Minkyung Oh

Adjunctive varenicline treatment with antipsychotic medications for cognitive impairments in people with schizophrenia: a randomized double-blind placebo-controlled trial.

The aim of this study is to examine the effects of treatment with varenicline, a partial agonist at the α4β2 and full agonist at the α7 nicotine acetylcholine receptor, on cognitive impairments in people with schizophrenia. In all, 120 clinically stable people with schizophrenia participated in randomized, double-blind, placebo-controlled 8-week trial. Antipsychotic and concomitant medication doses remained fixed throughout the study. Varenicline was titrated up to 1 mg twice daily for weeks 2–8. Neuropsychological, clinical, and safety assessments were administered at baseline and weeks 1, 2, 4, and 8. In the primary analyses of neurocognitive differences at week 8, no varenicline–placebo differences were significant. In secondary longitudinal analyses, varenicline improved compared with placebo on the Digital Symbol Substitution Test (p=0.013) and the Wisconsin Card Sorting Test non-perseverative errors (p=0.043). Some treatment effects were different between smokers and non-smokers. In smokers, Continuous Performance Test hit reaction time (p=0.008) and Stroop Interference (p=0.004) were reduced for varenicline compared with placebo, while there were no treatment differences in non-smokers. No significant treatment main effects or interactions were noted for total scores on the Positive and Negative Syndrome Scale or the Scale for the Assessment for Negative Symptoms. Our findings suggest beneficial effects of adjunctive varenicline treatment with antipsychotics for some cognitive impairments in people with schizophrenia. In some cases, effects of treatment varied between smokers and non-smokers. Further study is required to assess the functional significance of these changes.

Effect of CYP2C9 and VKORC1 genotypes on early-phase and steady-state warfarin dosing in Korean patients with mechanical heart valve replacement.

Objectives The effect of CYP2C9 and vitamin K epoxide reductase complex subunit 1 (VKORC1) genotypes was evaluated for the early-phase and steady-state warfarin dosing in Korean patients with mechanical heart valve replacement. Methods The genotypes of CYP2C9 variants including CYP2C9*3, CYP2C9*13, and CYP2C9*14, and VKORC1 1173C>T were assessed for the association with warfarin dosing in 265 patients whose data were collected for warfarin dose; international normalized ratio (INR), comedication, comorbidity, and other clinical characteristics. Results In the early phase of warfarin therapy, the combined genotypes of CYP2C9 and VKORC1 caused statistically significant difference in warfarin dose from day 7 of warfarin dosing and the subsequent time course of dose increase showed significant difference among the three different genotypes (P<0.001). Compared with patients with CYP2C9 wild type, the patients with heterozygous CYP2C9 variants have delayed time to reach stable dose [adjusted hazard ratio (HRadj): 0.48; 95% confidence interval (CI): 0.27–0.85] and tended to have high risk for the first INR greater than 3.5 (HRadj: 1.64; 95% CI: 0.98–2.75). The patients with the VKORC1 CT genotype showed no significant difference in the time to reach stable dose but statistically significant low HR for time to first INR greater than 3.5 compared with those with VKORC1 TT genotype (HRadj: 0.25; 95% CI: 0.13–0.51). The observed warfarin maintenance dose was best explained by a model including covariates of age, weight, concurrent congestive heart failure/cardiomyopathy, INR-increasing drugs, aspirin, dietary supplements, and CYP2C9 and VKORC1 genotypes (R2=0.56). Conclusion The heterozygous CYP2C9 and VKORC1 genotypes influence warfarin dosing in an early phase as well as steady state of warfarin therapy in Korean patients with mechanical heart valve replacement.

Pilomatricomas: the diagnostic value of ultrasound.

ObjectiveThe purpose of this study was to analyze statistically significant diagnostic factors for pilomatricoma on the basis of ultrasonographic features.MethodsSonographic images were retrospectively reviewed from 44 pilomatricomas, and from 43 control subjects with other subcutaneous tumors. Two radiologists determined the tumoral shape, margin, echotexture, echogenicity, posterior shadowing, posterior enhancement, hypoechoic rim, internal calcification, and vascularity.ResultsThe reliable diagnostic factors for pilomatricoma were hypoechogenicity (P < 0.001), heterogenicity (P < 0.05), internal calcification (P < 0.001), hypoechoic rim (P < 0.001), and posterior shadowing (P < 0.001). Scattered dots were the most common patterns of internal calcification. A combination of hypoechogenicity, heterogenicity, internal calcification of scattered-dot pattern, and a hypoechoic rim was a statistically significant difference between the two groups (P < 0.001; odds ratio, 21).ConclusionsThe features of heterogeneous echotexture, internal echogenic foci in scattered-dot pattern, and a hypoechoic rim or posterior shadowing itself could be discriminative ultrasonographic criteria for differentiating pilomatricomas from other subcutaneous tumors.

The Contributions of Cytochromes P450 3A4 and 3A5 to the Metabolism of the Phosphodiesterase Type 5 Inhibitors Sildenafil, Udenafil, and Vardenafil

The role of the genetically polymorphic CYP3A5 in the metabolism of CYP3A substrates is unclear. We investigated the contributions of the CYP3A4 and CYP3A5 isoforms to the metabolism of the phosphodiesterase type 5 inhibitors (PDE5Is) sildenafil, udenafil, and vardenafil. In vitro incubation studies of sildenafil N-demethylation, udenafil N-dealkylation, and vardenafil N-deethylation were conducted using recombinant CYP3A enzymes and 15 human liver microsome (HLM) preparations with predetermined CYP3A5 genotypes. Recombinant CYP3A4 and CYP3A5 both produced N-desalkyl metabolites of sildenafil, udenafil, and vardenafil. The catalytic efficiency (Clint = Vmax/apparent Km) of the rCYP3A5 isoform for vardenafil N-deethylation was about 3.2-fold that of rCYP3A4, whereas the intrinsic clearance rates for N-dealkylation of both sildenafil and udenafil were similar between rCYP3A5 and rCYP3A4. The metabolite formation activity was higher in HLMs heterozygous for the CYP3A5*3 allele (n = 9) than in HLMs homozygous for CYP3A5*3 (n = 6). These findings suggest that CYP3A5 and CYP3A4 play a significant role in the metabolism of PDE5Is. The genetic polymorphism of CYP3A5 may contribute to interindividual variability in the disposition of PDE5Is, especially vardenafil. Further in vivo studies are needed to confirm the effects of CYP3A5 genotypes on the pharmacokinetics of PDE5Is.

Acute symptomatic seizures in CNS infection

To determine the frequency and aetiology of acute symptomatic seizures in central nervous system (CNS) infections and to assess the clinical factors predicting the occurrence of the seizures, we retrospectively reviewed the medical records of patients diagnosed with CNS infections from 2000 to 2005. One hundred and forty‐seven patients were included in the study. The clinical variables between those with and without acute symptomatic seizures were compared. Of the 147 patients, 23% (34/147) had acute symptomatic seizures. A significant relation between clinical variables and the occurrence of acute symptomatic seizures was found: encephalitis as the aetiology of the CNS infection, Glasgow Coma Scale (GCS) ≤12, and neurological deficits. By multiple logistic regression analysis, age of onset >42 years, encephalitis, and GCS ≤12 were found to be independently significant clinical variables for predicting the occurrence of acute symptomatic seizures. Encephalitis and GCS ≤12 are significant clinical variables for predicting the occurrence of acute symptomatic seizures in CNS infection, suggesting that patients with a greater extent of parenchymal damage are more vulnerable to acute symptomatic seizures.

Bone mineral density and osteoporosis risk in older patients with schizophrenia.

Objective: People with schizophrenia are at a higher risk for osteoporosis. The authors investigated the prevalence of low bone density and its risk factors in older Korean patients with schizophrenia. Method: In cross-sectional study, 327 inpatients with schizophrenia were screened. Among them, 229 patients older than 50 years participated in this study. The control group consisted of healthy volunteers who were of similar ages (n = 125). Bone density was measured in the lumbar spine and the neck, trochanter, and ward regions of the right proximal femur by dual-energy x-ray absorptiometry. Clinical variables such as alcohol use, cigarette smoking, and fracture history were obtained. The Student t test, Pearson &khgr;2 test, Wilcoxon rank sum test, and logistic regression analysis were used. Results: The prevalence of osteoporosis was significantly higher in patients with schizophrenia compared with healthy controls (34.9% vs 18.4%, P = 0.0043). Within the schizophrenia group, female subjects had a significantly higher prevalence of osteoporosis than male subjects (48.4% vs 25.7%, P = 0.0014); however, no sex differences were identified in the healthy control group. The actual bone density and t scores in patients with schizophrenia were significantly lower in all sites than in healthy controls. Among patients with schizophrenia, smokers and alcohol abuser showed lower bone density compared with those who did not smoke or drink. The lifetime prevalence of fracture was significantly higher in patients with schizophrenia (24.0%) compared with healthy controls (5.6%; P = 0.001). Conclusions: Our results emphasize that older patients with schizophrenia are at risk for low bone density. Cigarette smoking and alcohol abuse are associated with low bone density in patients with schizophrenia.

CYP2C19 poor metabolizer is associated with clinical outcome of clopidogrel therapy in acute myocardial infarction but not stable angina.

Background—More intensive platelet suppression is required in patients with acute myocardial infarction (AMI) than in those with stable angina because of differential platelet activation between AMI and stable angina. In this context, CYP2C19 genotype leading to reduced active metabolite formation may profoundly affect the clinical outcome of clopidogrel therapy in patients with AMI compared with those with stable angina. Methods and Results—Effects of CYP2C19 genotypes on the clinical outcome of clopidogrel therapy were evaluated in 2188 patients (532 patients with AMI and 1656 patients with stable angina) undergoing percutaneous coronary intervention. The primary clinical outcome was a composite of major adverse cardiac and cerebrovascular events defined as death from any cause, nonfatal myocardial infarction, or stroke during 1 year of clopidogrel therapy. Compared with extensive metabolizer, the CYP2C19 poor metabolizer was significantly associated with higher risk of major adverse cardiac and cerebrovascular events in patients with AMI (hazard ratio, 2.88; 95% confidence interval, 1.27–6.53; P=0.011). However, this finding was not seen in patients with stable angina. A significant interaction between CYP2C19 genotypes and disease subsets of AMI and stable angina was identified with respect to major adverse cardiac and cerebrovascular events (adjusted interaction P=0.045). The patients with AMI showed lower percent inhibition of P2Y12 compared with patients with stable angina in CYP2C19 poor metabolizer or CYP2C19 intermediate metabolizer genotype groups but not in CYP2C19 extensive metabolizer genotype group. Conclusions—CYP2C19 poor metabolizer is associated with poor clinical outcome of clopidogrel therapy in Asian patients with AMI but not in those with stable angina possibly because of differential requirement of platelet suppression in patients with AMI and stable angina. Clinical Trial Registration Information—URL: clinicaltrials.gov. Identifier: NCTO1239914.

Increased expression of soluble inducible costimulator ligand (ICOSL) in patients with systemic lupus erythematosus

To investigate the level of costimulating molecules in systemic lupus erythematosus (SLE), we assessed the plasma concentrations of soluble forms of costimulatory molecules such as programmed death-1 (PD-1), B7-H1 (also called PD-L1 or CD274) and inducible costimulator ligand (ICOSL) in patients with SLE. Plasma concentrations of soluble PD-1, B7-H1 and ICOSL were measured by ELISA using plasma samples from 57 SLE patients with or without the active disease, 21 rheumatoid arthritis (RA) patients and 35 healthy subjects. We also evaluated surface ICOSL expression on B cells using flow cytometry to gain a better understanding of ICOSL expression. To compare the level of ICOSL mRNA expression, reverse transcriptase-polymerase chain reaction (RT-PCR) was performed using total RNA from peripheral blood mononuclear cells (PBMCs) isolated from eight healthy subjects and 11 patients with SLE. The concentration of plasma ICOSL was significantly higher in patients with SLE compared with healthy subjects (P = 0.005). Plasma ICOSL concentrations in patients with active SLE were also significantly higher than those of either patients with inactive SLE or patients with RA (P = 0.001, P = 0.015, respectively). Plasma ICOSL concentrations in patients with SLE correlated modestly with the SLE disease activity index score (r = 0.298, P = 0.024). We also found a significant inverse correlation between the soluble ICOSL expression and the surface ICOSL expression on B cells (r = −0.690, P = 0.001). However, ICOSL mRNA levels of patients with SLE were comparable with those of the control subjects. There was also no significant difference in plasma B7-H1 concentrations between groups, and plasma PD-1 was not detectable in any of the groups. The plasma concentration of soluble ICOSL might be correlated to the disease severity of lupus. The increased levels of ICOSL in active lupus suggest that this pathway is involved in the pathogenesis of SLE. The mechanism and physiological role of soluble ICOSL in the pathogenesis of SLE, however, remains to be investigated.

Effects of genetic polymorphisms of OPRM1, ABCB1, CYP3A4/5 on postoperative fentanyl consumption in Korean gynecologic patients.

OBJECTIVE Fentanyl, a μ-opioid receptor agonist, is a substrate of P-glycoprotein. Its metabolism is catalyzed by CYP3A4 and CYP3A5. The aim of this study was to investigate the association between postoperative fentanyl consumption and genetic polymorphisms of μ-opioid receptor (OPRM1), ABCB1 (gene encoding P-glycoprotein), CYP3A4 and CYP3A5 in Korean patients. METHODS 196 female patients scheduled to undergo total abdominal hysterectomy or laparoscopic assisted vaginal hysterectomy under general anesthesia were enrolled in this study. Intravenous patient-controlled analgesia with fentanyl was provided postoperatively. Cumulative fentanyl consumption was measured during the first 48 hours postoperatively. The severity of pain at rest was assessed with the visual analogue scale. OPRM1 118A>G, ABCB1 2677G>A/T, ABCB1 3435C>T, CYP3A4*18 and CYP3A5*3 variant alleles were genotyped. The effects of genetic and non-genetic factors on fentanyl requirements were evaluated with multiple linear regression analysis. RESULTS The 24-hour cumulative fentanyl doses were significantly associated with pain core, weight and type of surgery (p < 0.05). The 48-hour cumulative fentanyl doses were significantly associated with pain score, type of surgery and history of PONV or motion sickness (p < 0.05). Genetic polymorphisms were not associated with fentanyl requirements. CONCLUSION In Korean gynecologic patients, no association was found between genetic factors and postoperative fentanyl consumption.

Change in cytokines in patients with warts after contact immunotherapy with squaric acid dibutylester

A wart is a skin lesion caused by infection with human papillomavirus (HPV). Contact immunotherapy is one of the many therapeutic options that have been used to treat warts; however, the effectiveness of contact immunotherapy differs from patient to patient, and the cause of this variation in clinical response is unclear.