Oral p38 Mitogen-Activated Protein Kinase Inhibition With BIRB 796 for Active Crohn’s Disease: A Randomized, Double-Blind, Placebo-Controlled Trial

Schreiber, Stefan; Feagan, Brian G.; D’Haens, Geert R.; Colombel, Jean–Frédéric; Geboes, Karel; Yurcov, Mikhail; Isakov, Vasily; Головенко, О. В.; Bernstein, Çharles N.; Ludwig, D.; Winter, Trevor A.; Meier, Ulrich; Yong, C; Steffgen, Jürgen

doi:10.1016/j.cgh.2005.11.013

Cited by 169 publications

(123 citation statements)

References 30 publications

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“…In line with this suggestive data, F-actin content, motility, and chemotaxis of PMNs are reduced upon treatment with this compound (60). However, albeit this strong rationale for MAPK inhibitors in intestinal inflammation, most compounds had dose-limiting adverse effects unrelated to immunosuppression in the subsequent clinical trials (61), which points to the limits of inhibiting promiscuous pleiotropic signaling pathways for specific therapies.…”

Section: Discussionmentioning

confidence: 55%

G Protein-Coupled Receptor 43 Is Essential for Neutrophil Recruitment during Intestinal Inflammation

Sina

Gavrilova²,

Förster³

et al. 2009

The Journal of Immunology

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318

291

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Molecular danger signals attract neutrophilic granulocytes (polymorphonuclear leukocytes (PMNs)) to sites of infection. The G protein-coupled receptor (GPR) 43 recognizes propionate and butyrate and is abundantly expressed on PMNs. The functional role of GPR43 activation for in vivo orchestration of immune response is unclear. We examined dextrane sodium sulfate (DSS)-induced acute and chronic intestinal inflammatory response in wild-type and Gpr43-deficient mice. The severity of colonic inflammation was assessed by clinical signs, histological scoring, and cytokine production. Chemotaxis of wild-type and Gpr43-deficient PMNs was assessed through transwell cell chemotactic assay. A reduced invasion of PMNs and increased mortality due to septic complications were observed in acute DSS colitis. In chronic DSS colitis, Gpr43−/− animals showed diminished PMN intestinal migration, but protection against inflammatory tissue destruction. No significant difference in PMN migration and cytokine secretion was detected in a sterile inflammatory model. Ex vivo experiments show that GPR43-induced migration is dependent on activation of the protein kinase p38α, and that this signal acts in cooperation with the chemotactic cytokine keratinocyte chemoattractant. Interestingly, shedding of L-selectin in response to propionate and butyrate was compromised in Gpr43−/− mice. These results indicate a critical role for GPR43-mediated recruitment of PMNs in containing intestinal bacterial translocation, yet also emphasize the bipotential role of PMNs in mediating tissue destruction in chronic intestinal inflammation.

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Section: Discussionmentioning

confidence: 55%

G Protein-Coupled Receptor 43 Is Essential for Neutrophil Recruitment during Intestinal Inflammation

Sina

Gavrilova²,

Förster³

et al. 2009

The Journal of Immunology

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318

291

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“…Candidates for p38␣ bypass might include other p38 isoforms or NF-B, ERK, activator protein 1, and/or JNK pathways. A substantial early decline in CRP levels with subsequent elevation was also seen with BIRB796 in Crohn's disease (19). There was no decrease in plasma exposures of pamapimod at any dosage level (data not shown), suggesting that metabolism did not account for the lack of effect.…”

Section: Discussionmentioning

confidence: 83%

“…In terms of efficacy, VX-745 was shown to result in a significantly better ACR20 response than placebo in a phase II study, but development was stopped because of preclinical toxicity findings (18). Doramapimod (BIRB796), showed no efficacy in Crohn's disease (19). Scio-469 was efficacious in the relief of dental pain (20) and has been tested in phase IIa and IIb trials, but the results are unreported.…”

Section: Discussionmentioning

confidence: 99%

“…Finally, GI AEs have been reported with other p38 inhibitors in smaller studies and may be a target-related class toxicity perhaps associated with infection or changes in gut flora. Elevation of transaminase levels has occurred with p38 inhibitors as well (19). Preclinical data suggest that p38 is also found in myocardium, developing tissues, skeletal muscle, and hematopoietic cells as well as in the immune system, liver, and central nervous system (26).…”

Section: Discussionmentioning

confidence: 99%

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Evaluation of the efficacy and safety of pamapimod, a p38 MAP kinase inhibitor, in a double‐blind, methotrexate‐controlled study of patients with active rheumatoid arthritis

Cohen

Cheng

Chindalore

et al. 2009

Arthritis & Rheumatism

214

142

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Results. Patients assigned to receive MTX and pamapimod had similar demographics and baseline characteristics. At week 12, fewer patients taking pamapimod had an ACR20 response (23%, 18%, and 31% in the 50-, 150-, and 300-mg groups, respectively) compared with patients taking MTX (45%). Secondary efficacy end points showed a similar pattern. AEs were typically characterized as mild and included infections, skin disorders, and dizziness. Pamapimod was generally well tolerated, but the 300-mg dose appeared to be more toxic than either the 2 lower doses or MTX.Conclusion. The present results showed that pamapimod was not as effective as MTX in the treatment of active RA.Parenteral biologic therapies that selectively neutralize proinflammatory cytokines such as tumor necrosis factor ␣ (TNF␣) and interleukin-1␤ (IL-1␤) or their receptors, such as the IL-6 receptor, substantially improve signs and symptoms of rheumatoid arthritis (RA), reduce the number of swollen and tender joints, and ClinicalTrials.gov identifier: NCT00303563.

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“…VX-702, an orally active p38 kinase inhibitor, has completed two phase II trials involving 130 patients with rheumatoid arthritis (55). Another p38 inhibitor, BIRB 796, has completed a multi-center trial in 284 patients with Crohn's disease (56). The PRECEPT trial tested the mixed lineage kinase inhibitor CEP-1347, which blocks JNK and p38 signaling, in patients with Parkinson's disease.…”

Section: Clinical Potential For Sapk Blockadementioning

confidence: 99%

The role of stress-activated protein kinase signaling in renal pathophysiology

Liu

Nikolic-Paterson

2008

Braz J Med Biol Res

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Two major stress-activated protein kinases are the p38 mitogen-activated protein kinase (MAPK) and the c-Jun amino terminal kinase (JNK). p38 and JNK are widely expressed in different cell types in various tissues and can be activated by a diverse range of stimuli. Signaling through p38 and JNK is critical for embryonic development. In adult kidney, p38 and JNK signaling is evident in a restricted pattern suggesting a normal physiological role. Marked activation of both p38 and JNK pathways occurs in human renal disease, including glomerulonephritis, diabetic nephropathy and acute renal failure. Administration of small molecule inhibitors of p38 and JNK has been shown to provide protection from renal injury in different types of experimental kidney disease through inhibition of renal inflammation, fibrosis, and apoptosis. In particular, a role for JNK signaling has been identified in macrophage activation resulting in up-regulation of pro-inflammatory mediators and the induction of renal injury. The ability to provide renal protection by blocking either p38 or JNK indicates a lack of redundancy for these two signaling pathways despite their activation by common stimuli. Therefore, the stress-activated protein kinases, p38 and JNK, are promising candidates for therapeutic intervention in human renal diseases.

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Oral p38 Mitogen-Activated Protein Kinase Inhibition With BIRB 796 for Active Crohn’s Disease: A Randomized, Double-Blind, Placebo-Controlled Trial

Cited by 169 publications

References 30 publications

G Protein-Coupled Receptor 43 Is Essential for Neutrophil Recruitment during Intestinal Inflammation

G Protein-Coupled Receptor 43 Is Essential for Neutrophil Recruitment during Intestinal Inflammation

Evaluation of the efficacy and safety of pamapimod, a p38 MAP kinase inhibitor, in a double‐blind, methotrexate‐controlled study of patients with active rheumatoid arthritis

The role of stress-activated protein kinase signaling in renal pathophysiology

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