| 1. |
- Carle, Vanessa, et al.
(författare)
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Development of Selective FXIa Inhibitors Based on Cyclic Peptides and Their Application for Safe Anticoagulation
- 2021
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 64:10, s. 6802-6813
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Tidskriftsartikel (refereegranskat)abstract
- Coagulation factor XI (FXI) has emerged as a promising target for the development of safer anticoagulation drugs that limit the risk of severe and life-threatening bleeding. Herein, we report the first cyclic peptide-based FXI inhibitor that selectively and potently inhibits activated FXI (FXIa) in human and animal blood. The cyclic peptide inhibitor (Ki = 2.8 ± 0.5 nM) achieved anticoagulation effects that are comparable to that of the gold standard heparin applied at a therapeutic dose (0.3-0.7 IU/mL in plasma) but with a substantially broader estimated therapeutic range. We extended the plasma half-life of the peptide via PEGylation and demonstrated effective FXIa inhibition over extended periods in vivo. We validated the anticoagulant effects of the PEGylated inhibitor in an ex vivo hemodialysis model with human blood. Our work shows that FXI can be selectively targeted with peptides and provides a promising candidate for the development of a safe anticoagulation therapy.
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| 2. |
- Goto, Junko, et al.
(författare)
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Interdialytic weight gain of less than 2.5% seems to limit cardiac damage during hemodialysis
- 2021
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Ingår i: International Journal of Artificial Organs. - : SAGE Open. - 0391-3988 .- 1724-6040. ; 44:8, s. 539-550
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To investigate if a single low-flux HD induces a rise in cardiac biomarkers and if a change in clinical approach may limit such mechanism.Material and methods: A total of 20 chronic HD patients each underwent three different study-dialyses. Dialyzers (low-flux polysulfone, 1.8 sqm) had been stored either dry or wet (Wet) and the blood level in the venous chamber kept low or high. Laboratory results were measured at baseline, 30 and 180 min, adjusted for the effect of fluid shift. Ultrasound measured microemboli signals (MES) within the return line.Results: Hemodialysis raised cardiac biomarkers (p < 0.001): Pentraxin 3 (PTX) at 30 min (by 22%) and at 180 min PTX (53%), Pro-BNP (15%), and TnT (5%), similarly for all three HD modes. Baseline values of Pro-BNP correlated with TnT (rho = 0.38, p = 0.004) and PTX (rho = 0.52, p < 0.001). The changes from pre- to 180 min of HD (delta-) were related to baseline values (Pro-BNP: rho = 0.91, p < 0.001; TnT: rho = 0.41, p = 0.001; PTX: rho = 0.29, p = 0.027). Delta Pro-BNP (rho = 0.67, p < 0.001) and TnT (rho = 0.38, p = 0.004) correlated with inter-dialytic-weight-gain (IDWG). Biomarkers behaved similarly between the HD modes. The least negative impact was with an IDWG <= 2.5%. Multiple regression analyses of the Wet-High mode does not exclude a relation between increased exposure of MES and factors such as release of Pro-BNP.Conclusion: Hemodialysis, independent of type of dialyzer storage, was associated with raised cardiac biomarkers, more profoundly in patients with higher pre-dialysis values and IDWG. A limitation in IDWG to <2.5% and prolonged ultrafiltration time may limit cardiac strain during HD, especially in patients with cardiovascular risk.
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| 3. |
- Goto, Junko, et al.
(författare)
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Myocardial markers are highly altered by higher rates of fluid removal during hemodialysis
- 2024
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Ingår i: Hemodialysis International. - : John Wiley & Sons. - 1492-7535 .- 1542-4758. ; 28:1, s. 17-23
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Although hemodialysis is lifesaving in patients with kidney failure extensive interdialytic weight gain (IDWG) between dialyses worsens the prognosis. We recently showed a strong correlation between IDWG and predialytic values of cardiac markers. The aim of the present study was to evaluate if the cardiac markers N-terminal pro-B-type natriuretic peptide (proBNP) and troponin T were influenced by IDWG and speed of fluid removal (ultrafiltration-rate).Methods: Twenty hemodialysis patients performed in total 60 hemodialysis (three each). Predialytic values of proBNP and troponin T and changes from predialysis to 180 min hemodialysis (180–0 min) were compared with the IDWG calculated in percent of body weight. The ultrafiltration-rate was adjusted (UF-rateadj) to IDWG: (100 × weight gain between dialysis [kg])/(estimated body dry weight [kg] × length of hemodialysis session [hours]).Results: UF-rateadj correlated (Spearman) with (1) predialytic values of IDWG (r = 0.983, p < 0.001), proBNP (r = 0.443, p < 0.001), and troponin T (r = 0.296, p = 0.025); and (2) differences in proBNP180–0min (r = 0.572, p < 0.001) and troponin T180–0min (r = 0.400, p = 0.002). UF-ratesadj above a breakpoint of 0.60 caused more release of proBNP180–0min (p = 0.027). Remaining variables in multiple regression analysis with ProBNP180–0min as dependent factor were predialytic proBNP (p < 0.001) and the ultrafiltration-rate (p < 0.001).Conclusion: Higher UF-rateadj during dialysis was correlated to increased levels of cardiac markers. Data support a UF-rateadj lower than 0.6 to limit such increase. Further studies may confirm if limited fluid intake and a lower UF-rateadj should be recommended to prevent cardiac injury during dialysis.
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