Profiling of endogenous metabolites and changes in intestinal microbiota distribution after GEN-001 (Lactococcus lactis) administration.

This study aimed to identify metabolic biomarkers and investigate changes in intestinal microbiota in the feces of healthy participants following administration of Lactococcus lactis GEN-001. GEN-001 is a single-strain L. lactis strain isolated from the gut of a healthy human volunteer. The study was conducted as a parallel, randomized, phase 1, open design trial. Twenty healthy Korean males were divided into five groups according to the GEN-001 dosage and dietary control. Groups A, B, C, and D1 received 1, 3, 6, and 9 GEN-001 capsules (1 × 1011 colony forming units), respectively, without dietary adjustment, whereas group D2 received 9 GEN-001 capsules with dietary adjustment. All groups received a single dose. Fecal samples were collected 2 days before GEN-001 administration to 7 days after for untargeted metabolomics and gut microbial metagenomic analyses; blood samples were collected simultaneously for immunogenicity analysis. Levels of phenylalanine, tyrosine, cholic acid, deoxycholic acid, and tryptophan were significantly increased at 5-6 days after GEN-001 administration when compared with predose levels. Compared with predose, the relative abundance (%) of Parabacteroides and Alistipes significantly decreased, whereas that of Lactobacillus and Lactococcus increased; Lactobacillus and tryptophan levels were negatively correlated. A single administration of GEN-001 shifted the gut microbiota in healthy volunteers to a more balanced state as evidenced by an increased abundance of beneficial bacteria, including Lactobacillus, and higher levels of the metabolites that have immunogenic properties.

Nurses' Assessment of Sedation of Patients With Mental Illness: Scale Development and Validation.

The current study aimed to determine the reliability and validity of a tool for evaluating the sedation of patients with mental illness. A literature review and focus group interviews were used to develop the initial questionnaire. The scale was tested on a sample of 412 representative patients and analyzed using exploratory factor analysis, concurrent validity, and internal consistency. The final scale comprised 14 items across four factors related to sedation of patients with mental illness: arousal, affect, cognitive status, and physical performance. The scale has high sensitivity and specificity and can discriminate among levels of sedation for patients with mental illness. [Journal of Psychosocial Nursing and Mental Health Services, 58(12), 22-31.].

Cactus (Opuntia humifusa) water extract ameliorates loperamide-induced constipation in rats.

BACKGROUND: Korean cactus Cheonnyuncho (Opuntia humifusa) is rich in pectin, phenols, flavonoids, and minerals such as calcium and phosphorus. Some Koreans drink Cheonnyuncho juice prepared by grinding Cheonnyuncho with water. Cheonnyuncho is well known for its functional properties and antioxidant effects, but its effect on constipation has not been sufficiently studied. METHODS: Loperamide (2 mg/kg) was injected subcutaneously to induce constipation in rats. The animals were divided into four groups: a normal group (NOR), constipation control group (CON), and two constipation groups receiving the Cheonnyuncho extract (CE) at two different concentrations in drinking water, 3% (L-CE group) and 6% (H-CE group), for 25 days. RESULTS: The fecal pellet numbers of NOR and L-CE were significantly increased from 35.67 ± 2.09 (CON) to 50.60 ± 1.38 and 46.50 ± 2.91 after loperamide treatment, respectively (p < 0.05). The water content of fecal excretions was significantly enhanced in only the L-CE group (33.05 ± 0.49%) compared to control (23.38 ± 1.26%) (p < 0.05) after loperamide treatment. The oral intake of CE (L-CE and H-CE groups) significantly increased levels of the intestinal transit ratio (45.25 ± 1.86% and 41.05 ± 2.47%, respectively) compared to the CON group (32.15 ± 2.05%) (p < 0.05). Treatment with the low concentration of CE significantly increased fecal levels of acetic, propionic, butyric, and valeric acids, as well as the total short-chain fatty acid (SCFA) concentration. Histological analyses revealed that the thickness of the distal colon also increased in the CE-treated groups in a dose-dependent manner. CONCLUSIONS: Constipation decreased when CE was fed to the rats. In particular, the fecal pellet number and water content, as well as histological parameters such as distal colon thickness, improved. The CE treatment also increased the fecal SCFA content. These results show that the extract of Cheonnyuncho (O. humifusa) alleviated the symptoms of loperamide-induced constipation.

Cactus cladodes (Opuntia humifusa) extract minimizes the effects of UV irradiation on keratinocytes and hairless mice.

CONTEXT: Cactus cladodes [Opuntia humifusa (Raf.) Raf. (Cactaceae)] is one of the cactus genera, which has long been used as a folk medicine for skin disorders. OBJECTIVE: This study investigated the skincare potential of cactus cladodes extract (OHE), including its ability to regulate ultraviolet B (UVB)-induced hyaluronic acid (HA) production. MATERIALS AND METHODS: Gene expression levels of hyaluronic acid synthases (HASs) and hyaluronidase (HYAL) were measured in UVB-irradiated HaCaT cells with OHE treatment (10, 25, 50, 100 µg/mL) by real-time polymerase chain reaction (PCR). The HA content was analyzed in hairless mice (SKH-1, male, 6 weeks old) treated with OHE for 10 weeks by using enzyme-linked immunosorbent assay (ELISA). Haematoxylin and eosin (H&E) and immunohistological staining were performed to examine epidermal thickness and levels of CD44 and hyaluronic acid-binding protein (HABP). RESULTS: HA synthases (HAS,1 HAS2, HAS3) mRNA levels were increased by 1.9-, 2.2- and 1.6-fold, respectively, with OHE treatment (100 µg/mL), while UVB-induced increase of hyaluronidase mRNA significantly decreased by 35%. HA content in animal was decreased from 42.9 to 27.1 ng/mL by OHE treatment. HAS mRNA levels were decreased by 39%, but HYAL mRNA was increased by 50% in OHE group. CD44 and HABP levels, which were greatly increased by UVB-irradiation, were reduced by 64 and 60%, respectively. Epidermal thickness, transepidermal water loss (TEWL), and erythema formation was also decreased by 45 (45.7 to 24.2 µm), 48 (48.8 to 25 g/h/m2) and 33%, respectively. CONCLUSION: OHE protects skin from UVB-induced skin degeneration in HaCaT cells and hairless mice.

Effects of HM30181, a P-glycoprotein inhibitor, on the pharmacokinetics and pharmacodynamics of loperamide in healthy volunteers.

AIMS: HM30181 is a third generation P-glycoprotein (P-gp) inhibitor currently under development. The objectives of this study were to evaluate the effects of a single dose of HM30181 on the pharmacodynamics and pharmacokinetics of loperamide, a P-gp substrate, and to compare them with those of quinidine. METHODS: Eighteen healthy male subjects were administered loperamide alone (period 1) or with loperamide plus quinidine or HM30181 in period 2 or 3, respectively. In period 3, subjects randomly received one of three HM30181 doses: 15, 60 or 180 mg. Changes in pupil size, alertness, oxygen saturation and the oral bioavailability of loperamide were assessed in each period. In addition, the pharmacokinetics of HM30181 were determined. RESULTS: Pupil size, alertness and oxygen saturation did not change over time when loperamide alone or loperamide plus HM30181 was administered while HM30181 significantly increased the systemic exposure to loperamide, i.e. the geometric mean ratio (90% confidence interval) of AUC(0,tlast ) for loperamide with and without HM30181 was 1.48 (1.08, 2.02). Co-administered quinidine significantly increased the systemic exposure to loperamide 2.2-fold (1.53, 3.18), which also markedly reduced pupil size, resulting in a decrease of 24.7 mm h in the area under the effect curve of pupil size change from baseline compared with loperamide alone. CONCLUSIONS: HM30181 inhibits P-gp mainly in the intestinal endothelium, which can be beneficial because pan-inhibition of P-gp, particularly in the brain, could lead to detrimental adverse events. Further studies are warranted to investigate adequately the dose-exposure relationship of HM30181, along with its duration of effect.

Comparison of pectoralis major and serratus anterior muscle activities during different push-up plus exercises in subjects with and without scapular winging.

To examine the differences between men with and without scapular winging in the electromyographic (EMG) amplitude and activity ratio between the pectoralis major (PM) and serratus anterior (SA) during 3 push-up plus exercises: (a) the standard push-up plus (SPP), (b) the knee push-up plus (KPP), and (c) the wall push-up plus (WPP), and to determine which exercise induced the lowest PM/SA ratio in each group. Twenty-eight men participated in this study (13 scapular winging group: age, 21.8 ± 2.1 years; 15 control group: age, 23.3 ± 2.0 years). Surface EMG of the PM, SA, and activity ratio between the PM and SA were collected during 3 push-up plus exercises, and the EMG data were expressed as a percentage of the reference voluntary contraction (%RVC). The normalized PM activity for subjects in the scapular winging group was significantly greater than that in the control group (79.16 ± 6.65 %RVC vs. 39.66 ± 6.19 %RVC, p ≤ 0.05). The normalized SA activity was significantly lower in the scapular winging group compared with the control group (39.80 ± 4.09 %RVC vs. 56.28 ± 3.81 %RVC, p ≤ 0.05) and was significantly decreased in the following order: SPP > KPP > WPP; 77.09 ± 5.12 %RVC > 39.48 ± 3.38 %RVC > 27.55 ± 3.07 %RVC, p < 0.016). The PM/SA EMG ratio was significantly greater in the scapular winging group compared with that in the control group across all exercises and was significantly lower during SPP than that during KPP and WPP in both groups (1.13 ± 0.58 vs. 0.53 ± 0.25 for SPP, 3.50 ± 2.07 vs. 0.92 ± 0.63 for KPP, 4.04 ± 3.13 vs. 1.19 ± 0.66 for WPP, p < 0.016). Greater PM activity was found in the scapular winging group, and the SPP is an optimal exercise for subjects with scapular winging, where maximum SA activation with minimal PM activation is desired.

The growth of screening-detected pure ground-glass nodules after 10 years of stability.

BACKGROUND: It remains uncertain how long pure ground-glass nodules (pGGNs) detected on low dose computed tomography (LDCT) should be followed. Further studies with longer follow-up periods are needed to determine the optimal follow-up duration for pGGNs. RESEARCH QUESTION: What is the percentage of enlarging nodules among pGGNs that have remained stable for 10 years? STUDY DESIGN AND METHODS: This was a retrospective cohort study originating from subjects with pGGNs detected on LDCT scans between 1997 and 2006, whose natural courses were reported in 2013. We re-analyzed all the follow-up data until July 2022. The study subjects were followed by our institutional guidelines until they were no longer a candidate for definitive treatment. The growth of the pGGNs was defined as an increase in the diameter of the entire nodule by 2 mm or more or the appearance of new solid portions within the nodules. RESULTS: A total of 89 patients with 135 pGGNs were followed for a median of 193 months. Of 135 pGGNs, 23 (17.0%) increased in size, and the median time to the first detection of a size change was 71 months. Of the 23 growing pGGNs, 122 were detected on the first LDCT, and 13 were newly detected on the follow-up CT scan. An increase in size was observed within 5 years in 8 nodules (34.8%), between 5 and 10 years in 12 nodules (52.2%) and after 10 years in 3 nodules (13.0%). Fifteen nodules were histologically confirmed as adenocarcinoma by surgery. Among the 76 pGGNs stable for 10 years, 3 (3.9%) increased in size. INTERPRETATION: Among pGGNs that remained stable for 10 years, 3.9% eventually grew, indicating that some pGGNs can grow even after a long period of stability. We suggest that pGGNs may need to be followed for more than 10 years to confirm growth.

The influence of isolated femur and tibia rotations on patellar tendon stress: A sensitivity analysis using finite element analysis.

The purpose of this study was to determine the influence of frontal and transverse plane rotations of the femur and tibia on peak maximum principal stress in the patellar tendon. Using finite element modeling, patellar tendon stress profiles of eight healthy individuals were obtained during a simulated squatting task (45° of knee flexion). The femur and tibia of each model were rotated 10° (in 2° increments) along their respective axes beyond that of the natural degree of rotation. This process was repeated for the transverse plane (internal and external rotation) and frontal plane (adduction and abduction). Quasi-static loading simulations were performed to quantify peak maximum principal stress in patellar tendon. Internal and external rotations of the femur and tibia that exceeded 4° beyond that of the natural rotation resulted in progressively greater patellar tendon stress (p < 0.05). Incremental femur and tibia adduction and abduction resulted in an increase in patellar tendon stress, but only at the end range of motions evaluated. These results suggest that tibiofemoral rotations in the frontal and transverse planes have the potential to influence patellar tendon stress. In particular, patellar tendon stress is highly sensitive to small degrees of tibia and/or femur motions in the transverse plane.

Persons with Patellar Tendinopathy Exhibit Greater Patellar Tendon Stress during a Single-Leg Landing Task.

PURPOSE: This study aimed to compare peak maximum principal stress in the patellar tendon between persons with and without patellar tendinopathy during a simulated single-leg landing task. A secondary purpose was to determine the biomechanical predictor(s) of peak maximum principal stress in the patellar tendon. METHODS: Using finite element (FE) modeling, patellar tendon stress profiles of 28 individuals (14 with patellar tendinopathy and 14 pain-free controls) were created at the time of the peak knee extensor moment during single-leg landing. Input parameters to the FE model included subject-specific knee joint geometry and kinematics, and quadriceps muscle forces. Independent t -tests were used to compare the peak maximum principal stress in the patellar tendon and biomechanical variables used as input variables to the FE model (knee flexion, knee rotation in the frontal and transverse planes and the peak knee extensor moment) between groups. A stepwise regression model was used to determine the biomechanical predictor(s) of peak maximum principal stress in the patellar tendon for both groups combined. RESULTS: Compared with the control group, persons with patellar tendinopathy exhibited greater peak maximum principal stress in the patellar tendon (77.4 ± 25.0 vs 60.6 ± 13.6 MPa, P = 0.04) and greater tibiofemoral joint internal rotation (4.6° ± 4.6° vs 1.1° ± 4.2°, P = 0.04). Transverse plane rotation of the tibiofemoral joint was the best predictor of peak maximum principal stress in the patellar tendon ( r = 0.51, P = 0.01). CONCLUSIONS: Persons with patellar tendinopathy exhibit greater peak patellar tendon stress compared with pain-free individuals during single-leg landing. The magnitude of peak patellar tendon stress seems to be influenced by the amount of tibiofemoral rotation in the transverse plane.

Persons with patellar tendinopathy exhibit anatomical features that alter knee extensor mechanics: A comparison of persons with and without symptoms.

It has been postulated that anatomical features of the patellofemoral joint may alter knee extensor mechanics in a way that may contribute to excessive patellar tendon loading. The purpose of this study was to compare the knee extensor mechanics in persons with and without patellar tendinopathy. Twenty-eight individuals participated (14 with patellar tendinopathy and 14 pain-free controls). Sagittal magnetic resonance images of the knee were acquired at the knee flexion angle that corresponded to the knee flexion angle at the time of peak knee extensor moment during a single-leg landing task. Measurements of patellar tendon/quadriceps tendon force ratio, quadriceps moment arm, patellar tendon moment arm, and patellar height (Insall-Salvati ratio) were obtained. Independent t-tests were used to compare the variables of interest between groups. When compared to the control group, the patellar tendinopathy group exhibited significantly a greater patellar tendon/quadriceps tendon force ratio (Mean ± SD, 1.0 ± 0.1 vs 0.8 ± 0.1, p < 0.05), a larger quadriceps moment arm (Mean ± SD, 23.9 ± 2.0 mm vs 22.1 ± 2.9 mm, p < 0.05), a smaller patellar tendon moment arm (Mean ± SD, 24.2 ± 1.7 mm vs 26.3 ± 2.4 mm, p < 0.05) and a greater Insall-Salvati ratio (Mean ± SD, 1.2 ± 0.1 vs 1.1 ± 0.1, p < 0.05). These results suggest that persons with patellar tendinopathy may experience greater forces in the patellar tendon for a given level of quadriceps force.

Treatment of macular degeneration using embryonic stem cell-derived retinal pigment epithelium: preliminary results in Asian patients.

Embryonic stem cells hold great promise for various diseases because of their unlimited capacity for self-renewal and ability to differentiate into any cell type in the body. However, despite over 3 decades of research, there have been no reports on the safety and potential efficacy of pluripotent stem cell progeny in Asian patients with any disease. Here, we report the safety and tolerability of subretinal transplantation of human embryonic-stem-cell (hESC)-derived retinal pigment epithelium in four Asian patients: two with dry age-related macular degeneration and two with Stargardt macular dystrophy. They were followed for 1 year. There was no evidence of adverse proliferation, tumorigenicity, ectopic tissue formation, or other serious safety issues related to the transplanted cells. Visual acuity improved 9-19 letters in three patients and remained stable (+1 letter) in one patient. The results confirmed that hESC-derived cells could serve as a potentially safe new source for regenerative medicine.

Microemulsion formulation of clonixic acid: solubility enhancement and pain reduction.

Clonixic acid is currently marketed as a salt form because of its poor water-solubility. However, the commercial dosage form causes severe pain after intramuscular or intravenous injection. To improve the solubility of clonixic acid and to reduce pain on injection, clonixic acid was incorporated into oil-in-water microemulsions prepared from pre-microemulsion concentrate composed of varying ratios of oil and surfactant mixture. As an oil phase for drug incorporation, up to 14% castor oil could be included in the pre-microemulsion concentrate without a significant increase in droplet size. Both drug contents and droplet size increased as the weight ratio of Tween 20 to Tween 85 decreased. Taken together, when microemulsions were prepared from pre-microemulsion concentrate composed of 5:12:18 weight ratio of castor oil:Tween 20:Tween 85, clonixic acid could be incorporated at 3.2 mg mL(-1) in the microemulsion with a droplet size of less than 120 nm. The osmotic pressure of this microemulsion was remarkably lower than the commercial formulation, irrespective of the dilution ratios. The rat paw-lick test was used to compare pain responses among formulations. The microemulsion formulation significantly reduced the number of rats licking their paws as well as the total licking time, suggesting less pain induction by the microemulsion formulation. The pharmacokinetic parameters of clonixic acid after intravenous administration of the clonixic acid microemulsion to rats were not significantly different from those of the commercial formulation, lysine clonixinate. The present study suggests that microemulsion is an alternative formulation for clonixic acid with improved characteristics.

A comparison of the reliability of the trochanteric prominence angle test and the alternative method in healthy subjects.

A wide range of intra- and inter-rater reliabilities of the trochanteric prominence angle test (TPAT) has been reported. We introduced the transcondylar angle test (TCAT) as an alternative to the TPAT and using a smartphone as a reliable measurement tool for femoral neck anteversion (FNA) measurement. The reliabilities of the TPAT and the TCAT, the reliability of using a smartphone as a clinical measurement tool, and the correlation between the difference value of medial knee joint space (KJS) between rest and tested positions and the difference value between the TPAT and TCAT were assessed. Two physical therapists independently determined the reliabilities of the TPAT with a digital inclinometer, the TCAT with a digital inclinometer, and the TCAT with a smartphone in 19 hips of 10 healthy subjects (5 male and 5 female, 22.2 ± 1.69 years). The medial KJS in rest and the tested position were assessed using a sonography. The intra-class correlation coefficients (ICC) for the intra-rater reliabilities of TPAT with a digital inclinometer (ICC = 0.92), TCAT with a digital inclinometer (ICC = 0.94) and a smartphone (ICC = 0.95) in both testers were substantial. The inter-rater reliability of TPAT with a digital inclinometer was fair (ICC = 0.48) while TCAT with a digital inclinometer (ICC = 0.89) and a smartphone (ICC = 0.85) were substantial. The correlation between the difference value of medial KJS between rest and tested positions and the difference value between TPAT and TCAT was low and statistically non-significant (r = 0.114; p = 0.325). The TCAT would be more reliable than the TPAT in inter-rater test. Using a smartphone is a clinically comparable measuring tool to a digital inclinometer.

Musculoskeletal predictors of movement quality for the forward step-down test in asymptomatic women.

STUDY DESIGN: Cross-sectional. OBJECTIVE: To investigate the interrater reliability of movement-quality ratings for the forward step-down (FSD) test and to compare hip muscle strength and lower extremity joint range of motion and muscle flexibility among asymptomatic women with different levels of movement quality. BACKGROUND: The interrater reliability of the FSD test has not yet been investigated. Additionally, it is not known whether differences in musculoskeletal measures exist among individuals with different levels of movement quality during the FSD test. METHODS: Two physical therapists assessed movement quality during the FSD test in 26 asymptomatic women (mean ± SD age, 22.7 ± 0.9 years). Hip muscle strength and lower extremity joint range of motion and muscle flexibility were also assessed. The interrater reliability of the FSD test was estimated by using the kappa coefficient and percent agreement. Differences in musculoskeletal measures based on movement quality were assessed by independent t tests. RESULTS: The kappa coefficient and percent agreement for rating the quality of movement on the FSD test were 0.80 (95% confidence interval: 0.57, 1.00) and 85%, respectively. The subjects with moderate movement quality had significantly less strength of the hip abductors, less knee flexion range of motion measured in prone (quadriceps flexibility), and less hip adduction range of motion measured in sidelying (iliotibial band/tensor fascia latae flexibility) compared to those with good movement quality. CONCLUSION: There was good agreement for the rating of movement quality during the FSD test, and there were physical attributes that distinguished those with moderate from those with good quality of movement.

Effect of isometric horizontal abduction on pectoralis major and serratus anterior EMG activity during three exercises in subjects with scapular winging.

The aim of this study was to determine the effect of isometric horizontal abduction using Thera-Band during three exercises (forward flexion, scaption, and wall push-up plus) in subjects with scapular winging by investigating the electromyographic (EMG) amplitude of the pectoralis major, serratus anterior and the pectoralis major/serratus anterior activity ratio. Twenty-four males with scapular winging participated in this study. The subjects performed the forward flexion, scaption, and wall push-up plus with and without isometric horizontal abduction using Thera-Band. Surface EMG was used to collect the EMG data of the pectoralis major and serratus anterior during the three exercises. Two-way repeated analyses of variance with two within-subject factors (isometric horizontal abduction condition and exercise type) were used to determine the statistical significance of pectoralis major and serratus anterior EMG activity and the pectoralis major/serratus anterior EMG activity ratio. Pectoralis major EMG activity was significantly lower during forward flexion and wall push-up plus with isometric horizontal abduction, and serratus anterior EMG activity was significantly greater with isometric horizontal abduction. Additionally, the pectoralis major/serratus anterior activity ratio was significantly lower during the forward flexion and wall push-up plus with isometric horizontal abduction. The results of this study suggest that isometric horizontal abduction using Thera-Band can be used as an effective method to facilitate the serratus anterior activity and to reduce excessive pectoralis major activity during exercises for activating serratus anterior.

The pharmacokinetics and safety of a fixed-dose combination of acetylsalicylic acid and clopidogrel compared with the concurrent administration of acetylsalicylic acid and clopidogrel in healthy subjects: a randomized, open-label, 2-sequence, 2-period, single-dose crossover study.

BACKGROUND: Dual antiplatelet therapy with clopidogrel plus acetylsalicylic acid (ASA) is used for the treatment of acute coronary syndrome. A combined formulation of ASA and clopidogrel has been developed to provide dosing convenience and improve adherence. OBJECTIVE: This study was designed to compare the pharmacokinetic properties and safety profile of a fixed-dose combination formulation of ASA and clopidogrel with concurrent administration of each agent in healthy male Korean volunteers. METHODS: This single-dose, randomized, open-label, 2-period crossover study was conducted in 64 healthy Korean volunteers. Equal numbers of eligible participants were randomly assigned to receive either the fixed-dose combination of ASA 100 mg and clopidogrel 75 mg or the free combination of each agent followed by a 7-day washout period and then administration of the alternate formulation. Serial blood samples were collected immediately before and after dosing for 24 hours. The safety profile was evaluated by using adverse events (AEs), which were assessed by physical examination, vital signs, ECGs, clinical laboratory tests, and interviews. The 2 formulations were considered to be bioequivalent if the 90% CIs for the log-transformed C(max) and AUC(0-last) values were within the predetermined range of 0.8 to 1.25. RESULTS: Sixty-four volunteers (mean [SD] age, 27.51 [8.15] years; weight, 68.55 [7.86] kg; height, 173.80 [5.94] cm) were enrolled, and 63 completed the study. For ASA, the 90% CIs for the geometric mean ratios of C(max) and AUC(0-last) were 0.9483 to 1.1717 and 0.9946 to 1.1020, respectively. For salicylic acid, the 90% CIs were 0.9614 to 1.0396 for C(max) and 0.9778 to 1.0163 for AUC(0-last). For clopidogrel, the 90% CIs were 0.9809 to 1.2562 for C(max) and 0.9674 to 1.2073 for AUC(0-last). Six of the 20 AEs reported were drug related: decreased hemoglobin levels (n = 2), fever (n = 1), and headache (n = 1) with the test formulation and increased alanine aminotransferase levels (n = 1) and dyspepsia (n = 1) with the reference formulation. All of the drug-related AEs were transient and mild in severity. CONCLUSIONS: The fixed-dose combination of ASA and clopidogrel 100 mg/75 mg did not meet the regulatory criteria for bioequivalence as defined by the Korea Food and Drug Administration. Both formulations were well tolerated in these healthy male Korean subjects. ClinicalTrials.gov Identifier: NCT01448330.

Pharmacokinetic interactions between eperisone hydrochloride and aceclofenac: a randomized, open-label, crossover study of healthy Korean men.

BACKGROUND: Eperisone hydrochloride, a centrally acting muscle relaxant, is a calcium antagonist that causes vasodilation and antispastic actions. Aceclofenac, an anti-inflammatory analgesic and antipyretic drug, has similar efficacy and improved gastrointestinal tolerance compared with other nonsteroidal anti-inflammatory drugs, such as diclofenac. Although eperisone hydrochloride and aceclofenac are frequently coadministered, no published studies have reported on the pharmacokinetic interactions between these 2 drugs. OBJECTIVE: The aim of this study was to investigate any pharmacokinetic interactions between eperisone hydrochloride and aceclofenac in healthy Korean men. METHODS: This was a randomized, open-label, crossover study. Each participant was randomly assigned to 1 of 6 treatment sequences and received eperisone hydrochloride (3 doses of 50 mg each), aceclofenac (2 doses of 100 mg each), or both as a single dose with a 7-day washout period between each dose. Blood samples were collected ≤ 24 hours after dosing, and plasma eperisone hydrochloride and aceclofenac concentrations were determined using validated LC/MS-MS. Pharmacokinetic analyses were conducted using noncompartmental methods. A safety profile was determined using the measurement of vital signs, ECG, and clinical laboratory tests. RESULTS: A total 24 of men were enrolled, and all completed the study. The geometric mean ratios (90% CIs) of the Cmax and AUC0-∞ values for eperisone were 1.18 (0.828-1.673) and 1.12 (0.836-1.507), respectively. The geometric mean ratios (90% CIs) of the Cmax and AUC0-∞ for aceclofenac were 0.93 (0.847-1.022) and 1.01 (0.979-1.036), respectively. A total of 7 adverse events were reported in 7 men. All adverse events were mild, and no significant differences were found between treatment groups. CONCLUSION: No clinically significant pharmacokinetic differences exist between 150 mg eperisone hydrochloride and 200 mg aceclofenac when administrated as a monotherapy or in combination.

Pharmacokinetic and pharmacodynamic properties of a new long-acting granulocyte colony-stimulating factor (HM10460A) in healthy volunteers.

BACKGROUND: HM10460A is a newly developed recombinant human granulocyte colony-stimulating factor with long-lasting characteristics. This factor is expected to be used for chemotherapy-related neutropenic conditions. OBJECTIVE: The aim of the present study was to evaluate the pharmacokinetics and pharmacodynamics of HM10460A following subcutaneous administration to healthy Korean subjects. METHODS: A randomized, double-blind, placebo-controlled, escalating single-dose study was conducted in 40 healthy Korean subjects. The subjects were allocated to single-dose groups of 5, 15, 45, 135 or 350 µg/kg, or placebo. Serial blood samples for pharmacokinetic/pharmacodynamic analyses were collected up to 22 days, and urine samples for pharmacokinetic analysis were collected up to 3 days after subcutaneous administration of HM10460A. The serum and urine concentrations were analyzed by enzyme-linked immunosorbent assay. RESULTS: Most of the serum concentrations in the 5 and 15 µg/kg dosing groups were below the lower limit of quantification (LLOQ). The median times to the peak concentration (T(max)) of HM10460A in the 45, 135, and 350 µg/kg dosing groups were 8.0, 14.0, and 24.0 h, respectively. The mean ± standard deviation values of the dose-normalized maximum concentration (C(max)) and dose-normalized area under the concentration-time curve (AUC(last)) for the 45, 135, and 350 µg/kg dosing groups were 14.13 ± 6.37, 66.19 ± 38.71, and 34.65 ± 19.69 µg/L/mg, respectively, and 265.0 ± 124.1, 2144 ± 1232, and 1386 ± 701.2 µg h/L/mg, respectively. The concentrations of HM10460A in the urine were below the LLOQ in all of the subjects. In all of the dosing groups, the area under the effect-time curve (AUEC(last)) of both the absolute neutrophil count (ANC) and the CD34(+) cell count increased as the dose increased. CONCLUSION: HM10460A showed dose-dependent pharmacokinetic characteristics, and the systemic exposure of HM10460A was positively correlated with the ANC and CD34(+) cell counts.

Tolerability and pharmacokinetics of a new P-glycoprotein inhibitor, HM30181, in healthy Korean male volunteers: single- and multiple-dose randomized, placebo-controlled studies.

BACKGROUND: HM30181 is an oral P-glycoprotein (P-gp) inhibitor developed to enhance the oral bioavailability of P-gp substrate drugs. OBJECTIVE: The objective of this study was to investigate the tolerability and pharmacokinetic properties of HM30181 after single and multiple oral administrations to healthy Korean male volunteers. The study was performed to meet regulatory criteria for marketing the test product in South Korea. METHODS: A dose-block-randomized, double-blind, placebo-controlled, dose-escalation study was performed in 180-, 360-, 600-, and 900-mg single-dose groups and 60-, 180-, and 360-mg multiple-dose groups with 10 subjects (8 active; 2 placebo) per group. In the single-dose study, blood and urine samples were collected for up to 120 hours after drug administration. In the multiple-dose study, subjects received the study drug or placebo orally once daily for 5 days. Blood samples were collected up to 624 hours after the last dose, and up to 24 hours after the first dose to evaluate the accumulation index. Urine samples were collected up to 120 hours after the last dose. Pharmacokinetic analysis was performed using noncompartmental methods. Adverse events were collected by the spontaneous reporting of the subjects or when subjects were asked general health-related questions. RESULTS: Thirty and 70 healthy male volunteers completed the single- and multiple-dose studies, respectively. Mean (SD) age and body weight of subjects in the single administration group were 24.0 (1.8) years and 68.8 (7.4) kg, respectively, and those of the multiple administration group were 24.5 (2.6) years and 67.6 (7.7) kg, respectively. The plasma concentrations peaked at 14 to 42 hours and declined with t(½) of 75.7 to 169.3 hours after single administration, and peaked at 5.5 to 8.0 hours and declined with t(½) of 153.5 to 215.2 hours after multiple administrations. C(max) and area under the concentration curve within dosing intervals (AUC(τ)) increased dose dependently after single administration; however, dose-dependent increases in C(max) and AUC(τ) were not observed after multiple administrations. The fraction of drug excreted unchanged in urine was minimal, with values <0.01% in all dose groups. HM30181 accumulated after multiple administrations with an accumulation index of 4.0 to 7.4. All adverse events reported were mild in intensity; there were no serious adverse events reported. The most frequently reported adverse event was gastrointestinal disorder. CONCLUSIONS: HM30181 was well tolerated after oral administration within the dose range evaluated, with the exception of the repeated administration of 360 mg, for which gastrointestinal disorders were frequently reported. The systemic exposure of HM30181 was relatively low, and dose proportional properties of HM30181 were not observed.

Pharmacokinetic comparison of controlled- and immediate-release formulations of dexibuprofen after single and multiple oral doses in fasting healthy male Korean volunteers.

BACKGROUND: Dexibuprofen is a pure S(+)-enantiomer product of racemic ibuprofen. A new extended-release form of dexibuprofen has recently been developed. OBJECTIVE: We aimed to compare pharmacokinetic characteristics of controlled-release (CR) and immediate-release (IR) formulations of dexibuprofen after single and multiple oral doses in fasting healthy male Korean volunteers. METHODS: Both single- and multiple-dose studies used an open-label, randomized, 2-way, crossover design. In the single-dose study, 24 subjects were administered a 600-mg CR or 300-mg IR formulation. In the multiple-dose study, 24 subjects were administered a 600-mg CR formulation q12h or 300-mg IR formulation q6h. Pharmacokinetic parameters of dexibuprofen were determined by noncompartmental analysis. RESULTS: All formulations used in the single- and multiple-dose studies were well tolerated, and there were no severe adverse events. In the single-dose study, the mean (SD) AUC(0-t) was 155.60 (40.94) µg/h/mL for the CR formulation and 161.11 (37.50) µg/h/mL for the IR formulation; the mean (SD) C(max) values were 22.71 (6.64) and 23.77 (4.91) µg/mL, respectively; and the median T(max) values were 2.01 hours and 2.00 hours, respectively. The geometric mean ratios (90% CI) of the CR to IR formulations were 0.96 (0.92-1.00) for AUC(0-t) and 1.00 (0.87-1.14) for C(max). In the multiple-dose study, the mean (SD) AUC(0-τ) values for CR and IR were 129.70 (23.72) µg/h/mL and 150.04 (27.09) µg/h/mL, respectively; the mean (SD) C(max,ss) values were 24.51 (5.12) and 21.69 (5.21) µg/mL, respectively; and the median T(max.ss) values were 2.51 hours and 5.25 hours, respectively. The geometric mean ratios (90% CI) of the CR to IR formulations were 0.86 (0.81-0.91) for AUC(0-τ) and 1.13 (1.03-1.24) for C(max). CONCLUSIONS: The pharmacokinetic parameters of single and multiple administrations of dexibuprofen did not differ for the IR and CR formulations in this small, selected group of healthy male Korean subjects. Both formulations were well tolerated.