Effect of CYP3A4 metabolism on sex differences in the pharmacokinetics and pharmacodynamics of zolpidem.

To investigate pharmacokinetic and pharmacodynamic differences of zolpidem between males and females and their causes, including CYP3A4 activity. A single oral dose of zolpidem (10 mg) was administered to 15 male and 15 female healthy subjects. Blood samples were collected up to 12 h post-dose to determine plasma zolpidem concentrations. Pharmacokinetic parameters were obtained using non-compartmental analysis. Digit symbol substitution test, choice reaction time, and visual analog scale of sleepiness were used to evaluate pharmacodynamics. We measured CYP3A4 activity using 4ß-hydroxycholesterol, an endogenous metabolite. Mean maximum plasma concentration and area under the plasma concentration-time curve were higher for females than for males (9.9% and 32.5%, respectively); other pharmacokinetic parameters showed no significant differences. Pharmacodynamic scores for females showed delayed recovery compared with that for males. CYP3A4 activity was higher in females than in males (p = 0.030). There was no serious adverse event, and adverse event incidence was not different between the sexes. Zolpidem exposure was about 30% higher in females than in males. Delayed pharmacodynamic score recovery in females could be related to higher zolpidem concentrations. Although apparent clearance was lower in females, systemic clearance might not be the cause of the different exposures to zolpidem.

Neuroimaging in Randomized, Multi-Center Clinical Trials of Endovascular Treatment for Acute Ischemic Stroke: A Systematic Review.

Appropriate use and analysis of neuroimaging techniques is an inevitable aspect of clinical trials for patients with acute ischemic stroke. Neuroimaging examinations were recently used to define the core eligibility criteria and outcomes in acute ischemic stroke research. Recent clinical trials for endovascular treatment in acute ischemic stroke have also demonstrated the efficacy or safety of endovascular treatment using various imaging modalities as well as clinical indices. Furthermore, independent imaging reviews and imaging core laboratory assessments are essential to manage and analyze imaging data in order to enhance the reliability of the outcomes. Therefore, we systematically reviewed the use of neuroimaging in recent randomized clinical trials for endovascular treatment of acute ischemic stroke in order to provide a thorough summary, which would serve as a resource guiding the use of appropriate imaging protocols and analyses in future clinical trials for acute ischemic stroke. This review will help researchers select appropriate imaging biomarkers among the various imaging protocols available and apply the selected type of imaging examination for each study in accordance with the academic purpose.

MRI for prediction of hemorrhagic transformation in acute ischemic stroke: a systematic review and meta-analysis.

BACKGROUND: Hemorrhagic transformation increases mortality and morbidity in patients with acute ischemic stroke. PURPOSE: The purpose of this study is to evaluate the diagnostic performance of magnetic resonance imaging (MRI) for prediction of hemorrhagic transformation in acute ischemic stroke. MATERIAL AND METHODS: A systematic literature search of MEDLINE and EMBASE was performed up to 27 July 2018, including the search terms "acute ischemic stroke," "hemorrhagic transformation," and "MRI." Studies evaluating the diagnostic performance of MRI for prediction of hemorrhagic transformation in acute ischemic stroke were included. Diagnostic meta-analysis was conducted with a bivariate random-effects model to calculate the pooled sensitivity and specificity. Subgroup analysis was performed including studies using advanced MRI techniques including perfusion-weighted imaging, diffusion-weighted imaging, and susceptibility-weighted imaging. RESULTS: Nine original articles with 665 patients were included. Hemorrhagic transformation is associated with high permeability, hypoperfusion, low apparent diffusion coefficient (ADC), and FLAIR hyperintensity. The pooled sensitivity was 82% (95% confidence interval [CI] 61-93) and the pooled specificity was 79% (95% CI 71-85). The area under the hierarchical summary receiver operating characteristic curve was 0.85 (95% CI 0.82-0.88). Although study heterogeneity was present in both sensitivity (I2=67.96%) and specificity (I2=78.93%), a threshold effect was confirmed. Studies using advanced MRI showed sensitivity of 92% (95% CI 70-98) and specificity of 78% (95% CI 65-87) to conventional MRI. CONCLUSION: MRI may show moderate diagnostic performance for predicting hemorrhage in acute ischemic stroke although the clinical significance of this hemorrhage is somewhat uncertain.

ZNF133 is associated with infliximab responsiveness in patients with inflammatory bowel diseases.

BACKGROUND AND AIM: Infliximab has been widely prescribed for treating inflammatory bowel disease (IBD). However, the response rates to infliximab differ among patients. Therefore, we aimed to identify the genetic and clinical markers that predict infliximab response. METHODS: A total of 139 Korean patients with IBD who received infliximab were classified according to infliximab response as follows: (i) primary response vs nonresponse and (ii) sustained response vs loss of response. We performed an association study using whole-exome sequencing data to identify genetic variants associated with infliximab response. Candidate variants were validated in 77 German patients with IBD. Stepwise multivariate logistic regression was performed to identify predictors. RESULTS: We found five candidate variants that were associated with primary nonresponse to infliximab (P < 5 × 10-6 ). Of the five variants, rs2228273 in ZNF133 was validated in German (combined P = 6.49 × 10-7 ). We also identified the best genetic variant (rs9144, P = 4.60 × 10-6 ) associated with the loss of infliximab response. In multivariate regression analysis, rs2228273 (P = 2.10 × 10-5 ), concurrent azathioprine/6-mercaptopurine use, and bodyweight at the first infliximab use (< 50 kg) were associated with primary nonresponse. In addition, the Crohn's disease activity index at the first infliximab use and rs9144 (P = 0.001) were independently associated with the loss of response in patients with Crohn's disease. CONCLUSIONS: We identified clinical and genetic markers associated with infliximab response in IBD patients. Our findings could provide insights to maximize the efficacy of infliximab therapy in IBD patients.

Perfusion CT for prediction of hemorrhagic transformation in acute ischemic stroke: a systematic review and meta-analysis.

OBJECTIVE: To investigate the diagnostic performance of perfusion CT for prediction of hemorrhagic transformation in acute ischemic stroke. METHODS: A computerized literature search of Ovid MEDLINE and EMBASE was conducted up to October 29, 2018. Search terms included acute ischemic stroke, hemorrhagic transformation, and perfusion CT. Studies assessing the diagnostic performance of perfusion CT for prediction of hemorrhagic transformation in acute ischemic stroke were included. Two reviewers independently evaluated the eligibility of the studies. A bivariate random effects model was used to calculate the pooled sensitivity and pooled specificity. Multiple subgroup analyses were performed. RESULTS: Fifteen original articles with a total of 1134 patients were included. High blood-brain barrier permeability and hypoperfusion status derived from perfusion CT are associated with hemorrhagic transformation. The pooled sensitivity and specificity were 84% (95% CI, 71-91%) and 74% (95% CI, 67-81%), respectively. The area under the hierarchical summary receiver operating characteristic curve was 0.84 (95% CI, 0.81-0.87). The Higgins I2 statistic demonstrated that heterogeneity was present in the sensitivity (I2 = 80.21%) and specificity (I2 = 85.94%). CONCLUSION: Although various perfusion CT parameters have been used across studies, the current evidence supports the use of perfusion CT to predict hemorrhagic transformation in acute ischemic stroke. KEY POINTS: • High blood-brain barrier permeability and hypoperfusion status derived from perfusion CT were associated with hemorrhagic transformation. • Perfusion CT has moderate diagnostic performance for the prediction of hemorrhagic transformation in acute ischemic stroke. • The pooled sensitivity was 84%, and the pooled specificity was 74%.

Influence of CYP2D6 Polymorphism on the Pharmacokinetic/Pharmacodynamic Characteristics of Carvedilol in Healthy Korean Volunteers.

BACKGROUND: Carvedilol is commonly used to treat hypertension as a ß- and α1-adrenoreceptor blocker, but it is metabolized by CYP2D6, and CYP2D6*10 allele is dominant in Asian population. The objective of this study was to assess the influence of CYP2D6 polymorphisms on the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of carvedilol in healthy Korean volunteers. METHODS: A PK/PD study for a single and multiple dosing of carvedilol were conducted. All volunteers in 3 genotypic groups received single oral dose of carvedilol 12.5 mg for 3 days, then 25 mg QD for 5 days, and 12.5 mg QD for another 3 days. PK parameters for carvedilol and its three metabolites were determined using non-compartmental analysis. For PD properties, blood pressure, heart rate, and the chronotropic dose 25 (CD25) value were obtained. RESULTS: The IM_2 group with two *10 alleles (intermediate metabolizers) exhibited lower clearance of carvedilol as well as higher area under the curve (AUC) for O-desmethyl carvedilol. The ratio of CD25 to baseline at multiple dosing was significantly higher in the combined IM group (IM_1 and IM_2) than in the EM group, however, the ratio of CD25 after single and multiple dosing and the other PD markers were not significantly different between the 3 genotypic groups compared with the baseline. CONCLUSION: These findings showed that CYP2D6 genotype influenced the PK characteristics of carvedilol and no differences in PD response were observed in Korean healthy volunteers. Registered at the ClinicalTrials.gov, NCT02286934.

Correlations between renal function and the total kidney volume measured on imaging for autosomal dominant polycystic kidney disease: A systematic review and meta-analysis.

PURPOSE: To provide a systematic summary of total kidney volume (TKV) as an imaging biomarker in clinical trials for autosomal dominant polycystic kidney disease (ADPKD), focusing on the correlation between TKV and renal function. METHODS: A computerized literature search was performed using MEDLINE and EMBASE databases for studies that evaluated the correlation between TKV and the glomerular filtration rate (GFR) and between the TKV growth rate and GFR decline rate. A meta-analysis was performed to generate the summary correlation coefficient (r). A qualitative review was performed to evaluate the characteristics of TKV as an imaging biomarker. RESULTS: Eighteen articles including a total sample size of 2835 patients were retrieved. Meta-analysis revealed substantial correlations between TKV and GFR [r, -0.520; 95% confidence interval (CI), -0.60 to -0.43] and between the TKV growth rate and GFR decline rate [r, -0.320; 95% CI, -0.54 to -0.10]. The quantitative review revealed that baseline TKV can affect the TKV growth rate and GFR decline rate, such that patients with a higher baseline TKV showed faster TKV growth and GFR decline. There was significant variability in image acquisition and analysis methods. CONCLUSION: There were significant negative correlations between TKV and GFR as well as between TKV growth and GFR decline rates, suggesting that TKV imaging is a useful biomarker in clinical trials. However, standardization-or at least trial-specific standardization-of image acquisition and analysis techniques is required to use TKV as a reliable biomarker.

Effects of CYP2C19 Genetic Polymorphisms on PK/PD Responses of Omeprazole in Korean Healthy Volunteers.

The aim of this study was to examine the effects of CYP2C19*2 and *3 genetic polymorphisms on omeprazole pharmacokinetic (PK) and pharmacodynamic (PD) responses. Twenty-four healthy Korean volunteers were enrolled and given 20 mg omeprazole orally once daily for 8 days. The genotypes of CYP2C19 single nucleotide polymorphisms (SNPs) (*2, *3, and *17) were screened. The plasma concentrations of omeprazole, omeprazole sulfone, and 5-hydroxy (5-OH) omeprazole were determined by liquid chromatography with tandem mass spectrometry (LC-MS/MS). The noncompartmental method was used for the determination of PK parameters. Change of mean pH and proportion (%) of time of gastric pH above 4.0 were estimated. The poor metabolizer (PM) group had the lowest metabolic ratio and exhibited the highest area under the curve (AUC) for omeprazole among the CYP2C19 phenotype groups. The PM group showed the greatest change of mean pH and the highest % time of gastric pH above 4.0. The relationship between AUC of omeprazole and % time of gastric pH above 4.0 was confirmed. The study demonstrates that CYP2C19*2 and *3 influence the PKs and PDs of omeprazole in Korean healthy volunteers.

The influences of SLCO1B1 and ABCB1 genotypes on the pharmacokinetics of simvastatin, in relation to CYP3A4 inhibition.

AIM: To investigate the combined effects of SLCO1B1 and ABCB1 genotypes on the pharmacokinetics of simvastatin and its active metabolite simvastatin acid, in relation to CYP3A4 inhibition. METHODS: We conducted a single-dose pharmacokinetic study of simvastatin in 26 healthy volunteers screened for their SLCO1B1 c.521T>C and ABCB1 c.1236C>T-2677G>T-3435C>T genotypes, with and without amlodipine pretreatment. The genetic effects and drug-interaction effect on simvastatin pharmacokinetic parameters were analyzed using a linear-mixed model. RESULTS: The SLCO1B1 c.521T>C variant significantly increased exposure to simvastatin acid by around 40% (p < 0.05), similar to that caused by the amlodipine pretreatment. The ABCB1 gene showed no influence on exposure to simvastatin or simvastatin acid. CONCLUSION: Only SLCO1B1, not ABCB1 genotype, is likely to be associated with simvastatin-induced myopathy. SLCO1B1 genotyping may be particularly beneficial in simvastatin users who are co-administered CYP3A4 inhibitors.

Hepatoprotective effect of pinoresinol on carbon tetrachloride-induced hepatic damage in mice.

Forsythiae Fructus is known to have diuretic, anti-bacterial, and anti-inflammatory activities. This study examined the hepatoprotective effects of pinoresinol, a lignan isolated from Forsythiae Fructus, against carbon tetrachloride (CCl(4))-induced liver injury. Mice were treated intraperitoneally with vehicle or pinoresinol (25, 50, 100, and 200 mg/kg) 30 min before and 2 h after CCl4 (20 microl/kg) injection. In the vehicle-treated CCl(4 )group, serum aminotransferase activities were significantly increased 24 h after CCl4 injection, and these increases were attenuated by pinoresinol at all doses. Hepatic glutathione contents were significantly decreased and lipid peroxidation was increased after CCl4 treatment. These changes were attenuated by 50 and 100 mg/kg of pinoresinol. The levels of protein and mRNA expression of inflammatory mediators, including tumor necrosis factor-alpha, inducible nitric oxide synthase, and cyclooxygenase-2, were significantly increased after CCl4 injection; and these increases were attenuated by pinoresinol. Nuclear translocation of nuclear factor-kappaB (NF-kappaB) and phosphorylation of c-Jun, one of the components of activating protein 1 (AP-1), were inhibited by pinoresinol. Our results suggest that pinoresinol ameliorates CCl4)-induced acute liver injury, and this protection is likely due to anti-oxidative activity and down-regulation of inflammatory mediators through inhibition of NF-kappaB and AP-1.

Palmatine attenuates D-galactosamine/lipopolysaccharide-induced fulminant hepatic failure in mice.

Palmatine is an isoquinoline alkaloid from Coptis chinensis, an herbal medicine used to treat various inflammatory diseases such as gastritis, edema and dermatitis. The present study examined the cytoprotective properties of palmatine on d(+)-galactosamine (GalN)/lipopolysaccharide (LPS)-induced fulminant hepatic failure. Mice were intraperitoneally given GalN (700 mg/kg)/LPS (10 microg/kg). Palmatine (25, 50, 100, and 200mg/kg) was administered 1h before GalN/LPS. GalN/LPS increased the mortality and serum aminotransferase activities. These increases were attenuated by palmatine. GalN/LPS increased hepatic lipid peroxidation and decreased the contents of reduced glutathione. Palmatine did not affect the lipid peroxidation and glutathione content. GalN/LPS increased the circulating levels of tumor necrosis factor (TNF)-alpha, interleukin-6 (IL-6) and IL-10. Palmatine prevented the increase of serum TNF-alpha and augmented that of serum IL-10. GalN/LPS treatment also increased the levels of TNF-alpha, IL-6 and IL-10 mRNA expression in liver tissue. Palmatine decreased the TNF-alpha mRNA expression and increased the IL-10 mRNA expression. Palmatine attenuated the apoptosis of hepatocytes, as evidenced by the TUNEL method and capase-3 analysis. Our data suggest that palmatine alleviates GalN/LPS-induced liver injury by modulating the cytokine response and inhibiting apoptosis.

Inhibition of aroclor 1254-induced depletion of stored calcium prevents the cell death in catecholaminergic cells.

The relationship between depleting effects of polychlorinated biphenyls (PCBs) on the intracellular calcium store and PCBs-induced cell death in dopaminergic cells has not been fully evaluated. Here, we evaluated the effects of inhibitors of the release of ER-stored calcium on the cytotoxicities induced by 10 microg/ml of Aroclor 1254 (A1254; polychlorinated biphenyl mixture) in a catecholaminergic cell-line, CATH.a cells. Exposure to A1254 produced an elevation in free calcium ([Ca2+]i) in the presence or absence of extracellular calcium and decreased in cell viability. From our results, we deduced that the A1254-induced elevation of [Ca2+]i resulted from the depletion of ER-stored calcium. The [Ca2+)]i elevation was dramatically inhibited by an inositol 1,4,5-triphosphate receptor (IP3R) antagonist, and slightly inhibited by a ryanodine receptor (RyR) blocker. IP3R blockers conferred significant protection against A1254-induced cell death, as did RyR blockers, but calcium chelators or NMDA blockers did not. However, none of these reagents inhibited the depletion of intracellular dopamine by A1254 indicating that the mechanism of PCB-induced dopamine depletion may be independent of calcium alterations. Taken together, these data suggest that agents inhibiting the receptor-mediated depletion of stored calcium can prevent the A1254-induced cell death, but not modulate the A1254-induced intracellular dopamine depletion in CATH.a cells.

Effect of Holotrichia diomphalia larvae on liver fibrosis and hepatotoxicity in rats.

Holotrichia diomphalia larvae, one of the most widely used Korean folk medicinal preparations, have long been used for the treatment of chronic liver cirrhosis. The present study was undertaken to clarify whether extract of Holotrichia diomphalia larvae could prevent acute liver damage and liver fibrosis in rats. A single administration of Holotrichia diomphalia protected rats from acute liver damage induced by carbon tetrachloride (200 micro l/kg, i.p.) and beta-D-galactosamine (600mg/kg, i.p.). This was evidenced by the lowered serum aminotransferase (ALT, AST) activities in rats treated with Holotrichia diomphalia. The hepatic cirrhosis was induced by 28 days of bile duct ligation/scission in rats. The four-week treatment with Holotrichia diomphalia reduced the serum ALT, AST, alkaline phosphatase activities, and hydroxyproline content in the liver and improved the histological appearance of the liver sections. The present results led us to conclude that Holotrichia diomphalia larvae can reduce the degree of hepatocellular damage and may become a promising antifibrotic agent for liver fibrosis/cirrhosis.