Developing Antidote Controlled Antiplatelet Therapies By Targeting The Vwf ‐ Gp Ib‐Ix‐V Interaction

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106054/1/jth02400.pd

Evaluation of MR/fluoroscopy-guided portosystemic shunt creation in a swine model

PURPOSE: To evaluate three different percutaneous portosystemic shunts created with magnetic resonance (MR) imaging and fluoroscopy guidance in a swine model. MATERIALS AND METHODS: In stage 1 of the experiment, an active MR intravascular needle system was created for needle tracking and extracaval punctures. Twenty inferior vena cava (IVC)/superior mesenteric vein (SMV)/portal vein (PV) punctures were performed in 10 swine (weight, 40-45 kg) in a 1.5-T short-bore interventional MR imager. With use of a real-time MR imaging sequence, the needle was guided through the IVC and into the SMV or PV (N = 20 punctures). After confirmation, a wire was advanced into the portal venous system under MR imaging guidance (N = 20). In stage 2, animals were transferred to the radiographic fluoroscopy suite for deployment of shunts. Three different shunts were evaluated in this study: (i) a commercial stent-graft, (ii) a prototype bridging stent, and (iii) a prototype nitinol vascular anastomotic device. Postprocedural necropsy was performed in all animals. RESULTS: Successful MR-guided IVC/SMV punctures were performed in all 20 procedures (100%). All three shunts were deployed. Stent-grafts had the poorest mechanism for securing a shunt. The vascular anastomotic device and the bridging stent had more secure anchoring mechanisms but also had higher technical failure rates (50% and 40%, respectively). When deployed successfully, the vascular anastomotic device resulted in no bleeding at the sites of punctures at necropsy. CONCLUSION: Percutaneous shunts and vascular anastomoses between the portal mesenteric venous system and IVC were successfully created with use of a combination of MR imaging and conventional fluoroscopy for guidance. © SIR, 2006

Visible light-mediated photocatalytic oxidative cleavage of activated alkynes via hydroamination: a direct approach to oxamates

The direct oxidative cleavage of activated alkynes via hydroamination has been described using organic photocatalyst under visible-light irradiation at room temperature. In this reaction, the single electron oxidation of an in situ formed enamine followed by radical coupling with an oxidant finally delivers the oxamate. The key features of this photocatalytic reaction are the mild reaction conditions, metal-free organic dye as a photocatalyst, and TBHP playing a dual role as "O" source and for the regeneration of the photocatalyst. This journal is © The Royal Society of Chemistry

Clinical relevance of heparin-PF4 complex antibody in DVT after total joint replacement

<p>Abstract</p> <p>Background</p> <p>Antibodies to the heparin-platelet factor-4 (HPF-4) complex (HIT antibodies) have been observed in patients with heparin-induced thrombocytopenia (HIT). These antibodies are thought to be involved in thrombosis through activation of platelet/endothelial cells. This prospective study was conducted to determine the incidence of post-operative HIT antibodies to assess the associated risk of deep vein thrombosis (DVT) in patients undergoing total knee arthroplasty (TKA) or total hip arthroplasty (THA).</p> <p>Methods</p> <p>We studied 104 patients who underwent unilateral primary TKA (n = 44) and primary THA (n = 60) with short-duration prophylaxis (1–2 days of a fixed dose of unfractionated heparin). HIT antibodies were assayed using a sandwich-type ELISA before the operation and after heparin treatment (post-operative day 7).</p> <p>Results</p> <p>In the clinical outcome, the incidence of symptomatic DVT was 15.4% (16/104, TKA; 10, THA 6) and pulmonary embolism (PE) was not observed. The total seroconversion rate of HIT antibodies at post-operative day 7 was 34.6% (36/104). Among 36 seroconverted patients, 11 (30.6%) developed symptomatic DVT and 5 out of 68 of the non-seroconverted patients (7.4%) developed symptomatic DVT. The incidence for DVT was significantly higher in the seroconverted patients compared with that of the non-seroconverted patients (odds ratio 5.5, 95%CI: 1.7–17.6 <it>p </it>= 0.0028). Furthermore, in the patients with symptomatic DVT, the titer of HIT antibodies at post-operative day 7 was significantly higher compared with those without symptomatic DVT.</p> <p>Conclusion</p> <p>Our data therefore suggest that seroconversion for HIT antibodies generated by heparin is associated with a risk of DVT in patients undergoing total joint replacement.</p

Oral Thromboprophylaxis Following Total Hip or Knee Replacement: Review and Multicentre Experience with Dabigatran Etexilate

The risk of venous thromboembolism (VTE) in patients undergoing total knee or hip replacement surgery is high. As a result, thromboprophylaxis is highly recommended. While current thromboprophylactic agents, such as low molecular weight heparins (LMWH) and vitamin K antagonists, are safe and effective their use can be problematic. Therefore, there is a need for alternative anticoagulants that are as safe and effective as conventional agents, but are more convenient and easier to use. Dabigatran etexilate, a direct thrombin inhibitor, is one such anticoagulant. For VTE prevention following major orthopaedic surgery, dabigatran etexilate shows similar efficacy and safety to the LMWH enoxaparin, and is approved for use in more than 75 countries, including Europe and Canada. Here, we summarize and discuss the experiences of four German clinics that have recently introduced dabigatran etexilate into clinical practice. Overall, dabigatran etexilate was well received by patients, surgeons and nurses, and compared favourably with enoxaparin. Staff appreciated the oral, single-dose administration of dabigatran etexilate. Patient satisfaction was high, especially in those individuals who had previously used LMWHs. In this review, we also address a number of questions that were asked by patients or staff; this will be of relevance to orthopaedic surgeons and nurses. We conclude that, in these four German clinics, dabigatran etexilate offered an effective oral alternative to existing thromboprophylactic agents in patients undergoing major orthopaedic surgery

MR fluoroscopy in vascular and cardiac interventions (review)

Vascular and cardiac disease remains a leading cause of morbidity and mortality in developed and emerging countries. Vascular and cardiac interventions require extensive fluoroscopic guidance to navigate endovascular catheters. X-ray fluoroscopy is considered the current modality for real time imaging. It provides excellent spatial and temporal resolution, but is limited by exposure of patients and staff to ionizing radiation, poor soft tissue characterization and lack of quantitative physiologic information. MR fluoroscopy has been introduced with substantial progress during the last decade. Clinical and experimental studies performed under MR fluoroscopy have indicated the suitability of this modality for: delivery of ASD closure, aortic valves, and endovascular stents (aortic, carotid, iliac, renal arteries, inferior vena cava). It aids in performing ablation, creation of hepatic shunts and local delivery of therapies. Development of more MR compatible equipment and devices will widen the applications of MR-guided procedures. At post-intervention, MR imaging aids in assessing the efficacy of therapies, success of interventions. It also provides information on vascular flow and cardiac morphology, function, perfusion and viability. MR fluoroscopy has the potential to form the basis for minimally invasive image–guided surgeries that offer improved patient management and cost effectiveness

Stereoselective Aminoiodination of Activated Alkynes with Organoiodine(III) Reagents and Amines via Multiple-Site Functionalization: Access to Iodinated Enamines and N -Aryl Indoles

A stereoselective aminoiodination of activated alkynes with PhI(OAc)2 and amines via multiple‐site functionalization to afford (Z)diethyl 2‐(diphenylamino)‐3‐iodomaleate derivatives with superior yields has been described. The key feature of this reaction is the incorporation of iodide and aryl group concurrently in the same molecule in a stereoselective manner by employing PhI(OAc)2 as electrophilic reagent as well as iodide and aryl group source. The high stereoselectivity of the reaction can be explained based on the structure of the possible intermediates, the conformations of which controlled by the hydrogen bonding, steric hindrance and electrostatic attractions. This reaction proceeds under mild conditions, providing various dialkyl 2‐(diphenylamino)‐3‐iodomaleates by a single operation starting from activated alkynes. The robustness of our strategy is revealed by making of bis [dialkyl 2‐(diphenylamino)‐3‐iodomaleate] derivatives involving formation of four new C‐N bonds and two C–I bonds in a single step. The synthesized inactive 3° enamines [dialkyl 2‐(diphenylamino)‐3‐iodomaleates] could be further transformed into highly substituted indoles via Pd catalyzed C–H and C–I activation under non‐acidic conditions

Nickel-Catalyzed Aerobic Oxidative Isocyanide Insertion: Access to Benzimidazoquinazoline Derivatives via Sequential Double Annulation Cascade (SDAC) strategy

An efficient protocol for the synthesis of quinazoline derivatives through nickel-catalyzed ligand/base-free oxidative isocyanide insertion under aerobic conditions with intramolecular bis-amine nucleophiles has been developed. A one-pot sequential double annulation cascade (SDAC) strategy involving an opening of isatoic anhydride and annulation to benzimidazole and further nickel-catalyzed intramolecular isocyanide insertion has also been demonstrated. The method is operationally simple to implement with wide substrates and represents a new approach for multiple C-N bond formations. The methodology has been successfully applied for the syntheses of hitherto unreported imidazo fused benzimidazoquinazoline via deprotection-GBB reaction sequence. Further, the florescence study reveals the potential of the present strategy for discovery of highly fluorescent probes