Introduction
Potential pleiotropic effects of edoxaban in inflammation, atherosclerosis, and stroke
Test system | Type and number of individuals | Duration | Edoxaban application | Intervention | Main results | |
---|---|---|---|---|---|---|
Millenaar et al. 2020 [24] | ApoE−/− knockout mice | Ctr: Control (N = 3–5) | 8 Weeks | Oral/chow | Cholesterol-rich diet and femoral artery ligation | Difference in hind-limb perfusion restoration: no significant difference |
Warf: Warfarin 3 g/kg + vitamin K1 1 g/kg (N = 8) | Lowest amounts of plaque tissue and fibrosis in aortic sinus with Edo (plaque tissue: p = 0.024 vs. Ctr; p = 0.14 vs. Warf; fibrosis: p = 0.027 vs. Ctr; p = 0.081 vs. Warf) | |||||
Edo: edoxaban 375 mg/kg (N = 5–6) | ||||||
Almengló et al. 2020 [1] | HUVEC | Ctr: Control (N = n.a.) | n.a. | Added to cell culture medium | HUVEC cells ± Edo, FXa, or Edo + FXa | Edo enhanced HUVEC cell viability and growth |
Edo: edoxaban (N = n.a.) | Edo counteracted FXa-induced pro-migratory and pro-inflammatory effects | |||||
FXa: factor Xa (N = n.a.) | Edo inhibited adhesion of platelets and PBMCs to endothelial cells and counteracted FXa-induced expression of adhesion molecules | |||||
Edo + FXa (N = n.a.) | – | |||||
Tsujino et al. 2019 [38] | Beagles implanted with ventricular pacemaker | Sham (N = 6) | 19 Days Edo +14 days ventricular tachypacing | Oral/chow | Ventricular tachypacing (VTP) ± Edo | Prolongation of AF by VTP was suppressed by Edo (p < 0.01 vs. Ctr; p = n. s. vs. sham) |
Ctr: placebo (N = 6) | Increase in atrial fibrotic area by VTP was suppressed by Edo (p < 0.01 vs. Ctr) | |||||
Edo: edoxaban 2.0 mg/kg/day (N = 6) | Increase in PAR‑2 and in fibronectin expression by VTP was suppressed by Edo (both p < 0.05 vs. Ctr) | |||||
Mollenhauer and Rudolph (unpublished data) | C57/B6J mice implanted with AngII osmotic minipumps | Ctr (N = 5–8) | 14 Days | Oral/chow | AngII minipumps (1.5 ng/g/min) ± oral Edo | Edo significantly reduced number and length of AngII-induced AF episodes (p < 0.05) |
AngII: angiotensin II (N = 5–9) | Edo did not reduce AngII induced fibrosis or enhanced collagen I expression | |||||
AngII + Edo: angiotensin II + edoxaban 0.25 mg/mouse/day (N = 5–15) | No changes in PAR‑2 expression by AngII + edoxaban | |||||
Edo significantly attenuated AngII induced increase in expression of thrombopoetin, IL-17, IL‑4, INFγ, IL‑5 and MCP5 | ||||||
Wiedmann et al. 2020 [41] | Human potassium channels expressed in Xenopus laevis oocytes | Edoxaban 1 µM (N = 7) | n.a. | Added to bath solution | Voltage clamp stimulation ± NOAC | NOACs did not significantly alter peak current amplitudes of potassium channels KV11.1, KV1.5, KV4.3, Kir2.1, Kir2.2, or K2P2.1 |
Apixaban 1 µM (N = 7) | ||||||
Rivaroxaban 1 µM (N = 9) | No significant effect of NOACs on current-voltage relationships | |||||
Dabigatran 1 µM (N = 5) | ||||||
Bukowska et al. 2020 [5] | Cell lines A549 (human lung carcinoma cells; model for type II alveolar epithelial cells) and Calu3 (human bronchial adenocarcinoma cells) | Ctr: control | n.a. | Added to cell culture medium | A549 or Calu3 cells ± FXa ± Edo, vorapaxar, or GB83 | Edo prevented FXa-induced increase in ERK1/2 activation and in the expression of pro-inflammatory cytokines; PAR‑1 inhibitor vorapaxar showed similar effects |
FXa: factor Xa 25 nmol/l | ||||||
FXa + Edo: FXa + edoxaban 1 µmol/l | Edo prevented FXa-induced mitochondrial alteration with restricted capacity for ATP generation; similar effects seen with vorapaxar and GB83 (PAR‑2 inhibitor) | |||||
FXa + Vorapaxar 10 µmol/l | ||||||
FXa + GB83 10 µmol/l | FXa did not increase apoptosis or cause metabolic cellular dysfunction | |||||
Bieber et al. 2020 [3] | C57/B6J mice subjected to tMCAO | Ctr: vehicle (N = 3–9) | 24 h (or 7 days for MRI) | Oral gavage via gastric tube | Induction of stroke by tMCAO and treatment with Edo or VKA | Edo significantly reduced infarct volumes on day 1 after stroke (p < 0.001 vs Ctr; p < 0.05 vs. VKA) |
Edo: edoxaban 3.3 mg/kg body weight (N = 3–9) | Edo improved neurological outcome (p < 0.05 vs. Ctr; p = n. s. vs. VKA) and function of the blood-brain barrier on day 1 after stroke (p < 0.05 vs. Ctr and vs. VKA for leakage into ipsilateral hemisphere) | |||||
VKA: phenprocoumon 0.3 mg/kg body weight (N = 3–9) | Edo reduced cerebral expression of pro-inflammatory cytokines IL-1β (p < 0.05 vs. Ctr and vs. VKA) and IL‑6 (p < 0.01 vs. Ctr, p = n. s. vs. VKA) | |||||
Oe et al. 2016 [25] | Diabetic nephropathy mouse model (Akita mutation in insulin2 gene and eNOS knockout) | eNOS+/+DM: untreated non-DN control (N ≥ 5) | 3 Months | Oral | Induction of diabetic nephropathy by eNOS knockout and insulin2 Akita mutation ± Edo | DM increased renal FXa mRNA; knockout of eNOS in DM mice led to diabetic nephropathy with increased mRNA expression levels for pro-inflammatory and pro-fibrotic cytokines Tgfb, Pai1, Col1, Col4, and Tnfa (p < 0.05 vs. eNOS+/+DM Ctr for all), and for Par1 and Par2 (p < 0.05 for Par1, p = n. s. for Par2 vs. eNOS+/+DM Ctr) |
eNOS+/+DM + Edo: edoxaban-treated non-DN mice (N ≥ 5) | Edo significantly reduces Pai1, Col1, Col4, and Tnfa levels and Par1 and Par2 levels in eNOS−/−DM mice (p < 0.05 vs. eNOS−/−DM Ctr for all) | |||||
eNOS−/−DM: untreated DN control (N ≥ 5) | Edo significantly reduced mesangial matrix score in eNOS−/−DM mice (p < 0.001 vs eNOS−/−DM Ctr) | |||||
eNOS−/−DM + Edo: edoxaban (50 mg/kg/day) treated DN mice (N ≥ 5) | Par2 knockout ameliorated DN (shown with additional knockout mouse model) | |||||
Hiramoto et al. 2023 [21] | Colon26–inoculated BALB/C mice | Untr: untreated mice | 7 Days inoculation period + 21 days treatment | Oral/feeding needle | Inoculation of mice with Colon26 cancer cells ± treatment with NOAC | Edo significantly reduced tumor growth in Colon26-inoculated mice (p < 0.01 vs. Ctr); similar effects were seen with Dabi and Riva (p < 0.05 vs. Ctr for both) |
Ctr: Colon26-inoculated mice + water | ||||||
Edo: Colon26-inoculated mice + edoxaban 10 mg/kg/mouse (N = 5) | TF, PAI‑1, IL‑6, and MMP‑2 plasma levels are significantly elevated in Colon26-inoculated mice (p < 0.01 vs. untr for all); Edo significantly reduced these plasma levels in Colon26-inoculated mice (p < 0.01 vs. Ctr for all) | |||||
Riva: Colon26-inoculated mice + rivaroxaban 5 mg/kg/mouse (N = 5) | PAR‑1 and PAR‑2 expression was significantly increased in Colon26-inoculated mice (p < 0.01 vs. untr); Edo significantly reduced PAR‑2, but not PAR‑1 expression levels (p < 0.01 vs. Ctr for PAR-1) | |||||
Dabi: Colon26-inoculated mice + dabigatran 50 mg/kg/mouse (N = 5) | Edo treatment led to increased apoptosis and elevated p53 protein levels in tumor tissues of Colon26-inoculated mice (p < 0.01 vs. Ctr) |