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Effect of age, gender and food on the pharmacokinetics of flesinoxan
P Poster Presentations
36
IP-1-51 Effectof Gender, Age and Smoking on Doses and Plasma Levelsof Neuroleptics in Schizophrenia
KK.K Salokangas , T. Taiminen, E. Syvalahti , S. Saarijarvi, H. Lehto, H. Niem i, V. Ahola. Department of Psychiatry; University of Turku, Turku University Centra Hospital, Turku, Finland Accordin g to the oestrogen hypothesis patient's gender and age interact with daily doses of neurolept ics in schizophrenia. Smoking habit, very common among psychiatric patients, which also has an effect on use of neuroleptics has not been controlled in these studies, however. The objective of this study was study the effect of gender, age and smoking on daily doses and plasma levels of neuroleptics in schizophren ia. 90 outpatients suffering from schizophrenic disorder (DSM-III-R) with stable psychotropic med ication and stable clinical state were included in a double-blind placebo-controlled trail. Data on duration of illness, weight and height, smoking habit, use of neuroleptics and global functional ability were collected and blood test were taken at the basic interview. Daily doses and plasma levels of unmetabolized neuroleptic s were converted into chlorpromazine equivalents. Doses of neuroleptics correlated significantly (r =0.436) with their unmetabolized plasma fraction. Smokers had significantly higher doses than non-smokers; gender and age has no significant independent effect but a clear interaction: daily doses increased in smoke rs with age, especially in female smokers. There were no significant associa tions in plasma levels of unmetabolized neuroleptics. The main conclusion was that cigarette smoking is related to the higher neuroleptic doses in schizophrenic patients. Secondly, the daily use of neu roleptics seems to decre ase with age in non-smokers; in smokers the age effect may be opposite. In post-menopausal smoking females, high neurolept ics doses may be explained by interaction of nicotine stimulation and decreased oestrogen secretion.
I p-1-sl
Age Effecton the Plasma Levels of Various Psychotropic Drugs
M. Kamimura, N. Yamaguchi, Y. Morokawa, T. Ohta, H. Fujimaki, A. Aoba. Department of Psychiatry, St. Marianna University School of
Medicine, Kanagawa, Japan Plasm a level of various psychotropic drugs including haloperidol, brornperidol, chlorpromazine, dosulepine, setiptyline (tetracyclic antidepressant) and lormetazepam were measured to clarify the age effect on their main metabolic pathwa y in 286 psychiatric patients. By dividing the plasma levels by the dose per day, the plasma level dose ratio was taken as an index of systemic clearance in the liver. In patients treated with haloperid ol and bromperidol, there were not significant correlations between the plasma level dose ratio and the age of the subjects, suggesting that the age does not affect the reduction process of haloperidol and bromperidol. In patients treated with dosulepine, there was significant positive correlatio n between the ratio and the age, suggesting that the demeth ylation process in the liver was delayed by aging. We also found significant positive correlations in the patient s treated with setiptyline and lormetazepam between the ratio and the age. However the increases of the ratios were begun after the patients age were beyond 75 years old. These results suggest that the effect of age on the metabolic clearance of the drug varies greatly with the metabolic pathways of the respective drugs. Therefore, it is advisable to select the drugs by carefully evaluating the metaboli c pathways of psychotropic drugs to be used in treating elderly patients.
IP-1-71 Effect of Age, Gender and Food on the Pharmacokinetics of Flesinoxan
W. Strobel 2 . 1 Solvay Duphar B. v., P.O. Box 900, 1380 DA Weesp, The Netherlands; 2 LAB GmbH & Co, Neu Ulm, Germany
J. Van Harten
I,
C. Boon
I,
Introduction. Flesinoxan is a phenylpiperazine 5HT-agonisl, which is in phase III development for the treatment of depression and anxiety. The aim of the study was to determ ine the influence of age, gender and food on the pharmacokinetics of flesinoxan. [Also psychomotor perform ance was assessed in this study] .
Methods. 35 Subjects (12 aged 21-35 years; 12 aged 65-74 years; 12 aged 75-84 years; 18 men and 17 women) received f1 esinoxan in this parallel group study. On Days I and 8 they received, in a randomized order, 0.5 mg flesinoxan with and without food. On Days 10-17 they received multiple dose flesinoxan (1.0 mg BID). The kinetics of flesinoxan was assessed on Days I, 8 and 17. Results and conclusion. Concomitant food intake did not affect the bioavailability of flesinoxan (AUC and Cmax ), but absorption was delayed. The AUC of flesinoxan was ~ 50% higher in females over 65 years compared with males of all 3 ages groups and young females. The half-life of f1esinoxan was shorter in the young (~ 6 hours ) than in the elderly (8-9 hours). Flesinoxan was well tolerated, particularly in the subjec ts of both sexes over 65.
IP-1 -S! Improvement 5ertraline and Nortriptyline: Heart Rate, Cognitive and Quality of Lifein Depressed Elderly W. McEntee, G. Ko, E. Richter. FutureHealth-Care Research Center,
Sarasota, FL; Pfizer Inc, New York, USA Twelve investigational sites in the United States participated in this parallel-group study to evaluate the relative safe ty and efficacy of sertraline and nortriptyline in the treatment of geriatric depression. Following a 1- 2 week placebo washout, patients were random ized to 12 weeks of double-blind treatment with either sertraline (50-1 50 mg) or nortriptyline (25- 100 mg). All Patients (n = 204; mean age 68 yrs) met DSM-III-R criteria for Major Depressive Disorder. Baseline Hamilton Depre ssion Scores and endpoint change for sertraline were 24.7 and -12.6 versus 25.0 and -1 1.7 for nortriptyline (NS between groups, p < O.OOl for both groups vs baseline). Over 70% of nortriptyline completers had plasma nortriptyline levels of > 50 nglml (ie within the therapeutic range). Sertraline concentrations were dose-proportional. Supine and standing heart rate (HR, beats per minute) were measured at baseline through weeks twelve. The mean baseline supine HR for sertraline was 70.1 for sertraline and 70.3 for nortriptyline. By the end of week one, the change was -0. 72 for sertraline (n.s.) and +3.2 bpm for nortriptyline (p < 0.0 I change from baseline and compared to sertraline at week one). This pattern persisted for every week throughout the study for both standing as well as supine HR. Measures of cognitive improveme nt, the Shopping List Task and the Digit Symb ol Substitution Test showed superior baseline to end point changes for sertraline over nortript yline (p < 0.05 in favor of sertraline on both). Quality of life items including individual comparisons on items of physical , social, psychological health and leisure time satisfaction improved to a significantly greater extent at end point on sertraline compared with nortriptyline. These result s suggest that, while both compounds have antidepressant efficacy, sertraline has advantages with regard s to physical and psychological health in older depressed patients.
IP-1-9 1 No Age-Related Change in Platelet Tritiated Paroxetine Binding in Humans
D. Marazziti. L. Palego, L. Delr Osso, M. Fancelli, A. Rossi, A. Lucacchini, G.B. Cassano. Institute of Psychiatry and "lstituto
Policattedra Discipline Biologiche ", University of Pisa, Pisa, Italy A sodium - and temperature dependent serotonin (5HT) transporter in platelets shows striking similarities with that present in the central nervous system. Tricyclic antidepressants (TCAs) and selective 5HT reuptake inhibitors (SSRIs) are the most potent drugs interacting at the level of the 5HT transporter and, tritiated imipramine C H-IMI), a TCA , has been widely used to label it. The 5HT reuptake and the >H-IMI bindin g have been deeply investigated in depressed subjects, most of the studies reporting a decreased maximal velocity of the uptake and of the number of IMI sites. However, a direct link between the 5HT uptake and the IMI binding has never been demonstrated. In fact, the biochemical relationships bewteen the different sites which are part of the 5HT transporter are still elusive. The lack of correlations is generally expla ined by site heterogeneity for 3H-IMI. In recent years, it has been demonstrated that the more selective ligand, 3H-paroxetine CH.Par) binds to a single site probably corresponding to the neuronal transporter. Since there exist con-
36
IP-1-51 Effectof Gender, Age and Smoking on Doses and Plasma Levelsof Neuroleptics in Schizophrenia
KK.K Salokangas , T. Taiminen, E. Syvalahti , S. Saarijarvi, H. Lehto, H. Niem i, V. Ahola. Department of Psychiatry; University of Turku, Turku University Centra Hospital, Turku, Finland Accordin g to the oestrogen hypothesis patient's gender and age interact with daily doses of neurolept ics in schizophrenia. Smoking habit, very common among psychiatric patients, which also has an effect on use of neuroleptics has not been controlled in these studies, however. The objective of this study was study the effect of gender, age and smoking on daily doses and plasma levels of neuroleptics in schizophren ia. 90 outpatients suffering from schizophrenic disorder (DSM-III-R) with stable psychotropic med ication and stable clinical state were included in a double-blind placebo-controlled trail. Data on duration of illness, weight and height, smoking habit, use of neuroleptics and global functional ability were collected and blood test were taken at the basic interview. Daily doses and plasma levels of unmetabolized neuroleptic s were converted into chlorpromazine equivalents. Doses of neuroleptics correlated significantly (r =0.436) with their unmetabolized plasma fraction. Smokers had significantly higher doses than non-smokers; gender and age has no significant independent effect but a clear interaction: daily doses increased in smoke rs with age, especially in female smokers. There were no significant associa tions in plasma levels of unmetabolized neuroleptics. The main conclusion was that cigarette smoking is related to the higher neuroleptic doses in schizophrenic patients. Secondly, the daily use of neu roleptics seems to decre ase with age in non-smokers; in smokers the age effect may be opposite. In post-menopausal smoking females, high neurolept ics doses may be explained by interaction of nicotine stimulation and decreased oestrogen secretion.
I p-1-sl
Age Effecton the Plasma Levels of Various Psychotropic Drugs
M. Kamimura, N. Yamaguchi, Y. Morokawa, T. Ohta, H. Fujimaki, A. Aoba. Department of Psychiatry, St. Marianna University School of
Medicine, Kanagawa, Japan Plasm a level of various psychotropic drugs including haloperidol, brornperidol, chlorpromazine, dosulepine, setiptyline (tetracyclic antidepressant) and lormetazepam were measured to clarify the age effect on their main metabolic pathwa y in 286 psychiatric patients. By dividing the plasma levels by the dose per day, the plasma level dose ratio was taken as an index of systemic clearance in the liver. In patients treated with haloperid ol and bromperidol, there were not significant correlations between the plasma level dose ratio and the age of the subjects, suggesting that the age does not affect the reduction process of haloperidol and bromperidol. In patients treated with dosulepine, there was significant positive correlatio n between the ratio and the age, suggesting that the demeth ylation process in the liver was delayed by aging. We also found significant positive correlations in the patient s treated with setiptyline and lormetazepam between the ratio and the age. However the increases of the ratios were begun after the patients age were beyond 75 years old. These results suggest that the effect of age on the metabolic clearance of the drug varies greatly with the metabolic pathways of the respective drugs. Therefore, it is advisable to select the drugs by carefully evaluating the metaboli c pathways of psychotropic drugs to be used in treating elderly patients.
IP-1-71 Effect of Age, Gender and Food on the Pharmacokinetics of Flesinoxan
W. Strobel 2 . 1 Solvay Duphar B. v., P.O. Box 900, 1380 DA Weesp, The Netherlands; 2 LAB GmbH & Co, Neu Ulm, Germany
J. Van Harten
I,
C. Boon
I,
Introduction. Flesinoxan is a phenylpiperazine 5HT-agonisl, which is in phase III development for the treatment of depression and anxiety. The aim of the study was to determ ine the influence of age, gender and food on the pharmacokinetics of flesinoxan. [Also psychomotor perform ance was assessed in this study] .
Methods. 35 Subjects (12 aged 21-35 years; 12 aged 65-74 years; 12 aged 75-84 years; 18 men and 17 women) received f1 esinoxan in this parallel group study. On Days I and 8 they received, in a randomized order, 0.5 mg flesinoxan with and without food. On Days 10-17 they received multiple dose flesinoxan (1.0 mg BID). The kinetics of flesinoxan was assessed on Days I, 8 and 17. Results and conclusion. Concomitant food intake did not affect the bioavailability of flesinoxan (AUC and Cmax ), but absorption was delayed. The AUC of flesinoxan was ~ 50% higher in females over 65 years compared with males of all 3 ages groups and young females. The half-life of f1esinoxan was shorter in the young (~ 6 hours ) than in the elderly (8-9 hours). Flesinoxan was well tolerated, particularly in the subjec ts of both sexes over 65.
IP-1 -S! Improvement 5ertraline and Nortriptyline: Heart Rate, Cognitive and Quality of Lifein Depressed Elderly W. McEntee, G. Ko, E. Richter. FutureHealth-Care Research Center,
Sarasota, FL; Pfizer Inc, New York, USA Twelve investigational sites in the United States participated in this parallel-group study to evaluate the relative safe ty and efficacy of sertraline and nortriptyline in the treatment of geriatric depression. Following a 1- 2 week placebo washout, patients were random ized to 12 weeks of double-blind treatment with either sertraline (50-1 50 mg) or nortriptyline (25- 100 mg). All Patients (n = 204; mean age 68 yrs) met DSM-III-R criteria for Major Depressive Disorder. Baseline Hamilton Depre ssion Scores and endpoint change for sertraline were 24.7 and -12.6 versus 25.0 and -1 1.7 for nortriptyline (NS between groups, p < O.OOl for both groups vs baseline). Over 70% of nortriptyline completers had plasma nortriptyline levels of > 50 nglml (ie within the therapeutic range). Sertraline concentrations were dose-proportional. Supine and standing heart rate (HR, beats per minute) were measured at baseline through weeks twelve. The mean baseline supine HR for sertraline was 70.1 for sertraline and 70.3 for nortriptyline. By the end of week one, the change was -0. 72 for sertraline (n.s.) and +3.2 bpm for nortriptyline (p < 0.0 I change from baseline and compared to sertraline at week one). This pattern persisted for every week throughout the study for both standing as well as supine HR. Measures of cognitive improveme nt, the Shopping List Task and the Digit Symb ol Substitution Test showed superior baseline to end point changes for sertraline over nortript yline (p < 0.05 in favor of sertraline on both). Quality of life items including individual comparisons on items of physical , social, psychological health and leisure time satisfaction improved to a significantly greater extent at end point on sertraline compared with nortriptyline. These result s suggest that, while both compounds have antidepressant efficacy, sertraline has advantages with regard s to physical and psychological health in older depressed patients.
IP-1-9 1 No Age-Related Change in Platelet Tritiated Paroxetine Binding in Humans
D. Marazziti. L. Palego, L. Delr Osso, M. Fancelli, A. Rossi, A. Lucacchini, G.B. Cassano. Institute of Psychiatry and "lstituto
Policattedra Discipline Biologiche ", University of Pisa, Pisa, Italy A sodium - and temperature dependent serotonin (5HT) transporter in platelets shows striking similarities with that present in the central nervous system. Tricyclic antidepressants (TCAs) and selective 5HT reuptake inhibitors (SSRIs) are the most potent drugs interacting at the level of the 5HT transporter and, tritiated imipramine C H-IMI), a TCA , has been widely used to label it. The 5HT reuptake and the >H-IMI bindin g have been deeply investigated in depressed subjects, most of the studies reporting a decreased maximal velocity of the uptake and of the number of IMI sites. However, a direct link between the 5HT uptake and the IMI binding has never been demonstrated. In fact, the biochemical relationships bewteen the different sites which are part of the 5HT transporter are still elusive. The lack of correlations is generally expla ined by site heterogeneity for 3H-IMI. In recent years, it has been demonstrated that the more selective ligand, 3H-paroxetine CH.Par) binds to a single site probably corresponding to the neuronal transporter. Since there exist con-