Predicting the systemic exposure and lung concentration of nafamostat using physiologically-based pharmacokinetic modeling

Nafamostat has been actively studied for its neuroprotective activity and effect on various indications, such as coronavirus disease 2019 (COVID-19). Nafamostat has low water solubility at a specific pH and is rapidly metabolized in the blood. Therefore, it is administered only intravenously, and its distribution is not well known. The main purposes of this study are to predict and evaluate the pharmacokinetic (PK) profiles of nafamostat in a virtual healthy population under various dosing regimens. The most important parameters were assessed using a physiologically based pharmacokinetic (PBPK) approach and global sensitivity analysis with the Sobol sensitivity analysis. A PBPK model was constructed using the SimCYP® simulator. Data regarding the in vitro metabolism and clinical studies were extracted from the literature to assess the predicted results. The model was verified using the arithmetic mean maximum concentration (Cmax), the area under the curve from 0 to the last time point (AUC0-t), and AUC from 0 to infinity (AUC0-∞) ratio (predicted/observed), which were included in the 2-fold range. The simulation results suggested that the 2 dosing regimens for the treatment of COVID-19 used in the case reports could maintain the proposed effective concentration for inhibiting severe acute respiratory syndrome coronavirus 2 entry into the plasma and lung tissue. Global sensitivity analysis indicated that hematocrit, plasma half-life, and microsomal protein levels significantly influenced the systematic exposure prediction of nafamostat. Therefore, the PBPK modeling approach is valuable in predicting the PK profile and designing an appropriate dosage regimen.

Bioanalytical methods for the detection of duloxetine and thioctic acid in plasma using ultra performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS)

Duloxetine and thioctic acid (TA) are standard drugs for treating diabetic neuropathy, a primary complication associated with diabetes. In this study, ultra performance liquid chromatography coupled with tandem mass spectrometry methods was successfully developed and validated for quantifying duloxetine and TA in biological samples. The protein precipitation method was used to extract duloxetine, TA and their internal standards from beagle dog plasma. A Hypersil Gold C18 column (150 × 2.1 mm, 1.9 μm) was used for the experiment. Isocratic elution with 0.1% formic acid in acetonitrile (A) and 0.1% formic acid (B) was used for duloxetine, whereas a gradient elution with 0.03% acetic acid (A) and acetonitrile (B) was used for TA. The validated parameters included linearity, sensitivity, accuracy, precision, selectivity, matrix effect, stability, and recovery under different conditions. The linear ranges of the calibration curves for duloxetine and TA were 5–800 ng/mL and 5–1,000 ng/mL, respectively. An intra- and inter-run precision of ± 15% can be observed in all quality control samples. These methods were successfully used for pharmacokinetics (PKs) studies in beagle dogs to compare PK differences in a fixed-dose combination including duloxetine and TA and co-administration of the 2 drugs.

Determination of candesartan or olmesartan in hypertensive patient plasma using UPLC-MS/MS

Candesartan and olmesartan are angiotensin II receptor blockers (ARBs) used for the treatment of hypertension and heart failure. Quantitation methods for candesartan and olmesartan were developed using ultra-high performance liquid chromatography-tandem mass spectrometry following protein precipitation. Candesartan was separated using 5 mM ammonium formate (A) and 100% acetonitrile (B) and olmesartan was separated using 2 mM ammonium formate with 0.1% formic acid (A) and 100% acetonitrile (B). Separation was performed using an isocratic method with a Thermo hypersil GOLD C18 column. Electrospray ionization was used for analyte ionization and detection of candesartan, olmesartan, and the internal standards by multiple reaction monitoring. Developed method showed excellent linearity (r > 0.99) in the concentration range of 2–500 ng/mL for candesartan and 5–2,500 ng/mL for olmesartan. were 86.70–108.8% for candesartan and 87.87–112.6% for olmesartan. These methods were able to successfully measure plasma candesartan or olmesartan concentrations in hypertensive patients. This study can be used for pharmacokinetic studies of candesartan or olmesartan in humans.

Physiologically-based pharmacokinetic model for clozapine in Korean patients with schizophrenia

Clozapine has been used as a treatment of schizophrenia. Despite its large interindividual variability, few reports addressed the physiologically-based pharmacokinetic modeling and simulation (PBPK M&S) of clozapine in patients. This study aimed to develop a PBPK M&S of clozapine in Korean patients with schizophrenia. PBPK modeling for clozapine was constructed using a population-based PBPK platform, the SimCYP® Simulator (V19;Certara, Sheffield, UK). The PBPK model was developed by optimizing the physiological parameters of the built-in population and compound libraries in the SimCYP® Simulator. The model verification was performed with the predicted/observed ratio for pharmacokinetic parameters and visual predictive checks (VPCs) plot. Simulations were performed to predict toxicities according to dosing regimens. From published data, 230 virtual trials were simulated for each dosing regimen. The predicted/observed ratio for the area under the curve and peak plasma concentration was calculated to be from 0.78 to 1.34. The observation profiles were within the 5th and 95th percentile range with no serious model misspecification through the VPC plot. A significant impact on age and gender was found for clozapine clearance. The simulation results suggested that 150 mg twice a day and 150 mg three times a day of clozapine have toxicity concerns. In conclusion, a PBPK model was developed and reasonable parameters were made from the data of Korean patients with schizophrenia. The provided model might be used to predict the pharmacokinetics of clozapine and assist dose adjustment in clinical settings.

Quantification of apixaban in human plasma using ultra performance liquid chromatography coupled with tandem mass spectrometry

Apixaban, an inhibitor of direct factor Xa, is used for the treatment of venous thromboembolic events or prevention of stroke. Unlike many other anticoagulant agents, it does not need periodic monitoring. However, monitoring is still required to determine the risk of bleeding due to overdose or surgery. Usually, apixaban concentrations are indirectly quantified using an anti-factor Xa assay. However, this method has a relatively narrow analytical concentration range, poor selectivity, and requires an external calibrator. Therefore, the goal of current study was to establish an analytical method for determining plasma levels of apixaban using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). To this end, apixaban was separated using 2.5 mM ammonium formate (pH 3.0) (A) and 100% methanol containing 0.1% formic acid (B) using the gradient method with a Thermo hypersil GOLD column. The mass detector condition was optimized using the electrospray ionization (ESI) positive mode for apixaban quantification. The developed method showed sufficient linearity (coefficient of determination [r² ≥ 0.997]) at calibration curve ranges. The percentage (%) changes in accuracy, precision, and all stability tests were within 15% of the nominal concentration. Apixaban concentration in plasma from healthy volunteers was quantified using the developed method. The mean maximum plasma concentration (C(max)) was 371.57 ng/mL, and the median time to achieve the C(max) (T(max)) was 4 h after administration of 10 mg apixaban alone. Although the results showed low extraction efficiency (~16%), the reproducibility (% change was within 15% of nominal concentration) was reliable. Therefore, the developed method could be used for clinical pharmacokinetic studies.

Determination of donepezil in human plasma using ultra performance liquid chromatography-tandem mass spectrometry

An ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the quantification of donepezil in human plasma. Donepezil and donepezil-D4 were extracted from human plasma by liquid-liquid extraction using a mixture of hexane and ethyl acetate (70:30 v/v). The extracted samples were analyzed using a Thermo Hypersil Gold C18 column with 5% acetic acid in 20 mM ammonium acetate buffer (pH 3.3) and 100% acetonitrile as a mobile phase with the 60:40 (v:v) isocratic method, at a flow rate of 0.3 mL/min. The injection volume was 3 µL, and the total run time was 3 min. Inter- and intra-batch accuracies ranged from 98.0% to 110.0%, and the precision was below 8%. The developed method was successfully applied to the quantification of donepezil in human plasma. The mean (standard deviation) maximum concentration and the median (range) time to maximum concentration were 8.6 (2.0) ng/mL and 2.0 h (1.0~5.0 h), respectively, in healthy Koreans after oral administration of 5 mg donepezil.

Development of a UPLC-MS/MS method for the therapeutic monitoring of L-asparaginase

This study aimed to develop a UPLC-MS/MS method for determining plasma levels of L-aspartic acid and L-asparagine and the activity of L-asparaginase. L-aspartic acid, L-asparagine, and L-aspartic acid-2,3,3-d3 were extracted from human plasma by protein precipitation with sulfosalicylic acid (30%, v/v). The plasma samples were analyzed using an Imtakt Intrada amino acid analysis column with 25 mM ammonium formate and 0.5% formic acid in acetonitrile as the mobile phase with step gradient method at a flow rate of 0.5 mL/min. The injection volume was 5 µL, and the total run time was 15 min. Inter- and intra-batch accuracies (%) ranged from 96.62–106.0% for L-aspartic acid and 89.85–104.8%, for L-asparagine, and the coefficient of variation (CV%) did not exceed 7%. The validation results for L-aspartic acid and L-asparagine satisfied the specified criterion, however, the results for L-asparaginase activity assay showed a borderline validity. This study could be a foundation for further development of therapeutic drug monitoring systems using UPLC-MS/MS.

The Effect of a Hospital Life Guidance Movie for Elderly In-patients / 기본간호학회지

PURPOSE: This study was done to determine how a hospital life guidance movie enhanced the understanding of hospital life by elderly in-patients. METHOD: A non-equivalent control group post-test design was used for the study. The experimental group watched a movie on guidance for hospital life while an in-patient control group read corresponding guidance booklets. The understanding and satisfaction from the respective programs for the two groups were surveyed with a questionnaire. The data were analyzed using SPSS. RESULTS: The group which watched the movie had a better understanding of hospital life than the group which read the booklets. The patients who watched the movie also expressed more satisfaction with their guide program than the patients who only read the booklets. Understanding of hospital life had relevance to satisfaction with the given program. CONCLUSION: The results of this study suggests that a movie on hospital life provides better guidance which helps the prospective patients understand and adapt better to their hospital life. Therefore, this type of movie is considered to be an effective medium to provide guidance to elderly in-patients.

Influence of Different Methods of Cutting Ampules on Drug Contamination by Glass Flakes from the Ampule / 기본간호학회지

PURPOSE: This study was done to examine how medication contamination in a single-dose glass ampule is affected by minute glass flakes generated in different methods of cutting the ampule. METHOD: Sixty medicationcontaining glass ampules were randomly assigned to two groups. The number of glass flakes, resulting from two different cutting methods (with cotton and without cotton), were counted under the microscope. Contamination was evaluated by extracted the medication with a syringe and culturing it in E. coli, coliform, and aerobic bacteria culture media. Result: Fewer glass flakes were found in the ampules when the ampule was cut with cotton. The use of cotton, however, did not significantly change the degree of drug contamination. CONCLUSION: Although minute glass flakes generated in the ampule cutting operation did not significantly contaminate the medication and the use of cotton decreased the number of glass flakes in the ampules, glass flakes injected into the blood and tissues of the patient remain a risk factor. Therefore, pre-filled syringes or syringes with filters would be alternative methods and safeguards against the possible injection of glass flakes generated while cutting the ampule.

The Effect of Music Therapy on the Physiological and Psychological Status of Women College Students Based on Their Preference of Music / 성인간호학회지

PURPOSE: This study was intended to determine how the choice of music affects the physiological and psychological status of women college student during music therapy. METHODS: A nonequivalent experimental group pretest-posttest design was used. 19 out of 54 subjects were assigned to listen to their favorite music and 17 to their unfavorite music for 20 minutes using MP3 players and headphones. Anxiety, blood pressure, pulse and blood glucose levels of the subjects were measured before treatment. The data was analyzed by Mann-Whitney and Wilcoxon signed rank test using the SPSS/WIN 10.0 program. RESULTS: The result showed that systolic blood pressure, blood glucose and anxiety level decreased significantly in the favorite music group. however systolic blood pressure, pulse rate and anxiety level increased significantly in the unfavorite music group. The favorite music group showed a significantly higher level of satisfaction than the unfavorite music group. CONCLUSION: Choice of music affects the physiological and psychological status of an individual. Favorite music listening would enhance the effect of music therapy. Therefore, selection of music must be considered in light of the subject's preference and characteristics.

The Effect of Music Therapy on the Physiological and Psychological Status of Women College Students Based on Their Preference of Music / 성인간호학회지

PURPOSE: This study was intended to determine how the choice of music affects the physiological and psychological status of women college student during music therapy. METHODS: A nonequivalent experimental group pretest-posttest design was used. 19 out of 54 subjects were assigned to listen to their favorite music and 17 to their unfavorite music for 20 minutes using MP3 players and headphones. Anxiety, blood pressure, pulse and blood glucose levels of the subjects were measured before treatment. The data was analyzed by Mann-Whitney and Wilcoxon signed rank test using the SPSS/WIN 10.0 program. RESULTS: The result showed that systolic blood pressure, blood glucose and anxiety level decreased significantly in the favorite music group. however systolic blood pressure, pulse rate and anxiety level increased significantly in the unfavorite music group. The favorite music group showed a significantly higher level of satisfaction than the unfavorite music group. CONCLUSION: Choice of music affects the physiological and psychological status of an individual. Favorite music listening would enhance the effect of music therapy. Therefore, selection of music must be considered in light of the subject's preference and characteristics.

Effects of the Respiration Exercise Program through the Pan-flute on the Physiological and Psychological Status of the Elderly / 성인간호학회지

PURPOSE: This study was intended for the enhancement of the elderly's quality of life helping them overcome their physiological changes about aging and reinforcing their vitality. METHODS: An nonequivalent control group post-test design was used for the study. The methods to perform the abdominal respiration exercise and to blow the pan-flute were demonstrated to 31 experimental subjects and 36 control subjects. The eight-week 30 minute daily home respiration exercise recipes were prescribed to the subjects. Mobile spirometers were used to measure FVC, FEV1, FFV1 / FVC, SaO2, breathing discomfort. Daily life satisfaction scores were recorded. Music therapy accompanied the eight-week respiration program. A post-test was performed in the same manner as the pre-test. The gathered data were analysed by SPSS/WIN program. RESULTS: 1) The pulmonary function and daily life satisfaction were significantly improved in the experimental group. 2) Both the experimental and control groups did not show significant differences in SaO2. 3) The breathing discomfort was significantly reduced in the experimental group. CONCLUSION: The respiration exercise program for the elderly through the pan-flute improves the respiration activity of the elderly and enhances their daily life satisfaction scores. Therefore, this program produces effects in enhancing the quality of life for the elderly.

Effects of Taping Therapy on the Deformed Angle of the Foot and Pain in Hallux Valgus Patients / 간호학회지

PURPOSE: This study was to examine the effects of Taping therapy on the deformed angle of the foot and pain in hallux valgus patients. METHOD: The subjects were 24 feet from 15 patients who were diagnosed withhallus valgus at the orthopedic department of K University Hospital in Seoul. Taping therapy was conducted 15 times overall during a four-week period. Data was analyzed using descriptive statistics and t-test. RESULT: The deformed angle of the foot of the hallus valgus patients significantly improved from 21.95(4.38) to 18.75(4.80) after Taping therapy. Pain significantly decreased from 4.73(1.56) to 3.45(2.21) after Taping therapy. CONCLUSION: The result shows that Taping therapy is effective in improving the deformed angle of the foot and in decreasing pain in the hallux valgus patients.

A Study on the Elderly Patients Hospitalized by the Fracture from the Fall / 간호학회지

PURPOSE: To identify age, gender, medication, seasons and place of fall, and areas of the fractures from the fall among the hospitalized elderly patients in order to provide the basic data for future fall prevention program for the elderly. METHODS: This study was conducted for 106 elderly patients admitted into a university hospital by fractures from the fall during the period from January 1, 1999 to December 31, 1999. Data on the age, gender, medication, season and place of the fall, areas of the fracture were collected based on their medical records. RESULT: The age range of the subjects were from 60 to 96 years old. The subjects were aged between 60-69 years old 49(46.2%), between 70-79 years old 31(29.2%), between 80-89 years old 24(22.6%), and over 90 years old 2(1.9%). Male patients comprised was 34(28.3%), while female patients comprised 76(71.7%). The fall occurred in Winter most frequently 34(32%). The place of the fall included room 81(76.4%), streets 13(12.3%), bathroom 6(5.7%), stair 4(3.8%), and mountain 2(1.9%). Twenty-two subjects (20.8%) had medication regularly, while 84 subjects (79.2%) had no medication. The areas of the fracture from the fall included upper extremities 20(18.9%) and lower extremities 86(81.1%). Radius fracture (7.5%) was the area where the fracture occurred most frequently in upper extremities and femur fracture (52.8%) was the area where the fracture occurred most frequently in lower extremities. A significant difference was found in the fracture area by age, season and place of the fall (p<.05). No significant difference was found in the fracture area by gender and medication. In all age groups, seasons and places of the fall, occurrence of fracture in lower extremity was significantly higher than that in upper extremity.