Prospective observational study of the impact of plasma colistin levels in patients with carbapenem-resistant Acinetobacter baumannii pneumonia.

OBJECTIVES: Colistin, an important drug to treat carbapenem-resistant Acinetobacter baumannii (CRAB) infections, has a narrow therapeutic window with nephrotoxicity. This study was conducted to determine the importance of colistin concentrations in predicting nephrotoxicity when treating CRAB pneumonia with colistin. METHODS: A prospective cohort study was performed in one teaching hospital from May 2015 to January 2018. Patients with CRAB pneumonia were treated with intravenous colistin methanesulfonate (CMS) at 2.5-5.0 mg/kg/day. On Days 3 and 4, plasma colistin and CMS concentrations were determined by six serial blood samples (immediately prior to dosing and 1 h and 4 h after the end of infusion). RESULTS: The 25 patients included in the analysis had hospital-acquired pneumonia caused by CRAB. Nephrotoxicity occurred in five patients (20%) on Day 7. There was no difference in clinical characteristics of patients with or without nephrotoxicity. The maximum plasma CMS concentration (mean ± standard deviation) was significantly higher in patients with nephrotoxicity on Day 7 than those without nephrotoxicity (15.3 ± 4.2 mg/L vs. 8.3 ± 3.8 mg/L; P = 0.014). The maximum plasma colistin concentration (Cmax,col) was significantly higher in the nephrotoxicity group on Day 7 (4.8 ± 2.0 mg/L vs. 2.1 ± 1.0 mg/L; P = 0.002). Cmax,col was lower in patients with microbiological failure than those without microbiological failure (1.92 mg/L vs. 3.01 mg/L; P = 0.038). CONCLUSION: This study confirmed that plasma levels of CMS and colistin, especially maximum levels, are important for predicting nephrotoxicity in patients with CRAB pneumonia. [ClinicalTrials.gov ID NCT02482961].

Prevalence and characteristics of isolated nocturnal hypertension in the general population.

BACKGROUND/AIMS: Ascertaining the prevalence of isolated nocturnal hypertension (INHT) in the general population and identifying the characteristics of patients with INHT may be important to determine patients who should receive 24- hour ambulatory blood pressure (BP) measurements. This study aimed to evaluate the prevalence and characteristics of INHT in the general population. METHODS: Of 1,128 participants (aged 20 to 70 years), we analyzed 823 who had valid 24-hour ambulatory BP measurements and were not on antihypertensive drug treatment. RESULTS: The prevalence of INHT in the study was 22.8%. Individuals with INHT had a higher office, 24-hour, and daytime and nighttime ambulatory systolic and diastolic BPs compared to individuals with sustained day-night normotension. INHT was more prevalent in individuals with masked hypertension (MH) than in those with sustained hypertension (59.8% vs. 15.6%, p < 0.001). Among individuals with INHT, 92.6% had MH. Among individuals with office BP-based prehypertension, 34.5% had both INHT and MH. The prevalence of INHT was highest in individuals with office BP-based prehypertension. INHT was an independent determinant of MH after adjustment for age, sex, body mass index, diabetes, low-density-lipoprotein cholesterol, 24-hour systolic and diastolic BP, systolic and diastolic BP dipping, and systolic and diastolic BP non-dipping. CONCLUSION: The present study showed that INHT is not uncommon and is a major determinant of MH. Our findings strongly suggest the use of 24-hour ambulatory BP measurement for individuals within the prehypertension range of office BP owing to the high prevalence of INHT and MH in this population.

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. Accuracies 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.

Quantitation of plasma and biliary cefpiramide concentrations in human samples using high-performance liquid chromatography.

Cefpiramide is frequently used to treat biliary infections. However, no bioanalytical method has been validated to quantitate cefpiramide in human samples, particularly in bile. Therefore, this study was conducted to develop a simple, selective and validated high-performance liquid chromatographic method to determine cefpiramide in human plasma and bile. A protein precipitation procedure was used to extract cefpiramide and cefoperazone (internal standard, IS) from 200 µl of plasma and bile. Utilizing a Capcell Pak C18 column (4.6 × 250 mm), cefpiramide and IS were separated using the timed-gradient mobile phase consisting of 0.1 m sodium acetate (pH 5.2) and acetonitrile at a flow rate of 1 ml/min with photodiode array detector (wavelength set at 273 nm). The calibration curves showed linearity at concentrations ranging from 1 to 150 µg/ml in both plasma and bile (r2 > 0.999). The within- and between-run coefficients of variation (CVs) for plasma samples were 0.570-4.43 and 1.10-2.76%, respectively; for bile samples, the within- and between-day precision (CV) was 0.814-6.34 and 2.05-4.00%, respectively. Our newly developed bioanalytical method was successfully employed to quantify cefpiramide concentrations in both plasma and bile at multiple time points in patients with acute cholangitis.

Possibility of pharmacokinetic drug interaction between a DPP-4 inhibitor and a SGLT2 inhibitor.

Type 2 diabetes mellitus is a multifactorial condition characterized by high level of sugar in the blood. To control hyperglycemia, combination therapy is recommended if monotherapy fails to achieve glycemic control. The combination of a dipeptidyl peptidase-4 (DPP-4) inhibitor and a sodium-glucose cotransporter type 2 (SGLT2) inhibitor is a promising option of the combination therapies in terms of safety as well as efficacy. Despite of the value of combination therapy of these two agents, the pharmacokinetic drug interactions between these two classes of agents have been evaluated in a few drugs. Thus, we reviewed the potential pharmacokinetic drug interaction based on the in vitro metabolism- and transporter-mediated drug interaction information as well as drug interaction studies in human, between a DPP-4 inhibitor and a SGLT2 inhibitor which are marketed in South Korea.

Quantification of metronidazole in human bile fluid and plasma by liquid chromatography-tandem mass spectrometry.

This study was conducted to develop a highly selective, sensitive, and validated method for quantifying metronidazole in human plasma and bile fluid. Metronidazole and metronidazole-d4 (internal standard) were extracted from 100 µL of plasma and bile fluid by liquid-liquid extraction. Liquid chromatography with a Hydrosphere C18 column (50 × 2.0 mm) was performed using 10 mM ammonium formate (pH 4.0) and acetonitrile (20:80, v/v) as the mobile phase. Triple quadrupole mass spectrometry was operated with an electrospray ionization interface in multiple reaction monitoring and positive ion modes. The calibration curves were linear for bile and plasma samples over the range of 50-20,000 ng/mL (r2 > 0.999). The intra- and inter-day coefficients of variation (CVs) for plasma ranged from 2.50% to 7.85% and 3.11% to 16.9%, respectively; for bile, the intra-and inter-run precision (CVs) ranged from 2.76% to 13.2% and 3.16% to 11.5%, respectively. The mean extraction recovery for metronidazole ranged from 76.5% to 82.1% in plasma and from 78.8% to 87.8% in bile, respectively. Our proposed analytical method was successfully applied to determine metronidazole concentrations in bile as well as in plasma at multiple time points in a patient with acute cholangitis.

Combined effects of Scutellaria baicalensis with metformin on glucose tolerance of patients with type 2 diabetes via gut microbiota modulation.

Metformin is a widely prescribed antidiabetic agent, whereas Scutellaria baicalensis (SB) is a commonly used medicinal herb for treatment of type 2 diabetes (T2D). Gut microbiota is involved in pathophysiology of metabolic diseases including T2D, and intestinal microbiota may be one of the important therapeutic targets for the ailment. This study was conducted to investigate the effects of SB combined with metformin on treatment of T2D while evaluating changes in the gut microbiota composition. Patients with T2D were randomized into control and treatment groups. Subjects who had already been prescribed metformin were allotted to additional SB (3.52 g/day) group or placebo group. The initial treatment session was 8 wk, and after washout period for 4 wk they were crossed over to the opposite treatment for another 8 wk. The influence of SB and placebo on the intestinal microbiota was analyzed by MiSeq system based on 16S rRNA gene. Glucose tolerance was lower in the SB group than the placebo group. Similarly, the relative RNA expression of TNF-α was significantly reduced after SB treatment. SB treatment influenced the gut microbiota, especially Lactobacillus and Akkermansia, which showed remarkable increases after SB treatment. Some subjects showed high liver enzyme levels after SB treatment, and their microbiota composition at baseline differed with subjects whose liver enzymes were not affected. We also predicted that selenocompound metabolism was increased and naphthalene degradation was decreased after SB treatment. These results suggest that SB with metformin treatment may improve the glucose tolerance and inflammation and influence the gut microbiota community in T2D.

Difference in 24-hour urine sodium excretion between controlled and uncontrolled patients on antihypertensive drug treatment.

The objective of this study was to evaluate the association between sodium intake and blood pressure (BP) control in hypertensive patients taking antihypertensive medications by using 24-hour urine collection and 24-hour ambulatory BP. This is a cross-sectional community-based study and conducted in 2011 and 2012. A total of 1128 participants were recruited from five cities in Korea. Among them, 740 participants who had complete 24-hour urine collection and valid 24-hour ambulatory BP data were included in this study. Participants were divided into four groups: normotensives (NT, n = 441), untreated hypertensive patients (UTHT, n = 174), controlled hypertensive patients (CHT, n = 62), and uncontrolled hypertensive patients (UCHT, n = 63). UCHT and CHT groups showed higher mean age than NT and UTHT groups. UCHT and UTHT groups showed higher 24-hour systolic BP (SBP) and diastolic BP (DBP) than NT and CHT groups. UCHT group had the highest level of 24-hour urine sodium. Multivariate analysis adjusted with age, gender, body mass index, estimated glomerular filtration rate, and use of diuretics showed higher level of 24-hour urine sodium in UCHT group than that in CHT group. Multivariate logistic regression analysis revealed independent association of the amount of 24-hour urine sodium with uncontrolled BP in hypertensive patients on antihypertensive drug treatment. Higher level of 24-hour urine sodium excretion in uncontrolled hypertensive patients suggests that excessive sodium intake could be associated with blunted BP lowering efficacy of antihypertensive medications.

Comparison of Salbutamol Delivery Efficiency for Jet versus Mesh Nebulizer Using Mice.

Recent reports using a breathing simulator system have suggested that mesh nebulizers provide more effective medication delivery than jet nebulizers. In this study, the performances of jet and mesh nebulizers were evaluated by comparing their aerosol drug delivery efficiencies in mice. We compared four home nebulizers: two jet nebulizers (PARI BOY SX with red and blue nozzles), a static mesh nebulizer (NE-U22), and a vibrating mesh nebulizer (NE-SM1). After mice were exposed to salbutamol aerosol, the levels of salbutamol in serum and lung were estimated by ELISA. The residual volume of salbutamol was the largest at 34.6% in PARI BOY SX, while the values for NE-U22 and NE-SM1 mesh nebulizers were each less than 1%. The salbutamol delivery efficiencies of NE-U22 and NE-SM1 were higher than that of PARI BOY SX, as the total delivered amounts of lung and serum were 39.9% and 141.7% as compared to PARI BOY SX, respectively. The delivery efficiency of the mesh nebulizer was better than that of the jet nebulizer. Although the jet nebulizer can generate smaller aerosol particles than the mesh nebulizer used in this study, the output rate of the jet nebulizer is low, resulting in lower salbutamol delivery efficiency. Therefore, clinical validation of the drug delivery efficiency according to nebulizer type is necessary to avoid overdose and reduced drug wastage.

Dose-response association of 24-hour urine sodium and sodium to potassium ratio with nighttime blood pressure at older ages.

AIMS: We investigated the dose-response association of 24-hour urine sodium and potassium with 24-hour ambulatory blood pressure. DESIGN: Cross-sectional community-based study. METHODS: Among the 1128 participants in the community-based cross-sectional survey, 740 participants (aged 20-70 years) with complete 24-hour urine collection and valid 24-hour ambulatory blood pressure monitoring were included in the study. Participants were grouped into younger (<55 years, n = 523) and older (≥55 years, n = 217). RESULTS: In the older population, nighttime blood pressure linearly increased with 24-hour urine sodium and the sodium to potassium ratio. For 24-hour urine sodium, adjusted ß was 0.171 (95% confidence interval (CI) 0.036-0.305) for nighttime systolic blood pressure and 0.144 (95% CI 0.012-0.276) for nighttime diastolic blood pressure. For the 24-hour urine sodium to potassium ratio, adjusted ß was 0.142 (95% CI 0.013-0.270) for nighttime systolic blood pressure and 0.144 (95% CI 0.018-0.270) for nighttime diastolic blood pressure. The 24-hour blood pressure linearly increased with the 24-hour urine sodium to potassium ratio and adjusted ß was 0.133 (95% CI 0.003-0.262) for 24-hour systolic blood pressure and 0.123 (95% CI 0.003-0.244) for 24-hour diastolic blood pressure. Daytime blood pressure and 24-hour systolic blood pressure showed a significant but non-linear association with 24-hour urine sodium among the older population. In the younger population, 24-hour urine sodium, potassium and the sodium to potassium ratio were not associated with ambulatory blood pressure. CONCLUSION: In the older population, 24-hour urine sodium and the sodium to potassium ratio showed a linear and positive association with nighttime blood pressure, and 24-hour urine sodium was associated with 24-hour systolic blood pressure and daytime blood pressure in a non-linear fashion.

Comparative Pharmacokinetics of a Controlled-release Pregabalin Tablet (GLA5PR GLARS-NF1) and an Immediate-release Pregabalin Capsule in Healthy Male Volunteers.

PURPOSE: Pregabalin is a widely used drug for the management of neuropathic pain. This study compared the pharmacokinetics of the GLA5PR GLARS-NF1 tablet, a 150-mg controlled-release formulation of pregabalin taken once daily, with those of a 75-mg immediate-release (IR) capsule formulation of pregabalin taken twice daily with a 12-h interval between doses. METHODS: Two separate studies, single dose and multiple dose, were conducted with a sequence-randomized, open-label crossover design. In the single-dose study, 30 participants each received 3 treatments: two 75-mg IR capsules taken 12 h apart, each after a high-fat meal (SRF treatment); a single 150-mg GLA5PR GLARS-NF1 tablet taken after a high-fat meal (STF treatment); and a single 150-mg GLAR5PR GLARS-NF1 tablet taken in an overnight-fasted state (ST treatment). In the multiple-dose study, 24 participants each received 2 treatments, both of which occurred over 3 days: one 75-mg IR capsule in the evening after a standardized meal and a second 75-mg IR capsule the following morning after a standardized meal, for 3 days (MRF treatment); and a single 150-mg GLA5PR GLARS-NF1 tablet in the evening after a standardized meal, for 3 days (MTF treatment). Blood samples for pharmacokinetic assessments were collected over the 36 h following drug administration in each treatment period. FINDINGS: In the single-dose study, the geometric mean ratios (GMRs) of the Cmax and the AUClast values of the GLA5PR GLARS-NF1 tablet to those of the IR capsules (STF/SRF) were 1.047 (90% CI, 0.971-1.129) and 0.757 (90% CI, 0.694-0.826), respectively. In the multiple-dose study, the GMRs (MTF/MRF) of the Cmax and the AUC values over the dosing interval were 1.277 (90% CI, 1.210-1.348) and 0.974 (90% CI, 0.933-1.017), respectively. The systemic pregabalin exposure from the GLA5PR GLARS-NF1 tablet was higher in the fed state than in the fasted state; GMRs (STF/ST): Cmax, 1.458 (90% CI, 1.353-1.573) and AUClast, 1.655 (90% CI, 1.518-1.804). IMPLICATIONS: The overall pregabalin exposure after multiple administrations of GLA5PR GLARS-NF1 tablets was comparable to that after multiple administrations of the IR capsules. A single administration of the GLA5PR GLARS-NF1 tablet produced lower overall pregabalin exposure than that of the same dose administered in 2 IR capsules taken every 12 h. A high-fat diet significantly increased the bioavailability of the GLA5PR GLARS-NF1 tablet. ClinicalTrials.gov identifiers: NCT01638273 and NCT02326987.

Utility of Integrated Analysis of Pharmacogenomics and Pharmacometabolomics in Early Phase Clinical Trial: A Case Study of a New Molecular Entity.

In this report, we present a case study of how pharmacogenomics and pharmacometabolomics can be useful to characterize safety and pharmacokinetic profiles in early phase new drug development clinical trials. During conducting a first-in-human trial for a new molecular entity, we were able to determine the mechanism of dichotomized variability in plasma drug concentrations, which appeared closely related to adverse drug reactions (ADRs) through integrated omics analysis. The pharmacogenomics screening was performed from whole blood samples using the Affymetrix DMET (Drug-Metabolizing Enzymes and Transporters) Plus microarray, and confirmation of genetic variants was performed using real-time polymerase chain reaction. Metabolomics profiling was performed from plasma samples using liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. A GSTM1 null polymorphism was identified in pharmacogenomics test and the drug concentrations was higher in GSTM1 null subjects than GSTM1 functional subjects. The apparent drug clearance was 13-fold lower in GSTM1 null subjects than GSTM1 functional subjects (p ＜ 0.001). By metabolomics analysis, we identified that the study drug was metabolized by cysteinylglycine conjugation in GSTM functional subjects but those not in GSTM1 null subjects. The incidence rate and the severity of ADRs were higher in the GSTM1 null subjects than the GSTM1 functional subjects. Through the integrated omics analysis, we could understand the mechanism of inter-individual variability in drug exposure and in adverse response. In conclusion, integrated multi-omics analysis can be useful for elucidating the various characteristics of new drug candidates in early phase clinical trials.

A Pharmacometabolomic Approach to Predict Response to Metformin in Early-Phase Type 2 Diabetes Mellitus Patients.

Metformin is a first-line medication for type 2 diabetes mellitus (T2DM). Based on its universal use, the consideration of inter-individual variability and development of predictive biomarkers are clinically significant. We aimed to identify endogenous markers of metformin responses using a pharmacometabolomic approach. Twenty-nine patients with early-phase T2DM were enrolled and orally administered metformin daily for 6 months. A total of 22 subjects were included in the final analysis. Patients were defined as responders or non-responders based on changes in their glycated haemoglobin A1c (HbA1c) from baseline, over 3 months. Urine metabolites at baseline, as well as at the 3 and 6 month follow-ups after the start of treatment were analysed using gas chromatography-mass spectrometry and evaluated with multivariate analyses. Metabolites distinguishable between the two response groups were obtained at baseline, as well as at the 3 and 6 month follow-ups, and significantly different metabolites were listed as markers of metformin response. Among the identified metabolites, citric acid, myoinositol, and hippuric acid levels showed particularly significant differences between the non-responder and responder groups. We thus identified different metabolite profiles in the two groups of T2DM patients after metformin administration, using pharmacometabolomics. These results might facilitate a better understanding and prediction of metformin response and its variability in individual patients.

Survey on the undergraduate curriculum in clinical pharmacology and interns' prescribing ability in South Korea.

Appropriate prescription writing is one of the critical medical processes affecting the quality of public health care. However, this is a complex task for newly qualified intern doctors because of its complex characteristics requiring sufficient knowledge of medications and principles of clinical pharmacology, skills of diagnosis and communication, and critical judgment. This study aims to gather data on the current status of undergraduate prescribing education in South Korea. Two surveys were administered in this study: survey A to 26 medical schools in South Korea to gather information on the status of undergraduate education in clinical pharmacology; and survey B to 244 intern doctors in large hospitals to gather their opinions regarding prescribing education and ability. In survey A, half of the responding institutions provided prescribing education via various formats of classes over two curriculums including lecture, applied practice, group discussions, computer-utilized training, and workshops. In survey B, we found that intern doctors have the least confidence when prescribing drugs for special patient populations, especially pregnant women. These intern doctors believed that a case-based practical training or group discussion class would be an effective approach to supplement their prescribing education concurrently or after the clerkship in medical schools or right before starting intern training with a core drug list. The results of the present study may help instructors in charge of prescribing education when communicating and cooperating with each other to improve undergraduate prescribing education and the quality of national medical care.

Visual Fatigue Induced by Viewing a Tablet Computer with a High-resolution Display.

PURPOSE: In the present study, the visual discomfort induced by smart mobile devices was assessed in normal and healthy adults. METHODS: Fifty-nine volunteers (age, 38.16 ± 10.23 years; male : female = 19 : 40) were exposed to tablet computer screen stimuli (iPad Air, Apple Inc.) for 1 hour. Participants watched a movie or played a computer game on the tablet computer. Visual fatigue and discomfort were assessed using an asthenopia questionnaire, tear film break-up time, and total ocular wavefront aberration before and after viewing smart mobile devices. RESULTS: Based on the questionnaire, viewing smart mobile devices for 1 hour significantly increased mean total asthenopia score from 19.59 ± 8.58 to 22.68 ± 9.39 (p < 0.001). Specifically, the scores for five items (tired eyes, sore/aching eyes, irritated eyes, watery eyes, and hot/burning eye) were significantly increased by viewing smart mobile devices. Tear film break-up time significantly decreased from 5.09 ± 1.52 seconds to 4.63 ± 1.34 seconds (p = 0.003). However, total ocular wavefront aberration was unchanged. CONCLUSIONS: Visual fatigue and discomfort were significantly induced by viewing smart mobile devices, even though the devices were equipped with state-of-the-art display technology.

The Effect of Genetic Polymorphisms in SLCO2B1 on the Lipid-Lowering Efficacy of Rosuvastatin in Healthy Adults with Elevated Low-Density Lipoprotein.

Rosuvastatin is an HMG-CoA reductase inhibitor widely used for treating hypercholesterolaemia. We investigated whether genetic polymorphisms in solute carrier organic anion transporter 2B1 (SLCO2B1) affect the lipid-lowering effect of rosuvastatin in healthy adults with elevated low-density lipoprotein (LDL). This study included 18 volunteers with LDL levels above 130 mg/dL. Rosuvastatin (20 mg) was administered once a day for 8 weeks. Blood samples were drawn before and after the 8-week treatment to measure changes in lipid levels. The presence of single nucleotide polymorphisms (SNPs) of SLCO2B1 (c.935G>A and c.1457C>T), SLCO1B1 (c.521C>T, c.388A>G and c.-11187G>A) and ABCG2 (c.421C>A) was determined by genotyping. Responses to rosuvastatin were compared between wild-type and variant genotypes using permutation test on each polymorphism. In volunteers with SLCO2B1 c.935G>A (rs12422149) variant, rosuvastatin was less effective at lowering LDL (mean % decrease: GG 62.8% GA 50.6% AA 49.3%, p = 0.012) and apoprotein B (mean % decrease: GG 52.1% GA 42.8% AA 42.8%, p = 0.036). Regarding SLCO2B1 c.1457C>T (rs2306168) SNP, there was no significant difference between wild-type and variant genotypes. This study demonstrated that SLCO2B1 c.935G>A (rs12422149) polymorphism influenced the lipid-lowering effects of rosuvastatin in volunteers with hypercholesterolaemia.

A first-in-human, double-blind, placebo-controlled, randomized, dose escalation study of DWP05195, a novel TRPV1 antagonist, in healthy volunteers.

OBJECTIVES: DWP05195 is a transient receptor potential vanilloid 1 (TRPV1) antagonist developed for managing pain. The purpose of this study was to evaluate the pharmacodynamics pharmacokinetics, safety, and tolerability of DWP05195 in healthy subjects. This was a first-in-human randomized, double-blinded, placebo-controlled, dose escalation study. SUBJECTS AND METHODS: DWP05195 or placebo was administered as a single dose of 10-600 mg in the single-dose study and as 100-400 mg once daily for 8 days in the multiple-dose studies. Each study group consisted of 10 subjects (study drug-to-placebo ratio was 8:2). For pharmacodynamics assessment, the heat pain threshold (HPtr), heat pain tolerance (HPtol), perfusion intensity, and flare area ratio of cutaneous blood flow were measured. Safety and tolerability were evaluated throughout the study. RESULTS: The maximum plasma concentrations and area under the plasma concentration-time curve from zero to the last measurable time dose-dependently increased. HPtr and HPtol tended to increase more after DWP05195 administration than after placebo administration. HPtr and HPtol tended to dose-dependently increase after administration of DWP05195. Cutaneous blood flow was reduced as the dose of DWP05195 increased during the multiple-dose study. DWP05195 was well tolerated up to 600 and 400 mg single- and multiple-dose administrations, respectively. CONCLUSION: The pharmacological activity of DWP05195, measured using HPtr and HPtol, increased as expected in a dose-dependent manner owing to increased systemic exposure, indicating that DWP05195 can be used as a TRPV1 antagonist for pain management.

Relationship between 24-h urine sodium/potassium ratio and central aortic systolic blood pressure in hypertensive patients.

Studies evaluating the relationship between measured 24-h urine sodium (24HUNa), potassium (24HUK) and aortic blood pressure (BP) are rare, and no such study has been performed with an Asian population. We evaluated the relationship between 24HUNa, 24HUK, casual BP, 24-h ambulatory BP and aortic BP by analyzing data from 524 participants with valid 24-h urine collection, 24-h ambulatory BP and central BP measurements (mean age 48.1±9.8 years, 193 men). Hypertension was defined as a 24-h ambulatory BP ⩾130/80 mm Hg or current treatment for hypertension (n=219). The participants with hypertension and high 24HUNa (mean 210.5±52.0 mmol per day, range 151.0-432.0) showed higher 24-h systolic (P=0.037) and diastolic BP (P=0.037) and aortic systolic BP (AoSBP, P=0.038) than the participants with hypertension and low 24HUNa (mean 115.7±25.0 mmol per day, range 45.6-150.0), adjusted for confounders. The participants with hypertension and a high ratio of 24HUNa and 24HUK (24HUNa/24HUK, mean 4.03±1.00, range 2.93-7.96) had higher AoSBP than the participants with hypertension and a low 24HUNa/24HUK ratio (mean 2.13±0.54, range 0.53-2.91), adjusted for confounders (P=0.026). The participants with hypertension demonstrated a significant linear relationship between AoSBP and 24HUNa/24HUK ratio that was independent of 24HUNa, according to the multiple regression analysis (P=0.047). In hypertensive patients, 24HUNa/24HUK was positively and more strongly related to AoSBP compared with 24HUNa alone. The result indicates that high sodium and low potassium intake may increase the subsequent risk of cardiovascular disease by elevating AoSBP.

Estimating 24-Hour Urine Sodium From Multiple Spot Urine Samples.

The authors developed an equation to estimate 24-hour urine sodium (24HUNa) using the average of three spot urine (SU) samples (morning-first, morning, and evening) from 74 individuals and validated this equation using the average of three SU samples (morning-first, daytime, and evening) from 174 additional individuals. Compared with previously published equations using a single SU sample, the currently developed equation using the average of three SU samples showed much lower bias from measured 24HUNa (-2.9 vs >10 mmol/24 h). The intraclass and concordance correlation coefficients of the proposed equation using the average of three SU samples were 0.909 and 0.832, respectively. The limits of agreement were -64.1-58.3 mmol/24 h and approximately 100 mmol/24 h for the currently developed and previously published equations, respectively. All equations showed a tendency to overestimate or underestimate 24HUNa in a manner dependent on the level of 24HUNa but irrespective of the number of SU samples considered. Nonetheless, among the currently tested equations, our equation using the average of three SU samples provided the best estimation of 24HUNa at a population level.

Prevalence of Masked Hypertension: a Population-Based Survey in a Large City by Using 24-Hour Ambulatory Blood Pressure Monitoring.

BACKGROUND AND OBJECTIVES: We estimated the prevalence of hypertension and hypertension subtypes in a large semi-urban city in Korea, using 24-hour ambulatory blood pressure monitoring (ABPM) in a randomly selected sample population. SUBJECTS AND METHODS: A random sample (aged 20-65 years) from a city with an adult population of approximately 600000 was selected by using a list-assisted random digit dialing method. The 24-hour ABPM and conventional blood pressure measurement (CBPM) of these individuals were obtained. RESULTS: Among the 496 participants, valid 24-hour ABPM and CBPM were obtained from 462 (93%) individuals. The estimated prevalence of hypertension in Goyang was 17.54% by CBPM and 32.70% by 24-hour ABPM (p<0.01). In the age stratified analysis, both CBPM and 24-hour ABPM showed increased prevalence of hypertension with age. The estimated prevalence of masked hypertension was 16.22% and that of white-coat hypertension was 1.08%. Men had a higher prevalence of masked hypertension than women (20.79% vs. 11.86%, p=0.0295). The estimated prevalence of masked hypertension was 17.5%, 20.58%, 24.34%, and 13.29% in the age categories of 30s, 40s, 50s, and 60s, respectively. The estimated prevalence of masked uncontrolled hypertension was 26.79% in patients with hypertension who were taking antihypertensive medications. CONCLUSION: The estimated prevalence of hypertension by 24-hour ABPM was higher than that by CBPM, revealing high prevalence of masked hypertension. The high prevalence of masked hypertension supports the adoption of ABPM in the national population survey and clinical practice to improve public health and reduce health care costs.