Perioperative Bridging Therapy with Enoxaparin in Patients Requiring Interruption of Long-Term Oral Anticoagulant Therapy: A Multicenter Cohort Study.

作者: Turpie, A.G.G. ; Spyropolos, A.C. ; Dunn, A.S. ; Sirko, S.P.

AbstractIntroduction The interruption of long-term oral anticoagulant (OAC) therapy for surgery or other invasive procedures puts patients at increased risk of thromboembolic events. Perioperative ‘bridging’ anticoagulant therapy may reduce this risk; however, the efficacy and safety has not been established. We tested the hypothesis that once daily enoxaparin is a safe and efficacious perioperative bridging therapy in patients on long-term OACs for high-risk atrial fibrillation or prior DVT.Methods This prospective, multicenter, cohort study included 283 patients requiring bridging therapy due to major or minor surgery or an invasive procedure. Procedures were categorized as major surgery (defined as surgery lasting ≥1 hour), minor surgery or invasive procedures. Warfarin was discontinued 5 days prior to the procedure. Enoxaparin (1.5 mg/kg once daily) was started 3 days prior to, and continued until the morning before, the procedure. Warfarin was restarted the evening of the procedure and enoxaparin was reinitiated 12–24 hours post-procedure and continued until the INR was therapeutic. The primary efficacy endpoint was the incidence of thromboembolism from warfarin cessation to 28 days post-procedure. The primary safety endpoint was incidence of major hemorrhage from first dose of enoxaparin until 24 hours after the last dose. A subgroup analysis of the risk of major hemorrhage for the major surgery, minor surgery, and invasive procedure groups was performed.Results A total of 260 patients received enoxaparin (intention-to-treat group). Of these, 81 (31.2%) were receiving OAC therapy for DVT, 176 (67.7%) for atrial fibrillation, 15 (5.8%) for both, and 3 (1.1%) for other reasons. Thromboembolic events occurred in 4 patients (1.5%): 1 pulmonary embolism (during the warfarin follow-up period) in a patient with prior DVT (1/96; 1.0%), and 3 arterial events (1 peripheral arterial thromboembolism and 2 transient ischemic attacks) in atrial fibrillation patients (3/176; 1.7%). Major hemorrhages occurred in 3.5% (9/260) of the patients (table). All except 1 major hemorrhage occurred in patients undergoing major surgery (8/37; 21.6%). None of the hemorrhages were intracranial, retroperitoneal, or intraocular, were fatal, or required intervention.Conclusion Use of enoxaparin in accordance with the bridging regimen described is feasible and safe in patients undergoing minor surgery or an invasive procedure. Most major hemorrhages occurred in patients undergoing major surgery. Further studies are needed to optimize bridging therapy with enoxaparin in patients undergoing major surgery.Intervention (n*) Major surgery (37) Minor surgery (68) Invasive procedure (145) *Ten patients in the ITT population received enoxaparin but did not undergo the procedure.†Bleeding with a decrease in Hbg ≥3 g/dL (transfusion of any units of RBC or whole blood = 1 g/dL decrease in Hbg); transfusion of ≥2 units of blood products; intracranial, retroperitoneal, or intraocular hemorrhage; hemorrhage requiring intervention or resulting in death. Bleeding not classified as major hemorrhage was defined as minor. Major hemorrhages† (%) 8 (21.6%) - 1 (0.7%) Procedure associated with major hemorrhage (hemorrhages/procedures performed TKR (4/6), THR (1/4), Abdominal hernia repair (1/1), Abdominal stent (1/1), Aortofemoral construction (1/1) - Colonoscopy (1/38) Venous thromboembolism (%) 1 (2.7%) - - Arterial thromboembolism (%) 2 (5.4%) - 1 (0.7%)

2004-03-01·American Journal of Therapeutics4区 · 医学

Pharmacoscintigraphic Comparison of HMR 1031, a VLA-4 Antagonist, in Healthy Volunteers Following Delivery Via a Nebulizer and a Dry Powder Inhaler

4区 · 医学

Article

作者: Kirkesseli, Stephane ; Jensen, Bradford K ; Shah, Bharti ; Wellington, Sheree ; Newman, Stephen ; Wray, H ; Randall, Linda ; Rohatagi, Shashank ; Zhang, Jie ; Paccaly, Dominique ; Chapel, Sunny

A pharmacoscintigraphic study was conducted to compare the dose deposition of HMR 1031 from the existing nebulizer formulation and the new Ultrahaler device to help determine the doses for future phase 2 trials. This was a single-dose, open-label, randomized, two-way crossover study in which HMR 1031 (3 mg) was delivered by the Ultrahaler and the Pari LC Star nebulizer to 12 healthy male subjects. For both treatments, the formulations were radiolabeled with technetium-99m pertechnetate such that a maximum of 10 MBq was delivered on each study day. Scintigraphic images were acquired immediately after dosing to estimate the percentage of the dose delivered to the lungs and oropharynx. Serial plasma samples were collected up to 12 hours post-dose on each occasion and analyzed for HMR 1031 by a LC/MS/MS method with a lower limit of quantitation of 10 pg/mL (0.01 ng/mL). Pharmacokinetic parameters were calculated for HMR 1031 using noncompartmental methods. No serious adverse events were reported. The systemic absorption of HMR 1031 following inhalation administration was relatively rapid, with median T(max) values of 0.5 hours and 1.0 hours post-dose after administration via Ultrahaler and nebulizer, respectively. The mean plasma AUC(0-12) (Ultrahaler, 15.8 ng*h/mL; nebulizer, 11.1 ng*h/mL) and C(max) (Ultrahaler, 4.96 ng/mL; nebulizer, 2.28 ng/mL) values were approximately 42% and 118% higher for the Ultrahaler compared with the nebulizer. The mean terminal half-life of HMR 1031 was similar after administration from both devices (2.91 and 3.18 hours). Based on the scintigraphic data, the lung deposition of HMR 1031 after administration by Ultrahaler (24.6% of the administered dose) was approximately 37% higher compared with the lung deposition from the nebulizer (18.0% of the administered dose). This observation was in agreement with the relative difference in the plasma AUC values achieved after administration of the two formulations. The in vivo results based on the scintigraphic data were also comparable with those from in vitro studies for the Ultrahaler. Based on the ratio of the dose delivered by both the formulations, the required doses for the future Ultrahaler formulation can be predicted.

2001-04-01·Journal of molecular microbiology and biotechnology

Expression and isolation of antimicrobial small molecules from soil DNA libraries.

Article

作者: Phillips, T ; Long, H ; Gilman, M ; Aldredge, T ; Lynch, B A ; August, P R ; Grossman, T H ; Sundaramoorthi, R ; Narula, S ; Tiong, C L ; MacNeil, I A ; Tyler, A ; Holt, D ; Osburne, M S ; Loiacono, K A ; Minor, C

Natural products have been a critically important source of clinically relevant small molecule therapeutics. However, the discovery rate of novel structural classes of antimicrobial molecules has declined. Recently, increasing evidence has shown that the number of species cultivated from soil represents less than 1% of the total population, opening up the exciting possibility that these uncultured species may provide a large untapped pool from which novel natural products can be discovered. We have constructed and expressed in E. coli a BAC (bacterial artificial chromosome) library containing genomic fragments of DNA (5-120kb) isolated directly from soil organisms (S-DNA). Screening of the library resulted in the identification of several antimicrobial activities expressed by different recombinant clones. One clone (mg1.1) has been partially characterized and found to express several small molecules related to and including indirubin. These results show that genes involved in natural product synthesis can be cloned directly from S-DNA and expressed in a heterologous host, supporting the idea that this technology has the potential to provide novel natural products from the wealth of environmental microbial diversity and is a potentially important new tool for drug discovery.

100 项与 Aventis Pharma Japan 相关的药物交易

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100 项与 Aventis Pharma Japan 相关的转化医学

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