Anti-Inflammatory Effect and Low Ulcerogenic Activity of Etodolac, a Cyclooxygenase-2 Selective Non-Steroidal Anti-Inflammatory Drug, on Adjuvant-Induced Arthritis in Rats

Terabe, Masaki; Inoue, Naoki; Yoshida, Eri; Matsui, Masami; Ukai, Yojiro; Yano, Jun–Ichi

doi:10.1159/000069536

Cited by 13 publications

(10 citation statements)

References 30 publications

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“…17,18) The obtained conjugate, chondroitin sulfate-glycyl-prednisolone (CS-GP), was found to act as a macromolecular prodrug of PD and to promote anti-arthritic effects of PD, 18) in which efficacy was evaluated using rats with adjuvant-induced arthritis. 19,20) From the previous results of the pharmacokinetics in healthy rats, it was suggested that good retention of CS-GP in the plasma should facilitate drug distribution to the arthritic site based on the EPR effect. As the used CS has a molecular weight (MW) of only several tens of thousands, 17) its EPR effect might be not very high.…”

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confidence: 99%

Chondroitin Sulfate–Glycyl-Prednisolone Conjugate as Arthritis Targeting System: Localization and Drug Release in Inflammatory Joints

Onishi

Yoshida

Matsuyama

2014

Biological & Pharmaceutical Bulletin

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Chondroitin sulfate-glycyl-prednisolone conjugate (CS-GP) was previously demonstrated to exhibit superior anti-arthritic effects compared to prednisolone (PD) alone. In this study, CS-GP was examined for its pharmacokinetic features and tropism for inflammatory joints using rats with adjuvant-induced arthritis in order to identify the mechanism of the potential enhancement. After intravenous injection (2.5 mg PD eq./ kg), CS-GP yielded an area under the curve (AUC) of the total (free conjugated) drug much higher than that of PD alone. After intravenous administration at the same dose, the drug distribution to the hind paw inflammatory joints was investigated. For PD alone, the PD concentration was 1.2-1.7 µg/g at 1 h and fell to 0.12-0.14 µg/g at 24 h. In contrast, CS-GP maintained the total concentration in the range of 0.55-0.97 µg/g for 1-24 h, and maintained the free PD concentration at 0.06-0.16 µg/g for 1-24 h. Furthermore, at 24 h after intravenous administration (2.5 mg PD eq./kg), CS-GP exhibited a higher total drug concentration in arthritic rats than in healthy rats. These findings suggested that CS-GP may have the ability to target inflammatory joints. As the apparent molecular weight of CS-GP became greater in plasma, it might interact with blood components and cause high plasma retention and good tropism to the inflammatory sites. Enhancement of the anti-inflammatory potential of CS-GP was found to be due to good maintenance of drug levels in the inflamed area.

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confidence: 99%

Chondroitin Sulfate–Glycyl-Prednisolone Conjugate as Arthritis Targeting System: Localization and Drug Release in Inflammatory Joints

Onishi

Yoshida

Matsuyama

2014

Biological & Pharmaceutical Bulletin

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“…Destruction of articular cartilage and bone is attributed to a host of proteases, e.g., serine proteases, matrix metalloproteases, and cathepsins, secreted by the pannus tissue (4,5). In induced arthritis in animals the pannus formation and infiltration of macrophages and granulocytes is recapitulated (6), making this a useful model for studying RA pathogenesis and screening candidate therapeutic interventions (7)(8)(9).…”

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confidence: 99%

Reduced expression and proteolytic susceptibility of lubricin/superficial zone protein may explain early elevation in the coefficient of friction in the joints of rats with antigen‐induced arthritis

Elsaid¹,

Jay²,

Chichester³

2007

Arthritis & Rheumatism

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Objective. To investigate the effect of arthritis development and progression on the integrity and function of lubricin and the relationship of lubricin to cartilage damage in a rat antigen-induced arthritis model.Methods. Arthritis was induced in the right knee joints, using methylated bovine serum albumin and Freund's complete adjuvant. Whole joint friction measurements were performed ex vivo with a modified Stanton pendulum configuration, and coefficients of friction ( ) were determined. Levels of messenger RNA (mRNA) for lubricin, cathepsin B, and interleukin-1␤ (IL-1␤) in synovial tissue from control and affected joints were determined by quantitative polymerase chain reaction. Lubricin staining in cartilage was performed using a lubricin-specific monoclonal antibody.Results. The values in excised right joints following arthritis induction were significantly (P < 0.001) higher than those in excised left joints. Lubricin mRNA expression levels in synovial tissue on days 4 and 7 after arthritis induction were significantly (P < 0.001) lower in the right joints compared with the left joints, whereas levels of cathepsin B and IL-1␤ mRNA expression on days 4, 7, and 14 were significantly (P < 0.001) higher in the right joints than the left joints. Lubricin staining was diminished in cartilage from the right joints compared with the left joints.Conclusion. Elevated coefficients of friction in arthritic joints occur concurrently with enhanced proteolytic degradation by up-regulated cathepsin B and other proteases, as well as decreased lubricin synthesis by synovial fibroblasts and superficial zone chondrocytes. Loss of joint lubrication is an early event in inflammatory arthropathy. Restoring chondroprotection and preventing potential wear-induced cartilage degradation may require lubricin supplementation in synovial fluid.

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“…When we previously compared the gastric mucosal ulcerogenic activity of racemic etodolac and other NSAIDs (meloxicam, dicrofenac and indomethacin) in AIA and normal rat models, 7) racemic etodolac showed the lowest ulcerogenic activity in both models. Here, we compared the gastric mucosal ulcerogenic activity of racemic etodolac and its enantiomers in normal rats (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Etodolac is widely known as a COX-2-selective inhibitor. [5][6][7] It has good clinical anti-inflammatory efficacy and a good safety profile for the GI tract. 8) Many NSAIDs are chiral and are marketed as the racemate (which contains equal amounts of each enantiomer).…”

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confidence: 99%

The Enantiomers of Etodolac, a Racemic Anti-inflammatory Agent, Play Different Roles in Efficacy and Gastrointestinal Safety

Inoue

Nogawa

Ito

et al. 2011

Biological & Pharmaceutical Bulletin

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The therapeutic effects of non-steroidal anti-inflammatory drugs (NSAIDs) include anti-pyretic, analgesic and anti-inflammatory effects, while their adverse effects are primarily gastrointestinal (GI) and renal toxicity. The major therapeutic and adverse effects are mediated by the inhibition of cyclooxygenase (COX), which catalyzes the rate-limiting step in the formation of prostanoids from arachidonic acid. [1][2][3] There are two membrane-bound COX isoenzymes, the constitutively expressed COX-1 and the highly inducible COX-2. 4) COX inhibitors include conventional NSAIDs and COX-2-selective inhibitors. Conventional NSAIDs, at therapeutic doses, are non-selective COX inhibitors and inhibit both isoenzymes. The anti-inflammatory benefits of NSAIDs are primarily due to COX-2 inhibition, while inhibition of COX-1 often elicits GI toxicity. Etodolac is widely known as a COX-2-selective inhibitor. 5-7) It has good clinical anti-inflammatory efficacy and a good safety profile for the GI tract. 8) Many NSAIDs are chiral and are marketed as the racemate (which contains equal amounts of each enantiomer). The anti-inflammatory activity of NSAIDs and their inhibition of prostaglandin synthetase is largely stereospecific in favor of the S-enantiomer. 9) Etodolac too is a racemate consisting of S-and R-enantiomers, and S-etodolac inhibits prostaglandin synthesis in sheep vesicular glands and decreases hind-paw volume in established adjuvant arthritic rats. 10) Neuropathic pain is a common symptom caused by injury to peripheral or central nerves, and it can result from pathological changes induced by metabolic disease, viral infection, traumatic injury or chemotherapeutically induced nerve damage. Clinically, neuropathic pain is characterized by mechanical and thermal allodynia, hyperalgesia and spontaneous ongoing pain that are often refractory to treatment. 11) Patients with neuropathic pain do not respond to NSAIDs, and resistance or insensitivity to opiates is common. 12) We recently reported that etodolac attenuates allodynia in a mouse model of neuropathic pain. 13) The mechanism of the anti-allodynic effects of etodolac has not yet been established, but COX inhibition is unlikely to be involved because the COX inhibitors indomethacin and celecoxib do not attenuate the allodynia. There is still a question which enantiomer of etodolac produces the anti-allodynic effect in mice. And there is also a question whether the ulcerogenic activity of etodolac is attributable to the S-enantiomer alone.In the present study, we evaluated the inhibitory effects of the enantiomers of etodolac on COX-1 and COX-2. We also investigated the beneficial actions of racemic etodolac and its enantiomers, especially their anti-inflammatory effects, antiallodynic effects and ulcerogenic activity, in mouse and rat models. S-Etodolac, but not R-etodolac, inhibited COX-2 and showed anti-inflammatory and anti-allodynic effects, while R-etodolac showed a gastroprotective effect that may explain the low GI toxicity of racemic etodolac. MATERIALS AND...

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Anti-Inflammatory Effect and Low Ulcerogenic Activity of Etodolac, a Cyclooxygenase-2 Selective Non-Steroidal Anti-Inflammatory Drug, on Adjuvant-Induced Arthritis in Rats

Cited by 13 publications

References 30 publications

Chondroitin Sulfate–Glycyl-Prednisolone Conjugate as Arthritis Targeting System: Localization and Drug Release in Inflammatory Joints

Chondroitin Sulfate–Glycyl-Prednisolone Conjugate as Arthritis Targeting System: Localization and Drug Release in Inflammatory Joints

Reduced expression and proteolytic susceptibility of lubricin/superficial zone protein may explain early elevation in the coefficient of friction in the joints of rats with antigen‐induced arthritis

The Enantiomers of Etodolac, a Racemic Anti-inflammatory Agent, Play Different Roles in Efficacy and Gastrointestinal Safety

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