deterioration. CIBIC-plus is done at visit 2, 3, 4, and 5 (baseline, week 4, week 13, and month 5 or in an early interruption of the ingestion of the test medication). Only a trained CIBIC classifier can perform the test. The MMSE is a very brief test of cognitive functions, which includes orientation in time and place, instant recall, short-term memory, and the ability to perform serial subtractions or inverse spelling, skills construction type and the use of language. The MMSE assessment is derived from the sum of the points assigned to each completed task. A possible, total assessment is 30. The MMSE will be carried out in visit 1 (selection). Secondary efficacy variables include ADAS-cog / 11 and ADCS / ADL assessment. The ADCS / ADL test is discussed below: The ADCS / ADL assessment is a measurement of the assessment of the evaluation based on the informant of item 23, broadly applicable to the appropriate daily activities for patients in the medium to moderate category of the condition of Alzheimer's The elements 23 are selected for measurement from a large set of 45 elements, studied by Galasko et al (Alzheimer's Disease and Associated Disorders, Vol 11, Suppl 2, 1997). These individual items are valued from 0-3 to 0-7, depending on the question, with a total, possible value of 78. A higher score indicates a patient with a higher performance. The elements and the evaluation is as follows: Eating (0 -3) Walking (0-3) Cleaning (0-3) Bathing (0-3) Grooming (0-3) Dressing clothes selection (0-3) Physical performance (0-4) Telephone (0-5) Television (0-3) Conversation (0-3) Serve (0-3) Handling of personal belongings (0-3) Collection of beverages (0-3) Preparation of a food or snack (0-4) Trash removal (0-3) Walking out of the house (0-4) Shopping (0-4) Comply with commitments (0-3) Ability to be calm (0-3) Common cases (0-3) Read (0-2) Write (0-3) Spend times (0-3) Household appliances (0-4) ). Neuropsychiatric behavior is monitored through a test known as The Neuropsychiatric Inventory (NPl) (Cummings, J.L. et al., Neurology, 44: 2308-2314, 1994). The NPl covers 10 domains of behavior registered in patents suffering from Alzhaimer: delirium, hallucinations, agitation / aggression, dysphoria, anxiety, euphoria, apathy, disinhibition, irritability / instability and aberrant motor behavior. For each, the abnormal, dominant behavior may be absent (value 0) or present. If present, the frequency and severity of the abnormal behavior is classified based on the responses for a set of behaviors with respect to the relevant sub-issues that dominate. The severity is classified from 1 to 3 as average, moderate or marked. The frequency is classified from 1 to 4 as occasionally, sometimes, frequently and very frequently. The product of frequency and severity (maximum value = 12) is calculated for each domain. A total of NPl is calculated as the sum of the products of frequency and severity (maximum value = 120). The NPl is carried out in visits 2, 3, 4 and 5 (reference line, week 4, week 13, and month 5 or in the early interruption of the trial medication). All data are compared between the treatment-placebo groups, 8 mg / day, 16 mg / day and 24 mg / day galantamine. Comparisons of treatment groups (with a particular focus on placebo differences) were made at each scheduled time interval and for each endpoint imputation scheme. These comparisons are based on the change of the reference line valuations for the efficiency parameters with the reference line (for example, ADAS-cog / 11) and the original valued for the efficiency parameters without the reference line (for example, CIBIC-plus). For continuous data, a two-way analysis of the model (ANOVA) of variation with the treatment and the researcher as the factors, is used to compare the treatment groups for the change of baseline data. The interaction between the treatment and the researcher is examined. The impact of the valuation of the reference line on the change from the reference line is evaluated. If the assessment of the reference line is found to be a relevant prediction mechanism (p <; 10), an analysis of the co-variation model (ANCOVA) is used to evaluate the effects of the treatment and the interaction between the treatment and the valuation of the reference line is examined. If parametric methods are considered inappropriate (assumption of violated normality), nonparametric methods such as two-way ANOVA are used. directions in the classified data, the Van Elteren test, to control, by the researcher. Continuing, the ANOVA procedure, Fisher's LSD, is used for pairwise comparisons between each galantamine group and the placebo group. A linear contrast on the main effect for the treatment is used to test the dose response relationship. For the variables of ordinary category, such as the CIBIC-plus assessment, the Van Elteren test that the researcher controls, is used for the comparison between the group. For nominal data (for example, percentages of cases), the Cochran-Mantel-Haenszel test for the general association that the researcher controls is used. A linear contrast on the proportion of patients who remain the same or improve, is used to test the increase in response, by increasing the dose. If a significant proportion of subjects, prematurely discontinuous, additional analyzes are performed to evaluate the impact on the results. In addition to the analysis per visit, the method to analyze repeated continuous measurements is used to evaluate the effective treatment over time. The safety of the drug is also monitored during the study. Blood samples for biochemistry and hematology and random urine sample for urinalysis are taken at each visit and at the completion for all efficacy tests. The systolic and diastolic blood pressure is measured in the sitting position, the pulse and vital signs are recorded at each visit.

The demographic characteristics of the patient and the baseline are well balanced across all treatment groups (Table 1). The cognitive performance of the baseline for these patients with Alzheimer's disease is medium to moderate when measured through the MMSE and ADAS-cog / 11 assessments, of approximately 18 and 28 to 20.

TABLE 1 Demographic and baseline characteristics The number of patients randomized among the four treatment groups is 978. The total number of patients completing this test is high (approximately 80%), with a relatively uniform percentage of interruption due to adverse cases, it is relatively frequent and evenly distributed among all treatment groups (see table 2).

TABLE 2 Interruption of medical test treatment a: most of the interruptions are due, among other reasons, to the withdrawal of consent. In this study there are two endpoints of primary efficacy according to widely used international standards: change in ADAS-cog / 11 valuation in month 5 compared to baseline and CIBIC-plus valuation in month 5. As shown in Table 3 and Figure 1, a significant treatment effect, according to statistics, is shown for the galantamine treatment groups of 16 and 24 mg / day compared to the placebo for ADAS-cog / 11. The results of the analysis based on the last observation of sum and follow data (LOCF), corroborates the result based on the observed data. The galantamine group of 8 mg / day is significantly different from placebo for the case observed but not for LOCF. Galantamine at a dose of 24 mg / day does not appear to be significantly more effective than 16 mg / day. However, the duration of exposure for the target dose differs by 1 month between the two treatment groups (two months versus three months, respectively).

TABLE 3 Change of reference line in ADAS-cog / 11 in month 5 The lowest rating indicates a better condition. The P values, based on the two-way ANOVA model. • Significantly more effective than placebo: *: p < 0.05; **: P < 0.01; ***: P < 0.001; approximate meaning:. : 0.05 < p-value < 0.10. • Significantly more effective than 8 mg / day: +: p < 0.05; *: p < 0.01. For the CIBIC-plus evaluation in month 5, the percentage of patients with improved or no change is significantly higher with the treatment of galantamine with 16 or 24 mg / day compared to placebo or 8 mg / day of galantamine (table 4). After 5 months of treatment, 64 to 68% of patients with 24 or 16 mg / day of galantamine show improvements or remain unchanged from the baseline compared to 47 to 51% with placebo or 8 mg / day of galantamine. The analysis of the imputed data in the LOCF endpoint provides similar results. There is an increase in relation to the dose, apparent in the percentage of patients that show an improvement or that remain unchanged in CIBIC-plus (figure 2).

TABLE 4 CIBIC-plus in month 5 for improved valuations or without change The P value of the Van Elteren test on the 7-point scale Significantly more effective than the placebo: *: p < 0.05; **: p < 0.01; ***: p < 0.001. Significantly more effective than 8 mg / day: + p < 0.05; *: p < 0.01. In month 5 there were significantly more patients who responded with unchanged or improved titrations with 16 and 24 mg / day of galantamine compared to placebo or 8 mg / day of galantamine. The patients who responded with the ADAS-cog / 11 changes of the baseline of 7 or more points, occurred in 15.9% and 22.3% of the patients in the 16 and 24 mg / day groups, respectively, in comparison with the placebo group (7.6%). Usually there is a high percentage Cumulative patients with galantamine treatment responded with minimal improvement of any magnitude compared with placebo (figure 3).

TABLE 5 Analysis of the responders based on the change in ADAS- cog / 11 valuation of the baseline in month 5 P value based on the CMH test Significantly higher percentage of responders than placebo: *: p < 0.05; **; ? < 0.01; ***; p = 0.001; significantly higher percentage of responders than 8 mg / day: + p < 0.05; *: p < 0.01; approximate meaning: *: 0.05 < p-value < 0.10; the difference between 16 and 24 mg / day of approximate value: 0.05 < p-value < 0.10.

An additional, secondary indication captures all changes in activities of daily living performance (ADL) when measured through the scale (ACDS / ADL) of the daily activities of the cooperative study of Alzheimer's disease. As previously mentioned, this scale is composed of 23 elements that have been tested and validated in patients with Alzheimer's disease of medium to moderately severe category. The treatment of galantamine with 16 or 24 mg / day for 5 months is, according to the statistics, more effective to maintain the total ADL valuation in the baseline levels than the placebo treatment or 8 mg / day of galantamine ( box 6). The dose-related effect of galantamine treatment is apparent in Figure 4 showing the change in total ADL assessment over time.

TABLE 6 Change in the total ADL valuation of the reference line in month 5 A higher rating indicates an improvement condition. P values based on a two-way ANOVA model. Significantly more effective than placebo: **; p < 0.01; ***: p = 0.001; Signifier more effective than 8 mg / day: + p < 0.05; *: p = O.01. An advantage is observed, according to the statistic, significant (p <0.05) in the change in the total NPl valuation in month 5 in relation to the baseline for 16 and 24 mg / day of galantamine compared to a deterioration with placebo or 8 mg / day of galantamine (table 7 and figure 5). An increase in the assessment indicates a worsening in the condition. In this way, we observed a maintenance of the neuropsychiatric behavior observed with galantamine at 16 and 24 mg / day.

TABLE 7 m i n the total NPl valuation of the reference line in month 5 Higher scores indicate a worsened condition. The P values based on the two-way ANOVA model. Significantly more effective than placebo: *: p < 0.05 The most common adverse cases are equally distributed across treatment groups with the exception of cases that are associated with cholinomimetic agents (Table 8). Of these related cases, nausea, vomiting and anorexia show an occurrence related to the dose, which is relatively low in incidence.

TABLE 8 Incidence of the most frequent adverse cases (< 5%): (%) of the number of patients For the majority of adverse cases of clinical interest, as shown in Table 9, there are no differences or there are slight dose-related differences between the treatment groups. For bradycardia, there is a higher incidence for patients treated with galantamine compared to placebo but there is no apparent dose-related association. For syncope, there is a slight increase in relation to the dose in the incidence with 24 mg / day of galantamine, without However, 3 of these cases occurred at a lower dose during the assessment, and are therefore attributed to a lower dose of galantamine. Consequently, the incidences shown in Table 6 are very likely to have been overestimated for the occurrence of syncope in very high doses. In addition, 10 of 18 patients who experienced an episode of syncope took a concomitant cardiovascular medication that included beta blockers, calcium channel blockers, ACE inhibitors, and / or diuretics. Of these 18 patients, 11 have an active cardiovascular disease indicated in their past medical history. Therefore, a majority of patients who experienced syncope have either a cardiovascular condition or are in cardiovascular medical treatment.

TABLE 9 Adverse cases of clinical interest The incidence of serious adverse events is comparable across all treatment groups and (with the exception of syncope) they do not show trends in relation to dose (Table 10). The four adverse cases, serious more frequent with galantamine and with an incidence of at least 1% of patients in any group are injury, syncope, fainting and myocardial infarction. There are no increases in relation to the dose in adverse, serious cases related to Gl. The only serious adverse event showing a relationship with the dose is syncope, however, for reasons already provided, these percentages may be an overestimation.

TABLE 10 Serious adverse cases (with D2 patients in any group) In the whole test, 11 deaths occurred. There are no patterns related to the dose apparent in the occurrence of these deaths. The investigator did not consider that the death was related to the medical treatment of the test. The results of this example confirm that treatment with either 16 mg / day or 24 mg / day of galantamine leads to an improvement, according to the statistics, that is significant in neuropsychiatric behavior, when it is determined through NPl assessment in the month 5 in relation to the line of reference with 16 and 24 mg / day compared to a deterioration with placebo or 8 mg / day of galantamine. All scientific publications and patent documents are listed here for reference. The present invention has been described with respect to the preferred embodiments. However, it will be obvious to those skilled in the art that a number of variations and modifications can be made without departing from the scope of the invention as described in the following claims.

Claims (11)

NOVELTY OF THE INVENTION CLAIMS

1. - The use of an effective amount of galantamine or a pharmaceutically acceptable salt thereof, for the production of a medicament for the treatment of neuropsychiatric behavior associated with the Alzheimer's disease.

2. The use as claimed in claim 1, wherein the galantamine is administered from about 1 mg to about 100 mg per day.

3. The use as claimed in claim 2, wherein the galantamine is administered from about 5 mg to about 50 mg per day.

4. The use as claimed in claim 3, wherein the galantamine is administered from about 16 mg to about 32 mg per day.

5. The use as claimed in claim 4, wherein the galantamine is administered in a dose of about 24 mg per day, where the dose is reached after a dose assessment 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 dose of about 24 mg / day and up.

6. The use as claimed in claim 4, wherein the galantamine is administered at a dose of about 32 mg per day, wherein said dose is reached after an assessment of 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 dose daily dose of 32 mg / day and above.

7. The use as claimed in claim 4, wherein the galantamine is administered in a dose of about 16 mg to about 24 mg of galantamine, wherein the dose is reached after a titration of about 2 to about 10 weeks with the initial dose of about 8 mg increasing to a final dose of about 16 mg to about 24 mg.

8. The use as claimed in claim 7, wherein the galantamine is administered in a dose of about 24 mg / day, wherein said dose is reached after a dose assessment of about 8 mg / day for about 2 weeks to about 4 weeks, followed by a dose of about 16 mg / day for about 2 weeks to about 4 weeks, followed by a daily dose of about 24 mg / day and up.

9. The use as claimed in claim 7, wherein the galantamine is administered in a dose of about 24 mg / day, where the dose is reached after a dose assessment of about 8 mg / day for about 4 weeks, followed by a dose of about 16 mg / day, for about 4 weeks, followed by the daily dose of about 24 mg / day and up.

10. The use as claimed in claim 4, wherein the galantamine is administered in a dose of about 16 mg / day, wherein the The dose is reached after an evaluation of a dose of about 8 mg / day for about 2 weeks to about 4 weeks, followed by the daily dose of about 16 mg / day and up.

11. The use as claimed in claim 9, wherein the galantamine is administered in a dose of about 16 mg / day, where the dose is reached after a dose assessment of about 8 mg / day for about 4 weeks, followed by the daily dose of about 16 mg / day and up.