title: A randomized, double-blind, one-week study comparing effects of a novel COX-2 inhibitor and naproxen on the gastric mucosa.
abstract: CS-706 is a novel cyclooxygenase-2 (COX-2) inhibitor with potent analgesic, anti-inflammatory, and antitumor properties in animal models. This one-week, multicenter study was undertaken to assess the safety and tolerability of CS-706 and to compare the effects of CS-706 versus naproxen on acute gastrointestinal (GI) mucosal injury. Healthy men and women (n=160) without evidence of underlying gastroduodenal lesions were randomized to placebo, 100 mg CS-706 once daily, 200 mg CS-706 once daily, or 500 mg naproxen twice daily, administered for 7 days. On Day 8, subjects underwent a posttreatment upper GI endoscopy to assess development of gastroduodenal petechiae, erosions, and ulcers. Inhibition of COX-1 and COX-2 activity over the 24-hr postdose interval on Day 7 was determined in 48 subjects (12 per treatment group). CS-706 was safe and well tolerated. The extent of upper GI mucosal injury for both CS-706 dose groups was statistically significantly less than that for naproxen (P < 0.001) and was similar to placebo (P=0.615 and P=0.115 for 100 and 200 mg CS-706, respectively). No subject in placebo or either CS-706 treatment group had gastroduodenal ulcers, compared with 11 (28.2%) subjects treated with naproxen (P < 0.001). Both doses of CS-706 inhibited COX-2 activity to a similar extent as naproxen, whereas neither dose of CS-706 showed meaningful inhibition of platelet COX-1. In contrast, naproxen nearly completely inhibited COX-1 over the dosing interval. We conclude that CS-706, dosed up to 200 mg once daily, has an acute, upper GI toxicity profile similar to that of placebo and significantly superior to that of naproxen.
authors.affiliation: Daiichi Sankyo Pharma Development, Edison, NJ 08837, USA. jmoberly@daiichisankyo-us.com
authors.forename: James B
authors.initials: JB
authors.lastname: Moberly
authors.forename: Stuart I
authors.initials: SI
authors.lastname: Harris
authors.forename: Dennis S
authors.initials: DS
authors.lastname: Riff
authors.forename: James Craig
authors.initials: JC
authors.lastname: Dale
authors.forename: Tara
authors.initials: T
authors.lastname: Breese
authors.forename: Patrick
authors.initials: P
authors.lastname: McLaughlin
authors.forename: Janet
authors.initials: J
authors.lastname: Lawson
authors.forename: Yaping
authors.initials: Y
authors.lastname: Wan
authors.forename: Jianbo
authors.initials: J
authors.lastname: Xu
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Truitt
mesh_terms: D000328:Adult; D051545:Cyclooxygenase 1 / Q000097:blood; D051546:Cyclooxygenase 2 / Q000097:blood; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004381:Duodenal Ulcer / Q000139:chemically induced; D004386:Duodenum / Q000187:drug effects; D016099:Endoscopy, Gastrointestinal; D005260:Female; D005753:Gastric Mucosa / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects; D008297:Male; D008565:Membrane Proteins / Q000097:blood; D008875:Middle Aged; D009288:Naproxen / Q000008:administration & dosage / Q000009:adverse effects*; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects*; D012016:Reference Values; D013276:Stomach Ulcer / Q000097:blood / Q000139:chemically induced* / Q000473:pathology; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects*; D013997:Time Factors; D014481:United States
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D008565:Membrane Proteins; D011758:Pyrroles; D013449:Sulfonamides; D009288:Naproxen; C514354:apricoxib; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human