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Moderate influence of the debrisoquine genotype on the steady-state concentrations of the enantiomers of mianserin
44S
Poster session I
BIOL. PSYCHIATRY 1997:42:15-2975
114-1241
Short- and long-term behavioral environmental adaptation In experimental hepatic encephalopathy
G. Apelqvlst, B. Hindfelt 1, G. Andersson 2, F. Bengtsson. Department of elin Pharm, Lund, Sweden, 1 Department of Neurology. MalmtJ Lund Univ, Lund. Sweden. 2 Department of Oncology Immunology. Phannacia AB. Lund. Sweden Hepatic encephalopathy (HE) is a neuropsychiatric syndrome arising as a consequence of liver failure due to e.g. liver cirrhosis. Impaired cognitive function have been reported In humans suffering from HE. However, no such atteration has been found in experimental hepatic encephalopathy. i.e. In portacaval shunted rats (PCS). neither in swim latency test nor In different maze tests or In passive avoidance tests. The adaptive and learning capacity was studied as short- (within-session) and long-term (between-session) habituation of exploratory behavior In portacaval shunted rats and sham-operated controls. Locomotor and rearing activity was measured four consecutive nights In an open-field during 60 or 5 minutes with 24 hours between each session. The results show lower locomotor and rearing activity in PCS vs sham• operated rats during both the first 6O-mln and the 5-min-test period. During the follOWing three 6O-mln-test period no such differences could be de• tected, whereas during the 5-mln test-periods the differences persisted. Furthermore, sham-operated rats displayed a dramatic decreased In these activities between test episodes. This normal drop In activity rate upon re• peated testing were not displayed by the PCS rats. Within both the 6o-min• test periods and the 5-min-test periods both PCS and sham-operated rats showed similar drop In locomotor and rearing activity. The present study show evidence for a disrupted long-term habituation capacity In PCS rats, but no evidence for short·term habituation deficiency and may thus shed some new light on the possible cognitive dysfunction associated with experimental HE.
114-1251
Diminished central fatigue by Inhibition of the L-system transporter for the uptake of tryptophan
T. Yamamoto 1, L.M. Castell 2 , E.A. Newsholme 2. 1 Health Science Laboratory. Tezukayama University. Nara, Japan, 2 Department of Biochemistry. University of Oxford, Oxford, UK There is evidence that tryptophan, the precursor of 5-hydroxytryptamine (5-HT) Is Involved in central fatigue. Tryptophan Is the only amino acid that binds to albumin In the blood. Free tryptophan competes with branched amino acids (BCM) for entry across the L-system of the blood-brain barrier. In analbuminemlc rats, running to fatigue produced a remarkable increase of tryptophan, 5-hydroxytryptophan (5-HTP) and 5-HT concentrations in the striatal synaptosomes. Administration of either BCM or the Inhibitor 2-amlnobicyclo[2,2, t Iheptane-2-carboxylic acid (SCH), which is specific for the L-system, resulted In increased run time In rats in comparison with those treated with saline and albumin (p < 0.001). SCM or BCH treatments led to decreased tryptophan uptake and a decrease In the 5-HTP level in synaptosomes Isolated from the strialum of exhausted rats (p < 0.025). Furthermore, following Incubation In medium supplemented with 200 nM and 2 /LM tryptophan, 5-HT release from striatal synaptosomes stimulated by K+. increased significantly by 28% and 70"/. respectively, compared with the control. Thus. in vitro. the release of 5-HT depends upon the extracellular tryptophan concentration. These results support the view that an elevated 5-HT level may be Involved in central fatigue, which can be diminished by Inhibition of the L-system. Supported by a grant from the Tezukayama Gakuen.
114-1261
JL 13, a promising atypical antipsychotic: A review of Its preclinical profile
J.-F. Uegeois 1.3. J. Bruhwyler 2 , J. Damas 3, J. Delarge 1, J. Geczy2. 1 University of Uege, Lab. Medicinal Chemistry, U~e, Belgium, 3 University of Uege. Lab. Physiology, Uege, Belgium, 2 Therabel Research, Brussels. Belgium The search for Improved clozaplne-like compounds has resulted in the selection of a new molecule, JL 13. Uke clozapine, JL 13 did not an• tagonize apomorphine-induced stereotypy and did not produce catalepsy but antagoniZed apomorphine-Induced climbing In rodents. It was Inac• tive against d-amphetarnine-induced stereotypy but antagonized d-amphet• amine-Induced hyperactiVity In the mouse. JL 13, like clozapine, was able to
antagonize (±)-DOI-Induced head-twitches In the mouse. In the open-field test in the rat and forced swimming test In the mouse a high similarity was noted between the two drugs in the same dose range. In a complelC temporal regulation schedule in the dog, JL 13 showed a high resemblance with clozapine without inducing sialorrtlea, palpebral ptosis or any significant motor side effects. In rats trained to discriminate clozapine, JL 13 Induced a generalization level (700/0) never encountered with risperidone (40%), olanzapine (38%) or sertindole (50%). In a drug discrimination procedure In the squirrel monkey, JL 13 produced a full substitution of clozapine. On the basis of these preclinical data, it would therefore be predicted that JL 13 will have an atypical profile with a lower propensity to Induce undesirable extrapyramidal symptoms than currently available antipsychotic drugs.
114-1271
Event-related desynchronlsation In healthy volunteers and postacute schizophrenic patients
V. Eichert. Psychiatric Department, University of Bonn, Bonn, Gennany 20 postacute schizophrenic patients with predominantly negative and basic symptoms (30.6 ± 6.5 years, d, SANS 40.75 ± 6.2, NL steady state medication with 390 ± 308 CPZ-equlvJdie) and 18 healthy volunteers (29.2 ± 6.0 years. male) participated ina P300 experiment (150 1000, 30 2000 Hz tones. lSI 2s). For the target segments the event-related desynchronisation of the alpha-band (7.5-13 Hz) was calculated In steps of 125 msec. The patients showed a reduced amplitude as well as a shorter duration of the ERO. In both groups the ERD amplitUde reached its maximum in the time window between 375 and 500 msec. Significant differences In the ERD amplitude were already found between 125 and 250 msec (pz: 116.5 vs. 88.7%, P=0.018; 02: 106.8 vs. 81.4%, P= 0.001) furthermore between 250 and 375 ms (Fz: 106.8 vs. 73.1 %, P= 0.004; C3: 108.2 vs. 76.8%. P = 0.004; Pz: 96.0 vs. 53.0%, P = 0.001; 02: 96.3 vs. 57.8%, P = 0.000; 01: 93.7 vs. 60.4%, p 0.003). The results are in line with the assumption of a reduced cortical reagibility during information processing In schizophrenia.
=
114-1281
Moderate Influence of the debrlsoqulne genotype on the steady-state concentrations of the enantiomers of mianserin
C.B. Eap, C.A. de Mendon~ Lima, K. Powell, P. Baumann. Departement Universitaire de Psychiatr/e. Lausanne, Suisse. Switzerland Five to ten percent of the caucasian population are poor metabollzers (PM) of debrisoqulne and of more than 40 other drugs, due to the genetically inherited lack of an enzyme called cytochrome P450II06 (CYP2D6). They may. therefore, develop high concentrations of these drugs and may be more susceptible to drug-related side effects. In a recent single-dose study, it has been shown that the elimination of mianserin (MIA) and of its main metabolite, desmethylmianserin (DMIA), Is dependent on CYP2D6 actiVity. We measured the steady-state concentrations of the enantiomers of MIA and DMIA in 28 extensive metabolizers (EM), one PM and one patient receiving very high doses of MIA and paroxetlne, the latter drug being a strong CYP2D6 inhibitor. Our results confirm those of a slnglfHlose study In that CYP2D6 is probably involved In the metabolism of MIA and DMIA with an enantioselectivity for the (S)-enantiomer of MIA. However, our study does not suggest that CYP206 is a major determinant of the steady-state concentrations of (S)- and (R)-MIA, and of (S)- and (R)-OMIA. From a clinical point of view, our results suggest that PMs of debrisoquine. who represent up to 10% of the Caucasian population, are not likely to suffer from high dose-related side-effects due to Impaired metabolism when treated with MIA. Furthermore, comedications which are strong CYP206 Inhibitors are less likely to Inhibit the metabolism of MIA than some other antidepressants which depend more on this enzyme for their metabolism.
114-1291
EEG abnormalities In schizophrenic patients Who treated with clozaplne
E. Tezcan, M. Atmaca, F. Olke~lu, M. Kul~lu. C. Karabulut Firat University Medical School. Elazig, Turkey In our study. EEG findings and occurrence of seizures In patients with refractory schizophrenia treated with clozapine has been conducted. Materials: The study group consisted of 14 schizophrenic patients hos• pitalized in June 1995-October 1996 In Firat University Medical Facu Hospital. Routine awake EEG recordings were performed prior the trea~ ment. and after the patients reached the dose of 600 mg clozapine per day
Poster session I
BIOL. PSYCHIATRY 1997:42:15-2975
114-1241
Short- and long-term behavioral environmental adaptation In experimental hepatic encephalopathy
G. Apelqvlst, B. Hindfelt 1, G. Andersson 2, F. Bengtsson. Department of elin Pharm, Lund, Sweden, 1 Department of Neurology. MalmtJ Lund Univ, Lund. Sweden. 2 Department of Oncology Immunology. Phannacia AB. Lund. Sweden Hepatic encephalopathy (HE) is a neuropsychiatric syndrome arising as a consequence of liver failure due to e.g. liver cirrhosis. Impaired cognitive function have been reported In humans suffering from HE. However, no such atteration has been found in experimental hepatic encephalopathy. i.e. In portacaval shunted rats (PCS). neither in swim latency test nor In different maze tests or In passive avoidance tests. The adaptive and learning capacity was studied as short- (within-session) and long-term (between-session) habituation of exploratory behavior In portacaval shunted rats and sham-operated controls. Locomotor and rearing activity was measured four consecutive nights In an open-field during 60 or 5 minutes with 24 hours between each session. The results show lower locomotor and rearing activity in PCS vs sham• operated rats during both the first 6O-mln and the 5-min-test period. During the follOWing three 6O-mln-test period no such differences could be de• tected, whereas during the 5-mln test-periods the differences persisted. Furthermore, sham-operated rats displayed a dramatic decreased In these activities between test episodes. This normal drop In activity rate upon re• peated testing were not displayed by the PCS rats. Within both the 6o-min• test periods and the 5-min-test periods both PCS and sham-operated rats showed similar drop In locomotor and rearing activity. The present study show evidence for a disrupted long-term habituation capacity In PCS rats, but no evidence for short·term habituation deficiency and may thus shed some new light on the possible cognitive dysfunction associated with experimental HE.
114-1251
Diminished central fatigue by Inhibition of the L-system transporter for the uptake of tryptophan
T. Yamamoto 1, L.M. Castell 2 , E.A. Newsholme 2. 1 Health Science Laboratory. Tezukayama University. Nara, Japan, 2 Department of Biochemistry. University of Oxford, Oxford, UK There is evidence that tryptophan, the precursor of 5-hydroxytryptamine (5-HT) Is Involved in central fatigue. Tryptophan Is the only amino acid that binds to albumin In the blood. Free tryptophan competes with branched amino acids (BCM) for entry across the L-system of the blood-brain barrier. In analbuminemlc rats, running to fatigue produced a remarkable increase of tryptophan, 5-hydroxytryptophan (5-HTP) and 5-HT concentrations in the striatal synaptosomes. Administration of either BCM or the Inhibitor 2-amlnobicyclo[2,2, t Iheptane-2-carboxylic acid (SCH), which is specific for the L-system, resulted In increased run time In rats in comparison with those treated with saline and albumin (p < 0.001). SCM or BCH treatments led to decreased tryptophan uptake and a decrease In the 5-HTP level in synaptosomes Isolated from the strialum of exhausted rats (p < 0.025). Furthermore, following Incubation In medium supplemented with 200 nM and 2 /LM tryptophan, 5-HT release from striatal synaptosomes stimulated by K+. increased significantly by 28% and 70"/. respectively, compared with the control. Thus. in vitro. the release of 5-HT depends upon the extracellular tryptophan concentration. These results support the view that an elevated 5-HT level may be Involved in central fatigue, which can be diminished by Inhibition of the L-system. Supported by a grant from the Tezukayama Gakuen.
114-1261
JL 13, a promising atypical antipsychotic: A review of Its preclinical profile
J.-F. Uegeois 1.3. J. Bruhwyler 2 , J. Damas 3, J. Delarge 1, J. Geczy2. 1 University of Uege, Lab. Medicinal Chemistry, U~e, Belgium, 3 University of Uege. Lab. Physiology, Uege, Belgium, 2 Therabel Research, Brussels. Belgium The search for Improved clozaplne-like compounds has resulted in the selection of a new molecule, JL 13. Uke clozapine, JL 13 did not an• tagonize apomorphine-induced stereotypy and did not produce catalepsy but antagoniZed apomorphine-Induced climbing In rodents. It was Inac• tive against d-amphetarnine-induced stereotypy but antagonized d-amphet• amine-Induced hyperactiVity In the mouse. JL 13, like clozapine, was able to
antagonize (±)-DOI-Induced head-twitches In the mouse. In the open-field test in the rat and forced swimming test In the mouse a high similarity was noted between the two drugs in the same dose range. In a complelC temporal regulation schedule in the dog, JL 13 showed a high resemblance with clozapine without inducing sialorrtlea, palpebral ptosis or any significant motor side effects. In rats trained to discriminate clozapine, JL 13 Induced a generalization level (700/0) never encountered with risperidone (40%), olanzapine (38%) or sertindole (50%). In a drug discrimination procedure In the squirrel monkey, JL 13 produced a full substitution of clozapine. On the basis of these preclinical data, it would therefore be predicted that JL 13 will have an atypical profile with a lower propensity to Induce undesirable extrapyramidal symptoms than currently available antipsychotic drugs.
114-1271
Event-related desynchronlsation In healthy volunteers and postacute schizophrenic patients
V. Eichert. Psychiatric Department, University of Bonn, Bonn, Gennany 20 postacute schizophrenic patients with predominantly negative and basic symptoms (30.6 ± 6.5 years, d, SANS 40.75 ± 6.2, NL steady state medication with 390 ± 308 CPZ-equlvJdie) and 18 healthy volunteers (29.2 ± 6.0 years. male) participated ina P300 experiment (150 1000, 30 2000 Hz tones. lSI 2s). For the target segments the event-related desynchronisation of the alpha-band (7.5-13 Hz) was calculated In steps of 125 msec. The patients showed a reduced amplitude as well as a shorter duration of the ERO. In both groups the ERD amplitUde reached its maximum in the time window between 375 and 500 msec. Significant differences In the ERD amplitude were already found between 125 and 250 msec (pz: 116.5 vs. 88.7%, P=0.018; 02: 106.8 vs. 81.4%, P= 0.001) furthermore between 250 and 375 ms (Fz: 106.8 vs. 73.1 %, P= 0.004; C3: 108.2 vs. 76.8%. P = 0.004; Pz: 96.0 vs. 53.0%, P = 0.001; 02: 96.3 vs. 57.8%, P = 0.000; 01: 93.7 vs. 60.4%, p 0.003). The results are in line with the assumption of a reduced cortical reagibility during information processing In schizophrenia.
=
114-1281
Moderate Influence of the debrlsoqulne genotype on the steady-state concentrations of the enantiomers of mianserin
C.B. Eap, C.A. de Mendon~ Lima, K. Powell, P. Baumann. Departement Universitaire de Psychiatr/e. Lausanne, Suisse. Switzerland Five to ten percent of the caucasian population are poor metabollzers (PM) of debrisoqulne and of more than 40 other drugs, due to the genetically inherited lack of an enzyme called cytochrome P450II06 (CYP2D6). They may. therefore, develop high concentrations of these drugs and may be more susceptible to drug-related side effects. In a recent single-dose study, it has been shown that the elimination of mianserin (MIA) and of its main metabolite, desmethylmianserin (DMIA), Is dependent on CYP2D6 actiVity. We measured the steady-state concentrations of the enantiomers of MIA and DMIA in 28 extensive metabolizers (EM), one PM and one patient receiving very high doses of MIA and paroxetlne, the latter drug being a strong CYP2D6 inhibitor. Our results confirm those of a slnglfHlose study In that CYP2D6 is probably involved In the metabolism of MIA and DMIA with an enantioselectivity for the (S)-enantiomer of MIA. However, our study does not suggest that CYP206 is a major determinant of the steady-state concentrations of (S)- and (R)-MIA, and of (S)- and (R)-OMIA. From a clinical point of view, our results suggest that PMs of debrisoquine. who represent up to 10% of the Caucasian population, are not likely to suffer from high dose-related side-effects due to Impaired metabolism when treated with MIA. Furthermore, comedications which are strong CYP206 Inhibitors are less likely to Inhibit the metabolism of MIA than some other antidepressants which depend more on this enzyme for their metabolism.
114-1291
EEG abnormalities In schizophrenic patients Who treated with clozaplne
E. Tezcan, M. Atmaca, F. Olke~lu, M. Kul~lu. C. Karabulut Firat University Medical School. Elazig, Turkey In our study. EEG findings and occurrence of seizures In patients with refractory schizophrenia treated with clozapine has been conducted. Materials: The study group consisted of 14 schizophrenic patients hos• pitalized in June 1995-October 1996 In Firat University Medical Facu Hospital. Routine awake EEG recordings were performed prior the trea~ ment. and after the patients reached the dose of 600 mg clozapine per day