1.A Randomized Dose-Escalation Study of the Safety and Anti-Inflammatory Activity of the p38 Mitogen-Activated Protein Kinase Inhibitor Dilmapimod in Severe Trauma Subjects at Risk for Acute Respiratory Distress Syndrome.
Christie JD1, Vaslef S, Chang PK, May AK, Gunn SR, Yang S, Hardes K, Kahl L, Powley WM, Lipson DA, Bayliffe AI, Lazaar AL. Crit Care Med. 2015 Sep;43(9):1859-69. doi: 10.1097/CCM.0000000000001132.
OBJECTIVES: There are no current pharmacological therapies for the prevention or treatment of acute respiratory distress syndrome. Early dysregulated inflammation likely plays a role in acute respiratory distress syndrome development and possibly acute respiratory distress syndrome outcomes. p38 mitogen-activated protein kinase is central to the regulation of multiple inflammatory mediators implicated in acute organ dysfunction and is the target for a novel class of cytokine-suppressive anti-inflammatory drugs. In preclinical models, p38 inhibitors reduce lung injury following pancreatitis and burn injury.
2.Gene expression changes caused by the p38 MAPK inhibitor dilmapimod in COPD patients: analysis of blood and sputum samples from a randomized, placebo-controlled clinical trial.
Betts JC1, Mayer RJ2, Tal-Singer R2, Warnock L1, Clayton C1, Bates S1, Hoffman BE2, Larminie C1, Singh D3. Pharmacol Res Perspect. 2015 Feb;3(1):e00094. doi: 10.1002/prp2.94. Epub 2014 Dec 9.
The p38 mitogen-activated protein kinase (MAPK) intracellular signaling pathway responds to a variety of extracellular stimuli, including cytokines, Toll-like receptor agonists, and components of cigarette smoke to influence the expression of proinflammatory mediators. Activation of p38 MAPK is increased within the lungs of chronic obstructive pulmonary disease (COPD) patients. In clinical trials, treatment of COPD patients with p38 MAPK inhibitors has been shown to reduce systemic inflammation plasma biomarkers C-reactive protein (CRP) and fibrinogen. As CRP and fibrinogen have been associated with poor clinical outcomes in COPD patients, such as mortality, exacerbation, and hospitalization, we analyzed gene expression data from COPD subjects treated with dilmapimod with the aim of understanding the effects of p38 MAPK inhibition on the inflammatory genome of immune cells within the systemic circulation. Whole blood and induced sputum samples were used to measure mRNA levels by gene array and PCR.
3.Clinical trial of the p38 MAP kinase inhibitor dilmapimod in neuropathic pain following nerve injury.
Anand P1, Shenoy R, Palmer JE, Baines AJ, Lai RY, Robertson J, Bird N, Ostenfeld T, Chizh BA. Eur J Pain. 2011 Nov;15(10):1040-8. doi: 10.1016/j.ejpain.2011.04.005. Epub 2011 May 14.
Current treatments of neuropathic pain arising from conditions such as nerve injury/compression are only partially effective, and limited in their use by side-effects. p38 mitogen-activated protein kinase (MAPK) is involved in the regulation and synthesis of inflammatory mediators, and is the target for a novel class of cytokine-suppressive anti-inflammatory drugs. p38 inhibitors may reduce neuronal sensitisation in preclinical models of neuropathic pain, particularly where there is a substantial inflammatory component. An exploratory, multicentre, double-blind, placebo-controlled, two-period, cross-over trial was undertaken to evaluate the effect of dilmapimod (SB-681323), a selective p38 MAPK inhibitor, on neuropathic pain symptoms and signs. Fifty patients with nerve trauma, radiculopathy or carpal tunnel syndrome were randomised; 43 patients completed the study. Eligible patients received oral dilmapimod and placebo twice daily for 2 weeks, with an intervening washout period of 2-4 weeks.
4.A randomized, placebo-controlled study of the effects of the p38 MAPK inhibitor SB-681323 on blood biomarkers of inflammation in COPD patients.
Singh D1, Smyth L, Borrill Z, Sweeney L, Tal-Singer R. J Clin Pharmacol. 2010 Jan;50(1):94-100. doi: 10.1177/0091270009347873. Epub 2009 Oct 30.
The p38 mitogen-activated protein kinase (MAPK) signaling upregulates inflammation and is known to be increased in chronic obstructive pulmonary disease (COPD). The authors assessed the pharmacology of the novel p38 MAPK inhibitor SB-681323 using blood biomarkers in COPD. Seventeen COPD patients (forced expiratory volume in 1 second 50%-80% predicted) using short-acting bronchodilators participated in a double-blind, double-dummy, randomized, crossover study. Patients received single oral doses of SB-681323 7.5 mg and 25 mg, prednisolone 10 mg and 30 mg, and placebo. Blood was obtained predose and at 1, 2, 6, and 24 hours postdose. Whole-blood sorbitol-induced phosphorylated (p) heat shock protein (HSP) 27 levels as a marker of p38 pathway activation and lipopolysaccharide-induced tumor necrosis factor (TNF)-alpha production were assessed. Both doses of SB-681323, but not prednisolone, significantly (P < .0001) reduced weighted mean (WM) pHSP27 (0-6 hours) by 58% compared with placebo.