Reversal of apixaban anticoagulation by four-factor prothrombin complex concentrates in healthy subjects: a randomized three-period crossover study.

Essentials Prothrombin complex concentrates (PCCs) may reverse the effect of factor Xa (FXa) inhibitors. We conducted an open-label, randomized, placebo-controlled, three-period crossover study in 15 subjects. Both PCCs rapidly reversed apixaban-mediated decreases in mean endogenous thrombin potential. Four-factor PCC administration had no effect on apixaban pharmacokinetics or anti-FXa activity. SUMMARY: Background Currently, there is no approved reversal agent for direct activated factor Xa (FXa) inhibitors; however, several agents are under investigation, including prothrombin complex concentrates (PCCs). Objective This open-label, randomized, placebo-controlled, three-period crossover study assessed the effect of two four-factor PCCs on apixaban pharmacodynamics and pharmacokinetics in 15 healthy subjects. Methods Subjects received apixaban 10 mg twice daily for 3 days. On day 4, 3 h after apixaban, subjects received a 30-min infusion of 50 IU kg-1 Cofact, Beriplex P/N (Beriplex), or saline. Change in endogenous thrombin potential (ETP), measured with a thrombin generation assay (TGA), was the primary endpoint. Secondary endpoints included changes in other TGA parameters, prothrombin time (PT), International Normalized Ratio (INR), activated partial thromboplastin time, anti-FXa activity, apixaban pharmacokinetics, and safety. Results Apixaban-related changes in ETP and several other pharmacodynamic measures occurred following apixaban administration. Both PCCs reversed apixaban's effect on ETP; the differences in adjusted mean change from pre-PCC baseline to end of infusion were 425 nm min (95% confidence interval [CI] 219.8-630.7 nm min; P < 0.001) for Cofact, and 91 nm min (95% CI - 31.3 to 212.4 nm min; P > 0.05) for Beriplex. Both PCCs returned ETP to pre-apixaban baseline levels 4 h after PCC infusion, versus 45 h for placebo. For both PCCs, mean ETP peaked 21 h after PCC initiation, and then slowly decreased over the following 48 h. Both PCCs reversed apixaban's effect on TGA peak height, PT, and INR. Apixaban pharmacokinetic and anti-FXa profiles were consistent across treatments. Conclusions Cofact and Beriplex reversed apixaban's steady-state effects on several coagulation assessments.

Short-term therapy with atorvastatin or fenofibrate does not affect plasma ghrelin, resistin or adiponectin levels in type 2 diabetic patients with mixed hyperlipoproteinaemia.

Lipid-lowering therapy is associated with reduced cardiovascular risk. The aim of the present study was to investigate whether lipid-lowering therapy might be associated with changes in the concentrations of metabolically important hormone concentrations. We performed a randomised cross-over open-label trial with atorvastatin (10 mg/day) and fenofibrate (200 mg/day), each for 6 weeks separated by a 6-week washout period in 13 patients (5 men, 8 women, age 60.0+/-6.8 years, body mass index 30.0+/-3.0 kg/m2) with type 2 diabetes mellitus and mixed hyperlipoproteinaemia. Plasma ghrelin (RIA, Phoenix Pharmaceuticals, Mountain View, CA, USA), adiponectin (ELISA, Biovendor, Heidelberg, Germany) as well as resistin (ELISA, Linco Research, St. Charles, MO, USA) concentrations were measured before and after atorvastatin as well as before and after fenofibrate. Ghrelin (462+/-84 pg/ml before vs. 464+/-102 pg/ml after atorvastatin, n.s.; 454+/-85 pg/ml before vs. 529+/-266 pg/ml after fenofibrate, n.s.), resistin (24.4+/-7.4 pg/ml before vs. 23.7+/-9.1 pg/ml after atorvastatin, n.s.; 23.4+/-8.2 pg/ml before vs. 19.9+/-5.5 pg/ml after fenofibrate, n.s.), adiponectin (10.89+/-5.33 pg/ml before vs. 12.41+/-5.75 pg/ml after atorvastatin, n.s.; 12.58+/-9.87 pg/ml before vs. 10.27+/-5.23 pg/ml after fenofibrate, n.s.) and insulin levels did not change significantly during lipid-lowering therapy. In patients with type 2 diabetes and mixed hyperlipoproteinaemia, short-term atorvastatin as well as fenofibrate therapy had no significant effects on adiponectin, ghrelin or resistin levels.

Effects of atorvastatin versus fenofibrate on lipoprotein profiles, low-density lipoprotein subfraction distribution, and hemorheologic parameters in type 2 diabetes mellitus with mixed hyperlipoproteinemia.

Diabetic dyslipoproteinemia characterized by hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol, and often elevated low-density lipoprotein (LDL) cholesterol with predominance of small, dense LDL is a strong risk factor for atherosclerosis. It is unclear whether fibrate or statin therapy is more effective in these patients. We compared atorvastatin (10 mg/day) with fenofibrate (200 mg/day), each for 6 weeks separated by a 6-week washout period in 13 patients (5 men and 8 women; mean age 60.0+/-6.8 years; body mass index 30.0+/-3.0 kg/m2) with type 2 diabetes mellitus (hemoglobin A1c 7.3+/-1.1%) and mixed hyperlipoproteinemia (LDL cholesterol 164.0+/-37.8 mg/dl, triglycerides 259.7+/-107 mg/dl, HDL cholesterol 48.7+/-11.0 mg/dl) using a randomized, crossover design. Lipid profiles, LDL subfraction distribution, fasting plasma viscosity, red cell aggregation, and fibrinogen concentrations were determined before and after each drug. Atorvastatin decreased all LDL subfractions (LDL cholesterol, -29%; p <0.01) including small, dense LDL. Fenofibrate predominantly decreased triglyceride concentrations (triglycerides, -39%; p <0.005) and induced a shift in LDL subtype distribution from small, dense LDL (-31%) to intermediate-dense LDL (+36%). The concentration of small, dense LDL was comparable during therapy to both drugs (atorvastatin 62.8+/-19.5 mg/dl, fenofibrate 63.0+/-18.1 mg/dl). Both drugs induced an increase in HDL cholesterol (atorvastatin +10%, p <0.05; fenofibrate +11%, p = 0.06). In addition, fenofibrate decreased fibrinogen concentration (-15%, p <0.01) associated with a decrease in plasma viscosity by 3% (p <0.01) and improved red cell aggregation by 15% (p <0.05), whereas atorvastatin did not affect any hemorheologic parameter. We conclude that atorvastatin and fenofibrate can improve lipoprotein metabolism in type 2 diabetes. However, the medications affect different aspects of lipoprotein metabolism.

Influence of frequency of anthelmintic treatment on the growth rate of Australian Friesian Sahiwal heifers.

A group of 42 Australian Friesian Sahiwal heifers was divided into 3 groups. Two groups received levamisole at different frequencies; once every 3 months or once per month at the rate of 4.45 mg of the phosphate base/kg; while the third group was untreated. Treatments were applied between 9 and 23 weeks of age, after weaning. A fourth group of 7 Friesian calves of equivalent age were initially not treated and were used as a comparison with the Australian Friesian Sahiwal control group. Bodyweights of cattle and faecal egg counts were measured every 2 weeks and larval cultures were performed on samples with high egg counts. A significant (P less than 0.05) increase in weight gain was recorded in the Australian Friesian Sahiwal heifers treated once per month compared with once every 3 months and the untreated group. The group of Friesian calves had to be treated after 7 weeks due to weight loss and poor body condition.