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Efficacy and tolerability of two galantamine titration regimens in patients switched from donepezil
S800
Poster Presentations P4
persist in advanced dementia. A case for person-centered, validating care of Alzheimer’s patients, regardless of their severity, is made.
P4-268
EFFICACY AND TOLERABILITY OF TWO GALANTAMINE TITRATION REGIMENS IN PATIENTS SWITCHED FROM DONEPEZIL
Ute Richarz1, Knut Engedal2, Bonnie Davis3, Maren Gaudig4, John Han5, Barbara Schaeuble4, 1Janssen Cilag Switzerland, Baar, Switzerland; 2 Norwegian Centre for Dementia Research, Oslo, Norway; 3Synaptec Inc., New York, New York, United States; 4Janssen Cilag GmbH, Neuss, Germany; 5PRD U.S.A., Titusville, New Jersey, United States. Background: Acetylcholinesterase inhibitors (AChEI) are a standard treatment for patients with mild-to-moderate Alzheimer’s disease (AD), but some patients will experience loss of treatment effect or poor tolerability. Introduction of an alternative AChEI may be beneficial. Aim: The study evaluated two different galantamine titration regimens in patients receiving donepezil for whom a switch of treatment was medically necessary. While the primary objective of the study was to compare fast and slow galantamine titration regimens, post - hoc analyses provide information on patients who switched from donepezil to galantamine. Methods: Open-label, 12-weeks flexible dose study including patients with mild to moderate AD transitioning from Donezepil. Screening was followed by a 7 day washout period. Patients were subsequently randomly allocated to either fast titration (8mg/ week increments) or slow titration (8mg/4week increments) of Galantamine to a target dose between 16mg/day to 24mg/day. Efficacy and safety outcomes included ADAS-cog/11, safety and tolerability parameters. Results: 89 subjects were randomly allocated to fast (n ¼ 44) or slow (n ¼ 45) titration and completed by 43 subjects in each arm. At week 12, the mean (95% CI) improvement from screening in ADAS-cog/11 score was -2.6 (-4.3; 0.8) in the fast titration arm and -0.6 (-2.1; 1.0) in the slow titration arm (Table 2). In the pooled galantamine group, the mean change from screening at week 12 was -1.6 (-2.7; -0.4; p ¼ 0.002), and ADAS-cog/11 score was also significantly improved vs. screening at week 6 and week 12 in subjects who had received donepezil for > 6 months. Overall, 54/80 subjects (67.5%) maintained or improved ADAS-cog/11 score at week 12, with 28/80 (35.0%) and 14/80 (17.5%) experiencing an improvement of ¼ 4 and ¼ 7 points, respectively. Galantamine was generally well tolerated. Most common adverse events were nausea (5.6%) and bradycardia (4.5%) with a similar incidence in both treatment regimen. SAEs reported in 6 patients were unrelated to study drug. Conclusions: Galantamine treatment appears to be beneficial in AD patients who have previously failed to benefit from treatment with donepezil.
P4-269
THE EFFECTS OF A MULTIPROFESSIONAL COGNITIVE AND FUNCTIONAL REHABILITATION PROGRAM FOR PATIENTS WITH ALZHEIMER’S DISEASE AND MILD COGNITIVE IMPAIRMENT
Glenda Santos1, Luciane Ortega2, Monica Yassuda3, Orestes Forlenza4, Paula Nunes5, 1Psychiatry Institute, University of Sao Paulo, Sao Paulo, Brazil; 2Department & Institute of Psychiatry - University of S~ao Paulo, S~ao Paulo, Brazil; 3School of Arts, Sciences and Humanities, University of S~ao Paulo, Sao Paulo, Brazil; 4Institute of Psychiatry of University of S~ao Paulo, S~ ao Paulo - S.P., Brazil; 5Institute of Psychiatry of University of Sao Paulo, Sao Paulo, Brazil. Background: To evaluate the effects of a multidisciplinary rehabilitation program on cognitive, quality of life and depression symptoms in patients with Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI). Methods: Patients with MCI and mild to moderate AD were recruited at a university-based memory clinic. Eligible patients (n ¼ 76 total, AD ¼ 62 MCI ¼ 14) were assigned to a 12-week stimulation program, which was provided by a multiprofessional team. The intervention consisted of group sessions of memory training (including computer-assisted methods), recreational and expressive activities through painting, verbal expression
and writing, physiotherapy and physical training. Treatment was administered twice a week in 6-hour gatherings at a day-hospital facility. Both groups were evaluated at baseline and at the end of the intervention. Instruments used: Mini-Mental State Examination (MMSE), Quality of Life in Alzheimer’s disease Scale and Geriatric Depression Scale (GDS). Results: We found a significant improvement in MCI patients in the MMSE (before: 27.6 6 1.7, after: 28.4 6 1.5; p ¼ 0.005). No significant differences in the MMSE were found in patients with AD (before: 21.2 6 3.8, after: 22.4 6 4.6; p ¼ 0.591). The intervention brought reduction in depression symptoms as measured in the GDS for both MCI (before: 7.6 6 5.0, after: 6.5 6 4.7; p ¼ 0.011) and AD patients (before: 4.7 6 3.0, after: 3.4 6 2.0; p < 0.001). According to the AD patients, this intervention was also beneficial their quality of life (before: 35.2 6 5.5, after: 36.7 6 4.7; p ¼ 0.040). Conclusions: The completion of the present multiprofessional rehabilitation program was associated with a significant improvement in quality of life for AD patients and a significant decrease in depressive symptoms in patients with AD and MCI. In addition, we found mild benefits on global cognitive function in patients with MCI. These results give support to the cost-effectiveness of this intervention for patients with cognitive problems. In spite of the progressive nature of AD, structured nonpharmacological interventions can yield adjunct and clinically relevant benefits in the treatment of dementia.
P4-270
THE GAMMA-SECRETASE MODULATOR CHF5074 ELICITS NEUROPROTECTION AND INCREASES HISTONE ACETYLATION IN PRIMARY CORTICAL NEURONS EXPOSED TO OXYGEN GLUCOSE DEPRIVATION
Ilenia Sarnico1, Annamaria Lanzillotta1, Caterina Branca1, Marina Benarese1, Vanessa Porrini1, PierFranco Spano1, Bruno Imbimbo2, Marina Pizzi1, 1University of Brescia, Brescia, Italy; 2Chiesi Farmaceutici, Parma, Italy. Background: CHF5074 is a new gamma-secretase modulator in clinical development for the treatment of Alzheimer’s disease (AD). Recent studies have shown that CHF5074 can induce astrocyte stellation independently from gamma-secretase modulation (JAD 2010; 22: 1135-55). These results prompt us to investigate on neuroprotective activity of CHF5074 in experimental models unrelated to A-beta accumulation. Much research is actually focused on epigenetic mechanism regulating histone acetylation and involved in process of chromatin remodeling, microtubule dynamics, metabolism and ageing with relevance in different complex, late-onset neurodegenerative diseases. Histone deacetylase inhibitors have proved to be neuroprotective in animal models of AD and brain ischemia. The aim of our study was to investigate the effect of CHF5074 in mouse primary cortical neurons exposed to oxygen glucose deprivation (OGD), a cell-based model of brain ischemia. The effect of CHF5074 was compared to that elicited by ibuprofen and other neuroprotective agents, the sirtuin activator resveratrol and the HDAC inhibitor MS-275. Methods: Fifteen days embryonic C57BL/6 mice were harvested with caesarean section from anaesthetized pregnant dams. Cerebral cortices were isolated and dissociated by manual dispersion. The cells were plated in Neurobasal medium supplemented with 2% B27, 0.5 mM L-glutamine and 50 U/mL penicillin/streptomi^ cin. At 10 days in vitro near pure cortical neurons were exposed to OGD at 37A C for 3 hours. At the end of the OGD period, cortical neurons were allowed to recover for 24 hours in Neurobasal medium containing 0.4% B27 supplement, under normoxic conditions and with or without the test drugs. We analyzed the effect of CHF5074 in the concentration range eliciting anti-amyloidogenic activity, from 1-30 mM, ibuprofen at 500 mM, resveratrol at 30 mM and MS275 at 1 mM. Neuronal injury and neuroprotection were evaluated by measuring the amount of lactate dehydrogenase (LDH) released into the culture medium. To test histone acetylation, nuclear extracts were prepared 6 hours after the OGD exposure and nuclear proteins were processed for Western blot analysis by using antibody specific for histone H3 acetylated on K9/18 residues. Results: Near ^ pure cortical neurons were exposed to CHF5074 from 1 to 30 AmM during the OGD period and the following 24 hour recovery. In another set of experiments, CHF5074 was added only after the OGD exposure. When compared
Poster Presentations P4
persist in advanced dementia. A case for person-centered, validating care of Alzheimer’s patients, regardless of their severity, is made.
P4-268
EFFICACY AND TOLERABILITY OF TWO GALANTAMINE TITRATION REGIMENS IN PATIENTS SWITCHED FROM DONEPEZIL
Ute Richarz1, Knut Engedal2, Bonnie Davis3, Maren Gaudig4, John Han5, Barbara Schaeuble4, 1Janssen Cilag Switzerland, Baar, Switzerland; 2 Norwegian Centre for Dementia Research, Oslo, Norway; 3Synaptec Inc., New York, New York, United States; 4Janssen Cilag GmbH, Neuss, Germany; 5PRD U.S.A., Titusville, New Jersey, United States. Background: Acetylcholinesterase inhibitors (AChEI) are a standard treatment for patients with mild-to-moderate Alzheimer’s disease (AD), but some patients will experience loss of treatment effect or poor tolerability. Introduction of an alternative AChEI may be beneficial. Aim: The study evaluated two different galantamine titration regimens in patients receiving donepezil for whom a switch of treatment was medically necessary. While the primary objective of the study was to compare fast and slow galantamine titration regimens, post - hoc analyses provide information on patients who switched from donepezil to galantamine. Methods: Open-label, 12-weeks flexible dose study including patients with mild to moderate AD transitioning from Donezepil. Screening was followed by a 7 day washout period. Patients were subsequently randomly allocated to either fast titration (8mg/ week increments) or slow titration (8mg/4week increments) of Galantamine to a target dose between 16mg/day to 24mg/day. Efficacy and safety outcomes included ADAS-cog/11, safety and tolerability parameters. Results: 89 subjects were randomly allocated to fast (n ¼ 44) or slow (n ¼ 45) titration and completed by 43 subjects in each arm. At week 12, the mean (95% CI) improvement from screening in ADAS-cog/11 score was -2.6 (-4.3; 0.8) in the fast titration arm and -0.6 (-2.1; 1.0) in the slow titration arm (Table 2). In the pooled galantamine group, the mean change from screening at week 12 was -1.6 (-2.7; -0.4; p ¼ 0.002), and ADAS-cog/11 score was also significantly improved vs. screening at week 6 and week 12 in subjects who had received donepezil for > 6 months. Overall, 54/80 subjects (67.5%) maintained or improved ADAS-cog/11 score at week 12, with 28/80 (35.0%) and 14/80 (17.5%) experiencing an improvement of ¼ 4 and ¼ 7 points, respectively. Galantamine was generally well tolerated. Most common adverse events were nausea (5.6%) and bradycardia (4.5%) with a similar incidence in both treatment regimen. SAEs reported in 6 patients were unrelated to study drug. Conclusions: Galantamine treatment appears to be beneficial in AD patients who have previously failed to benefit from treatment with donepezil.
P4-269
THE EFFECTS OF A MULTIPROFESSIONAL COGNITIVE AND FUNCTIONAL REHABILITATION PROGRAM FOR PATIENTS WITH ALZHEIMER’S DISEASE AND MILD COGNITIVE IMPAIRMENT
Glenda Santos1, Luciane Ortega2, Monica Yassuda3, Orestes Forlenza4, Paula Nunes5, 1Psychiatry Institute, University of Sao Paulo, Sao Paulo, Brazil; 2Department & Institute of Psychiatry - University of S~ao Paulo, S~ao Paulo, Brazil; 3School of Arts, Sciences and Humanities, University of S~ao Paulo, Sao Paulo, Brazil; 4Institute of Psychiatry of University of S~ao Paulo, S~ ao Paulo - S.P., Brazil; 5Institute of Psychiatry of University of Sao Paulo, Sao Paulo, Brazil. Background: To evaluate the effects of a multidisciplinary rehabilitation program on cognitive, quality of life and depression symptoms in patients with Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI). Methods: Patients with MCI and mild to moderate AD were recruited at a university-based memory clinic. Eligible patients (n ¼ 76 total, AD ¼ 62 MCI ¼ 14) were assigned to a 12-week stimulation program, which was provided by a multiprofessional team. The intervention consisted of group sessions of memory training (including computer-assisted methods), recreational and expressive activities through painting, verbal expression
and writing, physiotherapy and physical training. Treatment was administered twice a week in 6-hour gatherings at a day-hospital facility. Both groups were evaluated at baseline and at the end of the intervention. Instruments used: Mini-Mental State Examination (MMSE), Quality of Life in Alzheimer’s disease Scale and Geriatric Depression Scale (GDS). Results: We found a significant improvement in MCI patients in the MMSE (before: 27.6 6 1.7, after: 28.4 6 1.5; p ¼ 0.005). No significant differences in the MMSE were found in patients with AD (before: 21.2 6 3.8, after: 22.4 6 4.6; p ¼ 0.591). The intervention brought reduction in depression symptoms as measured in the GDS for both MCI (before: 7.6 6 5.0, after: 6.5 6 4.7; p ¼ 0.011) and AD patients (before: 4.7 6 3.0, after: 3.4 6 2.0; p < 0.001). According to the AD patients, this intervention was also beneficial their quality of life (before: 35.2 6 5.5, after: 36.7 6 4.7; p ¼ 0.040). Conclusions: The completion of the present multiprofessional rehabilitation program was associated with a significant improvement in quality of life for AD patients and a significant decrease in depressive symptoms in patients with AD and MCI. In addition, we found mild benefits on global cognitive function in patients with MCI. These results give support to the cost-effectiveness of this intervention for patients with cognitive problems. In spite of the progressive nature of AD, structured nonpharmacological interventions can yield adjunct and clinically relevant benefits in the treatment of dementia.
P4-270
THE GAMMA-SECRETASE MODULATOR CHF5074 ELICITS NEUROPROTECTION AND INCREASES HISTONE ACETYLATION IN PRIMARY CORTICAL NEURONS EXPOSED TO OXYGEN GLUCOSE DEPRIVATION
Ilenia Sarnico1, Annamaria Lanzillotta1, Caterina Branca1, Marina Benarese1, Vanessa Porrini1, PierFranco Spano1, Bruno Imbimbo2, Marina Pizzi1, 1University of Brescia, Brescia, Italy; 2Chiesi Farmaceutici, Parma, Italy. Background: CHF5074 is a new gamma-secretase modulator in clinical development for the treatment of Alzheimer’s disease (AD). Recent studies have shown that CHF5074 can induce astrocyte stellation independently from gamma-secretase modulation (JAD 2010; 22: 1135-55). These results prompt us to investigate on neuroprotective activity of CHF5074 in experimental models unrelated to A-beta accumulation. Much research is actually focused on epigenetic mechanism regulating histone acetylation and involved in process of chromatin remodeling, microtubule dynamics, metabolism and ageing with relevance in different complex, late-onset neurodegenerative diseases. Histone deacetylase inhibitors have proved to be neuroprotective in animal models of AD and brain ischemia. The aim of our study was to investigate the effect of CHF5074 in mouse primary cortical neurons exposed to oxygen glucose deprivation (OGD), a cell-based model of brain ischemia. The effect of CHF5074 was compared to that elicited by ibuprofen and other neuroprotective agents, the sirtuin activator resveratrol and the HDAC inhibitor MS-275. Methods: Fifteen days embryonic C57BL/6 mice were harvested with caesarean section from anaesthetized pregnant dams. Cerebral cortices were isolated and dissociated by manual dispersion. The cells were plated in Neurobasal medium supplemented with 2% B27, 0.5 mM L-glutamine and 50 U/mL penicillin/streptomi^ cin. At 10 days in vitro near pure cortical neurons were exposed to OGD at 37A C for 3 hours. At the end of the OGD period, cortical neurons were allowed to recover for 24 hours in Neurobasal medium containing 0.4% B27 supplement, under normoxic conditions and with or without the test drugs. We analyzed the effect of CHF5074 in the concentration range eliciting anti-amyloidogenic activity, from 1-30 mM, ibuprofen at 500 mM, resveratrol at 30 mM and MS275 at 1 mM. Neuronal injury and neuroprotection were evaluated by measuring the amount of lactate dehydrogenase (LDH) released into the culture medium. To test histone acetylation, nuclear extracts were prepared 6 hours after the OGD exposure and nuclear proteins were processed for Western blot analysis by using antibody specific for histone H3 acetylated on K9/18 residues. Results: Near ^ pure cortical neurons were exposed to CHF5074 from 1 to 30 AmM during the OGD period and the following 24 hour recovery. In another set of experiments, CHF5074 was added only after the OGD exposure. When compared