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.

Performance comparison of first-order conditional estimation with interaction and Bayesian estimation methods for estimating the population parameters and its distribution from data sets with a low number of subjects.

BACKGROUND: Exploratory preclinical, as well as clinical trials, may involve a small number of patients, making it difficult to calculate and analyze the pharmacokinetic (PK) parameters, especially if the PK parameters show very high inter-individual variability (IIV). In this study, the performance of a classical first-order conditional estimation with interaction (FOCE-I) and expectation maximization (EM)-based Markov chain Monte Carlo Bayesian (BAYES) estimation methods were compared for estimating the population parameters and its distribution from data sets having a low number of subjects. METHODS: In this study, 100 data sets were simulated with eight sampling points for each subject and with six different levels of IIV (5%, 10%, 20%, 30%, 50%, and 80%) in their PK parameter distribution. A stochastic simulation and estimation (SSE) study was performed to simultaneously simulate data sets and estimate the parameters using four different methods: FOCE-I only, BAYES(C) (FOCE-I and BAYES composite method), BAYES(F) (BAYES with all true initial parameters and fixed ω 2 ), and BAYES only. Relative root mean squared error (rRMSE) and relative estimation error (REE) were used to analyze the differences between true and estimated values. A case study was performed with a clinical data of theophylline available in NONMEM distribution media. NONMEM software assisted by Pirana, PsN, and Xpose was used to estimate population PK parameters, and R program was used to analyze and plot the results. RESULTS: The rRMSE and REE values of all parameter (fixed effect and random effect) estimates showed that all four methods performed equally at the lower IIV levels, while the FOCE-I method performed better than other EM-based methods at higher IIV levels (greater than 30%). In general, estimates of random-effect parameters showed significant bias and imprecision, irrespective of the estimation method used and the level of IIV. Similar performance of the estimation methods was observed with theophylline dataset. CONCLUSIONS: The classical FOCE-I method appeared to estimate the PK parameters more reliably than the BAYES method when using a simple model and data containing only a few subjects. EM-based estimation methods can be considered for adapting to the specific needs of a modeling project at later steps of modeling.

Identification of differentially expressed miRNAs associated with chronic kidney disease-mineral bone disorder.

The purpose of this study is to characterize a meta-signature of differentially expressed mRNA in chronic kidney disease (CKD) to predict putative microRNA (miRNA) in CKD-mineral bone disorder (CKD-MBD) and confirm the changes in these genes and miRNA expression under uremic conditions by using a cell culture system. PubMed searches using MeSH terms and keywords related to CKD, uremia, and mRNA arrays were conducted. Through a computational analysis, a meta-signature that characterizes the significant intersection of differentially expressed mRNA and expected miRNAs associated with CKD-MBD was determined. Additionally, changes in gene and miRNA expressions under uremic conditions were confirmed with human Saos-2 osteoblast-like cells. A statistically significant mRNA meta-signature of upregulated and downregulated mRNA levels was identified. Furthermore, miRNA expression profiles were inferred, and computational analyses were performed with the imputed microRNA regulation based on weighted ranked expression and putative microRNA targets (IMRE) method to identify miRNAs associated with CKD occurrence. TLR4 and miR-146b levels were significantly associated with CKD-MBD. TLR4 levels were significantly downregulated, whereas primiR- 146b and miR-146b were upregulated in the presence of uremic toxins in human Saos-2 osteoblast-like cells. Differentially expressed miRNAs associated with CKD-MBD were identified through a computational analysis, and changes in gene and miRNA expressions were confirmed with an in vitro cell culture system.

Development and validation of a modified Korean version of the Pharmacy Services Questionnaire (PSQ-K) for the quality assessment of community pharmacy services.

Patient-reported outcome (PRO) measures and validated instruments have become integral in assessing the quality of healthcare delivery, including pharmaceutical care services. The Pharmacy Services Questionnaire (PSQ) measures patient satisfaction with pharmaceutical care. In this study, we developed a modified Korean version of the PSQ (PSQ-K) and evaluated its validity and reliability. The PSQ-K was developed using a strict translation and cultural-adaptation procedure. A validation study was performed in six community pharmacies in Korea. A total of 300 respondents completed three questionnaires (a brief questionnaire for social demographics and clinical characteristics, the PSQ-K, and the 5-level EuroQoL Group's 5-dimension [EQ-5D-5L]). Standard validity and reliability analyses were performed. The internal consistency of the PSQ-K was high for all scales (Cronbach's α > 0.9). The PSQ-K indicated good discriminant and divergent validity. Known-group comparisons revealed that the PSQ-K was able to distinguish between respondents differing in socio-demographic characteristics, such as gender, level of education, and household income. In conclusion, the PSQ-K is a highly reliable and valid PRO instrument for assessing the level of satisfaction with community pharmacy services.

Topical Recombinant Human Epidermal Growth Factor for Oral Mucositis Induced by Intensive Chemotherapy with Hematopoietic Stem Cell Transplantation: Final Analysis of a Randomized, Double-Blind, Placebo-Controlled, Phase 2 Trial.

The aim of this study was to evaluate the efficacy and safety of recombinant human epidermal growth factor (rhEGF) oral spray for oral mucositis (OM) induced by intensive chemotherapy with hematopoietic stem cell transplantation. In this phase 2 study, patients were randomized to either rhEGF (50 microg/mL) or placebo in a 1:1 ratio. The primary endpoint was incidence of National Cancer Institute (NCI) grade ≥2 OM. A total of 138 patients were enrolled in this study. In the intention-to-treat analysis, rhEGF did not reduce the incidence of NCI grade ≥2 OM (p = 0.717) nor reduce its duration (p = 0.725). Secondary endpoints including the day of onset and duration of NCI grade ≥2 OM, the incidence of NCI grade ≥3 OM and its duration, and patient-reported quality of life were also similar between the two groups. In the per-protocol analysis, however, the duration of opioid analgesic use was shorter in the rhEGF group (p = 0.036), and recipients in the rhEGF group required a lower cumulative dose of opioid analgesics than those in the placebo group (p = 0.046), among patients with NCI grade ≥2 OM. Adverse events were mild and transient. This study found no evidence to suggest that rhEGF oral spray reduces the incidence of OM. However, further studies are needed to investigate the effect of rhEGF on OM-induced pain reduction after intensive chemotherapy.

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.

Carborane-containing urea-based inhibitors of glutamate carboxypeptidase II: Synthesis and structural characterization.

Glutamate carboxypeptidase II (GCPII) is a zinc metalloprotease on the surface of astrocytes which cleaves N-acetylaspartylglutamate to release N-acetylaspartate and glutamate. GCPII inhibitors can decrease glutamate concentration and play a protective role against apoptosis or degradation of brain neurons. Herein, we report the synthesis and structural analysis of novel carborane-based GCPII inhibitors. We determined the X-ray crystal structure of GCPII in complex with a carborane-containing inhibitor at 1.79Å resolution. The X-ray analysis revealed that the bulky closo-carborane cluster is located in the spacious entrance funnel region of GCPII, indicating that the carborane cluster can be further structurally modified to identify promising lead structures of novel GCPII inhibitors.

Anti-Fatigue Effects of Fermented Rhodiola rosea Extract in Mice.

Rhodiola rosea is a perennial plant which grows in the alpine regions of Europe and Asia. Although the protective effects of R. rosea extract from fatigue due to exercise stress have been reported, studies on fermented R. rosea extract remain insufficient to date. Therefore, this study was conducted to examine the protective effects of fermented R. rosea extract against fatigue and exercise stress. As a result, fermented R. rosea extract was found to significantly increase swimming time, hepatic superoxide dismutase content, and serum lactate dehydrogenase in mice, while decreasing serum blood urea nitrogen content compared to R. rosea extract. Given the above results, it is considered that fermented R. rosea extract effectively protects against fatigue caused by strenuous exercise.

Analysis of pharmacogenomic variants associated with population differentiation.

In the present study, we systematically investigated population differentiation of drug-related (DR) genes in order to identify common genetic features underlying population-specific responses to drugs. To do so, we used the International HapMap project release 27 Data and Pharmacogenomics Knowledge Base (PharmGKB) database. First, we compared four measures for assessing population differentiation: the chi-square test, the analysis of variance (ANOVA) F-test, Fst, and Nearest Shrunken Centroid Method (NSCM). Fst showed high sensitivity with stable specificity among varying sample sizes; thus, we selected Fst for determining population differentiation. Second, we divided DR genes from PharmGKB into two groups based on the degree of population differentiation as assessed by Fst: genes with a high level of differentiation (HD gene group) and genes with a low level of differentiation (LD gene group). Last, we conducted a gene ontology (GO) analysis and pathway analysis. Using all genes in the human genome as the background, the GO analysis and pathway analysis of the HD genes identified terms related to cell communication. "Cell communication" and "cell-cell signaling" had the lowest Benjamini-Hochberg's q-values (0.0002 and 0.0006, respectively), and "drug binding" was highly enriched (16.51) despite its relatively high q-value (0.0142). Among the 17 genes related to cell communication identified in the HD gene group, five genes (STX4, PPARD, DCK, GRIK4, and DRD3) contained single nucleotide polymorphisms with Fst values greater than 0.5. Specifically, the Fst values for rs10871454, rs6922548, rs3775289, rs1954787, and rs167771 were 0.682, 0.620, 0.573, 0.531, and 0.510, respectively. In the analysis using DR genes as the background, the HD gene group contained six significant terms. Five were related to reproduction, and one was "Wnt signaling pathway," which has been implicated in cancer. Our analysis suggests that the HD gene group from PharmGKB is associated with cell communication and drug binding.

Combined interaction of multi-locus genetic polymorphisms in cytarabine arabinoside metabolic pathway on clinical outcomes in adult acute myeloid leukaemia (AML) patients.

Cytarabine arabinoside (ara-C) is the key agent for treating acute myeloid leukaemia (AML). Here, we genotyped 139 single nucleotide polymorphisms (SNPs) within the ara-C transport and metabolic pathway using the Illumina Golden Gate Assay in 97 patients with previously non-treated de novo AML other than M3. DCK rs4694362 (CC genotype) was a significant poor prognostic factor for overall survival (OS) (hazard ratio [HR], 33.202 [95% confidence interval (CI), 4.937-223.273], P<0.0001, P(Bonferroni)=0.017). SLC29A1 rs3734703 (AA or AC genotype) in combination with TYMS rs2612100 (AA genotype) was significantly associated with shorter relapse free survival (RFS) (HR, 17.630 [95% CI, 4.829-64.369], P<0.0001, P(Bonferroni)=0.021). These SNPs showed moderate or large inter ethnic divergence in allele frequencies from African or Caucasian populations. The results of our study suggest that a single SNP and SNP-SNP interactions may help to predict the drug response and provide a guide in developing individualised chemotherapy for AML patients receiving ara-C based chemotherapy.

Recombinant human epidermal growth factor on oral mucositis induced by intensive chemotherapy with stem cell transplantation.

Oral mucositis (OM) is one of the most common and debilitating complications in patients undergoing intensive chemotherapy followed by hematopoietic stem cell transplantation (HSCT). The aim of this study was to evaluate the efficacy and safety of recombinant human epidermal growth factor (rhEGF) oral spray for OM induced by intensive chemotherapy followed by HSCT. Patients were randomly assigned to either the rhEGF group or placebo group. The severity of OM and self-reported quality of life (QOL) were assessed daily. A total of 58 patients were analyzed. Baseline characteristics were similar between the two groups. The incidence of NCI grade ≥ 2 OM was higher in the rhEGF group (78.6% vs. 50%, P = 0.0496). However, the duration of OM in patients with NCI grade ≥ 2 tended to be shorter in the rhEGF group (8.5 days vs. 14.5 days, P = 0.262). The QOL analysis in patients with World Health Organization (WHO) grade ≥ 3 OM showed that rhEGF significantly reduced limitations in swallowing (P = 0.039) and drinking (P = 0.042). The duration of hospitalization (P = 0.047), administration of total parenteral nutrition (P = 0.012), and the usage of opioid analgesics (P = 0.018) were significantly shorter in the rhEGF group with WHO grade ≥ 3 OM. Adverse events were mild and similar between the two groups. In conclusion, this analysis showed that rhEGF did not reduce the incidence of NCI grade ≥ 2 OM. However, the patients with WHO grade ≥ 3 OM in the rhEGF group showed better results compared to the placebo group for several secondary endpoints.

Cardioprotective effect of early dexrazoxane use in anthracycline treated pediatric patients.

Anthracyclines play a major role in chemotherapeutic regimens for a variety of pediatric cancers, but produce undesirable dose-related cardiotoxicity. Dexrazoxane reduces early myocardial injury during anthracycline treatment, but data remain insufficient to fully understand its cardioprotective effectiveness in treating pediatric cancers and additional research is necessary to find efficient methods of dexrazoxane administration. Therefore, we retrospectively evaluated the cardioprotective effect of dexrazoxane against anthracyclines in 258 pediatric cancer patients who had received any anthracyclines from January 1997 to May 2005 at a tertiary teaching hospital in Korea. The results of this study suggest that the early use of dexrazoxane protects against the development of cardiotoxicity during anthracycline treatment in pediatric cancer patients. Further studies involving larger pediatric cancer patients are needed to evaluate the cardioprotective effect of dexrazoxane at higher cumulative doses of anthracyclines and on late-onset cardiotoxicity in long-term survivors.

Effectiveness of palonosetron versus other serotonin 5-HT3 receptor antagonists in triple antiemetic regimens during multiday highly emetogenic chemotherapy.

BACKGROUND: The second-generation serotonin 5-HT(3) receptor antagonist palonosetron has shown improved efficacy in the prevention of both acute and delayed chemotherapy-induced nausea and vomiting (CINV). However, there have been no randomized controlled trials supporting the preferential use of palonosetron in triple antiemetic regimens for patients receiving multiday highly emetogenic chemotherapy (HEC). OBJECTIVE: To compare the effectiveness of palonosetron-based and first-generation 5-HT(3) receptor antagonist-based triple antiemetic regimens in cancer patients receiving multiday HEC. METHODS: This was a review and analysis of medical record data. A total of 115 patients who had received multiday HEC were included and grouped into a palonosetron-based antiemetic group (n = 73) or a first-generation 5-HT(3) receptor antagonist-based antiemetic group (n = 42). Data on CINV were collected in 24-hour intervals for 120 hours after the start of chemotherapy. RESULTS: Complete response rates did not differ significantly between the 2 groups during any of the 3 phases: acute (0-24 hours), p = 0.877; overlap (24-120 hours), p = 0.997; and overall (0-120 hours), p = 0.723. The proportion of patients with complete control was similar between the groups during each phase: acute, p = 0.862; overlap, p = 0.838; and overall, p = 0.828. There was also no significant difference in other end points between the 2 groups. Among all patients, females experienced significantly more acute nausea (p = 0.040) and vomiting (p = 0.046) than males. Compared with nondrinkers, patients who consumed alcohol had a lower overall incidence of vomiting (p = 0.020). CONCLUSIONS: Within a triple antiemetic regimen, a palonosetron-based antiemetic regimen was not significantly different from regimens based on first-generation 5-HT(3) receptor antagonists in preventing CINV during multiday HEC.

Ethnic variability in the allelic distribution of pharmacogenes between Korean and other populations.

OBJECTIVE: We examined the differences in allele frequencies for pharmacogenes among the Korean (KOR), Chinese (CHB), Japanese (JPT), Caucasian (CEU), and Nigerian (YRI) populations. METHODS: Fifty-seven pharmacogenes were selected from the imputed Korean Association REsource and HapMap databases. Minor allele frequencies were analyzed using the sample size-modified single nucleotide polymorphism-specific fixation index (FST) and the χ-test with Bonferroni's correction. Geneset analysis was also carried out to identify pharmacogenes that have significantly different allele frequencies among the various populations tested. RESULTS: The KOR population was the most divergent group from the YRI population (FST: 0.079) but very similar to the CHB and JPT populations (FST: 0.003). VKORC1 showed a large population divergence in the KOR-YRI (0.439) comparison. CYP3A4 was also highly divergent in the KOR-YRI (FST: 0.361) comparison. The calcium signaling pathway gene set was divergent in all pairwise population comparisons. CONCLUSION: In terms of the 57 pharmacogenes studied, there were no significant differences among the KOR, CHB, and JPT populations. However, the YRI and CEU populations were significantly differentiated from the three Eastern Asian groups. Future pharmacogenomics studies can utilize the polymorphisms identified in this study, as these variants may have important implications for the selection of highly informative single nucleotide polymorphisms for future clinical trials.

Copy number variations in normal karyotype acute myeloid leukaemia and their association with treatment response.

Copy number variation (CNV) has been reported to be associated with chemotherapy response, which affects disease prognosis. Here, we determined the frequency of genome-wide cytogenetic CNV aberrations in Korean patients with normal karyotype (NK) acute myeloid leukaemia (AML) and tested whether these genomic variations contribute to differences in Ara-C and anthracycline-based chemotherapy responses. Bone marrow aspirates and blood from 30 previously untreated de novo NK-AML patients were provided at the time of diagnosis for copy number analysis. Possible associations between cytogenetic aberrations and clinical parameters were analysed. CNVs were identified in 23 (76.7%) of the 30 cases tested. Multivariate analyses controlled for other clinical co-variates showed that patients having copy number loss had a decreased probability of complete remission (OR, 0.015 [95% CI, 0-0.737], p = 0.035). Patients who had a copy number gain of more than four regions tended to have shorter event-free survival (EFS) (p = 0.083) with multivariate analysis showing that CNV increase is an independent predictive factor for shorter EFS (HR, 22.104 [95% CI, 1.644-297.157], p = 0.020). In addition, we identified candidate genes that may be involved in Ara-C and anthracycline drug response in Korean patients with NK-AML. These results suggest that CNVs may affect the success of Ara-C and anthracycline-based chemotherapy in Korean patients with NK-AML.

Effects of acidic polysaccharides from gastrodia rhizome on systolic blood pressure and serum lipid concentrations in spontaneously hypertensive rats fed a high-fat diet.

The effects of acidic polysaccharides purified from Gastrodia rhizome on blood pressure and serum lipid levels in spontaneously hypertensive rats (SHR) fed a high-fat diet were investigated. Acidic polysaccharides were purified from crude polysaccharides by DEAE-Sepharose CL-6B. Thirty-six male SHR were randomly divided into three groups: Gastrodia rhizome crude polysaccharide (A), acidic polysaccharide (B) groups, and a control group (C). A 5-week oral administration of all treatment groups was performed daily in 3- to 8-week-old SHRs with a dose of 6 mg/kg of body weight/day. After 5 weeks of treatment, total cholesterol in the acidic polysaccharide group, at 69.7 ± 10.6 mg/dL, was lower than in the crude polysaccharide group (75.0 ± 6.0 mg/dL) and the control group (89.2 ± 7.4 mg/dL). In addition, triglyceride and low-density lipoprotein cholesterol levels in the acidic polysaccharide group were lower than in the crude polysaccharide and control groups. The atherogenic index of the acidic polysaccharide group was 46.3% lower than in the control group. Initial blood pressure after the initial three weeks on the high-fat diet averaged 195.9 ± 3.3 mmHg among all rats. Compared with the initial blood pressure, the final blood pressure in the control group was increased by 22.8 mmHg, whereas it decreased in the acidic polysaccharide group by 14.9 mmHg. These results indicate that acidic polysaccharides from Gastrodia rhizome reduce hypertension and improve serum lipid levels.

Clinical and genetic factors affecting tacrolimus trough levels and drug-related outcomes in Korean kidney transplant recipients.

PURPOSE: The purpose of this study was to characterize the effects of clinical and genetic variables on the pharmacokinetics and complications of tacrolimus during the first year after kidney transplantation. METHODS: One hundred and thirty-two Korean kidney recipients who received tacrolimus were genotyped for ABCB1 (exons 12, 21, and 26) and CYP3A5 (intron 3). Tacrolimus trough levels, dose, or dose-adjusted trough levels and complications were compared among patients during the early stage (3, 7, 14, 30, and 90 days) and up to 1 year according to the genotypes. RESULTS: A donor source-adjusted linear mixed model with multilevel analysis adjusting for age, body weight, hematocrit, and serum creatinine showed that CYP3A5 genotype is associated with dose-adjusted level of tacrolimus (p < 0.001). The influence of ABCB1 polymorphisms on the pharmacokinetics or complications of tacrolimus was less certain in our study. The incidence of acute rejections was significantly higher in recipients of cadaveric donor kidney (p < 0.05). CONCLUSIONS: A generalized estimating equation model analysis showed that alopecia and hyperlipidemia were associated with dose-adjusted level of tacrolimus (p < 0.001). Genotype of CYP3A5 variants along with significant clinical covariates may be useful in individualizing tacrolimus therapy in kidney transplantation patients.

Population pharmacokinetics of cyclosporine in Korean adults undergoing living-donor kidney transplantation.

STUDY OBJECTIVE: To estimate the population pharmacokinetic parameters of cyclosporine in Korean adults undergoing living-donor kidney transplantation, and to identify clinical factors affecting cyclosporine pharmacokinetics. DESIGN: Retrospective cohort study. SETTING: Single, 1600-bed, tertiary care academic medical center in Seoul, South Korea. PATIENTS: Seventy-four living-donor kidney transplant recipients (mean age 42 yrs) receiving oral cyclosporine microemulsion as an immunosuppressant between January 1, 2001, and August 31, 2006. MEASUREMENTS AND MAIN RESULTS: Using nonlinear mixed-effects modeling (NONMEM) with first-order absorption and elimination, a total of 2394 whole-blood cyclosporine concentrations from the 74 patients were analyzed. The effects of several clinical covariates on cyclosporine pharmacokinetic parameters were evaluated over 12 months after transplantation. The absorption rate constant was fixed at 1.28 hour(-1), and the following population pharmacokinetic estimates were calculated: cyclosporine clearance 43.6 L/hour, apparent volume of distribution 1990 L, and interpatient variability for clearance (coefficient of variation) 17.69%. The clinical factors (covariates) that significantly affected cyclosporine pharmacokinetics were postoperative days, prednisolone dose (in mg/day), total bilirubin level (mg/dl), current body weight (in kg), and concurrent use of amlodipine. CONCLUSION: This population pharmacokinetic model identified important sources of variability in cyclosporine pharmacokinetics. The model will help calculate cyclosporine dose requirements in renal transplant recipients according to specific clinical factors affecting cyclosporine clearance, and it will also be useful for therapeutic drug monitoring.

Psychological distress as a negative survival factor for patients with hematologic malignancies who underwent allogeneic hematopoietic stem cell transplantation.

STUDY OBJECTIVE: To evaluate the influence of distress on overall survival of patients with hematologic malignancies who underwent allogeneic stem cell transplantation (allo-SCT) and to analyze the possible risk factors for death. DESIGN: Retrospective cohort study. SETTING: Large tertiary care teaching hospital. PATIENTS: Seventy-seven patients (aged ≥ 15 yrs) with hematologic malignancies who underwent allo-SCT between January 2000 and August 2007; 20 patients with distress history were matched in a 1:3 ratio with 57 patients without distress history. MEASUREMENTS AND MAIN RESULTS: The primary outcome was overall survival, defined as the time from allo-SCT to disease-related death or last date of follow-up. Secondary outcomes were time to hematologic recovery (absolute neutrophil count ≥ 500 cells/mm³) from day of allo-SCT, length of hospital stay, and opioid usage. Sociodemographic information and clinical characteristics were analyzed for possible risk factors. Patient history of psychological distress resulted in a significantly higher mortality rate in the first year after allo-SCT (hazard ratio [HR] 3.05, 95% confidence interval [CI] 1.48-6.28, p=0.001) and led to a shorter overall survival rate (HR 1.63, 95% CI 0.86-3.10, p=0.133). However, psychological distress had no effect on hospital length of stay, hematologic recovery time, opioid usage status, or dose of opioid analgesics used. Factors associated with death after allo-SCT in the univariate analysis (p<0.05) were high-relapse risk disease, umbilical cord blood SCT, total-body irradiation-containing conditioning regimen, and higher educational background. In the multivariate analysis, high relapse risk (HR 3.85, 95% CI 1.81-8.20, p<0.001) and total-body irradiation-containing conditioning regimen (HR 3.50, 95% CI 1.29-9.51, p=0.01) were identified as risk factors for death. CONCLUSION: A history of psychological distress before allo-SCT, after adjusting for other patient- and disease-related prognostic factors, had a significant influence on early death in the first year after transplantation.

Establishment of a new Glivec-resistant chronic myeloid leukemia cell line, SNUCML-02, using an in vivo model.

OBJECTIVE: In this study, we report a newly established chronic myeloid leukemia (CML) cell line, SNUCML-02, which is resistant to imatinib and describe its biological characteristics. MATERIALS AND METHODS: Mononuclear cells were obtained from the bone marrow of a CML patient in blast crisis and were cultured in Dulbecco's modified Eagle's medium/F12 containing 20% fetal bovine serum. After 2 months of primary culture, these cells were injected into nonobese diabetic/severe combined immune-deficient mice via tail vein. Eight weeks after injection, mice were sacrificed and ex vivo culture was performed from the bone marrow cells isolated from the mice. The established cell line was named as SNUCML-02 and the biological features were characterized by cytogenetic analysis, fluorescence in situ hybridization, reverse transcriptase polymerase chain reaction, sequencing analysis, cell proliferation assay, and Western blot analysis. RESULTS: Cytogenetic studies using conventional G-banding and fluorescent in situ hybridization of SNUCML-02 demonstrated classical Philadelphia chromosome, (9;22)(q34;q11.2), and other abnormalities, such as add(11)(q23), +19 and +der(9;22). SNUCML-02 has the same BCR-ABL fusion transcript as was seen in K562 cells, but has no mutations in the ABL kinase domain. SNUCML-02 was more resistant to imatinib (STI571, Gleevec, Glivec) than other CML cell lines (K562, Kcl22, and BV173). SNUCML-02 has constitutive activation of extracellular signal-regulated kinase phosphorylation. In addition, interleukin-3 induced c-ABL phosphorylation and constitutively enhanced extracellular signal-regulated kinase phosphorylation was not inhibited by imatinib in SNUCML-02. CONCLUSION: SNUCML-02 is a new established cell line with a relatively high level of resistance to imatinib, which is useful for investigating the pathogenesis of CML progression, and will be useful in developing optimal therapeutic strategies for this ailment.