Changes in ulcerogenic response to non-steroidal anti-inflammatory drugs (NSAIDs) in adjuvant arthritic rats]

Gastroenteropathy is the most common among patients who use non-steroidal anti-inflammatory drugs (NSAIDs) for the treatment of inflammatory disorders. It is known that rheumatoid arthritic (RA) patients are more susceptible to NSAID-induced gastropathy than other NSAID users. This article reviewed our recent studies concerning the influence of arthritis on gastric mucosal integrity in adjuvant-induced arthritic rats. The gastric mucosal lesions induced by indomethacin, one of conventional NSAIDs, were markedly aggravated in arthritic rats. Likewise, the healing of chronic gastric ulcers induced by thermal cauterization was significantly delayed in arthritic rats. The underlying mechanisms of these phenomena observed in arthritic rats may be attributable to the enhancement of iNOS/NO pathway in the former and the less expression of various growth factors in the ulcerated mucosa, such as basic fibroblast growth factors (bFGF) or insulin-like growth factors (IGF-1) in the latter. In addition, we recently found that cyclooxygenase-2 (COX-2) selective inhibitors, such as rofecoxib or celecoxib, induced apparent gastric lesions in arthritic rats, suggesting that a caution should be paid on the use of COX-2 selective inhibitors in RA patients.     

Effect of celecoxib, a cyclooxygenase-2 inhibitor, on the pathophysiology of adjuvant arthritis in rat

We investigated the efficacy of celecoxib, a specific cyclooxygenase (COX)-2 inhibitor, on arthritic pathophysiology and confirmed its gastric safety in adjuvant-induced arthritis rats. Results were compared with those for loxoprofen, a non-selective COX inhibitor. Arthritis was induced by injection of 1 mg of Mycobacterium butyricum in 50 microl of liquid paraffin into the left footpad of Lewis rats. The drugs were given by twice daily oral administration for 10 days beginning 15 days after adjuvant injection, with celecoxib at 0.01-3 mg/kg/day and loxoprofen at 0.01-3 mg/kg/day. Celecoxib significantly inhibited paw swelling, hyperalgesic response, and joint destruction (radiographic and histopathological findings) in these arthritic rats. These effects of celecoxib were superior to those of loxoprofen. Further, the administration of loxoprofen (3 mg/kg/day) caused significant gastric lesions, whereas celecoxib at the same dose did not. These results suggest that COX-2-mediated prostaglandins may play an important role in the progression of pathophysiology in this model and that celecoxib may be a useful therapeutic agent for the treatment of rheumatoid arthritis, with greater safety than non-selective COX inhibitors.     

Enhancement of antinociception by co-administration of an opioid drug (morphine) and a preferential cyclooxygenase-2 inhibitor (rofecoxib) in rats

Synergism has been used to obtain analgesia at doses at which side effects are minimal. In addition, it has been demonstrated that inhibition of cyclooxygenase-2 is responsible for the therapeutic effects of nonsteroidal anti-inflammatory drugs (NSAIDs). The aim of this study was to evaluate the antinociceptive interaction between the preferential COX-2 inhibitor, rofecoxib and morphine. Several combinations were evaluated using the pain-induced functional impairment model (PIFIR), a rat model of arthritic pain. Surface of synergistic interaction (SSI) analysis and an isobolographic method were used to detect the antinociceptive potency of the drugs, given either individually or in combination. The surface of synergistic interaction was calculated from the total antinociceptive effect produced by the combination after subtraction of the antinociceptive effect produced by each individual drug. Male rats received orally morphine alone (10, 17.8, 31.6, 56.2 and 100.0 mg/kg), rofecoxib alone (3.2, 5.6, 10, 31.6, 56.2 and 74.0 mg/kg) or 12 different combinations of morphine and rofecoxib. Three combinations exhibited potentiation of antinociceptive effects (10 mg/kg of morphine with either 5.6, 10 or 31.6 mg/kg of rofecoxib), whereas the other nine combinations showed additive antinociceptive effects. The combination of morphine, 56.2 mg/kg (p.o.), and rofecoxib, 31.6 mg/kg (p.o.), produced the maximum antinociceptive effect (P<0.05). This combination caused gastric injuries less severe than those observed with indomethacin, i.e. it reduced ulcers and erosion formation. The synergistic antinociceptive effects of rofecoxib and morphine are important and suggest that combinations with drugs may decrease the side effects associated with the use of nonselective NSAIDs. Furthermore, the present results suggest that combinations containing opioid drugs and selective COX-2 inhibitors may have clinical utility in pain therapy.     

The anti-inflammatory effect of FR188582, a highly selective inhibitor of cyclooxygenase-2, with an ulcerogenic sparing effect in rats

The anti-inflammatory and ulcerogenic effects of FR188582, 3-chloro-5-[4-(methylsulfonyl) phenyl]-1-phenyl-1H-pyrazole, were investigated. In a recombinant human cyclooxygenase (COX) enzyme activity, FR188582 inhibited COX-2 with an IC50 value of 0.017 microM, and the inhibition of prostaglandin (PG) E2 formation by FR188582 was over 6000 times more selective for COX-2 than COX-1. Oral administration of FR188582 dose-dependently inhibited adjuvant arthritis. This effect was threefold more potent than that of indomethacin. FR188582 and indomethacin dose-dependently suppressed the formation of immunoreactive PGE2, but not immunoreactive leukotriene (LT) B4, in arthritic paw. Unlike indomethacin, FR188582 did not induce visible gastric lesions in rats at doses up to 32 mg/kg, p.o. Furthermore, FR188582 did not inhibit the level of immunoreactive PGE2 and immunoreactive 6-keto PGF1alpha in rat gastric mucosa. These results suggest that FR188582, a highly selective COX-2 inhibitor, has a potent anti-inflammatory effect mediated by inhibition of PGE2 in inflamed tissues. The safety profile of FR188582 appears to be improved over the safety profile of indomethacin.     

Pharmacological profile of FK881(ASP6537), a novel potent and selective cyclooxygenase-1 inhibitor

Nonsteroidal anti-inflammatory drugs (NSAIDs) are now understood to fall into one of two agent classes in clinical use. Traditional NSAIDs inhibit both cyclooxygenases-1 and 2 (COX-1, 2), which act as key enzymes catalyzing the same reaction in the production of prostaglandins (PGs), while the second class of NSAIDs selectively inhibit COX-2. Inhibition of the inducible COX-2 isoform is believed to be responsible for the therapeutic effects of NSAIDs, such as anti-inflammatory, analgesic, and antipyretic effects, while COX-1 inhibition results in side-effects on the gastrointestinal (GI) system. In the present study, however, we changed this notion that inhibiting only COX-1 causes adverse effects. We discovered FK881, a specific COX-1 inhibitor which exhibits a 650-fold ratio for human whole blood COX-1/COX-2 and rats in vivo. In rats, FK881 dose dependently inhibited carrageenan-induced paw edema (ED30: 22 mg/kg; diclofenac ED30: 3.6 mg/kg, rofecoxib ED30: 26 mg/kg) and paw swelling associated with adjuvant arthritis (ED50: 17 mg/kg; diclofenac ED50: 1.4 mg/kg, rofecoxib ED50: 1.8 mg/kg). Further, FK881 dose dependently inhibited acetic acid-induced writhing in mice (ED50: 19 mg/kg; diclofenac ED50: 14 mg/kg, rofecoxib ED50: >100 mg/kg) and adjuvant arthritis hyperalgesia in rats (ED50: 1.8 mg/kg; diclofenac ED50: 1.0 mg/kg, rofecoxib ED50: 0.8 mg/kg). However, unlike traditional NSAIDs, GI tolerability was improved, although the antipyretic effect of FK881 was weak (NOEL: >320 mg/kg; diclofenac NOEL: <1 mg/kg, rofecoxib NOEL: 100 mg/kg). These results suggest that FK881 may be useful in treating symptoms of rheumatoid arthritis and osteoarthritis.     

Effect of nimesulide, rofecoxib and celecoxib on gastric tissue glutathione level in rats with indomethacin-induced gastric ulcerations

Glutathione (GSH) is a tripeptide and a superoxide radical scavenger and it protects thiol protein groups required for maintaining the integrity of cell against oxidation. GSH is present in the stomach at high concentrations and plays an important role in maintaining the integrity of the gastric mucosa. We investigated whether oral administration of nimesulide, rofecoxib and celecoxib, selective COX-2 inhibitors, changed GSH level in the gastric tissue of indomethacin-treated rats. Thirty albino Wistar rats were used in this study. Animals were randomly assigned to five groups as follows: control group received only distilled water (group I). Nimesulide at a dose of 100 mg/kg (group II), rofecoxib at a dose of 25 mg/kg (group III) and celecoxib at a dose of 100 mg/kg (group IV) were intragastrically administered 5 min before indomethacin (25 mg/kg) treatment. Equal volume of distilled water was given to the indomethacin-administered group (group V). Indomethacin was administered intragastrically. Gastric tissue mean GSH level was significantly higher in nimesulide-given rats than in rofecoxib- and celecoxib-treated groups, there was not any significant difference between the nimesulide and control groups. Our study showed that although nimesulide prevented the indomethacin-induced gastric ulcers completely, rofecoxib and celecoxib did not prevent the indomethacin-induced ulcer formation. In conclusion, we propose that nimesulide exerts a prophylactic effect on the indomethacin-induced gastric ulcers by enhancing gastric GSH level.     

Co-administration of rofecoxib and tramadol results in additive or sub-additive interaction during arthritic nociception in rat

Over the decades, nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids are the most commonly used analgesics in the management of acute and chronic pain. In order to assess a possible antinociceptive interactions, the antinociceptive effects of rofecoxib p.o., a preferential inhibitor of cyclooxygenase-2, and tramadol-hydrochloride p.o., an atypical opioid analgesic, administered either separately or in combination, were determined using a rat model of arthritic pain. The data were interpreted using the surface of synergistic interaction (SSI) analysis and an isobolographic analysis to establish the nature of the interaction. The SSI was calculated from the total antinociceptive effect produced by the combination after subtraction of the antinociceptive effect produced by each individual drug. Female rats received orally rofecoxib alone (1.0, 1.8, 3.2, 5.6, 10.0, 17.8, 31.6 and 56.2 mg/kg), tramadol alone (1.8, 3.2, 5.6, 10.0, 17.8, 31.6 and 56.2 mg/kg) or 12 different combinations of rofecoxib plus tramadol. Five combinations exhibited various degrees of sub-additive (i.e. less than the sum of the effects produced by the each drug alone) antinociceptive effects (3.2 mg/kg tramadol with 7.8 mg/kg rofecoxib; 5.6 mg/kg tramadol with either 10.0 or 17.8 mg/kg rofecoxib; 10.0 mg/kg tramadol with either 10.0 or 17.8 mg/kg rofecoxib), whereas the other 7 combinations showed additive antinociceptive effects (i.e. the sum of the effects produced by each agent alone). Three combination of rofecoxib+tramadol (10.0+5.6, 10.0+10.0, and 17.8+5.6 mg/kg respectively) presented high sub-additive interactions (P<0.002: Q=9.5). The combination rofecoxib (17.8 mg/kg)+tramadol (10.0 mg/kg) caused gastric injuries less severe than those observed with indomethacin, but more severe than those obtained with rofecoxib or tramadol in single administration. The antinociceptive interaction of rofecoxib and tramadol suggests that combinations with these drugs may have no clinical utility in pain therapy.     

Behavioral effects of delta-opioid receptor agonists: potential antidepressants?

Gastroenteropathy is the most common among patients who use non-steroidal anti-inflammatory drugs (NSAIDs) for treatment of inflammatory disorders. It is known that rheumatoid arthritic patients are more susceptible to NSAID-induced gastropathy than other NSAID users. This article reviewed our recent studies concerning the influence of arthritic conditions on gastric ulcerogenic response to NSAID and healing response of chronic gastric ulcers in rats. Gastric lesions induced by indomethacin, one of the conventional NSAIDs, were markedly aggravated in arthritic rats. This increased ulcerogenic response in arthritic rats was attributable to nitric oxide production due to up-regulation of inducible nitric oxide synthase. In arthritic rat stomachs, cyclooxygenase (COX)-2 was also up-regulated, where COX-2 selective inhibitors such as rofecoxib or celecoxib provoked gross lesions, although they caused no damage in normal rats. In addition, the healing of chronic gastric ulcers was also delayed in arthritic rats because of less expression of various growth factors such as basic fibroblast growth factors or insulin-like growth factors. Based on these findings, it is concluded that arthritic conditions alter the mucosal ulcerogenic and healing responses in the stomach. Especially, caution should be paid on the use of COX-2 selective inhibitors in rheumatoid arthritic patients.     

Pharmacological profile of celecoxib, a specific cyclooxygenase-2 inhibitor

The pharmacological profile of celecoxib (CAS 169590-42-5, SC-58635), a specific cyclooxygenase-2 (COX-2) inhibitor, was investigated. Celecoxib inhibited COX-2-mediated prostaglandin E2 (PGE2) production in human dermal fibroblasts (IC50 = 91 nmol/l), whereas it was a weak inhibitor of COX-1-mediated PGE2 production in human lymphoma cells (IC50 = 2800 nmol/l). In in vivo studies, the effects of celecoxib were compared with those of nonsteroidal anti-inflammatory drugs (NSAIDs) in acute rat models of hyperalgesia and pyrexia. Celecoxib abrogated carrageenan-induced hyperalgesia in the hind paw accompanied by a decrease in PGE2 content in paw exudates and cerebrospinal fluid in a dose-related manner, with an ED30 = 0.81 mg/kg. Its analgesic potency was comparable to those of NSAIDs. In lipopolysaccharide-induced pyrexia, the anti-pyretic potency of celecoxib was equal to that of NSAIDs. On the other hand, in a gastric toxicity study in rats, single oral administration of celecoxib had no effect on gastric mucosa or mucosal PGE2 content at doses up to 200 mg/kg. Additionally, celecoxib did not inhibit thromboxane B2 production of calcium ionophore-stimulated peripheral blood of rats or arachidonic acid-induced aggregation of human platelets. These findings suggest that celecoxib might be a safe and effective alternative to NSAIDs for clinical use.     

Covalent binding of radioactivity from [14C]rofecoxib, but not [14C]celecoxib or [14C]CS-706, to the arterial elastin of rats.

Rofecoxib is a cyclooxygenase-2 (COX-2) inhibitor that has been withdrawn from the market because of an increased risk of cardiovascular (CV) events. With a special focus on the arteries, the distribution profiles of radioactivity in rats orally administered [14C]rofecoxib were investigated in comparison with two other COX-2 inhibitors, [14C]celecoxib and [14C]CS-706 (2-(4-ethoxyphenyl)-4-methyl 1-(4-sulfamoylphenyl)-1H-pyrrole), a novel selective COX-2 inhibitor. Whole-body autoradioluminography and quantitative determination of the tissue concentrations showed that considerable radioactivity is retained by and accumulated in the thoracic aorta of rats after oral administration of [14C]rofecoxib, but not [14C]celecoxib or [14C]CS-706. Acid, organic solvent, and proteolytic enzyme treatments of aorta retaining high levels of radioactivity from [14C]rofecoxib demonstrated that most of the radioactivity is covalently bound to elastin. In agreement with this result, the radioactivity was found to be highly localized on the elastic fibers in the aorta by microautoradiography. The retention of radioactivity on the elastic fibers was also observed in the aortic arch and the coronary artery. These findings indicate that [14C]rofecoxib and/or its metabolite(s) are covalently bound to elastin in the arteries. These data are consistent with the suggestion of modified arterial elasticity leading to an increased risk of CV events after long-term treatment with rofecoxib.     

Anti-inflammatory effect and low ulcerogenic activity of etodolac,a cyclooxygenase-2 selective non-steroidal anti-inflammatory drug,on adjuvant-induced arthritis in rats

Adjuvant arthritic rats are known to be more susceptible to gastric damage induced by non-steroidal anti-inflammatory drugs (NSAIDs) than are normal rats. We compared the relative gastric safety profile of etodolac with those of meloxicam, diclofenac sodium and indometacin in adjuvant arthritic rats and normal rats or mice. As a measure of the safety profiles of NSAIDs, we used the safety index, the ratio of the dose that elicits gastric mucosal lesions to the effective dose as an anti-inflammatory or analgesic compound. The anti-inflammatory or analgesic effects of NSAIDs were assessed by paw swelling in adjuvant arthritic rats, and either carrageenin-induced paw edema or brewer's yeast-induced hyperalgesia, as well as acetic acid-induced writhing, in normal rats or mice. In addition, we also investigated the effects of these NSAIDs on human COX-1 and COX-2 activity. Etodolac and other NSAIDs inhibited paw swelling and caused gastric mucosal lesions in adjuvant arthritic rats in a dose-dependent manner. Etodolac showed the highest UD(50) value and safety index among these NSAIDs in arthritic rats. In normal rats, etodolac also showed the highest UD(50) value and safety index, except when its effects were assessed by acetic acid-induced writhing. Etodolac and meloxicam showed selectivity for human COX-2 over COX-1. In contrast, diclofenac sodium and indometacin were selective for COX-1. These results suggest that etodolac, a COX-2 selective NSAID, has anti-inflammatory effects with a better safety profile for the stomach than do non-selective NSAIDs, including diclofenac sodium and indometacin, in adjuvant arthritic as well as normal rats.     

Role of direct cytotoxic effects of NSAIDs in the induction of gastric lesions

A major clinical problem encountered with the use of non-steroidal anti-inflammatory drugs (NSAIDs), is gastrointestinal complications. We previously reported that NSAIDs induce both necrosis and apoptosis in vitro. We here examined the cyclooxygenase (COX) dependency of this cytotoxic effect of NSAIDs and its involvement in NSAID-induced gastric lesions. Necrosis and apoptosis by NSAIDs was observed with all selective COX-2 inhibitors except rofecoxib and was not inhibited by exogenously added prostaglandin E2, suggesting that cytotoxicity of NSAIDs seems to be independent of the inhibition of COX. Intravenously administered indomethacin, which completely inhibited COX activity at gastric mucosa, did not produce gastric lesions. Orally administered selective COX-2 inhibitors, which did not inhibit COX at gastric mucosa, also did not produce gastric lesions. Interestingly, a combination of the oral administration of each of all selective COX-2 inhibitors except rofecoxib with the intravenous administration of indomethacin clearly produced gastric lesions. These results suggest that in addition to COX inhibition by NSAIDs, direct cytotoxicity of NSAIDs may be involved in NSAID-induced gastric lesions.     

AHR-10037, a non-steroidal anti-inflammatory compound of low gastric toxicity

AHR-10037 is an anti-inflammatory compound possessing analgesic and antipyretic properties and a high therapeutic index. AHR-10037 was comparable to indomethacin in suppressing acute (Evans blue-carrageenan pleural effusion) and chronic (adjuvant-induced arthritis) inflammation. There was a delayed onset of antipyresis (yeast-induced hyperthermia in rats), analgesia (acetylcholine-induced abdominal constriction in mice) and inhibition of caster oil-induced diarrhea in rats. Antipyresis occurred 3 hours after administration of AHR-10037, 4 mg/kg, PO. vs 1 hour after administration of acetylsalicylic acid, 100 mg/kg, PO; maximum analgesic activity (ED50 = 4.1 mg/kg) occurred at 4 hours. AHR-10037 was inferior to indomethacin in suppressing castor oil-induced diarrhea in rats. The therapeutic index of AHR-10037 (relating acute anti-inflammatory potency to gastric toxicity potency relative to indomethacin) ranged from 56-91. The pharmacological profile suggests that AHR-10037 is a prodrug converted in vivo to a cyclooxygenase inhibitor.     

Celecoxib inhibits 5-lipoxygenase

Celecoxib is a selective cyclooxygenase-2 (COX-2) inhibitor used in the therapy of inflammatory and painful conditions. Various COX-2-independent pharmacological effects, such as a chemo-preventive and tumor-regressive activity have been suggested, but the respective non-COX-2 targets of celecoxib are still a matter of research. We now demonstrate that celecoxib inhibits 5-lipoxygenase (5-LO), a key enzyme in leukotriene (LT) biosynthesis. Celecoxib suppressed 5-LO product formation in ionophore A23187-activated human polymorphonuclear leukocytes (IC(50) approximately 8 microM). Similarly, celecoxib inhibited LTB(4) formation in human whole blood (IC(50) approximately 27.3 microM). Direct interference of 5-LO with celecoxib was visualized by inhibition of enzyme catalysis both in cell homogenates and with purified 5-LO (IC(50) approximately 23.4 and 24.9 microM, respectively). Related lipoxygenases (12-LO and 15-LO) were not affected by celecoxib. Other COX-2 inhibitors (etoricoxib and rofecoxib) or unselective NSAIDs (non-steroidal anti-inflammatory drugs, diclofenac) failed to inhibit 5-LO. In rats which received celecoxib (i.p.), the blood LTB(4) levels were dose-dependently reduced with an ED(50) value approximately 35.2 mg/kg. Together, celecoxib is a direct inhibitor of 5-LO in vitro and in vivo. These findings provide a potential molecular basis for some of the described COX-2-independent pharmacological effects of celecoxib.     

Cyclo-oxygenase-1 inhibition increases acid secretion by modulating H+,K+-ATPase expression and activation in rabbit parietal cells

1. In the present study, we evaluated the role of cyclo-oxygenase (COX)-1 and COX-2 on gastric acid secretion in rabbit isolated parietal cells and gastric glands by examining [(14)C]-aminopyrine uptake, prostaglandin (PG) E(2) synthesis and COX-1, COX-2 and proton pump expression at baseline and after treatment with various concentrations of specific COX-1 (SC-560), COX-2 (5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methyl-sulphonyl)phenyl-2 (5H)-furanone; DFU) and non-specific COX (indomethacin) inhibitors. 2. In parietal cells, SC-560 and indomethacin, over the concentration range 10(-8) to 10(-4) mol/L, dose-dependently increased basal and 10(-4) mol/L histamine-stimulated aminopyrine uptake and inhibited PGE(2) synthesis, whereas DFU (10(-8) to 10(-5) mol/L) had no effect. However, at 10(-4) mol/L, DFU augmented histamine-stimulated aminopyrine uptake by 135% and inhibited PGE(2) synthesis by 39%, indicating an inhibition of COX-1 at this higher concentration. 3. The SC-560-, DFU- and indomethacin-induced augmentation of histamine-stimulated aminopyrine uptake was reduced to basal levels after 10(-5) mol/L lansoprazole treatment in parietal cells and gastric glands, whereas 10(-4) mol/L ranitidine only partially inhibited such augmentation. 4. Only COX-1 was detected in parietal cells. However, both COX-1 and COX-2 were expressed in gastric glands, with relative protein density of COX-1 being sixfold higher than that of COX-2. Protein levels of COX-1 in parietal cells and those of COX-1 and COX-2 in gastric glands remained unchanged, regardless of inhibitor treatment, either alone or with histamine. 5. Parietal cell proton pump expression was significantly enhanced by 10(-5) mol/L SC-560 and 10(-4) mol/L indomethacin (by 29 and 31%, respectively) and pump activity was enhanced by 61 and 65%, respectively. In contrast, 10(-5) mol/L DFU had no effect. 6. In conclusion, the data indicate that inhibition of COX-1- but not COX-2-derived PGE(2) synthesis is involved in augmentation of non-steroidal anti-inflammatory drug-induced gastric acid secretion in parietal cells by enhancing expression and activation of the proton pump.     

Covalent binding of rofecoxib, but not other cyclooxygenase-2 inhibitors, to allysine aldehyde in elastin of human aorta.

In rats, it has been reported that rofecoxib, a cyclooxygenase-2 (COX-2) inhibitor, reacts with the aldehyde group of allysine in elastin to give a condensation covalent adduct, thereby preventing the formation of cross-linkages in the elastin and causing degradation of the elastic fibers in aortas in vivo. Acid, organic solvent, and proteolytic enzyme treatments of human aortic homogenate after incubation with [(14)C]rofecoxib demonstrated that most of the radioactivity is covalently bound to elastin. The in vitro covalent binding was inhibited in the presence of beta-aminopropionitrile, D-penicillamine, and hydralazine, which suggested that the aldehyde group of allysine in human elastin was relevant to the covalent binding. The in vitro covalent binding of [(14)C]rofecoxib was significantly decreased by the addition of only nonradiolabeled rofecoxib but not the other COX-2 inhibitors, celecoxib, valdecoxib, etoricoxib, and CS-706 [2-(4-ethoxyphenyl)-4-methyl 1-(4-sulfamoylphenyl)-1H-pyrrole], a novel selective COX-2 inhibitor. All the above COX-2 inhibitors except for rofecoxib had no reactivity with the aldehyde group of benzaldehyde used as a model compound of allysine aldehyde under a physiological pH condition. On the other hand, no retention of the radioactivity of [(14)C]rofecoxib was observed in human aortic endothelial cells in vitro, suggesting that rofecoxib is not retained in aortic endothelial cells in vivo. These results suggest that rofecoxib, but not other COX-2 inhibitors, is capable of covalently binding to the aldehyde group of allysine in human elastin. This might be one of the main causes of cardiovascular events by rofecoxib in clinical situations.     

Anti-inflammatory, analgesic and anti-pyretic activities of a new anti-inflammatory compound, 2-[4-(3-methyl-2-butenyl)phenyl] propionic acid (TA), in experimental animals

Anti-inflammatory, analgesic and anti-pyretic activities of orally administered TA were investigated in experimental animals. Against acetic acid-induced vascular permeability in mice, carrageenin-induced hind paw edema in rats and ultra-violet ray-induced erythema in guinea pigs, TA produced a dose related inhibition at doses of 40-160 mg/kg, 10-40 mg/kg and 10-40 mg/kg, respectively. TA produced no inhibition against histamine-induced vascular permeability even at a dose of 200 mg/kg in rats. Cotton pellet-induced granuloma and adjuvant-induced arthritis in rats were significantly inhibited by repeated administration of TA at a dose of 50 mg/kg/day for 6 days and 25 mg/kg/day for 6 days, respectively. TA showed a dose related analgesic effect at a dose of 50-200 mg/kg in acetic acid writhing, Randall-Selitto and adjuvant arthritic pain methods. A high dose of TA was needed to produce an analgesic effect in the pressure method using mice. TA produced an anti-pyretic effect against the pyrexia induced by yeast in rats. On the other hand, TA showed no effect against normal body temperature in rats. These results suggest that anti-inflammatory, analgesic and anti-pyretic activities of TA are generally a little weaker than those of ibuprofen, and the mode of action of TA is similar to that of a typical acidic non-steroidal anti-inflammatory drug such as ibuprofen, indomethacin or phenylbutazone. The ulcerogenic activity of TA was about 2 and 4 times weaker than that of ibuprofen in rats and mice, respectively. TA showed a protective effect against gastric necrosis induced by HCl.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of specific inhibition of cyclo-oxygenase-1 and cyclo-oxygenase-2 in the rat stomach with normal mucosa and after acid challenge

1. Effects of the cyclo-oxygenase (COX)-1 inhibitor SC-560 and the COX-2 inhibitors rofecoxib and DFU were investigated in the normal stomach and after acid challenge. 2. In healthy rats, neither SC-560 nor rofecoxib (20 mg kg(-1) each) given alone damaged the mucosa. Co-treatment with SC-560 and rofecoxib, however, induced severe lesions comparable to indomethacin (20 mg kg(-1)) whereas co-administration of SC-560 and DFU (20 mg kg(-1) each) had no comparable ulcerogenic effect 5 h after dosing. 3. SC-560 (20 mg kg(-1)) inhibited gastric 6-keto-prostaglandin (PG) F(1alpha) by 86+/-5% and platelet thromboxane (TX) B(2) formation by 89+/-4% comparable to indomethacin (20 mg kg(-1)). Rofecoxib (20 mg kg(-1)) did not inhibit gastric and platelet eicosanoids. 4. Intragastric HCl elevated mucosal mRNA levels of COX-2 but not COX-1. Dexamethasone (2 mg kg(-1)) prevented the up-regulation of COX-2. 5. After acid challenge, SC-560 (5 and 20 mg kg(-1)) induced dose-dependent injury. Rofecoxib (20 mg kg(-1)), DFU (5 mg kg(-1)) and dexamethasone (2 mg kg(-1)) given alone were not ulcerogenic but aggravated SC-560-induced damage. DFU augmented SC-560 damage 1 but not 5 h after administration whereas rofecoxib increased injury after both treatment periods suggesting different time courses. 6. Gastric injurious effects of rofecoxib and DFU correlated with inhibition of inflammatory PGE(2). 7. The findings show that in the normal stomach lesions only develop when both COX-1 and COX-2 are inhibited. In contrast, during acid challenge inhibition of COX-1 renders the mucosa more vulnerable suggesting an important role of COX-1 in mucosal defence in the presence of a potentially noxious agent. In this function COX-1 is supported by COX-2. In the face of pending injury, however, COX-2 cannot maintain mucosal integrity when the activity of COX-1 is suppressed.     

Differential effect of FR122047, a selective cyclo-oxygenase-1 inhibitor, in rat chronic models of arthritis

We investigated the effects of FR122047 (1-[(4,5-bis(4-methoxyphenyl)-2-thiazoyl)carbonyl]-4-methylpiperazine hydrochloride), a selective cyclo-oxygenase (COX)-1 inhibitor, in rat type II collagen-induced arthritis (CIA) and adjuvant-induced arthritis (AIA). Using an ex vivo rat whole blood assay, FR122047 (0.032 - 3.2 mg kg(-1)) inhibited COX-1-derived thromboxane (TX) B(2) production with ED(50) value of 0.059 mg kg(-1), indicating that it was orally active, but did not inhibit lipopolysaccharide-induced prostaglandin (PG) E(2) production derived by COX-2. Oral administration of FR122047 showed a dose-dependent anti-inflammatory effect in rat CIA with ED(50) value of 0.56 mg kg(-1). This drug also dose dependently suppressed the levels of PGE(2) and TXB(2) in CIA rat paws with ED(50) values of 0.24 and 0.13 mg kg(-1), respectively. FR122047 had no effect in rat AIA model. In contrast, indomethacin, a non-selective COX inhibitor, was anti-inflammatory and reduced the formation of PGs in AIA rat paws. Unlike indomethacin, chronic treatment of FR122047 did not damage the stomach mucosa in CIA rats. These results demonstrate that COX-1 contributes to the oedema and the formation of PGE(2) and TXB(2) in rat CIA model, but not in rat AIA model. We conclude that FR122047 has an orally active and anti-inflammatory effect mediated by inhibition of PGE(2) and TXB(2) produced by COX-1 at a site of inflammation induced by type II collagen and it may be a useful tool for studying the involvement of COX-1 in various in vivo models of inflammation.     

Development of intestinal, but not gastric damage caused by a low dose of indomethacin in the presence of rofecoxib

The ulcerogenic effect of rofecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, on the gastrointestinal mucosa was investigated in the presence of a low dose of indomethacin. Indomethacin at 3 mg/kg did not cause any damage in both the stomach and small intestine, despite inhibiting prostaglandin (PG) production. Rofecoxib had no effect on PG production and did not cause any damage in these tissues. In the presence of indomethacin, however, rofecoxib provoked damage in the small intestine but not the stomach. Indomethacin at 3 mg/kg induced hypermotility and COX-2 expression in the intestine but not in the stomach, both in an atropine-sensitive manner. These results suggest that a low dose of indomethacin produces damage in the small intestine but not in the stomach when administered together with rofecoxib. The PG deficiency caused by a low dose of indomethacin produces hypermotility and COX-2 expression in the small intestine, and results in damage when COX-2 is inhibited. It is assumed that the hypermotility response is a key event in the expression of COX-2 and thereby important in the development of mucosal damage in the gastrointestinal tract.