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Toxicological information

Exposure related observations in humans: other data

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Administrative data

Endpoint:
exposure-related observations in humans: other data
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well-conducted ex vivo clinical study

Data source

Reference
Reference Type:
publication
Title:
Cyclooxygenase-1 and Cyclooxygenase-2 selectivity of widely used nonsteroidal anti-inflammatory drugs
Author:
Cryer B, Feldman M
Year:
1998
Bibliographic source:
Am. J. Med., 104, 413-421

Materials and methods

Type of study / information:
Inhibitory effects of the drugs on COX-1 and COX-2 in blood and their ability to inhibit prostaglandin synthesis in the stomach
Endpoint addressed:
not applicable
Test guideline
Qualifier:
no guideline required
Principles of method if other than guideline:
volunteer ex vivo clinical study
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Salicylic acid from Sigma Chemical Co., St Louis, Missouri

Method

Ethical approval:
other: Study approved by the Human Studies Subcommittee of the Dallas Department of Veterans Affairs Medical Center
Details on study design:
16 non-smoking healthy volunteers (6 men, 10 non-pregnant women) between the ages of 23 and 46 years, not currently taking NSAIDs or other potentially confounding medications..
25 NSAIDs including salicylic acid and acetylsalicylic acid were studied.
Exposure assessment:
measured
Details on exposure:
Venous blood was obtained on study days 1 and 10 for COX-1 and COX-2 whole blood assays. Each subject underwent endoscopy with mucosal biopsy. NSAIDs were studied at 6 concentrations ranging from 0 to 100 µM (n = 5 for each). Blood was assayed each day for serum-generated thromboxane B2 synthesis (COX-1 assay) and for lipopolysaccharide-stimulated prostaglandin E2 synthesis (COX-2 assay). In addition, gastric biopsies from the same volunteers were incubated with each drug ex vivo and mucosal prostaglandin E2 synthesis measured.

Results and discussion

Results:
The concentrations (IC50) of the test compounds that inhibited 50% of cyclooxygenase (COX) activity in blood and gastric mucosa for SA, ASA and the most and least potent of the tested drugs were:

COX-1 IC50:
Ketoprofen: 0.11 uM (ranked 1/25)
ASA: 4.45 uM (ranked 10/25)
SA: >100 uM (ranked 24/25)
Salsalate: > 100 uM (ranked 25/25)

COX-2 IC50:
Diclofenac: 0.01 uM (1/25)
ASA: 13.88 uM (ranked 16/25)
SA: 14.08 uM (ranked 18/25)
Salsalate: 39,90 uM (ranked 25/25)

Gastric mucosa:
ASA: 0.03 uM (ranked 1/25)
SA:: > 100 uM (ranked 20/25)
Dexamethasone: > 100 uM (ranked 25/25)

SA did not inhibit COX-1 up to the highest concentration tested and had low COX-2 inhibitory potency.
ASA had low COX-1 and COX-2 inhibitory potencies, with moderate selectivity for COX-1. ASA had the most potent effect on gastric mucosa, with SA having no effect.

Any other information on results incl. tables

Inhibitory effects of NSAIDs on gastric prostaglandin E2 synthesis correlated withCOX-1 inhibitory potency in blood (P<0.001) and withCOX-1 selectivity (P<0.01), but not withCOX-2 inhibitory potency. EvenCOX-2 "selective" NSAIDs still had sufficientCOX-1 activity to cause potent inhibitory effects on gastric prostaglandin E2 synthesis at concentrations achieved in vivo. No currently marketed NSAID, even those that areCOX-2 selective, spare gastricCOXactivity at therapeutic concentrations. Thus, all NSAIDs should be used cautiously until safer agents are developed.

Applicant's summary and conclusion

Conclusions:
SA does not inhibit COX-1, has low COX-2 inhibitory potency and has no effect on gastric mucosa.
Executive summary:

An ex vivo clinical study (Cryer, 1998) investigated the COX-selectivity of several NSAIDs in healthy men and women. The effects of the drugs was measured in whole blood and the effects of the same drugs in the stomach were studied by measuring ex vivo rates of prostaglandin synthesis in human gastric mucosal biopsies exposed to these agents. Inhibitory effects of the drugs onCOX-1 andCOX-2 in blood with their ability to inhibit prostaglandin synthesis in the stomach were compared. 25 anti-inflammatory, analgesic and other drugs of interest –including acetylsalicylic acid, salicylic acid - were studied at 6 concentrations ranging from 0 to 100 µM (n = 5 for each). Blood was assayed each day for serum-generated thromboxane B2 synthesis (COX-1 assay) and for lipopolysaccharide-stimulated prostaglandin E2 synthesis (COX-2 assay). In addition, gastric biopsies from the same volunteers were incubated with each drug ex vivo and mucosal prostaglandin E2 synthesis measured.

SA did not inhibitCOX-1 up to the highest concentration tested and had lowCOX-2 inhibitory potency.

ASA had lowCOX-1 andCOX-2 inhibitory potencies, with moderate selectivity forCOX-1. ASA had the most potent effect on gastric mucosa, with SA having no effect.

Inhibitory effects of NSAIDs on gastric prostaglandin E2 synthesis correlated withCOX-1 inhibitory potency in blood (P<0.001) and withCOX-1 selectivity (P<0.01), but not withCOX-2 inhibitory potency. EvenCOX-2 "selective" NSAIDs still had sufficientCOX-1 activity to cause potent inhibitory effects on gastric prostaglandin E2 synthesis at concentrations achieved in vivo. No currently marketed NSAID, even those that areCOX-2 selective, spare gastricCOXactivity at therapeutic concentrations. Thus, all NSAIDs should be used cautiously until safer agents are developed.