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Pro-cognitive properties of SUVN-G1010034, a potent selective H3 antagonist in animal models of cognition
Poster Presentations: P4 (ADL). Caregivers recorded their impression of change. Results: Mean 6SD baseline scores were: MMSE 16.763.7 (Range10-26/30); 12 domains NPI-Q severity 7.8362.51 points (Range3-13/36); 12 domains NPI-Q distress (caregiver distress) 11.2164.80 points (Range3-20/60); Katz-ADLs 3.7761.35 points (Range1-6/6).Mean MMSE score showed an improvement from baseline of +1.0 point at month 6 (95% confidence interval [CI] +0.8 to +1.2), p<.0001; and +1.6 points at month 12 (95% CI +1.3 to +1.8); p<.0001.Mean NPI-Q severity score showed improvement from baseline, at month 6 (-1.47 points; 95% CI -1.12 to -1.82) and at month 12 (-2.47 points; 95% CI -2.17 to -2.77); all p<.0001. Mean NPI-Q distress score improved from baseline, at month 6 and month12; -1.91 points (95% CI -1.46 to -2.36); and -3.66 points (95% CI -3.16 to -4.16), respectively; all p<.0001. Mean Katz-ADLs score improved from baseline, at month 6 by +0.21 point (95% CI 60.16), P ¼ 0.01; and at month 12 by +0.57 point (95% CI 60.17), p<.0001. Adverse events were reported in 12.8% of patients; most were transient and mild. Caregivers impressions of change compared with baseline were 61.7% ameliorated, 12.7% stabilized. Conclusions: The results are consistent with those from controlled trials and support that Donepezil is effective in the treatment of mild to moderate Alzheimer’s disease in everyday practice. Patients tolerated donepezil well, and showed clear clinical benefit, with improvements in cognitive function, reduction in neuropsychiatric symptoms, and in caregivers distress.
P4-234
THE COLLECTED RESEARCH ON MEDICAL FOOD BIOEFFICACY IN ALZHEIMER’S DISEASE
Sari Edelstein, Simmons College, Boston, Massachusetts, United States. Background: A medical, also called functional, food contains one or more phytonutrients is defined by the Academy of Nutrition and Dietetics as, “any altered food or ingredient that could give a beneficial effect beyond that provided by nutrients that it traditionally contains.” The study of the use of functional foods in Alzheimer’s disease for cognitive or memory improvement is in its infancy, but shows some promise as shown in the current review of literature. Methods: This summation of medical food trials from the current literature hopes to quantify the bioefficacy of the use of specific phytonutrients in Alzheimer’s disease. Results: A chart will quantify the collected research studies and their findings of functional foods and their corresponding phytonutrients that have shown to be some benefit in the treatment of Alzheimer’s disease exhibiting anti-inflammatory, antioxidant, immunostimulatory (at the level of the mucus membrane) and induction of antioxidant enzymes. Conclusions: Medical food may have a place in the treatment of Alzheimer’s disease. This research updates the current axis of progress in this area of nutritional study.
P4-235
PRO-COGNITIVE PROPERTIES OF SUVNG1010034, A POTENT SELECTIVE H3 ANTAGONIST IN ANIMAL MODELS OF COGNITION
Ramakrishna Nirogi, Vishwottam Kandikere, Nageswararao Muddana, Dhanalakshmi Shanmuganathan, Kancharla Baburao, Swayam Sampurna Mohanty, Saravana Kumar Marimuthu, Devender Reddy Ajjala, Shantaveer Irappanavar, Arunkumar Manoharan, Abinash Das, Ramoji Kosuru, Anil Shinde, Amol Deshpande, Ramasastri Kambhampati, Venkat Reddy Mekala, Mohammed Abdul Faheem, Rama Mohan Garikapati, Inderjeet Singh Bhatia, Suven Life Sciences, Ltd, Hyderabad, India. Background: Endogenous histamine plays an important role in learning and memory and H 3 receptor antagonists have the potential to be therapeutic agents for the treatment of impaired cognitive function, which is
P717
a key characteristic of Alzheimer’s disease and other neuropsychiatric diseases. The histamine H 3 receptors are widely distributed in the central nervous system and regulate histamine as well as the activity of other neurotransmitters like acetylcholine, noradrenaline, dopamine and serotonin. SUVN-G1010034 has nanomolar affinity (binding Ki 3 nM) for human H 3 receptors. Methods: Pharmacokinetic and brain penetration was evaluated in male Wistar rats. In-vivo receptor occupancy was carried at various dose levels using non-radiolabled GSK-189254 as a tracer. SUVN-G1010034 was evaluated in H 3 agonist induced dipsogenia assay and rat models of cognition like object recognition task and Morris water maze task. Brain microdialysis was carried out to study the effect of SUVN-G1010034 on histamine and acetylcholine levels. Results: SUVN-G1010034 had adequate bioavailability and good brain penetration in preclinical species. The ED 50 value for H 3 receptor occupancy was found to be 0.35 mg/kg, p.o. SUVN-G1010034 blocked the H 3 agonist induced dipsogenic behaviour through the functional blockade of H 3 receptors. SUVN-G1010034 reversed the time induced memory deficit in novel object recognition task and scopolamine induced spatial memory deficit in Morris water maze task. Following oral administration, significant increase in histamine and acetylcholine levels was observed. Conclusions: SUVN-G1010034 is a potent, selective H 3 receptor antagonist and showed procognitive properties in animal models of cognition by modulating histaminergic and cholinergic neurotransmission. R esults from the present study indicate that SUVN-G1010034 could be of therapeutic utility for the treatment of cognitive deficits in Alzheimer’s disease.
P4-236
PLASMA CONCENTRATION OF RIVASTIGMINE FROM EXELONÒ PATCH IN TAIWANESE: A BRIEF REPORT
Yuan-Han Yang1, Su-Hwei Chen2, Yi-Rou Wang2, 1Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; 2 School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan. Background: Rivastigmine has been approved in the treatment of Alzheimer’s disease (AD) for its pseudo-irreversible inhibitor of both acetylcholinesterase and butyrylcholinesterase. However, centrally induced cholinergic gastrointestinal side effects with oral cholinesterase inhibitors have been reported, so a transdermal delivery system, patch with two dosage: 4.6 mg/24 h (5 cm 2, 9 mg loaded dose of rivastigmine) and 9.5 mg/24 h (10 cm 2, 18 mg), for daily administration has been developed. The 9.5mg/24h one is used extensively as a maintained dosage in western countries, but given to the different heights, body weights, and body mass index (BMI) between western and eastern society, the dosage of Exelon in the treatment of AD could be adjusted according to its plasma concentration of rivastigmine. Methods: All procedures are approved by the Institutional Review Board. Two clinically diagnosed AD patients have been recruited into the study. The diagnosis of AD was made according to the DSM-IV criteria with referring to a series of neuropsychological assessments. Plasma concentrations of rivastigmine have measured by capillary electrophoresis for the two patients who have continuously treated with Exelon 5 cm 2 for at least a month. Results: Two AD patients, one female with body weight 58.4kg, height 162 cm, and BMI 22.3 and one male with body weight 77 kg, height 168 cm, and BMI 27.3, have been recruited. Concentration of rivastigmine was 20.13 ng/mL for the male and 24.14 ng/mL for the female. The concentrations of rivastigmine were different from that in AD patients in western countries used the same size ExelonÒ patch. Conclusions: The therapeutic dosages of ExelonÒ patch could be varied among different countries and races. The plasma concentration of rivastigmine and other factor could be monitored accordingly. A study with a large sample size has to be conducted to address these issues.
P4-234
THE COLLECTED RESEARCH ON MEDICAL FOOD BIOEFFICACY IN ALZHEIMER’S DISEASE
Sari Edelstein, Simmons College, Boston, Massachusetts, United States. Background: A medical, also called functional, food contains one or more phytonutrients is defined by the Academy of Nutrition and Dietetics as, “any altered food or ingredient that could give a beneficial effect beyond that provided by nutrients that it traditionally contains.” The study of the use of functional foods in Alzheimer’s disease for cognitive or memory improvement is in its infancy, but shows some promise as shown in the current review of literature. Methods: This summation of medical food trials from the current literature hopes to quantify the bioefficacy of the use of specific phytonutrients in Alzheimer’s disease. Results: A chart will quantify the collected research studies and their findings of functional foods and their corresponding phytonutrients that have shown to be some benefit in the treatment of Alzheimer’s disease exhibiting anti-inflammatory, antioxidant, immunostimulatory (at the level of the mucus membrane) and induction of antioxidant enzymes. Conclusions: Medical food may have a place in the treatment of Alzheimer’s disease. This research updates the current axis of progress in this area of nutritional study.
P4-235
PRO-COGNITIVE PROPERTIES OF SUVNG1010034, A POTENT SELECTIVE H3 ANTAGONIST IN ANIMAL MODELS OF COGNITION
Ramakrishna Nirogi, Vishwottam Kandikere, Nageswararao Muddana, Dhanalakshmi Shanmuganathan, Kancharla Baburao, Swayam Sampurna Mohanty, Saravana Kumar Marimuthu, Devender Reddy Ajjala, Shantaveer Irappanavar, Arunkumar Manoharan, Abinash Das, Ramoji Kosuru, Anil Shinde, Amol Deshpande, Ramasastri Kambhampati, Venkat Reddy Mekala, Mohammed Abdul Faheem, Rama Mohan Garikapati, Inderjeet Singh Bhatia, Suven Life Sciences, Ltd, Hyderabad, India. Background: Endogenous histamine plays an important role in learning and memory and H 3 receptor antagonists have the potential to be therapeutic agents for the treatment of impaired cognitive function, which is
P717
a key characteristic of Alzheimer’s disease and other neuropsychiatric diseases. The histamine H 3 receptors are widely distributed in the central nervous system and regulate histamine as well as the activity of other neurotransmitters like acetylcholine, noradrenaline, dopamine and serotonin. SUVN-G1010034 has nanomolar affinity (binding Ki 3 nM) for human H 3 receptors. Methods: Pharmacokinetic and brain penetration was evaluated in male Wistar rats. In-vivo receptor occupancy was carried at various dose levels using non-radiolabled GSK-189254 as a tracer. SUVN-G1010034 was evaluated in H 3 agonist induced dipsogenia assay and rat models of cognition like object recognition task and Morris water maze task. Brain microdialysis was carried out to study the effect of SUVN-G1010034 on histamine and acetylcholine levels. Results: SUVN-G1010034 had adequate bioavailability and good brain penetration in preclinical species. The ED 50 value for H 3 receptor occupancy was found to be 0.35 mg/kg, p.o. SUVN-G1010034 blocked the H 3 agonist induced dipsogenic behaviour through the functional blockade of H 3 receptors. SUVN-G1010034 reversed the time induced memory deficit in novel object recognition task and scopolamine induced spatial memory deficit in Morris water maze task. Following oral administration, significant increase in histamine and acetylcholine levels was observed. Conclusions: SUVN-G1010034 is a potent, selective H 3 receptor antagonist and showed procognitive properties in animal models of cognition by modulating histaminergic and cholinergic neurotransmission. R esults from the present study indicate that SUVN-G1010034 could be of therapeutic utility for the treatment of cognitive deficits in Alzheimer’s disease.
P4-236
PLASMA CONCENTRATION OF RIVASTIGMINE FROM EXELONÒ PATCH IN TAIWANESE: A BRIEF REPORT
Yuan-Han Yang1, Su-Hwei Chen2, Yi-Rou Wang2, 1Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; 2 School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan. Background: Rivastigmine has been approved in the treatment of Alzheimer’s disease (AD) for its pseudo-irreversible inhibitor of both acetylcholinesterase and butyrylcholinesterase. However, centrally induced cholinergic gastrointestinal side effects with oral cholinesterase inhibitors have been reported, so a transdermal delivery system, patch with two dosage: 4.6 mg/24 h (5 cm 2, 9 mg loaded dose of rivastigmine) and 9.5 mg/24 h (10 cm 2, 18 mg), for daily administration has been developed. The 9.5mg/24h one is used extensively as a maintained dosage in western countries, but given to the different heights, body weights, and body mass index (BMI) between western and eastern society, the dosage of Exelon in the treatment of AD could be adjusted according to its plasma concentration of rivastigmine. Methods: All procedures are approved by the Institutional Review Board. Two clinically diagnosed AD patients have been recruited into the study. The diagnosis of AD was made according to the DSM-IV criteria with referring to a series of neuropsychological assessments. Plasma concentrations of rivastigmine have measured by capillary electrophoresis for the two patients who have continuously treated with Exelon 5 cm 2 for at least a month. Results: Two AD patients, one female with body weight 58.4kg, height 162 cm, and BMI 22.3 and one male with body weight 77 kg, height 168 cm, and BMI 27.3, have been recruited. Concentration of rivastigmine was 20.13 ng/mL for the male and 24.14 ng/mL for the female. The concentrations of rivastigmine were different from that in AD patients in western countries used the same size ExelonÒ patch. Conclusions: The therapeutic dosages of ExelonÒ patch could be varied among different countries and races. The plasma concentration of rivastigmine and other factor could be monitored accordingly. A study with a large sample size has to be conducted to address these issues.