Btk Inhibitors as First Oral Atherothrombosis-Selective Antiplatelet Drugs?

Busygina, Kristina; Denzinger, Viola; Bernlochner, Isabell; Weber, Christian; Lorenz, Reinhard; Siess, Wolfgang

doi:10.1055/s-0039-1687877

Cited by 33 publications

(52 citation statements)

References 90 publications

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“…As we reported recently, FcγRIIA-stimulated platelet activation (aggregation, secretion, and P-selectin expression) and formation of platelet-neutrophil aggregates were completely suppressed by low concentrations of various Btk-inhibitors in vitro and by a single low oral dose of ibrutinib for several days ex vivo [13]. Further platelet-mediated mechanisms of vascular thrombosis, that are also blocked by Btk-inhibitors, are the activation of platelet glycoprotein (GP) VI by collagen exposed after endothelial injury and of GPIb by von Willebrand factor expressed on inflamed endothelium [14,15,16,17,18,19,20].…”

Section: Dear Sirmentioning

confidence: 99%

“…One must, however, be aware that patients treated with the irreversible covalent Btk-inhibitors ibrutinib, acalabrutinib, or zanubrutinib for B-cell malignancies show adverse reactions such as infections (grade 3 and higher in 18%-24% of the treated patients, mostly pneumonia) and frequently (50%) mild bleeding events [33,34,35]. One explanation for the latter might be the inhibition of the homologous kinase Tec in addition to Btk in platelets by these Btk-inhibitors [14,15].…”

Section: Dear Sirmentioning

confidence: 99%

“…New highly selective reversible or covalent Btk-inhibitors are being developed for the treatment of various autoimmune diseases aiming to inhibit autoantibody-producing B-cells and inflammatory myeloid cells [36,37,38,39]. The reversible Btk-inhibitor fenebrutinib does not inhibit the Btk homologous kinase Tec [37] that is a critical back-up pathway for maintaining physiologic hemostasis under Btk inhibition [14]. Indeed, in line with the absence of a bleeding phenotype of XLA patients, a recent clinical study detected no increased bleeding risk in fenebrutinibtreated patients [40].…”

Section: Dear Sirmentioning

confidence: 99%

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Selective inhibition of thromboinflammation in COVID-19 by Btk inhibitors

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Section: Dear Sirmentioning

confidence: 99%

Section: Dear Sirmentioning

confidence: 99%

Section: Dear Sirmentioning

confidence: 99%

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“…An alternative option is orally available inhibitors of the Bruton's tyrosine kinase that interfere with the downstream signaling of GPVI and GPIb. [36][37][38]…”

Section: Glycoprotein VImentioning

confidence: 99%

Novel Approaches to Fine-Tune Therapeutic Targeting of Platelets in Atherosclerosis: A Critical Appraisal

2020

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The pathogenesis of atherosclerotic vascular disease is driven by a multitude of risk factors intertwining metabolic and inflammatory pathways. Increasing knowledge about platelet biology sheds light on how platelets take part in these processes from early to later stages of plaque development. Recent insights from experimental studies and mouse models substantiate platelets as initiators and amplifiers in atherogenic leukocyte recruitment. These studies are complemented by results from genetics studies shedding light on novel molecular mechanisms which provide an interesting prospect as novel targets. For instance, experimental studies provide further details how platelet-decorated von Willebrand factor tethered to activated endothelial cells plays a role in atherogenic monocyte recruitment. Novel aspects of platelets as atherogenic inductors of neutrophil extracellular traps and particularities in signaling pathways such as cyclic guanosine monophosphate and the inhibitory adaptor molecule SHB23/LNK associating platelets with atherogenesis are shared. In summary, it was our intention to balance insights from recent experimental data that support a plausible role for platelets in atherogenesis against a paucity of clinical evidence needed to validate this concept in humans.

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“…It is noteworthy that statins can not only reduce the cholesterol level, but also play an anti-inflammatory role ( 3 ). This study, therefore, aims to more specifically reduce inflammatory activities during atherosclerosis using colchicine and interleukin (IL)-1β antibodies or other modes targeting IL-6 or IL-1 receptors ( 4 ).…”

Section: Introductionmentioning

confidence: 99%

circANRIL reduces vascular endothelial injury, oxidative stress and inflammation in rats with coronary atherosclerosis

Shi

Ji²,

Zhang

et al. 2020

Exp Ther Med

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Effects of circular antisense non-coding RNA in the INK4 locus (circANRIL) on vascular endothelial injury, oxidative stress and inflammation in rats with coronary atherosclerosis were studied by establishing a rat model of coronary atherosclerosis in which circANRIL was differentially expressed. A total of 40 healthy Sprague Dawley (SD) rats were randomly divided into research group (n=32) and control group (n=8). In research group, a rat model of coronary atherosclerosis was established without special treatment. The blood calcium (Ca 2+ ) and lipid levels in the two groups were compared. After cell transfection, the rats were divided into blank group (untransfected), negative group (transfected with blank vector), circANRIL group (transfected with circANRIL overexpression plasmid) and circANRIL inhibitor group (transfected with circANRIL silencer). Then the levels of lactate dehydrogenase (LDH), superoxide dismutase (SOD), malondialdehyde (MDA), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in each group were compared. Western blotting was adopted to detect the expressions of phosphorylated p38 mitogen-activated protein kinase (p-p38MAPK), p38MAPK and glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Finally, p-p38MAPK/GAPDH, p38MAPK/GAPDH and p-p38MAPK/p38MAPK were calculated. There were significant differences in the levels of serum Ca 2+ and lipid between control group and research group (P<0.05). Besides, differences in LDH, SOD, MDA, TNF-α and IL-6 in the supernatant in each group were statistically significant (P<0.05 or P<0.01). Moreover, there were statistically significant differences in the gray values of p-p38MAPK/GAPDH and p38MAPK/GAPDH and their ratio p-p38MAPK/p38MAPK in each group (P<0.05 or P<0.01). Inhibiting the expression of circANRIL in coronary heart disease cases can reduce vascular endothelial injury, oxidative stress and inflammation.

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Btk Inhibitors as First Oral Atherothrombosis-Selective Antiplatelet Drugs?

Cited by 33 publications

References 90 publications

Selective inhibition of thromboinflammation in COVID-19 by Btk inhibitors

Selective inhibition of thromboinflammation in COVID-19 by Btk inhibitors

Novel Approaches to Fine-Tune Therapeutic Targeting of Platelets in Atherosclerosis: A Critical Appraisal

circANRIL reduces vascular endothelial injury, oxidative stress and inflammation in rats with coronary atherosclerosis

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