International journal of clinical pharmacology and therapeutics (INT J CLIN PHARM TH )

Description

The International Journal of Clinical Pharmacology and Therapeutics appears monthly and publishes manuscripts containing original material with emphasis on the following topics: Clinical trials, Pharmacoepidemiology - Pharmacovigilance, Pharmacodynamics, Drug disposition and Pharmacokinetics, Quality assurance, Pharmacogenetics, Biotechnological drugs such as cytokines and recombinant antibiotics. Case reports on adverse reactions are also of interest.

  • Impact factor
    1.20
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    Impact factor
  • 5-year impact
    1.36
  • Cited half-life
    8.10
  • Immediacy index
    0.33
  • Eigenfactor
    0.00
  • Article influence
    0.35
  • Website
    International Journal of Clinical Pharmacology & Therapeutics website
  • Other titles
    International journal of clinical pharmacology and therapeutics, Clinical pharmacology and therapeutics
  • ISSN
    0946-1965
  • OCLC
    29934177
  • Material type
    Periodical
  • Document type
    Journal / Magazine / Newspaper

Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: In studying the comparative effectiveness of novel oral anticoagulants (NOACs) in orthopedic surgery and in non-valvular atrial fibrillation, previous meta-analyses have found no proof of difference in head-to-head indirect comparisons between individual agents. However, the question of their therapeutic equivalence remains unanswered. Objectives: The objective of this analysis was to test the equivalence of three NOACs (dabigatran, rivaroxaban, apixaban) in orthopedic surgery and four NOACs (dabigatran, rivaroxaban, apixaban, and edoxaban) in non-valvular atrial fibrillation. Methods: Standard pairwise meta-analysis and network meta-analysis for indirect comparisons were combined with equivalence testing. The endpoint was venous thromboembolism in orthopedic surgery and a composite of stroke or systemic embolism in atrial fibrillation. Comparisons were expressed as risk difference (RD). Margins for equivalence testing were derived from the original trials. Results: Our results indicate that rivaroxaban and apixaban (but not dabigatran) are equivalent for thromboprophylaxis in orthopedic surgery. In atrial fibrillation, all the four NOACs we tested were found to meet the criterion of therapeutic equivalence. Some concern, however, is raised by some findings focused on adverse events of these agents, in which the equivalence was not proven in all analyses. Conclusions: Regardless of clinical implications, our results can be the basis to develop local acquisition tenderings on NOACS. In Italy, a new law has been issued according to which equivalence analyses have become a mandatory prerequisite for local tenderings.
    International journal of clinical pharmacology and therapeutics 10/2014;
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    ABSTRACT: Objective: To compare the effects of postoperative patient-controlled intravenous analgesia (PCIA) with morphine, tramadol, or tramadol combined with lornoxicam on serum inflammatory cytokine production. Methods: 60 patients with an American Society of Anesthesiologists (ASA) physical status of I or II, undergoing radical correction of gastric cancer, were equally randomized to receive PCIA with morphine (M group), tramadol (T group), or tramadol combined with lornoxicam (L group). The visual analog scale (VAS) and Bruggemann comfort scale (BCS) scores were used to evaluate the postoperative analgesic efficacy. Serum levels of the interleukins (IL) IL-2, IL-6, and IL-10, and soluble IL-2 receptor (sIL-2R) were measured before anesthesia, 90 min after incision, and 24, 48, and 72 h after surgery. Results: No significant difference was found in the VAS, BCS, or baseline serum IL-2, IL-6, IL-10, or sIL-2R between the groups. At 90 min after incision, only the IL-6 levels increased (p < 0.05). At 24 h after surgery, the IL-2 levels decreased, with the M group having the lowest levels, while IL-6, IL-10, and sIL-2R levels increased, with the M group having the highest level and the L group having the lowest level (p < 0.05). At 48 h after surgery, the cytokine levels were starting to return to the baselines but still had statistical significance (p < 0.05). At 72 h after surgery, only the IL-6 levels had returned to their baseline. Conclusion: PCIA using tramadol combined with lornoxicam has less influence on inflammatory cytokines than morphine or tramadol alone in patients undergoing gastric cancer surgery.
    International journal of clinical pharmacology and therapeutics 10/2014;
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    ABSTRACT: Objective: The Food and Drug Administration (FDA) only requires bioequivalence testing of generic substitutions in order for them to be deemed equivalen to the original product. There may be a large difference of bioavailability among the generic drugs that especially have a narrow therapeutic index, and this may affect clinical outcomes. We aimed to determine whether switching from generic-to-generic equivalent anti-epileptic drugs (AEDs) in patients with epilepsy is associated with clinical outcomes. Methods: We performed a retrospective study using the electronic medical records of a tertiary hospital. Adults with a history of epilepsy who used a generic phenytoin and whose therapy was switched to another generic phenytoin between January 2012 and June 2013 were included (n = 80). We compared the drug concentration of phenytoin and seizure events before and after the switch. Results: After switching their generic phenytoin, 33 out of 80 patients (41%) suffered from increasing seizure events (pre-interchange period, 0.44 ± 0.97; post-interchange period, 1.24 ± 2.05; p < 0.0001). The number of medical visits for acute seizure significantly increased in the post-interchange period. The phenytoin serum concentration of all the patients was lesser in the post-interchange period than in the pre-interchange period. (pre-interchange period, 12.79 μg/mL; post-interchange period, 6.36 μg/mL; p < 0.0001). Among the patients with drug resistant epilepsy (DRE), 17 patients (84.2%) had increasing seizure events in the post-interchange period. Conclusions: We confirmed that there was a significant difference in bioavailability between generic phenytoin. Therefore, when using or switching generic anti-epileptic drugs, therapeutic drug monitoring must be done, and the patients' condition must be considered.
    International journal of clinical pharmacology and therapeutics 10/2014;
  • International journal of clinical pharmacology and therapeutics 10/2014;
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    ABSTRACT: Objective: To determine the relative bioavailability of ethinyl estradiol (EE) and gestodene (GSD) after application of a novel transdermal contraceptive patch vs. a a standard combined oral contraceptive (COC) pill (study 1), and to evaluate the pharmacokinetics (PK) of EE after application of the EE/GSD patch compared with an EE/norelgestromin (NGMN) patch (study 2). Materials: Participants were healthy, nonobese women aged 18 - 45 years (study 1) or 18 - 35 years (study 2). Compositions of study treatments were as follows: 0.55 mg EE/2.1 mg GSD (EE/GSD patch); 0.02 mg EE/0.075 mg GSD (standard COC); 0.6 mg EE/6 mg NGMN (EE/NGMN patch). Methods: In study 1, which consisted of 3 treatment periods (each followed by 7 patch- or pill-free days), treatments were administered in one of two randomized orders: either P-M-E (EE/GSD patch (P) every 7 days for 28 days → COC (M) once-daily for 21 days → two 7-day patch-wearing periods followed by one 10-day patch-wearing phase (E)), or the same treatments administered in sequence M-P-E. For study 2, participants received either the EE/GSD patch or EE/ NGMN patch for seven treatment cycles (one patch per week for 3 weeks followed by a 7-day patch-free interval). Results: In study 1, average daily exposure to EE was similar for treatments P and M; the mean daily area under the concentration-time curve (AUC) ratio of treatment P vs. treatment M for EE was 1.06 (90% confidence interval (CI): 0.964 - 1.16), indicating average daily delivery similar to oral administration of 0.019 - 0.023 mg EE. For unbound GSD, average daily exposure was lower for treatment P vs. treatment M. The mean AUC ratio of treatment P vs. treatment M for unbound GSD was 0.820 (90% CI: 0.760 - 0.885), indicating average daily delivery from the patch of 0.057 - 0.066 mg GSD. Prolonged patch wearing did not result in a distinct decline in GSD and EE serum concentrations. In study 2, AUC at steady state (AUC0-168,ss), average steady-state serum concentration, and maximum steady-state serum concentration for EE was 2.0 - 2.7-fold higher for the EE/NGMN patch vs. the EE/GSD patch. The EE/GSD patch was well tolerated in both studies. Conclusions: Based on the 90% CI of the AUC ratio of oral treatment vs. patch application for unbound GSD and EE, the daily doses of GSD and EE released from the EE/GSD patch over the 7-day application period provided the same systemic exposure as those recorded after daily oral administration of a COC containing 0.02 mg EE and 0.06 mg GSD. The EE/GSD patch showed reduced EE exposure compared with the EE/NGMN patch. Together with its good tolerability, these properties support the EE/GSD patch as an effective and well-tolerated alternative to available transdermal and oral contraceptives.
    International journal of clinical pharmacology and therapeutics 10/2014;
  • International journal of clinical pharmacology and therapeutics 10/2014; 52 Suppl 1:1-64.
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    ABSTRACT: Objective: To assess the overall exposure after a single dose of esomeprazole in children with gastroesophageal reflux disease (GERD). Materials: Oral esomeprazole administered as an intact capsule with 30 - 180 mL of water, or as an opened capsule mixed with as much as 1 tablespoon of applesauce followed by 30 - 180 mL of water. Methods: In this randomized, open-label study of children aged 1 - 11 years with endoscopically proven GERD, patients weighing 8 to < 20 kg were randomized to a single 5- or 10-mg oral dose of esomeprazole, and patients weighing >= 20 kg were randomized to a single 10- or 20-mg oral dose of esomeprazole. Esomeprazole exposure (AUC0-inf), AUC from zero to last measurable concentration (AUC0-t), maximum plasma concentration (Cmax), time to Cmax (tmax), terminal-phase half-life, apparent oral clearance, and apparent volume of distribution were determined. Results: 28 patients were randomized to receive esomeprazole: 14 patients weighing 8 to < 20 kg received esomeprazole 5 mg (n = 7) or 10 mg (n = 7), and 14 patients weighing >= 20 kg received esomeprazole 10 mg (n = 6) or 20 mg (n = 8). Children weighing 8 to < 20 kg had a 1.8-fold higher exposure with the 10-mg vs. 5-mg dose (AUC0-inf, 1.32 vs. 0.73 μmol x h/L respectively); children weighing =>20 kg had a 4.4-fold higher exposure with the 20-mg vs. 10-mg dose (AUC0-inf, 3.06 vs. 0.69 μmolx h/L). Cmax was 2.2-fold higher for the 10-mg vs. 5-mg dose (8 to < 20 kg) and 2.4-fold higher for the 20-mg vs.10-mg dose (=> 20 kg). Conclusions. The pharmacokinetics of single-dose esomeprazole were dose-dependent in children weighing => 20 kg but not in children weighing 8 to < 20 kg.
    International journal of clinical pharmacology and therapeutics 09/2014;
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    ABSTRACT: Objective: Sitafloxacin is a new fluoroquinolone with a broad spectrum of antibacterial activity, including grampositive and gram-negative bacteria. This study was to evaluate the pharmacokinetic characteristics of a single dose of sitafloxacin in healthy Chinese volunteers. Methods: This was a single-center, open-label, randomized-sequence study conducted in 12 subjects. Subjects were randomly assigned to receive single doses of 50, 100, and 200 mg of sitafloxacin in a 3-way crossover design with a 7-day washout period between administrations. Quantification was carried out using a validated high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method. Pharmacokinetic parameters were calculated and analyzed statistically. Safety assessments were conducted throughout the study. Results: After administration of single doses of 50, 100, and 200 mg, geometric mean estimate for sitafloxacin Cmax were 0.72, 1.62, and 2.73 μg/mL and the mean of AUClast were 3.97, 8.71, and 18.03 μg x h/mL, respectively. Sitafloxacin was rapidly absorbed, reaching Cmax ranged from 0.85 to 1.21 hours. The terminal half-life ranged from 5.19 to 6.28 hours. The Cmax and AUC last were proportional to the doses. The mean clearance, the half-life, and the volume of distribution were constant, irrespective of the dose. Conclusion: In healthy Chinese subjects, single dosing of sitafloxacin resulted in linear plasma pharmacokinetics.
    International journal of clinical pharmacology and therapeutics 09/2014;
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    ABSTRACT: Purpose: This study evaluated the bioequivalence of two types of topical loxoprofen patches, LX-A and LX-P, in healthy Chinese volunteers through a dermatopharmacokinetic approach. Method: Based on a pilot study, this study was designed as an open-label, self-controlled trial in 20 males. Subjects received application of two 3.2 — 3.2 cm2 pieces of LX-A and LX-P patches on their backs at randomly assigned positions simultaneously. Stratum corneum (SC) samples were taken with adhesive stripping tapes prior to patch application and at 20 hours and 24 hours postdose following removal of each loxoprofen patch, respectively. Bioassay was performed with a validated high performance liquid chromatography-tandem mass spectrometry method. Bioequivalence was evaluated through a power model on the total amount of loxoprofen at each post-application point and on the percentage change of SC loxoprofen content between the two time-points. Results Mean (± standard deviation) total amount of SC-sampled loxoprofen was similar between LX-A and LX-P at 20 hours (38,722 ± 7,171 ng vs. 39,309 ± 9,688 ng) and 24 hours (36,638 ± 8,149 ng vs. 37,426 ± 9,029 ng) post-administration. The corresponding point estimate (90% confidence interval, 90%CI) of LX-P to LX-A was 1.00 (0.92, 1.09) and 1.02 (0.93, 1.12), respectively. In addition, the 24 hour/20 hour ratio for SC content of loxoprofen was statistically comparable between LX-A and LX-P, with both the point estimate and the 90% CI falling into the range of (0.80, 1.25). Conclusion: Our study indicated that LX-P and LX-A are two bioequivalent topical formulations of loxoprofen.
    International journal of clinical pharmacology and therapeutics 09/2014;
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    ABSTRACT: Objectives: The purpose of the study was to identify the most sensitive analyte (i.e., encapsulated, free, and total forms) for assessing the bioequivalence (BE) of liposome drug products using Monte Carlo simulation. Methods: We proposed a liposome classification system that divided liposome drug products into four classes according to the extent of reticuloendothelial system uptake and in vivo release rate: class I: low reticuloendothelial system uptakerapid release rate; class II: low reticuloendothelial system uptake-slow release rate; class III: high reticuloendothelial system uptakerapid release rate; Class IV: high reticuloendothelial system uptake-slow release rate. In conjunction with the proposed classification scheme, a variety of drug classes were simulated to determine which analyte provides the most sensitive measure of BE. All drug classes were investigated in single and multiple dose studies. The sensitivity of analytes for measuring BE was evaluated using the power curve. Results and conclusions Our simulations indicated the encapsulated form provides the most accurate assessment BE for liposome drug products with low reticuloendothelial system uptake (i.e., class I and II). For liposome drug products with high reticuloendothelial system uptake (i.e., class III and IV), the free form provides the best indication BE. Measurement of total drug form to assess BE was preferred only for liposome drug products with low reticuloendothelial system uptake and slow release rates (i.e., class II liposomal drug product). In general, a single dose form is sufficient for demonstrating the BE of liposome drug products.
    International journal of clinical pharmacology and therapeutics 09/2014;
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    ABSTRACT: Objective: We assessed the effect of 1 x 300 mL/d and 3 x300 mL/d grapefruit juice (GFJ) on ambrisentan and bosentan pharmacokinetics in healthy volunteers. Methods: In the ambrisentan study, 12 healthy extensive metabolizers (EM) of CYP2C19 received therapeutic doses of ambrisentan (5 mg q.d. on study days 1 - 11) and GFJ (1 x 300 mL/d on study days 6 - 8 and 3 x 300 mL/d on study days 9 - 11). Ambrisentan pharmacokinetics was assessed on study days 5, 8, and 11. In the bosentan study, 16 healthy EM of CYP2C9, who were stratified into two groups (CYP3A5 expressors (n = 8) and CYP3A5 non-expressors (n = 8)), received bosentan (125 mg b.i.d. on study days 1 - 13) and GFJ (1 x 300 mL/d on study days 8 - 10 and 3 x 300 mL/d on study days 11 - 13). Bosentan pharmacokinetics was assessed on study days 7, 10, and 13. Results: Whereas 1 x 300 mL/d GFJ had no effect on the pharmacokinetics of ambrisentan and its metabolite, 3 x 300 mL/d GFJ increased the exposure with ambrisentan by 8% and the molar plasma metabolic ratio by 22% (both p < 0.05). Correspondingly, the apparent oral clearance of ambrisentan decreased to 92% (p < 0.05). GFJ slightly prolonged tmax of bosentan and increased the metabolic ratio of bosentan/hydroxy-bosentan by 19% (p < 0.05). Conclusion: GFJ had no clinically relevant effect on the pharmacokinetics or safety profile of ambrisentan and bosentan. Therefore, no dose adjustments are needed, and GFJ can be safely co-administered even at very high doses.
    International journal of clinical pharmacology and therapeutics 09/2014;
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    ABSTRACT: Objective: To compare the pharmacokinetic properties of two newly developed generic ambroxol formulations with a branded innovator product in healthy Chinese male volunteers. Methods: This was a single-dose, randomized, open-label, threeperiod crossover study in healthy volunteers aged 18 - 45 years under fasting conditions. Subjects were assigned to receive 1 of 2 test formulations or a reference tablet of ambroxol 30 mg. Each study period was separated by a 1-week washout phase. Blood samples were collected at pre-specified times. A non-compartmental mmethod was employed to determine pharmacokinetic properties (Cmax, tmax, AUC0-tlast, AUC0-inf) to test for bioequivalence. The predetermined regulatory range of 90% CI for bioequivalence was 80 - 125%. Results: 24 subjects were enrolled in and completed the study. The geometric mean Cmax values for the test tablet, test capsule, and reference product were 82.73, 85.36, 84.56 ng/mL, and their geometric mean AUC0-tlast (AUC0-inf) were 660.87 (753.49), 678.98 (756.79), and 639.41 (712.14) ng x h/mL, respectively. For test tablet vs. reference, the 90% CIs of the least squares mean test/reference ratios of Cmax, AUC0-tlast, and AUC0-infž were 91.2% to 104.9%, 96.5% to 110.7%, and 98.8% to 113.4%, respectively. For test capsule, the corresponding values were 94.1% to 108.3%, 99.2% to 113.7%, and 99.2% to 113.9%, respectively. No adverse events occurred during the study. Conclusions: The ambroxol 30 mg tablets and capsules were considered bioequivalent to the reference formulation in accordance with predetermined regulatory criteria.
    International journal of clinical pharmacology and therapeutics 09/2014;
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    ABSTRACT: Background: The aim of our study was to analyze the persistence with tamoxifen (TAM) and aromatase inhibitors (AIs) in postmenopausal women with hormone-receptor-positive breast cancer (BC) in early and late stage disease. Methods: This study based on data from The IMS Oncology Analyzer (OA) including retrospective longitudinal patient treatment histories from diagnosis for all cancer types. 4,626 patients with a diagnosis of breast cancer with current or terminated treatment with TAM or AIs between January 2003 and March 2012 in Germany were included. Results: Our results indicate a significantly increased risk for treatment discontinuation for patients in the age groups of 41 - 50 and 51 - 60 years compared to older patients as well as in patients with a stage IV tumor compared to patients with lower stage tumors. If treatment was initiated by a gynecologist, patients are less likely to discontinue their therapy compared to treatment initiated by an oncologist. Furthermore, the risk of therapy break up was significantly lower in patients treated in an office-based setting compared to the reference group of patients treated in general hospitals. Conclusion: In conclusion, persistence with endocrine treatment in woman with hormone-receptor-positive breast cancer is low, especially in later stage disease, and needs to be significantly increased to improve outcome in clinical practice. Further research is required to understand this complex, but important aspect.
    International journal of clinical pharmacology and therapeutics 09/2014;
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    ABSTRACT: Objective: The purpose of this study was to describe the population pharmacokinetics (PK) of tacrolimus (TAC) in 52 Chinese pediatric patients early after liver transplantation. Methods: Details of drug dose, sampling times and concentrations were collected retrospectively from routine therapeutic drug monitoring data from the first day after surgery. A total of 488 concentration data were obtained and analyzed by a nonlinear mixed-effect modeling (NONMEM) method. A number of demographic and clinical variables were tested for their influence on TAC PK parameters. Results: The PK of TAC were best described by a one-compartment model with first-order absorption and elimination. Apparent clearance (CL/F) and apparent volumes of distribution (V/F) in final population model were 5.72 L/h and 131 L, respectively. The absorption rate constant (Ka) was fixed in 4.48 h-1. The inter-individual variabilities in CL/F and V/F were 13.5% and 78.1%. In the final analysis performed in all 52 patients, the post-operation day (POD) and alanine aminotransferase (ALT) influenced TAC CL/F and V/F, and total protein (TP) was the only covariate retained on V/F. Conclusion: A population PK model of TAC was developed in Chinese pediatric patients early afte liver transplantation. It identified significant relationships between the PK of TAC and the characteristics of the patients. POD, ALT, and TP were identified as the main factors influencing the PK of TAC. The developed model could be useful to optimize individual pediatric TAC dosing regimen in routine clinical practice.
    International journal of clinical pharmacology and therapeutics 09/2014;
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    ABSTRACT: Tianeptine is widely used for controlling depressive symptoms.
    International journal of clinical pharmacology and therapeutics 09/2014; 52(9):817-23.
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    ABSTRACT: Once-daily darunavir/ritonavir (800/100 mg), plus other antiretrovirals, is recommended for HIV-1-infected patients. Low therapy adherence is linked with poor outcomes. Pill burden can impact adherence. An 800-mg darunavir tablet would reduce pill burden.
    International journal of clinical pharmacology and therapeutics 09/2014; 52(9):805-16.
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    ABSTRACT: Objectives: This study evaluates the effect of adherence to stain on hospitalization for cardiovascular disease and all-cause mortality in South Korea. Methods: We performed a national cohort study on 423,786 individuals using the Korean National Health Insurance Claims Database. The cohort was composed of individuals who were aged between 18 and 84 years, were newly treated with statin, and were followed from 2005 to 2009. Adherence to statin was calculated using medication possession ratio (MPR) and associations between adherence to statin and health outcomes were evaluated using Cox's proportional hazards regression analysis. Results: Of the study subjects, 41.9% were male, 7.4% were beneficiaries of a tax-financed medical aid program (MAP), 1.5% had prior cardiovascular disease (CVD), 13.0% had diabetes, and 27.5% had hypertension. Non-adherence to statin was found to be associated with an increased risk of cardiovascular hospitalization (HR 2.18, 95% CI: 2.02 - 2.35) and all-cause mortality (HR = 1.75, CI: 1.66 - 1.84). As the age of the study group increased, non-adherence was more strongly associated with the risk of hospitalization for CVD. In addition, the risk of hospitalization for CVD was relatively high in patients who were male, older or MAP beneficiaries, and who had hypertension, diabetes, and high Charlson's comorbidity index. Conclusions: This study supports that non-adherence to statin is associated with an elevated risk of hospitalization for cardiovascular disease and all-cause mortality.
    International journal of clinical pharmacology and therapeutics 08/2014;
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    ABSTRACT: A simple, rapid and sensitive high-power liquid chromatographic (HPLC) method for analysis of 5-fluorouracil (5-FU) in patient plasma was developed and validated to study clinical pharmacokinetics (PK). Plasma sample preparation was processed with ammonium acetate buffer (pH 3.5; 0.01M) followed by liquid-liquid extraction with isopropanol/ethyl acetate (15 : 85, v/v). Extraction recovery ranged from 87.55 to 95.26%. Separation was performed using a C18 column at 25 °C with UV detection at 265 nm. The isocratic mobile phase composed of acetonitrile-ammonium acetate buffer (pH 3.5; 0.01M) (2.5 : 97.5 v/v) at a flow rate of 0.8 mL/min. Retention time was less than 7 minutes. Standard curve was linear between 0.01 - 10 µg/mL and 10 - 100 µg/mL for plasma sample. The limit of quantification was 10 ng/mL. The intra- and interday precision was below 10% (RSD). The accuracy ranged from 85.24 to 104.14%. The analysis method is rapid because it needs neither time-consuming extraction procedures nor complex chromatographic condition. The method was successfully applied to access pharmacokinetics and plasma concentration at steady state (SSC) of 5-FU. The results showed the PK and SSC of 5-FU characterized by a large interpatient variability. To increase therapeutic response and reduce toxicity, we should optimize 5-FU dose by investigating PK behavior to obtain ideal SSC.
    International journal of clinical pharmacology and therapeutics 08/2014;
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    ABSTRACT: Objectives: Granulocyte macrophage colony-stimulating factor (GM-CSF) has been proved to be among the most important chemokines, playing a key role in rheumatoid arthritis (RA). However, the mechanism underlying the regulation of GM-CSF has not been established clearly yet. The aim of this study was to investigate the influence of paeonol in the expression of GM-CSF in fibroblast-like synoviocytes (FLS). Methods: The expression of GM-CSF was detected both at protein and mRNA levels in FLS after the stimulation of TNF-alpha at diverse concentrations and times. And then GM-CSF was detected again after pre-treatment with paeonol. Phosphorylation of PI3K/Akt and expression of NF-kappaB and p-IkappaBalpha were detected with western blot. Meanwhile, inhibitors of the pathways were used to investigate the mechanism of regulation of GM-CSF. Results: Recombinant TNF-alpha up-regulated GM-CSF in a concentration- and time-dependent manner in FLS, which was significantly suppressed by paeonol. Paeonol also exerted its ability to suppress the promoting effects of TNF-alpha on the phosphorylation of PI3K/Akt and activation of NF-kappaB pathway. Administration of the inhibitors LY294002, perifosine, BAY11-7082, and SC-514 confirmed the roles of PI3K/Akt and NF-kappaB on the production of GM-CSF. Furthermore, TNF-alpha induced proliferation, while paeonol suppressed proliferation of FLS. Conclusion: These results demonstrate that paeonol suppressed TNF-alpha-induced GM-CSF production via the PI3K/Akt/NF-kappaB pathway.
    International journal of clinical pharmacology and therapeutics 08/2014;
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    ABSTRACT: Objective: To evaluate the effects of siponimod (BAF312) on the pharmacokinetics (PK) and pharmacodynamics (PD) of a monophasic oral contraceptive (OC). Materials and methods: This was a phase 1, single-center, open-label, multipledose, single-sequence study in healthy females. Eligible subjects (n = 23) were exposed sequentially to two treatment periods: period 1 (OC alone) and period 2 (OC + siponimod) in two consecutive menstrual periods. PK parameters were assessed on day 21 of both treatment periods. Follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, and progesterone concentrations were measured at baseline and days 3, 6, 8, 11, 14, 16, 19, 21, and 23 of each period. Largest ovarian follicle size and sex hormone-binding globulin (SHBG) concentration were measured and Hoogland score was calculated at baseline and day 21 of each period. Safety and tolerability of siponimod was also assessed. Results: Co-administration (OC + siponimod) increased the AUCt,ss and Cmax,ss of levonorgestrel by 28% and 18%, respectively, but had no effect on the PK of ethinylestradiol. No significant changes in estradiol, FSH, and LH were noted with co-administration vs. OC alone. Progesterone levels < 5 nmol/L, largest follicle size < 10 mm, and Hoogland score of 1 on day 21 indicated lack of ovulation in all subjects during co-administration. Co-administration was well tolerated. Conclusion: In conclusion, PK and PD of the OC were not altered to a clinically significant extent and contraceptive efficacy was maintained with co-administration. Hence, OC as a contraceptive measure can be safely co-administered with siponimod.
    International journal of clinical pharmacology and therapeutics 08/2014;