Disease relevance of Diclophenac

• Treatment of biliary colic with diclofenac: a randomized, double-blind, placebo-controlled study [1].
• ATB-337 did not induce leukocyte adherence, whereas diclofenac did, and was more potent at reducing paw edema [2].
• Gastroduodenal ulcers were detected endoscopically in 33 (15%) patients treated with diclofenac and in eight (4%) in the celecoxib group (p<0.001) [3].
• METHODS: Seven days after induction of gastric ulcer with serosal acetic acid, daily oral treatment with antiinflammatory doses of diclofenac, nitrofenac, or vehicle was started [4].
• We report a prospective, single-center, randomized, double-blind controlled trial to determine if rectal diclofenac reduces the incidence of pancreatitis following cholangiopancreatography [5].

Psychiatry related information on Diclophenac

• METHODS: This was a randomized, double-blind, placebo-controlled study designed to compare the antihyperalgesic efficacy of topical (65 mg) and oral (93 mg) diclofenac via estimates of mechanical pain thresholds obtained at the site of induced inflammation with von Frey hairs [6].
• The effect of treatment with riluzole on locomotor activity was greater than that of treatment with diclofenac and was dose-dependent [7].
• The use of diclofenac was associated with a significantly more rapid return to calm wakefulness and had significantly less effect upon respiratory rate [8].
• METHODS: The effect of diclofenac on the developing embryo during the critical period of organogenesis was investigated by using a whole rat embryo culture model [9].
• The results showed that diclofenac sodium was significantly more effective than placebo in the treatment of nocturnal enuresis [10].

High impact information on Diclophenac

• Only diclofenac induced an upregulation of CD11b expression, suggesting an activating effect on neutrophils [11].
• No enzyme release was observed upon treatment of neutrophils with different NSAIDs, indicating a lack of degranulatory activity of NSAIDs, with the exception of diclofenac [11].
• Genetic susceptibility to diclofenac-induced hepatotoxicity: contribution of UGT2B7, CYP2C8, and ABCC2 genotypes [12].
• Repeated administration of diclofenac caused extensive small intestinal damage and reduced hematocrit by 50% [2].
• Diclofenac, but not ATB-337, elevated gastric granulocyte infiltration and expression of tumor necrosis factor alpha, lymphocyte function-associated antigen 1, and intercellular adhesion molecule 1 [2].

Chemical compound and disease context of Diclophenac

• METHODS: Five organic acids (sulindac, ibuprofen, ketoprofen, diclofenac, and norfloxacin) were infused into rats with biliary fistulas [13].
• After ulcer healing, patients who were negative for Helicobacter pylori were randomly assigned to celecoxib 200 mg twice a day plus omeprazole placebo once daily or diclofenac 75 mg twice daily plus omeprazole 20 mg once daily for 6 months [14].
• Three esophageal cancer cell lines (OE-33, OSC-1, and OSC-2) were treated with COX-inhibiting substances (diclofenac, rofecoxib, and SC-560) and the effect on expression of the four genes was determined [15].
• In vitro, arachidonic acid and diclofenac synergistically induced neuroblastoma cell death [16].
• OBJECTIVE: To perform a randomized, double-blind, crossover clinical trial of diclofenac + misoprostol versus acetaminophen in ambulatory patients with osteoarthritis of the hip or knee [17].

Biological context of Diclophenac

• METHODS: Hepatocanalicular conjugate export pump-deficient (TR-) rats were used to selectively block diclofenac enterohepatic circulation without interrupting bile flow [18].
• In the saline-perfused hindlimb of WT and eNOS -/- mice, marked N(omega)-nitro-l-arginine (l-NA, 300 micromol/liter)- and diclofenac-insensitive vasodilations in response to both bradykinin and acetylcholine (ACh) were observed, which were more pronounced than the agonist-induced vasodilation in the hindlimb of WT in the absence of l-NA [19].
• The diclofenac-induced activity also has the unusual property of being more sensitive to inhibition by acetaminophen (IC50 = 0.1-1.0 mM) than COX-2 induced with bacterial lipopolysaccharide [20].
• However, the activity evoked by high concentrations of diclofenac has a profoundly distinct COX active site that allows diclofenac, its inducer, to be washed readily from its active site [20].
• Inhibition of cyclooxygenase with diclofenac converted the ACh-induced vasodilation into vasoconstriction (-49% decrease of basal flow) [21].

Anatomical context of Diclophenac

• METHODS: Rats were treated orally with diclofenac (10-100 mg/kg) and killed after 1-24 hours, and their gastrointestinal (GI) tracts were evaluated for ulcer number and area [22].
• CONCLUSIONS: This study provides both biochemical and direct evidence of macroscopic injury to the small intestine in 68%-75% of volunteers resulting from 2 weeks' ingestion of slow-release diclofenac [23].
• One possibility is that reactive metabolites of diclofenac form adducts with enterocyte macromolecules, as previously shown for liver [22].
• The case of a 61-year-old man who gradually developed similar inflammatory changes in the ascending colon during prolonged intake of a slow-release form of diclofenac is presented, and the literature on nonsteroidal antiinflammatory drug-induced intestinal strictures is briefly reviewed [24].
• Diathermy DCH was performed without pedicle ligature or anal-canal dressing, and a diclofenac suppository was administered at the end of the procedure [25].

Associations of Diclophenac with other chemical compounds

• FINDINGS: 430 patients underwent endoscopy (celecoxib n=212, diclofenac n=218) [3].
• Among 259 patients without events, 222 underwent endoscopy (116 received celecoxib and 106 received diclofenac plus omeprazole) [14].
• Nitrofenac suppressed cyclooxygenase 1 activity to a similar extent as diclofenac [4].
• Cyclosporin and diclofenac interaction in rheumatoid arthritis [26].
• In the combined presence of diclofenac and N(G)-nitro-L-arginine (L-NNA), sinusoidal pressure oscillations (from 40 to 50 mm Hg, 4 minutes, 1.5 Hz) led to simultaneous oscillations in the external diameter of coronary artery segments, the amplitude of which were decreased by iberiotoxin and apamin and also by endothelial denudation [27].

Gene context of Diclophenac

• Intriguingly, removal of the negative charge from either 216 or 301 produced enzymes (E216A, E216K, and D301Q) with elevated levels (50-75-fold) of catalytic activity toward diclofenac, a carboxylate-containing CYP2C9 substrate that lacks a basic nitrogen atom [28].
• Determination of the crystal structure of a complex of diclofenac with murine COX-2 demonstrates that diclofenac binds to COX-2 in an inverted conformation with its carboxylate group hydrogen-bonded to Tyr-385 and Ser-530 [29].
• This study investigated whether biotransformation to metabolites (4'-hydroxy-aceclofenac, diclofenac, 4'-hydroxy-diclofenac) contributes to inhibitory effects on the cyclooxygenase (COX) isozymes in vitro and ex vivo [30].
• In conclusion, both COX-1-sparing and COX-2-inhibitory actions of aceclofenac may rest in its limited but sustained biotransformation to diclofenac [30].
• The disappearance of MPA did not correlate with either the activity metabolized via CYP2C9 (diclofenac 4'-hydroxylase activity) or the activity metabolized via CYP2C19 (S-mephenytoin 4'-hydroxylase activity) [31].

Analytical, diagnostic and therapeutic context of Diclophenac

• They received a single 75-mg (3 mL) intramuscular injection of diclofenac (n = 27) or similarly administered 3 mL of saline (n = 26) [1].
• Immediately after endoscopy, patients were given a suppository containing either 100 mg diclofenac or placebo [5].
• CONCLUSIONS: This trial shows that rectal diclofenac given immediately after endoscopic retrograde cholangiopancreatography can reduce the incidence of acute pancreatitis [5].
• We addressed this possibility by using immunohistochemistry to detect diclofenac adducts [22].
• No association could be evidenced with diclofenac intake, whatever the control group [32].

References