Pharmacokinetic comparison between a fixed-dose combination of fimasartan/amlodipine/ hydrochlorothiazide 60/10/25 mg and a corresponding loose combination of fimasartan/amlodipine 60/25 mg and hydrochlorothiazide 25 mg in healthy subjects

For the treatment of hypertension, fixed-dose combinations (FDCs) of antihypertensive drugs can provide complementary benefits from improved compliance and cost-effectiveness compared with loose combinations of corresponding drugs. A new FDC of fimasartan/ amlodipine/hydrochlorothiazide 60/10/25 mg is undergoing clinical development. A randomized, open-label, single-dose, 3-period, 3-sequence, partially replicated crossover phase 1 study was conducted to compare the pharmacokinetics (PKs) between the FDC of fimasartan/amlodipine/hydrochlorothiazide 60/10/25 mg and a loose combination of a dual-combination FDC (fimasartan/amlodipine 60/10 mg) and hydrochlorothiazide 25 mg. Sixty healthy subjects were randomized, and 55 subjects completed the study. Serial blood samples were collected, and plasma concentrations of fimasartan, amlodipine and hydrochlorothiazide were measured to analyze PK parameters. The PK profiles of the FDC were similar to those of the loose combinations. The geometric mean ratios (GMRs) and 90% confidence intervals (CIs) of the FDC to loose combinations for the maximum plasma concentration (Cmax ) and area under the curve until the last measurable time point (AUClast ) were within the conventional bioequivalent range of 0.80 to 1.25. The GMRs and 90% CIs of fimasartan, amlodipine and hydrochlorothiazide were 1.0163 (0.8681–1.1898), 0.9595 (0.9256–0.9946), and 1.1294 (1.0791–1.1821) for Cmax and 1.0167 (0.9347–1.1059), 0.9575 (0.9317–0.9841), and 1.0561 (1.0170–1.0967) for AUClast , respectively. Both the FDC and loose combinations were well tolerated. In conclusion, the FDC of fimasartan/amlodipine/ hydrochlorothiazide 60/10/25 mg showed similar PK profiles to those of the corresponding loose combination, and both treatments were well tolerated.

Clinical Case of a Transfusion-Associated Canine Mycoplasma haemocanis Infection in the Republic of Korea: A Case Report

This report describes the first clinical case of a transfusion-associated Mycoplasma haemocanis infection in a dog in Korea. A 6-year-old male Maltese underwent a red blood cell transfusion for idiopathic immune-mediated hemolytic anemia. Eighteen days after the blood transfusion, the recipient’s packed cell volume decreased and basophilic organisms were found on erythrocytes. A polymerase chain reaction and sequential analysis showed that both the donor dog and recipient dog had M. haemocanis. Six weeks after doxycycline administration, no organisms were detected and the recipient’s anemia had improved.

Parameter estimation for sigmoid E(max) models in exposure-response relationship

The purpose of this simulation study is to explore the limitation of the population PK/PD analysis using data from a clinical study and to help to construct an appropriate PK/PD design that enable precise and unbiased estimation of both fixed and random PD parameters in PK/PD analysis under different doses and Hill coefficients. Seven escalating doses of virtual drugs with equal potency and efficacy but with five different Hill coefficients were used in simulations of single and multiple dose scenarios with dense sampling design. A total of 70 scenarios with 100 subjects were simulated and estimated 100 times applying 1-compartment PK model and sigmoid E(max) model. The bias and precision of the parameter estimates in each scenario were assessed using relative bias and relative root mean square error. For the single dose scenarios, most PD parameters of sigmoid E(max) model were accurately and precisely estimated when the C(max) was more than 85% of EC₅₀, except for typical value and inter-individual variability of EC₅₀ which were poorly estimated at low Hill coefficients. For the multiple dose studies, the parameter estimation performance was not good. This simulation study demonstrated the effect of the relative range of sampled concentrations to EC₅₀ and sigmoidicity on the parameter estimation performance using dense sampling design.

Effect of High Glucose on Stress-Induced Senescence of Nucleus Pulposus Cells of Adult Rats

STUDY DESIGN: In vitro cell culture model. PURPOSE: We investigated the effect of diabetes mellitus (DM) on senescence of adult nucleus pulposus (NP) cells. OVERVIEW OF LITERATURE: DM is a major public health issue worldwide, especially adult-onset (type 2) DM. DM is also thought to be an important etiological factor in disc degeneration. Hyperglycemia is considered to be a major causative factor in the development of DM-associated diseases through senescence. However, little is known about the effects of DM on senescence in adult NP cells. METHODS: Adult NP cells were isolated from 24-week-old rats, cultured, and placed in either 10% fetal bovine serum (FBS, normal control) and 10% FBS plus two different high glucose concentrations (0.1 M or 0.2 M; experimental conditions) for 1 or 3 days. We identified and quantified the occurrence of senescence in adult rat NP cells using senescence-associated-beta-galactosidase (SA-beta-Gal) staining. We also investigated the expression of proteins related to the replicative senescence (p53-p21-pRB) and stress-induced premature senescence (p16-pRB) pathways. RESULTS: The mean SA-beta-Gal-positive percentage was increased in adult rat NP cells treated with high glucose in a dose- and time-dependent manner. Both high glucose levels increased the expression of p16 and pRB proteins in adult rat NP cells. However, the levels of p53 and p21 proteins were decreased in adult rat NP cells treated with both high glucose concentrations. CONCLUSIONS: The current study demonstrated that high glucose accelerated stress-induced senescence in adult rat NP cells in a dose- and time-dependent manner. Accelerated stress-induced senescence in adult NP cells could be an emerging risk factor for intervertebral disc degeneration in older patients with DM. These results suggest that strict blood glucose control is important in prevent or delaying intervertebral disc degeneration in older patients with DM.

Assessment of statistical power for covariate effects in data from phase I clinical trials

One of the important purposes in population pharmacokinetic studies is to investigate the relationships between parameters and covariates to describe parameter variability. The purpose of this study is to evaluate the model's ability to correctly detect the parameter-covariate relationship that can be observed in phase I clinical trials. Data were simulated from a two-compartment model with zero-order absorption and first-order elimination, which was built from valsartan's concentration data collected from a previously conducted study. With creatinine clearance (CLCR) being used as a covariate to be tested, 3 different significance levels of 0.001

A Study of Overactive Bladder for the Women Aged over 30 years

PURPOSE: This study was designed to provide the basic data for the development of the management program for overactive bladder by ascertaining its prevalence among Korean women aged over 30 years, and the factors related to its occurrence. MATERIALS AND METHODS: The study was performed by using self-questionnaires through the community-based cross sectional study from May to July, 2000. The subjects consisted of 2869 women, aged over 30 up to 89 years, among those who understood and responded to the questionnaires, and was residing in Seoul, Kyongki Kangwon, Chungchong, YongNam, HoNam, Cheju proinces. They also did not have known neurological problem and diabetes mellitus. The data were analyzed by Student t-test, chi2-test, and multiple logistic regression with using SAS program. RESULTS: The results were as follows ; 1. They all experienced at least one of frequency, urgency, nocturia, urge incontinence for the past one year and 52.3% of the subjects had experienced symptom at least once in 5 voidings. The highest prevalence of overactive bladder was 86.2% in the category for 70 to 89 years, 74.3% for the sixties, 45.3% for the forties, 42.5% for the thirties. In the symptoms of 1499 women among subject, 19.4% of them had nocturia, 18.2% frequency, 10.5% urgency, 9.6% urge incontinence, 9.5% frequency and urgency, 5.9% frequency and nocturia. 2. The age(OR = 1.041, 95% Cl = 1.027, 1.055) and the menopause(OR = 0.696, 95% Cl = 0.527, 0.919) were related to overactive bladder occurrence. CONCLUSIONS: The above findings indicated that about the half of the women aged over 30 years had symptoms for overactive bladder, and the prevalence was higher in old women and the women with menopause. So, the prevention and management programs for overactive bladder are required to be developed, and the primary screening programs based on community shall be developed.