Fibrates and risk of congenital malformations: a nationwide cohort study in South Korea.

PURPOSE: To examine the association between maternal prescriptions for fibrates and congenital malformations in live births. METHODS: Nationwide retrospective cohort study was conducted using the data sourced from the Korean National Health Insurance database. A cohort of 756,877 completed pregnancies linked to live-born infants in 215,600 women with dyslipidemia between 2012 and 2021. The study compared data on congenital anomalies between pregnancies who were exposed to fibrates and those who were not exposed to fibrates in the first trimester. Odds ratios (OR) were calculated by a multivariable analyses using logistic regression models to adjust for potential confounders. RESULTS: 260 pregnancies (0.12%) were exposed to fibrates during the first trimester. The prevalence of malformations in exposed offspirng was 10.77%, not significantly different compared with 9.68% in offspring of women who were not prescribed fibrates during pregnancy in patients with dyslipidemia (OR 1.13; 95% CI 0.75-1.70). CONCLUSION: This study implies that the use of fibrates during pregnancy may be safe, as it did not show any association with congenital anomalies. However, caution is warranted due to an elevated risk associated with prolonged exposure.

Synthesis and evaluation of multivalent nitroimidazole-based near-infrared fluorescent agents for neuroblastoma and colon cancer imaging.

Hypoxia is one of key characteristics of microenvironments of solid tumors, and evaluation of hypoxia status in solid tumors is important to determine cancer stage and appropriate treatment. In the present study, novel, multivalent, near-infrared (NIR) fluorescent imaging agents were developed to measure tumor hypoxia. These agents were synthesized using an amino acid as a backbone to connect mono-, bis-, or tris-2-nitroimidazole as a hypoxia-sensitive moiety to enhance uptake by the tumor and to attach sulfo-Cyanine 5.5 as an NIR fluorophore to visualize tumor accumulation. Studies of physical characteristics demonstrated that the novel NIR imaging agents showed suitable optical properties for in vitro and in vivo imaging and were stable in serum. In vitro cellular uptake studies in SK-N-BE(2) and SW620 cell lines demonstrated that NIR imaging agents bearing 2-nitroimidazole structures showed significantly higher tumor uptake in hypoxic cells than in normoxic cells. Moreover, in vivo optical imaging studies using SK-N-BE(2) and SW620 xenografted mice demonstrated that novel, multivalent, 2-nitroimadazole NIR imaging agents with two or three 2-nitroimidazole moieties showed higher uptake in tumor than the control agents with only one 2-nitroimidazole. These observations suggest that novel, multivalent, NIR agents could serve as potential optical imaging agents for evaluating tumor hypoxia.

Major Adverse Cardiovascular Events in Antidepressant Users Within Patients With Ischemic Heart Diseases: A Nationwide Cohort Study.

BACKGROUND: To evaluate the effect of antidepressants on the development of major adverse cardiovascular events (MACEs) in patients with ischemic heart disease (IHD), we analyzed the association between antidepressant use and the risk of MACE development. METHODS: Patients with depression and a history of IHD between 2008 and 2012 were identified by using the National Health Insurance Service database. A cohort was followed up for the development of MACE until the end of 2015. Hazard ratios (HRs) for myocardial infarction, stroke, and cardiovascular death were estimated by Cox proportional hazard regression in a propensity score-matched cohort. RESULTS: Over a median 4.2 years of follow-up, 2943 MACE occurred in 18,981 antidepressant users. Use of antidepressants was not associated with the incidence of MACE when compared with antidepressant nonusers (adjusted HR, 1.00; 95% confidence interval, 0.95-1.05). Among the analyses according to different classes of antidepressants, the increased risk of stroke was only observed in the subgroup of selective serotonin reuptake inhibitor (SSRI) users. Dose-response findings reported greater risk in those with higher doses of use (SSRIs with ≥1.0 defined daily dose; adjusted HR, 1.14; 95% confidence interval, 1.06-1.23), whereas duration response does not support association. CONCLUSIONS: Compared with antidepressant nonusers, use of antidepressants was not associated with occurrence of MACEs in patients with depression and IHD. Although the overall effect of antidepressants on the risk of MACE was neutral, careful monitoring of MACE development is recommended in high-dose SSRI users.

Nationwide prevalence of potential drug-drug interactions associated with non-anticancer agents in patients on oral anticancer agents in South Korea.

PURPOSE: We analyzed the prevalence and severity of potential drug-drug interactions (PDDIs) in Korean patients receiving oral anticancer agents (OAAs) during two different periods. METHODS: A cross-sectional study was conducted using the national insurance reimbursement database. The subjects were adult outpatients diagnosed with cancer and prescribed OAAs at least once in 2010 or 2014. PDDIs were identified using a database and the PDDI severity was categorized as category X (contraindications) or D (consideration of therapy modification). The associated factors for the occurrence of PDDIs were also analyzed. RESULTS: Among the 118,258 patients prescribed OAAs in 2014, approximately 59% were middle-aged, and approximately half were diagnosed with breast cancer. The number of comorbidities increased over time, and majority were diagnosed with gastrointestinal disorders, hyperlipidemia, and psychonervous disorders. The PDDIs due to protein kinase inhibitors (PKIs) with gastrointestinal/metabolic and neurological drugs increased 3.1- and 4.9-fold, respectively, over the 5 years, and 24.0% of the PDDIs fell into category X. Tamoxifen, the most commonly prescribed OAAs, caused the PDDIs with antidepressants through QTc prolongation or pharmacokinetic interaction. The PKIs prescription, cancer type like breast or hematologic cancer, and number of comorbidities or co-prescribing drugs were independently associated with the occurrence of PDDIs. CONCLUSIONS: The risk of PDDIs in patients receiving OAAs increases, particularly with the concomitant use of PKIs with gastrointestinal or psychiatric drugs and endocrine agents with antidepressants. Considering the potential risk of chronic concomitant use of these drug classes in outpatients, healthcare professionals should be made aware of the potential interactions.

Domperidone prescribing patterns in pediatric patients before and after safety warning in South Korea.

OBJECTIVE: In 2014, the Korean Ministry of Food and Drug Safety (MFDS) issued a safety warning to carefully consider adverse cardiac effects when prescribing domperidone for children. We conducted this study to compare the trends of domperidone prescription in pediatrics before and after the MFDS safety warning. MATERIALS: This study included patients < 18 years old who used national health insurance services within the year 2011 and the year 2016, sampled from Health Insurance Review Agency data. METHODS: We analyzed domperidone prescribing patterns including prescribed daily dosage, maximum period of continuous prescription, and number and types of co-prescribed medications and compared two different years pre and post safety warning. RESULTS: A total of 16,614 pediatric patients (1.74%) received domperidone prescriptions in 2011, and 11,317 patients (1.23%) in 2016. The probability of receiving at least one prescription in 2016 has been reduced by 30% compared to 2011. Gastritis was the most common indication in both years. The number of prescriptions containing a maximum daily dosage of over 30 mg was significantly lower in 2016. In the same time period, the number of cases with a maximum continuous prescription period of more than 7 days significantly decreased (p < 0.001). In addition, from 2011 to 2016, comorbid diseases of domperidone-treated patients were similar, but the number of co-prescriptions of interacting medication to domperidone decreased (p < 0.001). CONCLUSION: After the 2014 safety letter was released, the pattern of prescribing domperidone in pediatrics has enhanced drug safety for children in terms of frequency of prescriptions, maximum duration of domperidone use, and the prescription of drugs interacting with domperidone.

Synthesis and Evaluation of Multifunctional Fluorescent Inhibitors with Synergistic Interaction of Prostate-Specific Membrane Antigen and Hypoxia for Prostate Cancer.

Prostate cancer is one of the most common cancers in the world. It is widely known that prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancer, and hypoxia is a common characteristic of many solid tumors, including prostate cancer. In this study, we designed multifunctional fluorescent inhibitors to target PSMA and tumor hypoxia in order to increase the tumor uptake of inhibitors. Novel PSMA inhibitors were prepared using lysine as the backbone to connect three different functional groups: the glutamate-urea-lysine (GUL) structure for inhibiting PSMA, 2-nitroimidazole for the hypoxia-sensitive moiety, and a near-infrared fluorophore (sulfo-Cyanine 5.5). According to the in vitro PSMA binding assay, novel fluorescent inhibitors were demonstrated to have nanomolar binding affinities. Multifunctional inhibitor 2 with one 2-nitroimidazole had a similar inhibitory activity to inhibitor 1 that did not contain the hypoxia targeting moiety, but multifunctional inhibitor 3 with two 2-nitroimidazoles showed lower inhibitory activity than inhibitor 1 due to the bulky structure of the hypoxia-sensitive group. However, in vivo optical imaging and ex vivo biodistribution studies indicated that both multifunctional inhibitors 2 and 3 had higher accumulation in tumors than inhibitor 1 due to a synergistic combination of PSMA and hypoxia targeting moieties. These observations suggest that this novel multifunctional strategy might be a promising approach to improve the diagnosis and therapy of prostate cancer.

Association between atopic disease and anemia in pediatrics: a cross-sectional study.

BACKGROUND: Atopic diseases, such as atopic dermatitis, allergic rhinitis, and asthma, are inflammatory diseases common in pediatric patients. This study investigated whether these inflammatory atopic diseases were associated with anemia in pediatrics. METHODS: A cross-sectional study was conducted using a pediatric dataset from the Health Insurance Review and Assessment Service (HIRA) of South Korea in 2016. Multivariable logistic regression, adjusting for demographic covariates was used for analyse the association between atopic disease and iron deficiency anemia (IDA). RESULTS: A total of 846,718 pediatric patients were included in the study. Of these, 19,594 (2.31%) had a diagnosis of IDA. The logistic regression analyses including covariates revealed there were association between atopic disease and IDA. The adjusted OR (aOR) of IDA was 1.42 (95% CI, 1.37-1.47) for atopic dermatitis, 1.25 (95% CI, 1.21-1.29) for allergic rhinitis, and 1.71 (95% CI, 1.65-1.76) for asthma. IDA was more prevalent in patients with multiple comorbid atopic diseases, with aOR of 1.30 (95% CI, 1.25-1.35), 1.81 (95% CI, 1.73-1.89), and 2.58 (95% CI, 2.43-2.73) for 1, 2, or 3 atopic diagnoses. There was no evidence of multicollinearity among covariates. CONCLUSIONS: Our findings suggest that atopic disease was associated with IDA. Further study is needed to clarify the distinction between IDA and/or AI to better understand the cause of anemia in patients with inflammatory diseases.

Ginsenoside Compound K Induces Ros-Mediated Apoptosis and Autophagic Inhibition in Human Neuroblastoma Cells In Vitro and In Vivo.

Autophagy can result in cellular adaptation, as well as cell survival or cell death. Modulation of autophagy is increasingly regarded as a promising cancer therapeutic approach. Ginsenoside compound K (CK), an active metabolite of ginsenosides isolated from Panax ginseng C.A. Meyer, has been identified to inhibit growth of cancer cell lines. However, the molecular mechanisms of CK effects on autophagy and neuroblastoma cell death have not yet been investigated. In the present study, CK inhibited neuroblastoma cell proliferation in vitro and in vivo. Treatment by CK also induced the accumulation of sub-G1 population, and caspase-dependent apoptosis in neuroblastoma cells. In addition, CK promotes autophagosome accumulation by inducing early-stage autophagy but inhibits autophagic flux by blocking of autophagosome and lysosome fusion, the step of late-stage autophagy. This effect of CK appears to be mediated through the induction of intracellular reactive oxygen species (ROS) and mitochondria membrane potential loss. Moreover, chloroquine, an autophagy flux inhibitor, further promoted CK-induced apoptosis, mitochondrial ROS induction, and mitochondria damage. Interestingly, those promoted phenomena were rescued by co-treatment with a ROS scavenging agent and an autophagy inducer. Taken together, our findings suggest that ginsenoside CK induced ROS-mediated apoptosis and autophagic flux inhibition, and the combination of CK with chloroquine, a pharmacological inhibitor of autophagy, may be a novel therapeutic potential for the treatment of neuroblastoma.

Ginsenoside Rk1 Induces Apoptosis in Neuroblastoma Cells Through Loss of Mitochondrial Membrane Potential and Activation of Caspases.

Neuroblastoma (NB) is the most common childhood cancer, with a very poor prognosis. More than 60% of children with NB die within five years; therefore, a more effective therapy for NB is required. Although ginsenoside has been shown to significantly inhibit the growth of various cancers, the effect of ginsenoside Rk1 on neuroblastoma has not been known yet. Hence, we examined the anticancer effects of highly pure Rk1 on neuroblastoma cell lines. The apoptotic effects of Rk1 on neuroblastoma cells were examined using cell viability assay, flow cytometry and cell staining assay, and the change in gene expression levels were analysed using RT-PCR, western blots, and immunohistochemistry. The metastatic effect of Rk1 was monitored by wound healing assay, invasion and migration with Matrigels. Rk1 inhibited neuroblastoma cell viability dose-dependently. Rk1-induced apoptosis was investigated through nuclear condensation and mitochondrial membrane potential loss, and it showed that Rk1 can induce cell cycle arrest at the G0/G1 phase but also inhibit the metastatic ability of neuroblastoma cells. Moreover, Rk1 (30 mg/kg) injections markedly inhibited xenograft tumor growth. These findings demonstrate that Rk1 might be valuable in the development of anti-cancer agents for neuroblastoma treatment.

Network analysis of drug-related problems in hospitalized patients with hematologic malignancies.

PURPOSE: Network analysis was conducted to systematically analyze the relationship between causative drugs and types of drug-related problems (DRPs) in hospitalized patients with hematologic malignancies. METHODS: A total of 1187 DRPs identified in hematology wards between 2013 and 2015 were analyzed. DRPs were classified into 11 sub-domains for problems and 35 sub-domains for causes according to Pharmaceutical Care Network Europe classification. Causative drugs were classified by Anatomical Therapeutic Chemical code. Network analytic tool was used to represent the relationship between drugs, causes, and problems. In-degree centrality (CD-in) was calculated to identify major causes of DRPs. RESULTS: The following drugs accounted for more than 5% of DRP, including antibacterials (J01, 26.5%), drugs for acid-related disorders (A02, 11.5%), antiemetics (A04, 9.7%), antifungals (J02, 8.8%), and antineoplastic agents (L01, 7.0%). Inappropriate combinations (C1.3, CD-in of 161) of drugs for acid-related disorders, antifungals, and antineoplastic agents were major causes of DRPs and induced non-optimal effects of drug treatment (P1.2). Inappropriate dose adjustments (C3.6, CD-in of 151) of antibacterials lowered effects (P1.2) and increased side effects (P2.1). Missing necessary synergistic or preventive drugs, especially antiemetics, (C1.8, CD-in of 54) resulted in untreated indication (P1.4). CONCLUSIONS: DRPs were mainly related to medications for supportive care. More attention should be paid to interactions of drugs used for acid-related disorders, dose adjustment of antibacterials, and omission of antiemetics in hospitalized patients with hematologic malignancy.

Effectiveness of febuxostat in patients with allopurinol-refractory hyperuricemic chronic kidney disease
.

OBJECTIVE: As uncontrolled hyperuricemia has been associated with an increased risk of cardiovascular disease and the progression of chronic kidney disease (CKD), management of serum uric acid levels is important. The aim of this study was to evaluate the effectiveness of febuxostat in regulating uncontrolled hyperuricemia in patients with renal dysfunction. MATERIALS AND METHODS: We included patients with CKD and persistent uncontrolled hyperuricemia despite treatment with allopurinol. The primary outcome of the study, which was the overall response rate of febuxostat, was defined as the proportion of patients that achieved a serum uric acid level < 7.0 mg/dL. The secondary outcomes included the change in renal function and factors that might influence treatment outcomes. The safety outcome was evaluated based on the incidence of adverse reactions. RESULTS: A total of 111 patients who switched medication to febuxostat were included. Febuxostat treatment significantly lowered serum uric acid level and the response rates were above 70% at all the time points for 1 year. Febuxostat-treated patients demonstrated no significant change in renal function during the study period. A history of gout attack decreased the response rate of febuxostat (odds ratio (OR): 3.13, 95% confidence interval (CI): 1.08 - 9.06), whereas low-dose aspirin use significantly increased response rate (OR: 0.29, 95% CI: 0.09 - 0.92) in the first month. No patients experienced any severe adverse events. CONCLUSIONS: Febuxostat effectively lowered serum uric acid levels and was well tolerated in patients with CKD and allopurinol-refractory hyperuricemia.
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Prioritization of diseases for the development of a pharmaceutical care service model in South Korea using the analytic hierarchy process
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OBJECTIVE: Drug therapy plays a critical role in most chronic diseases. Effectiveness of pharmaceutical care services in the improvement of clinical, social, or economic outcomes has been scientifically proven through numerous studies. In South Korea, to optimize and standardize pharmaceutical care for patients with chronic metabolic diseases, the development of a pharmaceutical care service model is needed. MATERIALS: To determine the priority of diseases in developing pharmaceutical care service models, analytic hierarchny process (AHP)analysis was used. A survey questionnaire standardized with detailed evaluation areas and an index, to ensure sufficient understanding and identical standards of evaluators, was designed. It was prepared for pair-wise comparisons of individual criteria of candidate diseases. METHODS: Medical specialists and pharmacists who have clinical experience and expertise in chronic metabolic diseases or at least 10 years of experience in pharmacy practice were recruited. They responded to a survey consisting of nine sections by using the pair-wise comparison method. RESULTS: A total of seven candidate diseases were selected for prioritization. Diabetes mellitus was given the highest score of 0.2695, cardiovascular disease (0.2598) being the next, followed by chronic kidney disease (0.2000), and cerebrovascular diseases (0.1087). The criteria were weighted as follows: disease characteristics (0.4964), patient-oriented care (0.3649), and improvement in services (0.1386). CONCLUSION: Diabetes, cardiovascular diseases, and chronic kidney disease were found to have high priority in developing a pharmaceutical care service model in South Korea. In the future, further research for the development and application of pharmaceutical care services models for different types of diseases is required.
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Psychometric analysis of the Korean version of the high-dose chemotherapy specific quality of life questionnaire module from the European Organization for Research and Treatment of Cancer (EORTC QLQ-HDC29).

PURPOSE: We evaluated the psychometric properties of the Korean version of the European Organization for Research and Treatment of Cancer high-dose chemotherapy specific quality of life questionnaire module (EORTC QLQ-HDC29) when implemented with Korean patients by conducting a multicenter, longitudinal study in three Korean hospitals. METHODS: A total of 226 patients who scheduled to receive the HDC followed by hematopoietic stem cell transplantation (HSCT) were enrolled. The patients were asked to complete three questionnaires [the EORTC Core Questionnaire (QLQ-C30), QLQ-HDC29, and the Functional Assessment of Cancer Therapy-Bone Marrow Transplantation] at four points in time: before HSCT and 100, 180, and 365 days after HSCT. Standard validity and reliability analyses were performed. RESULTS: Internal consistency of the QLQ-HDC29 was generally acceptable, as tested by Cronbach's α, except for the scales body image and the inpatient issues. Cronbach's α values for the Korean version of the QLQ-HDC29 were almost in accordance with results of the original version, except for the scales body image (lower to the original QLQ-HDC29, α = 0.73) and impact on family (higher to the original QLQ-HDC29, α = 0.52). Known-group comparison analyses showed significantly higher symptom burdens in patients with poor performance status or graft versus host disease (similar to the original QLQ-HDC29). The QLQ-HDC29 indicated good convergent and discriminant validity and showed responsiveness to changes in line with a clinical course over time after HSCT. CONCLUSIONS: The QLQ-HDC29 is generally reliable and adequate to assess QoL in Korean patients undergoing HDC followed by HSCT.

Construction of a database for published phase II/III drug intervention clinical trials for the period 2009-2014 comprising 2,326 records, 90 disease categories, and 939 drug entities.

OBJECTIVES: To construct a database of published clinical drug trials suitable for use 1) as a research tool in accessing clinical trial information and 2) in evidence-based decision-making by regulatory professionals, clinical research investigators, and medical practitioners. MATERIALS: Comprehensive information obtained from a search of design elements and results of clinical trials in peer reviewed journals using PubMed (http://www.ncbi.nlm.ih.gov/pubmed). METHOD: The methodology to develop a structured database was devised by a panel composed of experts in medical, pharmaceutical, information technology, and members of Ministry of Food and Drug Safety (MFDS) using a step by step approach. A double-sided system consisting of user mode and manager mode served as the framework for the database; elements of interest from each trial were entered via secure manager mode enabling the input information to be accessed in a user-friendly manner (user mode). Information regarding methodology used and results of drug treatment were extracted as detail elements of each data set and then inputted into the web-based database system. RESULTS: Comprehensive information comprising 2,326 clinical trial records, 90 disease states, and 939 drugs entities and concerning study objectives, background, methods used, results, and conclusion could be extracted from published information on phase II/III drug intervention clinical trials appearing in SCI journals within the last 10 years. The extracted data was successfully assembled into a clinical drug trial database with easy access suitable for use as a research tool. The clinically most important therapeutic categories, i.e., cancer, cardiovascular, respiratory, neurological, metabolic, urogenital, gastrointestinal, psychological, and infectious diseases were covered by the database. Names of test and control drugs, details on primary and secondary outcomes and indexed keywords could also be retrieved and built into the database. The construction used in the database enables the user to sort and download targeted information as a Microsoft Excel spreadsheet. CONCLUSION: Because of the comprehensive and standardized nature of the clinical drug trial database and its ease of access it should serve as valuable information repository and research tool for accessing clinical trial information and making evidence-based decisions by regulatory professionals, clinical research investigators, and medical practitioners.

Influence of initial angiotensin receptor blockers on treatment persistence in uncomplicated hypertension: A nation-wide population-based study.

We identified 55 504 uncomplicated, treatment-naïve hypertensive patients who started angiotensin II receptor blockers (ARBs) in 2012 from national claims data. The proportion of patients remaining on any hypertension treatment at 12 months and the adherence rate were similar between the losartan cohort (66.82% and 68.25%) and the nonlosartan ARB cohort (67.48% and 69.01%). After adjusting for confounding factors, there was no difference in persistence (aHR 0.98, 95% confidence interval (CI) 0.95-1.01) on hypertension treatment between losartan and nonlosartan ARB cohort. Post hoc analysis showed that patients initially prescribed eprosartan, irbesartan (both, aHR 1.33), and telmisartan (aHR 1.11) were more likely to discontinue the initial drug, whereas valsartan initiators (aHR 0.96) were less likely compared with losartan initiators.

Copy number variability analysis of pharmacogenes in patients with lymphoma, leukemia, hepatocellular, and lung carcinoma using The Cancer Genome Atlas data.

OBJECTIVE: Individual differences in drug efficacy and toxicity remain an important clinical concern. We investigated copy number variation (CNV) frequencies for pharmacogenes using The Cancer Genome Atlas dataset. MATERIALS AND METHODS: One hundred and fifty-two pharmacogenes were selected from liver hepatocellular carcinoma, lung squamous cell carcinoma (LUSC), acute myeloid leukemia, and lymphoid neoplasm diffuse large B-cell lymphoma (DLBL). The germ line and somatic CNV frequencies were analyzed. RESULTS: We found CNVs with more than 1% frequency in drug-metabolizing enzymes including CYP2A6, CYP2D6, GSTP1, CYP2E1, GSTM1, GSTT1, and SULT1A1, drug transporters such as SLC19A1 and SLC28A1, and targets such as FHIT in normal tissue or blood. GSTM1 had the highest frequency for gene gain (45.45, 39.18, 31.01, and 34.77%, respectively) and for gene loss (18.18, 29.38, 20.89, and 26.68%, respectively) in DLBL, acute myeloid leukemia, liver hepatocellular carcinoma, and LUSC. P2RY12 and P2RY1 had the highest frequency for gene gain in LUSC (26.95 and 26.68%, respectively) whereas ABCB1 and ABL2 had the highest frequency for gene gain in DLBL (27.27%) in cancer tissue or blood. CONCLUSION: Germ line and somatic CNVs of pharmacogenes may play a role in determining individual variations in drug responses. Inclusion of CNVs in pharmacogenetic variations holds promise as biomarkers that can increase the benefits and reduce the risks of drug therapy on an individual level.

Population pharmacokinetics of cyclosporine in hematopoietic stem cell transplant patients: consideration of genetic polymorphisms.

BACKGROUND: Cyclosporine (CsA), which is used for graft-versus-host disease prophylaxis in allogeneic hematopoietic stem cell transplant (allo-HSCT), has a narrow therapeutic range and large interindividual and intraindividual pharmacokinetic variability. Nevertheless, population pharmacokinetic (PopPK) studies of CsA in allo-HSCT are scarce. OBJECTIVE: The goal of our study was to build a PopPK model of CsA in allo-HSCT in consideration of demographic, clinical, and genetic polymorphisms data. METHODS: A total of 34 adult allo-HSCT patients who received CsA were enrolled prospectively. Demographic, clinical, and CYP3A5 *1/*3, CYP2C19 *1/*2/*3, ABCB1 3435C>T, 1236C>T, 2677G>T/A, ABCC2 -24C>T, 1249G>A, VDR Bsml, Apal polymorphisms data were collected. A PopPK modeling was conducted with NONMEM program. RESULTS: A 1-compartment model with a 2-transit absorption compartment model was developed. After the stepwise covariate model building process, weight was incorporated into clearance (CL) as a power function model with the exponent value of 0.419. The final typical estimate of CL was 21.2 L/h; volume of distribution was 430 L; logit-transformed bioavailability was 1.49 (bioavailability: 81%); and transit compartment rate was 2.87/h. None of the genetic polymorphisms in CYP3A5, CYP2C19, ABCB1, ABCC2, and VDR were significant covariates in the pharmacokinetics of CsA. CONCLUSIONS: In our study, it was observed that weight had a significant effect on CL. Genetic polymorphisms did not affect CsA pharmacokinetics. Prospective studies with a larger number of participants is needed to validate the results of this study.

Persistence with Antihypertensive Medications in Uncomplicated Treatment-Naïve Patients: Effects of Initial Therapeutic Classes.

We aimed to assess one-year persistence with antihypertensive therapy (AHT) among newly treated uncomplicated hypertensive patients in Korea and to evaluate the effect of initial therapeutic classes on persistence. We retrospectively analyzed a random sample of 20% of newly treated uncomplicated hypertensive patients (n = 45,787) in 2012 from the National Health Insurance claims database. This group was classified into six cohorts based on initial AHT class. We then measured treatment persistence, allowing a prescription gap of 60 days. Adherence to AHT was assessed with the medication possession ratio. Calcium channel blockers (CCB, 43.7%) and angiotensin receptor blockers (ARB, 40.3%) were most commonly prescribed as initial monotherapy. Overall, 62.1% and 42.0% were persistent with any AHT and initial class at one year, respectively, and 64.2% were adherent to antihypertensive treatment. Compared with ARBs, the risk of AHT discontinuation was significantly increased with initial use of thiazide diuretics (hazard ratio [HR], 3.16; 95% confidence interval [CI] 2.96-3.74) and beta blockers (HR, 1.86; CI, 1.77-1.95) and was minimally increased with CCBs (HR, 1.12; CI, 1.08-1.15). In conclusion, persistence and adherence to AHT are suboptimal, but the differences are meaningful in persistence and adherence between initial AHT classes.

Functional analysis of a tannic-acid-inducible and hypoviral-regulated small heat-shock protein Hsp24 from the chestnut blight fungus Cryphonectria parasitica.

A small heat-shock protein gene, CpHsp24, of Cryphonectria parasitica was selected based on its expression pattern, which showed that it was tannic acid inducible and that its induction was severely hampered by a hypovirus. The predicted protein sequence of CpHsp24 consisted of a hallmark α-crystalline domain flanked by a variable N-terminal and a short C-terminal region. Disruption of CpHsp24 resulted in a slow growth rate under standard growth conditions. The CpHsp24-null mutant showed enhanced sensitivity to heat shock, which was consistent with Northern and Western analyses displaying the heat-shock induction of the CpHsp24 gene and protein, respectively. Virulence tests on the excised bark revealed a severe decrease in the necrotic area of the CpHsp24-null mutant. When the hypovirus was transferred, virus-containing CpHsp24-null progeny displayed severely retarded growth patterns with hypovirulent characteristics of reduced pigmentation and sporulation. Because the tannic-acid-inducible and hypoviral-suppressible expression and the severely impaired virulence are also characteristics of the laccase3 gene (lac3), lac3 expression in the CpHsp24-null mutant was also examined. The resulting lac3 induction was severely affected in the CpHsp24-null mutant, suggesting that CpHsp24 is important for lac3 induction and that CpHsp24 may act as a molecular chaperone for the lac3 protein.

Population pharmacogenetic pharmacokinetic modeling for flip-flop phenomenon of enteric-coated mycophenolate sodium in kidney transplant recipients.

PURPOSE: Enteric-coated mycophenolate sodium (EC-MPS) is effective and safe in preventing rejection after transplantation and is mainly transported by ABCs and OATPs and metabolized by UGTs. The genetic polymorphisms affect the inter-individual variation in drug disposition and elimination. The aims of this study were to develop a population pharmacokinetic (PK) model and to evaluate the influence of genetic and clinical factors on the PK of mycophenolic acid (MPA) in Korean renal transplant recipients. METHODS: Population analysis of EC-MPS was performed using non-linear mixed effects modeling (NONMEM). After clinical and genetic factors were evaluated using a stepwise covariate method, we selected clinically relevant covariates considering covariate effects. The final model was validated by bootstrap and visual predictive check. At last, we performed the model-based simulations in order to explore an optimal dose to achieve target area under the curve (AUC) in hypothetical scenarios. RESULTS: From 166 plasma concentrations (n=34), a time-lagged two-compartment with a flip-flop model best describes the PK of MPA. The covariate analysis identified lower creatinine clearance (CLcr) and SLCO1B1 variant genotype were correlated with lower MPA clearance, on the contrary, UGT1A9 variant had decreased distribution of MPA, contributing to lower absorption. When considering to UGT1A9, SLCO1B1 genotypes, and renal function, the new recommended dose of 540 mg twice daily resulted in a higher success of achieving the target AUC0-12h in the 30-60 mg.h/L. CONCLUSIONS: CLcr, UGT1A9 and SLCO1B1 genotypes seem to be promising parameters to predict the pharmacokinetics with flip-flop phenomenon of EC-MPS in transplant recipient having stable renal function. This model on clinical practice may help prevent overexposure and achieve a proper AUC in the Korean population.