Effect of the p38 MAPK inhibitor doramapimod on the systemic inflammatory response to intravenous lipopolysaccharide in horses.
SIRS
cytokine
endotoxemia
equine
sepsis
Journal
Journal of veterinary internal medicine
ISSN: 1939-1676
Titre abrégé: J Vet Intern Med
Pays: United States
ID NLM: 8708660
Informations de publication
Date de publication:
Sep 2020
Sep 2020
Historique:
received:
20
01
2020
revised:
24
06
2020
accepted:
26
06
2020
pubmed:
24
7
2020
medline:
29
6
2021
entrez:
24
7
2020
Statut:
ppublish
Résumé
Doramapimod, a p38 MAPK inhibitor, is a potent anti-inflammatory drug that decreases inflammatory cytokine production in equine whole blood in vitro. It may have benefits for treating systemic inflammation in horses. To determine whether doramapimod is well tolerated when administered IV to horses, and whether it has anti-inflammatory effects in horses in a low-dose endotoxemia model. Six Standardbred horses. Tolerability study, followed by a blinded, randomized, placebo-controlled cross-over study. Horses were given doramapimod, and clinical and clinicopathological variables were monitored for 24 hours. Horses then were treated with doramapimod or placebo, followed by a low dose infusion of lipopolysaccharide (LPS). Clinical variables (heart rate, rectal temperature, noninvasive blood pressure), leukocyte count and tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) concentrations were measured at multiple time points until 6 hours post-LPS infusion. No adverse effects or clinicopathological changes were seen in the safety study. When treated with doramapimod as compared to placebo, horses had significantly lower heart rates (P = .03), rectal temperatures (P = .03), and cytokine concentrations (P = .03 for TNF-α and IL-1β), and a significantly higher white blood cell count (P = .03) after LPS infusion. Doramapimod has clinically relevant anti-inflammatory effects in horses, likely mediated by a decrease in leukocyte activation and decrease in the release of pro-inflammatory cytokines. To evaluate its potential as a novel treatment for systemic inflammatory response syndrome in horses, clinical trials will be necessary to determine its efficacy in naturally occurring disease.
Sections du résumé
BACKGROUND
BACKGROUND
Doramapimod, a p38 MAPK inhibitor, is a potent anti-inflammatory drug that decreases inflammatory cytokine production in equine whole blood in vitro. It may have benefits for treating systemic inflammation in horses.
OBJECTIVE
OBJECTIVE
To determine whether doramapimod is well tolerated when administered IV to horses, and whether it has anti-inflammatory effects in horses in a low-dose endotoxemia model.
ANIMALS
METHODS
Six Standardbred horses.
METHODS
METHODS
Tolerability study, followed by a blinded, randomized, placebo-controlled cross-over study. Horses were given doramapimod, and clinical and clinicopathological variables were monitored for 24 hours. Horses then were treated with doramapimod or placebo, followed by a low dose infusion of lipopolysaccharide (LPS). Clinical variables (heart rate, rectal temperature, noninvasive blood pressure), leukocyte count and tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) concentrations were measured at multiple time points until 6 hours post-LPS infusion.
RESULTS
RESULTS
No adverse effects or clinicopathological changes were seen in the safety study. When treated with doramapimod as compared to placebo, horses had significantly lower heart rates (P = .03), rectal temperatures (P = .03), and cytokine concentrations (P = .03 for TNF-α and IL-1β), and a significantly higher white blood cell count (P = .03) after LPS infusion.
CONCLUSIONS AND CLINICAL IMPORTANCE
CONCLUSIONS
Doramapimod has clinically relevant anti-inflammatory effects in horses, likely mediated by a decrease in leukocyte activation and decrease in the release of pro-inflammatory cytokines. To evaluate its potential as a novel treatment for systemic inflammatory response syndrome in horses, clinical trials will be necessary to determine its efficacy in naturally occurring disease.
Identifiants
pubmed: 32700419
doi: 10.1111/jvim.15847
pmc: PMC7517855
doi:
Substances chimiques
Lipopolysaccharides
0
Naphthalenes
0
Pyrazoles
0
Tumor Necrosis Factor-alpha
0
p38 Mitogen-Activated Protein Kinases
EC 2.7.11.24
doramapimod
HO1A8B3YVV
Types de publication
Journal Article
Randomized Controlled Trial, Veterinary
Langues
eng
Sous-ensembles de citation
IM
Pagination
2109-2116Informations de copyright
© 2020 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC. on behalf of the American College of Veterinary Internal Medicine.
Références
Vet Immunol Immunopathol. 2020 Feb;220:109994
pubmed: 31877483
J Vet Intern Med. 2012 May-Jun;26(3):457-82
pubmed: 22428780
Shock. 1995 Jan;3(1):1-12
pubmed: 7850574
Shock. 2001 Jan;15(1):42-8
pubmed: 11198356
J Biol Chem. 2005 May 20;280(20):19472-9
pubmed: 15755732
J Pharmacol Exp Ther. 2000 Apr;293(1):281-8
pubmed: 10734180
Equine Vet J. 2005 Jul;37(4):371-83
pubmed: 16028631
Vet J. 2012 Jun;192(3):455-60
pubmed: 21974971
J Vet Intern Med. 2020 Sep;34(5):2109-2116
pubmed: 32700419
Clin Infect Dis. 2005 Nov 15;41 Suppl 7:S459-64
pubmed: 16237648
Circ Shock. 1989 Jul;28(3):235-48
pubmed: 2670308
Vet Clin North Am Equine Pract. 2014 Aug;30(2):337-51, vii-viii
pubmed: 25016495
Blood. 2003 Jun 1;101(11):4446-8
pubmed: 12576315
Arthritis Rheum. 2009 Feb;60(2):335-44
pubmed: 19180516
FEBS Lett. 2003 Jul 3;546(1):37-44
pubmed: 12829234
Arthritis Rheum. 2000 Jan;43(1):175-83
pubmed: 10643714
J Med Chem. 2010 Mar 25;53(6):2345-53
pubmed: 19950901
Arthritis Rheum. 2009 Feb;60(2):317-20
pubmed: 19180514
J Appl Toxicol. 2011 Oct;31(7):671-7
pubmed: 21328587
Int Rev Immunol. 1998;16(5-6):457-99
pubmed: 9646173
Vet Immunol Immunopathol. 2007 Aug 15;118(3-4):294-303
pubmed: 17614138
Equine Vet J. 2004 Jul;36(5):397-401
pubmed: 15253079
Ann Rheum Dis. 2010 Jan;69 Suppl 1:i77-82
pubmed: 19995751
Hepatol Res. 2014 May;44(5):571-83
pubmed: 23647831
J Pharmacol Exp Ther. 1996 Dec;279(3):1453-61
pubmed: 8968371
Am J Vet Res. 1992 May;53(5):753-6
pubmed: 1524301
Am J Vet Res. 1997 Nov;58(11):1291-9
pubmed: 9361895
Nat Struct Biol. 2002 Apr;9(4):268-72
pubmed: 11896401
Equine Vet J Suppl. 2000 Jun;(32):59-64
pubmed: 11202384
Intensive Care Med. 1993;19(5):265-72
pubmed: 8408935
Equine Vet J Suppl. 2011 Aug;(39):140-4
pubmed: 21790769
J Vet Pharmacol Ther. 2009 Apr;32(2):189-96
pubmed: 19290950
Am J Vet Res. 2009 Aug;70(8):1031-42
pubmed: 19645586
Inflamm Res. 2007 Apr;56(4):154-61
pubmed: 17522813
FEBS Lett. 2000 Oct 13;483(1):57-61
pubmed: 11033356
Equine Vet J. 2013 May;45(3):333-9
pubmed: 22943507
Clin Gastroenterol Hepatol. 2006 Mar;4(3):325-34
pubmed: 16527696
J Am Vet Med Assoc. 1999 Feb 1;214(3):382-90
pubmed: 10023402
Cell Signal. 2000 Jan;12(1):1-13
pubmed: 10676842
J Biol Chem. 1998 Sep 18;273(38):24832-8
pubmed: 9733787
Drugs. 1987 Jul;34(1):50-97
pubmed: 3308412
Equine Vet J. 2007 May;39(3):243-8
pubmed: 17520976
Vet Clin North Am Equine Pract. 2009 Aug;25(2):259-70
pubmed: 19580938
Equine Vet J. 1985 Mar;17(2):83-96
pubmed: 3987667
J Immunol. 2002 Apr 15;168(8):4070-7
pubmed: 11937566
J Vet Intern Med. 2010 Jul-Aug;24(4):940-8
pubmed: 20649751
J Biol Chem. 1999 Jan 1;274(1):264-9
pubmed: 9867839
J Am Vet Med Assoc. 2001 Jul 1;219(1):67-71
pubmed: 11439773
Res Vet Sci. 2013 Jun;94(3):682-6
pubmed: 23462621
Res Vet Sci. 2012 Feb;92(1):40-4
pubmed: 21093001
Am J Vet Res. 1990 Dec;51(12):1935-40
pubmed: 2085219
Scand J Infect Dis. 2003;35(9):535-44
pubmed: 14620132
Can Vet J. 2010 Jun;51(6):623-8
pubmed: 20808574
Nat Rev Drug Discov. 2003 Sep;2(9):717-26
pubmed: 12951578
Vet Immunol Immunopathol. 2009 Jun 15;129(3-4):192-9
pubmed: 19070370