The Experts below are selected from a list of 16872 Experts worldwide ranked by ideXlab platform
Chinatsu Sakata - One of the best experts on this subject based on the ideXlab platform.
-
Inhibitory effects of ASP6537, a selective Cyclooxygenase-1 Inhibitor, on thrombosis and neointima formation in rats.
Thrombosis research, 2017Co-Authors: Chinatsu Sakata, Tomihisa Kawasaki, Yoshiyuki Iwatsuki, Yumiko Moritani, Yoshiaki Morita, Hideaki HaraAbstract:Abstract Introduction Percutaneous coronary interventions (PCIs), such as balloon angioplasty and stent placement, are effective in the treatment of coronary artery disease. PCI has drawbacks, however, including acute thrombosis after the procedure and restenosis of the vascular lumen due to abnormal neointimal hyperplasia. ASP6537 is a selective COX-1 Inhibitor that has been investigated as a possible candidate for clinical development as an antiplatelet agent. In the present study, we evaluated the in vivo antithrombotic effect of ASP6537 and its effect on neointima formation after balloon angioplasty. Material and methods The antithrombotic effect of ASP6537 was examined using an arteriovenous shunt thrombosis model in rats while the effect of ASP6537 on neointima formation was evaluated in a rat carotid arterial balloon angioplasty model. Results In the thrombosis study, ASP6537 dose-dependently decreased the protein content of the thrombus, while no prolongation of template bleeding time was observed. In the neointima study, ASP6537 reduced neointima formation. Conclusions ASP6537 may be a promising agent for the prevention of acute thrombosis and restenosis after PCI in place of aspirin.
-
asp6537 a novel highly selective Cyclooxygenase 1 Inhibitor exerts potent antithrombotic effect without aspirin dilemma
Thrombosis Research, 2013Co-Authors: Chinatsu Sakata, Tomihisa Kawasaki, Yoshiaki Morita, Yasuko Kato, Masaki Abe, Kenichi Suzuki, Makoto Ohmiya, Toshiyuki Funatsu, Masamichi OkadaAbstract:Abstract Introduction Aspirin inhibits both the Cyclooxygenase (COX)-1-dependent production of thromboxane A2 (TXA2) in platelets and COX-2-dependent production of anti-aggregatory prostaglandin I2 (PGI2) in vessel walls, resulting in “aspirin dilemma.” Our objective is to investigate whether ASP6537 can overcome aspirin dilemma and exert a potent antithrombotic effect without a concurrent ulcerogenic effect. Methods We evaluated the Inhibitory effects of ASP6537 on recombinant human COX-1 (rhCOX-1) and rhCOX-2 activities using a COX-1/2 selectivity test. To determine whether ASP6537 induces aspirin dilemma, we examined the effects of ASP6537 on in vitro TXA2 and PGI2 metabolite production from platelets and isolated aorta of guinea pigs, and on plasma concentrations of TXA2 and PGI2 metabolites in aged rats. Finally, we evaluated the antithrombotic effects and ulcerogenic activity of ASP6537 using an electrically induced carotid arterial thrombosis model and a gastric ulcer model in guinea pigs. Results The IC50 ratios of rhCOX-2 to rhCOX-1 for ASP6537 and aspirin were > 142,000 and 1.63 fold, respectively. ASP6537 inhibited TXA2 production more selectively than aspirin in in vitro and in vivo TXA2/PGI2 production studies. ASP6537 exerted a significant antithrombotic effect at ≥ 3 mg/kg, while aspirin tended to inhibit thrombosis at 300 mg/kg but it was not statistically significant. Further, ASP6537 did not induce ulcer formation at 100 mg/kg, whereas aspirin exhibited an ulcerogenic effect at doses of ≥ 100 mg/kg. Conclusions ASP6537 functions as a highly selective COX-1 Inhibitor with a superior ability to aspirin for normalizing TXA2/PGI2 balance, and exerts antithrombotic effect without ulcerogenic effect.
Yoshiaki Morita - One of the best experts on this subject based on the ideXlab platform.
-
Inhibitory effects of ASP6537, a selective Cyclooxygenase-1 Inhibitor, on thrombosis and neointima formation in rats.
Thrombosis research, 2017Co-Authors: Chinatsu Sakata, Tomihisa Kawasaki, Yoshiyuki Iwatsuki, Yumiko Moritani, Yoshiaki Morita, Hideaki HaraAbstract:Abstract Introduction Percutaneous coronary interventions (PCIs), such as balloon angioplasty and stent placement, are effective in the treatment of coronary artery disease. PCI has drawbacks, however, including acute thrombosis after the procedure and restenosis of the vascular lumen due to abnormal neointimal hyperplasia. ASP6537 is a selective COX-1 Inhibitor that has been investigated as a possible candidate for clinical development as an antiplatelet agent. In the present study, we evaluated the in vivo antithrombotic effect of ASP6537 and its effect on neointima formation after balloon angioplasty. Material and methods The antithrombotic effect of ASP6537 was examined using an arteriovenous shunt thrombosis model in rats while the effect of ASP6537 on neointima formation was evaluated in a rat carotid arterial balloon angioplasty model. Results In the thrombosis study, ASP6537 dose-dependently decreased the protein content of the thrombus, while no prolongation of template bleeding time was observed. In the neointima study, ASP6537 reduced neointima formation. Conclusions ASP6537 may be a promising agent for the prevention of acute thrombosis and restenosis after PCI in place of aspirin.
-
asp6537 a novel highly selective Cyclooxygenase 1 Inhibitor exerts potent antithrombotic effect without aspirin dilemma
Thrombosis Research, 2013Co-Authors: Chinatsu Sakata, Tomihisa Kawasaki, Yoshiaki Morita, Yasuko Kato, Masaki Abe, Kenichi Suzuki, Makoto Ohmiya, Toshiyuki Funatsu, Masamichi OkadaAbstract:Abstract Introduction Aspirin inhibits both the Cyclooxygenase (COX)-1-dependent production of thromboxane A2 (TXA2) in platelets and COX-2-dependent production of anti-aggregatory prostaglandin I2 (PGI2) in vessel walls, resulting in “aspirin dilemma.” Our objective is to investigate whether ASP6537 can overcome aspirin dilemma and exert a potent antithrombotic effect without a concurrent ulcerogenic effect. Methods We evaluated the Inhibitory effects of ASP6537 on recombinant human COX-1 (rhCOX-1) and rhCOX-2 activities using a COX-1/2 selectivity test. To determine whether ASP6537 induces aspirin dilemma, we examined the effects of ASP6537 on in vitro TXA2 and PGI2 metabolite production from platelets and isolated aorta of guinea pigs, and on plasma concentrations of TXA2 and PGI2 metabolites in aged rats. Finally, we evaluated the antithrombotic effects and ulcerogenic activity of ASP6537 using an electrically induced carotid arterial thrombosis model and a gastric ulcer model in guinea pigs. Results The IC50 ratios of rhCOX-2 to rhCOX-1 for ASP6537 and aspirin were > 142,000 and 1.63 fold, respectively. ASP6537 inhibited TXA2 production more selectively than aspirin in in vitro and in vivo TXA2/PGI2 production studies. ASP6537 exerted a significant antithrombotic effect at ≥ 3 mg/kg, while aspirin tended to inhibit thrombosis at 300 mg/kg but it was not statistically significant. Further, ASP6537 did not induce ulcer formation at 100 mg/kg, whereas aspirin exhibited an ulcerogenic effect at doses of ≥ 100 mg/kg. Conclusions ASP6537 functions as a highly selective COX-1 Inhibitor with a superior ability to aspirin for normalizing TXA2/PGI2 balance, and exerts antithrombotic effect without ulcerogenic effect.
-
pharmacological profile of fk881 asp6537 a novel potent and selective Cyclooxygenase 1 Inhibitor
Biochemical Pharmacology, 2011Co-Authors: Junko Imanishi, Yoshiaki Morita, Eiji Yoshimi, Kanae Kuroda, Tomoko Masunaga, Kaoru Yamagami, Masako Kuno, Emi Hamachi, Satoshi Aoki, Fumie TakahashiAbstract:Nonsteroidal anti-inflammatory drugs (NSAIDs) are now understood to fall into one of two agent classes in clinical use. Traditional NSAIDs inhibit both Cyclooxygenases-1 and 2 (COX-1, 2), which act as key enzymes catalyzing the same reaction in the production of prostaglandins (PGs), while the second class of NSAIDs selectively inhibit COX-2. Inhibition of the inducible COX-2 isoform is believed to be responsible for the therapeutic effects of NSAIDs, such as anti-inflammatory, analgesic, and antipyretic effects, while COX-1 inhibition results in side-effects on the gastrointestinal (GI) system. In the present study, however, we changed this notion that inhibiting only COX-1 causes adverse effects. We discovered FK881, a specific COX-1 Inhibitor which exhibits a 650-fold ratio for human whole blood COX-1/COX-2 and rats in vivo. In rats, FK881 dose dependently inhibited carrageenan-induced paw edema (ED30: 22 mg/kg; diclofenac ED30: 3.6 mg/kg, rofecoxib ED30: 26 mg/kg) and paw swelling associated with adjuvant arthritis (ED50: 17 mg/kg; diclofenac ED50: 1.4 mg/kg, rofecoxib ED50: 1.8 mg/kg). Further, FK881 dose dependently inhibited acetic acid-induced writhing in mice (ED50: 19 mg/kg; diclofenac ED50: 14 mg/kg, rofecoxib ED50: >100mg/kg) and adjuvant arthritis hyperalgesia in rats (ED50: 1.8 mg/kg; diclofenac ED50: 1.0mg/kg, rofecoxib ED50: 0.8mg/kg). However, unlike traditional NSAIDs, GI tolerability was improved, although the antipyretic effect of FK881 was weak (NOEL: >320 mg/kg; diclofenac NOEL: <1mg/kg, rofecoxib NOEL: 100 mg/kg). These results suggest that FK881 may be useful in treating symptoms of rheumatoid arthritis and osteoarthritis.
Neal M Davies - One of the best experts on this subject based on the ideXlab platform.
-
high performance liquid chromatographic analysis of a selective Cyclooxygenase 1 Inhibitor sc 560 in rat serum application to pharmacokinetic studies
Journal of Pharmaceutical and Biomedical Analysis, 2004Co-Authors: Xiao Wei Teng, Neal M DaviesAbstract:Abstract A method of analysis of SC-560 (5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole) in biological fluids is necessary to study the kinetics of in vitro and in vivo metabolism. A simple high-performance liquid chromatographic method was developed for simultaneous determination of SC-560 and other products of metabolism in rat serum. Serum (0.1 ml) was precipitated with acetonitrile after addition of the internal standard, testosterone 17-propionate. Separation was achieved on a C8 column with UV-detection at 240 nm. The calibration curve was linear ranging from 0.02 to 100 μg/ml. The mean recovery was >86.7%. Precision of the assay was
-
formulation dependent pharmacokinetics bioavailability and renal toxicity of a selective Cyclooxygenase 1 Inhibitor sc 560 in the rat
Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, 2003Co-Authors: Xiao Wei Teng, Abdallalah K M Abumellal, Neal M DaviesAbstract:Purpose: To delineate formulation depen- dent pharmacokinetics and bioavailability of SC-560, a rel- atively new cycloooxygenase-1 (COX-1) specific Inhibitor, in the rat and examine its influence on the renal tubular enzyme, N-acetyl-beta-D-glucosaminidase (NAG), and urinary electrolytes. Methods: The pharmacokinetics of SC-560 was studied in Sprague-Dawley rats (n = 5 per group) after a single intravenous (iv) and oral dose (10 mg/ kg) in polyethylene glycol (PEG) 600 and a single oral dose (10 mg/kg) in 1% methylcellulose (MC). Serial blood sam- ples were collected via a catheter inserted in the right jugu- lar vein and serum samples were analysed for SC-560 using reverse phase HPLC. After oral administration of SC-560 in PEG, urine was also collected for 24 h and analysed for urinary sodium, chloride, and potassium as well as NAG. Results: After an iv dose (10 mg/kg) of SC-560, serum AUC, t 1/2, CL and V d were 9704 ± 4038 ng h/mL, 5.4 ± 0.8 h, 1.15 ± 0.46 L/h/kg and 9.1 ± 4.6 L/kg (mean +/ - SD, n = 5), respectively. Oral administration of 10 mg/kg SC-560-PEG and MC (n=5 rats) yielded serum AUC, C max , t max and t 1/2 of 1203.4 ± 130.3 and 523 ± 208 ng h/ mL, 218.5 ± 86.9 and 119.8 ± 15.5 ng/mL, 1.00 ± 1.8 and 2.0± 0 h, 3.7 ± 1.6 and 2.7 ± 1.7 h (mean +/- SD, n = 5), respectively. A single oral dose 10 mg/kg of SC-560 in PEG resulted in an increase in NAG excretion in urine and a reduction in 0-24 h urinary sodium, potassium, and chloride excretion. Conclusions: SC-560 extensively dis- tributes into rat tissues, and has a CL approaching hepatic plasma flow. The drug displays low <15% and formulation dependent bioavailability after oral administration and demonstrates kidney toxicity.
Hideaki Hara - One of the best experts on this subject based on the ideXlab platform.
-
Inhibitory effects of ASP6537, a selective Cyclooxygenase-1 Inhibitor, on thrombosis and neointima formation in rats.
Thrombosis research, 2017Co-Authors: Chinatsu Sakata, Tomihisa Kawasaki, Yoshiyuki Iwatsuki, Yumiko Moritani, Yoshiaki Morita, Hideaki HaraAbstract:Abstract Introduction Percutaneous coronary interventions (PCIs), such as balloon angioplasty and stent placement, are effective in the treatment of coronary artery disease. PCI has drawbacks, however, including acute thrombosis after the procedure and restenosis of the vascular lumen due to abnormal neointimal hyperplasia. ASP6537 is a selective COX-1 Inhibitor that has been investigated as a possible candidate for clinical development as an antiplatelet agent. In the present study, we evaluated the in vivo antithrombotic effect of ASP6537 and its effect on neointima formation after balloon angioplasty. Material and methods The antithrombotic effect of ASP6537 was examined using an arteriovenous shunt thrombosis model in rats while the effect of ASP6537 on neointima formation was evaluated in a rat carotid arterial balloon angioplasty model. Results In the thrombosis study, ASP6537 dose-dependently decreased the protein content of the thrombus, while no prolongation of template bleeding time was observed. In the neointima study, ASP6537 reduced neointima formation. Conclusions ASP6537 may be a promising agent for the prevention of acute thrombosis and restenosis after PCI in place of aspirin.
Giuseppe Montalto - One of the best experts on this subject based on the ideXlab platform.
-
the selective Cyclooxygenase 1 Inhibitor sc 560 suppresses cell proliferation and induces apoptosis in human hepatocellular carcinoma cells
International Journal of Molecular Medicine, 2006Co-Authors: Nadia Lampiasi, Daniela Fodera, Natale Dalessandro, Antonella Cusimano, Antonina Azzolina, Claudio Tripodo, Ada Maria Florena, Marta Ida Minervini, M Notarbartolo, Giuseppe MontaltoAbstract:Two isoforms of Cyclooxygenase (COX) are known, and to date most studies have implicated COX-2 in the development and progression of various human cancers. Increasing evidence suggests that COX-1 may also play a similar role. Indeed, we have recently observed that the dual COX-1/COX-2 Inhibitor indomethacin induces apoptosis in human hepatocellular carcinoma (HCC) cell lines more effectively than the selective COX-2 Inhibitors, possibly implicating COX-1 in HCC. In this study we investigated the expression of COX-1 in non-tumor and malignant human liver tissues, as well as the effects of the highly selective COX-1 Inhibitor SC-560 on cell growth and apoptosis in human HCC cell lines. Expression of COX-1 was detected in nearly all the samples assayed, although with a high variability between non-tumoral (NT) and malignant tissues. The percentage of COX-1 positive cells was significantly higher in the NT tissues than in the tumors (p<0.0001). In well-differentiated HCC COX-1 expression was significantly higher than in the poorly-differentiated tissues (p<0.05). SC-560 showed a dose- and time-dependent Inhibitory effect on HCC cell growth. The combination of the COX-1 Inhibitor with nimesulide and CAY10404, two selective COX-2 Inhibitors, resulted in additive effects on cell growth inhibition. SC-560 also inhibited colony formation in soft agar and induced apoptosis in HCC cells in a dose-dependent manner. Moreover, SC-560 decreased the levels of the anti-apoptotic proteins survivin and XIAP and activated caspase-3 and -7 in a dose- and time-dependent fashion. In conclusion, we report for the first time that the selective COX-1 Inhibitor SC-560 exhibits anti-tumor and apoptotic effects in human HCC cells. Overall, our previous and present results suggest that both COX-1 and COX-2 Inhibitors may have potential therapeutic implications in HCC patients.
