Gastrointestinal safety of AZD3582, a cyclooxygenase inhibiting nitric oxide donator: proof of concept study in humans.
BACKGROUND
Cyclooxygenase inhibiting nitric oxide donators (CINODs) are a new class of anti-inflammatory and analgesic drugs that may minimise gastrointestinal toxicity compared with standard non-steroidal anti-inflammatory drugs (NSAIDs) by virtue of nitric oxide donation.


METHODS
A proof of concept study of the gastrointestinal safety of AZD3582, the first CINOD available for human testing, was conducted. Thirty one subjects were randomised to receive placebo, naproxen 500 mg twice daily, or its nitroxybutyl derivative AZD3582 in an equimolar dose (750 mg twice daily) for 12 days in a double blind three period crossover volunteer study. At the start and end of each dosing period, gastroduodenal injury was assessed by endoscopy and small bowel permeability by differential urinary excretion of lactulose and L-rhamnose. Pharmacokinetic profiles were assessed at steady state.


RESULTS
On naproxen, the mean total number of gastroduodenal erosions was 11.5 (and one subject developed an acute ulcer) versus 4.1 on AZD3582 (p<0.0001). More than half of the subjects had no erosions on AZD3582. Differences were seen for both the stomach and duodenum. Naproxen increased intestinal permeability (lactulose:L-rhamnose ratio 0.030 before v 0.040 after treatment) whereas AZD3582 (0.029 before, 0.029 after; p=0.006 v naproxen) and placebo (0.030 before, 0.028 after; p<0.001 v naproxen) did not. The steady state bioavailability of naproxen metabolised from AZD3582 was 95% (95% confidence interval 87-101%) of that after naproxen administration.


CONCLUSIONS
This human study supports animal data showing reduced gastrointestinal toxicity with the CINOD AZD3582. The potential combination of effective pain relief and gastrointestinal protection offered by AZD3582 warrants further evaluation in human clinical studies.
Division of Gastroenterology, University Hospital Nottingham, Nottingham, UK. cj.hawkey@nottingham.ac.uk
C J
CJ
Hawkey
J I
JI
Jones
C T
CT
Atherton
M M
MM
Skelly
J R
JR
Bebb
U
U
Fagerholm
B
B
Jonzon
P
P
Karlsson
I T
IT
Bjarnason
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D001794:Blood Pressure / Q000187:drug effects; D002463:Cell Membrane Permeability / Q000502:physiology; D018592:Cross-Over Studies; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D004311:Double-Blind Method; D004378:Duodenal Diseases / Q000139:chemically induced / Q000503:physiopathology; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced* / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009281:Naphthalenes / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D009288:Naproxen / Q000009:adverse effects / Q000031:analogs & derivatives; D020030:Nitric Oxide Donors / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D013272:Stomach Diseases / Q000139:chemically induced / Q000503:physiopathology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D009281:Naphthalenes; D020030:Nitric Oxide Donors; C111751:naproxen-n-butyl nitrate; D009288:Naproxen