Abstract
Nonsteroidal anti-inflammatory drugs often cause development of significant GI lesions. Selective inhibitors of prostaglandin G/H synthase/cyclooxygenase-2 (PGHS-2) enzyme and some dual inhibitors of PGHS/5-lipoxygenase (5-LO) enzymes have been reported to be potent anti-inflammatory compounds that carry a much lower risk of having GI irritating effects. We have evaluated the anti-inflammatory effect and the GI safety profile of three new anti-inflammatory compounds: the selective PGHS-2 inhibitors NS-398 and PD 138387 and the PGHS/5-LO dual inhibitor PD 137968. All the compounds tested showed an anti-inflammatory activity in the carragenan footpad edema test in rats. None of these compounds caused either gastric damage 4 h after p.o. administration of 100 mg/kg in rats or inhibition of PGE2 synthesis in the stomach. However, when administered p.o. at an effective anti-inflammatory dose to rats with pre-existing acetic acid-induced gastric ulcer, NS-398 caused a statistically significant delay of ulcer healing. No impairment of the ulcer healing was observed with the other compounds evaluated. Derivatives of 2,6-di-tert-butylphenol, whose members may act as PGHS-1/PGHS-2 inhibitors, selective PGHS-2 inhibitors or PGHS/5-LO dual inhibitors, are novel anti-inflammatory compounds that are devoid of GI irritating effects and do not affect the rate of pre-existing gastric ulcer healing.
Footnotes
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Send reprint requests to: Antonio Guglietta, M.D., Ph.D., Parke-Davis Pharmaceutical Research Division, 2800 Plymouth Road, Ann Arbor, MI 48105.
- Abbreviations:
- 5-LO
- 5-lipoxygenase
- CFE
- carrageenan footpad edema
- CMC
- carboxymethylcellulose
- LPS
- lypopolysaccharide
- NSAID
- nonsteroidal anti-inflammatory drug
- PGH2
- prostaglandin H2
- PGHS
- prostaglandin G/H synthase/cyclooxygenase
- PGHS-1
- prostaglandin G/H synthase/cyclooxygenase-1
- PGHS-2
- prostaglandin G/H synthase/cyclooxygenase-2
- TxB2
- thromboxane B2
- TPP
- triphenyl phosphine
- IC50
- 50% inhibitory concentration
- PrP
- platelet-rich plasma
- Received September 29, 1997.
- Accepted May 8, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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