Pharmacokinetic and pharmacodynamic drug-drug interactions between evogliptin and empagliflozin or dapagliflozin in healthy male volunteers.

Evogliptin (EV) is a novel dipeptidyl peptidase-4 inhibitor (DPP4i) for glycemic control in patients with type 2 diabetes mellitus (T2DM). This study evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) interactions between EV and sodium glucose cotransporter-2 inhibitors (SGLT2i) in healthy volunteers since combination therapy of DPP4i and SGLT2i has been considered as an effective option for T2DM treatment. A randomized, open-label, multiple-dose, two-arm, three-period, three treatments, two-sequence crossover study was conducted in healthy Korean volunteers. In arm 1, subjects were administered 5 mg of EV once daily for 7 days, 25 mg of empagliflozin (EP) once daily for 5 days, and the combination once daily for 5 days (EV + EP). In arm 2, subjects were administered 5 mg of EV once daily for 7 days, 10 mg of dapagliflozin (DP) once daily for 5 days, and the combination once daily for 5 days (EV + DP). Serial blood samples were collected for PK analysis, and oral glucose tolerance tests were conducted for PD analysis. In each arm, a total of 18 subjects completed the study. All adverse events (AEs) were mild with no serious AEs. The geometric mean ratio and confidence interval of the main PK parameters (maximum concentration of the drug in plasma at steady state and area under the plasma drug concentration-time curve within a dosing interval at a steady state) between EV and either EP or DP alone were not significantly altered by co-administration. Administration of EV + EP or EV + DP did not result in significant PD changes, as determined by the glucose-lowering effect. Administration of EV + EP or EV + DP had no significant effects on the PK profiles of each drug. All treatments were well-tolerated.

Pharmacokinetics and safety of evogliptin in hepatically impaired patients.

AIMS: Evogliptin is a potent and selective dipeptidyl peptidase-4 inhibitor for glycaemic control in patients with type 2 diabetes mellitus. Since evogliptin is mainly eliminated through hepatic metabolism, we investigated the pharmacokinetics (PKs) and safety characteristics of evogliptin in Korean patients with mild or moderate hepatic impairment. METHODS: An open-label, parallel-group study was conducted in patients with mild or moderate hepatic impairment and healthy control subjects matched to each patient for sex, age and body mass index. A single dose (5 mg) of evogliptin was administered orally, and serial blood samples were collected over 120 h to assess the PK profile of evogliptin and its main metabolites (M7 and M8). RESULTS: Patients with mild hepatic impairment and their matched healthy controls showed similar maximum concentration (Cmax ) and area under the concentration-time curve values from 0 to 120 h (AUClast ); the geometric mean ratio (GMR) and 90% confidence interval (CI) were 1.04 (0.80, 1.35) and 1.01 (0.90, 1.14), respectively. Exposure to evogliptin (Cmax and AUClast ) was increased by about 40% in patients with moderate hepatic impairment-the GMR and 90% CI were 1.37 (1.09, 1.72) and 1.44 (1.18, 1.75), respectively. The metabolic ratios of M7 and M8 were lower in patients with moderate hepatic impairment than in matched healthy controls. Evogliptin was well tolerated by both patients and healthy subjects. CONCLUSION: Although evogliptin exposure was increased in patients with moderate hepatic impairment, the increase is unlikely to affect safety and efficacy adversely, and no dose adjustment is warranted.

The safety, pharmacodynamics, and pharmacokinetics of immediate-release formulation containing esomeprazole 20 mg/sodium bicarbonate 800 mg in healthy adult male.

BACKGROUND: Esomeprazole is the most effective treatment for acid-related disorders and is widely used with enteric coating due to rapid degradation in the acidic environment. However, the enteric-coated formulation delays absorption and onset of action. To overcome this limitation, an immediate-release formulation containing esomeprazole 20 mg and sodium bicarbonate 800 mg (IR-ESO) was developed. PURPOSE: To evaluate the safety, pharmacokinetics (PK), and pharmacodynamics of IR-ESO compared to those of esomeprazole 20 mg (ESO). METHODS: A randomized, open-label, multiple-dose, two-treatment, two-sequence crossover study was conducted in 40 healthy male subjects. Subjects received either IR-ESO or ESO for 7 days. After single and multiple dosing, blood samples were collected for PK analysis, and intragastric pH was assessed by 24-hr pH monitoring. RESULTS: Plasma esomeprazole exposure of IR-ESO was similar to that of ESO after single and multiple dosing. Time to peak concentration of IR-ESO (0.50-0.75 hr) was shorter than that of ESO (1.25-1.50 hr). Percentage changes in 24-hr integrated gastric acidity from baseline for IR-ESO were similar to those for ESO. In addition, mean time to maintain gastric pH >4 for 24 hr was similar for both drugs (IR-ESO 55.5-69.9% vs ESO 56.8-70.2%). Evaluation of time to first reach pH 4 after dosing indicated that IR-ESO showed a faster onset than ESO. All subjects found the drug tolerable, and there were no significant differences in adverse events between two drugs. CONCLUSION: This study showed that IR-ESO produced a rapid, safe and sustained gastric acid suppression (ClinicalTrials.gov: NCT03211143).

The Pythagorean theorem reveals the inherent companion of cardiac ejection fraction.

BACKGROUND: Quantification of ventricular performance requires a comprehensive metric which is manageable for patient care and clinical trials. Ejection fraction (EF) has been embraced as an attractive candidate. However, being a dimensionless ratio, EF has serious limitations. METHODS: We aim to identify what information is not recognized when limiting the volume-related analysis by exclusively relying on EF. This investigation applies the volume domain concept, relating end-systolic volume (ESV) to end-diastolic volume (EDV). This approach allows graphical identification of the information not covered by EF. Implications for atria, left ventricle (LV) and right ventricle (RV) are investigated in healthy individuals, and cardiac patient groups using various imaging modalities. RESULTS: The Pythagorean theorem indicates that the hypotenuse which relates any {EDV, ESV} combination to EF corresponds with the information not covered by the single metric EF. The impact of the recovered EF companion (EFC) is illustrated in healthy adults (N = 410, LV 2D echocardiography), heart transplant patients (N = 101, LV CT), individuals with heart failure (N = 197, biplane angiocardiography), for the RV with corrected Fallot (N = 124, MRI), diameters for left atrium (N = 49, MRI) and area for right atrium (N = 51, MRI). For any limited EF range we find a spectrum of EFC values, showing that the two metrics contain (partly) independent information, and emphasizing that the sole use of EF only partially conveys the full information available. CONCLUSIONS: The EFC is a neglected companion, containing information which is additive to EF. Analysis based on ESV and EDV is preferred over the use of EF.

Comparison of biosimilar filgrastim with a reference product: pharmacokinetics, pharmacodynamics, and safety profiles in healthy volunteers.

PURPOSE: Filgrastim, a granulocyte-colony stimulating factor, is used to treat patients with neutropenia, including neutropenic fever. Leucostim® is a recombinant filgrastim product tested for biosimilarity with its reference product, Neupogen®. We conducted a comparative clinical trial of the 2 products. PATIENTS AND METHODS: A randomized, open-label, 2-way crossover, single-dose Phase I study was conducted for 56 healthy subjects. After a 5 and 10 µg/kg single subcutaneous administration of test and reference product, pharmacokinetic and pharmacodynamic parameters (absolute neutrophil count and CD34+ cell count) were compared. During the study, safety tests and adverse event monitoring were performed. RESULTS: The test and the reference products had a comparable pharmacokinetic, pharmacodynamic, and safety profile. In both 5 and 10 µg/kg dosing, the 90% CIs of the test to reference ratio for primary parameters (peak plasma concentration and area under the plasma concentration vs time curve from time 0 extrapolated to the infinite time for plasma filgrastim concentration; maximal effect and area under the time-effect curve from time 0 to time of the last quantifiable effect for absolute neutrophil count) were within the 0.8-1.25 range. In addition, safety profiles between the 2 products were similar without any serious adverse events. CONCLUSION: This study has provided firm clinical evidence that the test filgrastim product is similar to its reference filgrastim product.

Epidemiology of Congenital Heart Disease with Emphasis on Sex-Related Aspects.

Gender differences in prevalence, manifestation, treatment outcomes, and prognosis have been well known for acquired heart disease such as coronary artery disease. Regarding congenital heart disease (CHD), it is recognized that the incidence of each congenital heart defect varies according to sex observed during a time span of more than 40 years. As diagnostic and surgical methods for CHD have achieved dramatic advances for the past decades, more newborns with CHD were able to survive and reach adulthood. Thereafter gender differences have begun to be reported on mortality, progress to pulmonary arterial hypertension, treatment outcomes, and prognosis in patients with CHD. However, it has been less known in the field of CHD yet, and this contribution describes information that is relatively well studied to date.

Pharmacokinetic drug interaction and safety after coadministration of clarithromycin, amoxicillin, and ilaprazole: a randomised, open-label, one-way crossover, two parallel sequences study.

PURPOSE: Ilaprazole, the latest proton pump inhibitor, can be used with clarithromycin and amoxicillin as a triple therapy regimen for eradicating Helicobacter pylori. The aim of this study was to evaluate pharmacokinetic drug interactions and safety profiles after coadministration of clarithromycin, amoxicillin, and ilaprazole. METHODS: A randomised, open-label, one-way crossover, two parallel sequences study was conducted in 32 healthy subjects. In part 1, the subjects received a single dose of ilaprazole 10 mg in period 1 and clarithromycin 500 mg and amoxicillin 1000 mg twice daily for 6 days in period 2. In part 2, the subjects received clarithromycin 500 mg and amoxicillin 1000 mg once in period 1 and ilaprazole 10 mg twice daily for 6 days in period 2. In both sequences, the three drugs were coadministrated once on day 5 in period 2. Pharmacokinetic evaluations of ilaprazole (part 1), and clarithromycin and amoxicillin (part 2) were conducted. RESULTS: Twenty-eight subjects completed the study. For ilaprazole, the peak concentration (Cmax) slightly decreased from 479 (ilaprazole alone) to 446 ng/mL (triple therapy) [Geometric least square mean ratio (90% confidence interval), 0.93 (0.70-1.22)]. The area under the concentration-time curve from 0 h to the last measurable concentration (AUClast) slightly increased from 3301 to 3538 µg·h/mL [1.07 (0.85-1.35)]. For clarithromycin, the Cmax slightly decreased from 1.87 to 1.72 µg/mL [0.90 (0.70-1.15)], and AUClast slightly increased from 14.6 to 16.5 µg·h/mL [1.09 (0.87-1.37)]. For amoxicillin, the Cmax slightly decreased from 9.37 to 8.14 µg/mL [0.86 (0.74-1.01)], and AUClast slightly decreased from 27.9 to 26.7 µg·h/mL [0.98 (0.83-1.16)]. These changes in the PK parameters of each drug were not statistically significant. CONCLUSIONS: The coadministration of ilaprazole, clarithromycin, and amoxicillin was tolerable and did not cause a significant PK drug interaction. Thus, a triple therapy regimen comprising ilaprazole, clarithromycin, and amoxicillin may be an option for the eradication of H. pylori. Clinicaltrials.gov number: NCT02998437.

Erratum: Pulmonary stenosis and pulmonary regurgitation: both ends of the spectrum in residual hemodynamic impairment after tetralogy of Fallot repair.

[This corrects the article on p. 235 in vol. 56, PMID: 23807889.].

Congestive hepatopathy after Fontan operation and related factors assessed by transient elastography.

OBJECTIVE: Congestive hepatopathy after a Fontan operation can have a major effect on long-term morbidity. We evaluated congestive hepatopathy in patients with Fontan circulation using transient elastography to determine which risk factors for hepatopathy are related to liver stiffness (LS). METHODS: We evaluated 46 patients with Fontan circulation and 26 with right side heart failure (RHF) and hepatic congestion using laboratory tests, the aspartate aminotransferase-to-platelet ratio index, ultrasonography, and transient elastography. RESULTS: The LS value was significantly greater in the Fontan group (21.1±8.0 kPa) than in the RHF group (10.0±9.0 kPa). The total bilirubin and albumin serum levels, white blood cell count, and aspartate aminotransferase to platelet ratio index correlated significantly with LS in the Fontan group. Of the risk factors, age at evaluation (r=0.42, P=.004), age at Fontan completion (r=0.51, P<.001), inferior vena cava diameter (r=0.35, P=.02), and spleen size (r=0.53, P=.002) correlated significantly with LS. Nineteen patients in the Fontan group (41.3%) had abnormal ultrasound findings, and the frequency of abnormal findings increased with increasing LS (P=.002). In the subgroup with the greatest LS value (≥30 kPa), 88.9% had abnormal ultrasound findings and 44.4% liver cirrhosis. Multivariate analysis revealed that age at Fontan procedure completion and total bilirubin were independent risk factors for hepatopathy. CONCLUSIONS: The present study revealed that congestive hepatopathy developed in a significant fraction of patients with long-term Fontan circulation and that transient elastography could be an easy and useful method to assess congestive hepatopathy in these patients.

Pulmonary stenosis and pulmonary regurgitation: both ends of the spectrum in residual hemodynamic impairment after tetralogy of Fallot repair.

Repair of tetralogy of Fallot (TOF) has shown excellent outcomes. However it leaves varying degrees of residual hemodynamic impairment, with severe pulmonary stenosis (PS) and free pulmonary regurgitation (PR) at both ends of the spectrum. Since the 1980s, studies evaluating late outcomes after TOF repair revealed the adverse impacts of residual chronic PR on RV volume and function; thus, a turnaround of operational strategies has occurred from aggressive RV outflow tract (RVOT) reconstruction for complete relief of RVOT obstruction to conservative RVOT reconstruction for limiting PR. This transformation has raised the question of how much residual PS after conservative RVOT reconstruction is acceptable. Besides, as pulmonary valve replacement (PVR) increases in patients with RV deterioration from residual PR, there is concern regarding when it should be performed. Regarding residual PS, several studies revealed that PS in addition to PR was associated with less PR and a small RV volume. This suggests that PS combined with PR makes RV diastolic property to protect against dilatation through RV hypertrophy and supports conservative RVOT enlargement despite residual PS. Also, several studies have revealed the pre-PVR threshold of RV parameters for the normalization of RV volume and function after PVR, and based on these results, the indications for PVR have been revised. Although there is no established strategy, better understanding of RV mechanics, development of new surgical and interventional techniques, and evidence for the effect of PVR on RV reverse remodeling and its late outcome will aid us to optimize the management of TOF.

Impact of pressure load caused by right ventricular outflow tract obstruction on right ventricular volume overload in patients with repaired tetralogy of Fallot.

OBJECTIVES: In correction of tetralogy of Fallot (TOF), surgical strategies to minimize right ventricular outflow tract (RVOT) enlargement have recently been preferred. However, we may be confronted with residual pulmonary stenosis (PS) combined with pulmonary regurgitation (PR), and how the pressure load affects these patients is not evident. METHODS: We compared 51 patients with PR and significant PS (PR with PS group) with 87 patients with PR without significant PS (PR group) using echocardiography and cardiac magnetic imaging. We evaluated the differences in parameters derived by magnetic resonance imaging between the 2 groups and the influence of the pressure load on right ventricular (RV) volume and function. RESULTS: Although the PR fraction was similar between the 2 groups, the PR with PS group showed significantly smaller RV end-diastolic volume (136.7 ± 26.5 mL/m(2) vs 151.2 ± 34.7 mL/m(2); P = .01), RV end-systolic volume (68.1 ± 23.7 mL/m(2) vs 80.2 ± 27.5 mL/m(2); P = .01), and slightly better RV ejection fraction (51.1% ± 9.8% vs 47.6% ± 8.9%; P = .03) than the PR group. For influence of the pressure load, PR fraction (r = -0.18, P = .03), RV end-diastolic volume (r = -0.25, P = .003), and RV end-systolic volume (r = -0.24, P = .005) were decreased as peak pressure gradient of PS was higher. Linear regression analysis revealed that both PR fraction and peak pressure gradient of PS were independent predictors for RV volume. CONCLUSIONS: Our study demonstrated that the RV pressure load prevented RV dilatation from chronic PR without systolic dysfunction. It is suggested that a proper relief of RVOT obstruction with acceptable residual stenosis is more advantageous than aggressive RVOT enlargement in the long-term outcome of repaired TOF.

Traumatic ventricular septal defect in a 4-year-old boy after blunt chest injury.

Traumatic ventricular septal defect (VSD) resulting from blunt chest injury is a very rare event. The mechanisms of traumatic VSD have been of little concern to dateuntil now, but two dominant theories have been described. In one, the rupture occurs due to acute compression of the heart; in the other, it is due to myocardial infarction of the septum. The clinical symptoms and timing of presentation are variable, so appropriate diagnosis can be difficult or delayed. Closure of traumatic VSD has been based on a combination of heart failure symptoms, hemodynamics, and defect size. Here, we present a case of a 4-year-old boy who presented with a traumatic VSD following a car accident. He showed normal cardiac structure at the time of injury, but after 8 days, his repeated echocardiography revealed a VSD. He was successfully treated by surgical closure of the VSD, and has been doing well up to the present. This report suggests that the clinician should pay great close attention to the patients injured by blunt chest trauma, keeping in mind the possibility of cardiac injury.

Morphologic Characteristics and Relating Factors to the Need of Technical Modification in Transcatheter Closure of Large Atrial Septal Defect (>/=25 mm).

BACKGROUND AND OBJECTIVES: The rigid coupling between the delivery wire and the right atrial disk has been occasionally encountered during transcatheter closure of atrial septal defect (ASD). Therefore the device frequently makes a perpendicular angle, and the leading edge of left atrial disk slips through the defect and prolapses into right atrium (RA) before it is properly placed in the septum. The purpose of this study is to investigate relating factors to the need of technical modification in transcatheter closure of large ASD and to evaluate relevant morphologic characteristics of atrial septal rim in this situation. SUBJECTS AND METHODS: From July, 2003 to May, 2007, 312 patients underwent transcatheter occlusion of ASD with Amplatzer Septal Occluder(R) (ASO, AGA medical corporation, Golden Valley, MN, USA) at Yonsei Cardiovascular Center and among them 109 patients had large ASD (>/=25 mm) and these patients were enrolled in our study. Patients were divided into two groups according to the deploying methods of the device (Group I: standard method, Group II: modified methods). Assessments of the defects and its surrounding rims were made by echocardiography. RESULTS: There were no differences between 2 groups in age, body weight and height except for balloon-stretched diameter (stop-flow technique) and device size. Group II patients with modified methods showed larger balloon-stretched diameter and device size than group I patients with standard method. The mean length of anterosuperior (AS) rim in group II was significantly shorter than group I (p<0.05). As the size of the device used in procedure increased, there was a trend towards increase in the need of modified methods. CONCLUSION: This study shows that AS rim deficiency and the size of ASD may be the relating factors to the need of technical modification in transcatheter closure of ASD. Therefore, when the initial try with standard method is not successful in large ASD with deficient AS rim, we suggest that changing strategy of implantation may save time and efforts and possibly reduce the risk of complications associated with prolonged procedure.

Programmed death-1 (PD-1) gene polymorphisms lodged in the genetic predispositions of Kawasaki Disease.

The purpose of this study is to investigate the association of programmed death-1 gene (PD-1) polymorphisms with genetic predispositions to Kawasaki disease (KD). A total of 73 patients with KD and 100 healthy controls were enrolled from 2007 to 2008. Two single nucleotide polymorphisms of the PD-1 gene, rs41386349 and rs2227981, were analyzed. Higher T allele frequency of rs41386349 was found in the patient group than the control group (p = 0.007, odds ratio (OR) = 1.9, 95% CI = 1.2-2.9). PD-1 rs2227981 polymorphism was not significant in patients with KD comparing with the control group (p = 0.4, OR = 1.2 (0.8-1.9)). Furthermore, no difference of PD-1 polymorphisms between patients with coronary artery dilatation (CAD) and those without CAD was found. Our data support the possibility that PD-1 gene polymorphism may be related with the genetic susceptibility of KD in Korean population.

Right ventricular restrictive physiology in repaired tetralogy of Fallot is associated with smaller respiratory variability.

BACKGROUND: Long-term outcomes of patients with repaired tetralogy of Fallot (TOF) are known to be related with right ventricular (RV) volume overload, severity of pulmonary insufficiency (PI) and the type of outflow repair. Right ventricular restrictive physiology (RVRP) has also been reported to interfere with several factors influencing the late result in repaired TOF patients. However, the mechanism and physiology of this unique myocardial property in the chronically overloaded right ventricle are not yet clearly understood. METHODS: We investigated 43 patients after repair of TOF to assess the relationships among biventricular diastolic function, volume characteristics, and influence of respiratory effort. The patients were classified into 3 groups; 15 patients with RVRP and significant PI (RP group, 35%), 19 without RVRP in the presence of significant PI (NR+PI group, 44%), and 9 without RP or significant PI (NR-PI group, 21%). Doppler spectrals obtained by echocardiography from systemic and pulmonary veins, main pulmonary artery (MPA), and both ventricular inlets, and biventricular diastolic function were compared according to the respiratory cycle. RESULTS: The RP group revealed higher pulmonary venous systolic/diastolic flow ratio (S/D ratio) and the NR+PI group showed larger velocity-time integral (VTI) ratio of total regurgitant/antegrade flow at the MPA and more respiratory variability in the systemic vein. CONCLUSION: RP is associated with less volume overload of the RV and smaller respiratory variability is also associated with the restrictive RV. The diastolic function and volume status of the RV may influence the diastolic properties of the left heart.