Search

A fixed-dose combination (FDC) of ezetimibe, atorvastatin, and amlodipine has been developed to improve medication adherence among patients with cardiovascular diseases. In a randomized, open-label, multiple-dose, fixed-sequence study involving 34 participants (Study 1), the potential drug-drug interaction between ezetimibe/atorvastatin FDC and amlodipine was evaluated. Additionally, a randomized, open-label, crossover study with 60 participants (Study 2) compared the pharmacokinetics (PKs) of ezetimibe/atorvastatin/amlodipine FDC to those of individual formulations. Co-administration of the ezetimibe/atorvastatin FDC and amlodipine did not significantly alter the PKs of either drug. However, amlodipine resulted in a slight increase in systemic exposure to atorvastatin by approximately 23%. Geometric mean ratios (FDC to individual formulations) and 90% confidence intervals of area under the time-concentration curve at steady state during dosing interval (AUC τ, ss ) and maximum concentration at steady state (C max, ss ) or amlodipine, atorvastatin, and ezetimibe were all within the bioequivalent range (0.8-1.25), confirming bioequivalence. Moreover, the FDC of ezetimibe, atorvastatin, and amlodipine exhibited comparable tolerability to corresponding individual formulations., (© 2024, The American College of Clinical Pharmacology.)

Delpazolid (LCB01-0371) is a novel oxazolidinone derivative with a good safety profile for treating gram-positive pathogenic infections such as Mycobacterium abscessus, a highly pathogenic drug-resistant Mycobacterium. In this study, we evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) of delpazolid after 14 days of multiple oral administration, using data from adult patients with pulmonary tuberculosis. 800 mg once a day, 400 mg twice a day, 800 mg twice a day, and 1200 mg once a day delpazolid for 14 days were tested in 63 patients with pulmonary tuberculosis. For PK blood collection, inpatient and outpatient scheduling were separately implemented. Plasma concentrations of delpazolid were measured at visits 2, 4, 6, and 8 in outpatients, and four sparse blood samples were measured in inpatients. PD models were sequentially fitted using individual PK parameter estimates obtained from PK compartmental models. For PK modeling, 180 plasma concentrations of delpazolid from 56 patients were included. A two-compartment mixed first- and zero-order absorption model best described the time course of plasma concentration. For the PD model, 448 bacterial titer data from 60 patients were used. The time course of bacterial titers (log 10 CFU/mL) was described by a model that consists of the growth and killing rate of bacteria with the sigmoid E max model. The PK-PD simulation suggested that the bacterial titers are the lowest on the 800 mg bid regimen among the four, consistent with observed data, as all regimens substantially decrease. In the dose-response relationship, the effectiveness of delpazolid was suggested., (© 2024, The American College of Clinical Pharmacology.)

Wave intensity analysis (WIA) uses simultaneous changes in pressure and flow velocity to determine wave energy, type, and timing of traveling waves in the circulation. In this study, we characterized wave propagation in the pulmonary artery in patients with pulmonary hypertension associated with left-sided heart disease (PHLHD) and the effects of dobutamine. During right heart catheterization, pressure and velocity data were acquired using a dual-tipped pressure and Doppler flow sensor wire (Combowire; Phillips Volcano), and processed offline using customized Matlab software (MathWorks). Patients with low cardiac output underwent dobutamine challenge. Twenty patients with PHLHD (all heart failure with reduced left ventricular ejection fraction) were studied. Right ventricular systole produced a forward compression wave (FCW), followed by a forward decompression wave (FDW) during diastole. Wave reflection manifesting as backward compression wave (BCW) following the FCW was observed in 14 patients. Compared to patients without BCW, patients with BCW had higher mean pulmonary artery pressure (28.7 ±  6.12 vs. 38.6 ± 6.5 mmHg, p  = 0.005), and lower pulmonary arterial capacitance (PAC: 2.88 ± 1.75 vs. 1.73 ± 1.16, p  = 0.002). Pulmonary vascular resistance was comparable. Mean pulmonary artery pressure of 34.5 mmHg (area under the curve [AUC]: 0.881) and PAC of 2.29 mL/mmHg (AUC: 0.833) predicted BCW. The magnitude of the FCW increased with dobutamine ( n  = 11) and correlated with pulmonary artery wedge pressure. Wave reflection in PHLHD is more likely at higher pulmonary artery pressures and lower PAC and the magnitude of reflected waves correlated with pulmonary artery wedge pressure. Dobutamine increased FCW but did not affect wave reflection., Competing Interests: Hoong Sern Lim received honoraria from Abbott and Abiomed unrelated to this work. The remaining authors declare no conflict of interest., (© 2024 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

This study evaluated the pharmacokinetics and pharmacodynamics of the antiplatelet agent prasugrel, and explored its optimal dose regimens via modeling and simulation using NONMEM. We measured platelet aggregation and the serial plasma concentrations of the inactive (R-95913) and active metabolites (R-138727) of prasugrel after a single oral dose of 10-60 mg in 20 healthy adult male volunteers. A pharmacokinetic model for R-95913 and R-138727, and a pharmacodynamic model between the concentration of R-138727 and maximal platelet aggregation measured by light transmittance were constructed. The predictability of the model for platelet aggregation was evaluated by comparing the model prediction values with the observed ones not used in the construction of the model. Pharmacokinetic data were best described by a 3-compartment models for R-95913, a 1-compartment model for R-138727 with transit compartment model for absorption delay, and first-pass metabolic conversion of R-95913 into R-138727 during absorption. The association-dissociation model between R-138727 and its receptor in platelets was applied for the inhibitory effect of prasugrel on platelet aggregation. Prasugrel rapidly inhibited platelet aggregation after oral administration, with a prolonged duration of action; however, the concentration of the active metabolite decreased rapidly, which may have been due to the slow dissociation rate of R-138727 from its target receptor in platelets. The external validation suggests that our model could be used to individualize prasugrel treatment in various clinical situations. Simulation showed rapid onset of inhibitory effect with great magnitude and consistent inhibition after therapeutic dose of prasugrel., (© 2022, The American College of Clinical Pharmacology.)

The application of logistic regression (LR) and Cox Proportional Hazard (CoxPH) models are well-established for evaluating exposure-response (E-R) relationship in large molecule oncology drugs. However, applying machine learning (ML) models on evaluating E-R relationships has not been widely explored. We developed a workflow to train regularized LR/CoxPH and tree-based XGboost (XGB) models, and derive the odds ratios for best overall response and hazard ratios for overall survival, across exposure quantiles to evaluate the E-R relationship using clinical trial datasets. The E-R conclusions between LR/CoxPH and XGB models are overall consistent, and largely aligned with historical pharmacometric analyses findings. Overall, applying this interpretable ML workflow provides a promising alternative method to assess E-R relationships for impacting key dosing decisions in drug development., (© 2022 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Pulmonary artery pulsatility index (PAPi) is a haemodynamic parameter that is derived from right atrial and pulmonary artery pulse pressures. A number of reports have described the prognostic value of PAPi in patients with advanced heart failure and cardiogenic shock. However, the derivation and physiological interpretation of this parameter have received little attention. This review will examine the physiological interpretation and clinical data for PAPi., (© 2019 The Authors. European Journal of Heart Failure © 2019 European Society of Cardiology.)

The osteoporosis incidence in postmenopausal patients on aromatase inhibitors (AI) is much higher than in those on tamoxifen, and adverse effects other than musculoskeletal disorders are less on AI than on tamoxifen. In this study we performed disease-progression modeling in postmenopausal patients with early breast cancer who had received 5 years of postoperative hormone therapy. Clinical data from postmenopausal patients who had received postoperative hormonal therapy and met the predefined selection criteria were retrospectively collected in an anonymized way. Disease-progression modeling and simulations were performed using NONMEM version 7.42. A first-order deterioration model with a combination of a symptomatic model (when a drug effect provides a transient bad effect by offsetting the severity of the disease) and a disease-modifying model (when a drug affects the disease progression rate) was used. Vitamin D supplementation was found to have a disease-modifying effect in osteoporosis, whereas AI decreased the bone mineral density by a t score of -0.21. However, after stopping the AI, the estrogen level reverted to normal, thereby reexercising protective effects against bone loss. In the simulation the probability of osteoporosis increased by 10% in the AI group compared with the other groups (tamoxifen, no-treatment group) during the medication period. Tamoxifen showed no significant effects in the final model., (© 2019, The American College of Clinical Pharmacology.)

Peptoids, oligomers of N-substituted glycines, have been attracting increasing interest due to their advantageous properties as peptidomimetics. However, due to the lack of chiral centers and amide hydrogen atoms, peptoids, in general, do not form folding structures except that they have α-chiral side chains. We have recently developed "peptoids with backbone chirality" as a new class of peptoid foldamers called α-ABpeptoids and demonstrated that they could have folding conformations owing to the methyl groups on chiral α-carbons in the backbone structure. Here we report α-ABpeptoid/β 3 -peptide oligomers as a unique peptidomimetic structure with a heterogeneous backbone. This hybrid structure contains a mixed α-ABpeptoid and β 3 -peptide residues arranged in an alternate manner. These α-ABpeptoid/β 3 -peptide oligomers could form intramolecular hydrogen bonding and have better cell permeability relative to pure peptide sequences. These oligomers were shown to adopt ordered folding structures based on circular dichroism studies. Overall, α-ABpeptoid/β 3 -peptide oligomers may represent a novel class of peptidomimetic foldamers and will find a wide range of applications in biomedical and material sciences., (© 2019 Wiley Periodicals, Inc.)

Amitriptyline is a tricyclic antidepressant that is metabolized mainly by CYP2C19 and CYP2D6 enzymes. Higher plasma levels of amitriptyline and its active metabolite, nortriptyline, are associated with an increased risk of adverse events including anticholinergic effects. The aim of this study was to evaluate the effects of CYP2C19 and CYP2D6 genetic polymorphisms on amitriptyline and nortriptyline pharmacokinetics. Twenty-four Korean healthy adult male volunteers were enrolled in the study after stratification by their CYP2C19 and CYP2D6 genotypes. Serial blood draws for pharmacokinetic analysis were made after a single oral 25-mg dose of amitriptyline was administered. Plasma amitriptyline and nortriptyline concentrations were measured by a validated liquid chromatography with tandem mass spectrometry. Population pharmacokinetic modeling analysis was conducted using NONMEM, which evaluated the effects of CYP2C19 and CYP2D6 genotypes on amitriptyline and nortriptyline pharmacokinetics. The biotransformation of amitriptyline into nortriptyline was significantly different between subjects with the CYP2C19*2/*2, *2/*3, and *3/*3 genotypes and those with the other genotypes, with an estimated metabolic clearance of 17 and 61.5 L/h, respectively. Clearance of amitriptyline through pathways other than biotransformation into nortriptyline was estimated as 18.8 and 30.6 L/h for subjects with the CYP2D6*10/*10 and *10/*5 genotypes and those with the other genotypes, respectively. This study demonstrated a quantitative effect of the CYP2C19 and CYP2D6 genotypes on amitriptyline and nortriptyline pharmacokinetics. Production of nortriptyline from amitriptyline was associated with CYP2C19 genotypes, and clearance of amitriptyline through pathways other than biotransformation into nortriptyline was associated with CYP2D6 genotypes. These observations may be useful in developing individualized, optimal therapy with amitriptyline., (© 2018, The American College of Clinical Pharmacology.)

This study aimed to evaluate the safety and tolerability of intravenous (IV) levetiracetam (LEV) as a monotherapy in children aged 1 month-16 years and to explore the pharmacokinetics (PK) of IV LEV and the time to seizure after IV then oral administration of LEV in pediatric children with epilepsy. Children diagnosed with acute unprovoked seizures requiring in-hospital IV LEV administration were included. After administration, the clinical seizure outcomes, side effects, and the Korean-Child Behavior Checklist were monitored and the PK and repeated time to seizure were analyzed via modeling using NONMEM software. Overall, 37 children with epilepsy were enrolled and underwent a PK analysis (median age, 4.6 years; median weight, 18.0 kg). Nine children (24.3%) had seizure recurrence during the follow-up period (median, 3.8 months) and 5 children (13.5%) experienced LEV-associated adverse events such as irritability (n = 2; 5.4%) and somnolence (n = 3; 8.1%). The plasma LEV concentrations after IV LEV were best described by a one-compartment linear PK model. Only body weight was associated with both the clearance and volume of distribution of LEV. The Weibull distribution model described the time to seizure recurrence well; no statistically significant predictor for the time to seizure was identified. Therefore, IV LEV was a well-tolerated and effective alternative in children with acute unprovoked seizures, and models for the PK and time to repeated seizure recurrence after LEV were successfully developed. In particular, the current use of a weight-based IV LEV dosing regimen in pediatric children is practical., (© 2018, The American College of Clinical Pharmacology.)

Udenafil is a phosphodiesterase-5 inhibitor used to treat erectile dysfunction. Although udenafil is not predominantly eliminated by the kidney, renal impairment can alter its secretion/transport pathways. Drug pharmacokinetics and safety must therefore be assessed in subjects with a renal impairment. We investigated the effects of impaired renal function on the pharmacokinetics and safety of a single 100-mg oral dose of udenafil in a single-dose, open-label, parallel-group study of 31 subjects. Cockcroft-Gault creatinine clearance was used to stratify these subjects into healthy controls (>80 mL·min -1 ) and individuals with mild (50 to ≤80 mL·min -1 ), moderate (30 to ≤50 mL·min -1 ), and severe (<30 mL·min -1 ) renal impairment. Pharmacokinetic measurements and safety assessments indicated that the geometric mean of the area under the concentration-time curve to the last measurement in mildly, moderately, and severely renally impaired subjects was 1.30- (90% CI 1.05-1.60), 1.62- (90% CI 1.28-2.06), and 1.60- (90% CI 1.28-2.01) fold higher, respectively, than the healthy controls. The geometric mean of the maximum observed concentration was 1.41- (90% CI 1.05-1.88), 2.02- (90% CI 1.47-2.79), and 1.65- (90% CI: 1.21-2.24) fold higher, respectively. Significant correlations were observed among the creatinine clearance, oral clearance, and maximum concentration of udenafil (P < .01). All adverse events were mild, and no subject discontinued the study. Udenafil administration was well tolerated in all groups. In view of the clinical relevance of drug exposure, our findings indicate that a dose adjustment of udenafil is warranted in subjects with moderate or severe renal impairment., (© 2018, The American College of Clinical Pharmacology.)

Although stroke is a leading cause of disability, the quantitative relationship between baseline clinical and imaging characteristics and long-term disability outcomes has rarely been studied. Prospectively collected clinical data from 405 patients with acute ischemic stroke including brain magnetic resonance images (MRIs) and disability outcomes assessed using the modified Rankin Scale (mRS) 3 month after the onset of disease were analyzed using a proportional odds cumulative logit model implemented in NONMEM. The relationship between the difference in lesion volume (DLV) - lesion volume measured by brain MRI 5 days later - lesion volume at the onset of the disease, and the mRS measured at 3 months (mRS3) was modeled first, and the potential covariates were tested. The E max model best described the relationship between DLV and the logit probability of each mRS3. DLV, baseline stroke severity, age, and diabetes mellitus were identified as significant predictors of the probabilities of mRS3. The quantitative model constructed in the current analysis will enable us to predict the long-term disabilities of the patients with acute ischemic stroke using the patient-specific MRI and other clinical information, which will be useful for individualizing therapies and for making the clinical development of a novel drug more efficient., (© 2017, The American College of Clinical Pharmacology.)

Purpose: Genetically encoded reporters can assist in visualizing biological processes in live organisms and have been proposed for longitudinal and noninvasive tracking of therapeutic cells in deep tissue. Cells can be labeled in situ or ex vivo and followed in live subjects over time. Nevertheless, a major challenge for reporter systems is to identify the cell population that actually expresses an active reporter., Methods: We have used a nucleoside analog, pyrrolo-2'-deoxycytidine, as an imaging probe for the putative reporter gene, Drosophila melanogaster 2'-deoxynucleoside kinase. Bioengineered cells were imaged in vivo in animal models of brain tumor and immunotherapy using chemical exchange saturation transfer MRI. The number of transduced cells was quantified by flow cytometry based on the optical properties of the probe., Results: We performed a comparative analysis of six different cell lines and demonstrate utility in a mouse model of immunotherapy. The proposed technology can be used to quantify the number of labeled cells in a given region, and moreover is sensitive enough to detect less than 10,000 cells., Conclusion: This unique technology that enables efficient selection of labeled cells followed by in vivo monitoring with both optical and MRI. Magn Reson Med 79:1010-1019, 2018. © 2017 International Society for Magnetic Resonance in Medicine., (© 2017 International Society for Magnetic Resonance in Medicine.)

Some prospective, randomized clinical trials, including ATAC and BIG 1-98, demonstrated superior treatment effect of third-generation aromatase inhibitors (AIs) versus tamoxifen in postoperative therapy for patients with breast cancer. In retrospective genotyping analyses of the 2 studies using tumor samples, no difference in the treatment effect of tamoxifen was observed by CYP2D6 genotypes. However, those analyses did not consider loss of heterozygosity that could have occurred when genotyping using tumor tissue. The present simulation study aimed to comparatively evaluate the treatment effect of tamoxifen versus AIs of anastrozole and letrozole by CYP2D6 genotypes. A meta-analysis was conducted to estimate disease-free survival (DFS) hazard ratios of CYP2D6 genotypes representing extensive metabolizers (EMs), HR W/W,TAM , versus intermediate metabolizers (IMs)/poor metabolizers (PMs), HR V/W,TAM , using previous study results in which genotypes were determined using blood samples. Based on known allele frequencies, the CYP2D6 genotype distribution of participants in ATAC and BIG 1-98 trials were simulated. Subsequently, DFS HRs of AIs versus tamoxifen by CYP2D6 genotypes (HR AI/TAM,W for EMs, HR AI/TAM,V for IMs/PMs) were estimated via regression analyses using NONMEM, based on the simulated genotype distributions, HR V/W,TAM , and HRs, of AIs versus tamoxifen (HR AI/TAM ) reported in the ATAC and BIG 1-98 trials. Median HR AI/TAM,V (95% prediction interval [PI]) was 0.43 (0.23-0.79) and 0.40 (0.22-0.73) for the ATAC and BIG 1-98 trials, respectively. However, the corresponding HR AI/TAM,W values were 0.97 (0.84-1.11) and 0.91 (0.77-1.08), respectively. These results suggest that in patients with the CYP2D6 genotype representing EMs, the treatment effect of tamoxifen is comparable to that of AIs., (© 2017, The American College of Clinical Pharmacology.)

GCC-4401C, an orally active direct factor Xa inhibitor that is similar to rivaroxaban, is currently under development for venous thromboembolic disease (VTE). The purpose of this study was to characterize the pharmacokinetics (PKs) and pharmacodynamics (PDs) of GCC-4401C by population modeling analysis and to predict proper dosage regimens compared to rivaroxaban using data from two phase I clinical studies. Plasma GCC-4401C concentrations over time were best described by a two-compartment linear model and body weight was associated with central volume of distribution. Relevant PD markers generally changed in a dose-dependent manner and were described well with sigmoid, simple maximum effect, or linear models. GCC-4401C was absorbed more rapidly than rivaroxaban. Comparisons based on simulations of PD marker changes over time suggest that 20 mg and 40 mg of GCC-4401C administered under fasted status are comparable to 10 mg and 20 mg of rivaroxaban under fed status., (© 2016 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Ivabradine, a selective inhibitor of the pacemaker current (If ), is used for heart failure and coronary heart disease and is mainly metabolized to S18982. The purpose of this study was to explore the pharmacokinetics (PK) of ivabradine and S18982 in healthy Korean volunteers. Subjects in a phase I study were randomized to receive 2.5, 5, or 10 mg of ivabradine administered every 12 hours for 4.5 days, and serial plasma and urine concentrations of ivabradine and S18982 were measured. The plasma PK of ivabradine was best described by a 2-compartment model with mixed 0- and first-order absorption, linked to a 2-compartment model for S18982. The introduction of interoccasional variabilities and period as covariate into absorption-related parameters improved the model fit. Urine data have been applied to estimate renal and nonrenal clearance, enabling a more detailed description of the elimination process. We developed a population PK model describing the plasma and urine PK of ivabradine and S18982 in healthy Korean adult males. This model might be useful for predicting the plasma and urine PK of ivabradine, potentially helping to identify the optimal dosing regimens in various clinical situations., (© 2015, The American College of Clinical Pharmacology.)

S-1 is an oral 5-fluorouracil agent containing tegafur, 5-chloro-2, 4-dihydroxypyridine (CDHP), and potassium oxonate. This study explored the pharmacokinetics of S-1 and pharmacokinetic changes after gastric surgery in patients with resectable gastric cancer who received pre- and postoperative S-1 plus docetaxel. Serial blood was drawn before and after gastrectomy from 37 patients for pharmacokinetic analysis. The pharmacokinetics of tegafur, 5-fluorouracil, and CDHP were analyzed by noncompartmental analysis (NCA) methods and by modeling. In modeling analysis, CHDP concentrations were incorporated in the model as a time-varying covariate that inhibits the clearance of 5-fluorouracil following an inhibitory Emax model. In NCA, the pharmacokinetics of tegafur and 5-FU before and after gastric surgery were similar, although average maximum concentrations of 5-FU were decreased with statistical significance after gastrectomy. Median Tmax of tegafur was shorter after surgery without statistical significance. In modeling analysis, tegafur was best fitted by mixed zero and first-order absorption. The only difference in the final pharmacokinetic model around gastrectomy was the presence of an absorption lag of 0.23 hours before surgery. Incorporation of CDHP concentrations significantly improved the model. Although some pharmacokinetic results showed statistically significant changes after gastrectomy, these differences seem to be too small to have any clinical implication., (© 2015, The American College of Clinical Pharmacology.)

Skin inflammation is the most common condition seen in dermatology practice and can be caused by various allergic reactions and certain toxins or chemicals. In the present study, we investigated the antiinflammatory effects of Saussurea lappa, a medicinal herb, and its marker compounds alantolactone, caryophyllene, costic acid, costunolide, and dehydrocostuslactone in the HaCaT human keratinocyte cell line. HaCaT cells were stimulated with tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ), and treated with S. lappa or each of five marker compounds. Chemokine production and expression were analyzed by enzyme-linked immunosorbent assay and reverse transcription-polymerase chain reaction, respectively. Phosphorylation of signal transducer and activator of transcription (STAT) 1 was determined by immunoblotting. Stimulation with TNF-α and IFN-γ significantly increased the production of the following chemokines: thymus-regulated and activation-regulated chemokine (TARC): regulated on activation, normal T-cell expressed and secreted (RANTES): macrophage-derived chemokine (MDC): and interleukin-8 (IL-8). By contrast, S. lappa and the five marker compounds significantly reduced the production of these chemokines by TNF-α and IFN-γ-treated cells. S. lappa and alantolactone suppressed the TNF-α and IFN-γ-stimulated increase in the phosphorylation of STAT1. Our results demonstrate that alantolactone from S. lappa suppresses TNF-α and IFN-γ-induced production of RANTES and IL-8 by blocking STAT1 phosphorylation in HaCaT cells., (Copyright © 2015 John Wiley & Sons, Ltd.)

The objective of current study is to assess the relationship between characteristics of patients with acute ischemic stroke and clinical recurrences to identify predictors for the prognosis by modeling and simulation. Primary endpoint was clinical recurrence of ischemic stroke, and secondary endpoint was occurrence of any of the following clinical recurrence of ischemic stroke, transient ischemic attack, acute coronary syndrome, or vascular deaths. Time to event models were developed by NONMEM(®) using prospectively collected clinical data from 270 patients over 5 years, where 7.0% and 9.3% of them experienced lesion recurrence on MRI at 1 month (LR1M) and clinical recurrence, respectively. Exponential models best described the data. LR1M and diabetes mellitus history were significant predictors for primary endpoint. Times to recurrence for patients with LRIM (+) and diabetes mellitus (+) were predicted to be 0.095 and 0.317 of those for patients with LRIM (-) and diabetes mellitus (-), respectively. LR1M was only predictor for secondary endpoint with predicted time to recurrence in patients with LR1M (+) compared to 0.141 of LR1M (-). Quantitative prediction of clinical recurrence using MRI could improve personalized therapy by identifying patients at risk of recurrence, and could enable efficient clinical trials by stratifying the patients., (© 2014, The American College of Clinical Pharmacology.)

Objective: Insulin-like growth factor binding protein 3 (IGFBP-3) is known to interfere with the NF-κB signaling pathway, and it effectively promotes apoptosis in tumor cells by a variety of mechanisms. NF-κB activation and apoptosis resistance of fibroblast-like synoviocytes (FLS) play pivotal roles in rheumatoid arthritis (RA). This study was undertaken to evaluate whether IGFBP-3 has antiarthritic effects., Methods: To deliver IGFBP-3, we used an adenovirus containing IGFBP-3 complementary DNA (AdIGFBP-3) or IGFBP-3 mutant that is devoid of IGF binding affinity but retains IGFBP-3 receptor binding ability (AdmtIGFBP-3). The regulatory roles of IGFBP-3 in inflammation and bone destruction were investigated in mice with collagen-induced arthritis (CIA)., Results: IGFBP-3 levels were significantly higher in patients with RA than in those with osteoarthritis (OA) and were notably higher in patients with active RA. AdIGFBP-3 suppressed NF-κB activation, chemokine production, and matrix metalloproteinase secretion induced by tumor necrosis factor α (TNFα) in RA FLS. AdIGFBP-3 sensitized RA FLS to TNFα-induced apoptosis in vitro and also significantly increased apoptosis in an in vivo model of Matrigel implants engrafted into immunodeficient mice. AdIGFBP-3-injected mice with CIA had attenuated arthritis severity and reduced radiologic and pathologic abnormalities. Moreover, AdIGFBP-3 down-regulated local and systemic levels of NF-κB-targeted proinflammatory cytokines. Of note, RA FLS and mice with CIA treated with AdmtIGFBP-3 exhibited similar effects as those treated with AdIGFBP-3., Conclusion: Our results suggest that both the inflammatory response and bone destruction are reduced with blockage of NF-κB activation and induction of apoptosis in RA FLS by IGFBP-3. Therefore, IGFBP-3 may have therapeutic potential in RA., (Copyright © 2014 by the American College of Rheumatology.)

Background: Various pacing studies have demonstrated an association between right ventricular pacing (RVp) and atrial fibrillation (AF), even after preserving atrioventricular (AV) synchrony. We aimed to assess the interaction between arterial stiffness, endothelial function and atrial high-rate episodes (AHRE) in patients with dual-chamber pacemakers., Methods: We studied 101 patients with dual-chamber pacemakers incorporated with sophisticated AF detection and therapy algorithms. Macrovascular endothelial dysfunction (ED) was measured by the relative change in aortic augmentation index (AIx), using carotid artery applanation tonometry in response to inhaled salbutamol and sublingual glyceryl trinitrate. Microvascular ED was measured by cutaneous laser Doppler flowmetry (LDF) in response to acetylcholine (Ach, endothelium dependent) and sodium nitroprusside (SNP, endothelium independent). Arterial stiffness was measured using carotid-femoral pulse wave velocity (PWVcf). 'Reservoir pressure' (Pr, MATLAB) describes the aortic 'cushioning' properties., Results: Mean age of the cohort was 72.1 ± 10.8 years; men (n = 69) 68.3%. Of 101 dual-chamber pacemaker patients, 23.8% (n = 24) had AHRE detected on the baseline pacemaker interrogation. PP, PWVcf and Pr were significantly higher in patients with AHRE compared with those without AHRE. The change in AIx with salbutamol (∆% AIx Sal) and acetylcholine-induced changes in LDF (Δ%LDF Ach) were lower in patients with AHRE compared with those without AHRE. In patients with AHRE, significant correlations were observed between%Vp and Δ%LDF Ach (P = 0.03) as well as between PP and Δ%LDF Ach (P = 0.05). On multivariate analysis, PP, Pr, PWVcf and ∆% AIx Sal remained as independent predictors of AHRE., Conclusion: In patients with dual-chamber pacemakers, both higher arterial stiffness and greater endothelial dysfunction independently predicted AHRE, irrespective of the degree (or mode) of pacing. Arterial stiffness and endothelial dysfunction may potentially contribute to the perpetuation of atrial arrhythmias beyond the adverse effects of ventricular pacing alone., (© 2013 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

Background: Endothelial damage/dysfunction may contribute to a prothrombotic state in patients with atrial fibrillation (AF) and the increased risk of thromboembolism and cardiovascular events. Raised plasma von Willebrand factor (vWf), an established marker of endothelial damage/dysfunction, has been associated with stroke and vascular events, at least in a clinical trial population. Soluble E-selectin (sE-sel) is another biomarker of endothelial activation/dysfunction, with more limited data on prognostic outcomes in AF., Objective: To assess the relationship between the levels of vWf, sE-sel and clinical adverse outcomes (including stroke, MI and all-cause mortality) in a 'real-world' community cohort of patients with AF., Methods: We studied 423 patients (mean age 72·7 ± 8·4 years, 55·6% male) with nonvalvular AF, with a median follow-up of 19 (9-31) months. Plasma vWf and sE-sel levels were measured using enzyme-linked immunosorbent assay (ELISA)., Results: There were 94 clinical adverse events (22·2%) observed during a median follow-up of 19 months. Patients with clinical events had significantly higher vWf (P < 0·001) and sE-sel levels at baseline (P < 0·001) compared with those who were event free. Kaplan-Meir analyses demonstrated that more clinical adverse events occurred in the upper tertile of vWf [upper vs. lowest tertile, RR 3·8, 95% CI (2·63-5·57), P < 0·001; upper vs. middle tertile, RR 10·5, 95% CI (5·33-20·60), P < 0·001]. Similarly, the highest tertile of sE-sel was associated with more adverse events [upper vs. lowest tertile, RR 3·7, 95% CI (2·51-5·31), P < 0·001; upper vs. middle tertile, RR 6·5, 95% CI (3·56-11·91), P < 0·001]., Conclusion: High plasma vWf and soluble E-selectin levels are associated with an increased risk of clinical adverse events (acute myocardial infarction, ischaemic stroke and all-cause mortality) in 'real-world' patients with AF. These soluble biomarkers may potentially aid clinical risk stratification in this common arrhythmia., (© 2013 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

Information about the QT interval from surface electrocardiograms (ECGs) is essential for surveillance of the proarrhythmia potential of marketed drugs. However, ECG records obtained in daily practice cannot be easily used for this purpose without labor-intensive manual effort. This study was aimed at constructing an open-access QT database, the Electrocardiogram Vigilance with Electronic Data Warehouse (ECG-ViEW). This longitudinal observational database contains 710,369 measurements of QT and associated clinical data from 371,401 patients. The de-identified database is freely available at http://www.ecgview.org.

Mitotic catastrophe provokes endopolyploidy, giant cell formation and, eventually, delayed cell death. Mitotic catastrophe is induced by defective cell cycle checkpoints and by some anticancer drugs, ionizing radiation and microtubule-destabilizing agents. RAD2 is a yeast homologue of XPG, which is a human endonuclease involved in nucleotide excision repair. Here we show that Rad2p overexpression alone, in the absence of extrinsic DNA damage, causes cell growth arrest and mitotic catastrophe. Interestingly, Rad2p-induced cell growth arrest is not caused by the catalytic activity of Rad2p but rather by its C-terminal region. Cells growth-arrested by Rad2p induction do not show apoptotic phenotypes and deletion of YCA1, a yeast caspase homologue, does not affect cell growth arrest by Rad2p induction. However, Rad2p-induced cell growth arrest is released by rad9 deletion but is not affected by downstream DNA damage checkpoint genes. These observations suggest that RAD2 has a function in coordinating cell cycle regulation and damaged DNA repair.

Background: The authors investigated whether ABCB1, ABCC2, and ABCG2 genetic polymorphisms affect pharmacokinetics (PK) of irinotecan and treatment outcome of patients with advanced nonsmall cell lung cancer (NSCLC)., Methods: Blood samples from 107 NSCLC patients treated with irinotecan and cisplatin chemotherapy were used for genotyping ABCB1 (1236C > T, 2677G > T/A, 3435C > T), ABCC2 (-24C > T, 1249G > A, 3972C > T), and ABCG2 (34G > A, 421C > A) polymorphisms. Genotypes were correlated with irinotecan-PK, toxicity, tumor response, and survival., Results: Among 8 polymorphisms, 3435TT and 2677TT were associated with AUC(SN-38G) and CL(SN-38G). When haplotypes are assigned, 2677TT/3435TT carriers showed significantly lower AUC(SN-38G) (P = .006), whereas 2677GG/3435CC carriers showed significantly higher AUC(SN-38) (P = .039). These findings suggest that 2677TT and 3435TT variants are associated with higher efflux activity. In toxicity, the 2677G/T or A was associated with grade 4 neutropenia. The 2677GG carriers showed significantly lower absolute neutrophil count during the 1(st) cycle (P = .012) as well as entire course of chemotherapy (P = .042). The 3435TT was associated with higher frequency of grade 3 diarrhea (P = .047). In tumor response, ABCC2 -24TT and 3972TT genotypes were associated with higher response rates (P = .031 and P = .048, [corrected] respectively) and longer progression-free survival (P = .010 and P = .019, [corrected] respectively), which was sustained in haplotype analysis., Conclusions: Specific polymorphisms of ABCB1 and ABCC2 can influence disposition and tumor response to irinotecan by regulating transporter activity. These findings may help to individualize irinotecan-based chemotherapy in patients with advanced NSCLC., (Copyright (c) 2007 American Cancer Society.)

Background: Combined chemotherapy with irinotecan and cisplatin (IP) is active in patients with nonsmall cell lung carcinoma (NSCLC). However, the optimal administration schedule needs to be defined to maximize its synergic effect. The authors evaluated the efficacy, toxicity, and pharmacokinetics (PK) of IP chemotherapy given on two administration sequences in chemotherapy-naive patients with NSCLC., Methods: Eighty eligible patients were assigned randomly to receive 1 of 2 irinotecan and cisplatin administration sequences on Day 1: irinotecan followed by cisplatin (I-P) (n = 39 patients) or cisplatin followed by irinotecan (P-I) (n = 41 patients). Treatment was comprised of irinotecan at a dose of 80 mg/m(2) intravenously on Days 1 and 8 and cisplatin at a dose of 60 mg/m(2) intravenously on Day 1 of a 21-day cycle for a maximum of 6 cycles. For PK analysis, serial plasma samples were obtained on Day 1 of the first cycle., Results: In total, 77 patients were assessable for efficacy. The overall response rate was 47%, and there was a trend in favor of P-I (54%) compared with I-P (39%). In multivariate logistic regression analysis, the P-I sequence and female gender were found to be significant predictors of a better response (P = 0.047 and P = 0.011, respectively). Overall toxicity profiles and PK parameters were similar in both arms., Conclusions: IP chemotherapy showed promising activity with a favorable 1-year survival rate. For future clinical use, the authors recommend administering cisplatin first and then irinotecan, because that sequence was associated with a higher response rate., (Copyright 2006 American Cancer Society.)

Background: Late rectal complication (LRC) was a major late complication in patients with uterine cervical carcinoma who were treated with a combination of external beam radiotherapy (EBRT) and high-dose-rate intracavitary irradiation (HDR-ICR). For the current study, the authors retrospectively evaluated dosimetric parameters that were correlated with LRC > or = Grade 2 in patients with uterine cervical carcinoma who were treated with curative radiotherapy, and they analyzed the appropriate dose estimates to the rectum that were predictive for LRC > or = Grade 2., Methods: Between July 1994 and September 2002, 157 patients who were diagnosed with Stage IB-IIIB cervical carcinoma and were treated with definitive radiotherapy were included. EBRT (41.4-66 grays [Gy] in 23-33 fractions) to the whole pelvis was delivered to all patients, with midline shielding performed after a 36-50.4 Gy external dose. HDR-ICR (21-39 Gy in 6-13 fractions to Point A) was administered at a rate of 2 fractions weekly after midline shielding of EBRT. LRC was scored using Radiation Therapy Oncology Group criteria. The total biologically effective dose (BED) at specific points, such as Point A (BED(Point A)), rectal point (BED(RP)), and maximal rectal point (BED(MP)), was determined by a summation of the EBRT and HDR-ICR components, in which the alpha/beta ratio was set to 3. Analyzed parameters included patient age, tumor size, stage, concurrent chemotherapy, ICR fraction size, RP ratio (dose at the rectal point according to the Point A dose), MP ratio (dose at the maximal rectal point according to the Point A dose), EBRT dose, BED(Point A), BED(RP), and BED(MP)., Results: The 5-year actuarial overall rate of LRC > or = Grade 2 in all patients was 18.4%. Univariate analysis showed that the RP ratio, MP ratio, EBRT dose, BED(Point A), BED(RP), and BED(MP) were correlated with LRC > or = Grade 2 (P < 0.05). Multivariate analysis showed that, of all clinical and dosimetric parameters evaluated, only BED(RP) was correlated with LRC > or = Grade 2 (P = 0.009). The 5-year actuarial rate of LRC > or = Grade 2 was 5.4% in patients with a BED(RP) < 125 Gy(3) and 36.1% in patients with a BED(RP) > or = 125 Gy(3) (P < 0.001)., Conclusions: BED(RP) was a useful dosimetric parameter for predicting the risk of LRC > or = Grade 2 and should be limited to < 125 Gy(3) whenever possible to minimize the risk of LRC > or = Grade 2 in patients with uterine cervical carcinoma who are treated with a combination of EBRT and HDR-ICR. Cancer 2005., (Copyright 2005 American Cancer Society.)

Background: The metabolic syndrome (MetS), predicting coronary heart disease (CHD), is a compound of risk factors including diabetes, obesity and hypertension. The relationship between the development of MetS, diabetes and CHD in patients with established hypertension is unclear. We hypothesized that patients with hypertension developing MetS are at increased risk of type II diabetes and CHD compared with patients who do not develop MetS., Materials and Methods: We prospectively studied 284 patients (100 with existing/established MetS) with hypertension but without diabetes and CHD over 4 years. MetS and diabetes were diagnosed by the modified NCEP and ADA criteria, and CHD risk by the Framingham risk equation; all patients had annual fasting blood sampling., Results: Over 4 years of follow up, 75 of the 184 patients (41%) initially free of MetS at baseline subsequently fulfilled the criteria for MetS. These patients (i.e. 'developing MetS') had higher baseline BMI, triglycerides and lower HDL cholesterol, with a higher calculated CHD risk (all P

Background: Tissue inhibitor of metalloproteinase-1 (TIMP-1) is associated with increased fibrosis of the extracellular matrix (ECM). Myocardial stiffness is a feature of diastolic dysfunction. We assessed circulating TIMP-1 as a marker of diastolic dysfunction in patients with type 2 diabetes mellitus (DM) and hypertension, who were compared with healthy controls., Methods: We recruited 54 patients (43 males; mean age 68 +/- 5 years) with treated type 2 DM (i.e. controlled glycaemia, hypertension, hyperlipidaemia), 35 (30 males; 69 +/- 8 years) treated nondiabetic hypertensives, and 31 healthy controls (18 males; 66 +/- 5 years). Circulating TIMP-1 was measured by ELISA. Using transthoracic echocardiography, the early (E) diastolic mitral inflow velocity was measured with pulse wave Doppler, and the early mitral annular velocity (e'), a recognized index of diastolic relaxation, was measured with tissue Doppler. The E/A ratio was also calculated and isovolumic relaxation time measured., Results: Mean e' levels differed significantly between controls, diabetics and hypertensives (P < 0.0001). Circulating TIMP-1 was significantly different between patients and controls (P = 0.006), but there was no statistically significant difference between the DM and hypertension group. In both groups, only e' was negatively correlated with TIMP-1 levels, with a stronger correlation among the hypertensive patients (Spearman r = -0.544, P = 0.001) when compared with the diabetic group (r = -0.341, P = 0.011)., Conclusion: Diastolic relaxation is impaired in diabetes and hypertensive patients. The relationship between TIMP-1 and e' may reflect increased myocardial fibrosis and consequent diastolic dysfunction, which may be more prominent in hypertension.

Background and Objectives: There have been considerable disagreements regarding the influence of MDR1 (ABCB1) polymorphisms on the disposition of P-glycoprotein (P-gp) substrates. We speculated that the unknown function of the A allele of exon 21 G2677T/A (Ala893Ser/Thr) provides one of the reasons for the contradictory results. This study was performed to clarify the effects of major MDR1 gene polymorphisms, including a variant A allele in exon 21, on fexofenadine pharmacokinetics., Methods: We investigated the occurrence of 3 high-frequency single-nucleotide polymorphisms (SNPs) in exons 12 (C1236T), 21 (G2677T/A), and 26 (C3435T) of the MDR1 gene in 232 healthy Koreans, using a polymerase chain reaction-restriction fragment length polymorphism method, and performed haplotype analysis on these 3 SNPs. A single oral dose of 180 mg fexofenadine hydrochloride was administered to 33 healthy Korean male volunteers, who were divided into 6 groups based on the MDR1 genotype for the G2677T/A polymorphism in exon 21 and the C3435T polymorphism in exon 26., Results: A strong linkage disequilibrium was observed among the 3 SNPs. The frequencies of the 4 major haplotypes, 1236C-2677A-3435C, C-G-C, T-G-C, and T-T-T, were 16.4%, 18.6%, 21.6%, and 32.2%, respectively. Fexofenadine disposition varied considerably among the groups. In the 2677AA/3435CC genotype group (n=3), the values of area under the concentration-time curve from time 0 to 24 hours [AUC(0-24)] were significantly lower (P=.014) than those of the other 5 genotype groups (GG/CC, GT/CT, TT/TT, GA/CC, and TA/CT). As compared with the 2677GG/3435CC subjects, the AUC(0-24) values were 17% lower in the 2677AA/3435CC subjects and 47% higher in the 2677TT/3435TT subjects (GG/CC versus AA/CC versus TT/TT, 4017 +/- 1137 ng . h/mL versus 3315 +/- 958 ng . h/mL versus 5934 +/- 2,064 ng . h/mL; P=.018). By stratification for genotypes at position 3435, homozygous 3435TT subjects were found to have significantly higher AUC(0-24) (P=.024) and maximum plasma concentration (P=.040) values than CC subjects [AUC(0-24), 5934 +/- 2064 ng . h/mL versus 3998 +/- 1241 ng . h/mL; maximum plasma concentration, 958 +/- 408 ng/mL versus 673 +/- 242 ng/mL]., Conclusions: The plasma concentrations of fexofenadine after a single oral administration were lower in 2677AA/3435CC subjects than in subjects with the other 5 genotype combinations of the SNPs of G2677T/A and C3435T. These findings confirm the importance of analyzing MDR1 haplotypes and provide a plausible explanation for the conflicting results regarding the effect of MDR1 polymorphisms on the disposition of P-gp substrates.

Objective: Our objective was to investigate the effect of the CYP3A5 genotype on the systemic clearance of midazolam in constitutive, inhibited, and induced metabolic conditions., Methods: Nineteen healthy volunteers were grouped with regard to the CYP3A5*3 allele, into homozygous wild-type (CYP3A5*1/*1, n = 6), heterozygous (CYP3A5*1/*3, n = 6), and homozygous variant-type (CYP3A5*3/*3, n = 7) subject groups. The pharmacokinetic profile of intravenous midazolam was characterized before and after itraconazole administration (200 mg once daily for 4 days) and also after rifampin (INN, rifampicin) pretreatment (600 mg once daily for 10 days), with a washout period of 2 weeks in between., Results: The pharmacokinetic profiles of midazolam and of its hydroxy metabolites did not show differences between the genotype groups under basal and induced metabolic conditions. However, during the inhibited metabolic state, the CYP3A5*3/*3 group showed a greater decrease in systemic clearance than was seen in the CYP3A5*1/*1 group (8.5 +/- 3.8 L. h(-1). 70 kg(-1) versus 13.5 +/- 2.7 L. h(-1). 70 kg(-1), P =.027). The 1'-hydroxymidazolam-to-midazolam area under the plasma concentration-time curve ratio was also significantly lower in the CYP3A5*3/*3 group (0.58 +/- 0.35 versus 1.09 +/- 0.37 for the homozygous wild-type group, P =.026)., Conclusions: The CYP3A5 genotype did not affect the pharmacokinetics of intravenous midazolam in the basal or induced states. However, during cytochrome P450 (CYP) 3A inhibition by itraconazole, individuals carrying the CYP3A5*1 allele were found to be less susceptible to changes in systemic clearance and showed higher 1'-hydroxymidazolam-to-midazolam area under the plasma concentration-time curve ratios, probably resulting from the relatively CYP3A4-specific inhibition caused by itraconazole.

To evaluate the pharmacokinetic and pharmacodynamic characteristics of YH1885, a novel proton pump inhibitor, a single-blind, randomized, placebo-controlled, dose-rising, parallel-group study was conducted in 46 healthy volunteers. The volunteers were randomly allocated to single dose groups of 60 mg, 100 mg, 150 mg, 200 mg, and 300 mg (6 subjects per dose, including 2 placebos) or to multiple-dose groups of 150 mg and 300 mg (once-daily dosing for 7 days; 8 subjects per dose, including 2 placebos). The multiple-dose study was conducted separately after the single-dose study. YH1885 was administered orally after overnight fasting. Serial blood samples, urine samples, and pharmacodynamic measurements were taken. Drug concentrations in plasma and urine were determined by liquid chromatography/mass spectrometry (LC/MS). Pharmacodynamic changes were evaluated by ambulatory intragastric pH monitoring and by serial measurements of serum gastrin concentrations. Assessments of safety and tolerability also were made. Plasma concentrations of YH1885 reached peak levels 1.3 to 2.5 hours after single-dose administration and then declined monoexponentially with a terminal half-life (t(1/2)) of 2.2 to 2.4 hours in dosage groups up to 200 mg in the single-dose study. YH1885 showed linear pharmacokinetic characteristics, and little accumulation occurred after multiple administrations. The parent drug was not detected in urine. Dose-related pharmacological effects were obvious for dose groups of 150 mg and higher in the single-dose study. The mean intragastric pH and the percentage of time at pH>4 were significantly increased. The onset of drug effect was rapid, and maximal effects were observed on the first day of administration during multiple dosing. Serum gastrin levels also showed rapid increases during dosing but with a weak dose-effect relationship. Neither serious nor dose-limiting adverse effects were observed. YH1885 was found to be safe and well tolerated and effectively inhibited acid secretion with dose-dependent increases in intragastric pH. The acid-suppressing efficacy of YH1885 needs to be further evaluated in patients with gastric acid-related diseases.

Objective: Our objective was to investigate ethnic differences in the oral pharmacokinetics of nifedipine and erythromycin, both typical cytochrome P4503A (CYP3A) substrates, in Koreans and Caucasians and to identify the nature of any correlations between the pharmacokinetic parameters of the two drugs., Methods: Twenty healthy male volunteers (10 Koreans and 10 Caucasians) received single oral doses of nifedipine (10 mg) or erythromycin (500 mg) in a randomized 2-way crossover study. Pharmacokinetic evaluations were performed, and parameters were compared for the two ethnic groups. During the nifedipine study period, hemodynamic measurements were conducted to determine the pharmacodynamic relevance of the pharmacokinetic differences., Results: Koreans showed area under the concentration-time curves (AUCs) for both drugs that were 1.6 to 1.7 times higher than those of Caucasians. This difference decreased to 1.3 when normalized for body weight. Significant correlation between the AUCs of the two drugs was not evident. Hemodynamic changes after nifedipine administration paralleled those of the pharmacokinetic differences, with significantly greater decreases in blood pressure and total peripheral resistance noted in Koreans., Conclusions: Koreans showed significantly lower oral clearances of nifedipine and erythromycin, probably because of genetic differences attributed to the CYP3A enzymes.

Cortisone has been reported to reduce significantly the plasma choline concentration in dogs within 30 min after its injection. However, in the present experiments hydrocortisone had no effect on the plasma choline concentration of mice, guinea-pigs and rabbits. The protective effect of hydrocortisone against the toxic effects of hemicholinium in mice which was described previously cannot, therefore, be attributed to changes in the concentration of plasma choline.