Efficacy and safety of CKD-495 in acute and chronic gastritis: A Phase III superiority clinical trial.

BACKGROUND: Despite the availability of numerous treatment options, many patients with gastritis experience only partial symptom relief. CKD-495, a newly developed product with the active ingredient extracted from Cinnamomum cassia Presl., has demonstrated anti-inflammatory and antioxidant activity in vitro and an in vivo protective effect against gastric damage by stimulating mucus secretion. This study compared the efficacy and safety of CKD-495 with Artemisiae argyi folium (AAF) for the treatment of acute and chronic gastritis. AAF, a gastric mucosa protective agent that promotes gastric mucosa regeneration, has been used clinically for about 20 years. METHODS: This phase III multicenter, randomized, double-blind, parallel-group trial (ClinicalTrials.gov; NCT04255589) assigned 242 patients with endoscopically-proven gastric mucosal erosions to receive CKD-495 75 mg (n = 122) or AAF 60 mg (n = 120), respectively, with placebo (for double-blind purposes) 3 times a day for 2 weeks. The primary efficacy endpoint was the erosion improvement rate. Secondary endpoints included erosion cure rates, and improvement rates for edema, redness, hemorrhage, and gastrointestinal (GI) symptoms. Drug-related adverse events were evaluated. RESULTS: The erosion improvement rate was significantly higher in the CKD-495 group than in the AAF group for both the full analysis set (55.9% vs 39.4%, P = .0063) and per-protocol set (54.6% vs 38.2%, P = .0084). In addition, the erosion improvement rate in patients with acute or chronic gastritis showed that the CKD-495 group had better improvement of erosion than the AAF group, especially in patients with chronic gastritis. Analysis of secondary endpoints, which included erosion cure rate and the improvement rates of edema, redness, hemorrhage, and GI symptoms, showed that the CKD-495 group was more effective than the AAF group. There were no significant between-group differences in safety profiles. No serious adverse events or adverse drug reactions occurred. CONCLUSIONS: These results demonstrate that CKD-495 75 mg is superior to AAF 60 mg in terms of the endoscopic improvement rate of erosions in patients with acute or chronic gastritis. This new mucoprotective agent, CKD-495, can be considered the therapy of choice for symptomatic relief and healing of gastritis.

Comparison of the Pharmacokinetics, Safety, and Tolerability of Two Empagliflozin Formulations in Healthy Korean Subjects.

Purpose: Empagliflozin is a sodium-glucose cotransporter 2 inhibitor that is commonly used for the treatment of type 2 diabetes mellitus. As cocrystal formulation can improve the chemical properties of drugs, CKD-370 was newly developed as a cocrystal formulation of empagliflozin with solvate L-proline. This study aimed to compare the pharmacokinetics, safety, and tolerability of these two empagliflozin formulations in healthy Korean subjects. Methods: A randomized, open-label, two-sequence, two-period crossover study was conducted on healthy Korean participants. The subjects received a single oral 25 mg dose of either test (CKD-370) or reference treatment (Jardiance®) tablet at each period. Plasma empagliflozin concentrations were determined using liquid chromatography with tandem mass spectrometry. Pharmacokinetic (PK) parameters were analyzed using non-compartmental methods. The primary PK parameters included the maximum concentration (Cmax) and the area under the concentration-time curve from 0 to last (AUClast). The safety of both formulations was monitored and evaluated. Results: A total of 28 healthy Korean adult subjects were randomized, and 27 subjects were included in the PK analysis. The mean ± standard deviation values of the primary PK parameters, Cmax and AUClast after administration of the test treatment, were 442.02 ± 103.37 µg/L and 3131.08 ± 529.30 µg·h/L, respectively, and those after administration of the reference treatment were 436.29 ± 118.74 µg/L and 3006.88 ± 514.21 µg·h/L, respectively. The geometric mean ratio and its 90% confidence interval of test to reference treatment for Cmax and AUClast were 1.0221 (0.9527-1.0967) and 1.0411 (1.0153-1.0677), respectively, which were within the commonly accepted bioequivalence criteria of 0.80 to 1.25. Both treatments were well-tolerated. Conclusion: The two formulations of empagliflozin showed similar PK characteristics and were generally well tolerated in healthy subjects.

Pharmacokinetic Comparison Between a Fixed-Dose Combination of Empagliflozin L-Proline/Metformin and Empagliflozin/Metformin in Healthy Korean Subjects.

Empagliflozin and metformin are oral antidiabetic drugs commonly used to treat type 2 diabetes mellitus as a combination therapy. This study aimed to compare the pharmacokinetics and safety of a newly developed fixed-dose combination of 5-mg empagliflozin L-proline and 1000-mg metformin with the reference drug. A randomized, open-label, single-dose, 2-period, 2-treatment, crossover study was conducted in healthy Korean subjects. The subjects received a single oral dose of reference drug or test drug at each period. The pharmacokinetic (PK) parameters were calculated using a noncompartmental method. The geometric mean ratios and 90% confidence intervals of the plasma maximum concentration (Cmax ) and area under the concentration-time curve from time zero to the last quantifiable concentration (AUClast ) were calculated. A total of 27 healthy subjects were included in the PK analysis. For empagliflozin, the geometric mean ratios (90% confidence intervals) of the test to reference drug for Cmax and AUClast were 1.03 (0.99-1.08) and 1.03 (1.00-1.06), respectively. For metformin, the corresponding values for Cmax  and AUClast were 0.99 (0.92-1.06) and 1.00 (0.94-1.06), respectively. In conclusion, a fixed-dose combination of empagliflozin L-proline and metformin showed similar PK characteristics to the reference drug, and both drugs were safe in healthy subjects.

Network Pharmacological Analysis on the Herbal Combinations for Mitigating Inflammation in Respiratory Tracts and Experimental Evaluation.

The regulation of inflammatory mediators, such as TNF-α, IL-6, IL-1ß, and leukotriene B4, could play a crucial role in suppressing inflammatory diseases such as COVID-19. In this study, we investigated the potential mechanisms of drug combinations comprising Ephedrae Herba, Schisandra Fructus, Platycodonis Radix, and Ginseng Radix; validated the anti-inflammatory effects of these drugs; and determined the optimal dose of the drug combinations. By constructing a herb-compound-target network, associations were identified between the herbs and tissues (such as bronchial epithelial cells and lung) and pathways (such as the TNF, NF-κB, and calcium signaling pathways). The drug combinations exerted anti-inflammatory effects in the RAW264.7 cell line treated with lipopolysaccharide by inhibiting the production of nitric oxide and inflammatory mediators, including TNF-α, IL-6, IL-1ß, and leukotriene B4. Notably, the drug combinations inhibited PMA-induced MUC5AC mRNA expression in NCI-H292 cells. A design space analysis was carried out to determine the optimal herbal medicine combinations using the design of experiments and synergy score calculation. Consequently, a combination study of the herbal preparations confirmed their mitigating effect on inflammation in COVID-19.

Molecular Mechanism of Cinnamomum cassia against Gastric Damage and Identification of Active Compounds.

Cinnamomum cassia is a natural product found in plants that has been used as a folk remedy for inflammation. In this study, we investigated the mechanism underlying the anti-inflammatory and antioxidant properties of C. cassia extract (ECC) in lipopolysaccharide (LPS)-induced murine RAW 264.7 cells, in comparison with 4-hydroxycinnamaldehyde, a C. cassia extract component. ECC and 4-hydroxycinnamaldehyde inhibited the production of nitrite oxide in a dose-dependent manner and did not show any change in cellular toxicity when treated with the same dose as that used in the nitrite assay. Moreover, they attenuated ROS accumulation after lipopolysaccharide (LPS) stimulation. ECC and 4-hydroxycinnamaldehyde decreased the mRNA and protein expression levels of inflammatory mediators (iNOS and COX-2) and cytokines such as TNF and IL-6. We also found that ECC and 4-hydroxycinnamaldehyde mitigated the phosphorylation of ERK, JNK, and transcription factors, such as NF-κB and STAT3, suppressing NF-κB nuclear translocation in LPS-activated macrophages. In addition, administration of ECC in a Sprague Dawley rat model of acute gastric injury caused by indomethacin significantly increased the gastric mucus volume. Analysis of serum and tissue levels of inflammatory mediators revealed a significant decrease in serum PGE2 and myeloperoxidase levels and a reduction in gastric iNOS, COX-2, and p65 protein levels. Collectively, these results suggest that ECC has antioxidant and anti-inflammatory effects and is a potential candidate for curing gastritis.

Mitigation of Gastric Damage Using Cinnamomum cassia Extract: Network Pharmacological Analysis of Active Compounds and Protection Effects in Rats.

Gastritis is a common disease worldwide that is caused by various causes such as eating habits, smoking, severe stress, and heavy drinking, as well as Helicobacter pylori infections and non-steroidal anti-inflammatory drugs. Cinnamomum cassia is a tropical aromatic evergreen tree commonly used as a natural medicine in Asia and as a functional food ingredient. Studies have reported this species' anti-obesity, anti-diabetic, and cardiovascular disease suppression effects. We evaluated the potential effects of C. cassia using non-steroidal anti-inflammatory drugs (NSAIDs), ethanol (EtOH), and ethanol/hydrochloric acid (HCl)-induced gastric mucosal injury models. C. cassia extracts reduced the area of gastric mucosa injury caused by indomethacin, NSAID, EtOH, and EtOH/HCl. We also applied a network pharmacology-based approach to identify the active compounds, potential targets, and pharmacological mechanisms of C. cassia against gastritis. Through a network pharmacology analysis, 10 key components were predicted as anti-gastritis effect-related compounds of C. cassia among 51 expected active compounds. The NF-κB signaling pathway, a widely known inflammatory response mechanism, comprised a major signaling pathway within the network pharmacology analysis. These results suggest that the anti-gastritis activities of C. cassia may be induced via the anti-inflammatory effects of key components, which suppress the inflammation-related genes and signaling pathways identified in this study.

Pharmacokinetic properties and bioequivalence of gefitinib 250 mg in healthy Korean male subjects.

Gefitinib is an anti-cancer drug used to treat non-small cell lung cancer. The objective of this study was to compare the pharmacokinetics and evaluate the bioequivalence of 2 orally administered gefitinib 250 mg tablets in healthy Korean subjects. A randomized, open-label, single-dose, crossover bioequivalence study was conducted. A total of 50 healthy male volunteers were randomized into 2 sequence groups. During each treatment, the subjects received the test or reference formulation of 250 mg gefitinib with a washout period of 21 days. The plasma samples were collected at pre-dose and up to 144 hours post-dose, and plasma drug concentrations were measured using validated liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were calculated, and the formulations were considered as bioequivalent if the 90% confidence intervals (CIs) of the geometric mean ratios were within the bioequivalence limits of 0.8 to 1.25. Forty-one subjects completed the study and were included in the pharmacokinetic analysis. The 90% CIs of the geometric mean ratios of the test formulation to the reference formulation were 0.8115 to 0.9993 for maximum plasma concentration and 0.9119 to 1.0411 for area under the plasma concentration versus time curve from dosing to the last measurable concentration. There were no serious or unexpected adverse events during the study. In healthy Korean adult subjects, the test and reference formulations of gefitinib 250 mg had similar pharmacokinetic parameters and similar plasma concentration-time profiles. The test formulation of gefitinib met the regulatory criteria for assuming bioequivalence. Both formulations were safe and well-tolerated.

The safety and efficacy of CKD-497 in patients with acute upper respiratory tract infection and bronchitis symptoms: a multicenter, double-blind, double-dummy, randomized, controlled, phase II clinical trial.

BACKGROUND: Acute upper respiratory tract infection (AURI) together with acute bronchitis is the most common illness worldwide. Botanical medicines used as expectorants and antitussives have proven to be effective while also having excellent safety margins. We aimed at evaluating the efficacy and safety of a new botanical drug, CKD-497, in patients with AURI and acute bronchitis. METHODS: In this phase 2 study, 225 patients were enrolled and randomly assigned to one of four treatment groups: placebo (n=55), Synatura® (n=49), CKD-497 200 mg (n=68), or CKD-497 300 mg (n=53). The study drugs were administered three times daily over the course of 7 days. Primary endpoint was the change in the bronchitis severity score (BSS) from baseline to day 7. Secondary endpoint was evaluated based on clinical response rates on days 4 and 7. A safety analysis was also performed. RESULTS: Between baseline and day 7, the mean BSS scores decreased significantly in each group (P<0.001): -4.04±1.85, -4.31±1.47, -4.09±1.48, and -4.28±1.69. However, neither the CKD-497 nor Synatura® group showed any significant effect on the difference in BSS change (P=0.75). The rate of clinical response was higher in the CKD-497 300 mg group as compared to the placebo only on day 4 (36% vs. 18%; P<0.05) and those having more severe bronchitis (phlegm score ≥3) showed a significant reduction of total BSS in the Synatura® and CKD-497 groups (P=0.042). No significant adverse events were observed in either of the CKD-497 groups. CONCLUSIONS: CKD-497 and even the positive control drug had no significant effect on BSS change in this phase 2 clinical trial. However, CKD-497 300 mg had a mild but significant clinical improvement in early bronchitis patients with more severe phlegm. Considering both efficacy and safety, a future study using 300 mg of CKD-497 with a shorter-term endpoint is warranted in patients with more severe bronchitis symptoms.

Standardized Extract of Atractylodis Rhizoma Alba and Fructus Schisandrae Ameliorates Coughing and Increases Expectoration of Phlegm.

Cough and phlegm frequently occur in respiratory diseases like upper respiratory tract infections, acute bronchitis, and chronic obstructive pulmonary diseases. To relieve these symptoms and diseases, various ingredients are being used despite the debates on their clinical efficacy. We aimed to investigate the effects of the extract CKD-497, composed of Atractylodis Rhizoma Alba and Fructus Schisandrae, in relieving cough and facilitating expectoration of phlegm. CKD-497 was found to inhibit inflammatory mediators such as interleukin-8 (IL-8) and tumor necrosis factor α (TNF-α) in lipopolysaccharide (LPS)-treated mouse macrophages and transient receptor potential cation channel 1 (TRPV-1)-overexpressed human bronchial epithelial cells stimulated by capsaicin. CKD-497 decreased the viscosity of the mucin solution. During in vivo experiments, CKD-497 reduced coughing numbers and increased expectoration of phlegm via mucociliary clearance enhancement. Collectively, these data suggest that CKD-497 possesses potential for cough and phlegm expectoration treatment.

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

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

Pharmacokinetics of a Lobeglitazone/Metformin Fixed-Dose Combination Tablet (CKD-395 0.5/1000 mg) Versus Concomitant Administration of Single Agents and the Effect of Food on the Metabolism of CKD-395 in Healthy Male Subjects.

This study aimed to compare the pharmacokinetic profile of combined CKD-395 0.5/1000 mg treatment with that of the coadministration of lobeglitazone sulfate 0.5 mg and metformin hydrochloride (HCl) extended-release (XR) 1000 mg and assess the effect of food on the pharmacokinetics of CKD-395 0.5/1000 mg. Two clinical trials were conducted as part of an open-label, single-dose, randomized, 2-period, 2-sequence crossover study. In study 1, a total of 26 subjects received either CKD-395 0.5/1000 mg as a test drug or coadministration of lobeglitazone sulfate 0.5 mg and metformin HCl XR 1000 mg individually as a reference treatment under fed conditions. In study 2, a total of 16 subjects received CKD-395 0.5/1000 mg treatment under either fasted or fed conditions. Blood samples were collected at intervals from 0 to 48 hours. In study 1, the geometric mean ratios and 90% confidence intervals of pharmacokinetic parameters for lobeglitazone and metformin were all within 80%-125% in the fed condition. In study 2, there were no high-fat meal effects on the area under the curve extending up to the last sampling time (AUClast ) of lobeglitazone, but there was a decrease in the maximum plasma concentration (Cmax ) of lobeglitazone by approximately 32% in the fed condition. Although the AUClast of metformin increased by approximately 70% in the fed condition, there was no effect of food on the Cmax of metformin, which is consistent with the already-established food effect on metformin HCl XR. No adverse drug reactions or serious adverse events were observed. This study suggests that CKD-395 0.5/1000 mg exhibits similar exposure and absorption rates to coadministration of single agents and is well tolerated under both fasted and fed conditions.

Early formulation development of CKD-519, a new CETP inhibitor, for phase 1 clinical study based on in vitro and in vivo evaluation.

CKD-519, a potent cholesteryl ester transfer protein (CETP) inhibitor, is a clinical candidate being developed for the treatment of dyslipidemia. It is considered a Biopharmaceutical Classification System II compound with low solubility and high permeability. The objective of this study was to develop early formulations focusing on the dissolution rate of the compound to achieve dose-dependent exposure. High performance formulation strategies including solid dispersion (SD) and a self-microemulsifying drug delivery system (SMEDDS) were investigated and their in vivo and in vitro correlations were also evaluated in monkeys along with dose optimization in human volunteers. The SD granules were prepared in a fluid bed granulator using microcrystalline cellulose and mannitol as carriers. Poloxamer 407 and Eudragit E PO were each found to be a suitable solubilizing agent and polymer for the improvement of the CKD-519 dissolution rate. Pharmacokinetic studies in monkeys showed that the SD tablets exhibited better absorption than the SMEDDS in a dose-dependent manner from 1.5 mg to 100 mg. The mannitol-based SD tablet formulations were bioequivalent. However, pharmacokinetics studies in humans showed that the dose was saturable above 100 mg of CKD-519. This study was performed to determine how to develop early formulations for clinical studies and to identify rational formulation development strategies for CKD-519 to establish the pharmaceutical proof-of-concept in humans.

Pharmacokinetics and bioequivalence of 0.5 mg lobeglitazone tablets in healthy male subjects
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OBJECTIVE: This study was conducted to evaluate the pharmacokinetics and bioequivalence of two formulations of -DuvieTM (0.5-mg lobeglitazone sulfate). MATERIALS AND METHODS: This study was designed as an open-label, randomized, single-dose, crossover bioequivalence study in healthy male subjects. A total of 28 subjects were randomized into two groups: one group received the test drug, 0.5-mg DuvieTM tablets, which have formulations available on the global market; and the other group received the reference drug, the initially-approved 0.5-mg DuvieTM tablets. Plasma samples were collected for up to 48 hours after drug treatment and were analyzed for lobeglitazone using validated liquid chromatography-tandem mass spectrometry. Individual pharmacokinetic properties were determined by noncompartmental methods. Safety assessments were performed. RESULTS: 28 subjects completed the study and were included in the pharmacokinetic analysis. The mean (standard deviation) values of -AUClast for the test and reference formulations were 367.49 (157.92) and 362.40 (140.05) ng×h/mL, respectively. The mean (standard deviation) values of Cmax for the test and reference formulations were 50.35 (6.94) and 49.29 (6.71) ng/mL, respectively. The 90% confidence intervals for AUClast and Cmax were 0.9150 - 1.1088 and 0.9879 - 1.0561, respectively. All adverse events were mild, and there were no serious adverse events. CONCLUSION: This study suggests that the two lobeglitazone tablet formulations have similar exposure and absorption rates. Therefore, the newly-developed formulation of the 0.5-mg DuvieTM tablet is expected to contribute to the treatment of patients with type 2 diabetes.
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New tablet formulation of tacrolimus with smaller interindividual variability may become a better treatment option than the conventional capsule formulation in organ transplant patients.

To evaluate the pharmacokinetic (PK) and tolerability profiles of a new tablet formulation of tacrolimus and its interindividual variability (IIV) in the systemic exposure, and to compare them with those of the conventional capsule formulation, a randomized, open-label, two-treatment, two-period, two-sequence, crossover study was performed in 47 healthy males. The capsule or tablet formulation of tacrolimus was orally administered, and serial blood samples were collected up to 96 hours after dosing. Whole-blood tacrolimus concentration was determined using liquid chromatography-tandem mass spectrometry. The maximum whole-blood tacrolimus concentration (Cmax) and the area under the whole-blood tacrolimus concentration-time curve from 0 hour to the last quantifiable concentration (AUClast) were compared between the two formulations. The similarity factor (f2) of the in vitro dissolution profiles was calculated. The geometric mean ratio (90% confidence interval) of tablet to capsule was 0.9680 (0.8873-1.0560) and 1.0322 (0.9359-1.1385) for Cmax and AUClast, respectively. The IIV of Cmax and AUClast of the tablet was smaller than the capsule. The f2 values were >50 in all media. Both formulations were well tolerated. Thus, the tablet formulation of tacrolimus has smaller IIV in the systemic exposure than capsule, while having comparable PK and tolerability profiles, which may render it as a better treatment option for organ transplant patients.

Single-dose, randomized crossover comparisons of different-strength imatinib mesylate formulations in healthy Korean male subjects.

BACKGROUND: Imatinib mesylate is used to treat chronic myeloid leukemia and advanced gastrointestinal stromal tumors. OBJECTIVE: The purpose of this study was to compare the pharmacokinetics of 2 different strengths of the imatinib formulation containing 100 mg (reference) and 400 mg (test) to satisfy the regulatory requirement for marketing. METHODS: A single-center, randomized, single-dose, open-label, 2-period, 2-sequence, comparative crossover study with a 14-day washout period was conducted in 30 healthy male volunteers. Plasma samples for the drug analysis were collected up to 72 hours after drug treatment. Participants received either the reference (4 tablets of 100-mg imatinib) or the test (1 tablet of 400-mg imatinib) formulation during the first period and the alternative formulation during the second period. The safety profiles and tolerability of the 2 formulations were also assessed based on physical examinations, laboratory tests, a 12-lead ECG, and vital signs. RESULTS: Thirty participants were initially enrolled; their mean (SD) age, height, weight, and body mass index were 24.9 (2.0) years (range, 23-30 years), 174 (5) cm (range, 164-185 cm), 69.9 (2.0) kg (range, 54.1-87.4 kg), and 23.0 (2.0) kg/m(2) (range, 18.5-26.9 kg/m(2)); 28 healthy participants completed both treatment periods. Two subjects did not complete the study because they withdrew consent for personal reasons. The observed mean (SD) Cmax, AUC0-last, and AUC0-∞ values for the reference formulation were 1792 (357) ng/mL, 28,485 (6274) ng · h/mL, and 29,079 (6371) ng · h/mL, respectively. Corresponding values for the test formulation were 1710 (312) ng/mL, 27,222 (4624) ng · h/mL , and 27,872 (4751) ng · h/mL. The geometric mean ratios (90% CIs) between the 2 formulations at the 400-mg dose of imatinib were 0.9579 (0.9054-1.0136) for Cmax, 0.9652 (0.9174-1.0155) for AUC0-last, and 0.9679 (0.9203-1.0179) for AUC0-∞, respectively. During the study period, 6 adverse events (3 for the reference and 3 for the test formulation) were reported; all were transient, mild, and resolved completely during the treatment period. There were 4 cases of nausea and 1 case each of dizziness and oropharyngeal pain. Four adverse events were considered related to the study drugs. CONCLUSIONS: The results showed that despite the different strengths of the 2 imatinib formations, the test and reference formulations both met the regulatory criteria for pharmacokinetic equivalence at a dose of imatinib 400 mg in these healthy Korean male subjects. Both imatinib formulations seemed to be generally well tolerated. ClinicalTrials.gov identifier: NCT01270984.

Alteration of media composition and light conditions change morphology, metabolic profile, and beauvericin biosynthesis in Cordyceps bassiana mycelium.

Metabolic alterations of Cordyceps bassiana mycelium were investigated under the following culture medium and light conditions: dextrose agar supplemented with 0.5% yeast extract (SDAY) medium with light (SL), SDAY medium without light (SD), nut medium without light (ND), and iron-supplemented SDAY medium without light (FD). The levels of asparagine, aspartic acid, glutamic acid, glutamine, histidine, lysine, ornithine, and proline were significantly higher under SD and SL conditions. The levels of most of the alcohols, saturated fatty acids, unsaturated fatty acids, fatty acid esters, sterols, and terpenes were higher under the ND condition than in the other conditions, but beauvericin was not detectable under the ND condition. The FD condition was favorable for the enhanced production of aminomalonic acid, malic acid, mannonic acid, and erythritol. Thus, the metabolic characteristics of C. bassiana can be manipulated by varying the cultivation conditions, rendering this fungus potentially favorable as a nutraceutical and medicinal resource.

Simple preparative gas chromatographic method for isolation of menthol and menthone from peppermint oil, with quantitative GC-MS and (1) H NMR assay.

The quantitative performance of a simple home-built preparative gas chromatography (prep-GC) arrangement was tested, incorporating a micro-fluidic Deans switch, with collection of the target compound in a deactivated uncoated capillary tube. Repeat injections of a standard solution and peppermint sample were made into the prep-GC instrument. Individual compounds were eluted from the trapping capillary, and made up to constant volume. Chloronaphthalene internal standard was added in some cases. Recovered samples were quantitatively assayed by using GC-MS. Calibration linearity of GC-MS for menthol standard area response against number of injections (2-20 repeat injections) was excellent, giving R(2) of 0.996. For peppermint, menthol correlation over 2-20 repeated injections was 0.998 for menthol area ratio (versus IS) data. Menthone calibration for peppermint gave an R(2) of 0.972. (1) H NMR spectroscopy was conducted on both menthol and menthone. Good correspondence with reference spectra was obtained. About 80 µg of isolated menthol and menthone solute was collected over a sequence of 80 repeat injections from the peppermint sample, as assayed by 600 MHz (1) H NMR analysis (∼100% recovery for menthol from peppermint). A procedure is proposed for prediction of number of injections required to acquire sufficient material for NMR detection.

Two-step pilot-scale biofilter system for the abatement of food waste composting emission.

A pilot-scale two-step biofilter system was evaluated in treating food waste composting emission for 220 days. Wood chips were packed at the bottom section while mixture of rock wool and earthworm compost (6% w/v) was packed at the top section. Inlet ammonia concentration was found to be dominant and intermittent. The overall ammonia removal of over 98% was achieved, 70% of which was removed in the wood chip section. The highest ammonia elimination capacity was determined to be 39.43 g-NH(3)/m(3)/h at 99.5% removal efficiency. From biodegradation kinetic analysis, the maximum removal rate, V(m), of the wood chip section was determined to be 200 g-NH(3)/m(3)/h and the saturation constant, K(s), 180 mg/m(3). For the rock wool-earthworm cast mixture section, the V(m) was 87 g-NH(3)/m(3)/h and K(s) was 87 mg/m(3). Complete removal of hydrogen sulfide and most trace compounds were achieved by the biofilter. Highest hydrogen sulfide elimination rate was 0.22 g-H(2)S/m(3)/h. The biofilter was optimized from 24 to 16 s EBRT with resulting low average pressure drops of 16 and 29 mm H(2)O/m, respectively.

Effects of pollutant concentration ratio on the simultaneous removal of NH3, H2S and toluene gases using rock wool-compost biofilter.

The biological treatment of a tri-component mixed waste gas system in BRC1 and BRC2 biofilters packed with rock wool-compost media was studied. The model gases were NH(3), H(2)S and toluene. The gases were fed initially at about 50-55 ppm each. H(2)S was found to have the shortest start-up while toluene had the longest. Under two different NH(3):H(2)S:toluene concentration ratios of 250:120:55 and 120:220:55 (in ppm) for BRC1 and BRC2, the removal efficiencies of NH(3), H(2)S and toluene were found to be affected by their respective loading rate. On the other hand, toluene removal was observed to be inhibited at H(2)S concentration of 220 ppm as well. Almost complete removal of NH(3) and H(2)S was achieved when loading rate was applied up to 16.14 g-NH(3)/(m(3) bed h) and 36.09 g-H(2)S/(m(3) bed h), respectively. The maximum elimination capacity for NH(3) was determined to be 23.67 g-NH(3)/(m(3) bed h) at 78.6% removal efficiency and for H(2)S, 38.50 g-H(2)S/(m(3) bed h) at 68.1% removal efficiency. The maximum toluene elimination capacity was 30.75 g-toluene/(m(3) bed h) at 87.9% removal efficiency when the concentration of NH(3):H(2)S:toluene was 250:120:55 in BRC1, and was 16.60 g-toluene/(m(3) bed h) at 45.5% removal efficiency when the concentration of NH(3):H(2)S:toluene was 120:220:55 in BRC2. The pressure drops along both columns were low and the ratio of bed compactions over biofilter height was observed to be less than 0.02.

Effects of barefoot habituation in winter on thermal and hormonal responses in young children--a preliminary study.

This study investigated how socks-wearing habit or habitual barefoot in the cold winter affected skin temperatures of distal lower extremities, the urinary excretion of adrenaline, noradrenaline and cortsisol in young children. In Experiment I for preschool children, the measurements of foot and leg skin temperatures were conducted for 30 min in the classroom controlled at 23+/-2 degres C and 50+/-5%RH, and the excretion of urinary catecholamines and cortisol during nocturnal sleep were analyzed. In Experiment II for elementary school children, nocturnal secretion of urinary catecholamines and cortisol was analyzed. While leg skin temperature tended to be lower in barefoot group than in socks group during Experiment I, foot skin temperature was not significantly different between the two groups. Fall of leg skin temperature during 30 min measurement tended to be smaller in barefoot group than in socks group. Urine volume and urinary excretion of cortisol tended to be greater in barefoot group than in socks group for preschool children. Urinary noradrenaline was significantly greater and cortisol tended to be greater in barefoot group than in socks group for elementary school children. Considering that most of the findings shown above were in the proximity of the established level of statistical significance, it was provisionally concluded that young children with barefoot habituation might show more effective cold adaptation of metabolic type than those without the habituation do, by keeping their skin temperatures higher even in the cold and enhancing the metabolic rate.