Biological effects of p38 MAPK inhibitor losmapimod does not translate to clinical benefits in COPD

Pascoe, Steven; Costa, María J.; Marks-Kończalik, Joanna; McKie, Elizabeth; Yang, Shuying; Scherbovsky, Pablo Sáez

doi:10.1016/j.rmed.2017.07.002

Cited by 20 publications

(14 citation statements)

References 27 publications

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“…Clinical trials using p38 MAPK inhibitors in COPD patients have yielded mixed results [ 49 , 50 , 51 ]. However, narrow spectrum p38 MAPK inhibitors and targeted suppression of inflammation post exacerbation have shown promise [ 52 , 53 , 54 ].…”

Section: Discussionmentioning

confidence: 99%

Dexamethasone and p38 MAPK inhibition of cytokine production from human lung fibroblasts

Higham

Singh

2020

Fundamemntal Clinical Pharma

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Lung fibroblasts are involved in airway inflammation and remodelling in COPD. We report an investigation of the effects of combining a p38 MAPK inhibitor with a corticosteroid on cytokine production by a human lung fibroblast cell line and primary fibroblasts obtained from human lung tissue. Our main interest was to determine whether additive or synergistic anti‐inflammatory effects would be observed. We observed inhibition of IL‐6 and CXCL8 secretion from both lung fibroblast models by dexamethasone (maximal inhibition 40–90%) and the p38 MAPK inhibitor BIRB (maximal inhibition 30–60%), used alone and evidence of increased anti‐inflammatory effects when used in combination. This combination effect was more apparent for TNF‐a stimulated cytokine production (maximal inhibition increased by 10–20%). Interaction ratio analysis showed this enhanced effect to be additive rather than synergistic interaction. Similar results were obtained using both fibroblast cell culture models. Combining a p38 MAPK to corticosteroids may help reduce fibroblast mediated inflammation in COPD.

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Section: Discussionmentioning

confidence: 99%

Dexamethasone and p38 MAPK inhibition of cytokine production from human lung fibroblasts

Higham

Singh

2020

Fundamemntal Clinical Pharma

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“…Nevertheless, there were considerable side effects at the highest dose tested ( Watz et al, 2014 ). Of interest, further studies discard any effect of losmapimod on exacerbations ( Pascoe et al, 2017 ).…”

Section: Chronic Obstructive Pulmonary Diseasementioning

confidence: 99%

Novel Immunomodulatory Therapies for Respiratory Pathologies

Tavares

Galvão

Ferrero

2022

Comprehensive Pharmacology

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“…More specific p38 MAP kinase inhibitors were well-tolerated in a studies of COPD patients displaying an adequate safety profile but resulting in increased drug-related adverse events compared to placebo (Pascoe et al, 2017;Watz, Barnacle, Hartley, & Chan, 2014). In a phase II trial of the oral p38α MAP kinase inhibitor, PH-797804 given to patients with COPD was shown to demonstrate improvements in lung function parameters and dyspnoea relative to placebo.…”

Section: Side Effects Of P38 Map Kinase Inhibitionmentioning

confidence: 99%

Treating exuberant, non-resolving inflammation in the lung; Implications for acute respiratory distress syndrome and COVID-19

Gilroy

Maeyer

Tepper

et al. 2021

Pharmacology & Therapeutics

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While COVID-19, the disease driven by SARS-CoV-2 has ignited interest in the host immune response to this infection, it has also highlighted the lack of treatment options for the damaging inflammatory responses driven by pathogens that precipitate the acute respiratory distress syndrome (ARDS). With the global prevalence of SARS-CoV-2 and the likelihood of a second winter spike alongside seasonal flu, the need for effective and targeted anti-inflammatory agents is even more pressing. Here we discuss the aetiology of COVID-19 and the common signalling pathways driven by SARS-CoV-2, namely p38 MAP kinase. We highlight that p38 MAP kinase becomes elevated with increasing age, thereby driving many of the inflammatory pathways that precipitate death in old people with the added drawback of impairing vaccine efficacy in this susceptible age group. Finally, we review drugs available to inhibit p38 MAP kinase, their risks-versus-benefits as well as suggested dosing regimen to combat over-exuberant innate immune responses and potentially reverse vaccine inefficacy in older patients.

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Biological effects of p38 MAPK inhibitor losmapimod does not translate to clinical benefits in COPD

Abstract: Losmapimod treatment did not reduce the rate of exacerbations in, subjects with COPD at high risk of exacerbation and ?2% blood eosinophils. These data do not support its use as a therapy in COPD in addition to standard of care.

Cited by 20 publications

References 27 publications

Dexamethasone and p38 MAPK inhibition of cytokine production from human lung fibroblasts

Dexamethasone and p38 MAPK inhibition of cytokine production from human lung fibroblasts

Novel Immunomodulatory Therapies for Respiratory Pathologies

Treating exuberant, non-resolving inflammation in the lung; Implications for acute respiratory distress syndrome and COVID-19

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