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Effects of benzodiazepines on conscious and automatic memory processes
P Poster Presentations
186
IP-18-22I Denvatlves Ne~ A~ticon~UlsiveCompounds of Sulfonamide Line
1 P-19-1 I Flesinoxan Improves Cognition in The Healthy Elderly
H. Zlenko, V. Mamchur, L. Kasjan, O. Krasnovskaja, A. Kasyan,
1. Van Harten, M. Olff, K. Wesnes, W. Strobel.
V. Butchenko, H. Demchenko, V. Opryshko. Dnipropetrovsk State
Medical Academy; Ukraine Dnipropetrovsk State University, Ukraine The anticonvulsive activity of 16 new bi- and polycyclic sulfonamides derivatives were investigated depend ing on inclusion of the nitro-groups, the chlorine and fluorine atoms into molecules and on the hydrogenation of compounds as well. Experiment s with white rats were carried out. Corasole convulsions were model of spastic status (100 mglkg ilp). The degree of anticonvulsive activity vas determined by increase in term life, decrease in convulsive fits durability. survival of the animals. It was established that intensity of anticonvulsive activity ranges from 12 to 402%. Steric peculiarities connected with exo- and endo-isomeres presence affect anticonvulsive activity differently depending on a specific compound structure. Taking into account data on anticonvulsive activity of narcotic analgetic series the determination of analgetic effect of some compounds of sulfonamide derivatives line vas of a high value. So the C-8 compound containing two nitro-groups had quite a sensible analgetic activity (increase in pain threshold by 162%) under moderate. but particularly pronounced anticonvulsive effect (96%). Most of compounds possess moderate toxicity, LDso ranges from 400 to 1200 mg/kg. Investigation of original sulfonamide derivatives shows promise as a way to develop new medicines for convulsive status.
IP.18-23! Convulsive and Anticonvulsive Influence of Some
1 Solvay Duphar B. v.. lVeesp, The Netherlands; 2 Cognitive Drug Research Ltd., Reading, Berks, UiK; 3 LAB GmbH & Co. Neu-Ulm, Germany
Introduction. Flesinoxan is a phenylpiperazine 5HT-agonist, which is in phase III development for the treatment of depression and anxiety. In this study the influence of flesinoxan on psychomotor performance was investigated, as well as the effect of age on psychomotor performance. [Also pharmacokinetics was assessed in this study]. Methods. 52 Subjects (17 2 1-35 years: 1& 65-74 years, 17 75-84 years; 27 men and 25 women) participated in this double-blind parallelgroup study, in which half of the subjects received flesinoxan (0.5 mg single dose, and the 1.0 mg BlD ), and the other subjects placebo. Two "young" subjects dropped out. Psychomotor performance (cognitive function testing. Bond Lader VAS, Sleep Questionnaire, Body Sway) was measured before and I hour after SD and MD flesinoxan (or placebo) dosing. Results. Multiple dose flesinoxan improved cognitive function , particularly in the very elderly subjects. Beneficial effects were seen on 3 of the 4 (a priori defined) primary outcome variables (Digit Vigilance Speed, Immediate Word Recall Accuracy, Word Recognition Sensitivity). and these were supported by the secondary outcome variables. Effects after single dosing were less prominent. Flesinoxan was well tolerated, particularly in the elderly. Conclusions. Flesinoxan shows clear evidence of possessing cognition enhancing properties.
L-Asparagic Acid Derivatives
M. Karnri, N.S. Sapronov. Department ofNeuropharmacology, Institute
of Experimental Medicine, St. Petersburg, Russia It is known that exciting amino acids (EAA) play an important role in mammalian brain function including sensory information, memor y, behavior and convulsive reactions. That is why the search of substances capable decrease convulsions by means of blockade of EAA receptors is in a great interest, In the work there were investigated five new synthesized at the department of Neuropharmacology N-methyl-D -asparagic acid (NMDA, I) derivatives: N-allyl-(II), N-butyl-(III), N-pentyl-(IV), N-cyclohexyl-(V), N-benzyl (VI) asparagic acid. Convulsive and anticonvulsive activity of these compounds were examined in mice after injection into lateral ventricle (i,v.) of brain. Dose-depended convulsive activity was found in all substances investigated. l n the next series of experiments there was studied the ability of the drugs using in subconvulsive doses to prevent the convulsive reaction induced by i.v, NMDA injection. It was discovered, that most of compounds potentiated convulsive effect of NMDA while III decreased sufficiently the seizures on NMDA. The results of EAA receptors except N-butyl derivatives showing the properties of a partial agonist of NMDA receptors. The data says on perspective way of search new anticonvulsants within Lvasparagic acid derivatives.
IP.18-24 ! The Effects of Zonisamide and other Antiepileptic Drugs when Administered Incombination on the Seizure-Susceptible EI Mouse
M. Nomaguchi . L Nagatomo, Y. Akasaki, F. Nagase. M. Uchida. M. Tgakigawa Department ofNeuropsychiatry, Faculty of Medicine,
Kagoshima University, Kagoshima; Japan To elucidate the effects of Zonisamide (ZNSj and Phenobarbital (PB). Valproic acid (VPA) or Phenytoin (PHT) in combination, we investigated serum and brain concentrations of ZNS as well as anticonvulsive effects in the seizure-susceptible EL mouse. The administration of ZNS paired with PB, or VPA, or PHT intraperitoneally suppressed convulsive seizure significantly as compared with injection of ZNS alone. Serum ZNS concentration was essentially unchanged after the combined administration of ZNS and PB, whereas brain ZNS concentration tended to rise in proportion to the higher dose of PB. Changes in ZNS concentrations in serum and brain following admini stration of ZNS paired with the other two drugs were similar to those following injection of ZNS and PB in combination.
IP.19-21 Effects 0.1 Benzodiazepines on Conscious and Automatic Memory Processes
J.M. Danion , P. Vidailhet, M. Kazes, F. Kauffmann-Muller, D. Grange .
INSERM Unite 405, Hopitaux Universitaires de Strasbourg, France Recent studies exploring benzodiazep ine memory effects have used the distinction between explicit and implicit tasks. There is now increasing evidence that implicit tasks can be "contaminated" by conscious use of memory and that unconscious (automatic) use of memory can contaminate implicit tasks. leading to mistaken estimates of their respective influences on memory performance. The aim of the present double-blind , double-placebo study was to assess memory effects of diazepam and lorazepam using a process-dissociation procedure in a stem-completion task, this procedure providing uncontaminated estimates of conscious and automatic memory processes. The memory task was administrated to sixty healthy volunteers randomly assigned to one of 3 parallel groups (placebo, diazepam 0.3 mglkg, lorazepam 0.038 mglkg). Lorazepam markedly reduced conscious as well as automatic influences of memory. Diazepam also reduced conscious use of memory, albeit to a lesser extent than lorazepam, but did not decrease the influence of automatic memory. Secondary analyses showed that when the deleterious effect on conscious use of memory was equated between a diazepam subgroup and the Iorazepam group, only lorazepam impaired the automatic use of memory. This study strongly suggests a qualitative difference in memory effects of the two benzodiazepines.
IP- 19-3 / ,mpairment of Fine Short·Term Memory
Mechanisms with some Neurotropic Drugs
N.S. Sapronov, LL Stepanov. Department of Neuropharmacology.
Institute for Experimental medicine, St. Petersburg, Russia We investigated the effect of some neurotropic medicines on short-term memory formation with the test of memorization of ten unknown words during 10 trials in one session in a group of 16 adult male volunteers. All medicines under testing facilitated memorization. shifting the curve of dynamics upward. However. the medicines divided into two groups. The first group (Nootropil, Dibasol, Bemethyl) did not alter the shape of learning curve, i.e. experimental data were fitted significantly with exponential mathematical model in the form of Y = B3'exp (- B2'X) + B4' (1 - exp (- B2X)). It means that the medicines stimulated the same brain machinery that operates during memory formation in normal con-
186
IP-18-22I Denvatlves Ne~ A~ticon~UlsiveCompounds of Sulfonamide Line
1 P-19-1 I Flesinoxan Improves Cognition in The Healthy Elderly
H. Zlenko, V. Mamchur, L. Kasjan, O. Krasnovskaja, A. Kasyan,
1. Van Harten, M. Olff, K. Wesnes, W. Strobel.
V. Butchenko, H. Demchenko, V. Opryshko. Dnipropetrovsk State
Medical Academy; Ukraine Dnipropetrovsk State University, Ukraine The anticonvulsive activity of 16 new bi- and polycyclic sulfonamides derivatives were investigated depend ing on inclusion of the nitro-groups, the chlorine and fluorine atoms into molecules and on the hydrogenation of compounds as well. Experiment s with white rats were carried out. Corasole convulsions were model of spastic status (100 mglkg ilp). The degree of anticonvulsive activity vas determined by increase in term life, decrease in convulsive fits durability. survival of the animals. It was established that intensity of anticonvulsive activity ranges from 12 to 402%. Steric peculiarities connected with exo- and endo-isomeres presence affect anticonvulsive activity differently depending on a specific compound structure. Taking into account data on anticonvulsive activity of narcotic analgetic series the determination of analgetic effect of some compounds of sulfonamide derivatives line vas of a high value. So the C-8 compound containing two nitro-groups had quite a sensible analgetic activity (increase in pain threshold by 162%) under moderate. but particularly pronounced anticonvulsive effect (96%). Most of compounds possess moderate toxicity, LDso ranges from 400 to 1200 mg/kg. Investigation of original sulfonamide derivatives shows promise as a way to develop new medicines for convulsive status.
IP.18-23! Convulsive and Anticonvulsive Influence of Some
1 Solvay Duphar B. v.. lVeesp, The Netherlands; 2 Cognitive Drug Research Ltd., Reading, Berks, UiK; 3 LAB GmbH & Co. Neu-Ulm, Germany
Introduction. Flesinoxan is a phenylpiperazine 5HT-agonist, which is in phase III development for the treatment of depression and anxiety. In this study the influence of flesinoxan on psychomotor performance was investigated, as well as the effect of age on psychomotor performance. [Also pharmacokinetics was assessed in this study]. Methods. 52 Subjects (17 2 1-35 years: 1& 65-74 years, 17 75-84 years; 27 men and 25 women) participated in this double-blind parallelgroup study, in which half of the subjects received flesinoxan (0.5 mg single dose, and the 1.0 mg BlD ), and the other subjects placebo. Two "young" subjects dropped out. Psychomotor performance (cognitive function testing. Bond Lader VAS, Sleep Questionnaire, Body Sway) was measured before and I hour after SD and MD flesinoxan (or placebo) dosing. Results. Multiple dose flesinoxan improved cognitive function , particularly in the very elderly subjects. Beneficial effects were seen on 3 of the 4 (a priori defined) primary outcome variables (Digit Vigilance Speed, Immediate Word Recall Accuracy, Word Recognition Sensitivity). and these were supported by the secondary outcome variables. Effects after single dosing were less prominent. Flesinoxan was well tolerated, particularly in the elderly. Conclusions. Flesinoxan shows clear evidence of possessing cognition enhancing properties.
L-Asparagic Acid Derivatives
M. Karnri, N.S. Sapronov. Department ofNeuropharmacology, Institute
of Experimental Medicine, St. Petersburg, Russia It is known that exciting amino acids (EAA) play an important role in mammalian brain function including sensory information, memor y, behavior and convulsive reactions. That is why the search of substances capable decrease convulsions by means of blockade of EAA receptors is in a great interest, In the work there were investigated five new synthesized at the department of Neuropharmacology N-methyl-D -asparagic acid (NMDA, I) derivatives: N-allyl-(II), N-butyl-(III), N-pentyl-(IV), N-cyclohexyl-(V), N-benzyl (VI) asparagic acid. Convulsive and anticonvulsive activity of these compounds were examined in mice after injection into lateral ventricle (i,v.) of brain. Dose-depended convulsive activity was found in all substances investigated. l n the next series of experiments there was studied the ability of the drugs using in subconvulsive doses to prevent the convulsive reaction induced by i.v, NMDA injection. It was discovered, that most of compounds potentiated convulsive effect of NMDA while III decreased sufficiently the seizures on NMDA. The results of EAA receptors except N-butyl derivatives showing the properties of a partial agonist of NMDA receptors. The data says on perspective way of search new anticonvulsants within Lvasparagic acid derivatives.
IP.18-24 ! The Effects of Zonisamide and other Antiepileptic Drugs when Administered Incombination on the Seizure-Susceptible EI Mouse
M. Nomaguchi . L Nagatomo, Y. Akasaki, F. Nagase. M. Uchida. M. Tgakigawa Department ofNeuropsychiatry, Faculty of Medicine,
Kagoshima University, Kagoshima; Japan To elucidate the effects of Zonisamide (ZNSj and Phenobarbital (PB). Valproic acid (VPA) or Phenytoin (PHT) in combination, we investigated serum and brain concentrations of ZNS as well as anticonvulsive effects in the seizure-susceptible EL mouse. The administration of ZNS paired with PB, or VPA, or PHT intraperitoneally suppressed convulsive seizure significantly as compared with injection of ZNS alone. Serum ZNS concentration was essentially unchanged after the combined administration of ZNS and PB, whereas brain ZNS concentration tended to rise in proportion to the higher dose of PB. Changes in ZNS concentrations in serum and brain following admini stration of ZNS paired with the other two drugs were similar to those following injection of ZNS and PB in combination.
IP.19-21 Effects 0.1 Benzodiazepines on Conscious and Automatic Memory Processes
J.M. Danion , P. Vidailhet, M. Kazes, F. Kauffmann-Muller, D. Grange .
INSERM Unite 405, Hopitaux Universitaires de Strasbourg, France Recent studies exploring benzodiazep ine memory effects have used the distinction between explicit and implicit tasks. There is now increasing evidence that implicit tasks can be "contaminated" by conscious use of memory and that unconscious (automatic) use of memory can contaminate implicit tasks. leading to mistaken estimates of their respective influences on memory performance. The aim of the present double-blind , double-placebo study was to assess memory effects of diazepam and lorazepam using a process-dissociation procedure in a stem-completion task, this procedure providing uncontaminated estimates of conscious and automatic memory processes. The memory task was administrated to sixty healthy volunteers randomly assigned to one of 3 parallel groups (placebo, diazepam 0.3 mglkg, lorazepam 0.038 mglkg). Lorazepam markedly reduced conscious as well as automatic influences of memory. Diazepam also reduced conscious use of memory, albeit to a lesser extent than lorazepam, but did not decrease the influence of automatic memory. Secondary analyses showed that when the deleterious effect on conscious use of memory was equated between a diazepam subgroup and the Iorazepam group, only lorazepam impaired the automatic use of memory. This study strongly suggests a qualitative difference in memory effects of the two benzodiazepines.
IP- 19-3 / ,mpairment of Fine Short·Term Memory
Mechanisms with some Neurotropic Drugs
N.S. Sapronov, LL Stepanov. Department of Neuropharmacology.
Institute for Experimental medicine, St. Petersburg, Russia We investigated the effect of some neurotropic medicines on short-term memory formation with the test of memorization of ten unknown words during 10 trials in one session in a group of 16 adult male volunteers. All medicines under testing facilitated memorization. shifting the curve of dynamics upward. However. the medicines divided into two groups. The first group (Nootropil, Dibasol, Bemethyl) did not alter the shape of learning curve, i.e. experimental data were fitted significantly with exponential mathematical model in the form of Y = B3'exp (- B2'X) + B4' (1 - exp (- B2X)). It means that the medicines stimulated the same brain machinery that operates during memory formation in normal con-