Tolerability and Pharmacokinetics of Delayed-Release Dimethyl Fumarate Administered With and Without Aspirin in Healthy Volunteers

Background

Delayed-release dimethyl fumarate (DR-DMF) has cytoprotective and antiinflammatory properties and has recently been approved in the United States as an oral treatment for relapsing forms of multiple sclerosis. The most common adverse events associated with DR-DMF are flushing and gastrointestinal (GI) events, the incidences of which diminish over time.

Objective

The purpose of this study was to evaluate the tolerability and pharmacokinetic (PK) profile of DR-DMF with or without concomitant acetylsalicylic acid (aspirin), a cyclooxygenase inhibitor.

Methods

Healthy volunteers (N = 56) were randomized to receive different dosing regimens of DR-DMF or matching placebo with or without pretreatment with 325 mg aspirin for 4 days. Plasma levels of the active metabolite monomethyl fumarate were assessed on days 1 and 4. Flushing and GI events were assessed using patient-reported scales. Potential flushing mediators were explored.

Results

DR-DMF showed a safety, tolerability, and PK profile consistent with previous clinical experience, with no evidence of accumulation. Pretreatment with aspirin had no effect on the primary PK parameters, AUC_0–10h, or C_max. Flushing severity, assessed by 2 subject-reported rating scales, was generally mild and was rated highest at the start of treatment. Pretreatment with aspirin reduced flushing incidence and intensity without affecting GI events or the PK profile of DR-DMF. In some DR-DMF–treated individuals, plasma concentrations of a prostaglandin D₂ (PGD₂) metabolite were increased.

Conclusions

In healthy volunteers, DR-DMF was well tolerated over 4 days of dosing, with a PK profile consistent with that previously reported and no evidence of accumulation. Aspirin pretreatment reduced the incidence and intensity of flushing without affecting GI events or the DR-DMF PK profile. Elevated levels of PGD₂ in some DR-DMF–treated individuals suggest that flushing may be, at least in part, prostaglandin mediated. ClinicalTrials.gov identifier: ID: NCT01281111.     

Mesenteric Venous Thrombosis Associated with Oral Contraceptives: A Case Report

Small-bowel infarction resulting from mesenteric venous thrombosis is a rare but life-threatening complication to which young women taking oral contraceptives are liable. The patient characteristically presents with an “acute abdomen” after a variable prodromal period of vague abdominal pain. The correct diagnosis can be made from the macroscopic appearance at laparotomy, provided the surgeon is alert to the condition. An accurate diagnosis is important, as anticoagulation measures must be instituted early to counter the commonly associated thromboembolic phenomena.     

环孢菌素A阻断人HL-60抗药性细胞于G1期而诱导敏感细胞凋亡

进一步研究了抗三尖杉酯碱的HL-60细胞(HR20)抗细胞凋亡的机制及该抗性和抗药性的关系。结果表明,环孢菌素A(CsA)20,10μg·ml^-1诱导HL-60细胞发生凋亡,而阻断HR20细胞于G₁期,就不能诱导细胞发生凋亡。低浓度的CsA明显增加柔红霉素在HR20细胞内的积聚,其逆转抗药性作用与阻断细胞周期运行无关。CsA10μg·ml^-1处理HR20细胞,可引起50kDa的蛋白质高度磷酸化。结果提示:环孢菌素A阻断抗三尖杉酯碱的HL-60细胞于G₁期,而诱导敏感的HL-60细胞发生凋亡,其阻断作用与抗药性无关。     

Hot Off the Press: Peripheral Intravenous Cannula Insertion and Use in the Emergency Department

This is a prospective before–after study comparing peripheral intravenous cannulation (PIVC) placement and usage rates following a 10‐week‐long multimodal intervention provided to medical and nursing staff working in a tertiary emergency department (ED). The intervention focused on improving appropriate use of PIVCs in an emergency setting by emphasizing to clinicians that a PIVC should only be placed if it was believed there was more than an 80% chance that it would be used. Patients were eligible for the study if they presented to the ED and were >18 years of age. Patients were excluded from the study if they were triage category 1, already had a PIVC placed in an ambulance, or were transferred from another hospital. Among the 4,172 patients included in the analysis, there was a 9.8% reduction in the number of PIVCs inserted (95% confidence interval [CI] = 6.8–12.87) and a 12% increase in PIVC usage (95% CI = 8.7%–17.0%) in the postintervention cohort.     

Hot Off the Press: Prehospital Advanced Cardiac Life Support for Out‐of‐hospital Cardiac Arrest

This retrospective cohort study examined the rate of survival to hospital discharge among adult patients with out‐of‐hospital cardiac arrest, comparing patients who received care only from basic cardiac life support (BCLS)‐trained emergency medical service (EMS) crews to patients who had an advanced cardiac life support (ACLS)‐trained EMS crew on scene at some point during the resuscitation. There was no difference in the primary outcome of rate of survival to hospital discharge (10.9% with ACLS care and 10.6% with BCLS care, p = 0.67).