Pharmacological profile of FK881(ASP6537), a novel potent and selective cyclooxygenase-1 inhibitor
| Autor: | Tomoko Masunaga, Junko Imanishi, Katsuya Nakamura, Eiji Yoshimi, Kanae Kuroda, Fumie Takahashi, Kaoru Yamagami, Seitaro Mutoh, Emi Hamachi, Masako Kuno, Susumu Miyata, Yoshitaka Ohkubo, Yoshiaki Morita, Satoshi Aoki |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Male
Analgesic Pain CHO Cells Osteoarthritis In Vitro Techniques Pharmacology Carrageenan Biochemistry Rats Sprague-Dawley Mice Cricetulus Diclofenac Cricetinae medicine Animals Edema Humans Cyclooxygenase Inhibitors Stomach Ulcer Antipyretic Rofecoxib ED50 Acetic Acid Cyclooxygenase 2 Inhibitors biology business.industry Triazoles medicine.disease Arthritis Experimental Recombinant Proteins Rats Cyclooxygenase 2 Hyperalgesia Rats Inbred Lew Rheumatoid arthritis Cyclooxygenase 1 biology.protein Female Cyclooxygenase business medicine.drug |
| Zdroj: | Biochemical Pharmacology. 82:746-754 |
| ISSN: | 0006-2952 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect