J.S. Ko

Development and Comparison of a Warfarin-Dosing Algorithm for Korean Patients With Atrial Fibrillation

BACKGROUND The pharmacokinetics and pharmacodynamics of warfarin are affected by polymorphisms in the genes coding for cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1). OBJECTIVE The objective of this study was to develop a pharmacogenetic dosing algorithm for warfarin in Korean patients with atrial fibrillation and to compare it with the published pharmacogenetic dosing algorithms for accuracy to predict warfarin maintenance dose. METHODS Clinical and genetic data from 130 Korean patients with atrial fibrillation (mean [SD] age: 66.2 [13.3] years; gender, male/female: 86/44; mean body weight: 66.6 [11.6] kg) were used to create a dosing algorithm, which was validated against an independent group of patients (n = 108; mean age: 67.4 [10.1] years; gender, male/female: 69/39; mean body weight: 66.0 [10.9] kg). Validation cohort data for the 12 previously published dosing algorithms incorporating CYP2C9 and VKORC1 genotype information were also applied. RESULTS A multivariate regression model including the variables of age, VKORC1 and CYP2C9 genotype, body surface area, and statin status produced the best model for estimating the warfarin dose (R(2) = 0.62). Among the 12 algorithms that were compared, the predicted doses using algorithms derived from both the Swedish Warfarin Genetics (WARG) study and the Korean population study showed the best correlation with actual warfarin doses. Comparing the percentage of patients whose predicted dosages were within 20% of actual dosages, these algorithms showed similar overall performance. CONCLUSIONS This study derived and validated a multivariate regression model for daily warfarin dose requirements in Korean patients with atrial fibrillation. As no algorithm could be considered the best for all dosing ranges, it may be important to consider the characteristics or limitations of each dosing algorithm and the nature of a population in choosing the most appropriate pharmacogenetic dosing.

Greater hemodynamic instability with histidine-tryptophan-ketoglutarate solution than University of Wisconsin solution during the reperfusion period in living donor liver transplantation.

OBJECTIVE University of Wisconsin (UW) and histidine-tryptophan-ketoglutarate (HTK) solutions are the 2 most commonly used liver preservation solutions. The aim of this study was to compare cardiovascular stability, acid-base status, and potassium concentrations between patients who received grafts preserved in either UW or HTK solution in orthotopic liver transplantation (OLT). PATIENTS AND METHODS In this retrospective study, 87 patients who underwent living donor OLT were divided into 2 groups: UW (n = 28) and HTK (n = 59). Group HTK was subdivided into group NF-HTK (n = 31; nonflushed before reperfusion) and group F-HTK (n = 28; flushed before reperfusion). We determined mean arterial pressure (MAP) and heart rate every minute for 5 minutes after reperfusion and the maximum change in these values and incidence of postreperfusion syndrome (PRS). Body temperature, cardiovascular and acid-base parameters, as well as potassium concentrations were compared at 5 minutes before and 5 and 30 minutes after reperfusion. RESULTS The maximum decreases in MAP within 5 minutes after reperfusion were significantly greater in both the NF-HTK and the F-HTK groups. The rate of PRS was significantly greater in the NF-HTK compared with the UW group. Flushing with HTK solution decreased the rate of PRS; there was no significant difference between the F-HTK and UW groups. All serial changes in body temperature, cardiovascular and acid-base parameters, as well as potassium concentrations were similar among the 3 groups. CONCLUSIONS The incidence of PRS was greater using HTK compared with UW solution during the reperfusion period. Therefore, careful hemodynamic management is advised when using HTK solution.

Predictors of High Intraoperative Blood Loss Derived by Simple and Objective Method in Adult Living Donor Liver Transplantation

We conducted a risk factor analysis for high intraoperative blood loss (IBL) in 555 living donor liver transplantation (LDLT) cases with a simple and objective method of IBL estimation based on the concept of red cell mass (RCM): Lost RCM (mL) = patients estimated blood volume (mL) × (preoperative hematocrit in % - postoperative hematocrit in %) + (transfused leukocyte-depleted red blood cell in units × 213 × 70%) + (transfused Cell Saver blood in mL × 55%). Analysis of 33 preoperative variables revealed that Model for End-stage Liver Disease (MELD) score, albumin, the presence of ascites, and previous abdominal surgery were correlated with high IBL (lost RCM > 1000 mL) in multivariate logistical regression analysis. In conclusion, we found that MELD score, albumin, the presence of ascites, and previous abdominal surgery were significantly correlated with high IBL during adult LDLT.

The Relationship Between Inhalational Anesthetic Requirements and the Severity of Liver Disease in Liver Transplant Recipients According to Three Phases of Liver Transplantation

PURPOSE Orthotopic liver transplantation (OLT) patients are known to show decreased intraoperative anesthetic requirements compared with patients undergoing other liver surgeries. The aim of this study was to determine the relationship between inhalational anesthetic requirements and the severity of liver disease among OLT patients. METHODS Fifty patients undergoing first living donor OLT were divided into 2 groups: model for end-stage liver disease (MELD) score<20 (low-MELD group; n=25) versus, MELD score>or=20 (high-MELD group; n=25). Anesthesia was maintained with desflurane and inspired concentration was titrated to maintain the bispectral index between 40 and 50. Neither intraoperative opioid nor epidural or intrathecal analgesia was used. End-tidal desflurane concentration (ETdes) was measured every 5 minutes and averaged in 30-minute intervals. These values were divided into 3 phases: preanhepatic (P 0.5 hour, P 1 hour, and P 1.5 hours), anhepatic (A 0.5 hour, A 1 hour, A 1.5 hours, and A 2 hours), and postreperfusion (R 0.5 hour, R 1 hour, R 1.5 hours, R 2 hours, R 2.5 hours, and R 3 hours). Results were compared between the 2 groups. RESULTS The demographic and intraoperative data were similar between the 2 groups. ETdes to maintain comparable anesthetic depth was significantly lower during the preanhepatic and anhepatic phases in the high-MELD than the low-MELD group, but there was no significant difference during the postreperfusion period. CONCLUSIONS OLT patients with high MELD scores showed less inhalational anesthetic requirements during the preanhepatic and the anhepatic periods than those with low MELD scores.

Which Score System Can Best Predict Recipient Outcomes after Living Donor Liver Transplantation

INTRODUCTION Many scoring systems have been suggested to predict the outcomes of deceased donor liver transplantations. The aims of this study were to compare the Model for End-Stage Liver Disease (MELD) score with respect to other scores among patients who underwent living donor liver transplantation (LDLT) seeking to evaluate the best system to correlate with postoperative outcomes after LDLT. METHODS We analyzed retrospectively data from 202 adult patients who underwent LDLT from January 2008 to July 2010. We calculated preoperative MELD, MELD-sodium, MELD to serum sodium ratio (MESO), integrated MELD, United Kingdom MELD, Child-Turcotte-Pugh, Acute Physiology and Chronic Health evaluation II (APACHE II), and Sequential Organ Failure Assessment (SOFA) scores in all patients. We analyzed the correlation of each score with postoperative laboratory results, as well as survival at 1, 3, 6 and 12 months after LDLT. RESULTS There was significant positive correlation between all scores and peak total bilirubin during the first 7 days after LDLT. The MELD score showed the greatest correlation with peak total bilirubin (r=0.745). APACHE II and SOFA scores at 6 months and 1 year after LDLT and MESO score at 1 year after LDLT showed acceptable discrimination performance {area under the receiver operating characteristic curves (AUC)>0.7, while other scoring systems showed poor discrimination. However, the AUCs of each score were not significantly different from the MELD score AUC. CONCLUSION The MELD score most correlated with total bilirubin after LDLT, while the APACHE II and SOFA scores seemed to correlate with mortality after LDLT.

The protective effect of ischemic preconditioning against hepatic ischemic-reperfusion injury under isoflurane anesthesia in rats.

PURPOSE Apoptosis is a central mechanism of ischemic-reperfusion injury (IRI) to the liver. Among the methods to reduce IRI, ischemic preconditioning (IP) has been shown to confer protection. Therefore, the aim of this study was to determine if IP conferred protection against hepatic IRI under isoflurane anesthesia in rats and to investigate underlying protective mechanisms. MATERIALS AND METHODS Twenty-three rats weighing 270 to 300 grams were randomly divided into three groups: (1) the sham operated group (n = 5); (2) the non-IP group (n = 9; 45 minutes of hepatic ischemia followed by 2 hours of reperfusion); and (3) the IP group (n = 9); IP induced by 10 minutes of hepatic ischemia followed by 15 minutes of reperfusion before 45 minutes of prolonged hepatic ischemia). Anesthesia was maintained with isoflurane (1.5%). We compared the degrees of hepatic injury and expressions of B cell lymphoma 2 (Bcl-2) and caspase 3 and 8 mRNAs. RESULTS The IP group showed significantly lower levels of aspartate transaminase and alanine transaminase as well as reduced histological grades of hepatocyte injury compared with the non-IP group at 2 hours after reperfusion. At the corresponding time, the Bcl-2 mRNA level was 2-fold higher in the IP group. Caspase 3 mRNA levels were highest in the non-IP group significantly compared with the sham cohort. Similarly, caspase 8 mRNA levels were highest in the Non_IP group albeit not significancely. CONCLUSION IP protected against hepatic IRI under isoflurane anesthesia in rats. The mechanism of protection appeared to involve upregulation of Bcl-2 expression resulting in inhibited apoptosis.

Effect of active airway warming on body core temperature during adult liver transplantation.

INTRODUCTION Active inspired gas humidification (AH) preserves body heat and maintains normothermia intraoperatively. However, it is unclear whether AH shows comparable influences during liver transplantation (OLT), which may be affected by both large internal heat loss and external heat supply. Thus, the aim of this study was to evaluate the effect of AH compared with passive humidification (PH) on body temperature in OLT. MATERIALS AND METHODS Thirty-four adult patients undergoing living donor OLT were randomly enrolled into two groups: those given AH using a heated humidifier (HH group, n = 17) and those using a heat-and-moisture exchanger (HME group, n = 17). Both core and skin temperatures (Tc and Ts), as well as respiratory parameters, including static/dynamic lung compliances and PaO(2), were recorded at predetermined times. RESULTS Both Tc and Ts were consistently higher among the HH versus the HME group after 2 hours of anesthesia. Differences in Tc and Ts between the two groups increased gradually over time. The overall Tc during surgery was higher among the HH than the HME group (P = .023). The incidences of hypothermia were lower in the HH group at 3 hours of anesthesia, 1 and 3 hours of reperfusion, and at the end of surgery (P = .037, 0.024, 0.005, and 0.010 respectively). The duration of hypothermia was lower in the HH than the HME group (3.9 ± 3.5 hours versus 6.7 ± 3.3 hours, P = .025). Both groups showed no significant intraoperative changes in respiratory parameters; there were no postoperative respiratory complications. CONCLUSION Active humidification warms the patients body effectively, lessening the incidence and duration of hypothermia during OLT with no respiratory risks.

Subunit-specific mass spectrometry method identifies haptoglobin subunit alpha as a diagnostic marker in non-small cell lung cancer.

UNLABELLED Haptoglobin (Hp) subunits have been suggested as a potential serum marker for lung cancer. Research is intense on the application of Hp subunits to predict the cancer earlier. Nevertheless, it remains difficult to accurately measure the content of Hp subunits. We developed stable isotope dilution-multiple reaction monitoring mass spectrometry (SID-MRM-MS) capable of measuring Hp subunits (alpha and beta chains). Three isotopic analogs (NPANPVQ, TEGDGVYTLNDK and ILGGHLDAK for alpha, alpha2 and beta chain, respectively) were used as internal standard (IS) for SID-MRM-MS. Serum levels of each Hp subunit were measured in 210 clinical samples using SID-MRM-MS. A concentration ratio of each Hp subunit to total Hp was investigated. Secretion levels of alpha and beta chains were significantly increased in non-small cell lung cancer (NSCLC) compared to controls (P<0.0001). Alterations of the alpha chain ratio were more apparent than beta chain between controls and NSCLC (P=0.0001 and 0.338 for alpha and beta chains, respectively). In conclusion, this study provides not only an efficient quantitative method to determine each Hp subunit in crude sera, but also evidence that Hp alpha chain is a more prospective biomarker to diagnose NSCLC than beta chain. BIOLOGICAL SIGNIFICANCE Recent several studies have reported Hp as a potential biomarker for diagnosis of lung cancer. However a successful evaluation of the value of Hp subunits was not achieved on clinical samples. To evaluate the diagnostic performance of each Hp subunit, the development of an accurate quantitative assay of Hp subunits is necessary. In this regard, we employed a new analytical method using stable isotope dilution-multiple reaction monitoring mass spectrometry (SID-MRM-MS), capable of measuring Hp subunits in 210 clinical specimens. In this article, we measured the Hp subunit concentrations and Hp subunits/total Hp ratios in patients with NSCLC using SID-MRM-MS. This is the first report on the evaluation of each Hp subunit as a lung cancer marker using SID-MRM-MS. Consequently, we evaluated specific three tryptic peptides (e.g. NPANPVQ, TEGDGVYTLNDK and ILGGHLDAK for alpha, alpha2 and beta chain, respectively) with high specificity and sensitivity for determination of Hp subunits. Through future large prospective cohort studies, the clinical application of Hp subunits as complementary markers, especially Hp alpha, would be useful for the diagnosis of NSCLC.

Comparison of pharmacokinetics between sarpogrelate hydrochloride immediate-release formulation and controlled-release formulation.

OBJECTIVE Sarpogrelate hydrochloride is a selective 5-hydroxytryptamine receptor subtype 2A (5HT(2A)) antagonist that blocks serotonin-induced platelet aggregation. The aim of this study was to compare the pharmacokinetics of sarpogrelate and its metabolite after dosing with a controlledrelease (CR) formulation or an immediaterelease (IR) formulation. METHODS In this open-label, 2-period, 2-treatment crossover study, 36 healthy male subjects were evenly allocated to two groups in a sequence-randomized manner. In the first period, the first group received 100-mg sarpogrelate IR 3 times at a 6-h interval, and the second group received 300-mg sarpogrelate CR once. After a 7-day washout, the two groups switched their dosing schedule. Serial blood sampling was performed up to 24 hours after the first drug administration during each period. Plasma concentrations of sarpogrelate and its metabolite (M-1) were measured using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were calculated by noncompartmental methods. RESULTS There were no significant differences between two formulations in the pharmacokinetic properties in the time to reach maximum plasma concentration (C(max)) of sarpogrelate and its metabolite. The CR-to-IR geometric mean ratios, as measured by area under the plasma concentration-time curve (AUC) were 1.31 (90% confidence interval, 1.22 - 1.41) for sarpogrelate and 1.21 (1.14 - 1.29) for M-1. The C(max) was 0.98 (0.85 - 1.12) for sarpogrelate and 1.07 (0.96 - 1.19) for M-1. CONCLUSIONS After the administration of sarpogrelate hydrochloride CR and IR formulations using the same daily dose, AUCs were slightly higher for the CR formulation than for the IR formulation for both sarpogrelate and its metabolite M-1, but the C(max) values were similar.

Effect of genetic polymorphisms on the pharmacokinetics and efficacy of glimepiride in a Korean population

BACKGROUNDS Glimepiride is a commonly used sulfonylurea hypoglycemic agent. There is considerable interindividual variation in the response to sulfonylurea for patients with type 2 diabetes. The purpose of this study was to investigate whether genetic variations influence the efficacy of glimepiride in healthy Korean subjects. METHODS A single 2-mg oral dose of glimepiride was administered to 46 healthy volunteers. Serial blood sampling for 12h after oral dosing was performed for determination of plasma glimepiride, glucose and insulin levels. We tested the association of seven single nucleotide polymorphisms (SNPs) in four candidate genes with the efficacy of glimepiride. RESULTS Pharmacodynamic profiles for plasma glucose and insulin showed no statistically significant differences among genotype groups, and parameters were not different from one another. There were no association of the KCNJ11, NOS1AP, TCF7L2 and ABCC8 gene polymorphisms and the efficacy of glimepiride. CONCLUSIONS Knowledge of these polymorphisms provides no clinical useful information for the pharmacogenetic therapeutic approach for Korean patients with type 2 diabetes.