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P.1.g.006 A tolerability, safety and pharmacokinetic study of single and multiple oral doses of novel D3 partial agonist RGH-790 in healthy male volunteers
S208
P.1.g. Basic and clinical neuroscience − Cognitive neuroscience
P.1.g.006 A tolerability, safety and pharmacokinetic study of single and multiple oral doses of novel D3 partial agonist RGH-790 in healthy male volunteers K. Nagy1 ° , I. Laszlovszky1 , Z. M´arkus1 , G. N´emeth1 , G. Magyar2 , Z. Juh´asz2 , M. Kap´as2 , Z. Szombathelyi2 1 Gedeon Richter Plc., Medical Division, Budapest, Hungary; 2 Gedeon Richter Plc., Pharmacological and Drug Safety Research, Budapest, Hungary Purpose: RGH-790 is a novel D3 partial agonist for the potential treatment of impaired cognition. In three parts, the phase I study investigated the tolerability, safety and pharmacokinetics of a range of single and multiple oral doses of RGH-790 in healthy young male volunteers and characterized the effect of food on the bioavailability of a single dose. Methods: Part 1 was a single-dose, double-blind, randomized, placebo-controlled, dose escalating study in three cohorts of nine healthy male subjects randomized 6:3 to RGH-790 or placebo. Single doses of 0.5 mg, 1.0 mg and 2.5 mg were investigated. Part 2 was an open-label, randomized, two-way crossover study of the effect of food on pharmacokinetics of the single dose of 1.0 mg RGH-790. Part 3 was a multiple dose, double-blind, randomized, placebo controlled study in 5 cohorts of healthy male subjects with 9 volunteers in each cohort, randomized 6:3 to RGH-790 or placebo. Different dosing regimens were tested starting from 0.5 mg b.i.d. up to 8.0 mg b.i.d. Results: 82% of subjects receiving RGH-790 and 63% of subjects on placebo experienced any treatment emergent adverse event with most adverse events being ‘mild’ in intensity and none being ‘severe’. Most common adverse events likely to be related to RGH-790 were postural dizziness and nausea. Maximum tolerated single dose of RGH-790 was 2.5 mg. Higher single doses of RGH790 would be likely to have poor subject tolerability. In Part 2, single dose of 1.0 mg RGH-790 was better tolerated after a high fat breakfast than after an overnight fast. In Part 3, 5 cohorts were dosed for up to 19 days with dose escalation after every few days. Postural dizziness and nausea were the main adverse events, which tended to occur after dose-escalation but declined and often resolved completely within 2−3 days despite continued dosing suggesting development of tolerance. It should be noted that preclinical toxicology considerations limited dosing to 8 mg b.i.d. RGH 790. Pharmacokinetics of RGH-790 showed bi-exponential disposition. Mean terminal half-life values ranged from 13 to 17 hours. Maximum plasma concentrations of RGH-790 were generally attained at 1−1.8 hours post dose after single doses under fasting conditions. Food caused significant delay in absorption with lower peak plasma concentrations, but without altering AUC. Pharmacokinetics at steady-state showed approximate doseproportionality, both in terms of AUC and of peak plasma concentrations. Steady state plasma concentrations were reached within 2 to 4 days. Conclusion: Single and repeat doses of RGH-790 were reasonably well tolerated. Tolerance was apparent on repeat dosing with higher doses being well tolerated with resolution of adverse events after two or three days of dosing at that level. The tolerability, safety and pharmacokinetics of single and multiple doses of RGH790 support further evaluation of this compound in clinical trials. Disclosure statement: The authors are employees of and the study is sponsored by Gedeon Richter Plc, Hungary.
P.1.g.007 Differences of clinical and psychological characteristics among clusters of personality disorder by DSM-IV text revision criteria J.Y. Lee1 ° , J.K. Sakong2 , E.J. Cheon3 , S.H. Song4 , B.H. Koo3 1 CHA Gumi Medical Center, Psychiatry, Gumi, South-Korea; 2 Dongguk University Gyeongju Hospital, Psychiatry, Gyeongju, South-Korea; 3 Yeungnam University Medical Center, Psychiatry, Daegu, South-Korea; 4 Daedong Hospital, Psychiatry, Daegu, South-Korea Objectives: The purpose of this study was to find out differences of clinical features and psychological characteristics among patients with personality disorder clusters by Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) criteria. Methods: A total of 188 patients were enrolled in this study from October, 2006 to June, 2009. Patients with axis II personality disorder [cluster A (n = 8), cluster B (n = 121), cluster C (n = 59)] by DSM-IV-TR were included regardless of Axis I disorder. Patients with 2 or more personality disorders at the same time, mental retardations, or severe general medical conditions were excluded. All subjects completed neuropsychological tests including the Minnesota Multiphasic Personality Inventory (MMPI), the Symptom Checklist-90-Revised (SCL-90-R), the Personality Disorder Questionnaire (PDQ), and the Defense Style Questionnaire (DSQ). Student’s t-tests were used for differences among personality disorder clusters, and chi-square tests for categorical data. All data were analyzed using Statistical Package for Social Science (SPSS) version 17.0. Results: The results showed that somatization (p = 0.018) and hostility (p = 0.001) subscale scores of SCL-90-R were significantly increased in patients with cluster B personality disorders than cluster C personality disorders. Among validity scales of MMPI, lie (p = 0.001) and correction (p = 0.001) were significantly increased in patients with cluster C personality disorders. Among clinical scales of MMPI, depression (p = 0.008) and social introversion (p = 0.001) were significantly increased in patients with cluster C personality disorders, while psychopathic deviate (p = 0.003) and hypomania (p = 0.001) were significantly increased in patients with cluster B personality disorders. The scores of paranoid, antisocial, borderline, histrionic, narcissistic, and negativistic personality disorder of PDQ-IV were significantly increased in patients with cluster B personality disorders. Among defense styles of DSQ, The score of image distorting was significantly increased in patients with cluster B personality disorders. Among specific defense mechanisms of DSQ, the scores of neurotic denial, nondelusional projection, acting out, and affiliation were significantly increased in patients with cluster B personality disorders, while omnipotence was significantly increased in patients with cluster C personality disorders. The result of stepwise discriminant analysis with neuropsychological tests showed that the patients with personality disorders were significantly predicted by somatization of SCL-90-R, hypomania, social introversion, correction, psychopathic deviate, hypomania (exclusion) of MMPI, histrionic, borderline, avoidant personality disorder of PDQ, and nondelusional projection, omnipotence, acting out, affiliation of DSQ. Conclusion: It seems that hostility can be exposed more easily in patients with cluster B personality disorders so that cause interpersonal conflicts or problems more commonly. And they also have tendency of somatization or passive aggression in cluster B
P.1.g. Basic and clinical neuroscience − Cognitive neuroscience
P.1.g.006 A tolerability, safety and pharmacokinetic study of single and multiple oral doses of novel D3 partial agonist RGH-790 in healthy male volunteers K. Nagy1 ° , I. Laszlovszky1 , Z. M´arkus1 , G. N´emeth1 , G. Magyar2 , Z. Juh´asz2 , M. Kap´as2 , Z. Szombathelyi2 1 Gedeon Richter Plc., Medical Division, Budapest, Hungary; 2 Gedeon Richter Plc., Pharmacological and Drug Safety Research, Budapest, Hungary Purpose: RGH-790 is a novel D3 partial agonist for the potential treatment of impaired cognition. In three parts, the phase I study investigated the tolerability, safety and pharmacokinetics of a range of single and multiple oral doses of RGH-790 in healthy young male volunteers and characterized the effect of food on the bioavailability of a single dose. Methods: Part 1 was a single-dose, double-blind, randomized, placebo-controlled, dose escalating study in three cohorts of nine healthy male subjects randomized 6:3 to RGH-790 or placebo. Single doses of 0.5 mg, 1.0 mg and 2.5 mg were investigated. Part 2 was an open-label, randomized, two-way crossover study of the effect of food on pharmacokinetics of the single dose of 1.0 mg RGH-790. Part 3 was a multiple dose, double-blind, randomized, placebo controlled study in 5 cohorts of healthy male subjects with 9 volunteers in each cohort, randomized 6:3 to RGH-790 or placebo. Different dosing regimens were tested starting from 0.5 mg b.i.d. up to 8.0 mg b.i.d. Results: 82% of subjects receiving RGH-790 and 63% of subjects on placebo experienced any treatment emergent adverse event with most adverse events being ‘mild’ in intensity and none being ‘severe’. Most common adverse events likely to be related to RGH-790 were postural dizziness and nausea. Maximum tolerated single dose of RGH-790 was 2.5 mg. Higher single doses of RGH790 would be likely to have poor subject tolerability. In Part 2, single dose of 1.0 mg RGH-790 was better tolerated after a high fat breakfast than after an overnight fast. In Part 3, 5 cohorts were dosed for up to 19 days with dose escalation after every few days. Postural dizziness and nausea were the main adverse events, which tended to occur after dose-escalation but declined and often resolved completely within 2−3 days despite continued dosing suggesting development of tolerance. It should be noted that preclinical toxicology considerations limited dosing to 8 mg b.i.d. RGH 790. Pharmacokinetics of RGH-790 showed bi-exponential disposition. Mean terminal half-life values ranged from 13 to 17 hours. Maximum plasma concentrations of RGH-790 were generally attained at 1−1.8 hours post dose after single doses under fasting conditions. Food caused significant delay in absorption with lower peak plasma concentrations, but without altering AUC. Pharmacokinetics at steady-state showed approximate doseproportionality, both in terms of AUC and of peak plasma concentrations. Steady state plasma concentrations were reached within 2 to 4 days. Conclusion: Single and repeat doses of RGH-790 were reasonably well tolerated. Tolerance was apparent on repeat dosing with higher doses being well tolerated with resolution of adverse events after two or three days of dosing at that level. The tolerability, safety and pharmacokinetics of single and multiple doses of RGH790 support further evaluation of this compound in clinical trials. Disclosure statement: The authors are employees of and the study is sponsored by Gedeon Richter Plc, Hungary.
P.1.g.007 Differences of clinical and psychological characteristics among clusters of personality disorder by DSM-IV text revision criteria J.Y. Lee1 ° , J.K. Sakong2 , E.J. Cheon3 , S.H. Song4 , B.H. Koo3 1 CHA Gumi Medical Center, Psychiatry, Gumi, South-Korea; 2 Dongguk University Gyeongju Hospital, Psychiatry, Gyeongju, South-Korea; 3 Yeungnam University Medical Center, Psychiatry, Daegu, South-Korea; 4 Daedong Hospital, Psychiatry, Daegu, South-Korea Objectives: The purpose of this study was to find out differences of clinical features and psychological characteristics among patients with personality disorder clusters by Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) criteria. Methods: A total of 188 patients were enrolled in this study from October, 2006 to June, 2009. Patients with axis II personality disorder [cluster A (n = 8), cluster B (n = 121), cluster C (n = 59)] by DSM-IV-TR were included regardless of Axis I disorder. Patients with 2 or more personality disorders at the same time, mental retardations, or severe general medical conditions were excluded. All subjects completed neuropsychological tests including the Minnesota Multiphasic Personality Inventory (MMPI), the Symptom Checklist-90-Revised (SCL-90-R), the Personality Disorder Questionnaire (PDQ), and the Defense Style Questionnaire (DSQ). Student’s t-tests were used for differences among personality disorder clusters, and chi-square tests for categorical data. All data were analyzed using Statistical Package for Social Science (SPSS) version 17.0. Results: The results showed that somatization (p = 0.018) and hostility (p = 0.001) subscale scores of SCL-90-R were significantly increased in patients with cluster B personality disorders than cluster C personality disorders. Among validity scales of MMPI, lie (p = 0.001) and correction (p = 0.001) were significantly increased in patients with cluster C personality disorders. Among clinical scales of MMPI, depression (p = 0.008) and social introversion (p = 0.001) were significantly increased in patients with cluster C personality disorders, while psychopathic deviate (p = 0.003) and hypomania (p = 0.001) were significantly increased in patients with cluster B personality disorders. The scores of paranoid, antisocial, borderline, histrionic, narcissistic, and negativistic personality disorder of PDQ-IV were significantly increased in patients with cluster B personality disorders. Among defense styles of DSQ, The score of image distorting was significantly increased in patients with cluster B personality disorders. Among specific defense mechanisms of DSQ, the scores of neurotic denial, nondelusional projection, acting out, and affiliation were significantly increased in patients with cluster B personality disorders, while omnipotence was significantly increased in patients with cluster C personality disorders. The result of stepwise discriminant analysis with neuropsychological tests showed that the patients with personality disorders were significantly predicted by somatization of SCL-90-R, hypomania, social introversion, correction, psychopathic deviate, hypomania (exclusion) of MMPI, histrionic, borderline, avoidant personality disorder of PDQ, and nondelusional projection, omnipotence, acting out, affiliation of DSQ. Conclusion: It seems that hostility can be exposed more easily in patients with cluster B personality disorders so that cause interpersonal conflicts or problems more commonly. And they also have tendency of somatization or passive aggression in cluster B