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The anticoagulant edoxaban, an oral inhibitor of activated factor X, does not require monitoring. As initial treatment for acute venous thromboembolism, heparin–edoxaban was noninferior to heparin–warfarin and caused less bleeding. Venous thromboembolism is the third most common cardiovascular disease after myocardial infarction and stroke, affecting at least 700,000 persons annually in North America. 1 – 3 The standard treatment consists of low-molecular-weight heparin followed by vitamin K antagonists. 4 A number of studies have established that new oral anticoagulants with or without initial heparin therapy are effective alternatives. 5 – 8 Edoxaban is a direct inhibitor of activated factor X with a rapid onset of action. It is administered orally once daily and has proven antithrombotic efficacy. 9 – 11 The Hokusai-VTE study was a randomized, double-blind clinical trial that was conducted to evaluate edoxaban for the . . .

This trial compared genotype-guided dosing with standard dosing in patients with atrial fibrillation or venous thromboembolism initiating warfarin anticoagulation. Genotype-guided dosing was associated with a higher percentage of time in the therapeutic INR range of 2.0 to 3.0. Warfarin has proved to be effective in the management of thromboembolic disease 1 but has a narrow therapeutic index, with wide variation among patients in the daily doses required; this variation can lead to either excessive or insufficient anticoagulation. 2 An increase in the international normalized ratio (INR) above the therapeutic range confers a predisposition to bleeding, 3 which is a common cause of hospital admission. 4 Polymorphisms in two genes, CYP2C9 (involved in the metabolism of the pharmacologically more potent S -enantiomer of warfarin) and VKORC1 (involved in the vitamin K cycle), 5 , 6 together with age and body-surface area, account for about 50% . . .

In this trial, 1015 patients were assigned to the use of either a genotype-guided algorithm or a clinically guided algorithm for warfarin dosing during the first 5 days. At 4 weeks, there was no significant difference in the percentage of time in the therapeutic INR range. The need for clinical trials before widespread adoption of genotype-guided drug dosing and selection remains widely debated. 1 – 4 Warfarin therapy has served as a model for the potential for pharmacogenetics to improve patient care. 1 Observational studies have identified two genes, CYP2C9 and VKORC1, that are associated with variation in warfarin maintenance doses. However, the clinical utility of starting warfarin at the maintenance dose predicted by genotype-guided algorithms has been tested only in small trials, none of which were definitive. 5 – 8 In contrast, observational studies have suggested potential benefits from genotype-guided dosing. 9 , 10 In addition, previous clinical trials could not determine . . .

In a phase 2 trial, patients with mechanical heart valves were randomly assigned to receive either dabigatran or warfarin for anticoagulation. Dabigatran was associated with higher rates of ischemic stroke (5%, vs. 0% with warfarin) and major bleeding (4% vs. 2%). Prosthetic heart-valve replacement is recommended for many patients with severe valvular heart disease and is performed in several hundred thousand patients worldwide each year. 1 Mechanical valves are more durable than bioprosthetic valves 2 but typically require lifelong anticoagulant therapy. The use of vitamin K antagonists provides excellent protection against thromboembolic complications in patients with mechanical heart valves 3 but requires restrictions on food, alcohol, and drugs and lifelong coagulation monitoring. Because of the limitations of vitamin K antagonists, many patients opt for a bioprosthesis rather than a mechanical valve, despite the higher risk of premature valve failure requiring repeat valve-replacement surgery with . . .

In a randomized trial, 2218 patients with STEMI were assigned to prehospital treatment with either bivalirudin or heparin with optional glycoprotein IIb/IIIa inhibitors. At 30 days, the bivalirudin group had significantly less major bleeding than the heparin group. Primary percutaneous coronary intervention (PCI), which is the standard of care for the treatment of patients with ST-segment elevation myocardial infarction (STEMI), 1 , 2 requires adjunctive antithrombotic treatment with anticoagulants and antiplatelet agents. In the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial, 3 bivalirudin (Angiomax, Angiox, the Medicines Company), as compared with unfractionated heparin and routine use of glycoprotein IIb/IIIa inhibitors, reduced rates of major bleeding and death at 30 days, with a survival benefit that extended to 3 years, 4 albeit with an increased rate of acute stent thrombosis. A number of changes have occurred in clinical . . .

Abstract Rationale The biological mechanisms linking air pollution to cardiovascular events still remain largerly unclear. Objectives To investigate whether biological mechanisms linking air pollution to cardiovascular events occurred concurrently in human subjects exposed to urban air pollutants. Methods We recruited a panel of 76 young, healthy students from a university in Taipei. Between April and June of 2004 or 2005, three measurements were made in each participant of high-sensitivity C-reactive protein (hs-CRP), 8-hydroxy-2′-deoxyguanosine (8-OHdG), plasminogen activator fibrinogen inhibitor-1 (PAI-1), tissue-type plasminogen activator (tPA) in plasma, and heart rate variability (HRV). Gaseous air pollutants were measured at one air-monitoring station inside their campus, and particulate air pollutants were measured at one particulate matter supersite monitoring station 1 km from their campus. We used linear mixed-effects models to associate biological endpoints with individual air pollutants averaged over 1- to 3-day periods before measurements were performed. Measurements and Main Results We found that increases in hs-CRP, 8-OHdG, fibrinogen, and PAI-1, and decreases in HRV indices were associated with increases in levels of particles with aerodynamic diameters less than 10 μm and 2.5 μm, sulfate, nitrate, and ozone (O3) in single-pollutant models. The increase in 8-OHdG, fibrinogen, and PAI-1, and the reduction in HRV remained significantly associated with 3-day averaged sulfate and O3 levels in two-pollutant models. There were moderate correlations (r = -0.3) between blood markers of hs-CRP, fibrinogen, PAI-1, and HRV indices. Conclusions Urban air pollution is associated with inflammation, oxidative stress, blood coagulation and autonomic dysfunction simultaneously in healthy young humans, with sulfate and O3 as two major traffic-related pollutants contributing to such effects.

Abstract Rationale Idiopathic pulmonary fibrosis (IPF) is a devastating disease. Antiinflammatory therapies, including corticosteroids, are of no benefit. The role of monocytes and macrophages is therefore controversial. Objectives To define the role of monocytes and macrophages during lung fibrogenesis and resolution, and explore the phenotype of the cells involved. Methods We used multiple in vivo depletional strategies, backed up by adoptive transfer techniques. Further studies were performed on samples from patients with IPF. Measurements and Main Results Depletion of lung macrophages during fibrogenesis reduced pulmonary fibrosis as measured by lung collagen (P = 0.0079); fibrosis score (P = 0.0051); and quantitative polymerase chain reaction for surrogate markers of fibrosis Col1 (P = 0.0083) and α-smooth muscle actin (P = 0.0349). There was an associated reduction in markers of the profibrotic alternative macrophage activation phenotype, Ym1 (P = 0.0179), and Arginase1. The alternative macrophage marker CD163 was expressed on lung macrophages from patients with IPF. Depletion of Ly6Chi circulating monocytes reduced pulmonary fibrosis (P = 0.0052) and the number of Ym1-positive alternatively activated lung macrophages (P = 0.0310). Their adoptive transfer during fibrogenesis exacerbated fibrosis (P = 0.0304); however, adoptively transferred CD45.1 Ly6Chi cells were not found in the lungs of recipient CD45.2 mice. Conclusions We demonstrate the importance of circulating monocytes and lung macrophages during pulmonary fibrosis, and emphasize the importance of the alternatively activated macrophage phenotype. We show that Ly6Chi monocytes facilitate the progression of pulmonary fibrosis, but are not obviously engrafted into lungs thereafter. Finally, we provide empirical data to suggest that macrophages may have a resolution-promoting role during the reversible phase of bleomycin-induced pulmonary fibrosis.

Inflammation is a highly dynamic and complex adaptive process to preserve and restore tissue homeostasis. Originally viewed as an immune-privileged organ, the central nervous system (CNS) is now recognized to have a constant interplay with the innate and the adaptive immune systems, where resident microglia and infiltrating immune cells from the periphery have important roles. Common diseases of the CNS, such as stroke, multiple sclerosis (MS), and neurodegeneration, elicit a neuroinflammatory response with the goal to limit the extent of the disease and to support repair and regeneration. However, various disease mechanisms lead to neuroinflammation (NI) contributing to the disease process itself. Molecular imaging is the method of choice to try to decipher key aspects of the dynamic interplay of various inducers, sensors, transducers, and effectors of the orchestrated inflammatory response in vivo in animal models and patients. Here, we review the basic principles of NI with emphasis on microglia and common neurologic disease mechanisms, the molecular targets which are being used and explored for imaging, and molecular imaging of NI in frequent neurologic diseases, such as stroke, MS, neurodegeneration, epilepsy, encephalitis, and gliomas.

Ultralow molecular weight (ULAAW) heparins are sulfated glycans that are clinically used to treat thrombotic disorders. ULMW heparins range from 1500 to 3000 daltons, corresponding from 5 to 10 saccharide units. The commercial drug Arixtra (fondaparinux sodium) is a structurally homogeneous ULMW heparin pentasaccharide that is synthesized through a lengthy chemical process. Here, we report 10- and 12-step chemoenzymatic syntheses of two structurally homogeneous ULMW heparins (MW = 1778.5 and 1816.5) in 45 and 37% overall yield, respectively, starting from a simple disaccharide. These ULMW heparins display excellent in vitro anticoagulant activity and comparable pharmacokinetic properties to Arixtra, as demonstrated in a rabbit model. The chemoenzymatic approach is scalable and shows promise for a more efficient route to synthesize this important class of medicinal agent.

A genotype-guided dosing algorithm was compared with a clinical dosing algorithm in patients starting anticoagulation with acenocoumarol or phenprocoumon. There was no difference between the two groups in the percentage of time in the therapeutic INR range of 2.0 to 3.0. Coumarin anticoagulant agents such as acenocoumarol, phenprocoumon, and warfarin are frequently used for the prevention of stroke in patients with atrial fibrillation or for the treatment and prevention of venous thromboembolism. 1 In many countries, warfarin is used most frequently, but in some countries, acenocoumarol or phenprocoumon is prescribed. 2 Coumarin anticoagulant drugs have a narrow therapeutic window, and there are large interpatient and intrapatient variations in the dose requirement. The anticoagulant effect of these drugs is monitored by means of regular measurement of the international normalized ratio (INR). 3 A subtherapeutic INR is associated with an increased risk of stroke or thromboembolism, . . .