Pharmacokinetics, pharmacodynamics, and safety of fesomersen, a novel antisense inhibitor of factor XI, in healthy Chinese, Japanese, and Caucasian volunteers.

The inhibition of coagulation factor XI (FXI) presents an attractive approach for anticoagulation as it is not expected to increase the risk of clinically relevant bleeding and is anticipated to be at least as effective as currently available anticoagulants. Fesomersen is a conjugated antisense oligonucleotide that selectively inhibits the expression of FXI. The article describes three clinical studies that investigated the safety, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of fesomersen after subcutaneous (s.c.) injection to healthy participants. The studies included participants from diverse ethnic backgrounds (Caucasian, Japanese, and Chinese). Fesomersen demonstrated good safety and tolerability in all three studies. No major bleeding events were observed. After single-dose s.c. injection, fesomersen was rapidly absorbed into the systemic circulation, with maximum fesomersen-equivalent (fesomersen-eq) concentrations (Cmax) in plasma observed within a few hours. After reaching Cmax, plasma fesomersen-eq concentrations declined in a biphasic fashion. The PD analyses showed that the injection of fesomersen led to dose-dependent reductions in FXI activity and increases in activated partial thromboplastin time (aPTT). The maximum observed PD effects were reached between Day 15 and 30, and FXI activity and aPTT returned to near-baseline levels by Day 90 after a single dose. The PK/PD profiles after a single injection were similar among the various ethnic groups. Collectively, the study results suggest that fesomersen has a favorable safety profile and predictable and similar PK and PD profiles across Chinese, Japanese, and Caucasian participants.

The leaf extract of Ginkgo Biloba L. suppresses oxidized LDL-stimulated fibronectin production through an antioxidant action in rat mesangial cells.

1 The leaf extract of Ginkgo Biloba L. exhibits a variety of pharmacological effects through an antioxidant action. We examined the effects of the leaf extract (Ginkgolon-24) on the production of fibronectin induced by oxidized low-density lipoprotein (oxLDL) in rat mesangial cells. 2 Stimulation with oxLDL accelerated the production of fibronectin with the preceding generation of reactive oxygen species (ROS). Pretreatment with Ginkgolon-24 inhibited the oxLDL-induced fibronectin production as well as ROS generation. 3 oxLDL also elicited the activation of SP-1, nuclear factor-kappaB, and cAMP response element-binding protein, which are transcription factors involved in the fibronectin production. Among these activated transcription factors, Ginkgolon-24 inhibited the activation of SP-1 only. 4 Furthermore, 7-ketocholesterol, an oxidized lipid in oxLDL particles, induced the production of fibronectin and the activation of SP-1, which were also suppressed by Ginkgolon-24. 5 These results suggest that the leaf extract of Ginkgo Biloba L. inhibits the oxLDL-induced production of fibronectin probably through inhibitory effects on ROS generation and SP-1 activation in rat mesangial cells.

Involvement of reactive oxygen species and SP-1 in fibronectin production by oxidized LDL.

We examined the mechanisms responsible for the production of fibronectin induced by oxidized low-density lipoprotein (oxLDL) in rat mesangial cells. oxLDL accelerated the production of fibronectin with the preceding generation of reactive oxygen species (ROS). Pretreatment with N-acetylcysteine suppressed the oxLDL-induced fibronectin production as well as ROS generation. oxLDL also elicited the activation of SP-1, nuclear factor-kappaB, and cAMP response element-binding protein, but not activator protein-1. Among these activated transcription factors, N-acetylcysteine inhibited the activation of SP-1 only. 7-Ketocholesterol, an oxidized lipid in oxLDL particles, induced the production of fibronectin and the activation of SP-1, those which were suppressed by N-acetylcysteine. Furthermore, mithramycin A, an inhibitor of SP-1, also suppressed the oxLDL- and 7-ketocholesterol-stimulated production of fibronectin. These results suggest that oxLDL stimulates fibronectin production, at least in part, through the ROS-dependent activation of SP-1 in rat mesangial cells, and further that the ROS-dependent cellular responses may be elicited by 7-ketocholesterol.