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Biotech / Medical : Neurobiological Tech (NTII) -- Ignore unavailable to you. Want to Upgrade?

To: Cacaito who wrote (728)	12/3/1999 7:58:00 AM
From: Dr. John M. de Castro	Respond to of 1494

Effect of memantine (NMDA antagonist) on Parkinson's disease: a double-blind crossover randomized study. Clin Neuropharmacol 1999 Sep-Oct;22(5):273-6 Merello M, Nouzeilles MI, Cammarota A, Leiguarda R, Neurology Department, Raul Carrea Institute for Neurological Research (FLENI), Buenos Aires, Argentina. Our aim was to evaluate the effect of Memantine (1-amino 3,5-dimethyl-adamantane hydrochloride) on cardinal symptoms of Parkinson's disease and on the latency, duration, and magnitude of the response to a single dose of L-Dopa and on drug-induced dyskinesias. Twelve Hoehn-Yahr III-IV patients with idiopathic Parkinson's disease with motor fluctuations and drug-induced dyskinesias were randomized to the NMDA antagonist memantine or placebo in a cross-over design. A single-dose L-Dopa challenge was performed after each medication arm. A significant drug effect on the Unified Parkinson's Disease Rating Scale motor score was observed in "off" and "on" states (F(1,11) = 13.5; p < 0.003). No significant effect on drug-induced dyskinesias was seen. The results suggest that memantine may improve parkinsonian symptoms independently of dopaminergic drugs and, in contrast to recent findings with amantadine, it has no effect on drug-induced dyskinesias.

To: Cacaito who wrote (728)	12/3/1999 8:02:00 AM
From: Dr. John M. de Castro	Respond to of 1494

Protective Effects of Memantine Against Ischemia-Reperfusion Injury in Spontaneously Hypertensive Rats. Acta Neurochir (Wien) 1999 Oct 18;141(10):1107-1113 Dogan A, Eras MA, Raghavendra Rao VL, Dempsey RJ, Department of Neurological Surgery, University of Wisconsin and Veterans Administration Hospital, Madison, WI Memantine, an uncompetitive NMDA open-channel blocker, has been shown to be effective in preventing neuronal damage after permanent focal cerebral ischemia. Reperfusion after a long period of ischemia may aggravate the progression of neuronal damage. Those drugs that show protective effects after permanent cerebral ischemia, therefore, might fail to do so against ischemia-reperfusion injury. In this study we evaluated the effects of memantine on brain edema formation and ischemic injury volume after transient cerebral ischemia. Male Spontaneously Hypertensive Rats (SHR) weighing 250-300 g were anesthetized with halothane and subjected to 1 hour of temporary middle cerebral artery occlusion by an intraluminal suture. 20 mg/kg of memantine or saline were injected intraperitoneally 5 min. after the induction of ischemia. Physiological parameters and regional cerebral blood flow were monitored during the surgical procedure. Brain water content and ischemic injury volume were measured with the wet dry method and 2,3,5-triphenyl tetrazolium chloride monohydrate (TTC) staining, respectively, at 24 hours after occlusion. There were no statistically significant differences between the groups regarding physiological parameters during the procedure. Memantine treatment (n=9) reduced the brain water content significantly in the cortex compared to saline treatment (n=8; 83.1+/-0.7% vs. 84.5+/-1.5%, respectively, p<0.05). The total volume of ischemic brain injury was 300+/-49 mm(3) in the animals treated with saline (n=13). Treatment with 20 mg/kg memantine (n=14) reduced the ischemic injury volume to 233+/-61 mm(3) (P<0.01). These results demonstrate that the harmful effects of recirculation after a period of ischemia can be attenuated by the treatment of memantine, perhaps by its action at the NMDA receptors.

To: Cacaito who wrote (728)	12/3/1999 8:05:00 AM
From: Dr. John M. de Castro	Read Replies (1) \| Respond to of 1494

Behavioral effects and anticonvulsant efficacies of low-affinity, uncompetitive NMDA antagonists in mice. Psychopharmacology (Berl) 1999 Oct 4;146(3):280-289, Geter-Douglass B, Witkin JM, Drug Development Group, NIDA Addiction Research Center, NIH, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA Rationale: It has been hypothesized that low-affinity, uncompetitive N-methyl-d-aspartate (NMDA) antagonists may have therapeutic efficacy (e.g., in epilepsy, stroke, drug dependence) without the adverse side effects associated with high-affinity ligands (e.g., dizocilpine, phencyclidine). Objectives: To determine whether low-affinity NMDA antagonists have a larger predicted therapeutic window than high-affinity ligands. Methods: In Swiss-Webster mice, we compared the effects of uncompetitive antagonists having a range of affinities for the NMDA receptor ion channel [dizocilpine, memantine, ibogaine, amantadine and 5-aminocarbonyl-10,11-dihydro-5h-dibenzo[a,d] cyclohepten-5,10-imine (ADCI)] in three behavioral assays typically used to assess NMDA receptor antagonism. Behavioral side effects were compared with the efficacy of the compounds to protect against NMDA-induced seizures. Results: Only dizocilpine and memantine substituted fully in mice trained to discriminate dizocilpine from saline. Dizocilpine (K(i ) approximately 0.003 muM) protected against NMDA-induced convulsions at doses that produced ataxia and stimulation of locomotor activity. Conversely, memantine (K(i ) approximately 0.54 muM) prevented convulsions at doses that were 8- to 18-fold lower than those producing ataxia or effects on locomotion, respectively. Indeed, in contrast to dizocilpine, memantine did not stimulate locomotor activity but only produced dose-dependent reductions. The low-affinity antagonists ibogaine (K(i ) approximately 1 muM) and ADCI (K(i ) approximately 11 muM) protected against convulsions at doses that produced significant dizocilpine-like discriminative stimulus effects, ataxia and decreases in locomotor activity. Amantadine (K(i ) approximately 11 muM) was ineffective against NMDA-induced convulsions up to doses that produced significant behavioral side effects. Conclusions: These findings indicate that only certain low-affinity, uncompetitive NMDA antagonists (e.g., memantine) may have therapeutic efficacy at doses that do not produce an adverse side-effect profile. For other therapeutic endpoints, different estimates of efficacy and safety require derivation.