CA2310926C - A use of galantamine for the treatment of neuropsychiatric behaviour associated with alzheimer's disease - Google Patents
A use of galantamine for the treatment of neuropsychiatric behaviour associated with alzheimer's disease Download PDFInfo
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Abstract
Galantamine has be 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.
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
A USE OF GA:LANTAMINE FOR THE TREATMENT OF
NEUROPSYCHIt~TRIC BEHAVIOUR ASSOCIATED WITH ALZHEIMER'S
DISEASE
The present invention relates to the use of an effective amount of galantamine for the treatment of neuropsychiatric behaviour associated with Alzheimer's disease.
BACKGROUND C>F THE INVENTION
Galantamine is a reversible cholinesterase inhibitor that can be isolated from a number of different plant sources, including daffodil bulbs. Galantamine interacts competitively with the enzyme, acetylcholinesterase, and demonstrates a 10 to 50 fold selectivity for acetyl vs. but:yryl cholinesterase.
Galantamine has been used for the treatment of a number of chronic diseases, where life-long treatment rnay be necessary. Galantamine has been shown to be effective in the treatment of arthritic disorders (Canadian Patent application 2,251,114);
fatigue syndromes (Canadian Patent application 2,108,880); mania (Canadian Patent application 2,062,094);schizophrenia (Canadian Patent application 2,108,880);
memory dysfunction, including Alzheimer's Disease (United States Patent 4,663,318);
alcoholism (Canadian Patent 2,039,197); nicotine dependence (Canadian Patent application 2,153,570); disorders of attention (PCT publication WO 99/21561) and jet lag (Canadian Patent application 2,193,473).
However, none of the studies demonstrate the usefulness of galantamine for the treatment of neuropsychiatric behaviour associated with Alzheimer's disease.
SUNINIARY OF Tl-~ INVENTION
Thus, according to the present invention there is provided a use of of galantamine for the treatment of neuropsychiatric behaviour associated with Alzheimer's disease.
NEUROPSYCHIt~TRIC BEHAVIOUR ASSOCIATED WITH ALZHEIMER'S
DISEASE
The present invention relates to the use of an effective amount of galantamine for the treatment of neuropsychiatric behaviour associated with Alzheimer's disease.
BACKGROUND C>F THE INVENTION
Galantamine is a reversible cholinesterase inhibitor that can be isolated from a number of different plant sources, including daffodil bulbs. Galantamine interacts competitively with the enzyme, acetylcholinesterase, and demonstrates a 10 to 50 fold selectivity for acetyl vs. but:yryl cholinesterase.
Galantamine has been used for the treatment of a number of chronic diseases, where life-long treatment rnay be necessary. Galantamine has been shown to be effective in the treatment of arthritic disorders (Canadian Patent application 2,251,114);
fatigue syndromes (Canadian Patent application 2,108,880); mania (Canadian Patent application 2,062,094);schizophrenia (Canadian Patent application 2,108,880);
memory dysfunction, including Alzheimer's Disease (United States Patent 4,663,318);
alcoholism (Canadian Patent 2,039,197); nicotine dependence (Canadian Patent application 2,153,570); disorders of attention (PCT publication WO 99/21561) and jet lag (Canadian Patent application 2,193,473).
However, none of the studies demonstrate the usefulness of galantamine for the treatment of neuropsychiatric behaviour associated with Alzheimer's disease.
SUNINIARY OF Tl-~ INVENTION
Thus, according to the present invention there is provided a use of of galantamine for the treatment of neuropsychiatric behaviour associated with Alzheimer's disease.
In a further embodiment there is provided a method of treating neuropsychiatric behaviour associated with Alzheimer's disease by administering to a patient in need thereof a safe and effective dose of galanatamine or a pharmaceutically acceptable salt thereof.
BRIEF DESCRIPTION OF' THE DRAWINGS
These and other features of the invention will become more apparent from the following description in which reference is made to the appended drawings wherein:
FIGURE 1 shows the mean change from baseline by treatment group over time in ADAS-cog/11 (observed case).
FIGURE 2 shows the mean change from baseline by treatment group over time in CIBIC'-plus (observed case).
FIGURE 3 shows the cumulative percentage of patients with specified changed from baseline at Month 5 in ADAS-cog/11 scores.
FIGURE 4 shows the change: in ADL performance from baseline over time at Month 5.
FIGURE 5 shows the change in NPI score from baseline over time to Month 5.
DESCRIPTION OF PREFERRED EMBODIMENT
The present invention relates 1:o the use of an effective amount of galantamine for the treatment of neuropsychiatric: behaviour associated with Alzheimer's disease.
Galantamine, a tertiary alkaloid, has been isolated form the bulbs of the Caucasian snowdrops Galantanus woronowi (Proskurnina, N. F. and Yakoleva, A. P. 1952, Alkaloids of Galanthus woronowi. II. Isolation of a new alkaloid. (In Russian.) Zh.Obschchei Khim. (J. Gen. Chem.) 22, 1899-1902). It has also been isolated from the common snowdrop Galanthus nivalis (Boit, 1954) Chem. Ber. 87: 724-725.
Galantamine is a well-known acetylcholinesterase inhibitor which is active at nicotinic receptor sites but not on muscarinic receptor sites. It is capable of passing the blood-brain barrier in humans, and presents no severe side effects in therapeutically effective dosages.
BRIEF DESCRIPTION OF' THE DRAWINGS
These and other features of the invention will become more apparent from the following description in which reference is made to the appended drawings wherein:
FIGURE 1 shows the mean change from baseline by treatment group over time in ADAS-cog/11 (observed case).
FIGURE 2 shows the mean change from baseline by treatment group over time in CIBIC'-plus (observed case).
FIGURE 3 shows the cumulative percentage of patients with specified changed from baseline at Month 5 in ADAS-cog/11 scores.
FIGURE 4 shows the change: in ADL performance from baseline over time at Month 5.
FIGURE 5 shows the change in NPI score from baseline over time to Month 5.
DESCRIPTION OF PREFERRED EMBODIMENT
The present invention relates 1:o the use of an effective amount of galantamine for the treatment of neuropsychiatric: behaviour associated with Alzheimer's disease.
Galantamine, a tertiary alkaloid, has been isolated form the bulbs of the Caucasian snowdrops Galantanus woronowi (Proskurnina, N. F. and Yakoleva, A. P. 1952, Alkaloids of Galanthus woronowi. II. Isolation of a new alkaloid. (In Russian.) Zh.Obschchei Khim. (J. Gen. Chem.) 22, 1899-1902). It has also been isolated from the common snowdrop Galanthus nivalis (Boit, 1954) Chem. Ber. 87: 724-725.
Galantamine is a well-known acetylcholinesterase inhibitor which is active at nicotinic receptor sites but not on muscarinic receptor sites. It is capable of passing the blood-brain barrier in humans, and presents no severe side effects in therapeutically effective dosages.
Galantarnine has been used extensively as a curare reversal agent in anaesthetic practice in Eastern bloc countries (cf. review by Paskow, Galanthamine, Hdbk.
Exp.
Pharmac. 79.. 653-672, 1986) and also experimentally in the West (cf. Bretagne and Valetta, "Essais Cliniques en Anesthesiologie D'Un Nouvel Anticholinesterasique La Galanthaminf:," Anesth. Analges, 22, 285-292, 1965: Wislicki, "Nivalin (Galanthamine Hydrobromide), an Additional Decurarizing Agent, Some Introductory Observations," Brit. J. Anaesth. 39, 963-968, 1967; Consanitis et al., "A
Comparative Study of Galanthamine Hydrobromide and Atropine/Neostigmine in Conscious Volunteers," Der Anaesthesist, 416-421, 1971).
Galantamine has been markexed by the company Waldheim (Sanochemia Gruppe) as NivalinT"' in Germany and Austria since the 1970s for indications such as facial neuralgia.
In the present invention when we refer to galantamine we include within this term galantamine itself, derivatives and salts thereof, such as halides, for example galantamine hydrobromide.
For the purposes of the present invention galantamine and derivates and salts thereof may be formulated according to convention methods of pharmacy, together where appropriate with one or more pharmaceutically acceptable carriers, excipients or diluents, as is known in the art. Such formulations can take the form of tablets, capsules, solutions, or lozenges, pessaries, creams, suppositories or transdermal formulations, depending on the route of administration.
Galantamine has been used for the treatment of a number of chronic diseases, where 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);
fatigue syndromes (Canadian Patent application 2,108,880); mania (Canadian Patent application 2,062,094); sclaizophrenia (Canadian Patent application 2,108,880);
memory dysfunction, including Alzheimer's Disease (United States Patent 4,663,318);
alcoholism (Canadian Patent 2,039,197); nicotine dependence (Canadian Patent application 2,153,570); disorders of attention (PCT publication WO 99/21561) and jet lag (Canadian Patent application 2,193,473).
According to the present invention a safe and effective amount of galantamine can be used for the treatment of neuropsychiatric behaviour associated with Alzheimer's disease.
Precise dosage rates and regimes can be determined empirically by the medical practitioner, depending on individual circumstances. For example, if the compound is delivered orally, a daily dose of about 1 mg to about 100 mg. In a further example the compound can be delivered at about 5 mg to about 50 mg per day. In yet a further example the compound can be delivered at about 16 mg to about 32 mg per day.
Precise daily dosages can be; selected from 16 mg, 18 mg, 24 mg or 32 mg per day.
It is preferred that the daily dosage be divided into two or three equal dosages.
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 introduced to the drug slowly over a number of weeks.
In one embodiment of the present invention the patient is introduced to galantamine slowly from about 2 weeks to about 10 weeks, wherein the dose is 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 thereafter.
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 a week, followed by a maintenance dose of about 32 mg;/day thereafter.
In one embodiment of the present invention the patient receives a dose of about 8 mg/day for from about 2 weeks to about 4 weeks, followed by a dose of about 16 -$-mg/day for from af~out 2 weeks to about 4 weeks, followed by a maintenance dose of about 24 mg/day thereafter.
In one example of this embodiment the patient receives a dose of about 8 mg/day for about 4 weeks, followed by a dose of about 16 mg/day for about 4 weeks, followed by a maintenance dose of about 24 mg/day thereafter.
In a further embodiment of the present invention the patient receives a dose of about 8 mg/day for from about 2 'weeks to about 4 weeks, followed by a maintenance dose of about 16 mg/day thereafter. In one example of this embodiment the patient receives a dose of about 8 m;;/day for about 4 weeks, followed by a maintenance dose of about 16 mg/day thereafter.
According to the present invention, the neuropsychiatric behaviour associated with Alzheimer's Disease includes for example: delusions, hallucinations, agitation/aggression, dysphoria, anxiety, euphoria, apathy, disinhibition, irritability/lability and aberrant motor behavior.
The present invention is illustrated by the following example, which is not to be construed as limiting.
EXAMPLES
Patients diagnosed vvith Alzheimer's Disease (approximately 910) were randomized to one of four treatment arms: placebo; 8 weeks titration to galantamine 24 mg/day; 4 weeks titration to l;alantamine 16 mg/day, or galantamine 8 mg/day, no titration needed, for five months. Patients included in this study must have been diagnosed with Alzheimer's Disease, had an Alzheimer's Disease Assessment Scale (Rosen, W.G.
et al., Amer. J. Psychiatry, 14.1: 1356- 1364, 1984) cognitive portion (ADAS-cog-11) score of at least 18 and had a history of cognitive decline that was gradual at the onset and progressive over a period of at least six months.
The titration schedules for the various treatment arms are as follows:
Subjects in the Plac;ebo group received 21 weeks (5 months) of placebo medication.
Subjects in group Gal 24 received 4 weeks of 8 mg/day galantamine (4 mg, twice daily (bid)), 4 weeks of 16-mg/day galantamine (8 mg, bid) and 13 weeks of 24 mg/day galantamine (12 m~;, bid). Subjects in group Gal 16 received 4 weeks of 8 mg/day galantamine (4 mg, bid) and 17 weeks of 16-mg/day galantamine (8 mg, bid).
Subjects in group Gal 8 received 8 mg/day (4 mg, bid) immediately upon randomization and continued on that dose for 21 weeks.
All patients were .monitored throughout the study, with follow-up and cognitive evaluation at four cheeks, three months and five months after the start of the study.
The primary efficacy endpoints were the change from baseline ADAS-cog/11 and the CIBIC-plus score (~Cliniciar~'s Interview Based Impression of Change Plus Family Input) at month five . These t:wo tests together with the Mini-Mental State Examination (MMSE), which was performed at the screening stage, are discussed below:
The ADAS consists of two parts -- a cognitive subscale and a behavioral subscale. The behavioral subscale was not lie used in this study. The cognitive subscale, the ADAS--cog-11, consisted of Word Recall and Word Recognition memory tests, Object and Finger Naming, Commands,, Constructional Praxis, Ideational Praxis, Orientation, Remembering Test l(nstructions, Spoken language Ability, Comprehension of Spoken language and Word Finding Difficulty was the primary variable in this study.
In addition to the above specified items from the ADAS-cog-11, two additional ADAS
items were assessed: The Concentration and Distractibility item, originally part of the behavioral subscale, was performed and a Delayed Word Recall test (delayed recall of the word recall items) was added to give additional information regarding cognitive status. The expandf:d 13 item ADAS (ADAS-cog 13) was a secondary variable.
To reduce variability due to circadian fluctuations in cognitive status the ADAS was done always at the same time of the day, preferably before noon. Only a trained ADAS rater performed the test. Ideally the ADAS rater was not involved in the treatment of the subject and should have no access to AE (adverse event) reporting.
The ADAS was performed at visits 1, 2, 3, 4 and 5 (screening, baseline, week 4, week 13 and month 5 or upon early discontinuation of trial medication intake). For word recall and word recognition two parallel wordlists, list A and list B were employed.
List A was used at visits 1 and 3, List B at visits 2, 4, and 5 or upon early discontinuation of trial medication intake. For practical reasons the words for word recognition was presented only once. The total score of the 11 cognitive items on the original ADAS cognitive subscale (ADAS-cog/11, Range: 0-70) was recorded.
The CIBIC-plus score was a second primary variable. An independent, experienced and properly trained clinician provided a global impression of the subject's deterioration or improvement over the course of the trial, based on separate interviews with the subject and caregivers. If helpful, the CIBIC rater audiotaped or videotaped the baseline interview for future reference.
Change from baseline was rated on an 7 point scale, where 1 indicates markedly improved, 4 indicate, no change and 7 indicates markedly worse. The CIBIC-plus was performed at visit ~ , 3, 4, and S (baseline, week 4, week 13, and month 5 or upon early discontinuation of trial :medication intake). Only a trained CIBIC rater performed the test.
The MMSE is a veer brief test of cognitive functions including orientation to time and place, instantaneous recall, short-term memory, and ability to perform serial subtractions or reverse spelling, constructional capacities and the use of language. The MMSE score was derived from the sum of the points assigned to each completed task.
A total possible score is 30. The MMSE will be performed at visit 1(screening).
_$-Secondary efficacy variables include ADAS-cog/11 and the ADCS/ADL scale . The ADCS/ADL test is discussed below:
The ADCS/ADL scale is a 23-item informant-based assessment scale measuring widely applicable daily activities appropriate for patients in the mild to moderate category of Alzheimer's Disease. The 23 items were selected for measurement from the larger set of 45 items studied by Galasko et al (Alzheimer Disease and Associated Disorders, Vol 11, Suppl. 2, 1997j. These individual items were scored from 0-3 to 07, depending on the question, with a possible total score of 78. A higher score indicated a higher functioning patient.
The items and scoring were as follows:
Eating (0-3) Walking (0-3) Toileting (0-3) Bathing (0-3) Grooming (0-3) Dressing selection of ~~lothes (0-3) physical per:Formancf: (0-4) Telephone (0-5) Television (0-3) Conversation (0-3) Dishes (0-3) Managing personal belongings (0-3) Obtaining beverages (0-3) Making a meal or snack (0-~G) Disposal of garbage (0-3) Travel outside homf: (0-4) Shopping (0-4) Keeping appointments (0-3) Ability to be left alone (0-3) Current events (0-3 ) Reading (0-2) Writing (0-3) Hobbies (0-3) Household appliances (0-4) Neuropsychiatric bf;havior was monitored by a test known as The Neuropsychiatric Inventory (NPI) (Cummings, J.L. et al., Neurology, 44: 2308-2314, 1994). The NPI
covers 10 domains of behaviors reported in patients with Alzheimer's Disease:
delusions, hallucinations, agitation/aggression, dysphoria, anxiety, euphoria, apathy, disinhibition, irritability/lability and aberrant motor behavior. For each domain abnormal behavior c:an be absent (score 0) or present. If present, the frequency and severity of abnorm;~l behavior is rated based on answers to a set of subquestions regarding behavior; relevant to that domain. Severity was rated 1 to 3 as mild, moderate or marked. Frequency was rated 1 to 4 as occasionally, often, frequently and very frequently. The product of frequency and severity (maximum score = 12) was calculated for each domain. A total of NPI was calculated as the sum of the frequency and severity produces (maximum score = 120). The NPI was performed at visits 2, 3, 4 and 5 (baseline., week 4, week 13, and month S or upon early discontinuation of trial medication).
All data was compared among the treatment groups - placebo, galantamine 8 mg/day, 16 mg/day and 24 mg/day.
Between treatment ;groups comparisons (with particular focus on differences from placebo) were done at each scheduled time interval and for each endpoint imputation scheme. These comparisons will be based on the change from baseline scores for efficacy parameters with baseline (e.g., ADAS-cog/11) and the original scored for efficacy parameters without 'baseline e.g., CIBIC-plus).
For continuous data., a two-way analysis of variance (ANOVA) model with treatment and investigator as factors were used to compare the treatment groups for the change from baseline data. The interaction between treatment and investigator was examined.
The impact of the baseline score on change from baseline was evaluated. If the S baseline score was found to be a relevant predictor (p < 10), an analysis of covariance model (ANCOVA) 'was used to assess the treatment effects and the interaction between treatment and baseline score was examined. If the parametric methods were deemed inappropriate (normality assumption violated), nonparametric methods such as two-way ANOVA on rankedi data, Van Elteren test, controlling for investigator, was used.
Following ANOV~?,, Fisher's LSD procedure was used for pairwise comparisons between each galanthamine group and the placebo group. A linear contrast on the main effect for trea~:ment was used to test the dose response relationship.
For ordinal categorical variables such as the CIBIC-plus score, the Van Elteren test controlling for investigator was used for the between group comparison. For the nominal data (e.g. , events rates), the Cochran-Mantel-Haenszel test for general association controlling for investigator was used. A linear contrast on the proportion of patients that stay the same or improve was used to test for increasing response with increasing dose.
If a significant proportion of subjects discontinue prematurely, additional analyses were preformed to evaluate the impact on the results. In addition to the by-visit analysis, method for analysin~; continuous repeated measures were used to evaluate the treatment effect over time.
The safety of the drug was also monitored throughout the study. Blood samples for biochemistry and haematology and random urine sample for urinalysis were taken at each visit and at completion for all efficacy testing. Systolic and diastolic blood pressure were measured in tlae sitting position, pulse and vital signs were recorded at each visit.
Patient Demographics and baseline characteristics were to be well balanced across all treatment groups (T'able 1). The baseline cognitive performance for these Alzheimer's disease patients was mild to moderate as measured by the MMSE and ADAS-cog/11 scores of approximately 18 and 28 to 20.
Table 1: Demographics and baseline characteristics Trial disposition and atient characteristicsPlacebo GAL 8 m GAL 16 GAL 24 m m Total Number 286 140 279 273 of Patients Completed: N 2,40 (84 108 (77 219 (79 212 (78 ( % ) % ) % ) % ) % ) Gender Male 108 (38 50 (36 % 105 (38 90 (33 % ) ) % ) % ) Female 178 (62 90 (64 % 174 (62 183 (67 % ) ) % ) % ) Age: (Years) Mean (SE) 77.1 (0.46)76.0 (0.61)76.3 (0.49)77.7 (0.43) Median (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 % ) % ) % ) % ) Hispanic 3 3 5 4 Oriental 3 0 1 3 Other 0 0 1 3 Sum of MMSE:
Mean (SE) 1'7.7 (0.21)18.0 (0.30)17.8 (0.21)17.7 (0.23) Median (Min-Max)19 (10-22) 19.0 (10-22)19 (10-22)19.0 (10-22) Baseline ADAS-cog/11 -- 29.4 (0.63)27.8 (0.94)29.4 (0.66)29.0 (0.67) Mean (SE) 27 (10-61) 26 (11-62) 28 (10-62)27 (10-54) Median (Min-Max) The number of patients randomized among the four treatment groups was 978. The total number of patients completing this trail was high (approximately 80 % ) with a relatively even rate of discontinuation due to adverse events was relatively infrequent and evenly distributed among all treatment groups (see Table 2).
Table 2: Iliscontinuation of trial medication Trial termination reasonsPlacebo GAL GAL GAL
8 m /da 16 m /da 24 m /da Total patients 286 140 279 273 Total completed: N 240 (84 108 (77 219 (79 212 (78 ( ~o ) %) % ) % ) % ) Total discontinued 46 ( 16 32 (23 60 (22 61 (22 (DC): N ( % ) % ) % ) % ) % ) DC due to adverse c;vent20 (7 9 (6 % 19 (7 27 ( % ) ) % ) 10 %
) DC due to inefficacy 0 1 (1 % 0 2 (1 ) %) DC due to other' 23 (8 18 ( 13 29 ( 10 20 (7 % ) % ) % ) % ) DC due to ineligible: 0 0 4 (1 % 2 (1 to continue ) %) DC due to non-compliance3 ( 1 4 (3 % 7 (3 % 10 (4 % ) ) ) % ) DC due to withdrawal 0 0 1 (0.4 0 of consent % ) a: The majority of discontinuations due to other reasons were for withdrawal of consent.
In this study there were two primary efficacy endpoints according to widely used international standards: change in ADAS-cog/11 score at Month 5 compared to baseline and CIBIC-plus scare at Month 5.
As shown in Table 3 and Figure 1, a statistically significant treatment effect was shown for the 16 and 24 m~;/day galantamine treatment groups compared with placebo for the ADAS-cog/11. Re;~ults from analysis based on the last observation carried-forward (LOCF) data cor~ob~~rate the result based on observed data. The 8 mg/d~y galantamine group was significantly different from placebo for the observed case but not for the LOCF. Galantamin.e at a dose of 24 mg/day did not appear to be significantly more effective than 16 rrtg/day. However, the duration of exposure to the target dose differed by 1 month between the two treatment groups (two months versus three months respectively).
Table 3: Change from baseline in ADAS-cog/11 at Month 5 Placebo GAL 8mg GAL l6mQ GAL 24me Month 5: (observedn=225 n=101 n=208 n=211 case) Mean (SE) 1.8 (0.43)0.1 (0.58)*-1.5 (0.40)***t-1.8 (0.44)***t Month 5: (LOCF) n=255 n=126 n=253 n=253 Mean (SE) 1.7 (0.39)0.4 (0.52)0-1.4 (0.35)***~-1.4 (0.39)***~
Lower score matcates better condttton. Y-Values based on two-way ANOVA model.
Significantly n;.ore effective than placebo: *: ps0.05; **: ps0.01; ***:
ps0.001; Approached significance: 0: 0.05 <: p-value < 0.10.
~ Significantly rr,ore effective than 8 mg/day: t: ps0.05; t: ps0.01.
For the CIBIC-plus assessment at Month 5, the percent of patients with improved or unchanged scores was sig:nifucantly greater with galantamine treatment with 16 or 24 mg/day compared with 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 showed improvement or were unchanged from baseline compared with 47 % to 51 % with placebo or 8 mg/day of galantamine. The analysis of imputed data at LOCF
endpoint gave similar results. There was an apparent dose-related increase in the percentage of patients showing improvement or no change in the CIBIC-plus (Figure 2).
Table 4: CIBIC-plus at Month 5 for improved or unchanged scores Placebo GAL 8 mg GAL 16 mg GAL 24 mg Month 5: (observed.n=:237 n=106 n=212 n=212 case) Im roved/no char 11:? (47%)54 (51%) 143 (68%)***t136 (64%)***#
a n~;%) Month 5: (LOCF) n=263 n=128 n=255 n=253 Improved/no change1213 (49 68 (53 169 (66 162 (64 n~; % ) % ) % ) % )***t % )***t P-value from Van Elteren test on the 7-point scale Significantly more effective than placebo: *: ps0.05; **: ps0.01; ***:
ps0.001.
Significantly more effective than 8 mg/day: t: ps0.05; $: ps0.01.
At Month 5 there were significantly more patients who responded with no change or improved scores wish 16 and 24 mg/day of galantamine compared with placebo or mg/day of galantamine. Patients responding with ADAS-cog/ 11 changes from baseline of 7 or more points occurred in 15.9 % and 22.3 % of patients in the 16 and 24 mg/day groups, respectively, compared with the placebo group (7.6%). There was overall a higher cumulative percentage of patients with galantamine treatment who responded with a minimum irrtprovement of any magnitude compared with placebo (Figure 3).
Table 5: Rfsponders analysis based on change in ADAS-cog/11 score from baseline at Month 5 Definition of Placebo GAL 8 mg GAL 16 mg GAL 24 mQ
res ondc:=
n=225 n=101 n=208 n=211 Changes0 points 94 (41.8) 47 (46.5) 136 (65.4)***#137 (64.9)***$
n (%.) Changes-4 points44 (19.6) 26 (25.7) 74 (35.6)***078 (37.0)***t n (~o) Changes-7 pointsll7 (7.6) 14 (13.9) 33 (15.9)**47 n (fib) (22.3)***0 Changes-10 points8 (3.6) 6 (5.9) 15 (7.2) 22 ( 10.4)**
n ( % ) Y-value based on (:MH test Significantly higher percentage of responders than placebo: *: ps0.05; **:
ps0.01;
***: ps0.001;
Significantly higher percentage of responders than 8 mg/day: t: ps0.05; $:
ps0.01;
Approached ~;ignificance: 0: 0.05 < p-value < 0.10;
The differen<:e berivee;n 16 and 24 mg/day approached significance ~: 0.05 < p-vlaue < 0.10.
An additional secondary indication captures overall changes in Activities of daily Living (ADL) performances as measured by the Alzheimer's Disease Cooperative Study Activities of lJaily Living (ACDS/ADL) scale. As mentioned above this scale is comprised of 23 items that have been tested and validated in patients with mild to moderately severe ~~lzheilner's disease.
Galantamine treatment with 16 or 24 mg/day for 5 months was statistically more effective in maintaining the ADL total score at baseline levels than treatment with placebo or 8 mg/day of galantamine (Table 6). The dose-related effect of galantamine treatment is apparer.~t in Figure 4 that shows change of total ADL score over time.
Table 6: (:hange in Total ADL score from baseline at Month 5 Placebo GAL 8 mg GAL 16 m~ GAL 24 m Month 5: (observedn=235 n=106 n=212 n=212 case) Mean (SE) -4.0 (0.59)-3.1 (0.91)-0.5 (0.55)***t-1.6 (0.61)**
Month 5: (LOCF) n=262 n=129 n=255 n=253 Mean (SE) -3.8 (0.55)-3.2 (0.79)-0.7 (0.050)***~-1.5 (0.56)**
ritgner score matcates oetter conanton. r-values based on two-way ANOVA model.
Significantly more effective than placebo: **: p_<0.01; ***: ps0.001 Significantly more effective than 8 mg/day: t: p<_0.05; $: p<_0.01.
There was a statistically significant (p < 0.05) benefit seen in the change in the total NPI score at Month 5 relative to baseline for 16 and 24 mg/day of galantamine compared with a deterioration with placebo or 8 mg/day of galantamine (Table 7 and Figure 5). An increase in score indicated a worsening in condition. Thus, a maintenance of neunopsychiatric behaviour was observed with galantamine at 16 and 24 mg/day.
Table 7: Change in Total NPI score from baseline at Month 5 Placebo GAL 8 m GAL 16 m GAL 24 'm Month 5: (observedn=234 n=106 n=211 n=212 case) Mean (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 Mean (SE) ~ 2.0 (0.68)2.3 (1.00) -0.1 (0.71)*-0.0 (0.76)*
Higher score indicates worsened condition. p-Values based on two-way ANOVA
model.
~ Significantly more effective than placebo: *: p~0.05 The most common adverse events were evenly distributed across treatment groups with the exception of events that are associated with cholinomimetic agents (Table 8). Of these related event s, nausea, vomiting and anorexia showed a mild dose-related occurrence at a rela~:ively low incidence.
Table 8: Incidence of most frequent (z5%) adverse events: number (%) of patients Adverse event Placebo GAL 8 mg GAL 16 mg GAL 24 (Preferred mg term) Total all patients286 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 % ) Agitation 2'7 (9.4 21 ( 15.0 28 ( 10.0 22 (8.1 % ) % ) % ) % ) Depression 1:5 (5.2%)4 (2.9%) 24 (8.6%) 22 (8.%) Urinary tract 19 (6.6 11 (7.9 23 (8.2 22 (8.1 infection %) % ) % ) % ) Dizziness 10 (3.5 7 (5.0 % 15 (5.4 19 (7.0 % ) ) % ) % ) Injury 1:? (4.2%)5 (3.6%) 12 (4.3%) 16 (5.9%) Diarrhea 1'7 (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 1:3 (4.5%)5 (3.6%) 19 (6.8%) 13 (4.8%0 Weight decrease 4 (1.4%o) 2 (1.4%) 15 (5.4%) 13 (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 % ) ) ) % ) Edema peripheral7 (2.4 9 (6.4 % 8 (2.9 % 7 (2.6 % ) ) ) % ) For most adverse events of clinical interest, as shown in Table 9, there were either no differences or slight dose-related differences between treatment groups. For bradycardia, there was a higher incidence for patients treated with galantamine compared with placebo but there was no dose-related association apparent. For syncope, there was a slight dose-related increase in incidence with 24 mg/day of galantamine, however 3 of these cases occurred at a lower dose during titration, and are therefore attributable to a lower galantamine dose. Consequently, the incidences shown in Table 6 arE: very likely to be over-estimates for the occurrence of syncope at the higher doses. Furthermore, 10 of 18 patients who experienced a syncopal episode were taking concomitant cardiovascular medication including bata-blockers, calcium channel antagonists, ACE inhibitors, and/or diuretics. Of these 18 patients, 11 had - 1~ -active cardiovascular disease listed in their past medical history. Therefore, a majority of patients who experienced syncope had either a cardiovascular condition or were taking cardiovascular medication.
Table 9: Adverse events of clinical interest Adverse events Placebo GAL 8 mg GAL 16 GAL 24 (Prefe:rred mg mg term) Total all patients286 140 279 273 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 1 (0.7 % ) 3 (1.1%) 1 (0.4%) Syncope 2 (0.7%) 2 (1.4%) 5 (1.8%) 9 (3.3%) The incidence of serious adverse events was comparable across all treatment groups and (with the excepoion of syncope) showed no dose-related trends (Table 10).
The four most frequent ~,erious adverse events with galantamine and with an incidence of at least 1 % of patients in any group were injury, syncope, fall, and myocardial infarction. There ware no dose-related increases in GI-related serious adverse events.
The only serious adverse event that showed a dose-relationship was syncope, however, for reasons already ;provided, these rates may be an over-estimate.
Table 10: Serious adverse events (with z 2 patients in any group) Adverse Event (PreferredPlacebo GAL 8 mg GAL 16 GAL 24 mg term) mg Total all patients286 140 279 273 Total patients 31 ( 10. 14 ( 10.0 28 ( 10.0 35 ( 12.8 with amr SAE 8 % ) % ) % ) % ) Injury 4 (1.4%) I (0.7%) 1 (0.4%) 5 (1.8%) Syncope 2 (0.7%) 1 (0.7%) 4 (1.4%) 5 (1.8%) Asthenia 1 (0.3 0 (0.0 2 (0.7 1 (0.4 %
% ) % ) % ) ) Dyspnea 1 (0.3 0 (0.0 2 (0.7 3. ( 1.1 % ) % ) % ) % ) Pneumonia 4 ( 1.4 1 (0.7 2 (0.7 3 ( 1.1 % ) % ) % ) % ) Gi haemorrhage 0 (0.0 0 (0.0 0 (0.0 2 (0.7 %
% ) % ) % ) ) Vomiting 1 (0.3 0 (0.0 2 (0.7 1 (0.4 %
% ) % ) % ) ) Abdominal pain 1 (0.3 0 (0.0 2 (0.7 0 (0.0 %
% ) % ) % ) ) Diarrhea 1 (0.3 0 (0.0 3 ( 1.1 0 (0.0 %
% ) % ) % ) ) Nausea I (0.3 0 (0.0 2 (0.7 0 (0.0 %
% ) % ) % ) ) Basal cell carcinomaI) (0.0 0 (0.0 0 (0.0 2 (0.7 %
% ) % ) % ) ) Breast neoplasm :? (0.7 0 (0.0 0 (0.0 0 (0.0 %
female % ) % ) % ) ) Fall :3 (1.0%)4 (2.9%) 1 (0.4%) 3 (1.1%) Surgical intervention1 (0. 0 (0.0 3 ( 1.1 0 (0.0 %
3 % ) % ) % ) ) Thrombophlebitis I (0.3 0 (0.0 0 (0.0 2 (0.7 %
deep % ) % ) % ) ) Transient ischemic1 (0. 1 (0.7 2 (0. 7 0 (0.0 %
attack 3 % ) % ) % ) ) Myocardial infarction2 (0.7 3 (2.1 1 (0.4 1 (0.4 %
% ) % ) % ) ) Agitation l (0.3 2 ( 1.4 1 (0.4 0 (0.0 %
% ) % ) % ) ) Urinary tract infecti~~n0 (0.0 1 (0.7 2 (0.7 0 (0.0 %
% ) % ) % ) ) Cardiac failure 'L (0.7 0 (0.0 3 ( 1.1 0 (0.0 %
% ) % ) % ) ) Dehydration 0 (0.0 0 (0.0 3 ( 1.1 0 (0.0 %
% ) % ) % ) ) Sepsis :? (0.7 0 (0.0 0 (0.0 0 (0.0 %
% ) % ) % ) ) Throughout the trial there were 11 deaths. There was no apparent dose-related patterns in the occurrences o~E deaths. No death was considered by the investigator to be related to trail medication.
The results of this example confirmed that treatment with either 16 mg/day or 24/mg day of galantamine leads to statistically significant improvement in neuropsychiatric behaviour, as determined by the NPI score at month 5 relative to baseline with mg/day and 24 mg/day compared with a deterioration with placebo or 8 mg/day of galantamine.
The present invention has been described with regard to preferred embodiments.
However, it will be obvious to persons 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.
Exp.
Pharmac. 79.. 653-672, 1986) and also experimentally in the West (cf. Bretagne and Valetta, "Essais Cliniques en Anesthesiologie D'Un Nouvel Anticholinesterasique La Galanthaminf:," Anesth. Analges, 22, 285-292, 1965: Wislicki, "Nivalin (Galanthamine Hydrobromide), an Additional Decurarizing Agent, Some Introductory Observations," Brit. J. Anaesth. 39, 963-968, 1967; Consanitis et al., "A
Comparative Study of Galanthamine Hydrobromide and Atropine/Neostigmine in Conscious Volunteers," Der Anaesthesist, 416-421, 1971).
Galantamine has been markexed by the company Waldheim (Sanochemia Gruppe) as NivalinT"' in Germany and Austria since the 1970s for indications such as facial neuralgia.
In the present invention when we refer to galantamine we include within this term galantamine itself, derivatives and salts thereof, such as halides, for example galantamine hydrobromide.
For the purposes of the present invention galantamine and derivates and salts thereof may be formulated according to convention methods of pharmacy, together where appropriate with one or more pharmaceutically acceptable carriers, excipients or diluents, as is known in the art. Such formulations can take the form of tablets, capsules, solutions, or lozenges, pessaries, creams, suppositories or transdermal formulations, depending on the route of administration.
Galantamine has been used for the treatment of a number of chronic diseases, where 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);
fatigue syndromes (Canadian Patent application 2,108,880); mania (Canadian Patent application 2,062,094); sclaizophrenia (Canadian Patent application 2,108,880);
memory dysfunction, including Alzheimer's Disease (United States Patent 4,663,318);
alcoholism (Canadian Patent 2,039,197); nicotine dependence (Canadian Patent application 2,153,570); disorders of attention (PCT publication WO 99/21561) and jet lag (Canadian Patent application 2,193,473).
According to the present invention a safe and effective amount of galantamine can be used for the treatment of neuropsychiatric behaviour associated with Alzheimer's disease.
Precise dosage rates and regimes can be determined empirically by the medical practitioner, depending on individual circumstances. For example, if the compound is delivered orally, a daily dose of about 1 mg to about 100 mg. In a further example the compound can be delivered at about 5 mg to about 50 mg per day. In yet a further example the compound can be delivered at about 16 mg to about 32 mg per day.
Precise daily dosages can be; selected from 16 mg, 18 mg, 24 mg or 32 mg per day.
It is preferred that the daily dosage be divided into two or three equal dosages.
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 introduced to the drug slowly over a number of weeks.
In one embodiment of the present invention the patient is introduced to galantamine slowly from about 2 weeks to about 10 weeks, wherein the dose is 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 thereafter.
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 a week, followed by a maintenance dose of about 32 mg;/day thereafter.
In one embodiment of the present invention the patient receives a dose of about 8 mg/day for from about 2 weeks to about 4 weeks, followed by a dose of about 16 -$-mg/day for from af~out 2 weeks to about 4 weeks, followed by a maintenance dose of about 24 mg/day thereafter.
In one example of this embodiment the patient receives a dose of about 8 mg/day for about 4 weeks, followed by a dose of about 16 mg/day for about 4 weeks, followed by a maintenance dose of about 24 mg/day thereafter.
In a further embodiment of the present invention the patient receives a dose of about 8 mg/day for from about 2 'weeks to about 4 weeks, followed by a maintenance dose of about 16 mg/day thereafter. In one example of this embodiment the patient receives a dose of about 8 m;;/day for about 4 weeks, followed by a maintenance dose of about 16 mg/day thereafter.
According to the present invention, the neuropsychiatric behaviour associated with Alzheimer's Disease includes for example: delusions, hallucinations, agitation/aggression, dysphoria, anxiety, euphoria, apathy, disinhibition, irritability/lability and aberrant motor behavior.
The present invention is illustrated by the following example, which is not to be construed as limiting.
EXAMPLES
Patients diagnosed vvith Alzheimer's Disease (approximately 910) were randomized to one of four treatment arms: placebo; 8 weeks titration to galantamine 24 mg/day; 4 weeks titration to l;alantamine 16 mg/day, or galantamine 8 mg/day, no titration needed, for five months. Patients included in this study must have been diagnosed with Alzheimer's Disease, had an Alzheimer's Disease Assessment Scale (Rosen, W.G.
et al., Amer. J. Psychiatry, 14.1: 1356- 1364, 1984) cognitive portion (ADAS-cog-11) score of at least 18 and had a history of cognitive decline that was gradual at the onset and progressive over a period of at least six months.
The titration schedules for the various treatment arms are as follows:
Subjects in the Plac;ebo group received 21 weeks (5 months) of placebo medication.
Subjects in group Gal 24 received 4 weeks of 8 mg/day galantamine (4 mg, twice daily (bid)), 4 weeks of 16-mg/day galantamine (8 mg, bid) and 13 weeks of 24 mg/day galantamine (12 m~;, bid). Subjects in group Gal 16 received 4 weeks of 8 mg/day galantamine (4 mg, bid) and 17 weeks of 16-mg/day galantamine (8 mg, bid).
Subjects in group Gal 8 received 8 mg/day (4 mg, bid) immediately upon randomization and continued on that dose for 21 weeks.
All patients were .monitored throughout the study, with follow-up and cognitive evaluation at four cheeks, three months and five months after the start of the study.
The primary efficacy endpoints were the change from baseline ADAS-cog/11 and the CIBIC-plus score (~Cliniciar~'s Interview Based Impression of Change Plus Family Input) at month five . These t:wo tests together with the Mini-Mental State Examination (MMSE), which was performed at the screening stage, are discussed below:
The ADAS consists of two parts -- a cognitive subscale and a behavioral subscale. The behavioral subscale was not lie used in this study. The cognitive subscale, the ADAS--cog-11, consisted of Word Recall and Word Recognition memory tests, Object and Finger Naming, Commands,, Constructional Praxis, Ideational Praxis, Orientation, Remembering Test l(nstructions, Spoken language Ability, Comprehension of Spoken language and Word Finding Difficulty was the primary variable in this study.
In addition to the above specified items from the ADAS-cog-11, two additional ADAS
items were assessed: The Concentration and Distractibility item, originally part of the behavioral subscale, was performed and a Delayed Word Recall test (delayed recall of the word recall items) was added to give additional information regarding cognitive status. The expandf:d 13 item ADAS (ADAS-cog 13) was a secondary variable.
To reduce variability due to circadian fluctuations in cognitive status the ADAS was done always at the same time of the day, preferably before noon. Only a trained ADAS rater performed the test. Ideally the ADAS rater was not involved in the treatment of the subject and should have no access to AE (adverse event) reporting.
The ADAS was performed at visits 1, 2, 3, 4 and 5 (screening, baseline, week 4, week 13 and month 5 or upon early discontinuation of trial medication intake). For word recall and word recognition two parallel wordlists, list A and list B were employed.
List A was used at visits 1 and 3, List B at visits 2, 4, and 5 or upon early discontinuation of trial medication intake. For practical reasons the words for word recognition was presented only once. The total score of the 11 cognitive items on the original ADAS cognitive subscale (ADAS-cog/11, Range: 0-70) was recorded.
The CIBIC-plus score was a second primary variable. An independent, experienced and properly trained clinician provided a global impression of the subject's deterioration or improvement over the course of the trial, based on separate interviews with the subject and caregivers. If helpful, the CIBIC rater audiotaped or videotaped the baseline interview for future reference.
Change from baseline was rated on an 7 point scale, where 1 indicates markedly improved, 4 indicate, no change and 7 indicates markedly worse. The CIBIC-plus was performed at visit ~ , 3, 4, and S (baseline, week 4, week 13, and month 5 or upon early discontinuation of trial :medication intake). Only a trained CIBIC rater performed the test.
The MMSE is a veer brief test of cognitive functions including orientation to time and place, instantaneous recall, short-term memory, and ability to perform serial subtractions or reverse spelling, constructional capacities and the use of language. The MMSE score was derived from the sum of the points assigned to each completed task.
A total possible score is 30. The MMSE will be performed at visit 1(screening).
_$-Secondary efficacy variables include ADAS-cog/11 and the ADCS/ADL scale . The ADCS/ADL test is discussed below:
The ADCS/ADL scale is a 23-item informant-based assessment scale measuring widely applicable daily activities appropriate for patients in the mild to moderate category of Alzheimer's Disease. The 23 items were selected for measurement from the larger set of 45 items studied by Galasko et al (Alzheimer Disease and Associated Disorders, Vol 11, Suppl. 2, 1997j. These individual items were scored from 0-3 to 07, depending on the question, with a possible total score of 78. A higher score indicated a higher functioning patient.
The items and scoring were as follows:
Eating (0-3) Walking (0-3) Toileting (0-3) Bathing (0-3) Grooming (0-3) Dressing selection of ~~lothes (0-3) physical per:Formancf: (0-4) Telephone (0-5) Television (0-3) Conversation (0-3) Dishes (0-3) Managing personal belongings (0-3) Obtaining beverages (0-3) Making a meal or snack (0-~G) Disposal of garbage (0-3) Travel outside homf: (0-4) Shopping (0-4) Keeping appointments (0-3) Ability to be left alone (0-3) Current events (0-3 ) Reading (0-2) Writing (0-3) Hobbies (0-3) Household appliances (0-4) Neuropsychiatric bf;havior was monitored by a test known as The Neuropsychiatric Inventory (NPI) (Cummings, J.L. et al., Neurology, 44: 2308-2314, 1994). The NPI
covers 10 domains of behaviors reported in patients with Alzheimer's Disease:
delusions, hallucinations, agitation/aggression, dysphoria, anxiety, euphoria, apathy, disinhibition, irritability/lability and aberrant motor behavior. For each domain abnormal behavior c:an be absent (score 0) or present. If present, the frequency and severity of abnorm;~l behavior is rated based on answers to a set of subquestions regarding behavior; relevant to that domain. Severity was rated 1 to 3 as mild, moderate or marked. Frequency was rated 1 to 4 as occasionally, often, frequently and very frequently. The product of frequency and severity (maximum score = 12) was calculated for each domain. A total of NPI was calculated as the sum of the frequency and severity produces (maximum score = 120). The NPI was performed at visits 2, 3, 4 and 5 (baseline., week 4, week 13, and month S or upon early discontinuation of trial medication).
All data was compared among the treatment groups - placebo, galantamine 8 mg/day, 16 mg/day and 24 mg/day.
Between treatment ;groups comparisons (with particular focus on differences from placebo) were done at each scheduled time interval and for each endpoint imputation scheme. These comparisons will be based on the change from baseline scores for efficacy parameters with baseline (e.g., ADAS-cog/11) and the original scored for efficacy parameters without 'baseline e.g., CIBIC-plus).
For continuous data., a two-way analysis of variance (ANOVA) model with treatment and investigator as factors were used to compare the treatment groups for the change from baseline data. The interaction between treatment and investigator was examined.
The impact of the baseline score on change from baseline was evaluated. If the S baseline score was found to be a relevant predictor (p < 10), an analysis of covariance model (ANCOVA) 'was used to assess the treatment effects and the interaction between treatment and baseline score was examined. If the parametric methods were deemed inappropriate (normality assumption violated), nonparametric methods such as two-way ANOVA on rankedi data, Van Elteren test, controlling for investigator, was used.
Following ANOV~?,, Fisher's LSD procedure was used for pairwise comparisons between each galanthamine group and the placebo group. A linear contrast on the main effect for trea~:ment was used to test the dose response relationship.
For ordinal categorical variables such as the CIBIC-plus score, the Van Elteren test controlling for investigator was used for the between group comparison. For the nominal data (e.g. , events rates), the Cochran-Mantel-Haenszel test for general association controlling for investigator was used. A linear contrast on the proportion of patients that stay the same or improve was used to test for increasing response with increasing dose.
If a significant proportion of subjects discontinue prematurely, additional analyses were preformed to evaluate the impact on the results. In addition to the by-visit analysis, method for analysin~; continuous repeated measures were used to evaluate the treatment effect over time.
The safety of the drug was also monitored throughout the study. Blood samples for biochemistry and haematology and random urine sample for urinalysis were taken at each visit and at completion for all efficacy testing. Systolic and diastolic blood pressure were measured in tlae sitting position, pulse and vital signs were recorded at each visit.
Patient Demographics and baseline characteristics were to be well balanced across all treatment groups (T'able 1). The baseline cognitive performance for these Alzheimer's disease patients was mild to moderate as measured by the MMSE and ADAS-cog/11 scores of approximately 18 and 28 to 20.
Table 1: Demographics and baseline characteristics Trial disposition and atient characteristicsPlacebo GAL 8 m GAL 16 GAL 24 m m Total Number 286 140 279 273 of Patients Completed: N 2,40 (84 108 (77 219 (79 212 (78 ( % ) % ) % ) % ) % ) Gender Male 108 (38 50 (36 % 105 (38 90 (33 % ) ) % ) % ) Female 178 (62 90 (64 % 174 (62 183 (67 % ) ) % ) % ) Age: (Years) Mean (SE) 77.1 (0.46)76.0 (0.61)76.3 (0.49)77.7 (0.43) Median (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 % ) % ) % ) % ) Hispanic 3 3 5 4 Oriental 3 0 1 3 Other 0 0 1 3 Sum of MMSE:
Mean (SE) 1'7.7 (0.21)18.0 (0.30)17.8 (0.21)17.7 (0.23) Median (Min-Max)19 (10-22) 19.0 (10-22)19 (10-22)19.0 (10-22) Baseline ADAS-cog/11 -- 29.4 (0.63)27.8 (0.94)29.4 (0.66)29.0 (0.67) Mean (SE) 27 (10-61) 26 (11-62) 28 (10-62)27 (10-54) Median (Min-Max) The number of patients randomized among the four treatment groups was 978. The total number of patients completing this trail was high (approximately 80 % ) with a relatively even rate of discontinuation due to adverse events was relatively infrequent and evenly distributed among all treatment groups (see Table 2).
Table 2: Iliscontinuation of trial medication Trial termination reasonsPlacebo GAL GAL GAL
8 m /da 16 m /da 24 m /da Total patients 286 140 279 273 Total completed: N 240 (84 108 (77 219 (79 212 (78 ( ~o ) %) % ) % ) % ) Total discontinued 46 ( 16 32 (23 60 (22 61 (22 (DC): N ( % ) % ) % ) % ) % ) DC due to adverse c;vent20 (7 9 (6 % 19 (7 27 ( % ) ) % ) 10 %
) DC due to inefficacy 0 1 (1 % 0 2 (1 ) %) DC due to other' 23 (8 18 ( 13 29 ( 10 20 (7 % ) % ) % ) % ) DC due to ineligible: 0 0 4 (1 % 2 (1 to continue ) %) DC due to non-compliance3 ( 1 4 (3 % 7 (3 % 10 (4 % ) ) ) % ) DC due to withdrawal 0 0 1 (0.4 0 of consent % ) a: The majority of discontinuations due to other reasons were for withdrawal of consent.
In this study there were two primary efficacy endpoints according to widely used international standards: change in ADAS-cog/11 score at Month 5 compared to baseline and CIBIC-plus scare at Month 5.
As shown in Table 3 and Figure 1, a statistically significant treatment effect was shown for the 16 and 24 m~;/day galantamine treatment groups compared with placebo for the ADAS-cog/11. Re;~ults from analysis based on the last observation carried-forward (LOCF) data cor~ob~~rate the result based on observed data. The 8 mg/d~y galantamine group was significantly different from placebo for the observed case but not for the LOCF. Galantamin.e at a dose of 24 mg/day did not appear to be significantly more effective than 16 rrtg/day. However, the duration of exposure to the target dose differed by 1 month between the two treatment groups (two months versus three months respectively).
Table 3: Change from baseline in ADAS-cog/11 at Month 5 Placebo GAL 8mg GAL l6mQ GAL 24me Month 5: (observedn=225 n=101 n=208 n=211 case) Mean (SE) 1.8 (0.43)0.1 (0.58)*-1.5 (0.40)***t-1.8 (0.44)***t Month 5: (LOCF) n=255 n=126 n=253 n=253 Mean (SE) 1.7 (0.39)0.4 (0.52)0-1.4 (0.35)***~-1.4 (0.39)***~
Lower score matcates better condttton. Y-Values based on two-way ANOVA model.
Significantly n;.ore effective than placebo: *: ps0.05; **: ps0.01; ***:
ps0.001; Approached significance: 0: 0.05 <: p-value < 0.10.
~ Significantly rr,ore effective than 8 mg/day: t: ps0.05; t: ps0.01.
For the CIBIC-plus assessment at Month 5, the percent of patients with improved or unchanged scores was sig:nifucantly greater with galantamine treatment with 16 or 24 mg/day compared with 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 showed improvement or were unchanged from baseline compared with 47 % to 51 % with placebo or 8 mg/day of galantamine. The analysis of imputed data at LOCF
endpoint gave similar results. There was an apparent dose-related increase in the percentage of patients showing improvement or no change in the CIBIC-plus (Figure 2).
Table 4: CIBIC-plus at Month 5 for improved or unchanged scores Placebo GAL 8 mg GAL 16 mg GAL 24 mg Month 5: (observed.n=:237 n=106 n=212 n=212 case) Im roved/no char 11:? (47%)54 (51%) 143 (68%)***t136 (64%)***#
a n~;%) Month 5: (LOCF) n=263 n=128 n=255 n=253 Improved/no change1213 (49 68 (53 169 (66 162 (64 n~; % ) % ) % ) % )***t % )***t P-value from Van Elteren test on the 7-point scale Significantly more effective than placebo: *: ps0.05; **: ps0.01; ***:
ps0.001.
Significantly more effective than 8 mg/day: t: ps0.05; $: ps0.01.
At Month 5 there were significantly more patients who responded with no change or improved scores wish 16 and 24 mg/day of galantamine compared with placebo or mg/day of galantamine. Patients responding with ADAS-cog/ 11 changes from baseline of 7 or more points occurred in 15.9 % and 22.3 % of patients in the 16 and 24 mg/day groups, respectively, compared with the placebo group (7.6%). There was overall a higher cumulative percentage of patients with galantamine treatment who responded with a minimum irrtprovement of any magnitude compared with placebo (Figure 3).
Table 5: Rfsponders analysis based on change in ADAS-cog/11 score from baseline at Month 5 Definition of Placebo GAL 8 mg GAL 16 mg GAL 24 mQ
res ondc:=
n=225 n=101 n=208 n=211 Changes0 points 94 (41.8) 47 (46.5) 136 (65.4)***#137 (64.9)***$
n (%.) Changes-4 points44 (19.6) 26 (25.7) 74 (35.6)***078 (37.0)***t n (~o) Changes-7 pointsll7 (7.6) 14 (13.9) 33 (15.9)**47 n (fib) (22.3)***0 Changes-10 points8 (3.6) 6 (5.9) 15 (7.2) 22 ( 10.4)**
n ( % ) Y-value based on (:MH test Significantly higher percentage of responders than placebo: *: ps0.05; **:
ps0.01;
***: ps0.001;
Significantly higher percentage of responders than 8 mg/day: t: ps0.05; $:
ps0.01;
Approached ~;ignificance: 0: 0.05 < p-value < 0.10;
The differen<:e berivee;n 16 and 24 mg/day approached significance ~: 0.05 < p-vlaue < 0.10.
An additional secondary indication captures overall changes in Activities of daily Living (ADL) performances as measured by the Alzheimer's Disease Cooperative Study Activities of lJaily Living (ACDS/ADL) scale. As mentioned above this scale is comprised of 23 items that have been tested and validated in patients with mild to moderately severe ~~lzheilner's disease.
Galantamine treatment with 16 or 24 mg/day for 5 months was statistically more effective in maintaining the ADL total score at baseline levels than treatment with placebo or 8 mg/day of galantamine (Table 6). The dose-related effect of galantamine treatment is apparer.~t in Figure 4 that shows change of total ADL score over time.
Table 6: (:hange in Total ADL score from baseline at Month 5 Placebo GAL 8 mg GAL 16 m~ GAL 24 m Month 5: (observedn=235 n=106 n=212 n=212 case) Mean (SE) -4.0 (0.59)-3.1 (0.91)-0.5 (0.55)***t-1.6 (0.61)**
Month 5: (LOCF) n=262 n=129 n=255 n=253 Mean (SE) -3.8 (0.55)-3.2 (0.79)-0.7 (0.050)***~-1.5 (0.56)**
ritgner score matcates oetter conanton. r-values based on two-way ANOVA model.
Significantly more effective than placebo: **: p_<0.01; ***: ps0.001 Significantly more effective than 8 mg/day: t: p<_0.05; $: p<_0.01.
There was a statistically significant (p < 0.05) benefit seen in the change in the total NPI score at Month 5 relative to baseline for 16 and 24 mg/day of galantamine compared with a deterioration with placebo or 8 mg/day of galantamine (Table 7 and Figure 5). An increase in score indicated a worsening in condition. Thus, a maintenance of neunopsychiatric behaviour was observed with galantamine at 16 and 24 mg/day.
Table 7: Change in Total NPI score from baseline at Month 5 Placebo GAL 8 m GAL 16 m GAL 24 'm Month 5: (observedn=234 n=106 n=211 n=212 case) Mean (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 Mean (SE) ~ 2.0 (0.68)2.3 (1.00) -0.1 (0.71)*-0.0 (0.76)*
Higher score indicates worsened condition. p-Values based on two-way ANOVA
model.
~ Significantly more effective than placebo: *: p~0.05 The most common adverse events were evenly distributed across treatment groups with the exception of events that are associated with cholinomimetic agents (Table 8). Of these related event s, nausea, vomiting and anorexia showed a mild dose-related occurrence at a rela~:ively low incidence.
Table 8: Incidence of most frequent (z5%) adverse events: number (%) of patients Adverse event Placebo GAL 8 mg GAL 16 mg GAL 24 (Preferred mg term) Total all patients286 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 % ) Agitation 2'7 (9.4 21 ( 15.0 28 ( 10.0 22 (8.1 % ) % ) % ) % ) Depression 1:5 (5.2%)4 (2.9%) 24 (8.6%) 22 (8.%) Urinary tract 19 (6.6 11 (7.9 23 (8.2 22 (8.1 infection %) % ) % ) % ) Dizziness 10 (3.5 7 (5.0 % 15 (5.4 19 (7.0 % ) ) % ) % ) Injury 1:? (4.2%)5 (3.6%) 12 (4.3%) 16 (5.9%) Diarrhea 1'7 (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 1:3 (4.5%)5 (3.6%) 19 (6.8%) 13 (4.8%0 Weight decrease 4 (1.4%o) 2 (1.4%) 15 (5.4%) 13 (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 % ) ) ) % ) Edema peripheral7 (2.4 9 (6.4 % 8 (2.9 % 7 (2.6 % ) ) ) % ) For most adverse events of clinical interest, as shown in Table 9, there were either no differences or slight dose-related differences between treatment groups. For bradycardia, there was a higher incidence for patients treated with galantamine compared with placebo but there was no dose-related association apparent. For syncope, there was a slight dose-related increase in incidence with 24 mg/day of galantamine, however 3 of these cases occurred at a lower dose during titration, and are therefore attributable to a lower galantamine dose. Consequently, the incidences shown in Table 6 arE: very likely to be over-estimates for the occurrence of syncope at the higher doses. Furthermore, 10 of 18 patients who experienced a syncopal episode were taking concomitant cardiovascular medication including bata-blockers, calcium channel antagonists, ACE inhibitors, and/or diuretics. Of these 18 patients, 11 had - 1~ -active cardiovascular disease listed in their past medical history. Therefore, a majority of patients who experienced syncope had either a cardiovascular condition or were taking cardiovascular medication.
Table 9: Adverse events of clinical interest Adverse events Placebo GAL 8 mg GAL 16 GAL 24 (Prefe:rred mg mg term) Total all patients286 140 279 273 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 1 (0.7 % ) 3 (1.1%) 1 (0.4%) Syncope 2 (0.7%) 2 (1.4%) 5 (1.8%) 9 (3.3%) The incidence of serious adverse events was comparable across all treatment groups and (with the excepoion of syncope) showed no dose-related trends (Table 10).
The four most frequent ~,erious adverse events with galantamine and with an incidence of at least 1 % of patients in any group were injury, syncope, fall, and myocardial infarction. There ware no dose-related increases in GI-related serious adverse events.
The only serious adverse event that showed a dose-relationship was syncope, however, for reasons already ;provided, these rates may be an over-estimate.
Table 10: Serious adverse events (with z 2 patients in any group) Adverse Event (PreferredPlacebo GAL 8 mg GAL 16 GAL 24 mg term) mg Total all patients286 140 279 273 Total patients 31 ( 10. 14 ( 10.0 28 ( 10.0 35 ( 12.8 with amr SAE 8 % ) % ) % ) % ) Injury 4 (1.4%) I (0.7%) 1 (0.4%) 5 (1.8%) Syncope 2 (0.7%) 1 (0.7%) 4 (1.4%) 5 (1.8%) Asthenia 1 (0.3 0 (0.0 2 (0.7 1 (0.4 %
% ) % ) % ) ) Dyspnea 1 (0.3 0 (0.0 2 (0.7 3. ( 1.1 % ) % ) % ) % ) Pneumonia 4 ( 1.4 1 (0.7 2 (0.7 3 ( 1.1 % ) % ) % ) % ) Gi haemorrhage 0 (0.0 0 (0.0 0 (0.0 2 (0.7 %
% ) % ) % ) ) Vomiting 1 (0.3 0 (0.0 2 (0.7 1 (0.4 %
% ) % ) % ) ) Abdominal pain 1 (0.3 0 (0.0 2 (0.7 0 (0.0 %
% ) % ) % ) ) Diarrhea 1 (0.3 0 (0.0 3 ( 1.1 0 (0.0 %
% ) % ) % ) ) Nausea I (0.3 0 (0.0 2 (0.7 0 (0.0 %
% ) % ) % ) ) Basal cell carcinomaI) (0.0 0 (0.0 0 (0.0 2 (0.7 %
% ) % ) % ) ) Breast neoplasm :? (0.7 0 (0.0 0 (0.0 0 (0.0 %
female % ) % ) % ) ) Fall :3 (1.0%)4 (2.9%) 1 (0.4%) 3 (1.1%) Surgical intervention1 (0. 0 (0.0 3 ( 1.1 0 (0.0 %
3 % ) % ) % ) ) Thrombophlebitis I (0.3 0 (0.0 0 (0.0 2 (0.7 %
deep % ) % ) % ) ) Transient ischemic1 (0. 1 (0.7 2 (0. 7 0 (0.0 %
attack 3 % ) % ) % ) ) Myocardial infarction2 (0.7 3 (2.1 1 (0.4 1 (0.4 %
% ) % ) % ) ) Agitation l (0.3 2 ( 1.4 1 (0.4 0 (0.0 %
% ) % ) % ) ) Urinary tract infecti~~n0 (0.0 1 (0.7 2 (0.7 0 (0.0 %
% ) % ) % ) ) Cardiac failure 'L (0.7 0 (0.0 3 ( 1.1 0 (0.0 %
% ) % ) % ) ) Dehydration 0 (0.0 0 (0.0 3 ( 1.1 0 (0.0 %
% ) % ) % ) ) Sepsis :? (0.7 0 (0.0 0 (0.0 0 (0.0 %
% ) % ) % ) ) Throughout the trial there were 11 deaths. There was no apparent dose-related patterns in the occurrences o~E deaths. No death was considered by the investigator to be related to trail medication.
The results of this example confirmed that treatment with either 16 mg/day or 24/mg day of galantamine leads to statistically significant improvement in neuropsychiatric behaviour, as determined by the NPI score at month 5 relative to baseline with mg/day and 24 mg/day compared with a deterioration with placebo or 8 mg/day of galantamine.
The present invention has been described with regard to preferred embodiments.
However, it will be obvious to persons 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 (12)
1. A use of an effective amount of galantamine or a pharmaceutically acceptable salt thereof for treating neuropsychiatric behaviour associated with Alzheimer's disease.
2. The use of an effective amount of galantamine or a pharmaceutically acceptable salt thereof for the production of a medicament for treating neuropsychiatric behaviour associated with Alzheimer's disease.
3. The use of claim 1 or 2 wherein the galantamine is for use from about 1 mg to about 100 mg per day.
4. The use of claim 3 wherein the galantamine is for use from about 5 mg to about 50 mg per day.
5. The use of claim 4 wherein the galantamine is for use from about 16 mg to about 32 mg per day.
6. The use of claim 5 wherein the galantamine is for use at a first dosage of about 8 mg/day for about one week, followed by a second dosage of about 16 mg/day for about one week, followed by a final dosage of about 24 mg/day, thereafter.
7. The use of claim 5 wherein the galantamine is for use at a first dosage of about
8 mg/day for about one week, followed by a second dosage of about 16 mg/day for about one week, followed by a third dosage of about 24 mg/day for about one week, followed by a final dosage of about 32 mg/day, thereafter.
8. The use of claim 5 wherein the galantamine is for use from a dosage of about 8 mg/day to a final dosage of about 16 mg/day to about 24 mg/day; wherein said final dosage is reached in from about two to ten weeks.
8. The use of claim 5 wherein the galantamine is for use from a dosage of about 8 mg/day to a final dosage of about 16 mg/day to about 24 mg/day; wherein said final dosage is reached in from about two to ten weeks.
9. The use of claim 8 wherein the galantamine is for use at a first dosage of about 8 mg/day for about two weeks to about four weeks, followed by a second dosage of about 16 mg/day for from about two weeks to about four weeks, followed by a final dosage of about 24 mg/day, thereafter.
10. The use of claim 8 wherein the galantamine is for use at a first dosage of about 8 mg/day for about four weeks, followed by a second dosage of about 16 mg/day for about four weeks, followed by a final dosage of about 24 mg/day, thereafter.
11. The use of claim 8 wherein the galantamine is for use at an initial dosage of about 8 mg/day for from about two weeks to about four weeks, followed by a final dosage of about 16 mg/day, thereafter.
12. The use of claim 11 wherein the galantamine is for use at an initial dosage of about 8 mg/day for about four weeks, followed by a final dosage of about 16 mg/day, thereafter.
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|---|---|---|---|
| US19425900P | 2000-04-03 | 2000-04-03 | |
| US60/194,259 | 2000-04-03 |
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| RU2357734C2 (en) * | 2003-07-25 | 2009-06-10 | Ф.Хоффманн-Ля Рош Аг | COMBINATION OF mGluR2 RECEPTOR ANTAGONIST AND AChE ENZYME INHIBITOR FOR ACUTE ANDN/OR CHRONIC NEURALGIC DISEASES |
| DE10338544B4 (en) * | 2003-08-19 | 2017-08-31 | Janssen Pharmaceutica N.V. | Buccal formulations of galanthamine and their applications |
| CA2718411C (en) | 2008-03-27 | 2016-02-16 | Chase Pharmaceuticals Corporation | Use and composition for treating dementia |
| WO2013160728A1 (en) | 2012-04-26 | 2013-10-31 | Alma Mater Studiorum - Universita' Di Bologna | Dual targeting compounds for the treatment of alzheimer's disease |
| BG66818B1 (en) * | 2013-03-07 | 2019-01-31 | Berbee Beheer B. V. | Composition of hippeastrum papilio extract for the production of medicines and nutritional supplements |
| WO2016187339A1 (en) * | 2015-05-18 | 2016-11-24 | Synaptec Development Llc | GALANTAMINE CLEARANCE OF AMYLOIDß |
| WO2023036105A1 (en) * | 2021-09-09 | 2023-03-16 | 上海日馨医药科技股份有限公司 | Method for treating neurodegenerative disease |
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| DE19509663A1 (en) * | 1995-03-17 | 1996-09-19 | Lohmann Therapie Syst Lts | Process for the isolation of galanthamine |
| GB9600080D0 (en) * | 1996-01-04 | 1996-03-06 | Chiroscience Ltd | Resolution process |
| JP5558648B2 (en) | 1998-11-23 | 2014-07-23 | デイビス、ボニー | Administration formulation for acetylcholinesterase inhibitors |
| DK1140105T3 (en) * | 1998-12-24 | 2004-02-23 | Janssen Pharmaceutica Nv | Controlled release galantamine preparation |
| CA2310990A1 (en) * | 2000-04-03 | 2000-10-09 | Michael Pontecorvo | A use of galantamine for the treatment of alzheimer's disease; targeting the underlying cause of the disease |
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| SK15422002A3 (en) | 2003-04-01 |
| BR0109770A (en) | 2003-02-04 |
| PL361272A1 (en) | 2004-10-04 |
| KR20020086911A (en) | 2002-11-20 |
| NO20024746L (en) | 2002-11-28 |
| NO20024746D0 (en) | 2002-10-02 |
| MXPA02009777A (en) | 2003-03-27 |
| HUP0300566A3 (en) | 2004-10-28 |
| CA2310926A1 (en) | 2000-10-04 |
| RU2002129298A (en) | 2004-03-27 |
| WO2001074339A3 (en) | 2002-09-12 |
| JP2003528913A (en) | 2003-09-30 |
| IL152061A0 (en) | 2003-05-29 |
| AU2001265844B2 (en) | 2005-04-14 |
| HRP20020778A2 (en) | 2004-04-30 |
| EP1272192A2 (en) | 2003-01-08 |
| BG107093A (en) | 2003-06-30 |
| EE200200554A (en) | 2004-04-15 |
| ZA200207935B (en) | 2004-01-30 |
| CN1430514A (en) | 2003-07-16 |
| HUP0300566A2 (en) | 2003-06-28 |
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| WO2001074339A2 (en) | 2001-10-11 |
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