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Arzneimittel-Forschung
Editio Cantor KG
Arzneimittel-Forschung

Editio Cantor KG

0004-4172

Arzneimittel-Forschung/Journal Arzneimittel-Forschung
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    Ibudilast, a phosphodiesterase inhibitor, in combination with low-dose aspirin potently inhibits guinea pig carotid artery thrombosis without extending bleeding time and causing gastric mucosal injury

    9页
    查看更多>>摘要：A combination of low-dose aspirin (ASA) and a phosphodiesterase inhibitor has been clinically tried for the secondary prevention of atherothrombotic diseases. The in vivo antithrombotic property of ibudilast (CAS 50847-11-5), a phosphodiesterase 4 (PDE4) inhibitor, was evaluated in a photochemically-induced guinea pig carotid artery thrombosis model in combination with low-dose ASA. The time required to decrease the carotid artery blood flow to the reading "zeroo" was defined as the time to occlusion (TTO) of the artery through thrombogenesis. Each independent use of ASA (300mg/kg, p.o.) and ibudilast (3 and 10mg/kg, p.o.) significantly prolonged the TTO, and ASA (300mg/kg) significantly increased bleeding time (BT) and gastric mucosal injury. A selective PDE4 inhibitor rolipram (1 and 5mg/kg, p.o.) tended to prolong the TTO without extending BT. ASA (100mg/kg) plus ibudilast (3mg/kg) and ASA (100mg/kg) plus rolipram (5mg/kg) markedly prolonged the TTO compared with each agent alone. Interestingly, ASA (100mg/kg) plus ibudilast (3mg/kg) caused a longer TTO than ASA (300mg/kg) alone, without significant extension of BT and gastric mucosal injury as observed in ASA (300mg/kg). These results indicate that the combination of low-dose ASA and ibudilast has a more potent antithrombotic effect than ASA alone without increasing bleeding tendency and gastric mucosal injury. The potent in vivo antithrombotic effect of this combination may be brought about by an action that is associated with PDE4 inhibition of ibudilast.
      原文链接:
    • NSTL
    • Thieme Medical Publishers

    Virtual screening and synthesis of new chemical scaffolds as VEGFR-2 kinase inhibitors

    7页
    查看更多>>摘要：Background: VEGFR-2 tyrosine kinase inhibitors are currently receiving high interest in drug discovery process as anticancer agents. We have used virtual screening techniques in order to discover new scaffolds that can be used for developing new VEGFR-2 kinase inhibitors. Method: Similarity ensemble approach was used to reduce the chemical space of ZINC database to select a subset of compounds. A validated structure-based pharmacophore was developed and adopted to screen the selected subset. Initial hits mapped to the pharmacophore were filtered using docking and scoring. Selected compounds were synthesized and biologically tested. Results: Compound 9 showed very good cytotoxicity profile against the NCI 60 cancer cell lines, while compound 8 showed reasonable inhibition of VEGFR-2 tyrosine kinase. Conclusion: Stepwise virtual screening of databases such as ZINC may result in new scaffolds for developing VEGFR-2 kinase inhibitors.
      原文链接:
    • NSTL
    • Thieme Medical Publishers

    Pharmacokinetics and safety of eszopiclone in healthy Chinese volunteers: Data from a single-center, open-label, single and multiple dose, randomized, crossover pharmacokinetic study of eszopiclone under fasting conditions

    5页
    查看更多>>摘要：Objective: The main objective of this study was to investigate the pharmacokinetic characters of eszopiclone (CAS: 138729-47-2) after single and multiple-dose oral administration in healthy adult Chinese volunteers. Methods: In single-dose study, 12 subjects were given oral administrations of 1.5, 3 and 6mg eszopiclone in an open-label, randomized, crossover fashion. In multiple-dose study, 8 subjects were given 3mg eszopiclone once daily consecutively for 7 days. Blood samples were collected over 24h and plasma eszopiclone were determined using a validated liquid chromatography/mass spectrometry (LC/MS/MS) assay. The safety and tolerability of eszopiclone was evaluated by adverse events recording, physical examination, laboratory testing, vital signs, and 12-lead ECG findings. Results: The main pharmacokinetic parameters of eszopiclone after single-dose administration were as follows: doses of 1.5, 3 and 6mg; Cmax of 18.08±4.65, 38.29±15.41 and 76.38±23.34ng/ml; Tmax of 0.94±0.39, 1.04±0.63 and 1.08±0.51h; AUC0-24 of 110.90±23.06, 227.36±62.41 and 504.10±140.13ng*h/ml; elimination half-lives of 5.84±1.03, 5.53±1.91 and 6.17±1.23h. After multiple-dose administration, the steady-state levels of eszopiclone were achieved by the 4th day, and the main pharmacokinetic parameters were Css-max at 33.43±5.63ng/ml and AUCss (0-24) at 263.30±51.21ng*h/ml. The most common adverse event was bitter or abnormal taste. All the adverse events were judged as mild to moderate and resolved without any medication. Conclusion: The pharmacokinetic character of eszopiclone is linear and dose-proportional over the range of 1.5-6mg. The systemic exposure does not accumulate with once-daily administrations. Eszopiclone appears to have good safety and is well tolerated.
      原文链接:
    • NSTL
    • Thieme Medical Publishers

    Pharmacokinetics and bioequivalence evaluation of two brands of ciprofloxacin 500mg tablets in Iranian healthy volunteers

    5页
    查看更多>>摘要：Background: In the present study pharmacokinetics and bioequivalence of 2 brands of ciprofloxacin 500mg were evaluated in 24 healthy male volunteers after a single dose oral administration in an open, randomized, 2-way crossover study. Methods: Blood samples were taken before and within 12h after the administration of the drug. Plasma concentrations of ciprofloxacin were determined by a simple HPLC method with ultraviolet detection. The used method was validated for specificity, accuracy, precision and sensitivity. The mobile phase consisted of 0.025M phosphoric acid, acetonitrile, and triethylamine. Analytical column was 5 μm Eurosphere C8 with a Eurosphere C8 guard column. The detector wavelength was set at 278nm and the retention time was 10min. The pharmacokinetic parameters, including peak plasma concentrations and time needed to reach the peak were obtained directly from plasma concentration-time profiles. The area under the curve was calculated using non-compartmental methods. Results: The Cmax of 1476.8±319.9ng/mL and 1423.0±278.4ng/mL were attained in about 1.67 and 1.58h for test and reference formulations, respectively. The mean±SD values for AUC 0-were 9665.3±2880.2 and 9716.1±2572.1ng.hr/mL for test and reference formulations, respectively. The pharmacokinetics parameters AUC0-t, AUC0- and Cmax were calculated for bioequivalence after log-transformation of data. The 90% confidence intervals of test/reference for AUC0-t, AUC0- and Cmax were (95.6-109.9%), (91.8-106.3%) and (95.2-112.8%), respectively and all were within the bioequivalence acceptance range of 80-125%. Conclusion: These results indicate that 2 tested formulations are bioequivalent and thus could be prescribed interchangeably.
      原文链接:
    • NSTL
    • Thieme Medical Publishers

    Microwave-assisted synthesis of 1,3-benzothiazol-2(3 H)-one derivatives and analysis of their antinociceptive activity

    5页
    查看更多>>摘要：A rapid and efficient method was developed for synthesis of 6-acyl-1,3-benzothiazol-2(3H)-one derivatives under microwave irradiation (MWI) conditions. The reaction times were shortened compared to conventional heating. Additionally, we synthesized acetic acid and acetamide derivatives of 1,3-benzothiazol-2(3H)-one, 6-acyl-1,3-benzothiazol-2(3H)-one, 5-chloro-1,3-benzothiazol-2(3H)-one and 6-acyl-5-chloro-1,3-benzothiazol-2(3H)- one with the microwave-assisted method and analyzed their antinociceptive activity with the tail flick, tail clip, hot plate and writhing tests. Among the synthesized compounds, 3-[2-(4-ethylpiperazin-1-yl)-2-oxoethyl]-1,3- benzothiazol-2(3H)-one (6a), 5-chloro-3-{2-oxo-2-[4-(propan-2-yl) piperazin-1-yl]ethyl}-1,3-benzothiazol-2(3H)-one (7e) and 3-[2-(4- butylpiperazin-1-yl)-2-oxoethyl]-5-chloro-1,3-benzothiazol-2(3H)-one (8e) showed significant antinociceptive activity in the tail clip, tail flick, hot plate and writhing tests. Supporting Information available online at http://www.thieme-connect.de/ejournals/toc/amf.
      原文链接:
    • NSTL
    • Thieme Medical Publishers

    In vitro dissolution and in vivo bioequivalence evaluation of two brands of isosorbide 5-mononitrate sustained release tablets

    7页
    查看更多>>摘要：Background: The purpose of the present study was to test a sustained release-tablet newly formulated with synthetic paraffin and compare its bioequivalence to that of the Imdur? Long-Acting tablet, based on the guidelines of the Korean Food and Drug Administration. Methods: Dissolution test was performed in 4 different dissolution media. A LC/MS/MS method of isosorbide 5-mononitrate in human plasma was validated. In vivo bioequivalence tests of the 2 isosorbide 5-mononitrate tablets were performed in both preprandial and postprandial states. Results: A comparative dissolution test gave similar results for both tablets in all dissolution media tested: 40% dissolution in pH 1.2 at 2h and 80% dissolution in pH 4.0, pH 6.8, or water at 10h. In a bioequivalence study to compare 2 tablets, the mean total area under the curve (AUCt) and peak concentration (Cmax) in the fasted state were 8476.0ng·h/mL and 540.4ng/mL, respectively, for the Imdur? Long Acting Tablet 60mg, and 8701.4ng·h/mL and 564.2ng/mL, respectively, for the test tablet. The mean AUCt and Cmax in the fed state were 8793.5ng·h/mL and 559.9ng/mL, respectively, for the Imdur? Long-Acting tablet 60mg, and 8639.8ng·h/mL and 617.9ng/mL, respectively, for the test tablet. The 90% confidence intervals using log transformed data were within the acceptable range of 0.81.25. Conclusion: Based on these statistical analyses, we conclude that the test tablet is bioequivalent to the Imdur? Long-Acting tablet 60mg in both the preprandial and postprandial states.
      原文链接:
    • NSTL
    • Thieme Medical Publishers

    Neuroprotective action and free radical scavenging activity of guttiferone-A, a naturally occurring prenylated benzophenone

    7页
    查看更多>>摘要：Reactive oxygen species (ROS) are important mediators in a number of neurodegenerative diseases and molecules capable of scavenging ROS may be a feasible strategy for protecting neuronal cells. We previously demonstrated a powerful iron-chelating action of Guttiferone-A (GA), a naturally occurring polyphenol, on oxidative stress injuries initiated by iron overload. Here we addressed the neuroprotective potential of GA in hydrogen peroxide and glutamate-induced injury on rats primary culture of cortical neurons and PC12 cells, respectively, and antioxidant properties concerning scavenging and anti-lipoperoxidative activities in cell-free models. The decrease in cell viability induced by each of the toxins, assessed by [3-(4,5-dimethylthiazol-2- yl)-2,5-diphenyl tetrazolium bromide] (MTT) assay, was significantly attenuated by GA. In addition, GA was found to be a potent antioxidant, as shown by (i) inhibition of 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical reduction (EC 50=20.0μM), (ii) prevention against chemically or electrochemically generated superoxide radicals, (iii) inhibition of spontaneous brain lipid peroxidation and (iv) interference with the Fenton reaction. These results indicate that GA exerts neuroprotective effects against H 2O2 or glutamate toxicity and its antioxidant activity, demonstrated in vitro, could be at least partly involved. They also suggest a promising potential for GA as a therapeutic agent against neurodegenerative diseases involving ROS and oxidative damage.
      原文链接:
    • NSTL
    • Thieme Medical Publishers

    Antimicrobial and cytotoxicity potential of acetamido, amino and nitrochalcones

    5页
    查看更多>>摘要：Background: Chalcones constitute one of the major classes of natural products belonging to the flavonoid family, and they have been reported as having a range of important therapeutic activities, including some chalcones are effective as antimicrobial agents. Currently, the search for new structures with antimicrobial activity has been intensified due to the emergence of many strains resistant to antibiotics currently used to treat infectious diseases. Method: 3 chalcone series (amino, acetamido and nitrochalcones) were prepared (23 compounds) and evaluated for their antimicrobial and cytotoxic potential. The effects of substituents on their respective activities also was evaluated. Results & Conclusion: The results showed that 4 aminochalcones (2, 4, 8, 9), 3 acetoamidochalcones (10, 14, 18) and 3 nitrochalcones (20, 22, 23), exhibited antifungal effects. The aminochalcones were more toxic than the acetamidochalcones, while the nitrochalcones did not present any toxic effect. It was verified that there seems to be structure-activity correlation in some electron-donating and withdrawing substituents groups in rings A and B of the synthetized chalcone analogues and its antifungal and cytotoxic activity.
      原文链接:
    • NSTL
    • Thieme Medical Publishers

    Pharmacokinetics of ginkgolide B injection in beagle dogs

    4页
    查看更多>>摘要：Objective: A liquid chromatography-mass spectrometry method was developed, validated, and applied to the pharmacokinetic study with doses of 0.68, 2.73 and 10.92mg/kg of ginkgolide B in beagle dogs after intravenous infusion. Method: An aliquot of blood samples were collected, separated and quantitatively analyzed by liquid chromatography-mass spectrometry method with mobile phase of acetonitrile-0.02% ammonia solution (33:67, v/v) at a flow rate of 0.8mL/min on the UltimateTM XB-C18 column (5μm, 4.6×150mm). Results: The method was sensitive, accurate and convenient, and can be used for the determination of ginkgolide B in beagle dogs. The Cmax and AUC0- of GB increased with dose escalation, but ANOVA analyses showed that no significant difference was observed in other pharmacokinetic parameters between different doses. Conclusion: An LC/MS method was developed with good sensitivity, reproducibility and specificity. In the pharmacokinetic study of GB in beagle dogs, linear pharmacokinetics was found at doses from 0.62 to 10.92mg/kg after a single-dose intravenous infusion. Gender differences were not observed in the pharmacokinetics of GB.
      原文链接:
    • NSTL
    • Thieme Medical Publishers

    Interaction of 5-amino-1,3,4-thiadiazole-2-thiol and its violuric acid adduct with Pt(II) - Crystals structures, spectroscopic properties and cytotoxic activity

    4页
    查看更多>>摘要：The coordination properties of Pt(II) with 5-amino-1,3,4-thiadiazole-2- thiol [CAS 2349-67-9] (L 1) and its novel violurate adduct (L 2), both in solution and in solid state, are studied by means of conventional IR-spectroscopy, single crystal X-ray diffraction and thermal methods. The complex compounds of L 1 and L 2, with general formulas [Pt(C2H2N3S2) 2] and [Pt(C6H4N6S2O 3)(Cl)]Cl respectively, are obtained. Quantum chemical calculations of the ligands are performed with a view to obtain electronic structure and optical properties of the ligands L 1 and L 2, respectively. The cell viability of the ligands and metal complexes on a panel of human tumor cell lines is evaluated.
      原文链接:
    • NSTL
    • Thieme Medical Publishers