This study aimed to compare the pharmacokinetics of fixed-dose combination (FDC) tablet of rosuvastatin 20 mg/ezetimibe 10 mg with that of concurrent administration of individual rosuvastatin 20 mg tablet and ezetimibe 10 mg tablet in healthy subjects. A randomized, open label, single-dose, two-way crossover study was conducted. Subjects randomly received test formulation (FDC tablet of rosuvastatin 20 mg/ezetimibe 10 mg) or reference formulation (co-administration of rosuvastatin 20 mg tablet and ezetimibe 10 mg tablet). After 2 weeks of washout, subjects received the other treatment. Blood samples were collected up to 72 hours post-dose in each period. Plasma concentrations of rosuvastatin, ezetimibe and total ezetimibe (ezetimibe + ezetimibe glucuronide) were analyzed by liquid chromatography-tandem mass spectrometry (LC/MS/MS). The geometric mean ratio (GMR) of Cmax and AUClast (90% confidence interval, CI) for rosuvastatin was 1.036 (0.979–1.096) and 1.024 (0.981–1.070), respectively. The corresponding values for ezetimibe were 0.963 (0.888–1.043) and 1.021 (0.969–1.074), respectively. The corresponding values for total ezetimibe were 0.886 (0.835–0.940) and 0.983 (0.946–1.022), respectively. FDC tablet containing rosuvastatin 20 mg and ezetimibe 10 mg is bioequivalent to the co-administration of commercially available individual tablets of rosuvastatin and ezetimibe as GMR with 90% CI of Cmax and AUClast of rosuvastatin, ezetimibe and total ezetimibe were contained within conventionally accepted bioequivalence criteria.
Cross-Over Studies ; Ezetimibe ; Healthy Volunteers ; Mass Spectrometry ; Pharmacokinetics ; Plasma ; Rosuvastatin Calcium ; Tablets ; Therapeutic Equivalency

OBJECTIVE: To investigate the effect of smear layer on apical sealing ability in teeth obturated with mineral trioxide aggregate (MTA) Plus as retrofilling materials. METHODS: Fifty freshly extracted maxillary anterior teeth or premolars with single root canal were used in this study. All teeth were instrumented to master apical point 60# by using the stepback technique, obturated with lateral condensation technique, and then apical resected. A rootend cavity was then instrumented with an ultrasonic diamond-coated tip. Then the selected teeth were randomly and equally divided into two groups (n=25). In the experimental group (smear-), the teeth were irrigated with 0.17 g/L ethylenediaminetetraacetic acid (EDTA) to remove smear layer on the root-end cavity wall; in the control group (smear+), the teeth were irrigated with physiological saline. Five teeth were extracted to evaluate the cleanliness of root end cavity walls under a videomicroscope, respectively. The scanning electron microscope (SEM) evaluation was also performed for the presence of smear layer and open tubule. For the additional 40 teeth, the root-end cavities were filled with MTA Plus. The quantitative apical leakage of each teeth was evaluated by measuring the concentration of leaked sucrose in apical reservoir on 1, 7, 14, 21, 28, 35, 42, 49 and 56 days, respectively. The samples were stored at 37 °C and 100% humidity for 56 days. Statistical analysis was done with ANOVA for repeated measurement design data. RESULTS: Removal of the smear layer did not cause significantly less apical leaked sucrose than that when the smear layer was left intact for 56 days (P>0.05). There were statistically significant differences at the concentration of leaked sucrose among different observation time points (P<0.05). CONCLUSION It may be concluded that removing the smear layer may not be necessary in root-end cavities filled with MTA Plus.
Aluminum Compounds ; Calcium Compounds ; Dental Leakage ; Drug Combinations ; Edetic Acid ; Oxides ; Root Canal Filling Materials ; Root Canal Irrigants ; Root Canal Preparation ; Root Canal Therapy ; Silicates ; Smear Layer ; Sucrose/pharmacokinetics*

Atorvastatin and ezetimibe are frequently co-administered to treat patients with dyslipidemia for the purpose of low-density lipoprotein cholesterol control. However, pharmacokinetic (PK) drug interaction between atorvastatin and ezetimibe has not been evaluated in Korean population. The aim of this study was to investigate PK drug interaction between two drugs in healthy Korean volunteers. An open-label, randomized, multiple-dose, three-treatment, three-period, Williams design crossover study was conducted in 36 healthy male subjects. During each period, the subjects received one of the following three treatments for seven days: atorvastatin 40 mg, ezetimibe 10 mg, or a combination of both. Blood samples were collected up to 96 h after dosing, and PK parameters of atorvastatin, 2-hydroxyatorvastatin, total ezetimibe (free ezetimibe + ezetimibe-glucuronide), and free ezetimibe were estimated by non-compartmental analysis in 32 subjects who completed the study. Geometric mean ratios (GMRs) with 90% confidence intervals (CIs) of the maximum plasma concentration (C(max,ss)) and the area under the curve within a dosing interval at steady state (AUC(τ,ss)) of atorvastatin when administered with and without ezetimibe were 1.1087 (0.9799–1.2544) and 1.1154 (1.0079–1.2344), respectively. The corresponding values for total ezetimibe were 1.0005 (0.9227–1.0849) and 1.0176 (0.9465–1.0941). There was no clinically significant change in safety assessment related to either atorvastatin or ezetimibe. Co-administration of atorvastatin and ezetimibe showed similar PK and safety profile compared with each drug alone. The PK interaction between two drugs was not clinically significant in healthy Korean volunteers.
Atorvastatin Calcium* ; Cholesterol ; Cross-Over Studies ; Drug Interactions* ; Dyslipidemias ; Ezetimibe* ; Humans ; Lipoproteins ; Male ; Pharmacokinetics ; Plasma ; Volunteers*

Two separate studies were conducted to establish bioequivalence (BE) for two doses of atorvastatin/metformin sustained-release (SR) fixed dose combination (FDC) versus the same dosage of the individual component (IC) tablets in healthy male subjects under fed conditions (study 1, BE of atorvastatin/metformin SR 20/500 mg FDC; study 2, BE of atorvastatin/metformin SR 20/750 mg FDC). Each study was a randomized, open-label, single oral dose, two-way crossover design. Serial blood samples were collected pre-dose and up to 36 hours post-dose for atorvastatin and 24 hours for metformin. Plasma concentrations of atorvastatin, 2-OH atorvastatin and metformin were analyzed using a validated liquid chromatography tandem mass-spectrometry. A non-compartmental analysis was used to calculate pharmacokinetic (PK) variables and analysis of variance was performed on the lognormal-transformed PK variables. A total of 75 subjects completed the study 1 (36 subjects) and study 2 (39 subjects). The 90% confidence intervals for the adjusted geometric mean ratio of Cmax and the AUC0-t were within the predefined 0.80 to 1.25 range. The number of subjects reporting at least one adverse event following FDC treatments was comparable to that following IC treatments. The two treatments were well tolerated. Therefore, atorvastatin/metformin SR 20/500 mg and 20/750 mg FDC tablets are expected to be used as alternatives to IC tablets to decrease the pill burden and increase patient compliance.
Atorvastatin Calcium* ; Chromatography, Liquid ; Cross-Over Studies* ; Humans ; Male* ; Metformin* ; Patient Compliance ; Pharmacokinetics* ; Plasma ; Tablets* ; Therapeutic Equivalency

OBJECTIVE: To prepare the slow-release complex with rifampicin (RFP)-polylactic-co-glycolic acid (PLGA)-calcium phosphate cement (CPC) (RFP-PLGA-CPC complex), and to study its physical and chemical properties and drug release properties in vitro.
 METHODS: The emulsification-solvent evaporation method was adopted to prepare rifampicin polylactic acid-glycolic acid (RFP-PLGA) slow-release microspheres, which were divided into 3 groups: a calcium phosphate bone cement group (CPC group), a CPC embedded with RFP group (RFP-CPC group), and a PLGA slow-release microspheres carrying RFP and the self-curing CPC group (RFP- PLGA-CPC complex group). The solidification time and porosity of materials were determined. The drug release experiments in vitro were carried out to observe the compressive strength, the change of section morphology before and after drug release. 
 RESULTS: The CPC group showed the shortest solidification time, while the RFP-PLGA-CPC complex group had the longest one. There was statistical difference in the porosity between the CPC group and the RFP-CPC group (P<0.05); Compared to the RFP-PLGA-CPC complex group, the porosity in the CPC group and the RFP-CPC group were significantly changed (both P<0.01). There was significant difference in the compressive strength between the RFP- PLGA-CPC complex group and the CPC group (P<0.01), while there was significant difference in the compressive strength between the RFP-CPC group and the CPC group (3 days: P<0.05; 30 and 60 days: P<0.01). The change of the compressive strength in the CPC was not significant in the whole process of degradation. The sizes of PLGA microspheres were uniform, with the particle size between 100-150 μm. The microspheres were spheres or spheroids, and their surface was smooth without the attached impurities. There was no significant change in the section gap in the CPC group after soaking for 3 to 60 days. The microstructure change in the RFP-CPC group was small, and the cross section was formed by small particles. The pores of section in the RFP-PLGA-CPC complex group increased obviously, and PLGA microspheres gradually disappeared until the 60th day when there were only empty cavities left. The RFP-PLGA-CPC complex group had no obvious drugs sudden release, and the cumulative drug release rate was nearly 95% in the 60 days. The linear fitting was conducted for the drug release behavior of the complex, which was in accordance with zero order kinetics equation F=0.168×t.
 CONCLUSION The porosity of RFP-PLGA-CPC complex is significantly higher than that of CPC, and it can keep slow release of the effective anti-tuberculosis drugs and maintain a certain mechanical strength for a long time.
Bone Cements ; pharmacokinetics ; Calcium Phosphates ; pharmacokinetics ; Compressive Strength ; Delayed-Action Preparations ; pharmacokinetics ; Dental Cements ; pharmacokinetics ; Lactic Acid ; pharmacokinetics ; Materials Testing ; Microspheres ; Polyglycolic Acid ; pharmacokinetics ; Polylactic Acid-Polyglycolic Acid Copolymer ; Porosity ; Rifampin ; administration & dosage ; pharmacokinetics

In this study, UPLC-MS/MS was adopted to determine the contents of five ephedrine alkaloids (Norephedrine, Norpseudoephedrine, Ephedrine, Pseudoephedrine, Methylephedrine) in plasma and urine in rats after the combined administration of Ephedrae Herba-Gypsum Fibrosum and calculate relevant pharmacokinetic parameters, in order to discuss the effect of the combined administration of Ephedrae Herba-Gypsum Fibrosum on plasma pharmacokinetics and urinary excretion characteristics. According to the results, after being combined with Gypsum, the five ephedrine alkaloids showed similar pharmacokinetic changes, such as shortened t(max), accelerated absorption rate, but reduced AUC(0-t) and V(z)/F, which may be related to the increase in urine excretion. Besides, Gypsum was added to enhance C(max) of Pseudoephedrine and prolong MRT(0-t) of Methylephedrine, so as to enhance the anti-asthmatic effect of Ephedrae Herba and resist the toxic effect of Norephedrine and Ephedrine. This study proved the scientific compatibility of Ephedrae Herba-Gypsum Fibrosum and provided a reference for studies on the prescription compatibility regularity and relevant practices.
Alkaloids ; blood ; pharmacokinetics ; urine ; Animals ; Calcium Sulfate ; pharmacokinetics ; Drugs, Chinese Herbal ; pharmacokinetics ; Ephedra ; chemistry ; Male ; Rats ; Rats, Sprague-Dawley ; Urine ; chemistry

OBJECTIVETo evaluate whether ursolic acid can inhibit breast cancer resistance protein (BCRP)-mediated transport of rosuvastatin in vivo and in vitro.

METHODSFirstly, we explored the pharmacokinetics of 5-fluorouracil (5-FU, a substrate of BCRP) in rats in the presence or absence of ursolic acid. Secondly, we studied the pharmacokinetics of rosuvastatin in rats in the presence or absence of ursolic acid or Ko143 (inhibitor of BCRP). Finially, the concentration-dependent transport of rosuvastatin and the inhibitory effects of ursolic acid and Ko143 were examined in Madin-Darby Canine Kidney (MDCK) 2-BCRP421CC (wild type) cells and MDCK2-BCRP421AA (mutant type) cells.

RESULTSAs a result, significant changes in pharmacokinetics parameters of 5-FU were observed in rats following pretreatment with ursolic acid. Both ursolic acid and Ko143 could significantly affect the pharmacokinetics of rosuvastatin. The rosuvastatin transport in the BCRP overexpressing system was increased in a concentration-dependent manner. However, there was no statistical difference in BCRP-mediated transport of rosuvastatin betweent the wild type cells and mutant cells. The same as Ko143, ursolic acid inhibited BCRP-mediated transport of rosuvastatin in vitro.

CONCLUSIONUrsolic acid appears to be a potent modulator of BCRP that affects the pharmacokinetic of rosuvastatin in vivo and inhibits the transport of rosuvastatin in vitro.

ATP Binding Cassette Transporter, Sub-Family G, Member 2 ; ATP-Binding Cassette Transporters ; physiology ; Adenosine ; analogs & derivatives ; pharmacology ; Animals ; Biological Transport ; drug effects ; Diketopiperazines ; Heterocyclic Compounds, 4 or More Rings ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; pharmacokinetics ; Rats ; Rats, Sprague-Dawley ; Rosuvastatin Calcium ; pharmacokinetics ; Triterpenes ; pharmacology

Gambogic acid (GA) is an anticancer agent in phase ‖b clinical trial in China but its mechanism of action has not been fully clarified. The present study was designed to search the possible target-related proteins of GA in cancer cells using proteomic method and establish possible network using bioinformatic analysis. Cytotoxicity and anti-migration effects of GA in MDA-MB-231 cells were checked using MTT assay, flow cytometry, wound migration assay, and chamber migration assay. Possible target-related proteins of GA at early (3 h) and late stage (24 h) of treatment were searched using a proteomic technology, two-dimensional electrophoresis (2-DE). The possible network of GA was established using bioinformatic analysis. The intracellular expression levels of vimentin, keratin 18, and calumenin were determined using Western blotting. GA inhibited cell proliferation and induced cell cycle arrest at G2/M phase and apoptosis in MDA-MB-231 cells. Additionally, GA exhibited anti-migration effects at non-toxic doses. In 2-DE analysis, totally 23 possible GA targeted proteins were found, including those with functions in cytoskeleton and transport, regulation of redox state, metabolism, ubiquitin-proteasome system, transcription and translation, protein transport and modification, and cytokine. Network analysis of these proteins suggested that cytoskeleton-related proteins might play important roles in the effects of GA. Results of Western blotting confirmed the cleavage of vimentin, increase in keratin 18, and decrease in calumenin levels in GA-treated cells. In summary, GA is a multi-target compound and its anti-cancer effects may be based on several target-related proteins such as cytoskeleton-related proteins.
Antineoplastic Agents ; pharmacokinetics ; Apoptosis ; drug effects ; Breast Neoplasms ; drug therapy ; metabolism ; Calcium-Binding Proteins ; genetics ; Cell Line, Tumor ; Cell Migration Assays ; Cell Migration Inhibition ; drug effects ; Cell Proliferation ; drug effects ; Computational Biology ; methods ; Cytoskeleton ; metabolism ; Electrophoresis, Gel, Two-Dimensional ; Flow Cytometry ; Gene Expression ; Humans ; Keratin-18 ; genetics ; Oxidation-Reduction ; Protein Biosynthesis ; drug effects ; Protein Transport ; Proteomics ; methods ; Transcription, Genetic ; drug effects ; Ubiquitin-Specific Proteases ; pharmacokinetics ; Vimentin ; genetics ; Xanthones ; pharmacokinetics

The purpose of the current study was to examine the pharmacokinetic profiles and tissue distribution of clevidipine, an ultra-short-acting calcium antagonist in Beagle dogs and Sprague-Dawley rats, respectively. The pharmacokinetics and biodistribution of its primary metabolite H152/81 were also evaluated. Dogs received intravenous infusion of clevidipine at a dose rate of 17 μg/(kg·min), and rats were given intravenous administration of clevidipine at a dose of 5 mg/kg. Dog plasma and rat tissues were collected and assayed by HPLC-MS/MS. It was found that plasma clevidipine quickly reached the steady state concentration. The terminal half-life was short (16.8 min), pointing out a rapid elimination after the end of the infusion. The total clearance was 5 mL/(min·kg). In comparison, plasma concentration of H152/81 was increased more slowly and was significantly higher than that of clevidipine. After intravenous administration, clevidipine was distributed rapidly into all tissues examined, with the highest concentrations found in the brain, heart and liver. Maximal concentrations of clevidipine were found in most tissues at 10 min post-dosing. However, the proportion of clevidipine distributed in all tissues was quite small (0.042‰) compared to the total administration dose. It was suggested that clevidipine was mainly distributed in blood and it transformed to inactive metabolite rapidly.
Animals ; Calcium Channel Blockers ; pharmacokinetics ; pharmacology ; Dogs ; Dose-Response Relationship, Drug ; Organ Specificity ; drug effects ; Pyridines ; pharmacokinetics ; pharmacology ; Rats

OBJECTIVETo investigate the role of vancomycin-loaded calcium sulphate in the treatment of osteomyelitis.

METHODSWe implanted vancomycin-loaded calcium sulphate into 24 patients with traumatic osteomyelitis who were treated in our hospital from February 2008 to February 2010,and then the antibiotic concentrations in the lesions were measured.Bacterial culture results,inflammatory markers,as well as wound healing were observed.X-ray was performed in the location where the vancomycin-loaded calcium sulphate was implanted.The blood vancomycin level as well as liver and kidney functions were determined.

RESULTSThe vancomycin concentration in the lesion exceeded the effective therapeutic concentrations and the minimum inhibitory concentration,while the blood concentration was low.The liver and renal function remained normal.The safety profile was good,and the cure rate of osteomyelitis reached 100%.

CONCLUSIONSThe vancomycin-loaded calcium sulphate can release high-concentration vancomycin in the diseased sites without causing high blood concentration.Also,it can guide the regeneration of bones.Therefore,it is effective and safe in treating osteomyelitis.

Adolescent ; Adult ; Anti-Bacterial Agents ; therapeutic use ; Biocompatible Materials ; Calcium Sulfate ; therapeutic use ; Child ; Drug Carriers ; Female ; Humans ; Male ; Middle Aged ; Osteomyelitis ; therapy ; Vancomycin ; pharmacokinetics ; therapeutic use ; Young Adult