Pharmacokinetics of a new once-daily controlled-release sarpogrelate hydrochloride compared with immediate-release formulation and the effect of food.

WHAT IS KNOWN AND OBJECTIVE: Sarpogrelate is a selective 5-hydroxytryptamine receptor subtype 2A antagonist that inhibits platelet aggregation and vasoconstriction. The aim of this study was to compare the pharmacokinetics of a sarpogrelate controlled-release formulation (CR) with those of the immediate-release formulation (IR). The effect of food on the pharmacokinetics of CR sarpogrelate was also evaluated. METHODS: A randomized, open-label, 3-period, 3-treatment crossover study was conducted in 50 healthy male subjects. Subjects were allocated into one of six sequence groups. In one period, a 100-mg IR formulation was administered three times at 6-h intervals, and in the other two periods, a 300-mg CR formulation was administered once to fasting and once to fed subjects. Each period was separated by a 7-day washout period. Serial blood samples were collected up to 24 h after the first drug administration in each period. The plasma concentrations of sarpogrelate were analysed by liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were calculated by non-compartmental methods. RESULTS AND DISCUSSION: After the administration of the IR formulation, the plasma concentration reached a peak at 0·48 h and the drug was eliminated with a half-life (t1/2 ) of 0·7 h. After administration of the CR formulation, the plasma concentration reached a peak at 0·5 h and the drug was eliminated with a t1/2 of 3·23 h. The geometric mean ratios (CR/IR) for sarpogrelate area under the plasma concentration-time curve (AUC) and the maximum plasma drug concentration (Cmax) were 1·2040 (90% confidence interval (CI): 1·0992-1·3188) and 0·9462 (90% CI: 0·8504-1·0529). When CR was administered to fed subjects, the time to peak concentration was prolonged to 3·97 h and t1/2 was shortened to 1·45 h. The geometric mean ratios (fasting/fed) for sarpogrelate AUC and Cmax were 0·8573 (90% CI: 0·7687-0·9561) and 0·6452 (90% CI: 0·5671-0·7341). WHAT IS NEW AND CONCLUSION: After the administration of CR and IR formulations of the same daily dose of sarpogrelate hydrochloride, the overall systemic exposure was slightly higher for the CR than for the IR formulation, whereas peak concentration was comparable between the two formulations. Food reduced the bioavailability of sarpogrelate CR.

Frequency and risk factors of drug-induced liver injury during treatment of multidrug-resistant tuberculosis.

OBJECTIVES: To investigate the risk factors for drug-induced liver injury (DILI) during the treatment of multidrug-resistant tuberculosis (MDR-TB) and to compare the frequency of DILI in patients with and those without chronic liver disease (CLD). SETTING: This was a retrospective observational cohort study including 299 consecutive patients who started MDR-TB treatment from January 2009 to December 2013. DESIGN: Of the 299 patients, 35 had alcoholic liver disease (ALD group), 16 had hepatitis B virus infection (HBV group) and 11 had hepatitis C virus infection (HCV group). The remaining 237 patients without CLD were selected as the control group. RESULTS: DILI occurred in 29 (9.7%) patients. The frequency of DILI was significantly higher in the ALD (17.1%, P = 0.038), HBV (31.3%, P = 0.005) and HCV groups (27.3%, P = 0.037) than in the control group (6.3%). Among all patients taken together, having HBV and HCV infection were independent risk factors for the occurrence of DILI during MDR-TB treatment. CONCLUSION: DILI during MDR-TB treatment occurred more frequently in patients with CLD due to ALD, HBV and HCV infection than in those without CLD.

A comparative pharmacodynamic study of IY-81149 versus omeprazole in patients with gastroesophageal reflux disease.

OBJECTIVE: To evaluate and compare the pharmacodynamic effects of IY-81149 and omeprazole on gastric pH in patients with gastroesophageal reflux disease. METHODS: Sixty male and female volunteers with gastroesophageal reflux disease were enrolled in a double-blind, two-way, crossover, dose-ranging study. Subjects were randomized into three groups, with each group comparing the effect of one of three doses of IY-81149 (5, 10, or 20 mg) with 20 mg omeprazole. IY-81149 and omeprazole were administered once daily for 5 days. Continuous 24-hour pH measurements were performed before the first dose (baseline) and after the fifth dose in both periods. Gastric acid suppression was evaluated on the basis of the following parameters: AUC(0-24), median pH in a 24-hour interval (pHmedian), and the percent time in a 24-hour interval in which the gastric pH was greater than 4 (tpH > 4). The truncated AUC parameters AUC(0-8), AUC(8-16), and AUC(16-24) were also calculated. The effects of IY-81149 and omeprazole on gastric pH were compared by use of analyses of covariance. The dose-response relationship for IY-81149 was also evaluated. RESULTS: There were no statistically significant differences between 5 mg IY-81149 and 20 mg omeprazole in terms of AUC(0-24), pHmedian, tpH, 4, AUC(0-8), and AUC(8-16). IY-81149, at 10 mg, produced a significantly greater gastric acid suppression than omeprazole on the basis of the values of AUC(0-24), pHmedian, tpH > 4, AUC(8-16), and AUC(16-24). Administration of 20 mg IY-81149 produced a significantly greater gastric acid suppression on the basis of all parameters. All doses of IY-81149 were more effective than omeprazole during 16 to 24 hours after the dose was administered. CONCLUSIONS: Administration of 10 and 20 mg IY-81149 produced a statistically significantly greater and prolonged suppression of gastric pH than 20 mg omeprazole.

Constituents of the essential oil of the Cinnamomum cassia stem bark and the biological properties.

GC-MS analysis on the essential oil (CC-oil) of Cinnamomum cassia stem bark led to the identification of cinnamaldehyde (CNA, 1), 2-hydroxycinnamaldehyde (2-CNA), coumarin (2), and cinnamyl acetate. The major volatile flavor in CC-oil was found to be 2-CNA. Coumarin was first isolated from this plant by phytochemical isolation and spectroscopic analysis. CNA and CC-oil showed potent cytotoxicity, which was effectively prevented by N-acetyl-L-cysteine (NAC) treatment. Intraperitoneal administration with CNA considerably decreased malondialdehyde (MDA) formation and glutathione S-transferase activity in rats. These results suggest that CC-oil and CNA can regulate the triggering of hepatic drug-metabolizing enzymes by the formation of a glutathione-conjugate.

Racemization of lens crystalline constituents in UV-induced cataract evaluated by chiral GC/MS spectroscopy.

The racemization of amino acids is hypothesized to cause cataract by disrupting the crystalline's tertiary structure, which, in turn, alters the optical characteristics of the lens. To better understand the role of these modifications in cataractogenesis, the changes in stereoisomer ratio of amino acids from lens crystalline by UV-B-induced cataract in animal models were studied using chiral separation gas chromatography-single quadrupole mass spectroscopy. The anticataract action of a compound, ([1-(phenylmethyl)-1H-indazol-3-yl]oxy)acetic acid lysinate, was also evaluated by this method.

Syringin 4-O-beta-glucoside, a new phenylpropanoid glycoside, and costunolide, a nitric oxide synthase inhibitor, from the stem bark of Magnolia sieboldii.

Syringin 4-O-beta-glucoside (1), a new phenylpropanoid glycoside, and costunolide (2) were isolated from the stem bark of Magnolia sieboldii. The structures were determined by spectroscopic and chemical methods. Costunolide (2) exhibited strong nitric oxide synthase inhibitory activity in the endotoxin-activated murine macrophage, J774.1.

Induction Chemotherapy Followed by Concurrent Chemoradiotherapy in Locoregional Esophageal Cancer.

PURPOSE: The object of this study is to evaluate the efficacy and toxicity of induction chemotherapy followed by concomitant chemoradiotherapy in locoregional esophageal cancer. MATERIALS AND METHODS: Between December 1992 and December 1999, 43 patients with locoregional esophageal cancer were enrolled in this phase II trial. Patients were treated with 2-cycles of induction chemotherapy followed by concomitant chemoradiotherapy. F-P chemotherapy consists of 1,000 mg/m2/Day of 5-FU as continuous infusion on day 1~5 and 80 mg/m2 of cisplatin as an intravenous bolus on day 1 and was repeated every 3~4 weeks. All patients received 60 Gy of external beam radiation concomitantly with F-P chemotherapy; intraluminal brachytherapy was added in 12 patients. A total of 4 cycles of chemotherapy were delivered. No further treatment was planned in patients who achieved complete remission after completion of the treatment. RESULTS: Among the 43 patients entered, 35 patients completed the protocol. Of the 35 evaluable patients, 12 patients (34%) achieved complete response and 13 patients (37%) achieved partial response. In 26 of 33 patients, dysphagia was improved. At a median follow-up of 22 months, the 2-year and 5-year survival rates were 39% and 19%, respectively. The median survival duration of the complete responder group was 69 months (4~100 months) and the 2-year survival rate of the complete responder group was 82%. Toxicities were tolerable, comprised of mucositis and cytopenia. CONCLUSION: Induction chemotherapy followed by concurrent chemoradiotherapy in locoregional esophageal cancer is well tolerated and effective.