13-Week Repeated Oral Toxicity and Toxicokinetic Studies of Rabeprazole Sodium and Sodium Bicarbonate Combination in Dogs.

The subchronic toxicity and toxicokinetics of a combination of rabeprazole sodium and sodium bicarbonate were investigated in dogs by daily oral administration for 13 consecutive weeks with a 4-week recovery period. The dose groups consisted of control (vehicles), (5 + 200), (10 + 400), and (20 + 800) mg/kg of rabeprazole sodium + sodium bicarbonate, 20 mg/kg of rabeprazole sodium only, and 800 mg/kg of sodium bicarbonate only. Esophageal ulceration accompanied by inflammation was observed in only one animal in the male (20 + 800) mg/kg rabeprazole sodium + sodium bicarbonate group. However, the severity of the ulceration was moderate, and the site of occurrence was focally extensive; thus, it was assumed to be a treatment-related effect of rabeprazole sodium + sodium bicarbonate. In the toxicokinetics component of this study, systemic exposure to rabeprazole sodium (AUClast and Cmax at Day 91) was greater in males than females, suggesting sex differences. AUClast and Cmax at Day 91 were increased compared to those on Day 1 in a dose-dependent manner. A delayed Tmax and no drug accumulation were observed after repeated dosage. In conclusion, we suggest under the conditions of this study that the no-observed-adverse-effect level (NOAEL) of the combination of rabeprazole sodium + sodium bicarbonate in male and female dogs is (10 + 400) and (20 + 800) mg/kg, respectively.

Pharmacokinetic and Safety Comparison of Fixed-Dose Combination of Cilostazol/Rosuvastatin (200 + 20 mg) Versus Concurrent Administration of the Separate Components in Healthy Adults.

The combined cilostazol and rosuvastatin therapy is frequently used for coronary artery disease treatment. This open-label, 3 × 3 crossover clinical trial evaluated the pharmacokinetics and safety of a fixed-dose combination (FDC) of cilostazol/rosuvastatin (200 + 20 mg) versus a concurrent administration of the separate components (SCs) under both fasted and fed conditions. Among 48 enrolled healthy adults, 38 completed the study. Participants were administered a single oral dose of cilostazol/rosuvastatin (200 + 20 mg), either as an FDC or SCs in a fasted state, or FDC in a fed state, in each period of the trial. Blood samples were taken up to 48 hours after dosing, and plasma concentrations were analyzed using validated liquid chromatography-tandem mass spectrometry. The geometric mean ratios of FDC to SCs for area under the plasma concentration-time curve from time zero to the last quantifiable concentration (AUClast ) and maximum plasma concentration (Cmax ) were 0.94/1.05 and 1.06/1.15 for cilostazol and rosuvastatin, respectively (AUClast /Cmax ). Compared with that during fasting, fed-state administration increased the AUClast and Cmax for cilostazol by approximately 72% and 160% and decreased these parameters for rosuvastatin by approximately 39% and 43%, respectively. To conclude, the FDC is bioequivalent to the SCs, with notable differences in pharmacokinetics when administered in a fed state. No significant safety differences were observed between the treatments.

Pharmacokinetic Comparison Between a Fixed-Dose Combination of Atorvastatin/Omega-3-Acid Ethyl Esters and the Corresponding Loose Combination in Healthy Korean Male Subjects.

Purpose: Statins are widely used in combination with omega-3 fatty acids for the treatment of patients with dyslipidemia. The aim of this study was to compare the pharmacokinetic (PK) profiles of atorvastatin and omega-3-acid ethyl esters between fixed-dose combination (FDC) and loose combination in healthy subjects. Methods: A randomized, open-label, single-dose, 2-sequence, 2-treatment, 4-period replicated crossover study was performed. Subjects were randomly assigned to one of the 2 sequences and alternately received four FDC soft capsules of atorvastatin/omega-3-acid ethyl esters (10/1000 mg) or a loose combination of atorvastatin tablets (10 mg × 4) and omega-3-acid ethyl ester soft capsules (1000 mg× 4) for four periods, each period accompanied by a high-fat meal. Serial blood samples were collected for PK analysis of atorvastatin, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). PK parameters were calculated by a non-compartmental analysis. The geometric mean ratio (GMR) and its 90% confidence interval (CI) of the FDC to the loose combination were calculated to compare PK parameters. Results: A total of 43 subjects completed the study as planned. The GMR (90% CI) of FDC to loose combination for maximum concentration (Cmax) and area under the time-concentration curve from zero to the last measurable point (AUClast) were 1.0931 (1.0054-1.1883) and 0.9885 (0.9588-1.0192) for atorvastatin, 0.9607 (0.9068-1.0178) and 0.9770 (0.9239-1.0331) for EPA, and 0.9961 (0.9127-1.0871) and 0.9634 (0.8830-1.0512) for DHA, respectively. The intra-subject variability for Cmax and AUClast of DHA was 30.8% and 37.5%, respectively, showing high variability. Both the FDC and the loose combination were safe and well tolerated. Conclusion: The FDC of atorvastatin and omega-3-acid ethyl esters showed comparable PK characteristics to the corresponding loose combination, offering a convenient therapeutic option for the treatment of dyslipidemia.

Pharmacokinetic Interaction between Atorvastatin and Omega-3 Fatty Acid in Healthy Volunteers.

The interaction between statins and omega-3 fatty acids remains controversial. The aim of this phase 1 trial was to evaluate the pharmacokinetics of drug-drug interaction between atorvastatin and omega-3 fatty acids. Treatments were once-daily oral administrations of omega-3 (4 g), atorvastatin (40 mg), and both for 14 days, 7 days, and 14 days, respectively, with washout periods. The concentrations of atorvastatin, 2-OH-atorvastatin, docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) were determined with LC-MS/MS. Parameters of DHA and EPA were analyzed after baseline correction. A total of 37 subjects completed the study without any major violations. The geometric mean ratios (GMRs) and 90% confidence intervals (CIs) of the co-administration of a single drug for the area under the concentration-time curve during the dosing interval at steady state of atorvastatin, 2-OH-atorvastatin, DHA, and EPA were 1.042 (0.971-1.118), 1.185 (1.113-1.262), 0.157 (0.091-0.271), and 0.557 (0.396-0.784), respectively. The GMRs (90% Cis) for the co-administration at steady state of atorvastatin, 2-OH-atorvastatin, DHA, and EPA were 1.150 (0.990-1.335), 1.301 (1.2707-1.1401), 0.320 (0.243-0.422), and 0.589 (0.487-0.712), respectively. The 90% CIs for most primary endpoints were outside the range of typical bioequivalence, indicating a pharmacokinetic interaction between atorvastatin and omega-3.

Phytochemical studies of the phenolic substances in Aster glehni extract and its sedative and anticonvulsant activity.

On high performance liquid chromatography, the caffeoylquinic acid (CQ) occupying the highest proportion of the water-ethanol (7:3) extract of Aster glehni (Compositae) leaves was 3-Op-coumaroylquinic acid (46.10 ± 4.22 mg/g of dried weight) among CQs tested. The IC50 of the water-ethanol (7:3) extract was 4.23 ± 0.24 µg/mL in the peroxynitrite (ONOO(-))-scavenging assay. Phytochemical isolation from A. glehni extract yielded three kaempferol glycosides. The water-ethanol (7:3) extract and both p-coumaric acid and caffeic acid, phenylpropanoid moieties of CQs, had sedative effects in pentobarbital-induced sleeping time in mice and anticonvulsant effects in pentylenetetrazole-induced mice. Furthermore, the phenolic substance-rich W-E (7:3) extract of A. glehni could be used to treat anxiety or convulsion partly due to its peroxynitrite-scavenging mechanism.

Structure of a new echinocystic acid bisdesmoside isolated from Codonopsis lanceolata roots and the cytotoxic activity of prosapogenins.

We isolated a new saponin named codonoposide (1) from the roots of Codonopsis lanceolata (Campanulaceae) and characterized it as 3-O-[beta-D-xylopyranosyl(1-3)-beta-D-glucuronopyranosyl]-3beta,16alpha-dihydroxyolean-28-oic acid 28-O-[beta-D-xylopyranosyl (1-3)-alpha-L-rhamnopyranosyl (1-2)-alpha-L-arabinopyranosyl] ester by chemical, physicochemical, and 2DNMR techniques. Complete hydrolysis of 1 produced a sapogenin (1a), and the partial hydrolysis and further isolation afforded two prosapogenins (1b, 1c). The structures of 1a, 1b, and 1c were found to be 3beta,16alpha-dihydroxyolean-28-oic acid (echinocystic acid, 1a), 3-O-beta-D-glucuronopyranoside of 1a, and 3-O-beta-D-xylopyranosyl (1-3)-beta-D-glucuronopyranoside of 1a, respectively, on the basis of spectroscopic data. On MTT assay, 1a showed marginal cytotoxic activity whereas 1b exhibited more cytotoxicity than 1a. However, the bisdesmosylsaponin 1 exhibited no cytotoxicity (IC(50)>0.3 mM against tested cell lines). This result indicated that glycoside linkage of glucuronic acid at C-3 enhances the cytotoxicity of sapogenin (1a), and additive glycosylation of xylose to 1b strongly enhances the cytotoxicity of 3-O-monosaccharides (1b). Therefore, true forms of codonoposide for the cytotoxicity must be sapogenins or prosapogenins.