Tenidap, in contrast to several available nonsteroidal antiinflammatory drugs, potently inhibits the release of activated neutrophil collagenase

Blackburn, Warren D.; Heck, Louis W.; Loose, Leland D.; Chatham, W. Winn

doi:10.1002/art.1780340213

Cited by 33 publications

(13 citation statements)

References 22 publications

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“…Such results are considered indicative of DMARD-like therapeutic effects [5][6][7][8]. Moreover, inhibitory effects on degranulation observed in preclinical in vitro [9] and in vivo [10] studies are observed ex vivo in human neutrophils following tenidap treatment of arthritic patients [11,12]. In a crossover study in man, tenidap, but not the reference cyclooxygenase inhibitor piroxicam, reduced levels of IL-6, indicating that cytokine reduction is independent of cyclooxygenase inhibition [13].…”

Section: Introductionmentioning

confidence: 87%

Tenidap, a structurally novel drug for the treatment of arthritis: Antiinflammatory and analgesic properties

et al. 1996

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Tenidap is a new anti-rheumatic agent which has clinical properties characteristic of a disease modifying drug combined with acute antiinflammatory and analgesic activity. This paper details tenidap's cyclooxygenase (COX) inhibitory activity and the resulting pharmacological properties in experimental animals. Tenidap inhibited calcium ionophore-stimulated prostaglandin D2 synthesis by rat basophilic leukemia cells (COX-1) with an IC50 of 20 nM. In two different in vitro human test systems, tenidap inhibited COX-1 activity more potently than COX-2, although the relative potency ratio (COX-1/COX-2) differed markedly between the two systems. Tenidap inhibited the COX pathway when added to human blood in vitro (IC50, 7.8 mu M) and when administered orally to monkeys, rats and dogs (at 5, 2.5 and 10 mg/kg p.o., respectively) and COX activity measured ex vivo in blood collected 2 to 4 hours post dose. After oral administration to rats, tenidap inhibited carrageenan-induced paw edema with an ED50 of 14 mg/kg and inhibited the glucocorticoid-resistant UV erythema in guinea pigs with an ED50 of 1.4 mg/kg. It retained antiinflammatory activity in adrenalectomized rats indicating that this property is independent of adrenal stimulation. Oral administration of tenidap inhibited the development of adjuvant-induced polyarthritis in the rat and exhibited antinociceptive activity in the murine phenylbenzoquinone and rat acetic acid abdominal constriction tests. These data indicate that tenidap is an effective antiinflammatory and analgesic agent in animal models. These cyclooxygenase-dependent pharmacologic activities do not explain tenidap's disease modifying anti-arthritic properties but add a useful symptom modifying component to its clinical profile.

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Section: Introductionmentioning

confidence: 87%

Tenidap, a structurally novel drug for the treatment of arthritis: Antiinflammatory and analgesic properties

et al. 1996

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“…Tenidap sodium [(Z)-5-chloro-2,3 dihydro-3-(hydroxy-2-thienyl methy1ene)-Zoxo-1 H-indole-1-carboxamide, sodium salt] is a novel drug which has combined cyclooxygenase-and 5-lipoxygenaseinhibitory activity in vitro (15,16). Several of its properties, such as its ability to modulate cytokine synthesis (17), its in vitro activity in protecting cartilage integrity (18), its potent inhibitory action on the release of activated neutrophil collagenase (19), as well as its antiinflammatory and analgesic activities (20), make it an attractive antirheumatic drug. Recent findings also indicate that tenidap can reduce IL-1-stimulated MMP synthesis and expression by chondrocytes, by markedly reducing the level of IL-I receptor (21).…”

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confidence: 99%

Effects of tenidap on canine experimental osteoarthritis i. morphologic and metalloprotease analysis

Fernandes

Martel‐Pelletier

Otterness

et al. 1995

Arthritis & Rheumatism

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Objective. To examine the effects of tenidap and diclofenac on osteoarthritic lesions and metalloprotease activity in experimental osteoarthritis (OA).Methods. The anterior cruciate ligament of the right stifle joint of 25 mongrel dogs was sectioned by a stab wound. Seven dogs received no treatment, 6 were treated with oral omeprazole (20 mg/day), another 6 were treated with diclofenac (0.25 mg/kg/twice daily) plus omeprazole (20 mg/day), and 6 received oral tenidap (3 mg/kg/twice daily) plus omeprazole (20 mg/ day). The dogs received medication for 8 weeks; all dogs were killed at the end of this period. Eight normal dogs were used as controls. Lesions were evaluated macroscopically for the incidence and size of osteophytes and the area and grade of cartilage erosions on the condyles and plateaus, along with histologic evaluation of the severity of the cartilage lesions and synovial inflammation. Stromelysin and collagenase activities and the collagenase messenger RNA (mRNA) level were measured in cartilage and synovial membrane.Results. Compared with the untreated or omeprazole-treated OA groups, the dogs treated with tenidap exhibited significant reduction in the incidence (P 5 0.001) and size (P 5 0.0001) of osteophytes. Tenidap also significantly decreased the size and grade of cartilage macroscopic lesions, as well as the histologic severity of cartilage lesions on both condyles and plateaus. The histologic severity of synovial inflammatory reaction was also significantly reduced (P I 0.003) in the tenidap group. Tenidap markedly decreased stromelysin and collagenase activity in both cartilage (stromelysin P I 0.003; collagenase P I 0.01) and synovial membrane (stromelysin P 5 0.003; collagenase P 5 0.005). Moreover, tenidap also decreased the collagenase mRNA level in cartilage (P 5 0.005) and synovial membrane (P 5 0.002). Diclofenac slightly reduced the incidence and size of osteophytes and cartilage lesions, but these changes were not statistically significant. Diclofenac had no effect on the severity of synovial inflammation, metalloprotease activity, or collagenase expression.Conchsion. This study showed that tenidap had a more potent anti-osteoarthritic effect than diclofenac in this model. The effect of the drug in suppressing metalloprotease synthesis, a process known to play a major role in the pathophysiology of osteoarthritic lesions, may explain its mechanism of action.Transection of the anterior cruciate ligament of the dog knee leads to articular changes which resemble the morphologic and biochemical changes seen in human osteoarthritis (OA) (1-3). Cartilage lesions are probably related to mechanical as well as biochemical factors, including the enzymatic cleavage of matrix macromolecules (4). Matrix metalloproteases (MMP), such as collagenase and stromelysin, have been found to be significantly increased in OA cartilage and synovial membrane, in humans as well as in the experimental dog model (4-6). It is becoming more and more

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“…In contrast to many anti-inflammatory agents which are carboxylic acids, the acidic nature of tenidap derives from its enolic character. This compound demonstrates biological and clinical properties which distinguish it from NSAIDs [10][11][12][13][14][15][16]. Here we report that tenidap inhibits 5-lipoxygenase metabolism of arachidonic acid in vitro, but that this activity could not be demonstrated in three animal models.…”

Section: Introductionmentioning

confidence: 66%

Tenidap inhibits 5-lipoxygenase product formation in vitro, but this activity is not observed in three animal models

Carty

Sweeney

Griffiths

et al. 1997

Inflammation Research

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Tenidap, in contrast to several available nonsteroidal antiinflammatory drugs, potently inhibits the release of activated neutrophil collagenase

Cited by 33 publications

References 22 publications

Tenidap, a structurally novel drug for the treatment of arthritis: Antiinflammatory and analgesic properties

Tenidap, a structurally novel drug for the treatment of arthritis: Antiinflammatory and analgesic properties

Effects of tenidap on canine experimental osteoarthritis i. morphologic and metalloprotease analysis

Tenidap inhibits 5-lipoxygenase product formation in vitro, but this activity is not observed in three animal models

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