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.

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. @*Conclusions@#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.

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. @*Conclusions@#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.

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.

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.

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.

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.

Elevation of heart-femoral pulse wave velocity by short-term low sodium diet followed by high sodium diet in hypertensive patients with sodium sensitivity

BACKGROUND/OBJECTIVES: We compared changes in heart-femoral pulse wave velocity (hfPWV) in response to low sodium and high sodium diet between individuals with sodium sensitivity (SS) and resistance (SR) to evaluate the influence of sodium intake on arterial stiffness. SUBJECTS/METHODS: Thirty-one hypertensive and 70 normotensive individuals were given 7 days of low sodium dietary approach to stop hypertension (DASH) diet (LSD, 100 mmol NaCl/day) followed by 7 days of high sodium DASH diet (HSD, 300 mmol NaCl/day) during 2 weeks of hospitalization. The hfPWV was measured and compared after the LSD and HSD. RESULTS: The hfPWV was significantly elevated from LSD to HSD in individuals with SS (P = 0.001) independently of changes in mean arterial pressure (P = 0.037). Conversely, there was no significant elevation of hfPWV from LSD to HSD in individuals with SR. The percent change in hfPWV from the LSD to the HSD in individuals with SS was higher than that in individuals with SR. Subgroup analysis revealed that individuals with both SS and hypertension showed significant elevation of hfPWV from LSD to HSD upon adjusted analysis using changes of the means arterial pressure (P = 0.040). However, there was no significant elevation of hfPWV in individuals with SS and normotension. CONCLUSION: High sodium intake elevated hfPWV in hypertensive individuals with SS, suggesting that high sodium intake increases aortic stiffness, and may contribute to enhanced cardiovascular risk in hypertensive individuals with SS.

Elevation of heart-femoral pulse wave velocity by short-term low sodium diet followed by high sodium diet in hypertensive patients with sodium sensitivity

BACKGROUND/OBJECTIVES: We compared changes in heart-femoral pulse wave velocity (hfPWV) in response to low sodium and high sodium diet between individuals with sodium sensitivity (SS) and resistance (SR) to evaluate the influence of sodium intake on arterial stiffness. SUBJECTS/METHODS: Thirty-one hypertensive and 70 normotensive individuals were given 7 days of low sodium dietary approach to stop hypertension (DASH) diet (LSD, 100 mmol NaCl/day) followed by 7 days of high sodium DASH diet (HSD, 300 mmol NaCl/day) during 2 weeks of hospitalization. The hfPWV was measured and compared after the LSD and HSD. RESULTS: The hfPWV was significantly elevated from LSD to HSD in individuals with SS (P = 0.001) independently of changes in mean arterial pressure (P = 0.037). Conversely, there was no significant elevation of hfPWV from LSD to HSD in individuals with SR. The percent change in hfPWV from the LSD to the HSD in individuals with SS was higher than that in individuals with SR. Subgroup analysis revealed that individuals with both SS and hypertension showed significant elevation of hfPWV from LSD to HSD upon adjusted analysis using changes of the means arterial pressure (P = 0.040). However, there was no significant elevation of hfPWV in individuals with SS and normotension. CONCLUSION: High sodium intake elevated hfPWV in hypertensive individuals with SS, suggesting that high sodium intake increases aortic stiffness, and may contribute to enhanced cardiovascular risk in hypertensive individuals with SS.

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.

Influence of Simvastatin on Pharmacokinetics/Pharmacodynamics of Aspirin after Oral Co-administration in Healthy Volunteers

BACKGROUND: Both aspirin and simvastatin are prescribed as treatments or prevention of cardiovascular diseases. The aim of this study was to investigate the influence of simvastatin on pharmacokinetics and pharmacodynamics of aspirin after oral co-administration in healthy subjects. METHODS: Subjects were orally administered aspirin 100 mg for 7 days followed by co-administration of aspirin 100 mg and simvastatin 40 mg for 7 days once daily. A series of blood samples were collected before and till 24hours after drug administration on Day 1 (single-dose of aspirin), Day 7 (multiple-dose of aspirin) and Day 14 (multiple-dose of aspirin and simvastatin). The effects of simvastatin on pharmacokinetics of acetylsalicylic acid and salicylic acid were assessed with the 90 % confidence intervals (CIs) of thegeometric mean ratios (GMRs) of Day 14 over Day 7 for maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC0-24). Pharmacodynamics was assessed with maximal changes of platelet aggregation from baseline. RESULTS: Twenty-fourhealthy men aged 20 to 36 years were enrolled and 23 of them completed the study. GMRs (90 % CIs) of Cmax and AUC0-24 for acetylsalicylic acid were 1.21 (1.04 - 1.42) and 1.28 (1.19 - 1.38), respectively. For salicylic acid, GMRs of Cmax and AUC0-24 were 0.96 (0.91 - 1.00) and 1.00 (0.97 - 1.04), respectively. Maximal changes of platelet aggregation on Day 7 and Day 14 from baseline were not significantly different (p=0.41); 87.5 +/- 8.8 % and 87.3 +/- 9.2 %, respectively. CONCLUSION: Coadministration of simvastatin slightly increased the systemic exposure of acetylsalicylic acid with no changes of systemic exposure of salicylic acid or inhibition of platelet aggregation.

Ethnic Coefficients for Glomerular Filtration Rate Estimation by the Modification of Diet in Renal Disease Study Equations in the Korean Population

Race and ethnicity are influential in estimating glomerular filtration rate (GFR). We aimed to find the Korean coefficients for the Modification of Diet in Renal Disease (MDRD) study equations and to obtain novel proper estimation equations. Reference GFR was measured by systemic inulin clearance. Serum creatinine (SCr) values were measured by the alkaline picrate Jaffe kinetic method, then, recalibrated to CX3 analyzer and to isotope dilution mass spectrometry (IDMS). The Korean coefficients for the 4 and 6 variable MDRD and IDMS MDRD study equations based on the SCr recalibrated to CX3 and to IDMS were 0.73989/0.74254 and 0.99096/0.9554, respectively. Coefficients for the 4 and 6 variable MDRD equations based on the SCr measured by Jaffe method were 1.09825 and 1.04334, respectively. The modified equations showed better performances than the original equations. The novel 4 variable equations for Korean based on the SCr measured and recalibrated to IDMS were 107.904xSCr-1.009xage-0.02 (x0.667, if woman) and 87.832xSCr-0.882xage0.01 (x0.653, if woman), respectively. Modified estimations of the MDRD and IDMS MDRD study equations with ethnic coefficients and the novel equations improve the performance of GFR estimation for the overall renal function.