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Humans are continuously exposed to benzisothiazolinone (BIT), which is used as a preservative, through multiple routes. BIT is known to be a sensitizer; in particular, dermal contact or aerosol inhalation could affect the local toxicity. In this study, we evaluated the pharmacokinetic properties of BIT in rats following various routes of administration. BIT levels were determined in rat plasma and tissues after oral inhalation and dermal application. Although the digestive system rapidly and completely absorbed orally administered BIT, it underwent severe first-pass effects that prevented high exposure. In an oral dose escalation study (5–50 mg/kg), nonlinear pharmacokinetic properties showed that Cmax and the area under the curve (AUC) increased more than dose proportionality. In the inhalation study, the lungs of rats exposed to BIT aerosols had higher BIT concentrations than the plasma. Additionally, the pharmacokinetic profile of BIT after the dermal application was different; continuous skin absorption without the first-pass effect led to a 2.13-fold increase in bioavailability compared with oral exposure to BIT. The [14C]-BIT mass balance study revealed that BIT was extensively metabolized and excreted in the urine. These results can be used in risk assessments to investigate the relationship between BIT exposure and hazardous potential.

Descending necrotizing mediastinitis (DNM) is a rare form of mediastinal infection. Most cases are associated with esophageal rupture. DNM after a trigger point injection in the upper trapezius has not been described previously. We present a case of DNM after a trigger point injection in the upper trapezius. A 70-year-old man visited the emergency department with chest discomfort and fever after a trigger point injection in the left upper trapezius. Chest computed tomography showed evidence of DNM, and antibiotic therapy was immediately administered intravenously. Because of the risk of sudden death, poor prognosis due to underlying disease, and his age, he declined surgical treatment and died of septic shock. Although trigger point injections are generally considered safe, caution should be used in patients with an underlying disease or in the elderly. Early diagnosis, broad-spectrum antibiotics, and aggressive surgical management are essential to improve the prognosis.

Objective Bystander cardiopulmonary resuscitation (CPR) is an important factor associated with improved survival rates and neurologic prognoses in cases of out-of-hospital cardiac arrest. We assessed how factors related to CPR education including timing of education, period from the most recent education session, and content, affected CPR willingness. Methods In February 2012, trained interviewers conducted an interview survey of 1,000 Daegu citizens through an organized questionnaire. The subjects were aged ≥19 years and were selected by quota sampling. Their social and demographic characteristics, as well as CPR and factors related to CPR education, were investigated. Chi-square tests and multivariate logistic regression analyses were used to evaluate how education-related factors affected the willingness to perform CPR. Results Of total 1,000 cases, 48.0% were male. The multivariate analyses revealed several factors significantly associated with CPR willingness: didactic plus practice group (adjusted odds ratio [AOR], 3.38; 95% confidence interval [CI], 2.3 to 5.0), group with more than four CPR education session (AOR, 7.68; 95% CI, 3.21 to 18.35), interval of less than 6 months from the last CPR education (AOR, 4.47; 95% CI 1.29 to 15.52), and education with automated external defibrillator (AOR, 5.98; 95% CI 2.30 to 15.53). Conclusion The following were associated with increased willingness to perform CPR: practice sessions and automated electrical defibrillator training in public CPR education, more frequent CPR training, and shorter time period from the most recent CPR education sessions.

A change in the microstructure of Ti-Si alloys synthesized by high-energy mechanical milling through post-annealing significantly enhances their electrochemical performances as anode materials for lithium-ion batteries (LIBs). The microstructures of ball-milled and post-annealed powders are investigated using high-resolution transmission electron microscopy (HR-TEM). The Si phase is uniformly distributed on the silicide (TiSi2) matrix. The individual Si domains of the mechanical alloying (MA) sample consist of amorphous and crystalline regions with a diffuse interface between the two phases. When MA powder is annealed at 600 °C, the Si phase has a well-developed nanocrystalline microstructure: a multi-grain structure with random orientation of nanometric crystal domains. Annealing at 600 °C causes a significant improvement in electrochemical performance parameters like cycling stability and rate capability. However, when annealed at 800 °C, the electrochemical performances deteriorate due to an increase in the size of Si domains.

Nonvariceal upper gastrointestinal bleeding (NVUGIB) is a potentially life-threatening hospital emergency requiring hemodynamic stabilization and resuscitation. This study is carried out to determine whether hospital volume can influence outcome in patients with NVUGIB. This is a retrospective study with a prospective cohort database (KCT 0000514. cris.nih.go.kr). Eight teaching hospitals were divided into two different groups: high-volume centers (HVC, ≥60 NVUGIB patients/year, four clinics) and low-volume centers (LVC

Purpose: Work-related eye injuries have been reported with a variety of epidemiologic and clinical characteristics. We aimed to identify epidemiologic characteristics of work-related eye injuries and risk factors associated with severe injury in a large metropolitan city. Methods: This multicentre, retrospective, observational study used a prospective eye injury registry. We included patients with work-related eye injuries at four tertiary teaching hospitals in Daegu, South Korea, between August 2016 and July 2018. Severe injuries were defined as subjects fulfilled one or more of the following criteria: 1) presented with open globe injury; 2) required emergency eye surgery or observation after hospitalization; 3) developed eye injury-associated complications or 4) impaired final visual acuity. Results: The study included 1,424 patients. One hundred seventy-three patients (12.1%) had severe injuries. The median age and interquartile range (IQR; 25th and 75th percentiles) of the subjects were 48.0 years (IQR, 36.0–57.0), and the majority (91.9%) were male. Among the subjects, 61 patients (4.2%) suffered eye injuries despite the use of protective eyewear at the time of injury. Multivariable logistic regression analysis revealed age ≥70 years (odds ratio: 4.02, 95% confidence interval: 1.77–9.15), hammering/nailing (6.80, 2.80–16.53), and mowing (4.87, 1.77–9.15) as activities that conferred a high risk of ocular trauma with severe injury. Conclusion: Age over 70 years, hammering/nailing, and mowing were risk factors for severe injury from work-related ocular trauma. Severe eye injury could occur in spite of the use of protective eyewear; appropriate, well-fitting protective eyewear should be emphasized in the future.

We evaluated in vitro, the potential of the six pairs of ginsenoside isomers, stereoisomers at the chiral carbon on position 20, to inhibit the enzymatic activity of several UDP-glucuronosyltransferase (UGT) isoenzymes, major players in the human phase II drug metabolism. The results show that the tested six pairs of ginsenoside isomers exhibited stereoselective inhibitory effects of varying degrees on the ten UGT isoenzymes explored. Of the tested twelve stereoselective ginsenosides, 20(R)-Rg3 had the strongest inhibitory effect on the UGT1A8 isoform with the lowest IC50 value of 5.66±1.04μM. On the other hand, the (S)-isomers of Rg3 and Rh2 also exerted remarkable inhibition on UGT1A8, with IC50 values of 6.89±0.812μM and 5.85±0.821μM, respectively. Although the inhibitory effect was low, both 20(R)-PPT and 20(S)-PPT also inhibited UGT1A8 activity. Considering 1) that the relative contents of 20(R)-Rg3 in processed ginseng are high, 2) that higher exposure to (R)-isomers of ginsenosides occur in the intestine compared to that in the liver, and 3) the inhibitory effects of other ginsenosides on enzymatic activity [20(S)-Rg3, 20(S)-Rh2, 20(R)- and 20(S)-PPT], there may be a potential for herb-drug interactions between processed ginseng and UGT1A8 substrates when concomitantly administered.

Although the mortality rates for non-variceal upper gastrointestinal bleeding (NVUGIB) have recently decreased, it remains a significant medical problem. The main aim of this prospective multicenter database study was to construct a clinically useful predictive scoring system by using our predictors and compare its prognostic accuracy with that of the Rockall scoring system. Data were collected from consecutive patients with NVUGIB. Logistic regression analysis was performed to identify the independent predictors of 30-day mortality. Each independent predictor was assigned an integral point proportional to the odds ratio (OR) and we used the area under the curve to compare the discrimination ability between the new predictive model and the Rockall score. The independent predictors of mortality included age >65 years [OR 2.627; 95 % confidence interval (CI) 1.298–5.318], hemodynamic instability (OR 2.217; 95 % CI 1.069–4.597), serum blood urea nitrogen level >40 mg/dL (OR 1.895; 95 % CI 1.029–3.490), active bleeding at endoscopy (OR 2.434; 95 % CI 1.283–4.616), transfusions (OR 3.811; 95 % CI 1.640–8.857), comorbidities (OR 3.481; 95 % CI 1.405–8.624), and rebleeding (OR 10.581; 95 % CI 5.590–20.030). The new predictive model showed a high discrimination capability and was significantly superior to the Rockall score in predicting the risk of death (OR 0.837;95 % CI 0.818–0.855 vs. 0.761; 0.739–0.782; P = 0.0123). The new predictive score was significantly more accurate than the Rockall score in predicting death in NVUGIB patients. We need to prospectively validate the accuracy of this score for predicting mortality in NVUGIB patients.

Composite materials composed of titanium–silicon alloy (Ti–Si alloy) core and porous Si shell (core–shell (C/S) composite) are prepared, and their electrochemical performance as anode materials for lithium-ion batteries is reported. The C/S composites are fabricated by selective etching of the titanium silicide phase in the surface region of a Ti–Si alloy that consists of titanium silicide and Si phases. The Ti–Si alloy is mechanically alloyed (MA) by ball-milling a mixture containing elemental Si and TiH 2 . Prior to the etching treatment, some of the MA samples are annealed at temperatures ranging from 600 to 800 °C to further develop the crystalline structure; annealing leads to the increase in the crystallite size of the Si and silicide phases. Thereby, the core and shell structure of the C/S composites and their electrochemical behaviors are controlled. Electrodes prepared by blending the C/S composites with graphite show good cycle performance and rate capability.

ObjectiveThis study aimed to show the epidemiological characteristics and the difference in the risk factors and types of collision between older and younger drivers in Korea.MethodsWe collected data from the Emergency Department-based Injury In-depth Surveillance retrieved by the Korea Centers for Disease Control and Prevention from 2011 to 2015. We included injured drivers aged ≥ 18 years who were registered in the database, who were limited to drivers of four-wheeled vehicles. The enrolled patients were divided according to age into older (≥ 65 years) and younger (< 65 years) drivers. The total number of enrolled drivers was 37,511; 2,361 (6.3%) of them were older drivers. The epidemiological characteristics (e.g., age, sex, fatality rate) of traffic collision victims for 5 years were determined, and the risk factors (e.g., seat belt use) and types of collision (single- vs. multi-vehicle) between the two groups were compared.ResultsThe median age and interquartile range (IQR; 25th and 75th percentiles) of all drivers were 41.0 (IQR, 32.0-52.0), and 24,544 (65.4%) of them were men. The median age increased from 40.0 (IQR, 31.0-50.0) to 43.0 (IQR, 33.0-54.0) between 2010 and 2015 (P < 0.001). The proportion of older drivers increased from 5.0% to 8.4% annually during the study period (P < 0.001). Between 2010 and 2015, the fatality rate decreased from 3.1% to 1.2% (P = 0.287) for older drivers and from 0.9% to 0.5% (P = 0.009) for younger drivers. The proportion of single-vehicle collision (25.9% vs. 20.3%) was higher in older than in younger drivers (P < 0.001). Older drivers had a lower rate of seat-belt use than younger drivers (79.0% vs. 83.0%, P < 0.001).ConclusionsThe proportion of older drivers increased annually during the study period, and older drivers experienced more single-vehicle collision and used seat belt less frequently than younger drivers. A national policy support to reduce traffic collision in older drivers and public relation activities to enhance their seat belt use should be strengthened in the future.

Uva-ursi leaf is widely used to treat symptoms of lower urinary tract infections. Here, we evaluated the in vitro inhibitory effects of uva-ursi extracts on 10 major human UDP-glucuronosyltransferases (UGT) isoforms. Of the 10 tested UGT isoforms, uva-ursi extracts exerted the strongest inhibitory effect on UGT1A1-mediated β-estradiol 3-glucuronidation with the lowest IC50 value of 8.45 ± 1.56 μg/mL. To identify the components of uva-ursi extracts showing strong inhibitory effects against UGT1A1, the inhibitory effects of nine major constituents of the extracts were assessed. Among the tested compounds, gallotannin exerted the most potent inhibition on UGT1A1, followed by 1,2,3,6-tetragalloylglucose; both demonstrated competitive inhibition, with Ki values of 1.68 ± 0.150 μM and 3.55 ± 0.418 μM. We found that gallotannin and 1,2,3,6-tetragalloylglucose also inhibited another UGT1A1-specific biotransformation, SN-38-glucuronidation, showing the same order of inhibition. Thus, in vitro UGT1A1 inhibitory potentials of uva-ursi extracts might primarily result from the inhibitory activities of gallotannin and 1,2,3,6-tetragalloylglucose present in the extracts. However, in rats, co-administration with uva-ursi extracts did not alter the in vivo marker for UGT1A1 activity, expressed as the molar ratio of AUCSN-38 glucuronide/AUCSN-38, because plasma concentrations of gallotannin and 1,2,3,6-tetragalloylglucose may be too low to inhibit the UGT1A1-mediated metabolism of SN-38 in vivo. The poor oral absorption of gallotannin and 1,2,3,6-tetragalloylglucose in uva-ursi extracts might cause the poor in vitro-in vivo correlation. These findings will be helpful for the safe and effective use of uva-ursi extracts in clinical practice.

1. SKI3301, a standardized dried 50% ethanolic extracts of Sophora tonkinensis, contains four marker compounds (trifolirhizin, TF; (-)-maackiain, Maack; (-)-sophoranone, SPN, and (2-(2,4-dihydroxyphenyl)-5,6-methylenedioxybenzofuran, ABF), is being developed as an herbal medicine for the treatment of asthma in Korea. This study investigates the pharmacokinetic properties of SKI3301 extract in rats. 2. The dose-proportional AUCs suggest linear pharmacokinetics of TF, Maack, SPN and ABF in the SKI3301 extract intravenous dose range of 5-20 mg/kg. After the oral administration of 200-1000 mg/kg of the extract, TF and Maack exhibited non-linearity due to the saturation of gastrointestinal absorption. However, linear pharmacokinetics of SPN and ABF were observed. 3. The absorptions of TF, Maack, SPN and ABF in the extract were increased relative to those of the respective pure forms due to the increased solubility and/or the decreased metabolism by other components in the SKI3301 extract. 4. No accumulation was observed after multiple dosing, and the steady-state pharmacokinetics of TF, Maack, SPN and ABF were not significantly different from those after a single oral administration of the extract. 5. The pharmacokinetics of TF, SPN and ABF were not significantly different between male and female rats after oral administration of the extract, but a significant gender difference in the pharmacokinetics of Maack in rats was observed. 6. Our findings may help to comprehensively elucidate the pharmacokinetic characteristics of TF, Maack, SPN and ABF and provide useful information for the clinical application of SKI3301 extract.

A new, rapid, and sensitive liquid chromatography with tandem mass spectrometry method was developed for the determination of vitisin B and validated in rat plasma and urine using carbamazepine as an internal standard. The plasma (0.05 mL) or urine (0.2 mL) samples were extracted by liquid–liquid extraction with ethyl acetate and separated on an Eclipse Plus C18 column (100 × 4.6 mm, 3.5 μm) with a mobile phase consisting of acetonitrile and 0.1% formic acid water (60:40, v/v) at a flow rate of 0.7 mL/min. Detection and quantification were performed by mass spectrometry in selected reaction-monitoring mode with positive electrospray ionization. The calibration curves were recovered over the concentration ranges of 10−5000 ng/mL (correlation coefficients, r≥0.9833) in plasma and 5−2500 ng/mL (r≥0.9977) in urine, respectively. All validation data, including the specificity, precision, accuracy, recovery, and stability, conformed to the acceptance requirements. No matrix effects were observed. The developed method was successfully applied to pharmacokinetic studies of vitisin B following intravenous administration of 0.5 and 1 mg/kg and intraperitoneal injection of 5, 10, and 25 mg/kg to rats. This is the first report on the pharmacokinetic properties of vitisin B. The results provide a meaningful basis to evaluate preclinical or clinical applications of vitisin B.

In the present study, we evaluated the inhibitory potentials of finasteride for the major human hepatic UDP-glucuronosyltransferases (UGTs) (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15) in vitro using LC-MS/MS by specific marker reactions in human liver microsomes (except for UGT2B15) or recombinant supersomes (UGT2B15). Of the seven tested UGTs, finasteride potently, selectively, and competitively inhibited UGT1A4-mediated trifluoperazine-N-glucuronidation in human liver microsomes with an IC₅₀ value of 11.5 ± 1.78 μM and Ki value of 6.03 ± 0.291 μM. This inhibitory potency was similar to that of hecogenin, a well-known inhibitor of UGT1A4. However, finasteride did not seem to inhibit any of the other six UGTs: UGT1A1, UGT1A3, UGT1A6, UGT1A9, UGT2B7, or UGT2B15. Similarly, finasteride markedly inhibited UGT1A4 activity in recombinant human UGT1A4 supersomes, with a Ki value of 6.05 ± 0.410 μM. In addition, finasteride strongly inhibited UGT1A4-catalyzed imipramine-N-β-D-glucuronidation. However, on the basis of an in vitro-in vivo extrapolation, our data strongly suggested that finasteride is unlikely to cause clinically significant drug-drug interactions mediated via inhibition of the hepatic UGT enzymes involved in drug metabolism in vivo.

In this study, we evaluated inhibitory potentials of popularly-consumed berries (bilberry, blueberry, cranberry, elderberry, and raspberry ketones) as herbal supplements on UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7 in vitro. We also investigated the potential herb-drug interaction via UGT1A1 inhibition by blueberry in vivo. We demonstrated that these berries had only weak inhibitory effects on the five UGTs. Bilberry and elderberry had no apparent inhibitions. Blueberry weakly inhibited UGT1A1 with an IC50 value of 62.4±4.40 μg/mL and a Ki value of 53.1 μg/mL. Blueberry also weakly inhibited UGT2B7 with an IC50 value of 147±11.1 μg/mL. In addition, cranberry weakly inhibited UGT1A9 activity (IC50=458±49.7 μg/mL) and raspberry ketones weakly inhibited UGT2B7 activity (IC50=248±28.2 μg/mL). Among tested berries, blueberry showed the lowest IC50 value in the inhibition of UGT1A1 in vitro. However, the co-administration of blueberry had no effect on the pharmacokinetics of irinotecan and its active metabolite, SN-38, which was mainly eliminated via UGT1A1, in vivo. Our data suggests that these five berries are unlikely to cause clinically significant herb-drug interactions mediated via inhibition of UGT enzymes involved in drug metabolism. These findings should enable an understanding of herb-drug interactions for the safe use of popularly-consumed berries.

Objective Therapeutic hypothermia (TH) has become the standard strategy for reducing brain damage in the postresuscitation period. The aim of this study was to investigate current TH performance and outcomes in out-of-hospital cardiac arrest (OHCA) survivors using data from the Korean Hypothermia Network (KORHN) registry. Methods We used the KORHN registry, a web-based multicenter registry that includes 24 participating hospitals throughout the Republic of Korea. Adult comatose OHCA survivors treated with TH between 2007 and 2012 were included. The primary outcomes were neurological outcome at hospital discharge and in-hospital mortality. The secondary outcomes were TH performance and adverse events during TH. Results A total of 930 patients were included, of whom 556 (59.8%) survived to discharge and 249 (26.8%) were discharged with good neurologic outcomes. The median time from return of spontaneous circulation (ROSC) to the start of TH was 101 minutes (interquartile range [IQR], 46 to 200 minutes). The induction, maintenance, and rewarming durations were 150 minutes (IQR, 80 to 267 minutes), 1,440 minutes (IQR, 1,290 to 1,440 minutes), and 708 minutes (IQR, 420 to 900 minutes), respectively. The time from the ROSC to coronary angiography was 1,045 hours (IQR, 121 to 12,051 hours). Hyperglycemia (46.3%) was the most frequent adverse event. Conclusion More than one-quarter of the OHCA survivors (26.8%) were discharged with good neurologic outcomes. TH performance was appropriately managed in terms of the factors related to its timing, including cooling start time and rewarming duration.

1. Recently, we demonstrated that sarpogrelate is a potent and selective CYP2D6 inhibitor in vitro. Here, we evaluated the effect of sarpogrelate on the pharmacokinetics and pharmacodynamics of metoprolol in healthy subjects. 2. Nine healthy male subjects genotyped for CYP2D6*1/*1 or *1/*2 were included in an open-label, randomized, three treatment-period and crossover study. A single oral dose of metoprolol (100 mg) was administered with water (treatment A) and sarpogrelate (100 mg bid.; a total dose of 200 mg and treatment B), or after pretreatment of sarpogrelate for three days (100 mg tid.; treatment C). Plasma levels of metoprolol and α-hydroxymetoprolol were determined using a validated LC-MS/MS method. Changes in heart rate and blood pressure were monitored as pharmacodynamic responses to metoprolol. 3. Metoprolol was well tolerated in the three treatment groups. In treatment B and C groups, the AUCt of metoprolol increased by 53% (GMR, 1.53; 90% CI, 1.17-2.31) and by 51% (1.51; 1.17-2.31), respectively. Similar patterns were observed for the increase in Cmax of metoprolol by sarpogrelate. However, the pharmacodynamics of metoprolol did not differ significantly among the three treatment groups. 4. Greater systemic exposure to metoprolol after co-administration or pretreatment with sarpogrelate did not result in clinically relevant effects. Co-administration of both agents is well tolerated and can be employed without the need for dose adjustments.

The synthesis of Si nanoparticles by ultrasonication processing of porous Si powder and a novel method for preparing a high-capacity Si/C composite using this technique is reported. The porous Si powder is prepared by selectively etching the silicide phase of a Ti 24 Si 76 alloy consisting of Si and silicide phases. The particle size of the nanocrystalline Si is determined by the crystallite size of the Si and silicide phases in the alloy powder. Ultrasonication of the porous Si obtained from the mechanically alloyed Ti 24 Si 76 alloy generates nanocrystalline Si particles of size about 5 nm. Growth of the Si and silicide phases in the alloy is induced by annealing of the mechanically alloyed sample, with a consequent increase in the size of the Si particles obtained after ultrasonication. Application of the ultrasonication process to the fabrication of Si/C composite anode materials generates nanometer-scale Si particles in situ that are distributed in the matrix. Analysis of the phases obtained and evaluation of the distribution of the nanometer-scale Si particles in the composites via XRD/TEM measurements show that the nanometer-scale Si particles are effectively synthesized and uniformly distributed in the carbon matrix, leading to enhanced electrochemical performance of the Si/C composites.

We evaluated the potential of BST204, a purified dry extract of ginseng, to inhibit or induce human liver cytochrome P450 enzymes (CYPs) and UDP-glucuronosyltransferases (UGTs) in vitro to assess its safety. In vitro drug interactions of four bioactive ginsenosides of BST204, S-Rg3, R-Rg3, S-Rh2, and R-Rh2, were also evaluated. We demonstrated that BST204 slightly inhibited CYP2C8, CYP2D6, CYP2C9, and CYP2B6 activities with IC50 values of 17.4, 26.8, 31.5, and 49.7μg/mL, respectively. BST204 also weakly inhibited UGT1A1, UGT1A9, and UGT2B7 activities with IC50 values of 14.5, 26.6, and 31.5μg/mL, respectively. The potential inhibition by BST204 of the three UGT activities might be attributable to S-Rg3, at least in part, as its inhibitory pattern was similar to that of BST204. However, BST204 showed no time-dependent inactivation of the nine CYPs studied. In addition, BST204 did not induce CYP1A2, 2B6, or 3A4/5. On the basis of an in vivo interaction studies, our data strongly suggest that BST204 is unlikely to cause clinically significant drug-drug interactions mediated via inhibition or induction of most CYPs or UGTs involved in drug metabolism in vivo. Our findings offer a clearer understanding and possibility to predict drug-drug interactions for the safe use of BST204 in clinical practice.

BackgroundNationwide and regional interventions can help improve bystander cardiopulmonary resuscitation (CPR) awareness, knowledge, and the willingness. Periodic community investigation will help monitor the effect. This study aimed to compare the experience of CPR education, CPR knowledge, and CPR willingness, during a 5-year interval.MethodsThis is a pre and post study. Two surveys were done in February 2012 and December 2016. National and regional intervention including legislation promoting public involvement, standardizing CPR education programs, training CPR instructors, and installing supporting organizations were done at the period. In both surveys, respondents were selected via quota sampling in Daegu Metropolitan City and answered the survey through face-to-face interview. Respondents' general demographic characteristics, CPR educational experience, CPR knowledge and CPR willingness were questioned.ResultsTotal of 2141 respondents (1000 in 2012, 1141 in 2016) were selected. The percentage of respondents who received CPR education itself and recent education were higher after intervention compared to before intervention (36.2% vs. 55.1%, 16.9% vs. 30.1%, respectively). Correct knowledge of performing CPR seems to be improved overall (1.6% vs. 11.7%, odd ratio 14.28, 95% confidence interval 5.68-35.94). However, less respondents were willing to perform CPR on strangers (54.5% vs 35.0%).ConclusionNationwide and regional interventions to promote bystander CPR and CPR education were associated with increased CPR education experience and improved correct CPR knowledge in performing bystander CPR. Willingness to perform bystander CPR on family did not increase significantly and CPR willingness to strangers was decreased. Additional legal and technological measures should be implemented to promote bystander CPR.

A rapid, sensitive, simple and accurate LC–MS/MS method for the simultaneous quantitation of caffeine, and its three primary metabolites, theobromine, paraxanthine, and theophylline, in rat plasma was developed and validated. Chromatographic separation was performed on an Agilent Poroshell 120 EC-C18 column using 1 μg/mL acetaminophen as an internal standard. Each sample was run at 0.5 mL/min for a total run time of 7 min/sample. Detection and quantification were performed using a mass spectrometer in selected reaction-monitoring mode with positive electrospray ionization. The lower limit of quantification was 5 ng/mL for all analytes with linear ranges up to 5000 ng/mL for caffeine and 1000 ng/mL for its metabolites. The coefficient of variation for assay precision was less than 12.6%, with an accuracy of 93.5–114%. The assay was successfully applied to determine plasma concentrations of caffeine, theobromine, paraxanthine, and theophylline in rat administered various energy drinks containing the same caffeine content. Various energy drinks exhibited considerable variability in the pharmacokinetic profiles of caffeine and its three primary metabolites, even containing the same caffeine. Different additives of energy drinks might contribute to these results.

A simple, robust, and rapid LC-MS/MS method has been developed and validated for the simultaneous quantitation of clopidogrel and its active metabolite (AM) in human plasma. Tris(2-carboxyethyl)phosphine (TCEP) was used as a reducing agent to detect the AM as a disulfide-bonded complex with plasma proteins. Mixtures of TCEP and human plasma were deproteinized with acetonitrile containing 10 ng/mL of clopidogrel-d4 as an internal standard (IS). The mixtures were separated on a C18 RP column with an isocratic mobile phase consisting of 0.1% formic acid in acetonitrile and water (90:10, v/v) at a flow rate of 0.3 mL/min. Detection and quantification were performed using ESI-MS. The detector was operated in selected reaction-monitoring mode at m/z 322.0→211.9 for clopidogrel, m/z 356.1→155.2 for the AM, and m/z 326.0→216.0 for the IS. The linear dynamic range for clopidogrel and its AM were 0.05-20 and 0.5-200 ng/mL, respectively, with correlation coefficients (r) greater than 0.9976. Precision, both intra- and interday, was less than 8.26% with an accuracy of 87.6-106%. The validated method was successfully applied to simultaneously analyze clinical samples for clopidogrel and its AM.

Aim To investigate the incidence and general characteristics of sports-related eye injuries in patients visiting the Emergency Department. Methods A cross-sectional, multi-center, observational study. Patients with an injured eye who visited the Emergency Department at one of nine hospitals in Korea were enrolled. All data were prospectively collected between March and September 2010 using a questionnaire. Eye injuries that occurred during risky sports were examined by gender and age. Additionally, the rate of open globe injuries that occurred with and without protective eyewear was examined for each activity. Continuous variables were compared using Student's t-test and categorical variables were compared using Chi-square test. Results A total of 446 patients had sports-related eye injuries. Teenagers (10-19 years old) and young adults (20-29 years old) had the most eye injuries. Eye injuries accounted for 0.2% of Emergency Department patients. Baseball was the most common cause of sports-related eye injuries, followed by soccer and hiking. Protective gear was worn by 9.4% of all patients. Patients that were 30-39 years of age had the highest rate of protective gear use, followed by patients that were 40-49 years of age. The proportion of sports-related eye injuries that were open-globe injuries was highest for soccer and hiking. Conclusion Although injuries were most common in patients below the age of 10 years, these patients had the lowest rate of protective eyewear use. Injuries in adults over 40 years of age most commonly occurred during hiking, but the rate of protective eyewear use was low. Young athletes should be educated on and provided with protective eyewear and policies protective gear use should be established. For older adults, eye protection should be encouraged, especially during hiking.

Despite the widespread use of the five major xanthophylls astaxanthin, β-cryptoxanthin, canthaxanthin, lutein, and zeaxanthin as dietary supplements, there have been no studies regarding their inhibitory effects on hepatic UDP-glucuronosyltransferases (UGTs). Here, we evaluated the inhibitory potential of these xanthophylls on the seven major human hepatic UGTs (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7 and UGT2B15) in vitro by LC-MS/MS using specific marker reactions in human liver microsomes (except UGT2B15) or recombinant supersomes (UGT2B15). We also predicted potential dietary supplement-drug interactions for β-cryptoxanthin via UGT1A1 inhibition. We demonstrated that astaxanthin and zeaxanthin showed no apparent inhibition, while the remaining xanthophylls showed only weak inhibitory effects on the seven UGTs. β-Cryptoxanthin mildly inhibited UGT1A1, UGT1A3, and UGT1A4, with IC50 values of 18.8 ± 2.07, 28.3 ± 4.40 and 34.9 ± 5.98 μM, respectively. Canthaxanthin weakly inhibited UGT1A1 and UGT1A3, with IC50 values of 38.5 ± 4.65 and 41.2 ± 3.14 μM, respectively; and lutein inhibited UGT1A1 and UGT1A4, with IC50 values of 45.5 ± 4.01 and 28.7 ± 3.79 μM, respectively. Among the tested xanthophyll-UGT pairs, β-cryptoxanthin showed the strongest competitive inhibition of UGT1A1 (Ki, 12.2 ± 0.985 μM). In addition, we predicted the risk of UGT1A1 inhibition in vivo using the reported maximum plasma concentration after oral administration of β-cryptoxanthin in humans. Our data suggests that these xanthophylls are unlikely to cause dietary supplement-drug interactions mediated by inhibition of the hepatic UGTs. These findings provide useful information for the safe clinical use of the tested xanthophylls.

A liquid chromatography with atmospheric pressure chemical ionization tandem mass spectrometry method was developed and validated to investigate the pharmacokinetic properties of β-sitosterol, campesterol, and stigmasterol in rat plasma. Cholesterol-d6 was used as an internal standard. To avoid interference of the three phytosterols in rat plasma and minimize matrix effects, a small volume (10 μL) of 4% bovine serum albumin was used as a surrogate matrix for making calibrators and quality control samples. Rat plasma (10 μL) samples were extracted by liquid-liquid extraction with methyl tert-butyl ether and separated on a Kinetex C18 column. The detection was performed on a triple quadrupole tandem mass spectrometer in selected reaction monitoring mode using positive atmospheric pressure chemical ionization. This assay was linear over concentration ranges of 250-5000 ng/mL (β-sitosterol), 250-5000 ng/mL (campesterol), and 50-2000 ng/mL (stigmasterol). Additionally, a second set of quality controls made in rat plasma was also evaluated against calibration curves made using the surrogate matrix. All the validation data, including the specificity, precision, accuracy, recovery, matrix effect, stability, and incurred sample reanalysis conformed to the acceptance requirements. Our method was successfully applied to study the pharmacokinetics of three phytosterols in rats.

A new thermally cross-linkable hole injecting/transporting polymer, poly{[10-hexyl-10H-phenothiazine-3,7-diyl]-alt-[10-(6-hexyloxy-4-(2-methyl-acrylic acid benzyl ester))-10H-phenothiazine-3,7-diyl]} (PTMMA), was synthesized. From the HOMO energy level of thermally cured PTMMA (−4.95 eV), the polymer is a very good hole injection material. From the spectroscopic and electrochemical data, thermally cured PTMMA (c-PTMMA) film is very safe for the successive layer coating by the solution process. Bi-layer structured polymer light-emitting diode with c-PTMMA as a hole injection layer (HIL) and green-emitting copolymer (PF9B) as a emissive layer was fabricated successfully. The maximum efficiency and brightness of the device with c-PTMMA as a HIL (device II) are 0.34 cd/A and 854 cd/m2, respectively, which are superior to those of the device without c-PTMMA (device I, 0.039 cd/A and 228 cd/m2, respectively). Also, the turn-on electric field of device II (0.89 MV/cm) is much lower compared to that of device I (1.92 MV/cm). From the results, thermally cured PTMMA has not only good hole injection property but also good solvent resistant property for the successive layer coating.

Amlodipine besylate has been used in Korea for the treatment of hypertension for17 years, with well-established efficacy and tolerability. Amlodipine camsylate is a newer formulation developed for generic use. It has been assessed in terms of physical stability and pharmacokinetic and pharmacodynamic properties and been found to be effective in lowering blood pressure in preclinical and Phase I and II trials. However, to date, no studies have compared the clinical effectiveness of amlodipine camsylate and amlodipine besylate in treating hypertension.This study was designed to determine the effectiveness and tolerability of amlodipine camsylate compared with amlodipine besylate in Korean patients with mild to moderate hypertension.This Phase III, 8-week, prospective, randomized, double-blind, parallel-group study was conducted in 13 cardiology centers across the Republic of Korea. Male and female Korean patients aged 18 to 75 years having uncomplicated, mild to moderate, essential hypertension (sitting diastolic blood pressure [SiDBP] 90-110 mm Hg) and receiving no antihypertensives in the 2 weeks before randomization were eligible. Patients were randomly assigned to receive oral treatment with amlodipine camsylate or amlodipine besylate. For the first 4 weeks, patients received amlodipine 5 mg QD (morning). After 4 weeks, if either blood pressure wasor =140/or =90 mm Hg or SiDBP had not decreased byor =10 mm Hg from baseline, the dose of amlodipine was increased to 10 mg QD for 4 weeks. Trough blood pressure and heart rate were measured in duplicate with the patient in the sitting position at each clinic visit (baseline [week 0] and weeks 4 and 8 of treatment); mean values were calculated and recorded. At weeks 4 and 8, tolerability was assessed using history taking and laboratory analysis, and compliance was assessed using pill counts. The primary end point was change from baseline in SiDBP at week 8. Secondary end points were change from baseline in sitting systolic blood pressure (SiSBP) at week 8 in the total population and in the subgroup of patients who had previously received antihypertensive treatment versus those who had not.A total of 189 patients were enrolled (mean age, 53 years; 105 women, 84 men; mean body weight, 65.8 kg). One patient in the amlodipine camsylate group dropped out of the study at week 0 of treatment (this patient did not use any study medication) and was excluded from the modified intent-to-treat (ITT) analysis. Thus, 188 patients were treated and included in the ITT analysis (94 patients per treatment group; ITT analysis); 161 patients were included in the perprotocol (PP) analysis (n = 80 for amlodipine camsylate, n = 81 for amlodipine besylate) (14 patients in the amlodipine camsylate group and 13 patients in the amlodipine besylate group were excluded from the PP analysis due to consistent withdrawal or protocol violation). Mean (SD) SiSBP and SiDBP were significantly decreased from baseline in both groups (amlodipine camsylate, from 146.7 [12.3]/96.6 [5.4] to 127.9 [14.8]/83.4 [7.7] mm Hg [both, P0.001]; amlodipine besylate, from 146.8 [12.8]/96.7 [5.1] to 128.0 [10.1]/83.8 [7.5] mm Hg [both, P0.001]). The differences in SiSBP/SiDBP between the 2 groups at week 8 were not significant. The SiDBP response rates in the subgroups that had and had not been previously treated with antihypertensives were statistically similar (56/69 [81.2%] and 83/92 [90.2%], respectively). The prevalences of clinical adverse events (AEs) were not significantly different between the 2 treatment groups (amlodipine camsylate, 27.3 %; amlodipine besylate, 28.7%). The most common AEs were dizziness and dyspnea (both in 3/94 [3.2%] and 1/94 [1.1%] patients who received amlodipine camsylate and amlodipine besylate, respectively).The effectiveness and tolerability of amlodipine camsylate were not significantly different from those of amlodipine besylate in these Korean adults with mild to moderate hypertension.

In order to study the effect of the satisfaction level of the festival director system and perceived effectiveness on organizational effectiveness of mediation, descriptive statistical methods and multivariate statistical analysis were performed by obtaining a sample of over 350 festival officials with a focus on Seoul. The inter-item consistency was determined using Cronbach’s alpha and was more than 0.7. The reliability of the measurement instrument was good. Conducting exploratory factor analysis for the validation of measurement tools was the validity of the factor analysis measurement tool was secured. In order to investigate whether satisfaction of hypothetical festival director system and perceived effectiveness had a significant impact on the mediation of organizational effectiveness, eight sub-hypotheses were formulated analyzed with a focus on one major hypothesis. Seven of them were selected, and one was rejected. However, with regard to unexpectedly different results with the lack of previous studies, it is expected that follow-up studies will be actively conducted successful results will be obtained not only in theoretical systematization of this study area but also in practice.

Jae Hong Seo, Jung Bae Park, Woong-Kee Choi, Sunhwa Park, Yun Jin Sung, Euichaul Oh, Soo Kyung Bae College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon, South Korea Objective: Cilostazol is a Biopharmaceutical Classification System class II drug with low solubility and high permeability, so its oral absorption is variable and incomplete. The aim of this study was to prepare two sulfonate salts of cilostazol to increase the dissolution and hence the oral bioavailability of cilostazol.Methods: Cilostazol mesylate and cilostazol besylate were synthesized from cilostazol by acid addition reaction with methane sulfonic acid and benzene sulfonic acid, respectively. The salt preparations were characterized by nuclear magnetic resonance spectroscopy. The water contents, hygroscopicity, stress stability, and photostability of the two cilostazol salts were also determined. The dissolution profiles in various pH conditions and pharmacokinetic studies in rats were compared with those of cilostazol-free base.Results: The two cilostazol salts exhibited good physicochemical properties, such as nonhygroscopicity, stress stability, and photostability, which make it suitable for the preparation of pharmaceutical formulations. Both cilostazol mesylate and cilostazol besylate showed significantly improved dissolution rate and extent of drug release in the pH range 1.2–6.8 compared to the cilostazol-free base. In addition, after oral administration to rats, cilostazol mesylate and cilostazol besylate showed increases in Cmax and AUCt of approximately 3.65- and 2.87-fold and 3.88- and 2.94-fold, respectively, compared to cilostazol-free base.Conclusion: This study showed that two novel salts of cilostazol, such as cilostazol mesylate and cilostazol besylate, could be used to enhance its oral absorption. The findings warrant further preclinical and clinical studies on cilostazol mesylate and cilostazol besylate at doses lower than the usually recommended dosage, so that it can be established as an alternative to the marketed cilostazol tablet. Keywords: BCS class II, cilostazol, besylate, mesylate, acid addition reaction, dissolution

We established a rapid and simple liquid chromatography with tandem mass spectrometry method for the simultaneous determination of sarpogrelate and its active metabolite, M-1, in human plasma. Sarpogrelate, M-1, and the internal standard, ketanserin, were extracted from a 50 μL aliquot of human plasma by protein precipitation using acetonitrile. Chromatographic separation was performed on a Shim-pack GIS ODS C18 column (100 × 3.0 mm; 3 μm) with an isocratic mobile phase consisting of 10 mM ammonium acetate and acetonitrile (70:30, v/v) at a flow rate of 0.6 mL/min; the total run time was2.5 min. Mass spectrometric detection was conducted in selected reaction-monitoring mode with positive electrospray ionization at m/z 430.35 → 135.10 for sarpogrelate, m/z 330.30 → 58.10 for M-1, and m/z 395.70 → 188.85 for ketanserin. The linear ranges of concentration for sarpogrelate and M-1 were 1-1000 and 0.5-500 ng/mL, respectively. The coefficient of variation for the assay's precision was ≤9.95%, and the accuracy was 90.6-107%. All analytes were stable under various storage and handling conditions, and no relevant crosstalk and matrix effect was observed. This method was successfully applied to a pharmacokinetic study after oral administration of a 100 mg sarpogrelate tablet to healthy male Korean volunteers.

Macrolactin A (MA) and 7- O -succinyl macrolactin A (SMA), polyene macrolides containing a 24-membered lactone ring, show antibiotic effects superior to those of teicoplanin against vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus . MA and SMA are currently being evaluated as antitumor agents in preclinical studies in Korea. We evaluated the potential of MA and SMA for the inhibition or induction of human liver cytochrome P450 (CYP) enzymes and UDP-glucuronosyltransferases (UGTs) in vitro to assess their safety as new molecular entities. We demonstrated that MA and SMA are potent competitive inhibitors of CYP2C9, with K i values of 4.06 μM and 10.6 μM, respectively. MA and SMA also weakly inhibited UGT1A1 activity, with K i values of 40.1 μM and 65.3 μM, respectively. However, these macrolactins showed no time-dependent inactivation of the nine CYPs studied. In addition, MA and SMA did not induce CYP1A2, CYP2B6, or CYP3A4/5. On the basis of an in vitro-in vivo extrapolation, our data strongly suggested that MA and SMA are unlikely to cause clinically significant drug-drug interactions mediated via inhibition or induction of most of the CYPs involved in drug metabolism in vivo , except for the inhibition of CYP2C9 by MA. Similarly, MA and SMA are unlikely to inhibit the activity of UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7 enzymes in vivo . Although further investigations will be required to clarify the in vivo interactions of MA with CYP2C9-targeted drugs, our findings offer a clearer understanding and prediction of drug-drug interactions for the safe use of MA and SMA in clinical practice.

A simple, robust, and rapid LC-MS/MS method has been developed and validated for the simultaneous quantitation of clopidogrel and its active metabolite (AM) in human plasma. Tris(2-carboxyethyl)phosphine (TCEP) was used as a reducing agent to detect the AM as a disulfide-bonded complex with plasma proteins. Mixtures of TCEP and human plasma were deproteinized with acetonitrile containing 10 ng/mL of clopidogrel-d4 as an internal standard (IS). The mixtures were separated on a C18 RP column with an isocratic mobile phase consisting of 0.1% formic acid in acetonitrile and water (90:10, v/v) at a flow rate of 0.3 mL/min. Detection and quantification were performed using ESI-MS. The detector was operated in selected reaction-monitoring mode at m/z 322.0→211.9 for clopidogrel, m/z 356.1→155.2 for the AM, and m/z 326.0→216.0 for the IS. The linear dynamic range for clopidogrel and its AM were 0.05-20 and 0.5-200 ng/mL, respectively, with correlation coefficients (r) greater than 0.9976. Precision, both intra- and interday, was less than 8.26% with an accuracy of 87.6-106%. The validated method was successfully applied to simultaneously analyze clinical samples for clopidogrel and its AM.

Jee Sun Min,1 Doyun Kim,1 Jung Bae Park,1 Hyunjin Heo,1 Soo Hyeon Bae,2 Jae Hong Seo,1 Euichaul Oh,1 Soo Kyung Bae1 1Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, Bucheon, 2Department of Pharmacology, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul, South Korea Background: Evaluating the potential risk of metabolic drug–drug interactions (DDIs) is clinically important. Objective: To develop a physiologically based pharmacokinetic (PBPK) model for sarpogrelate hydrochloride and its active metabolite, (R,S)-1-{2-[2-(3-methoxyphenyl)ethyl]-phenoxy}-3-(dimethylamino)-2-propanol (M-1), in order to predict DDIs between sarpogrelate and the clinically relevant cytochrome P450 (CYP) 2D6 substrates, metoprolol, desipramine, dextromethorphan, imipramine, and tolterodine. Methods: The PBPK model was developed, incorporating the physicochemical and pharmacokinetic properties of sarpogrelate hydrochloride, and M-1 based on the findings from invitro and in vivo studies. Subsequently, the model was verified by comparing the predicted concentration-time profiles and pharmacokinetic parameters of sarpogrelate and M-1 to the observed clinical data. Finally, the verified model was used to simulate clinical DDIs between sarpogrelate hydrochloride and sensitive CYP2D6 substrates. The predictive performance of the model was assessed by comparing predicted results to observed data after coadministering sarpogrelate hydrochloride and metoprolol. Results: The developed PBPK model accurately predicted sarpogrelate and M-1 plasma concentration profiles after single or multiple doses of sarpogrelate hydrochloride. The simulated ratios of area under the curve and maximum plasma concentration of metoprolol in the presence of sarpogrelate hydrochloride to baseline were in good agreement with the observed ratios. The predicted fold-increases in the area under the curve ratios of metoprolol, desipramine, imipramine, dextromethorphan, and tolterodine following single and multiple sarpogrelate hydrochloride oral doses were within the range of ≥1.25, but

Astaxanthin, β-cryptoxanthin, canthaxanthin, lutein and zeaxanthin, the major xanthophylls, are widely used in food, medicine, and health care products. To date, no studies regarding the inhibitory effects of these xanthophylls on the nine CYPs isozymes have been reported. This study investigated the reversible and time-dependent inhibitory potentials of five xanthophylls on CYPs activities in vitro. The reversible inhibition results showed that the five compounds had only a weak inhibitory effect on the nine CYPs. Lutein did not inhibit the nine CYPs activities. Astaxanthin weakly inhibited CYP2C19, with an IC₅₀ of 16.2 μM; and β-cryptoxanthin weakly inhibited CYP2C8, with an IC₅₀ of 13.8 μM. In addition, canthaxanthin weakly inhibited CYP2C19 and CYP3A4/5, with IC₅₀ values of 10.9 and 13.9 μM, respectively. Zeaxanthin weakly inhibited CYP3A4/5, with an IC₅₀ of 15.5 μM. However, these IC₅₀ values were markedly greater than the Cmax values reported in humans. No significant IC₅₀ shift was observed in the time-dependent inhibition screening. Based on these observations, it is unlikely that these five xanthophylls from the diet or nutritional supplements alter the pharmacokinetics of drugs metabolized by CYPs. These findings provide some useful information for the safe use of these five xanthophylls in clinical practice.

In this paper, we proposed a new Physical Address Decoder using digital Hybrid demodulation techniques for the Blu-ray Disc System. The proposed new digital MSK demodulation technique and the STW demodulation technique are quite simple to realize compared to the conventional demodulation method. As a result, the hardware complexity of the physical address decoder was greatly reduced. Also, according to the experimental results, the performance of the new Physical Address Decoder proposed in this paper, was proved to be very stable and robust.

A stable modulation and demodulation technique of the physical address is essential to a HD-DVD system where the physical address is recorded in the form of a modulated wobble. Many modulation techniques have been introduced and adapted for HD-DVD experiments. Among them, the MSK (minimum shift keying) modulation is attracting more attention recently because it has many advantages for the HD-DVD system, such as continuous phase form, constant amplitude envelope, and so on. But the typical coherent MSK demodulator is composed of analog signal multipliers, integrators, and other complicated logic circuit blocks. Therefore, the hardware implementation of the demodulator is very complex and demodulation performance is quite dependent on individual devices. To solve these problems, we propose a new digital non-coherent MSK demodulation technique in this paper.

Background and Objectives: Morning hypertension is closely related to target organ damage and cardiovascular events. Little data is available concerning the baseline characteristics and comprehensive blood pressure analysis of hypertensive patients on treatment with morning hypertension. Subjects and Methods: We evaluated 1,087 hypertensive patients who had taken stable anti-hypertensive medication at least 6 months. The enrolled patients measured their home blood pressure for 7 days. Baseline characteristics and the laboratory data were analyzed. Morning hypertension was defined as a morning blood pressure ≥135/85 mm Hg and systolic or diastolic blood pressure difference between morning and evening exceeding 10 mm Hg. Results: One hundred seventy three patients with morning hypertension showed a preponderance of males, older patients, alcohol consumers, and greater waist circumference and waist-to-hip ratio despite the same body mass index. Impaired fasting glucose and metabolic syndrome were more prevalent in the patients with morning hypertension. The morn ing hypertensives took more anti-hypertensive drugs and displayed higher blood pressure in the clinic and at home. Conclusion: The worse clinical variables and relatively poorly controlled blood pressure of those with morning hypertension supports a potential relationship of morning hypertension with poor cardiovascular outcome. Morning blood pressure should be monitored at home for the optimal treatment of hypertension. (Korean Circ J 2011;41:733-743)