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Pilot study of the antifibrotic effects of the multikinase inhibitor pacritinib
in a mouse model of liver fibrosis
#MMPMID29785143
Al-Fayoumi S
; Hashiguchi T
; Shirakata Y
; Mascarenhas J
; Singer JW
J Exp Pharmacol
2018[]; 10
(?): 9-17
PMID29785143
show ga
BACKGROUND: Fibrotic diseases result from an exuberant response to chronic
inflammation. Myelofibrosis is the end result of inflammation in bone, caused by
an inflammatory process triggered by production of abnormal myeloid cells driven
by mutations affecting the JAK-STAT pathway. Inflammatory cytokine overproduction
leads to increased mesenchymal cell proliferation, culminating in fibrosis.
Although JAK2 inhibitors, such as the JAK1/2 inhibitor ruxolitinib and the
JAK2/FLT3/CSF1R/IRAK1 inhibitor pacritinib suppress abnormal clone expansion in
myelofibrosis, ruxolitinib does not appear to prevent or reverse bone-marrow
fibrosis in most patients. In two Phase III clinical trials, pacritinib, however,
demonstrated improvements in platelet counts and hemoglobin and reductions in
transfusion burden in some patients with baseline cytopenias, suggesting it may
improve bone-marrow function. Unlike ruxolitinib, pacritinib suppresses signaling
through IRAK1, a key control point for inflammatory and fibrotic signaling.
PURPOSE: To investigate potential antifibrotic effects of pacritinib in an animal
model of liver fibrosis relevant to the observed course of human disease.
METHODS: Pacritinib, negative control (vehicle), and positive control (the
angiotensin 2-receptor antagonist and PPAR? partial agonist telmisartan) were
assessed in the murine Stelic animal model, which mimics the clinically observed
progression from hepatic steatosis to nonalcoholic steatohepatitis, liver
fibrosis, and hepatocellular carcinoma. Histopathological analysis used
hematoxylin and eosin staining. Body and liver weight changes, nonalcoholic
fatty-liver disease activity scores, and plasma cytokeratin 18 fragment levels (a
biomarker of hepatic necrosis) were measured. RESULTS: Pacritinib-treated mice
had significantly (P<0.01) reduced fibrotic areas in liver compared to vehicle
control and significantly (P<0.05) lower levels of CK18. The antifibrotic effect
of pacritinib was comparable to that of telmisartan, but without significant
effects on fat accumulation. CONCLUSION: These results, the first to demonstrate
hepatic antifibrotic effects for pacritinib in an animal model of liver disease,
provide preliminary support for potential clinical applications of pacritinib in
fibrotic diseases other than myelofibrosis.
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