Poster Session I (PI 1-106)Displayed 8:00 am – 3:00 ... - Nature

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BACKGROUND: Most methods for measuring drug effects on
the CNS rely on subjective assessments. The present research project
focused on objective measures to assess the stimulant effect of armodafinil.
The hypothesis was that the drug-related effects on alertness,
EEG and drug concentrations are correlated.
METHODS: In a double-blind, placebo-controlled, cross-over
design, this study involved six healthy adults who participated were in
three sessions. In each session, the subjects underwent 24-hour sleep
deprivation after which a single oral dose of the test drug was administered
(placebo, armodafinil 150 mg or 250 mg). The subjects underwent
12-hour sleep deprivation post-dose during which psychomotor
vigilance task, go/no-go task, EEG recording and blood sampling were
simultaneously performed. Event-related potential (ERP) analysis was
conducted in BESA ® . A simultaneous PK/PD fitting was performed
using a non-linear mixed-effects approach in NONMEM 7.
RESULTS: Armodafinil effect on alertness was correlated with
the effect compartment drug concentrations by an E max model. The
population estimates of ke0, E max (fraction of baseline) and EC50
were 0.568 (± 0.219) h -1 , 0.345 (±0.031) and 2.77 (±1.82) μg mL -1 ,
respectively. The time-varying baseline was described by a quadratic
function. Armodafinil pharmacokinetics was best described by a onecompartment
model with first-order elimination and absorption with
lag-time. Overall, the increase in alertness was accompanied by an
increase in the amplitude of the positive ERP peak at around 380 ms
(Pearson’s correlation, r=-0.74, p=1.62.10 -7 ).
CONCLUSION: Armodafinil increased the alertness of sleep
deprived adults which showed to be correlated with the effect compartment
drug concentrations. A significant correlation between alertness
and event-related changes on EEG brings the possibility of utilizing
EEG to describe the armodafinil response.
PI-1
MIRTAZAPINE SUPPRESSES THE INCREASES IN PLASMA
LEVELS OF ADRENOCORTICOTROPIC HORMONE AND NEU-
ROPEPTIDE Y UNDER CONTINUAL STRESS EXPOSURE.
K. Arao, Y. Makihara, Y. Suzuki, T. Abe, Y. Sato, M. Takeyama; Oita
University Hospital, Oita, Japan. K. Arao: None. Y. Makihara:
None. Y. Suzuki: None. T. Abe: None. Y. Sato: None. M. Takeyama:
None.
BACKGROUND: Some depressions are presumed to result
from changes in levels of stress-related hormones released from the
hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous
system (SNS), represented by adrenocorticotropic hormone
(ACTH) and neuropeptide Y (NPY), respectively. Venipuncture for
blood sampling has been proposed to be a stress factor that increases
circulating ACTH and NPY levels. We examined the effects of mirtazapine
on plasma levels of ACTH- and NPY-like immunoreactive
substances (IS) in healthy subjects under continual stress induced by
repetitive venipunctures for blood sampling.
METHODS: An open-labeled crossover study was conducted
on eight healthy volunteers. Each subject was administered a single
oral dose of mirtazapine (15 mg, Reflex Tablet, Meiji Seika Co. Ltd.,
Osaka) or placebo at an interval of one month. Venous blood samples
were collected repetitively before and after each administration.
Plasma levels of ACTH- and NPY-IS were measured using a highly
sensitive enzyme immunoassay.
RESULTS: In the placebo group, plasma ACTH-IS levels at
240 min and NPY-IS levels at 40 min increased significantly compared
with the levels before administration, presumably due to stress.
Oral administration of mirtazapine resulted in significant decreases in
plasma ACTH-IS level at 60 and 240 min and NPY-IS level at 20 and
40 min compared with placebo administration.
CONCLUSION: A single oral dose of mirtazapine modulated
plasma levels of ACTH- and NPY-IS under stress conditions. These
findings suggest that the antidepressant activity of mirtazapine may
involve the suppression of not only the HPA axis but also the SNS.
PI-2
BOTH CYP2C19 AND PON1 GENOTYPES ARE ASSOCI-
ATED WITH THE CLINICAL OUTCOME OF CLOPIDOGREL
IN PATIENTS WITH ACUTE MYOCARDIAL INFARCTION BUT
NOT ANGINA.H. Kim, 1 K. Chang, 2 Y. Koh, 3 M. Park, 4 Y. Choi, 5
C. Park, 5 S. Lee, 6 M. Oh, 6 S. Lee, 6 E. Kim, 1 J. Shon, 1 E. Chu, 2
H. Park, 2 P. Kim, 2 S. Her, 4 D. Kim, 7 J. Lee, 3 H. Kim, 8 K. Yoo, 9
D. Jeon, 10 W. Chung, 2 K. Seung, 2 J. Shin 1 ; 1 Department of Pharmacology
and Clinical Pharmacology, Inje University College of Medicine
and Busan Paik Hospital, Busan, Korea, Republic of, 2 Cardiovascular
Center and Cardiology Division, Seoul St. Mary’s Hospital and College
of Medicine, The Catholic University of Korea, Seoul, Korea, Republic
of, 3 Department of Cardiology, Catholic University Uijeongbu
St. Mary’s Hospital, Uijeongbu, Korea, Republic of, 4 Department of
Cardiology, Catholic University Daejeon St. Mary’s Hospital, Daejeon,
Korea, Republic of, 5 Department of Cardiology, Catholic University
Yeouido St. Mary’s Hospital, Seoul, Korea, Republic of, 6 Department
of Pharmacology and PharmacoGenomics Research Center, Inje University
College of Medicine, Busan, Korea, Republic of, 7 Department
of Cardiology, Catholic University St. Paul’s Hospital, Seoul, Korea,
Republic of, 8 Department of Cardiology, Catholic University Bucheon
St. Mary’s Hospital, Bucheon, Korea, Republic of, 9 Department of
Cardiology, Catholic University St. Vincent’s Hospital, Suwon, Korea,
Republic of, 10 Department of Cardiology, Catholic University Incheon
St. Mary’s Hospital, Incheon, Korea, Republic of. H. Kim: None.
K. Chang: None. Y. Koh: None. M. Park: None. Y. Choi: None.
C. Park: None. S. Lee: None. M. Oh: None. S. Lee: None. E. Kim:
None. J. Shon: None. E. Chu: None. H. Park: None. P. Kim: None.
S. Her: None. D. Kim: None. J. Lee: None. H. Kim: None. K. Yoo:
None. D. Jeon: None. W. Chung: None. K. Seung: None. J. Shin:
None.
BACKGROUND: The effect of CYP2C19 and PON1 genotypes
on the clinical outcome of clopidogrel therapy are different in patients
with PCI from stable angina and from AMI, especially in Asian populations
whose genetic profiles of CYP2C19 PM and PON1 Q192R are
different from other ethnic populations. This study was addressed to
evaluate the effects of CYP2C19 and paraoxonase-1 (PON1) genotypes
on the clinical outcome of clopidogrel in the patients with angina
and acute myocardial infarction (AMI) after undergoing percutaneous
coronary intervention (PCI).
METHODS: From the genetic association study, the functional
variants of 7 candidate genes were evaluated for the clinical outcome
of clopidogrel therapy in 2188 patients (532 AMI and 1656 angina)
undergoing PCI. The primary clinical outcome was measured for
major cardiac and cerebrovascular event (MACCE) during 1 year
follow-up.
RESULTS: Both CYP2C19 poor metabolizer (PM) and PON1
QQ192 genotype were significantly associated with higher risk of
MACCE in patients who received emergency PCI from AMI, not an
elective PCI from angina. However, the effect on platelet P2Y12 reactivity
unit was only associated with CYP2C19 PM genotype, not by
PON1 QQ192 genotype. The risk of MACCE was highest when both
genotypes of CYP2C19 PM and PON1 QQ192 were combined in AMI
subpopulation (adjusted hazard ratio [HR] (95% confidence interval
[CI]), 10.16 (2.84-36.40), p