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Purpose: The purpose of this article is to describe the role of andexanet alfa as a reversal agent in the management of bleeding complications associated with direct oral anticoagulants (DOACs). Summary: Over the past several years, DOACs are increasingly being used in the management of patients with non-valvular atrial fibrillation or stroke prevention. Management of major bleeding in DOAC therapy includes supportive therapy and addressing any factors that are contributing to blood loss. Additionally, there may a need to expedite the removal of any anticoagulation effects by removing or neutralizing the anticoagulant. Until recently, there was no specific reversal agent for DOACs; management approaches were limited to util ©Wizing concentrated clotestern University oft Health Sciencesing factors or fresh frozen plasma. The FDA granted expedited approval of andexanet alfa as a specific reversal agent for the DOACs to meet this unmet need. Conclusion: In clinical trials, andexanet alfa demonstrated a significant reduction in anti-Xa activity in patients with a major bleeding event on apixaban or rivaroxaban. The clinical benefit of this anti-Xa activity reduction has yet to be demonstrated in a randomized controlled trial. The current lack of randomized controlled trials demonstrating clinical benefit and the high cost of the drug has limited the widespread use of this antidote.

Background & Aims Hospitalized patients with acute severe ulcerative colitis (ASUC) often require surgery. Although the tumor necrosis factor antagonist infliximab is an effective salvage therapy to prevent colectomy in patients with ASUC, optimal dosing is unclear. Calculated infliximab clearance has been associated with important outcomes in patients with ulcerative colitis, but its utility in patients with ASUC has not been established. We assessed the relationship between calculated the baseline infliximab clearance before infliximab salvage therapy and the requirement for colectomy in patients hospitalized for ASUC. Methods We obtained data from hospitalized patients with ASUC who initiated infliximab therapy. We then calculated the baseline infliximab drug clearance in these patients based on an existing formula. The primary aim was to compare clearance between patients who required colectomy 6 months later and patients who did not require colectomy. Receiver operating characteristic curve analyses evaluated clearance thresholds for colectomy. Multivariable logistic regression analysis evaluated factors associated with colectomy. Results In 39 patients with ASUC, the median baseline calculated clearance was higher in patients requiring colectomy at 6 months than in patients without colectomy (0.733 vs 0.569 L/d; P = .005). An infliximab clearance threshold of 0.627 L/d identified patients who required colectomy with 80.0% sensitivity and 82.8% specificity (area under the curve, 0.80). A higher proportion of patients with infliximab clearance of 0.627 L/d or more underwent colectomy within 6 months (61.5%) than patients with lower infliximab clearance values (7.7%) (P = .001). Multivariable analysis identified baseline infliximab clearance as the only factor associated with colectomy. The infliximab dose in the hospital was higher in patients who required colectomy. Results were similar at 30 days and 1 year. Conclusions In patients hospitalized with ASUC, higher values of calculated infliximab clearance before infliximab administration is associated with higher rates of colectomy. Although patients who required colectomies received higher doses, data on infliximab concentrations are lacking. Infliximab pharmacokinetic models are needed for patients with ASUC to allow comparative trials on clearance-based vs standard dosing.

Rhodiola rosea has been extensively used to improve physical and mental performance and to protect against stress. We, and others, have reported that R. rosea can extend lifespan in flies, worms, and yeast. However, its molecular mechanism is currently unknown. Here, we tested whether R. rosea might act through a pathway related to dietary restriction (DR) that can extend lifespan in a range of model organisms. While the mechanism of DR itself is also unknown, three molecular pathways have been associated with it: the silent information regulator 2 (SIR2) proteins, insulin and insulin-like growth factor signaling (IIS), and the target of rapamycin (TOR). In flies, DR is implemented through a reduction in dietary yeast content. We found that R. rosea extract extended lifespan in both sexes independent of the yeast content in the diet. We also found that the extract extended lifespan when the SIR2, IIS, or TOR pathways were genetically perturbed. Upon examination of water and fat content, we found that R. rosea decreased water content and elevated fat content in both sexes, but did not sensitize flies to desiccation or protect them against starvation. There were some sex-specific differences in response to R. rosea. In female flies, the expression levels of glycolytic genes and dSir2 were down-regulated, and NADH levels were decreased. In males however, R. rosea provided no protection against heat stress and had no effect on the major heat shock protein HSP70 and actually down-regulated the mitochondrial HSP22. Our findings largely rule out an elevated general resistance to stress and DR-related pathways as mechanistic candidates. The latter conclusion is especially relevant given the limited potential for DR to improve human health and lifespan, and presents R. rosea as a potential viable candidate to treat aging and age-related diseases in humans.