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Background Novel oral anticoagulants are approved in several indications: rivaroxaban, apixaban, and dabigatran for the prevention of venous thromboembolism after elective hip or knee replacement surgery, and edoxaban for hip or knee replacement surgery and hip fracture surgery (in Japan only); rivaroxaban for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE; and rivaroxaban, apixaban, and dabigatran for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. These agents overcome some limitations of traditional anticoagulants, are suggested to have no requirement for routine coagulation monitoring, and are administered orally. Rivaroxaban, apixaban, and dabigatran have different pharmacological characteristics, and guidance is needed on optimum doses and dosing intervals and the effects of renal or hepatic impairment, age, food, and other drugs. Dabigatran has stricter prescribing advice than rivaroxaban or apixaban for patients with moderate-to-severe renal impairment. All three drugs have restrictions on use in patients with hepatic impairment. Apixaban requires twice-daily dosing in all indications, whereas rivaroxaban and dabigatran are dosed once- or twice-daily depending on indication. Although head-to-head comparisons are lacking, the novel oral anticoagulants may show favorable cost–benefit relations compared with traditional vitamin K antagonists or no therapy. Aim This review summarizes the pharmacology of rivaroxaban, apixaban, edoxaban, and dabigatran, and the indications for which they are approved. Issues regarding the optimization of the use of these anticoagulants for the management of thromboembolic disorders will also be discussed.

The direct factor Xa (FXa) inhibitors rivaroxaban, apixaban and edoxaban, and the thrombin inhibitor dabigatran etexilate (dabigatran) have gained approval for use in several indications, most notably for the prevention and treatment of venous thromboembolism (VTE) and for the prevention of stroke in patients with atrial fibrillation. Hepatic impairment can affect the disposition of these anticoagulants considerably not only because of the hepatic metabolism of the direct FXa inhibitors but also because moderate to severely impaired hepatic function will affect coagulation. This review describes the key pharmacological properties of novel oral anticoagulants with special attention to patients with impaired hepatic function. In subjects with moderately impaired liver function (i.e. Child-Pugh classification B), the area under the plasma concentration–time curve (AUC) of rivaroxaban (10 mg single dose) is increased by 2.27-fold, which is paralleled by an increase in FXa inhibition. The AUC of apixaban (5 mg single dose) is increased by 1.09-fold, whereas the AUC of edoxaban (15 mg single dose) is decreased by 4.8 % and the AUC of dabigatran (150 mg single dose) is decreased by 5.6 %. Specific labelling restrictions for rivaroxaban, apixaban and dabigatran regarding impaired hepatic function are based on both the Child-Pugh classification and liver-related exclusion criteria applied in pivotal clinical trials. Rivaroxaban is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk, including cirrhotic patients classified as Child-Pugh B and C. Apixaban can be used with caution in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment or in patients with alanine aminotransferase and aspartate aminotransferase levels >2× upper limit of normal (ULN). Apixaban is not recommended in patients with severe hepatic impairment and is contraindicated in those with hepatic disease associated with coagulopathy and clinically relevant bleeding risk. Dabigatran is not recommended in patients with elevated liver enzymes (>2× ULN). Dabigatran is contraindicated in patients with hepatic impairment or liver disease expected to have any impact on survival. Currently, edoxaban is not available in the US or European markets. However, the Japanese label did not restrict use in hepatic dysfunction but advises care in patients with severe hepatic impairment.

Based on a PubMed search of the literature using the terms parecoxib, platelets, thromboxane, bleeding, and platelet aggregation, the effects of parecoxib on platelet function have not fully been established under clinical conditions. The aim of this study was to determine platelet aggregation, thromboxane B 2 (TxB 2) formation, and plasma concentrations with the use of parecoxib in postoperative pain management. This double-blind, randomized, parallelgroup trial was conducted at the University Hospital for Orthopedic Surgery, Friedrichsheim, Frankfurt, Germany. Male and female patients aged 18 to 55 years and scheduled to undergo routine partial meniscectomy (or a similar arthroscopic procedure) were eligible. All patients received dose-adjusted enoxaparin before surgery and parecoxib 40 mg BID or dipyrone 1000 mg QID. Blood samples were drawn before first injection (predose) and at 0.5, 2, and 6 hours after injection. Platelet aggregation (expressed as percentage of the maximal light transmittance [A max]) was induced with arachidonic acid (A maxAA) and collagen (A maxCO). TxB 2 formation was determined using enzyme-linked immunosorbent assay. This study included 26 patients. In both treatment groups, 8 males and 5 females, all white, were enrolled. In the dipyrone group, the mean age was 48 years (range, 32–61 years) and the mean weight was 85 kg (range, 63–122 kg); in the parecoxib group, the mean age was 47 years (range, 31–61 years) and the mean weight was 81 kg (range, 57–100 kg). Median (interquartile range [IQR]) predose values for A maxAA were 76% (65%–83%) in the parecoxib group and 87% (80%–89%) in the dipyrone group. At 0.5 hour after injection, A maxAA was 52% (5%–77%) with parecoxib and 8% (0%–11%) with dipyrone ( P = 0.004). At 2 hours after injection, A maxAA was 78% (72%–80%) in the parecoxib group versus 7% (5%–11%) in the dipyrone group ( P < 0.001). At 6 hours after study drug administration, no treatment differences were found. For A maxCO, no statistically significant differences were found. Consistent with the stronger inhibition of aggregation, patients who received dipyrone had lower TxB 2 formation values. Six hours after parecoxib administration, mean TxB 2 formation was significantly enhanced compared with predose values (132 ng/mL [IQR, 62–228 ng/mL] vs 185 ng/mL [IQR, 135–239 ng/mL]; P = 0.05). Platelet aggregation and TxB 2 formation were significantly lower for 6 hours in dipyronetreated patients compared with parecoxib-treated patients. In contrast, TxB 2 formation was increased with parecoxib 6 hours after administration compared with pretreatment values. In this small study, parecoxib did not affect platelet aggregation in a population of patients undergoing routine partial meniscectomy (or a similar arthroscopic procedure) under clinical conditions.

The clinical consequences of defects in C1 inhibitor function can be serious. A series of advances have improved the outlook for patients with hereditary angioedema. The latest development is an effective oral kallikrein inhibitor that reduces the attack rate by nearly 75%.

Introduction Glycoprotein VI (GPVI) is the major platelet receptor for collagen-mediated platelet adhesion and activation. SAR264565 is an anti-GPVI-Fab, binds to GPVI with high affinity, and blocks GPVI function in human platelets in vitro. Methods The effect of SAR26456 on platelet responsiveness in the blood of 21 healthy male subjects was investigated using Sakariassen’s ex vivo thrombogenesis perfusion chamber model on a collagen-coated surface under conditions mimicking arterial flow. Ex vivo effects of SAR264565 (10 and 100 μg/mL) were investigated before administration of aspirin or clopidogrel to study subjects (baseline), after aspirin (2× 300 mg) administration alone, and after combined aspirin (2× 300 mg)/clopidogrel (600 mg) administration. Additional ex vivo and in vitro platelet tests were also performed. Results Addition of SAR264565 to the perfusion chamber dose-dependently reduced platelet and fibrin deposition, reaching statistical significance at 100 μg/mL (415 ± 67 compared to 137 ± 36 platelets/cm 2 , [ p  < 0.01] and fibrin 0.095 ± 0.014 compared to 0.032 ± 0.008 μg/cm 2 , [ p  < 0.001]). Aspirin administration caused an additive and dose-dependent reduction of SAR264565-induced platelet and fibrin deposition. Combined aspirin/clopidogrel administration did not lead to additional SAR264565-induced inhibition of platelet or fibrin deposition. Conclusion GPVI antagonism by the anti-GPVI-Fab fragment SAR264565 dose-dependently inhibits platelet adhesion and fibrin formation on a collagen surface under arterial shear. Additive inhibition is observed after prior aspirin administration with no further amplification on top of a combination of aspirin with clopidogrel. Ex vivo antiplatelet tests confirmed a selective inhibiting effect of SAR264565 on collagen-induced platelet activation.

Background Certain disadvantages of the standard hematopoietic stem and progenitor cell (HSPC) mobilizing agent G-CSF fuel the quest for alternatives. We herein report results of a Phase I dose escalation trial comparing mobilization with a peptidic CXCR4 antagonist POL6326 (balixafortide) vs. G-CSF. Methods Healthy male volunteer donors with a documented average mobilization response to G-CSF received, following ≥6 weeks wash-out, a 1–2 h infusion of 500–2500 µg/kg of balixafortide. Safety, tolerability, pharmacokinetics and pharmacodynamics were assessed. Results Balixafortide was well tolerated and rated favorably over G-CSF by subjects. At all doses tested balixafortide mobilized HSPC. In the dose range between 1500 and 2500 µg/kg mobilization was similar, reaching 38.2 ± 2.8 CD34 + cells/µL (mean ± SEM). Balixafortide caused mixed leukocytosis in the mid-20 K/µL range. B-lymphocytosis was more pronounced, whereas neutrophilia and monocytosis were markedly less accentuated with balixafortide compared to G-CSF. At the 24 h time point, leukocytes had largely normalized. Conclusions Balixafortide is safe, well tolerated, and induces efficient mobilization of HSPCs in healthy male volunteers. Based on experience with current apheresis technology, the observed mobilization at doses ≥1500 µg/kg of balixafortide is predicted to yield in a single apheresis a standard dose of 4× 10E6 CD34+ cells/kg from most individuals donating for an approximately weight-matched recipient. Exploration of alternative dosing regimens may provide even higher mobilization responses. Trial Registration European Medicines Agency (EudraCT-Nr. 2011-003316-23) and clinicaltrials.gov (NCT01841476)

Purpose – This article reports on the findings of the Best Innovator competition, which was launched in Germany in 2003, to identify and communicate the best practices of innovation management of the country’s businesses. After ten years of research, the contest has not only been expanded to identify the most innovative companies in much of the developed world but also to document the success of their best practices over time. Design/methodology/approach – This article details five tested sets of best practices. Findings – A major research finding is the strong correlation between superior innovation management capabilities and sustainable, profitable growth. Another finding was that, given the mix of industries, the diversity of businesses and the range of sizes in the Best Innovator club, it is striking that there is no correlation between R&D budget and innovation. Practical implications – Best Innovators first develop and then manage their innovation portfolios. All of them pursue clarity on a fundamental question: what do we want our innovation strategy to do for us? Originality/value – The researchers found that to get their innovation strategies right, Best Innovators invest upfront in understanding market, technology and service dynamics. They are investing time more than money. Leaders can learn how Best Innovators address innovation management “from the market to the market” and manipulate five areas to improve their innovation performance and propel sustainable and profitable growth.

Purpose – The authors have collected key insights from the Best Innovator competition, launched in 2003. Six early-stage practices are critical. Design/methodology/approach – The Best Innovator competition, annual benchmarking against the best in innovation management, focuses on the how-to of innovation and examines what leading companies are doing to achieve better yield with their innovation strategies. Findings – By studying the competition winners, the researchers found a strong correlation between specific innovation management practices and sustainable, profitable growth. Practical implications – Best Innovators establish explicit expectations for making the business case for innovation. They name a specific set of deliverables to which they are committed. Originality/value – The article offers specific guidelines for setting the stage for continuous innovation that results in profitable offerings and services.

We have recently shown that in polymorphonuclear leukocytes, 11‐keto boswellic acids (KBAs) induce Ca2+ mobilisation and activation of mitogen‐activated protein kinases (MAPK). Here we addressed the effects of BAs on central signalling pathways in human platelets and on various platelet functions. We found that β‐BA (10 μM), the 11‐methylene analogue of KBA, caused a pronounced mobilisation of Ca2+ from internal stores and induced the phosphorylation of p38 MAPK, extracellular signal‐regulated kinase (ERK)2, and Akt. These effects of β‐BA were concentration dependent, and the magnitude of the responses was comparable to those obtained after platelet stimulation with thrombin or collagen. Based on inhibitor studies, β‐BA triggers Ca2+ mobilisation via the phospholipase (PL)C/inositol‐1,4,5‐trisphosphate pathway, and involves Src family kinase signalling. Investigation of platelet functions revealed that β‐BA (10 μM) strongly stimulates the platelet‐induced generation of thrombin in an ex‐vivo in‐vitro model, the liberation of arachidonic acid (AA), and induces platelet aggregation in a Ca2+‐dependent manner. In contrast to β‐BA, the 11‐keto‐BAs (KBA or AKBA) evoke only moderate Ca2+ mobilisation and activate p38 MAPK, but fail to induce phosphorylation of ERK2 or Akt, and do not cause aggregation or significant generation of thrombin. In summary, β‐BA potently induces Ca2+ mobilisation as well as the activation of pivotal protein kinases, and elicits functional platelet responses such as thrombin generation, liberation of AA, and aggregation. British Journal of Pharmacology (2005) 146, 514–524. doi:10.1038/sj.bjp.0706366

We have recently shown that in polymorphonuclear leukocytes, 11-keto boswellic acids (KBAs) induce Ca2+ mobilisation and activation of mitogen-activated protein kinases (MAPK). Here we addressed the effects of BAs on central signalling pathways in human platelets and on various platelet functions. We found that beta-BA (10 microM), the 11-methylene analogue of KBA, caused a pronounced mobilisation of Ca2+ from internal stores and induced the phosphorylation of p38 MAPK, extracellular signal-regulated kinase (ERK)2, and Akt. These effects of beta-BA were concentration dependent, and the magnitude of the responses was comparable to those obtained after platelet stimulation with thrombin or collagen. Based on inhibitor studies, beta-BA triggers Ca2+ mobilisation via the phospholipase (PL)C/inositol-1,4,5-trisphosphate pathway, and involves Src family kinase signalling. Investigation of platelet functions revealed that beta-BA (> or =10 microM) strongly stimulates the platelet-induced generation of thrombin in an ex-vivo in-vitro model, the liberation of arachidonic acid (AA), and induces platelet aggregation in a Ca2+-dependent manner. In contrast to beta-BA, the 11-keto-BAs (KBA or AKBA) evoke only moderate Ca2+ mobilisation and activate p38 MAPK, but fail to induce phosphorylation of ERK2 or Akt, and do not cause aggregation or significant generation of thrombin. In summary, beta-BA potently induces Ca2+ mobilisation as well as the activation of pivotal protein kinases, and elicits functional platelet responses such as thrombin generation, liberation of AA, and aggregation.