$332 P4, Degenerative and neurological disorders • Memantine monotherapy is effective and safe for the treatment of mild to moderate Alzheimer's disease: A randomized controlled trial E.R. Peskind I , S.Q. Po~in 2, N. Pomara 3, B.R. Ott4*, S. McDonald 5, Y. Xie 6, I. Gergel 7, 1University of Washington, Department of Psychiatry, Seattle, WA, U S,A.; 2 University of Califor~ia, Ir~i~e, Department of t~sychiatry, Zroi~e, CA, ~ ~A,; 3New York Unioer~ity Echool of Medicine, Nathan S, Kline Institute, Orangebur@, NY,, U i;,A,; 4Memorial Hospital of P,~ode Island, Department of Neurology, Pawtucket, zRI, ~E,A,; SForest Research Inxtitute, Medical Desvartment, Jersey City, NJ, ~S,A,; 6Forest i'~esearch Institute, Department of Biostatistics, Jersey City, NJ, rJS, A,; 7Forest Research Institute, Department of Clinical Research, Jersey Ci~, NJ, US.A. Mernantine is a low-moderate affinity, nncornpetitive NMDA re- ceptor antagonist approved for the treatment of moderate to severe Alzheimer's disease (AD). No well-controlled trials addressing mermntine monotherapy in patients with mild AD have previously been performed in the U.S. Thus, a 24-week, randomized, double- blind, parallel-arm, placebo-controlled, Phase IT[ trial was con- ducted in the U.S. to study the efficacy and safety of memantine in patients with mild to moderate AD. Outpatients who met inclusion criteria (e.g., probable AD, MMSE 10-22) were randomized to placebo or mernantine (10 rng b.i.d.). Primary outcomes were the Alzheimer's Disease Assessment Scale cognitive subscale (ADAS- cog), a measure of cognition, and the Clinician's Interview- Based Impression of Change-Plus Casegiver Input (CIt)IC-Plus), a measure &global status. Primary endpoints were analyzed using the Last Observation Carried Forward approach (LOCF), and the safely assessment was based on adverse events (AEs), clinical laboratory evaluations, EC CJs, and vital signs. Of 40.3 patients ran- domized and treated with memantine (n=201) or placebo (n=202), 82.1% of memantine-treated patients and 82.7% of placebo- treated patients completed the trial. Memantine-treated patients performed significantly better than placebo-treated patients on both primary outcome measures: the ADAS-cog (P=.003) and the CIBIC-Plus (P=.004). Memantine was safe and well tolerated and the incidence of AEs was similar for the memantine- and placebo-treated groups. These results demonstrate that memantine is effective and safe for patients with mild to moderate AlP. Taking previously published data into consideration, it appears that memantine is efficacious in providing cognitive and global benefit for patients at all stages clAD. • Memantine monotherapy increases brain metabolism (PET) and effectively treats mild to moderate Alzheim er's disease S.G. Potldn 1, S. Mc.:,Donald 2, I. Gergel 3 , G. Alva l , D.B. Keator 1 , I,H, Fallon 1, i U~ioersity of California, fruine Sol, col of Medicine, Department of P~ychiatry, Zrvine, CA, ~S,A,; 2Forest Research Institute, Medical Department, Jersey City, NZ U~E,A,; 3Forest i~esearch fnsti~te, Department of Clinical i~esearch, Jersey City, NJ, US, A, Mernantine is a low-moderate affinity, uncompetitive NMDA receptor antagonist approved for the treatment of moderate to severe Alzheimer's disease (AD). Positron emission tomography (PET) was utilized in this pilot study to assess the effects of memantine on regional cerebral hypometabolism in a subset of mild to moderate (MMSE 10-22) AD patients randomized to either memantine (20 my/day) or placebo in a 24-week, double- blind, placebo-controlled, Phase TIT clinical trial conducted in the U.S. Outpatients (N=403; ~>50 years of age) with diagnostic evidence (NINCDS-ADRDA criteria) and an MRI or CT scan consistent with probable AID were enrolled and randomized to me- mantine or placebo. PET was performed at baseline and at Week 24 on five memantine-treated patients and five placebo-treated patients. In the clinical trial, mernantine-treated patients performed significantly better than placebo-treated patients on both primary outcome measures using a Last Observation Carried Forward (LOCF) analysis: Alzheimer's Disease Assessment Scale cogni- tive subsoale (ADAS-oog; P=.003) and the Clinician's Interview- Based Impression of Change-Plus Caregiver Input (CIBIC-Plus; P=.004). PET revealed metabolic declines in glucose metabolism in brain regions of placebo-treated patients, including the orbital, cingulate, retrosplenial, and dorsal lateral prefrontal cortices. In contrast, memantine-treated subjects generally showed statistically significant metabolic increases in the same areas. These results suggest that memantine can reverse regionally-specific metabolic decreases associated with untreated mild to moderate AD. When combined with the statistically significant primary outcome mea- sures, these results demonstrate that memantine is efficacious in providing clinical benefit to patients with mild to moderate AD. ]P.4.024] Proroten, ultra-low doses of antibodies to S-100 protein, reduced brain damage in photochem ically-induced ph otothrorn bosis G.A. Romanova 1 , S.A. Sergeeva 2, T.A. Voronina 1 *, O.I. Epstein 2, I.L. Dugina 2, I.V. Barskov j . lZnstitute of Common and Pathological Pfo,siology RAM~ Moscow, Russian Federation; 2 "'Materia Medica Holding" i~esearcA and Production Company, Researcl~ Department, Moscow, Russian Federation Stroke is the third leading cause of death and the leading cause of disabilityin the world. Post-stroke period is characterized by neurological signs and symptoms, cognitive impairment and emo- tional instability. Therefore, a preparation with a broad spectrum of psychotropic activitiesshould meet current medical need. An earlierresearch showed thatproproten (ultra-lowdoses of antibod- ies to S-1 O0 protein),at first introduced as an anti-alcoholicprepa- ration in Russia in 1999, was able to reduce anxiety, depression and prevent craving (Voronina et 8,1.,2003). Animal studies proved that GABA-ergic system is partly involved in realisation of anx- iolytic action of proproten (Epstein et al., 2003). This study was aimed at revealing the cerebroprotectlve properties of proproten in photochemically-induced brain infarction. Experiments were carried out on male Wistar rats (150--250 g). In the photothrom- bosis model originally described by Watson et at (1986), bilateral infarctions were induced by a local photochemical reaction. Pro- proten was administered per os an hour after photothrombosis, then 2.5 ml/kg/day for 9 days. On day 9, the rats were exposed to passive avoidance test (PAT) designed to assess the impairment of cognitive functions, t)raln pathomorphological evaluation was performed on preparations stained with hematoxylin-eosine and cresil-violet by Nissl. After photothrombosis, rats showed inability to perform PAT. A significant reduction in retention latency (RL) was registered; RL decreased by 2.6 times (p<0.05). Course trea~nent with proproten recovered the latency; RL increased by 2.2 times as compared to untreated animals after ischemia.