soluble epoxide hydrolase inhibitor
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Author(s):  
Mona Mashayekhi ◽  
Celestine N. Wanjalla ◽  
Christian M. Warren ◽  
Joshua D. Simmons ◽  
Kakali Ghoshal ◽  
...  

Author(s):  
Zhen Cui ◽  
Bochuan Li ◽  
Yanhong Zhang ◽  
Jinlong He ◽  
Xuelian Shi ◽  
...  

Endothelial cells play a critical role in maintaining homeostasis of vascular function, and endothelial activation is involved in the initial step of atherogenesis. Previously, we reported that Abl kinase mediates shear stress–induced endothelial activation. Bosutinib, a dual inhibitor of Src and Abl kinases, exerts an atheroprotective effect; however, recent studies have demonstrated an increase in the incidence of side effects associated with bosutinib, including increased arterial blood pressure (BP). To understand the effects of bosutinib on BP regulation and the mechanistic basis for novel treatment strategies against vascular dysfunction, we generated a line of mice conditionally lacking c-Abl in endothelial cells (endothelial cell- Abl KO ). Knockout mice and their wild-type littermates ( Abl f/f ) were orally administered a clinical dose of bosutinib, and their BP was monitored. Bosutinib treatment increased BP in both endothelial cell- Abl KO and Abl f/f mice. Furthermore, acetylcholine-evoked endothelium-dependent relaxation of the mesenteric arteries was impaired by bosutinib treatment. RNA sequencing of mesenteric arteries revealed that the CYP (cytochrome P450)-dependent metabolic pathway was involved in regulating BP after bosutinib treatment. Additionally, bosutinib treatment led to an upregulation of soluble epoxide hydrolase in the arteries and a lower plasma content of eicosanoid metabolites in the CYP pathway in mice. Treatment with 1-Trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea, a soluble epoxide hydrolase inhibitor, reversed the bosutinib-induced changes to the eicosanoid metabolite profile, endothelium-dependent vasorelaxation, and BP. Thus, the present study demonstrates that upregulation of soluble epoxide hydrolase mediates bosutinib-induced elevation of BP, independent of c-Abl. The addition of soluble epoxide hydrolase inhibitor in patients treated with bosutinib may aid in preventing vascular side effects.


Molecules ◽  
2021 ◽  
Vol 26 (16) ◽  
pp. 5034
Author(s):  
Cindy B. McReynolds ◽  
Jun Yang ◽  
Alonso Guedes ◽  
Christophe Morisseau ◽  
Roberto Garcia ◽  
...  

There are few novel therapeutic options available for companion animals, and medications rely heavily on repurposed drugs developed for other species. Considering the diversity of species and breeds in companion animal medicine, comprehensive PK exposures in the companion animal patient is often lacking. The purpose of this paper was to assess the pharmacokinetics after oral and intravenous dosing in domesticated animal species (dogs, cats, and horses) of a novel soluble epoxide hydrolase inhibitor, EC1728, being developed for the treatment of pain in animals. Results: Intravenous and oral administration revealed that bioavailability was similar for dogs, and horses (42 and 50% F) but lower in mice and cats (34 and 8%, respectively). Additionally, clearance was similar between cats and mice, but >2× faster in cats vs. dogs and horses. Efficacy with EC1728 has been demonstrated in mice, dogs, and horses, and despite the rapid clearance of EC1728 in cats, analgesic efficacy was demonstrated in an acute pain model after intravenous but not oral dosing. Conclusion: These results demonstrate that exposures across species can vary, and investigation of therapeutic exposures in target species is needed to provide adequate care that addresses efficacy and avoids toxicity.


2021 ◽  
Vol 9 (2) ◽  
pp. 43
Author(s):  
Bedanta Bhattacharjee ◽  
Ritu Bharti ◽  
Karab Kalita ◽  
Nirupam Das ◽  
Abu Md Ashif Ikbal

2021 ◽  
Vol 64 (4) ◽  
pp. 1856-1872 ◽  
Author(s):  
Bruce D. Hammock ◽  
Cindy B. McReynolds ◽  
Karen Wagner ◽  
Alan Buckpitt ◽  
Irene Cortes-Puch ◽  
...  

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