Investigation of the anticoagulant activity of cyclic sulfated glycosaminoglycan mimetics.

Thrombotic disorders are among the leading causes of deaths worldwide. Anticoagulants are frequently prescribed for their prevention and/or treatment. Current anticoagulants, which target either thrombin or factor Xa, are plagued with a number of drawbacks, the most important of which is the increased risk of internal bleeding. To develop better antithrombotic agents, the anticoagulant activity of cyclic glycosaminoglycan mimetics was evaluated. Human plasma clotting assays and enzyme inhibition assays were exploited to evaluate the anticoagulant activity of sulfated ß-cyclodextrin (SBCD) and its three analogs: sulfated α-cyclodextrin, ß-cyclodextrin, and methylated ß-cyclodextrin. In normal human plasma, SBCD selectively doubled the activated partial thromboplastin time (APTT) at ∼9 µg/mL, with no effect on prothrombin time (PT) at the same concentration. Likewise, SBCD doubled APTT at ∼9 µg/mL and at ∼8 µg/mL in antithrombin-deficient plasma and heparin cofactor II-deficient plasma, respectively. Interestingly, the three SBCD derivatives were inactive at the highest concentrations tested which highlighted the importance of the sulfate groups and the size of the molecule. Enzyme assays revealed that SBCD inhibits factor XIa (FXIa) with an IC50 value of ∼20 µg/mL and efficacy of near 100%. SBCD did not inhibit other related proteins including thrombin, factor IXa, factor Xa, factor XIIa, factor XIIIa, plasmin, chymotrypsin, or trypsin at the highest concentrations tested demonstrating a significant selectivity. In Michaelis-Menten kinetics, SBCD decreased the VMAX and increased the KM of FXIa hydrolysis of a tripeptide chromogenic substrate indicating a mixed inhibition mechanism. Together, it appears that SBCD is a potent and selective inhibitor of human FXIa with substantial anticoagulant activity in human plasma. Overall, this study introduces SBCD as a promising lead for further development as a safer anticoagulant.

Vericiguat: A New Hope for Heart Failure Patients.

Heart failure with reduced ejection fraction (HFrEF) is the inability of the heart to adequately contract or eject blood. This heart is unable to produce adequate cardiac output to perfuse vital tissues. At a fundamental level, it is known that the cardioprotective pathway of nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate is impaired in heart failure patients. Vericiguat is a novel, orally used, small molecule, and direct stimulator of the soluble guanylate cyclase, and thus, it enhances the production of cyclic guanosine monophosphate. Vericiguat was approved by the FDA in January of 2021 to reduce the risk of cardiovascular death and heart failure hospitalization following a hospitalization for heart failure or need for outpatient IV diuretics, in adults with symptomatic chronic heart failure and ejection fraction less than 45%. In this review, we describe the chemical and mechanistic aspects, pharmacokinetics, adverse effects, and contraindications of vericiguat so as to facilitate its optimal therapeutic use.

First Therapeutic Approval for Eosinophilic Esophagitis.

Eosinophilic esophagitis (EE) is a chronic, immune-mediated or antigen-mediated esophageal disease. Treatment for patients with EE can be challenging with no previously approved medications. Current management strategies follow the four D's paradigm of drugs, dietary elimination, dilation, and disease anxiety and hypervigilance therapy. On 20 May 2022, dupilumab was approved by FDA for EE. A dose of 300 mg dupilumab weekly significantly improved signs and symptoms of EE compared to placebo in a phase 3 trial. The approval of dupilumab will fulfill an unmet need for the increasing number of patients with EE.