Jinwhan Cho

Influence of OATP1B1 Genotype on the Pharmacokinetics of Rosuvastatin in Koreans

This study was carried out to determine whether polymorphisms of organic anion‐transporting polypeptide 1B1 (OATP1B1) have an effect on rosuvastatin pharmacokinetics in Koreans. Among 200 subjects genotyped for OATP1B1 c.388A>G, and c.521T>C, 30 subjects were selected for the rosuvastatin pharmacokinetic study. The area under the concentration–time curve for 0 to infinity (AUC0–∞) of rosuvastatin for group 1 (*1a/*1a, *1a/*1b, *1b/*1b), group 2 (*1a/*15, *1b/*15), and group 3 (*15/*15) were 111±49.3, 126±45.2, and 191±31.0 ng h/ml, respectively, with significant differences among the three groups (P=0.0429) and between *15/*15 and the other groups (P=0.0181). The maximum plasma concentration (Cmax) also showed a significant difference between *15/*15 and the other groups (P=0.0181). There were no significant differences in rosuvastatin‐lactone pharmacokinetics among the three groups. The pharmacokinetic exposure of rosuvastatin was higher in the OATP1B1*15/*15 subjects than the others, suggesting a potential association between the OATP1B1 genetic polymorphisms and altered rosuvastatin pharmacokinetics in Korean populations.

Association between the dose of dopaminergic medication and the behavioral disturbances in Parkinson disease

OBJECTIVESnTo survey the point prevalence of impulse control and repetitive behavior disorders (ICRBs) in patients with Parkinson disease (PD) and to determine the relationship between PD medication dose and the risk of ICRBs.nnnMETHODSnA multicenter cross-sectional survey was applied to consecutive patients with PD over a 3-month period. The presence of ICRBs was screened using a modified version of the Minnesota Impulsive Disorders Interview that comprised five ICRB modules: compulsive buying, gambling, sexual behavior, eating, and punding. Data regarding the patients clinical features and concurrent anti-PD drugs were also collected during the interview. Adjusted odds ratios (ORs) of the daily doses of dopamine agonist and L-dopa for the development of an ICRB were calculated after adjustment for clinical variables.nnnRESULTSnAmong the 1167 patients recruited, 118 (10.1%) exhibited ICRBs. Punding was the most common ICRB (4.2%), followed by compulsive eating (3.4%), sexual behaviors (2.8%), buying (2.5%), and gambling (1.3%). Two or more ICRBs were present concomitantly in 34 of these 118 patients (28.8%). There were dose-response relationships between the dopamine agonist dose and the ORs for compulsive buying, gambling and sexual behaviors. On the other hand, the OR for punding was positively correlated with the dose of L-dopa. The OR for compulsive eating was not associated with the dose of dopamine agonist or L-dopa.nnnCONCLUSIONSnThe dose of dopaminergic medication is significantly associated with the development of ICRB, except compulsive eating, in PD.

Pharmacokinetic and pharmacodynamic interaction of lorazepam and valproic acid in relation to UGT2B7 genetic polymorphism in healthy subjects.

Pharmacokinetic and pharmacodynamic profiles of lorazepam and valproate were analyzed according to uridine 5′‐diphosphate‐glucuronosyltransferase (UGT)2B7 genotype in 14 healthy subjects with UGT2B15*2/*2 genotype. Systemic clearance of lorazepam (2 mg intravenously) and area under the concentration–time curve (AUC) of valproate (600 mg once daily for 4 days) were analyzed as pharmacokinetic parameters, and area under the effect–time curve (AUEC) of psychomotor coordination tests (Vienna) was used for pharmacodynamic parameter. No significant differences were found in systemic clearances of lorazepam by UGT2B7 genotype. AUCs of valproate showed an increasing tendency as the number of UGT2B7*2 alleles increased, but the difference was insignificant. Psychometric results were significant among the UGT2B7 genotype group (AUEC_tracking 261.5±298.9 in *1/*1, and 3,396.8±947 in *2/*2, P=0.047) when the two drugs were coadministered. Our study suggests that the UGT2B7 genotype probably affects lorazepam–valproate pharmacodynamic interaction, especially in subjects who have homovariant genotypes of UGT2B7 and UGT2B15, although the effects on the pharmacokinetics are less significant.

Evaluation of endogenous metabolic markers of hepatic CYP3A activity using metabolic profiling and midazolam clearance.

This study aimed to evaluate endogenous metabolic markers of hepatic cytochrome P450 (CYP)3A activity in healthy subjects using a metabolomics approach. Twenty‐four subjects received the following medication during the following three study periods: 1u2009mg of i.v. midazolam alone (control phase), 1u2009mg of i.v. midazolam after 4 days of pretreatment with 400u2009mg of ketoconazole once daily (CYP3A‐inhibited phase), and 2.5u2009mg of i.v. midazolam after 10 days of pretreatment with 600u2009mg of rifampicin once daily (CYP3A‐induced phase). During each study period, 24u2009h before and after the administration of midazolam, urine samples were collected at 12‐h intervals for metabolomic analyses. We derived an equation to predict midazolam clearance (CL) based on several of these markers. We demonstrated that a combination of the concentrations and ratios of several endogenous metabolites and the CYP3A5*3 genotype is a reliable predictive marker of hepatic CYP3A activity as assessed by i.v. administration of midazolam.

Ginsenoside-Rp1 inhibits platelet activation and thrombus formation via impaired glycoprotein VI signalling pathway, tyrosine phosphorylation and MAPK activation

Ginsenosides are the main constituents for the pharmacological effects of Panax ginseng. Such effects of ginsenosides including cardioprotective and anti‐platelet activities have shown stability and bioavailability limitations. However, information on the anti‐platelet activity of ginsenoside‐Rp1 (G‐Rp1), a stable derivative of ginsenoside‐Rg3, is scarce. We examined the ability of G‐Rp1 to modulate agonist‐induced platelet activation.

Differential genetic susceptibility in diphasic and peak-dose dyskinesias in Parkinson's disease†

To examine whether there is a differential genetic susceptibility in the diphasic and peak‐dose forms of levodopa‐induced dyskinesias (LID) in patients with Parkinsons disease (PD). The study cohort comprised 503 unrelated Korean PD patients who were treated with levodopa and had a disease duration of at least 5 years. The presence of LID was identified during a routine follow‐up and special care was taken to separate the two distinct forms of LID into diphasic and peak‐dose dyskinesias (PDSK). Genotyping was performed in the 503 patients and in 559 healthy controls to search for polymorphisms of DRD3 p.S9G, DRD2 Taq1A, GRIN2B c.2664C>T, c.366C>G, c.‐200T>G, and the promoter region of SLC6A4. A total of 229 patients expressed LID (peak‐dose in 205, diphasic in 57, and both in 33). The presence of diphasic dyskinesia (DDSK) was exclusively associated with the DRD3 p.S9G variant after adjusting for gender, age at PD onset, Hoehn & Yahr stage, and duration of levodopa treatment. Carrying the AA genotype was likely to shorten the onset of DDSK according to the duration of levodopa therapy (P = 0.02). The presence of PDSK was not significantly associated with any of the six genetic variants studied. There may be a genetic susceptibility in the development of DDSK in PD patients on chronic levodopa therapy, and its underlying pathophysiological mechanism might be distinct from that of PDSK.

Reliability of semiology description.

Objective:Seizure semiology is important for classifying patients epilepsy. Physicians usually get most of the seizure information from observers though there have been few reports on the reliability of the observers description. This study aims at determining the reliability of observers description of the semiology. Methods:We included 92 patients who had their habitual seizures recorded during video-EEG monitoring. We compared the semiology described by the observers with that recorded on the videotape, and reviewed which characteristics of the observers affected the reliability of their reported data. Results:The classification of seizures and the individual components of the semiology based only on the observer-description was somewhat discordant compared with the findings from the videotape (correct classification, 85%). The descriptions of some ictal behaviors such as oroalimentary automatism, tonic/dystonic limb posturing, and head versions were relatively accurate, but those of motionless staring and hand automatism were less accurate. The specified directions by the observers were relatively correct. The accuracy of the description was related to the educational level of the observers. Conclusions:Much of the information described by well-educated observers is reliable. However, every physician should keep in mind the limitations of this information and use this information cautiously.

Effects of repetitive transcranial magnetic stimulation on freezing of gait in patients with Parkinsonism.

PURPOSEnThe aim of this study was to investigate the site-specific effects of repetitive transcranial magnetic stimulation (rTMS) on freezing of gait (FOG) in patients with parkinsonism.nnnMETHODSnTwenty patients with parkinsonism and FOG were included. A single session of 10 Hz rTMS was applied over three different cortical regions of the dominant hemisphere: the primary motor cortex of the lower leg (M1-LL), the supplementary motor area (SMA), and the dorsolateral prefrontal cortex (DLPFC). We also performed sham stimulation as a control. The Timed Up and Go (TUG) test, Turn Steps and Turn Time in 180° turning, Unified Parkinsons Disease Rating Scale (UPDRS) part III, FOG Questionnaire (FOG-Q), and motor evoked potential (MEP) studies were performed before and after each intervention.nnnRESULTSnThere were significant improvements in TUG test times after rTMS over the M1-LL and the DLPFC. Improvement was significantly greater after the M1-LL stimulation than sham condition. The M1-LL and DLPFC stimulation also resulted in significant improvements in both the number of Turn Steps and Turn Time. UPDRS-III scores were significantly decreased after the M1-LL and DLPFC stimulation.nnnCONCLUSIONSnUse of 10 Hz rTMS on the M1-LL and DLPFC is therapeutically effective for FOG in patients with parkinsonism.

1300: Efficacy and safety of BI 1482694 (HM61713), an EGFR mutant-specific inhibitor, in T790M-positive NSCLC at the recommended phase II dose

s, ELCC 2016 Journal of Thoracic Oncology Vol. 11, Suppl. 4S (2016) S113–S142

Effect of external stress on the orientation distribution of ferrite

Abstract The effect of external stress on the orientation distribution of ferrite during the transformation was examined. Two types of carbon steel were used to evaluate the deviation angle of ferrite from the Kurdjumov–Sachs (K–S) relationship using electron backscattered diffraction. The K–S relationship was weakened when an external stress was applied during the transformation.