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Combination therapy for Alzheimer's disease: Memantine and cholinesterase inhibitors
P396
Poster Presentations: P2
dysfunction (e.g., left temporal in a patient with dysphasia). Clinical fluctuations and disease duration did not correlate with likelihood of detecting epileptiform activity. Conclusions: In this pilot investigation, people with MCI and early-onset AD had subclinical epileptiform abnormalities that were not observed in age-matched controls. This study is expanding enrollment to identify endophenotypes of people with early cognitive impairment who have epileptiform activity and could possibly benefit from FDA-approved antiepileptic medications. P2-378
COMBINATION THERAPY FOR ALZHEIMER’S DISEASE: MEMANTINE AND CHOLINESTERASE INHIBITORS
Klaus Schmidtke, Department of Neurogeriatrics, Ortenau Hospital, Offenburg-Gengenbach, Offenburg, Germany. Background: Two classes of drugs are licensed for the treatment of Alzheimer’s disease (AD): Cholinesterase inhibitors (ChEIs) and the NMDAantagonist memantine. These drugs have different and additive mechanisms of action, and there are no known interaction problems. This contribution analyses the available evidence for and against the effect of memantine when given in addition to a therapy with ChEIs. Methods: Review and analysis of existing clinical trials. Results: In one study of 404 AD patients who were on stable doses of donepezil and received additional placebo or memantine (20 mg), outcome for cognition was significantly better in the memantine group (effect size 0.21). A later responder analysis showed cognitive deterioration in 9 % for memantine add-on vs. 17% for placebo add-on. In another study of 433 mild-to-moderate patients who were on stable doses of any ChEI, the cognitive outcome parameter did not reach statistical significance in favour of memantine add-on. Reasons may be that decline in the placebo-add on group was small, patients were pre-treated with any ChEI (not donepezil-only), and mild-stage patients were included, in whom memantine is less efficacious. Later responder analyses of the moderate subgroup revealed that 25 % in the memantine group, but 32 % in the placebo group showed ‘clinically significant cognitive deterioration.’ Pooled analyses of both trials showed odds ratios of 0.62 for cognitive deterioration, 0.66 for deterioration of general impression, and 0.81 for deterioration of ADLs in favor of memantine. Conclusions: There is evidence that the combination of ChEI plus memantine in D is efficacious from the moderate stage onwards (MMSE 19-20). Starting add-on therapy earlier seems not to be beneficial. Whether memantine add-on acts as a disease-modifying therapy is unknown. A sustained acute effect of memantine add-on might also support a more favorable course due to better function, and due to greater resilience towards behavioral symptoms of dementia. P2-379
NOVEL ALZHEIMER’S THERAPEUTICS: ST101 ENHANCES ACETYLCHOLINE RELEASE THROUGH T-TYPE VOLTAGE-GATED CALCIUM CHANNEL
Kohji Fukunaga, Yui Yamamoto, Shigeki Moriguchi, Norifumi Shioda, Tohoku University, Sendai, Japan. Background: We recently developed novel cognitive enhancer, ST101 (spiro[imidazo[1,2- a]pyridine-3,2-indan]2(3 H)-one) which is under investigation of clinical trial phase 2 in United State as Alzheimer therapeutics. The impaired neurogenesis in olfactory bulbectomized (OBX) mice was improved by chronic administration with ST101 (JPET 2010;333:43-50). We also discovered that ST101 stimulates T-type voltage-gated calcium channels (T-VGCC) using patch clamp methods using mouse cortical neurons and neuro2A cells over-expressed T- VGCC, Cav3.1. Here we addressed the physiological relevance of activation of T-VGCC activation in the acetylcholine (ACh) release in mouse brain. Methods: We treated sham and OBX mice with 1.0 mg/kg ST101 and measured ACh release using microdialysis analysis. We also tested cognitive and memory behaviors using novel objective task and Y-maze task. Results: The acute intraperitoneal administration of ST101 (1 mg/kg) enhances the basal ACh release in dorsal hippocampus both in OBX and sham mice. Importantly, ST101 administration with 1mg/kg largely enhanced nicotine-induced ACh release in the
dorsal hippocampus in sham and OBX mice. The enhancement of ACh release was eliminated by T-type VGCC, mebefradil. As expected, decreases in calcium/calmodulin-dependent protein kinase II a (CaMKIIa), protein kinase C a (PKCa) and mitogen-activated protein kinase (ERK) phosphorylation were restored by ST101 (1 mg/kg) acute administration. The improved effects of ST101 on CaMKII a and PKCa phosphorylation were confirmed by increased phosphorylation of AMPA receptor subunit (GluR1), synapsin I and NMDA receptor subunit (NR1) phosphorylation in the hippocampus. Finally, acute ST101 administration improved spatial memory deficits and cognitive dysfunction as assessed by Y-maze tasks and no vel object recognition tasks, respectively, in OBX mice. Conclusions: Taken together, acute ST101 treatment enhances ACh release through T-type VGCC, thereby improving cognitive impairment in OBX mice. P2-380
CARING FOR THE CAREGIVER: BENEFITS FROM A DIFFERENT DOSAGE FORM
Konstantin Articus, Novartis Pharma GmbH, Nuremberg, Germany. Background: The care for patients with Alzheimers dementia puts a high burden on the caregiver. One of the time consuming daily tasks is the dispense of medication. While this may be trivial in the beginning, the increasing misunderstanding of the patient of his own condition leads to an ever increasing burden for the caregiver. Rivastigmin is the only cholinesterase inhibitor that is available as a transdermal patch. The patch was developed to reduce side effects that resulted from the sharp increase in plasma levels that were caused by the conventional oral form of rivastigmine. A previous study demonstrated that 7 out of 10 caregivers prefer the patch over a capsule. As it was not further evaluated we designed this study to detect further explanations. Methods: To analyse, whether a dosage form has an effect on the life of caregivers, we asked the following questions: How much time per day do you spent on: (1) dressing the patient? (2) controlling the appearance (incl. personal hygiene)? (3) administration of medication? In order to be able to compare different dosage forms, physicians were asked to dispense questionnaires to caregivers of patients which recently switched from oral medication to transdermal patches. The overall study setting was observational: in contrast to RCTs patients did enter the study after the treatment decision was made and the study protocol did not describe the further treatment. The observation period covered approx. 6 months. Results: 1104 patients in 220 sites were enrolled into this observational study. The mean MMSE at baseline was 19.0 6 5.1 points. Time spent for dressing the patient dropped from 56.2 6 102.2 to 49.5 6 88.6 minutes. Time spent for control of appearance dropped from 50.0 6 104.0 to 43.1 6 89.2 minutes. Time spent for dispense of medication dropped from 23.0 6 76.2 to 16.3 6 59.4 minutes. Conclusions: This study demonstrated that the treatment with a transdermal patch may offer additional benefits to the caregiver. Further studies are necessary to evaluate to what extend the time saved has a measurable effect on the quality of life of the caregiver. In addition confounding factors due to the observational nature of the study cannot be excluded.
P2-381
TARGETING A PRE-MRNA STRUCTURE WITH BIPARTITE ANTISENSE MOLECULES AND ANTISENSE CONJUGATES TOWARD MODULATION OF TAU ALTERNATIVE SPLICING
Lilia Rodriguez1, Yang Liu2, Eleanor Peacey2, Michael S. Wolfe2, Harvard Medical School, Boston, Massachusetts, United States; 2Center for Neurologic Disease, Boston, Massachusetts, United States.
1
Background: Alternative splicing of tau exon 10 generates isoforms containing 3 or 4 microtubule-binding repeats (3R and 4R tau, respectively). Mutations in the tau gene cause frontotemporal dementia with parkinsonism, demonstrating the critical role of tau in pathogenesis. Many of these mutations are found at the 5´ splice site of exon 10 and lead to increased inclusion of exon 10, shifting the balance to 4R tau. We have previously validated a hairpin structure at the exon 10-intron 10 boundary that regulates 3R versus 4R tau formation. Moreover, we have identified a small drug-like
Poster Presentations: P2
dysfunction (e.g., left temporal in a patient with dysphasia). Clinical fluctuations and disease duration did not correlate with likelihood of detecting epileptiform activity. Conclusions: In this pilot investigation, people with MCI and early-onset AD had subclinical epileptiform abnormalities that were not observed in age-matched controls. This study is expanding enrollment to identify endophenotypes of people with early cognitive impairment who have epileptiform activity and could possibly benefit from FDA-approved antiepileptic medications. P2-378
COMBINATION THERAPY FOR ALZHEIMER’S DISEASE: MEMANTINE AND CHOLINESTERASE INHIBITORS
Klaus Schmidtke, Department of Neurogeriatrics, Ortenau Hospital, Offenburg-Gengenbach, Offenburg, Germany. Background: Two classes of drugs are licensed for the treatment of Alzheimer’s disease (AD): Cholinesterase inhibitors (ChEIs) and the NMDAantagonist memantine. These drugs have different and additive mechanisms of action, and there are no known interaction problems. This contribution analyses the available evidence for and against the effect of memantine when given in addition to a therapy with ChEIs. Methods: Review and analysis of existing clinical trials. Results: In one study of 404 AD patients who were on stable doses of donepezil and received additional placebo or memantine (20 mg), outcome for cognition was significantly better in the memantine group (effect size 0.21). A later responder analysis showed cognitive deterioration in 9 % for memantine add-on vs. 17% for placebo add-on. In another study of 433 mild-to-moderate patients who were on stable doses of any ChEI, the cognitive outcome parameter did not reach statistical significance in favour of memantine add-on. Reasons may be that decline in the placebo-add on group was small, patients were pre-treated with any ChEI (not donepezil-only), and mild-stage patients were included, in whom memantine is less efficacious. Later responder analyses of the moderate subgroup revealed that 25 % in the memantine group, but 32 % in the placebo group showed ‘clinically significant cognitive deterioration.’ Pooled analyses of both trials showed odds ratios of 0.62 for cognitive deterioration, 0.66 for deterioration of general impression, and 0.81 for deterioration of ADLs in favor of memantine. Conclusions: There is evidence that the combination of ChEI plus memantine in D is efficacious from the moderate stage onwards (MMSE 19-20). Starting add-on therapy earlier seems not to be beneficial. Whether memantine add-on acts as a disease-modifying therapy is unknown. A sustained acute effect of memantine add-on might also support a more favorable course due to better function, and due to greater resilience towards behavioral symptoms of dementia. P2-379
NOVEL ALZHEIMER’S THERAPEUTICS: ST101 ENHANCES ACETYLCHOLINE RELEASE THROUGH T-TYPE VOLTAGE-GATED CALCIUM CHANNEL
Kohji Fukunaga, Yui Yamamoto, Shigeki Moriguchi, Norifumi Shioda, Tohoku University, Sendai, Japan. Background: We recently developed novel cognitive enhancer, ST101 (spiro[imidazo[1,2- a]pyridine-3,2-indan]2(3 H)-one) which is under investigation of clinical trial phase 2 in United State as Alzheimer therapeutics. The impaired neurogenesis in olfactory bulbectomized (OBX) mice was improved by chronic administration with ST101 (JPET 2010;333:43-50). We also discovered that ST101 stimulates T-type voltage-gated calcium channels (T-VGCC) using patch clamp methods using mouse cortical neurons and neuro2A cells over-expressed T- VGCC, Cav3.1. Here we addressed the physiological relevance of activation of T-VGCC activation in the acetylcholine (ACh) release in mouse brain. Methods: We treated sham and OBX mice with 1.0 mg/kg ST101 and measured ACh release using microdialysis analysis. We also tested cognitive and memory behaviors using novel objective task and Y-maze task. Results: The acute intraperitoneal administration of ST101 (1 mg/kg) enhances the basal ACh release in dorsal hippocampus both in OBX and sham mice. Importantly, ST101 administration with 1mg/kg largely enhanced nicotine-induced ACh release in the
dorsal hippocampus in sham and OBX mice. The enhancement of ACh release was eliminated by T-type VGCC, mebefradil. As expected, decreases in calcium/calmodulin-dependent protein kinase II a (CaMKIIa), protein kinase C a (PKCa) and mitogen-activated protein kinase (ERK) phosphorylation were restored by ST101 (1 mg/kg) acute administration. The improved effects of ST101 on CaMKII a and PKCa phosphorylation were confirmed by increased phosphorylation of AMPA receptor subunit (GluR1), synapsin I and NMDA receptor subunit (NR1) phosphorylation in the hippocampus. Finally, acute ST101 administration improved spatial memory deficits and cognitive dysfunction as assessed by Y-maze tasks and no vel object recognition tasks, respectively, in OBX mice. Conclusions: Taken together, acute ST101 treatment enhances ACh release through T-type VGCC, thereby improving cognitive impairment in OBX mice. P2-380
CARING FOR THE CAREGIVER: BENEFITS FROM A DIFFERENT DOSAGE FORM
Konstantin Articus, Novartis Pharma GmbH, Nuremberg, Germany. Background: The care for patients with Alzheimers dementia puts a high burden on the caregiver. One of the time consuming daily tasks is the dispense of medication. While this may be trivial in the beginning, the increasing misunderstanding of the patient of his own condition leads to an ever increasing burden for the caregiver. Rivastigmin is the only cholinesterase inhibitor that is available as a transdermal patch. The patch was developed to reduce side effects that resulted from the sharp increase in plasma levels that were caused by the conventional oral form of rivastigmine. A previous study demonstrated that 7 out of 10 caregivers prefer the patch over a capsule. As it was not further evaluated we designed this study to detect further explanations. Methods: To analyse, whether a dosage form has an effect on the life of caregivers, we asked the following questions: How much time per day do you spent on: (1) dressing the patient? (2) controlling the appearance (incl. personal hygiene)? (3) administration of medication? In order to be able to compare different dosage forms, physicians were asked to dispense questionnaires to caregivers of patients which recently switched from oral medication to transdermal patches. The overall study setting was observational: in contrast to RCTs patients did enter the study after the treatment decision was made and the study protocol did not describe the further treatment. The observation period covered approx. 6 months. Results: 1104 patients in 220 sites were enrolled into this observational study. The mean MMSE at baseline was 19.0 6 5.1 points. Time spent for dressing the patient dropped from 56.2 6 102.2 to 49.5 6 88.6 minutes. Time spent for control of appearance dropped from 50.0 6 104.0 to 43.1 6 89.2 minutes. Time spent for dispense of medication dropped from 23.0 6 76.2 to 16.3 6 59.4 minutes. Conclusions: This study demonstrated that the treatment with a transdermal patch may offer additional benefits to the caregiver. Further studies are necessary to evaluate to what extend the time saved has a measurable effect on the quality of life of the caregiver. In addition confounding factors due to the observational nature of the study cannot be excluded.
P2-381
TARGETING A PRE-MRNA STRUCTURE WITH BIPARTITE ANTISENSE MOLECULES AND ANTISENSE CONJUGATES TOWARD MODULATION OF TAU ALTERNATIVE SPLICING
Lilia Rodriguez1, Yang Liu2, Eleanor Peacey2, Michael S. Wolfe2, Harvard Medical School, Boston, Massachusetts, United States; 2Center for Neurologic Disease, Boston, Massachusetts, United States.
1
Background: Alternative splicing of tau exon 10 generates isoforms containing 3 or 4 microtubule-binding repeats (3R and 4R tau, respectively). Mutations in the tau gene cause frontotemporal dementia with parkinsonism, demonstrating the critical role of tau in pathogenesis. Many of these mutations are found at the 5´ splice site of exon 10 and lead to increased inclusion of exon 10, shifting the balance to 4R tau. We have previously validated a hairpin structure at the exon 10-intron 10 boundary that regulates 3R versus 4R tau formation. Moreover, we have identified a small drug-like