Potential adverse effects associated with inhibition of p38alpha/beta MAP kinases.
Inhibitors of p38 MAP kinases show promise for the treatment of inflammatory and immunological disorders and some cancers. There is a substantial body of experimental evidence across several organ systems suggesting that p38 also mediates developmental, differentiation and proliferation processes. As a consequence of the wide-ranging regulatory role of p38 kinase in diverse cellular processes, the possibility of adverse events resulting from undesired pharmacological activity is a major concern for the p38 inhibitor drug class. Taking into consideration the limitations of experimental modeling systems, together the data may indicate that profound inhibition of p38 has the potential to impact these processes during fetal or neonatal development. The difficulty comes in extrapolating these findings to predict potential adverse effects under conditions of partial inhibition of p38 activity, and in an adult population in which these processes are typically only recapitulated during repair or adaptive responses. As such, the goal of this review of the targets of p38 activity is to bring an awareness of the those organ systems that should be monitored for potential toxicity, as well as to present a potential mechanistic basis for such monitoring or for investigation of adverse effects that may develop with administration of a p38 inhibitor.
Dambach
Donna M
DM
Department of Discovery Toxicology, Bristol Myers Squibb, Pharmaceutical Research Institute, Princeton, NJ 08543, USA. Donna.Dambach@bms.com
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000009:adverse effects* / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D006410:Hematopoiesis / Q000187:drug effects; D006801:Humans; D007107:Immune System / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D048290:Mitogen-Activated Protein Kinase 11 / Q000037:antagonists & inhibitors*; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors*; D018482:Muscle, Skeletal / Q000187:drug effects; D009420:Nervous System / Q000187:drug effects; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D012098:Reproduction / Q000187:drug effects; D014018:Tissue Distribution / Q000187:drug effects
D004791:Enzyme Inhibitors; D020033:Protein Isoforms; D048290:Mitogen-Activated Protein Kinase 11; D048308:Mitogen-Activated Protein Kinase 14