Suppression of the clinical and cytokine response to endotoxin by RWJ-67657, a p38 mitogen-activated protein-kinase inhibitor, in healthy human volunteers.
Sepsis resulting in multiorgan failure and death is still a major problem in intensive care medicine, despite extensive attempts to interfere in the supposed underlying mechanism of a deranged immune system. This is not only due to the persistent lacunae in knowledge about the immune system in sepsis but also due to the lack of sufficient instruments for intervention. Inhibitors of the p38 mitogen-activated protein kinase (p38MAPK) have been used to study the signalling pathway of the immune response. In vitro and animal studies have demonstrated that blocking p38MAPK could mitigate the pro-inflammatory response and improve survival after endotoxaemia. Using an endotoxaemia model in healthy human volunteers we evaluated the attenuation of clinical and cytokine response to endotoxin after inhibition of p38MAPK by an oral dose of RWJ-67657, a pyrindinyl imidazole. We measured the clinical parameters temperature, blood pressure and heart rate. The proinflammatory cytokines tumour necrosis factor-alpha, interleukin-6 and interleukin-8 were measured by ELISA at various points during a 24-h period. Drug toxicity was evaluated by routine clinical and laboratory examinations. After a single dose dose of RWJ-67657 the temperature and blood pressure response remained at the basal level. The inhibition of TNF-alpha, IL-6 and IL-8 response was a dose dependent. With the maximum dosage, reduction in peak serum levels of the proinflammatory cytokines was greater than 90%. There was no drug-related toxicity.


CONCLUSIONS
We conclude that inhibition of p38MAPK by RWJ-67657 might be a tool to intervene in the deranged immune response in sepsis and other inflammatory diseases.
Fijen
J W
JW
Intensive and Respiratory Care Unit and Division of Immunology, Department of Internal Medicine, University Hospital Groningen, Groningen, The Netherlands. j.w.fijen@int.azg.nl
Zijlstra
J G
JG
De Boer
P
P
Spanjersberg
R
R
Tervaert
J W
JW
Van Der Werf
T S
TS
Ligtenberg
J J
JJ
Tulleken
J E
JE
D000328:Adult; D016207:Cytokines / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D019446:Endotoxemia / Q000150:complications / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D004731:Endotoxins / Q000633:toxicity; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005334:Fever / Q000139:chemically induced / Q000517:prevention & control*; D006801:Humans; D007022:Hypotension / Q000139:chemically induced / Q000517:prevention & control*; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D016207:Cytokines; D004731:Endotoxins; D004791:Enzyme Inhibitors; D007093:Imidazoles; D015850:Interleukin-6; D016209:Interleukin-8; D011725:Pyridines; C400277:RWJ 67657; D014409:Tumor Necrosis Factor-alpha; C044101:endotoxin, Escherichia coli; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases