Poller, L; Roberts, C; Ibrahim, S;
Based on the results of the previous European Action on Anticoagulation (EAA) multicenter study, a simplified minimum procedure is described for screening the safety and effectiveness of marketed programs for dosage of oral anticoagulant drugs (vitamin K antagonists). The aim was to demonstrate n...... study, that is, 57.5%. The simplified procedure proposed, although not an absolute guide to safety, is designed to screen against gross unreliability of a test program, without the need to repeat a massive clinical endpoint study for each and every program.......Based on the results of the previous European Action on Anticoagulation (EAA) multicenter study, a simplified minimum procedure is described for screening the safety and effectiveness of marketed programs for dosage of oral anticoagulant drugs (vitamin K antagonists). The aim was to demonstrate non...
Hoi Y Tong
Full Text Available There is a strong association between genetic polymorphisms and the acenocoumarol dosage requirements. Genotyping the polymorphisms involved in the pharmacokinetics and pharmacodynamics of acenocoumarol before starting anticoagulant therapy would result in a better quality of life and a more efficient use of healthcare resources. The objective of this study is to develop a new algorithm that includes clinical and genetic variables to predict the most appropriate acenocoumarol dosage for stable anticoagulation in a wide range of patients. We recruited 685 patients from 2 Spanish hospitals and 1 primary healthcare center. We randomly chose 80% of the patients (n = 556, considering an equitable distribution of genotypes to form the generation cohort. The remaining 20% (n = 129 formed the validation cohort. Multiple linear regression was used to generate the algorithm using the acenocoumarol stable dosage as the dependent variable and the clinical and genotypic variables as the independent variables. The variables included in the algorithm were age, weight, amiodarone use, enzyme inducer status, international normalized ratio target range and the presence of CYP2C9*2 (rs1799853, CYP2C9*3 (rs1057910, VKORC1 (rs9923231 and CYP4F2 (rs2108622. The coefficient of determination (R2 explained by the algorithm was 52.8% in the generation cohort and 64% in the validation cohort. The following R2 values were evaluated by pathology: atrial fibrillation, 57.4%; valve replacement, 56.3%; and venous thromboembolic disease, 51.5%. When the patients were classified into 3 dosage groups according to the stable dosage (21 mg/week, the percentage of correctly classified patients was higher in the intermediate group, whereas differences between pharmacogenetic and clinical algorithms increased in the extreme dosage groups. Our algorithm could improve acenocoumarol dosage selection for patients who will begin treatment with this drug, especially in extreme-dosage
... Receptor Blockers Angiotensin-Converting Enzyme (ACE) Inhibitors Antiarrhythmics Antiplatelet Therapy Aspirin Beta-Blockers Blood Thinners Calcium Channel Blockers Digitalis Medicines Diuretics Inotropic Agents Nitrates Statins, Cholesterol-Lowering Medicines Anticoagulants Related terms: ...
Full Text Available In Japan, low-dose rivaroxaban [15 mg QD/10 mg QD for creatinine clearance of 30-49 mL/min] was approved for clinical use in NVAF patients partly because of its unique pharmacokinetics in Japanese subjects. The aim of the study was to determine the anticoagulation intensity of rivaroxaban and its determinant factors in Japanese stroke patients.Consecutive stroke patients with NVAF admitted between July 2012 and December 2013 were studied. Prothrombin time (PT, activated partial thromboplastin time (aPTT, and estimated plasma concentration of rivaroxaban (Criv based on an anti-factor Xa chromogenic assay were measured just before and 4 and 9 h after administration at the steady state level of rivaroxaban. Determinant factors for Criv were explored using a linear mixed-model approach.Of 110 patients (37 women, 75±9 years old, 59 took 15 mg QD of rivaroxaban and 51 took 10 mg QD. Criv at 4 h was 186 ng/mL for patients taking 15 mg QD and 147 ng/mL for those taking 10 mg QD. Both PT and aPTT were positively correlated with Criv. Criv was 72% lower at 4 h in 15 patients receiving crushed tablets than in the other patients, and tablet crushing was significantly associated with lower Criv (adjusted estimate -0.43, 95% CI -0.60 to -0.26 after multivariate-adjustment.The anticoagulation effects of rivaroxaban in the acute stroke setting for Japanese NVAF patients were relatively low as compared with those in the ROCKET-AF and J-ROCKET AF trials. Tablet crushing, common in dysphagic patients, decreased Criv.
Jiménez, Yolanda; Poveda, Rafael; Gavaldá, Carmen; Margaix, María; Sarrión, Gracia
Oral anticoagulants (OACs) antagonizing vitamin K - fundamentally sodium warfarin and acenocoumarol - are widely used for preventing arterial thromboembolism in patients with atrial fibrillation and/or heart valve prostheses, and for the treatment and prevention of deep venous thrombosis and pulmonary embolism. The handling of these drugs requires correct monitorization and dose adjustment to obtain the desired therapeutic effect while minimizing the adverse effects associated both with excessive anticoagulation (which leads to bleeding) and with insufficient antithrombotic action (which can produce thrombosis). This is particularly important when patients must be subjected to surgical procedures such as tooth extractions. In this context, a number of management recommendations are available. The present study offers an update on the recommendations for the management of anticoagulated patients programmed for tooth extractions. In recent years, most studies do not recommend reducing or interrupting anticoagulation, or replacing it with heparin, prior to tooth extraction - provided therapeutic international normalized ration (INR) levels are maintained, with emphasis on the application of local measures such as antifibrinolytic agents, for the control of hemostasia.
Objectives Warfarin oral anticoagulant therapy (OAT) requires regular and frequent drug adjustment monitored by INR. Interindividual variability, drug and diet interferences, and genetics (VKORC1 and CYP2C9) make the maintenance/reaching of stable INR a not so easy task. HPLC assessment of warfarin/enantiomers was suggested as a valid monitoring-tool along with INR, but definite results are still lacking. We evaluated possible correlations between INR, warfarin/3’-hydroxywarfarin, and drug we...
Although sewer rat control is carried out in more than 80 % of all Danish municipalities, with usage of large amounts of anticoagulant rodenticides, knowledge on anticoagulant resistance among rats living in the sewers is limited. As rat problems in urban areas are believed to be related to sewer...... problems (70-90 % in UK and DK) unawareness of resistance amongst these populations of Brown rats may constitute a future control problem and knowledge on this issue has become crucial. Rats were captured in sewers from seven different locations in the suburban area of Copenhagen. Locations was chosen...... to represent different sewer rat management strategies i) no anticoagulants for approx. 20 years ii) no anticoagulants for the last 5 years and iii) continuous control for many years. Animals were tested for resistance to bromadiolone by Blood-Clotting Response test, as bromadiolone is the most frequently used...
Smokowski, Paul R; Guo, Shenyang; Wu, Qi; Evans, Caroline B R; Cotter, Katie L; Bacallao, Martica
Positive Action (PA) is a school-based intervention for elementary-, middle-, and high-school students that aims to decrease problem behaviors (e.g., violence, substance use) and increase positive behaviors (e.g., academic achievement, school engagement). PA has a long history of documented success achieving these aims, making it an Evidence Based Practice (EBP). Intervention research on EBP's has established the importance of implementation fidelity, especially with regard to program dosage; failure to properly implement an EBP can have negative consequences on targeted outcomes, especially if participants are exposed to a low dosage of the program (e.g., fewer lessons than specified). Much of the current research on PA has neglected to examine how program dosage impacts PA's effect on targeted outcomes. Using propensity score models, multiple imputation, and a 2-level hierarchical linear model, the current study fills this gap and examines how different dosages of PA as measured by years participating in PA and number of PA lessons, impacts adolescent internalizing symptoms, aggression, perceptions of school hassles, and self-esteem over a 3-year period. The current sample included middle school students in grades 6, 7, and 8 (N = 5,894). The findings indicate that students who received 3 years of the PA intervention and a high number of PA lessons had a significantly higher self-esteem score than those who received 0 years of PA or zero lessons. Participants who received 1 year of PA also reported significantly lower school hassle scores than those who received 0 years. Dosage had no statistically significant effects on aggression or internalizing score. Implications are discussed. (PsycINFO Database Record
Since 1960,so far,has half a century,long-term oral vitamin K antagonists (VKA) for anticoagulation main plan,but the shortcomings of the VKA but not allow to ignore:( 1 ) the VKA effect to be slow,VKA after diagnosis should be immediate treatment,this plan have to start with unfractionated heparin (UFH),low molecular weight heparin (LMWH) and fondaparinux injection,use 5 ～ 10 d transition again after oral VKA,this plan for outpatient greatly inconvenience;(2) in the use of heparin drugs there is also monitoring problem during or the occurrence of heparin induction thrombocytopenic thrombosis disease (HITT) risk;(3) VKA treatment vulnerable to food,drugs,to VKA considerations of the interference of the individual differences are of great reaction;(4)VKA treatment window,need to narrow in close monitoring of adjusting dosage benefits under,but the present survey indicates that at least a third of patients with clinically failed to control the INR within the scope of the treatment.So send development new anticoagulants,especially oral anticoagulants listed was imminent
@@ VTE of the main treatment for anticoagulant thera-py, anticoagulant therapy drug of choice for low molecu-lar weight heparin (LMWH) for the overwhelming major-ity of clinicians agree that long-term oral anticoagulant therapy is still Vit. K antagonist (mainly warfarin).
Reyes, Maria Regina; Brackett, Marc A.; Rivers, Susan E.; Elbertson, Nicole A.; Salovey, Peter
This study examined how training, dosage, and implementation quality of a social and emotional learning program, The RULER Approach, were related to students' social and emotional competencies. There were no main effects for any of the variables on student outcomes, but students had more positive outcomes when their teachers (a) attended more…
Full Text Available Implantation of prosthetic valve requires consideration for anticoagulation. The current guideline recommends warfarin on all mechanical valves. Dabigatran is the new generation anticoagulation medication which is taken orally and does not require frequent monitoring. This drug is approved for treatment for atrial fibrillation and venous thromboembolism, but the latest large trial showed that this drug increases adverse events when used for mechanical valve anticoagulation. On-X valve is the new generation mechanical valve which is considered to require less anticoagulation due to its flow dynamics. The latest study showed that lower anticoagulation level lowers the incidence of bleeding, while the risk of thromboembolism and thrombosis remained the same. Anticoagulation poses dilemma in cases such as pregnancy and major bleeding event. During pregnancy, warfarin can be continued throughout pregnancy and switched to heparin derivative during 6–12 weeks and >36 weeks of gestation. Warfarin can be safely started after 1-2 weeks of discontinuation following major bleeding episode.
Full Text Available Management of anticoagulation in elderly patients represents a particularly challenging issue. Indeed, this patient population is at high thromboembolic risk, but also at high hemorrhagic risk. Assessment of the benefit-risk balance of anticoagulation is the key point when decisions are made about introducing and/or continuing such treatments in the individual elderly patient. In order to maximise the safety of anticoagulation in the elderly, some specific considerations need to be taken into account, including renal insufficiency, modified pharmacodynamics of anticoagulants, especially vitamin K antagonists, and the presence of multiple comorbidities and concomitant medications. New anticoagulants could greatly simplify and possibly increase the safety of anticoagulation in the elderly in the near future.
Chih-Wen Cheng; Hang Wu; Thompson, Pamela J; Taylor, Julie R; Zehnbauer, Barbara A; Wilson, Karlyn K; Wang, May D
Patients with certain clotting disorders or conditions have a greater risk of developing arterial or venous clots and downstream embolisms, strokes, and arterial insufficiency. These patients need prescription anticoagulant drugs to reduce the possibility of clot formation. However, historically, the clinical decision making workflow in determining the correct type and dosage of anticoagulant(s) is part science and part art. To address this problem, we developed Anticoagulation Manager, an intelligent clinical decision workflow management system on iOS-based mobile devices to help clinicians effectively choose the most appropriate and helpful follow-up clotting tests for patients with a common clotting profile. The app can provide physicians guidance to prescribe the most appropriate medication for patients in need of anticoagulant drugs. This intelligent app was jointly designed and developed by medical professionals in CDC and engineers at Georgia Tech, and will be evaluated by physicians for ease-of-use, robustness, flexibility, and scalability. Eventually, it will be deployed and shared in both physician community and developer community.
daily anticoagulant therapy. The therapy necessitates close monitoring of coagulant activity, since excess doses of anticoagulant medicine may lead to life-threatening bleedings. Traditionally, patients on OAT are required to pay regular visits to a physician, who decides on drug dosage adjustments...... of the new concept is the training and continuous support and monitoring of the patients, and a center with these purposes has been established at Skejby Sygehus. The main instrument for monitoring the coagulant activity is the prothrombin time (PT). This is the time until clotting can be observed...... central aspects of the INR system, such as the inaccuracy of INR estimates based on a given path of calibrations. The main result states that, under weak regularity conditions, log (log (estimated INR)) is approximately normally distributed with mean log (log (true INR)). The variance is a function...
Full Text Available Background. Hyperthyroidism causes an increased hypoprothrombinemic response to warfarin anticoagulation. Previous studies have demonstrated that patients with hyperthyroidism require lower dosages of warfarin to achieve a therapeutic effect. As hyperthyroidism is treated and euthyroidism is approached, patients may require increasing warfarin dosages to maintain appropriate anticoagulation. We describe a patient’s varying response to warfarin during treatment of Graves’ disease. Case Presentation. A 48-year-old African American female presented to the emergency room with tachycardia, new onset bilateral lower extremity edema, gradual weight loss, palpable goiter, and generalized sweating over the prior 4 months. She was admitted with Graves’ disease and new onset atrial fibrillation. Primary stroke prophylaxis was started using warfarin; the patient developed a markedly supratherapeutic INR likely due to hyperthyroidism. After starting methimazole, her free thyroxine approached euthyroid levels and the INR became subtherapeutic. She remained subtherapeutic over several months despite steadily increasing dosages of warfarin. Immediately following thyroid radioablation and discontinuation of methimazole, the patient’s warfarin dose and INR stabilized. Conclusion. Clinicians should expect an increased response to warfarin in patients with hyperthyroidism and close monitoring of the INR is imperative to prevent adverse effects. As patients approach euthyroidism, insufficient anticoagulation is likely without vigilant follow-up, INR monitoring, and increasing warfarin dosages.
In patients with nonvalvular atrial fibrillation oral anticoagulation with the vitamin K antagonists acenocoumarol, phenprocoumon and warfarin reduces the risk of stroke by more than 60%, whereas single or double antiplatelet therapy is much less effective and sometimes associated with a similar ble
Koopmans, SA; VanRij, G
A questionnaire was sent to 240 members of the Netherlands Intraocular implant Club (NIOIC) to register their policy followed in 1993 with regard to anticoagulant therapy (ACT) and the use of aspirin in patients having cataract surgery. Ninety-one (32%) forms were suitable for analysis. Most eye sur
Malloy, Margaret; Acock, Alan; DuBois, David L; Vuchinich, Samuel; Silverthorn, Naida; Ji, Peter; Flay, Brian R
Organizational climate has been proposed as a factor that might influence a school's readiness to successfully implement school-wide prevention programs. The aim of this study was to evaluate the influence of teachers' perceptions of three dimensions of school organizational climate on the dosage and quality of teacher implementation of Positive Action, a social-emotional and character development (SECD) program. The dimensions measured were teachers' perceptions of (a) the school's openness to innovation, (b) the extent to which schools utilize participatory decision-making practices, and (c) the existence of supportive relationships among teachers (teacher-teacher affiliation). Data from 46 teachers in seven schools enrolled in the treatment arm of a longitudinal, cluster-randomized, controlled trial were analyzed. Teacher perceptions of a school's tendency to be innovative was associated with a greater number of lessons taught and self-reported quality of delivery, and teacher-teacher affiliation was associated with a higher use of supplementary activities. The findings suggest that perceptions of a school's organizational climate impact teachers' implementation of SECD programs and have implications for school administrators and technical assistance providers as they work to implement and sustain prevention programs in schools.
This study evaluated 44 separate medication withdrawal periods in 17 subjects who were attending a hospital anticoagulation clinic for management of anticoagulation medication. The data suggest that when anticoagulant withdrawal is needed for particular dental procedures, a 2-day hold is an effective period of medication withdrawal. No thromboembolic events were observed after any of the withdrawal periods. Further, no posttreatment hemorrhagic episodes were observed when the anticoagulant medication was reinstituted after dental treatment. Prothrombin time blood levels should be determined in the immediate pretreatment period, however, because the prothrombin time can fluctuate even in the best maintained patients.
Anderson, D. R.; Fernandez, L. A.
Indications for using standard anticoagulants, heparin and warfarin; the dosage and route of administration; the importance of monitoring therapy with reliable laboratory indices; and complications of therapy are discussed. Acetylsalicylic acid and ticlopidine can be used as antiplatelet agents. Because their effect on platelet function is not monitored clinically, their clinical indications are emphasized.
van Leeuwen, Y; Rombouts, E K; Kruithof, C J; van der Meer, F J M; Rosendaal, F R
BACKGROUND: Efforts to improve dosing quality in oral anticoagulant control include the use of computer algorithms. As current algorithms are simplistic and give dosage proposals in a small fraction of patients, we developed an algorithm based on principles of system and control engineering that giv
McQueen, H A; McBride, D; Miele, G; Bird, A.P.; Clinton, M
The Z and W sex chromosomes of birds have evolved independently from the mammalian X and Y chromosomes . Unlike mammals, female birds are heterogametic (ZW), while males are homogametic (ZZ). Therefore male birds, like female mammals, carry a double dose of sex-linked genes relative to the other sex. Other animals with nonhomologous sex chromosomes possess "dosage compensation" systems to equalize the expression of sex-linked genes. Dosage compensation occurs in animals as diverse as mamma...
Doonquah, Ladi; Mitchell, Anika D
Minor oral surgical procedures make up a significant part of the daily practice of dentistry. With the increased sophistication of medical technology and medications there is increased likelihood of performing surgery on patients who are being treated for conditions that require some type of anticoagulant therapy. These patients are at an increased risk for perioperative bleeding or thrombotic complications if anticoagulation is discontinued or the dosage is adjusted. Therefore, a fine balance needs to be obtained and adequate preparation of these patients is the key to establishing this balance. This article reviews suggested approaches to the management of such patients.
Full Text Available Jane Hoover-PlowJoseph J Jacobs Center for Thrombosis and Vascular Biology, Departments of Cardiovascular Medicine and Molecular Cardiology, Lerner Research Institute Cleveland Clinic, Ohio, USAAbstract: The coagulation and fibrinolytic pathways regulate hemostasis and thrombosis, and an imbalance in these pathways may result in pathologic hemophilia or thrombosis. The plasminogen system is the primary proteolytic pathway for fibrinolysis, but also has important proteolytic functions in cell migration, extracellular matrix degradation, metalloproteinase activation, and hormone processing. Several studies have demonstrated plasmin cleavage and inactivation of several coagulation factors, suggesting plasmin may be not only be the primary fibrinolytic enzyme, but may have anticoagulant properties as well. The objective of this review is to examine both in vitro and in vivo evidence for plasmin inactivation of coagulation, and to consider whether plasmin may act as a physiological regulator of coagulation. While several studies have demonstrated strong evidence for plasmin cleavage and inactivation of coagulation factors FV, FVIII, FIX, and FX in vitro, in vivo evidence is lacking for a physiologic role for plasmin as an anticoagulant. However, inactivation of coagulation factors by plasmin may be useful as a localized anticoagulant therapy or as a combined thrombolytic and anticoagulant therapy.Keywords: thrombosis, anticoagulant, cardiovascular disease, plasminogen’s protease, blood
Fareed, J; Iqbal, O; Cunanan, J; Demir, M; Wahi, R; Clarke, M; Adiguzel, C; Bick, R
bleeding problems at minimal dosages. Fondaparinux represents only one of the multiple pharmacologic effects of heparins. Thus, its therapeutic index will be proportionately narrower. The newer antiplatelet drugs have added a new dimension in the management of thrombotic disorders. The favorable clinical outcomes with aspirin and clopidogrel have validated COX-1 and P2Y12 receptors as targets for new drug development. Prasugrel, a novel thienopyridine, Cangrelor and AZD 6140 represent newer P2Y12 antagonists. Cangrelor and AZD 6140 are direct inhibitors, whereas Prasugrel requires metabolic activation. While clinically effective, recent results have prompted a closure of a clinical trial with Prasugrel due to bleeding. The newer anticoagulant and antiplatelet drugs are attractive, however, none of these are expected to replace the conventional drugs in polytherapeutic approaches. Heparins, warfarin and aspirin will continue to play a major role in the management of thrombotic and cardiovascular disorders for years to come.
Full Text Available Background. Oral anticoagulants have been used in the prevention of thromboembolic complications for over six decades. A rare, but possible problem in the application of these medications could be resistance to them. Case report. We presented a patient with nonocclusive thrombosis of the mechanical mitral prosthesis due to inadequately treated resistance to peroral anticoagulant therapy. Resistance to oral anticoagulant medications was proven by an increased dosage of warfarin up to 20 mg and, after that, acenokumarol to 15 mg over ten days which did not lead to an increase in the international normalized ratio (INR value over 1.2. On the basis of information that she did not take food rich in vitamin K or medications which could reduce effects of oral anticoagulants, and that she did not have additional illnesses and conditions that could cause an inadequate response to anticoagulant therapy, it was circumstantially concluded that this was a hereditary form of resistance. Because of the existing mechanical prosthetics on the mitral position, low molecular heparin has been introduced into the therapy. The patient reduced it on her own initiative, leading to nonocclusive valvular thrombosis. Conclusion. When associated complications like absolute arrhithmia does not exist, the finding of resistance to oral anticoagulant agents is an indication for the replacement of a mechanical prosthetic with a biological one which has been done in this patients.
Shai Friedland; Daniel Sedehi; Roy Soetikno
AIM: To review our experience performing polypectomy in anticoagulated patients without interruption of anticoagulation.METHODS: Retrospective chart review at the Veterans Affairs Palo Alto Health Care System. Two hundred and twenty five polypectomies were performed in 123 patients. Patients followed a standardized protocol that included stopping warfarin for 36 h to avoid supratherapeutic anticoagulation from the bowel preparation. Patients with lesions larger than 1 cm were generally rescheduled for polypectomy off warfarin. Endoscopic clips were routinely applied prophylactically.RESULTS: One patient (0.8%, 95% CI: 0.1%-4.5%)developed major post-polypectomy bleeding that required transfusion. Two others (1.6%, 95% CI:0.5%-5.7%) had self-limited hematochezia at home and did not seek medical attention. The average polyp size was 5.1 ± 2.2 mm.
Gleason, Lauren Jan; Friedman, Susan M
This article describes current literature and treatment plans for managing anticoagulation and antiplatelet agents in patients presenting with hip fractures. Indications for anticoagulation and antiplatelet agents are discussed, and management techniques for when patients present with hip fractures are reviewed.
... by heart Treatments + Tests What Are Anticoagulants and Antiplatelet Agents? Anticoagulants and antiplatelet agents are medicines that reduce blood clotting in an artery, a vein or the heart. Blood clots can block the ...
Gómez-Outes, Antonio; Suárez-Gea, Maria Luisa; Lecumberri, Ramón; Rocha, Eduardo; Pozo-Hernández, Carmen; Vargas-Castrillón, Emilio
The therapeutic armamentarium of parenteral anticoagulants available to clinicians is mainly composed by unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), fondaparinux, recombinant hirudins (i.e. bivalirudin, desirudin, lepirudin) and argatroban. These drugs are effective and safe for prevention and/or treatment of thromboembolic diseases but they have some drawbacks. Among other inconveniences, UFH requires regular anticoagulant monitoring as a result of variability in the anticoagulant response and there is a risk of serious heparin-induced thrombocytopaenia (HIT). LMWH, fondaparinux and recombinant hirudins are mainly cleared through the kidneys and their use in patients with severe renal insufficiency may be problematic. LMWH is only partially neutralized by protamine while fondaparinux and recombinant hirudins have no specific antidote. Novel anticoagulants in development for parenteral administration include new indirect activated factor Xa (FXa) inhibitors (idrabiotaparinux, ultra-low-molecular-weight heparins [semuloparin, RO-14], new LMWH [M118]), direct FXa inhibitors (otamixaban), direct FIIa inhibitors (flovagatran sodium, pegmusirudin, NU172, HD1-22), direct FXIa inhibitors (BMS-262084, antisense oligonucleotides targeting FXIa, clavatadine), direct FIXa inhibitors (RB-006), FVIIIa inhibitors (TB-402), FVIIa/tissue factor inhibitors (tifacogin, NAPc2, PCI-27483, BMS-593214), FVa inhibitors (drotrecogin alpha activated, ART-123) and dual thrombin/FXa inhibitors (EP217609, tanogitran). These new compounds have the potential to complement established parenteral anticoagulants. In the present review, we discuss the pharmacology of new parenteral anticoagulants, the results of clinical studies, the newly planned or ongoing clinical trials with these compounds, and their potential advantages and drawbacks over existing therapies.
Antz, Matthias; Hullmann, Bettina; Neufert, Christian; Vocke, Wolfgang
The correct anticoagulation regimen for prevention of thromboembolic events is essential in patients with atrial fibrillation. However, only a minority of patients receives anticoagulation according to the guidelines. The current guidelines are intended to make the indication for anticoagulation more simple and are summarized in the present article. This includes recommendations for chronic anticoagulation, prevention of thromboembolic events after cardioversion and in ablation of atrial fibrillation.
Full Text Available Amber L Beitelshees,1,* Deepak Voora,2,* Joshua P Lewis,1,* 1Program for Personalized and Genomic Medicine and Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD, USA; 2Center for Applied Genomics & Precision Medicine, Department of Medicine, Duke School of Medicine, Durham, NC, USA*All authors contributed equally to this work Abstract: In recent years, substantial effort has been made to better understand the influence of genetic factors on the efficacy and safety of numerous medications. These investigations suggest that the use of pharmacogenetic data to inform physician decision-making has great potential to enhance patient care by reducing on-treatment clinical events, adverse drug reactions, and health care-related costs. In fact, integration of such information into the clinical setting may be particularly applicable for antiplatelet and anticoagulation therapeutics, given the increasing body of evidence implicating genetic variation in variable drug response. In this review, we summarize currently available pharmacogenetic information for the most commonly used antiplatelet (ie, clopidogrel and aspirin and anticoagulation (ie, warfarin medications. Furthermore, we highlight the currently known role of genetic variability in response to next-generation antiplatelet (prasugrel and ticagrelor and anticoagulant (dabigatran agents. While compelling evidence suggests that genetic variants are important determinants of antiplatelet and anticoagulation therapy response, significant barriers to clinical implementation of pharmacogenetic testing exist and are described herein. In addition, we briefly discuss development of new diagnostic targets and therapeutic strategies as well as implications for enhanced patient care. In conclusion, pharmacogenetic testing can provide important information to assist clinicians with prescribing the most personalized and effective antiplatelet and
Llau, Juan V; Ferrandis, Raquel; López Forte, Cristina
Among the drugs most widely consumed by patients are both antiplatelet agents (aspirin, clopidogrel, ticlopidine) and anticoagulants (acenocoumarol, warfarin, low molecular weight heparin, fondaparinux). The use of these drugs in the perioperative period is an essential concern in patient care due to the need to balance the risk of bleeding against thrombotic risk (arterial or venous), which is increased in surgical patients. The present review highlights three main aspects. Firstly, withdrawal of antiplatelet agents is recommended between 1 week and 10 days before surgery to minimize perioperative bleeding. However, this practice has been questioned because patients without the required antiplatelet coverage may be at greater risk of developing cardiac, cerebral or peripheral vascular complications. Therefore, the recommendation of systematic antiplatelet withdrawal for a specific period should be rejected. Currently, risks should be evaluated on an individual basis to minimize the time during which the patient remains without adequate antiplatelet protection. Secondly, thromboprophylaxis is required in most surgical patients due to the high prevalence of venous thromboembolic disease. This implies the use of anticoagulants and the practice of regional anesthesia has been questioned in these patients. However, with the safety recommendations established by the various scientific societies, this practice has been demonstrated to be safe. Finally, "bridge therapy" in patients anticoagulated with acenocoumarol should be performed on an individual basis rather than systematically without taking into account the thrombotic risks of each patient. The perioperative period involves high arterial and venous thrombotic risk and the optimal use of antiplatelet agents and anticoagulants should be a priority to minimize this risk without increasing hemorrhagic risk. Multidisciplinary consensus is essential on this matter.
Full Text Available Franklin Michota Department of Hospital Medicine, Cleveland Clinic, Cleveland, OH, USA Abstract: Anticoagulation is an effective therapeutic means of reducing thrombotic risk in patients with various conditions, including atrial fibrillation, mechanical heart valves, and major surgery. By its nature, anticoagulation increases the risk of bleeding; this risk is particularly high during transitions of care. Established anticoagulants are not ideal, due to requirements for parenteral administration, narrow therapeutic indices, and/or a need for frequent therapeutic monitoring. The development of effective oral anticoagulants that are administered as a fixed dose, have low potential for drug-drug and drug-food interactions, do not require regular anticoagulation monitoring, and are suitable for both inpatient and outpatient use is to be welcomed. Three new oral anticoagulants, the direct thrombin inhibitor, dabigatran etexilate, and the factor Xa inhibitors, rivaroxaban and apixaban, have been approved in the US for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation; rivaroxaban is also approved for prophylaxis and treatment of deep vein thrombosis, which may lead to pulmonary embolism in patients undergoing knee or hip replacement surgery. This review examines current options for anticoagulant therapy, with a focus on maintaining efficacy and safety during transitions of care. The characteristics of dabigatran etexilate, rivaroxaban, and apixaban are discussed in the context of traditional anticoagulant therapy. Keywords: hemorrhagic events, oral anticoagulation, parenteral anticoagulation, stroke, transitions of care
Murakami, Takashi; Hina, Kazuyoshi; Higashiya, Shunichi; Kawamura, Hiroshi; Murakami, Masaaki; Kamikawa, Shigeshi; Komatsubara, Issei; Kusachi, Shozo
Background: Some patients with atrial fibrillation (AF) received underdoses of non-vitamin K antagonist oral anticoagulants (NOACs) in the real world. Underdosing is defined as administration of a dose lower than the manufacturer recommended dose. Objectives: To identify the efficacy and safety of underdosing NOACs as perioperative anticoagulation for atrial fibrillation ablation. Methods: We retrospectively analyzed patients who received rivaroxaban or dabigatran etexilate according to dosage: adjusted low dosage (reduced by disturbed renal function; n = 30), underdosage (n = 307), or standard dosage (n = 683). Non-vitamin K antagonist oral anticoagulants and dosing decisions were at the discretion of treating cardiologists. Results: Patients who received underdosed NOACs were older, more often female, and had lower body weight and lower renal function than those who received standard dosages. Activated clotting time at baseline in patients who received adjusted low dosage or underdosages was slightly longer than that in patients receiving standard dosages (156 ± 23, 151 ± 224, and 147 ± 24 seconds, respectively). Meaningful differences were not observed in other coagulation parameters. Adjusted low-, under-, and standard-dosing regimens did not differ in perioperative thromboembolic complications (0/30, 0.0%; 1/307, 0.3%; and 0/683, 0%, respectively) or major (0/30, 0.0%; 2/307, 0.6%; 3/683, 0.4%) and minor (1/30, 3.3%; 13/307, 4.2%; 25/683, 3.6%) bleeding episodes. When comparisons were performed for each NOAC, similar results were observed. Conclusions: With consideration of patient condition, age, sex, body weight, body mass index, and renal function, underdosing NOACs was effective and safe as a perioperative anticoagulation therapy for atrial fibrillation ablation. The therapeutic range of NOACs is potentially wider than manufacturer recommendations. PMID:28170360
Full Text Available Stroke is the leading cause of disability and the third leading cause of death . Anticoagulants have been used to treat patients with acute ischemic stroke for many years. Despite their widespread use, the usefulness of emergency anticoagulation is a subject of debate. Disagreements exist about the best agent to administer, the route of administration, the use of a bolus dose to start treatment, the level of anticoagulation required, and the duration of treatment. There are 2 types of anticoagulants: Parenteral and oral. Heparin is an anticoagulant that used parenteral. Oral anticoagulants are including Warfarin and new anticoagulants such as Dabigatrn,Rivaroxaban ,Apixaban and other newer drugs. In patients with noncardioembolic ischemic stroke or TIA antiplatelet agents are treatment of choice and preferred to anticoagulants. In cardioembolic ischemic stroke or TIA with high risk of reembolization anticoagulants are considered as preferred treatment. Warfarin, apixaban10mg/d ,Rivaroxaban20mg/d, and dabigatran 150 mg/d are all indicated for the prevention of recurrent stroke in patients with nonvalvular AF, whether paroxysmal or permanent.Also anticoagulant therapy is recommended for ischemic stroke or TIA patients in the setting of acute MI, atrial or ventricular thrombosis or dilated and restricted cardiomyopathy. Some valvular heart diseases are other indication for anticoagulant therapy in ischemic stroke or TIA patients. Ischemic Stroke or TIA in patients with Cerebral vein thrombosis and known hypercoagulable state specially anti phospholipid antibody syndrome are other indications for anticoagulant treatment.
Full Text Available Venous thromboembolism (VTE, consisting of deep vein thrombosis and pulmonary embolism, is a major clinical concern associated with significant morbidity and mortality. The cornerstone of management of VTE is anticoagulation, and traditional anticoagulants include parenteral heparins and oral vitamin K antagonists. Recently, new oral anticoagulant drugs have been developed and licensed, including direct factor Xa inhibitors (e.g. rivaroxaban, apixaban and edoxaban and thrombin inhibitors (e.g. dabigatran etexilate. This narrative review focusses on the characteristics of these direct anticoagulants and the main results of published clinical studies on their use in the prevention and treatment of VTE.
Ball, J H
An understanding of the primary mechanisms of hemostasis, including the coagulation pathways and the intrinsic, extrinsic, and common systems, is the basis for treating the anticoagulated patient. Two major anticoagulants are used for treating those who may be at risk for thromboembolic crisis. These drugs include Coumadin, which is an oral anticoagulant, and heparin, a parenteral anticoagulant, which is often used for acute thromboembolic episodes or for hospitalization protocols that include significant surgical procedures. The practitioner should be familiar with common dental drugs that can interact with anticoagulants and should consult with the patient's physician before administering any such drugs. By placing the patient into one of three dental treatment categories, appropriate anticoagulation therapy can be rendered to each patient according to his or her needs. Low-risk procedures require no change in anticoagulation medication. For moderate-risk procedures, withdrawal of anticoagulation medication 2 days before the procedure and verified with the PT the day of the procedure is indicated. For high-risk dental procedures, using a heparin protocol should be strongly considered. In all instances of dental treatment, the oral tissues should be treated atraumatically using local hemostatic measures for control of hemorrhage. Treating medically compromised patients who are on a variety of medications is becoming more common in dentistry today. Understanding the underlying disease and the appropriate protocol for treatment of anticoagulated patients reduces the risk of thromboembolism and hemorrhagic complications.
Full Text Available Introduction. Endotoxin, a component of the cell wall of Gram-negative bacteria is a major contributor to the pathogenesis of septic shock and multiple organ failure (MOF. Its entry into the bloodstream stimulates monocytes/macrophages which once activated produce and release cytokines, nitric oxide and other mediators that induce systemic inflammation, endothelial damage, organ dysfunction, hypotension (shock and MOF.The aim of this study is to evaluate the usefulness of a quantitative test for the dosage of endotoxin to determine the risk of severe Gram-negative sepsis. Materials and methods. In the period January 2009 - June 2011 we performed 897 tests for 765 patients, mostly coming from the emergency room and intensive care, of which 328 (43% women (mean age 53 and 437 (57% male (mean age 49. Fifty-nine patients, no statistically significant difference in sex, were monitored by an average of two determinations of EA.All patients had procalcitonin values significantly altered.The kit used was EAA (Endotoxin Activity Assay Estor Company, Milan, which has three ranges of endotoxin activity (EA: low risk of sepsis if <0.40 units, medium if between 0.40 and 0.59; high if 0.60. Results. 78 out of 765 patients (10% had a low risk, 447 (58% a medium risk and 240 (32% a high risk.The dosage of EA, combined with that of procalcitonin, has allowed a more targeted antibiotic therapy. Six patients in serious clinical conditions were treated by direct hemoperfusion with Toraymyxin, a device comprising a housing containing a fiber polypropylene and polystyrene with surface-bound polymyxin B, an antibiotic that removes bacterial endotoxins from the blood. Conclusions.The test is useful in risk stratification as well as Gram negative sepsis, to set and monitor targeted therapies, also based on the neutralization of endotoxin.
A major concern in the management of patients under anticoagulants is the potential for excessive bleeding after dental procedures. Recommendations for the administration of oral anticoagulants in conjunction with oral surgery range from complete withdrawal of anticoagulants to the maintenance of an unchanged therapy. Rising evidences show that the alteration of anticoagulation is not necessary for patients with INR of 4 or less previous to tooth extractions. Topical antifibrinolytics as tranexamic acid control successfully alveolar bleeding. It is time to stop interrupting anticoagulant therapy for oral surgery. A theoretical risk of hemorrhage after dental surgery in patients at therapeutic levels of anticoagulation exists but it is minimal and is greatly overweighed by the risk of thromboembolism after alteration of the anticoagulant therapy.
Pessin, M S; Estol, C J; Lafranchise, F; Caplan, L R
Cerebral hemorrhagic infarction visualized on CT, secondary to embolic stroke in an anticoagulated individual, is usually associated with clinically stable or improving neurologic signs; fear of transforming the hemorrhagic infarction into a hematoma, however, usually prompts cessation of anticoagulation until the blood has cleared on CT, despite the recognized risk of recurrent embolism during this non-anticoagulated period. We now report our experience with 12 patients with hemorrhagic infarction who remained anticoagulated. Eleven men and one woman, ages 33 to 77, developed hemorrhagic infarction while on heparin, warfarin, or both, for prevention of recurrent embolism. Patients were either continued on uninterrupted anticoagulation from stroke onset (n = 6), or anticoagulation was withheld for several days and then resumed (n = 4), or it was withheld for 5 and 14 days (n = 2) after stroke onset and then continued uninterrupted despite the CT appearance of hemorrhagic infarction. Eleven patients had a definite cardioembolic source for stroke (atrial fibrillation, seven; ventricular thrombus, two; and ventricular dyskinesia, two). One patient had carotid occlusion with local intra-arterial embolism. Hemorrhagic infarcts varied in size and were located in the middle cerebral artery territory in 11 patients and posterior cerebral artery territory in one. All patients remained clinically stable or improved on anticoagulation. Serial CTs showed fading hemorrhagic areas. When the risk of recurrent embolism is high, anticoagulation may be safely used in some patients with hemorrhagic infarction.
Eisenstein, Diana Hill
Many people receiving maintenance anticoagulation therapy require surgery each year in ambulatory surgery centers. National safety organizations focus attention toward improving anticoagulation management, and the American College of Chest Physicians has established guidelines for appropriate anticoagulation management to balance the risk of thromboembolism when warfarin is discontinued with the risk of bleeding when anticoagulation therapy is maintained. The guidelines recommend that patients at high or moderate risk for thromboembolism should be bridged with subcutaneous low-molecular-weight heparin or IV unfractionated heparin with the interruption of warfarin, and low-risk patients may require subcutaneous low-molecular-weight heparin or no bridging with the interruption of warfarin. The guidelines recommend the continuation of warfarin for patients who are undergoing minor dermatologic or dental procedures or cataract removal. The literature reveals, however, that there is not adequate adherence to these recommendations and guidelines. Management of anticoagulation therapy by a nurse practitioner may improve compliance and safety in ambulatory surgery centers.
Hylek, Elaine M
Atrial fibrillation (AF) is the most common significant cardiac rhythm disorder, and its prevalence is increasing worldwide. Atrial fibrillation confers a fivefold increased risk of stroke, and these strokes are associated with significant mortality and disability. The vitamin K antagonist, warfarin, has been the mainstay of anticoagulant therapy for patients with AF, reducing the risk of stroke by 65%. Despite its efficacy, warfarin remains underused in clinical practice because of its variable dose response, diet and medication interactions, and need for frequent monitoring. Stroke prevention in AF has entered an exciting therapeutic era with new classes of targeted anticoagulants that avoid the many pitfalls of the vitamin K antagonists. Dabigatran, an oral thrombin inhibitor, and the factor Xa inhibitors, rivaroxaban and apixaban, have demonstrated efficacy for stroke prevention and a reduced risk of intracranial hemorrhage relative to warfarin. Translating the efficacy of clinical trials into effective use of these novel agents in clinical practice will require an understanding of their pharmacokinetic profiles, dose selection, and management in select clinical situations.
Lin, Tao; Bai, Rong; Chen, Ying-wei; Yu, Rong-hui; Tang, Ri-bo; Sang, Cai-hua; Li, Song-nan; Ma, Chang-sheng; Dong, Jian-zeng
Anticoagulation of patients with cardiac tamponade (CT) complicating catheter ablation of atrial fibrillation (AF) is an ongoing problem. The aim of this study was to survey the clinical practice of periprocedural anticoagulation in such patients. This study analyzed the periprocedural anticoagulation of 17 patients with CT complicating AF ablation. Emergent pericardiocentesis was performed once CT was confirmed. The mean drained volume was 410.0 ± 194.1 mL. Protamine sulfate was administered to neutralize heparin (1 mg neutralizes 100 units heparin) in 11 patients with persistent pericardial bleeding and vitamin K1 (10 mg) was given to reverse warfarin in 3 patients with supratherapeutic INR (INR > 2.1). Drainage catheters were removed 12 hours after echocardiography confirmed absence of intrapericardial bleeding and anticoagulation therapy was restored 12 hours after removing the catheter. Fifteen patients took oral warfarin and 10 of them were given subcutaneous injection of LMWH (1 mg/kg, twice daily) as a bridge to resumption of systemic anticoagulation with warfarin. Two patients with a small amount of persistent pericardial effusion were given LMWH on days 5 and 13, and warfarin on days 6 and 24. The dosage of warfarin was adjusted to keep the INR within 2-3 in all patients. After 12 months of follow-up, all patients had no neurological events and no occurrence of delayed CT. The results showed that it was effective and safe to resume anticoagulation therapy 12 hours after removal of the drainage catheter. This may help to prevent thromboembolic events following catheter ablation of AF.
Full Text Available Abstract Background To study the link between the dosage of several antipsychotics and the prescription of antiparkinsonians in an observational study. Methods In the context of a national naturalistic prospective observational study, a database containing all the prescriptions from 100 French psychiatrists during the year 2002 was analysed. The inclusion criteria were a diagnosis of schizophrenia or schizoaffective disorder and age over 18. The mean dosage of antipsychotics with and without antiparkinsonians was compared. Since there were multiple prescriptions for a given subject, generalised mixed linear models were also used to study the link between antiparkinsonian prescription and antipsychotic dosage. Results antiparkinsonians were prescribed to 32,9% of the patients. Two groups of antipsychotics were observed relating to differences in dosage when an antiparkinsonian was co prescribed or not : a first group, where the mean dosage was higher with antiparkinsonians (risperidone, amisulpride and haloperidol and a second group (clozapine, olanzapine, in which antiparkinsonian co prescription was not related to the dosage of antipsychotics. Conclusion As a conclusion, it can be said that it is important to consider the dosage and the type of antipsychotic in the treatment of patients suffering of schizophrenia, because neurological side effects are frequent and can impair quality of life. Moreover the prescription of antiparkinsonians can lead to different side effects such anticholinergic effects.
Iba, T; Gando, S; Thachil, J
The current management of disseminated intravascular coagulation (DIC) is based on aggressive treatment of the underlying condition and resuscitation with appropriate blood products. Anticoagulant therapy has appeared and disappeared in the different guidelines and important documents detailing the treatment of DIC. For example, Surviving Sepsis Campaign (SSC) guidelines, the 'global standard' for the management of severe sepsis, had recombinant activated protein C highly recommended in the original version, but this was withdrawn in the latest version due to the lack of evidence. In contrast, recent international guidance released from the International Society on Thrombosis and Haemostasis has introduced the potential efficacy of other agents. In sepsis-related DIC, the basis for anticoagulant therapy comes from the mounting evidence for the anti-inflammatory effects which these agents possess and can prove beneficial in septic situations. Several studies have clearly shown the important cross-talk between coagulation and inflammation in patients with sepsis. More recently, neutrophil extracellular traps and damage-associated molecular patterns (DAMPs), especially histones, have been demonstrated to play a crucial role in the coagulopathy of sepsis. Once again, the natural anticoagulants have an important function in neutralizing the effects of DAMPs and histones. In this review, in addition to examining the important role of anticoagulants in the septic milieu, the clinical studies examining antithrombin, recombinant thrombomodulin and plasma-derived activated protein C are detailed. However, large-scale randomized controlled trials are yet to be performed, with important consideration of the timing, dosage and duration of treatment.
Heit, J A
Common indications for chronic anticoagulation include mechanical prosthetic heart valve, non-rheumatic atrial fibrillation, and venous thromboembolism. Perioperative management of the chronically anticoagulated patient is a complex medical problem, and includes the following issues: urgency of surgery, risk of thromboembolism in the absence of anticoagulation, bleeding risk, consequences of bleeding, ability to control bleeding physically, and duration of bleeding risk after the procedure. Most patients can be managed safely by stopping oral anticoagulants 4-5 days before surgery and restarting anticoagulation after the procedure at the patient's usual daily dose. In general, dental procedures and cataract extraction can be performed without interrupting anticoagulation. Most other procedures can be safely performed with an INR patients with double-wing prosthetic valves (e.g., St. Jude, Carbomedics) in the aortic position, uncomplicated atrial fibrillation, or a remote (>3 months) history of venous thromboembolism, oral anticoagulants can be stopped 4-5 days before surgery and restarted at the usual daily dose immediately after surgery. For other patients at higher risk of thrombosis, "bridging therapy" with outpatient low molecular weight heparin is safe and effective. For urgent procedures, a small dose of oral vitamin K usually will reduce the INR within 24-36 hours to a level sufficient for surgery and avoids exposure to transfused blood products.
Campos, Maria Manuel; Reis Santos, Isabel
Diagnosis criteria, pathogenic mechanisms, incidence and prevalence of the Antiphospholipid Syndrome are focused in a brief review. Hypoprothrombinemia (HPT) may be hereditary or acquired; the first is rare and with recessive autossomic transmission. We report the case of a 66-year-old white woman with Systemic Lupus Erythematosus (SLE), autoimmune haemolytic anaemia, periostitis, haematomas, bleeding leg ulcer and rectal haemorrhages; she had decreased levels of the prothrombin. Haemorrhagic episodes were related with the anti-prothrombin specificity of Lupus Anticoagulant (LA) detected. The SLE/LA/HPT association is less frequent than the correlated to SLE/LA/anti- ß2Glycoprotein I antibodies and was first reported in 1960 by Rapaport et al, in an 11-year- -old girl with severe haemorrhagic manifestations.
Cody A. Koch
Full Text Available Hemorrhage into the soft tissues of the airway represents a potentially life-threatening complication of long-term anticoagulation. We report the case of a chronically anticoagulated 37-year-old male who developed a spontaneous hematoma of the epiglottis secondary to a supra-therapeutic INR. Epiglottic hematoma should be considered in the differential of any anticoagulated patient presenting with upper airway compromise. The airway should be secured in a controlled fashion, and the coagulopathy should be rapidly corrected.
António, Natália; Castro, Graça; Ramos, Domingos; Machado, António; Gonçalves, Lino; Macedo, Tice; Providência, Luís A
The management of patients taking long-term oral anticoagulants who require dental surgery is still highly controversial. The risk of bleeding associated with dental treatment under oral anticoagulants must be weighed against the risk of thromboembolism associated with suspension of antithrombotic therapy. Mortality and morbidity associated with thromboembolic events are higher than those associated with hemorrhagic events after minor oral surgery procedures. Evidence-based information does not support oral anticoagulant suspension before minor oral surgery. The authors propose a management protocol for chronically anticoagulated patients who require a dental procedure, to reduce both thromboembolic risk and the risk of bleeding.
Full Text Available The data that episodes and sequels of venous thromboembolism (VTE are recorded in a significant percentage of patients receiving standard anticoagulants as VTE prophylaxis (unfractionated, low-molecular-weight heparin and vitamin K inhibitors as well as the fact that these drugs have significant limitations and that they may cause serious side-effects in some patients indicate the need for the introduction of new anticoagulant drugs. Fondaparinux, a selective inhibitor of Factor Xa, administered following major orthopedic surgeries having a high risk for the development of VTE, is more efficient than enoxaparin sodium used in European and North-American approved doses. The increased incidence of major bleeding (excluding fatal due to fondaparinux could be perhaps lowered by dosage reduction in patients with a mildly decreased creatinine clearance. Dabigatran, a peroral direct thrombin inhibitor, administered for VTE prophylaxis in elective hip and knee surgery, showed in to date studies the efficacy comparable (if dabigatran is given in both dosage regimes of 150 mg and 220 mg daily or superior (if dabigatran is given at a dose of 220 mg daily to enoxaparin administered in European-approved doses, while North American-approved doses of enoxaparin were superior than dabigatran in VTE reduction. No significant differences in bleeding rates were determined in any of the study groups. We consider that the introduction of new anticoagulants, including fondaparinux and dabigatran, will contribute to the establishment of a better safety profile and efficacy, and will also enable adequate therapy individualization for each patient depending on his/hers clinical characteristics. The introduction of novel peroral anticoagulants will, inter alia, significantly contribute to improvement in the quality of life, release the patient from numerous limitations in nutrition, interreaction, frequent laboratory monitoring, and also significantly improve therapeutic
Purcell, C A
Most anticoagulated patients can be safely managed for routine dental treatment in the outpatient setting by following appropriate guidelines. Management should be based on the present level of anticoagulation as assessed by tests, in particular the international normalised ratio (INR), which should be carried out as close to the intervention as possible. A philosophy of minimal, if any, alteration to the level of anticoagulation should be adopted. This is particularly true for procedures producing minimal bleeding such as scaling and cleaning which, in the past, have resulted in patients having their INR lowered, with its attendant risks. The patient's anticoagulation is potentially life-saving and, where at all possible, should be maintained at therapeutic levels when therapy for non-threatening conditions is planned.
Schrezenmeier, H; Müller, H; Gunsilius, E; Heimpel, H; Seifried, E
Pseudothrombocytopenia (PTP) is the phenomenon of falsely low platelet counts due to in vitro platelet clumping in the presence of platelet autoantibodies and anticoagulants. We assessed anticoagulant-dependence, time course of platelet counts and impact of different counter devices on the phenomenon. Blood of 10 persons with previously recognized pronounced EDTA-dependent PTP was collected into 7 different anticoagulants and counted after different intervals in parallel in a Coulter T540 and a Coulter STKS counter and by phase contrast microscopy. With the Coulter T540 model PTP was most pronounced in blood samples anticoagulated with EDTA, Na-oxalate or Na-citrate. In the STKS counter EDTA, heparin and oxalate presented as the worst anticoagulants. The time course of platelet counts was significantly different between the two counters. Our results demonstrate that PTP is not restricted to EDTA, but is also present with other anticoagulants. In contrast, pseudoleucocytosis was observed only in EDTA-anticoagulated blood in the Coulter T540 device. We investigated the expression of platelet integrins and activation antigens on platelets of persons with anticoagulant-dependent PTP and in healthy controls without PTP. In the presence of EDTA the expression of GpIIb/IIIa was significantly reduced in the PTP subjects compared to control. Activation antigens CD62, CD63 and thrombospondin-antigen were upregulated in the presence of EDTA. These alterations in the expression of platelet antigens could also be induced on platelets of normal donors by incubation with sera of PTP subjects and EDTA.(ABSTRACT TRUNCATED AT 250 WORDS)
Koenig-Oberhuber, V; Filipovic, M
In our daily anaesthetic practice, we are confronted with an increasing number of patients treated with either antiplatelet or anticoagulant agents. During the last decade, changes have occurred that make the handling of antithrombotic medication a challenging part of anaesthetic perioperative management. In this review, the authors discuss the most important antiplatelet and anticoagulant drugs, the perioperative management, the handling of bleeding complications, and the interpretation of some laboratory analyses related to these agents.
Aleman, Maria M; Holle, Lori A; Stember, Katherine G; Devette, Christa I; Monroe, Dougald M; Wolberg, Alisa S
Transglutaminases are a superfamily of isoenzymes found in cells and plasma. These enzymes catalyze the formation of ε-N-(γ-glutamyl)-lysyl crosslinks between proteins. Cystamine blocks transglutaminase activity and is used in vitro in human samples and in vivo in mice and rats in studies of coagulation, immune dysfunction, and inflammatory disease. These studies have suggested cystamine blocks fibrin crosslinking and has anti-inflammatory effects, implicating transglutaminase activity in the pathogenesis of several diseases. We measured the effects of cystamine on fibrin crosslinking, tissue factor-triggered plasma clot formation and thrombin generation, and coagulation factor enzymatic activity. At concentrations that blocked fibrin crosslinking, cystamine also inhibited plasma clot formation and reduced thrombin generation. Cystamine inhibited the amidolytic activity of coagulation factor XI and thrombin towards chromogenic substrates. These findings demonstrate that cystamine exhibits anticoagulant activity during coagulation. Given the close relationship between coagulation and inflammation, these findings suggest prior studies that used cystamine to implicate transglutaminase activity in disease pathogenesis warrant re-examination.
Maria M Aleman
Full Text Available Transglutaminases are a superfamily of isoenzymes found in cells and plasma. These enzymes catalyze the formation of ε-N-(γ-glutamyl-lysyl crosslinks between proteins. Cystamine blocks transglutaminase activity and is used in vitro in human samples and in vivo in mice and rats in studies of coagulation, immune dysfunction, and inflammatory disease. These studies have suggested cystamine blocks fibrin crosslinking and has anti-inflammatory effects, implicating transglutaminase activity in the pathogenesis of several diseases. We measured the effects of cystamine on fibrin crosslinking, tissue factor-triggered plasma clot formation and thrombin generation, and coagulation factor enzymatic activity. At concentrations that blocked fibrin crosslinking, cystamine also inhibited plasma clot formation and reduced thrombin generation. Cystamine inhibited the amidolytic activity of coagulation factor XI and thrombin towards chromogenic substrates. These findings demonstrate that cystamine exhibits anticoagulant activity during coagulation. Given the close relationship between coagulation and inflammation, these findings suggest prior studies that used cystamine to implicate transglutaminase activity in disease pathogenesis warrant re-examination.
Full Text Available Ana M Palacio,1–3 Irene Kirolos,2,3 Leonardo Tamariz1–3 1The Department of Medicine, Miller School of Medicine, University of Miami, 2The Veterans Affairs Medical Center, Miami, FL, USA; 3Division of Public Health Sciences, University of Miami, Miami, Florida, USA Background: New oral anticoagulants have similar efficacy and lower bleeding rates compared with warfarin. However, in case of bleeding there is no specific antidote to reverse their effects. We evaluated the preferences and values of anticoagulants of patients at risk of atrial fibrillation and those who have already made a decision regarding anticoagulation.Methods: We conducted a cross-sectional study of Veterans in the primary care clinics and the international normalized ratio (INR laboratory. We developed an instrument with patient and physician input to measure patient values and preferences. The survey contained a hypothetical scenario of the risk of atrial fibrillation and the attributes of each anticoagulant. After the scenario, we asked participants to choose the option that best fits their preferences. The options were: 1 has better efficacy at reducing risk of stroke; 2 has been in the market for a long period of time; 3 has an antidote to reverse the rare case of bleeding; 4 has better quality of life profile with no required frequent laboratory tests; or 5 I want to follow physician recommendations. We stratified our results by those patients who are currently exposed to anticoagulants and those who are not exposed but are at risk of atrial fibrillation.Results: We approached 173 Veterans and completed 137 surveys (79% response rate. Ninety subjects were not exposed to anticoagulants, 46 reported being on warfarin, and one reported being on dabigatran at the time of the survey. Ninety-eight percent of subjects stated they would like to participate in the decision-making process of selecting an anticoagulant. Thirty-six percent of those exposed and 37% of those
DU Xin; MA Chang-sheng; LIU Xiao-hui; DONG Jian-zeng; WANG Jun-nan; CHENG Xiao-jing
@@ Nonvalvular atrial fibrillation (NVAF) is the most common sustained cardiac arrhythmia in clinical practice, which if untreated results in a doubling of cardiovascular morbidity and mortality. AF is an independent predictor of stroke, with an annual risk 5 to 6 times higher than patients in sinus rhythm.1 During recent years, several randomised clinical trials conducted by investigators around the world involving 13 843 participants with NVAF have demonstrated convincingly the value of warfarin therapies for stroke prevention in high risk patients.2-8 However, the dose response of warfarin is complex and its activity is easily altered by concurrent medications, food interactions, alcohol and illnesses. Adherence to medical advice and routine monitoring of the international normalized ratio (INR) is important, because low anticoagulant intensity predisposes the patients to thromboembolic complications and high intensity to haemorrhage. Studies suggested that anticoagulant clinics could improve the quality of anticoagulation control,9 and anticoagulant clinics are common in western countries. However, in China, most AF patients taking warfarin usually attend the outpatient clinic of cardiology, while the quality of anticoagulation control is never investigated. We therefore assessed anticoagulation control in the outpatient clinic of cardiology, and the quality of anticoagulation control since the establishment of anticoagulant clinics.
Norris, John W
There are no reliable data from randomised trials to decide whether anticoagulants or antiplatelet agents are better to prevent further thromboembolic events after cervical arterial dissection. Most neurologists favour anticoagulants based on the underlying pathology and the likely course of acute post-dissection thromboembolism.
E.A. Akl; S. Gunukula; M. Barba; V.E.D. Yosuico; F.F. van Doormaal; S. Kuipers; S. Middeldorp; H.O. Dickinson; A. Bryant; H. Schuenemann
Background Anticoagulation may improve survival in patients with cancer through an antitumor effect in addition to the perceived antithrombotic effect. Objectives To evaluate the efficacy and safety of parenteral anticoagulants in patients with cancer with no therapeutic or prophylactic indication f
A survey of anticoagulation practice among German speaking microsurgeons – Perioperative management of anticoagulant therapy in free flap surgery [Erhebung über die antikoagulatorische Praxis unter deutschsprachigen Mikrochirurgen – Perioperatives Management der antikoagulatorischen Therapie bei freien Lappentransplantaten
Full Text Available [english] Background: Anticoagulation is a crucial element in microsurgery. Although various clinical studies and international surveys have revealed that anticoagulation strategies can vary and result in similar outcomes, anticoagulative regimen are far away from standardization. In Germany and german speaking countries standardized anticoagulation protocols concerning free flap surgery do not exist so far. Methods: To evaluate the current practice of clinics in Germany, Austria and Switzerland with specialization in microsurgery we performed a questionnaire surveying the perioperative regimen of anticoagulant and antiplatelet therapy in free flap surgery. The microsurgeons were interrogated on several anticoagulant, rheologic and antiplatelet medications, their dosage and perioperative frequency of application pre-, intra- and postoperative.Results: The questionnaire revealed that the used antithrombotic and perioperative regimens varied from department to department presumably based on the personal experience of the surgeon. Multiple approaches are used with a wide range of anticoagulants used either alone or in combination, with different intervals of application and different dosages. Conclusion: Therefore consensus meetings should be held in future leading to conduct prospective multicenter studies with formulation of standardized anticoagulative and perioperative protocols in microsurgery reducing flap failure to other than pharmacologic reasons.[german] Hintergrund: Die Antikoagulation stellt ein zentrales Element in der Mikrochirurgie dar. Zahlreiche klinische Studien und internationale Erhebungen zu antikoagulatorischen Strategien weisen eine grosse Varianz bei vergleichbaren Resultaten nach, entbehren jedoch einer Standardisierung. Auch in Deutschland und deutschsprachigen Ländern fehlen bislang standardisierte Regime zur Antikoagulation in der Mikrochirurgie.Methodik: Zur Erhebung der antikoagulatorischen Praxis unter
Gómez-Outes, Antonio; Suárez-Gea, Ma Luisa; Calvo-Rojas, Gonzalo; Lecumberri, Ramón; Rocha, Eduardo; Pozo-Hernández, Carmen; Terleira-Fernández, Ana Isabel; Vargas-Castrillón, Emilio
The history of the traditional anticoagulants is marked by both perseverance and serendipity. The anticoagulant effect of heparin was discovered by McLean in 1915, while he was searching for a procoagulant in dog liver. Link identified dicumarol from spoiled sweet clover hay in 1939 as the causal agent of the sweet clover disease, a hemorrhagic disorder in cattle. Hirudin extracts from the medicinal leech were first used for parenteral anticoagulation in the clinic in 1909, but their use was limited due to adverse effects and difficulties in achieving highly purified extracts. Heparins and coumarins (i.e.: warfarin, phenprocoumon, acenocoumarol) have been the mainstay of anticoagulant therapy for more than 60 years. Over the past decades, the drug discovery paradigm has shifted toward rational design following a target-based approach, in which specific proteins, or "targets", are chosen on current understandings of pathophysiology, small molecules that inhibit the target's activity may be identified by high-throughput screening and, in selected cases, these new molecules can be developed further as drugs. Despite the application of rational design, serendipity has still played a significant role in some of the new discoveries. This review will focus on the discovery of the main anticoagulant drugs in current clinical use, like unfractionated heparin, low-molecular-weight heparins, fondaparinux, coumarins (i.e.: warfarin, acenocoumarol, phenprocoumon), parenteral direct thrombin inhibitors (DTIs) (i.e.: argatroban, recombinant hirudins, bivalirudin), oral DTIs (i.e.: dabigatran) and oral direct factor Xa inhibitors (i.e.: rivaroxaban, apixaban).
Thromboembolic disease is a major leading cause of mortality and morbidity in industrialized countries. Currently, the management of these patients is challenging due to the availability of new drugs with proven efficacy and security compared to traditional oral vitamin K antagonists. These compounds are characterized by a predictable pharmacokinetic profile for which blood monitoring is not routinely needed. Nevertheless, some data have suggested inter-patient variability in the anticoagulant effect of these drugs, raising concerns about their effectiveness and safety. Although mass-spectrometry is the gold standard to determine drug plasma concentrations, this method is not widely available in every-day practice and some coagulation assays are commonly used to determine the anticoagulant effect of these drugs. The present review aims to summarize the current knowledge regarding the clinical question of how and when to monitor patients with new anticoagulant oral agents. PMID:26713281
Dijk, E.J. van; Koudstaal, P.J.; Roos, Y.B.; Brouwers, P.J.; Kappelle, L.J.
- Recent randomized controlled trials have shown that new oral anticoagulants (dabigatran, rivaroxaban en apixaban) in patients with atrial fibrillation are equally or more effective in preventing cerebral infarction than vitamin K antagonists (VKA).- New oral anticoagulants cause significant less i
Altman, R; Rouvier, J; Gurfinkel, E
For preventing thromboembolic events, the concurrent use of oral anticoagulant and antiplatelet drugs has been proposed. In prosthetic heart valves the use of moderate intensity anticoagulants [International Normalized Ratio (INR) 2-3] plus aspirin (100 mg/day) decreases the amount and severity of embolic episodes. The possibility that the same regimen could provide benefit in the prevention of thrombotic events in other arterial diseases is also indicated by the ATACS trial in unstable angina. The ongoing studies in ischemic heart diseases will also give the answer to this possibility.
Kovacs, Ferenc; Varga, Marina; Pataki, Zsolt; Rigo, Erzsebet
The knowledge of pseudothrombocytopenia (PTCP) is important for the accuracy of a clinical assessment and for avoiding unnecessary treatment. An elderly patient was hospitalized with left lung pneumonia. Severe thrombocytopenia [platelet (PLT) number: 18 × 109/L] without any clinical bleeding was found in ethylenediaminetetraacetic acid blood collection tube. PLT measurement was repeated in various anticoagulant [sodium citrate, lithium heparin, disodium oxalate, hirudin, and magnesium sulfate (Mg-sulfate)] sample collection tubes and all of them showed thrombocytopenia except with Mg-sulfate. To the best of our knowledge, PTCP with five anticoagulant sample collection tubes has not been reported earlier.
Ishida, Keiichi; Masuda, Masahisa; Kohno, Hiroki; Tamura, Yusaku; Matsumiya, Goro
Patients with antiphospholipid syndrome are at increased risk of developing thrombotic and hemorrhagic complications after cardiac surgery, and may have abnormal coagulation tests and develop thrombocytopenia after invasive procedures, which can complicate the perioperative management of anticoagulant therapy. We describe a patient with chronic thromboembolic pulmonary hypertension and antiphospholipid syndrome, who presented with prolonged activated partial thromboplastin and activated clotting times, and developed thrombocytopenia after the catheterization workup. We performed pulmonary endarterectomy and successfully managed anticoagulation by restricting heparin use at the time of surgery and monitoring the heparin effect by measuring heparin concentrations during cardiopulmonary bypass.
Marco Antonio Zapata Sampedro
Full Text Available Out-patients undergoing anticoagulant treatment are attended by nursing staff, working with doctors.To be able to provide adequate medical care, nurses must have the minimum knowledge and skills needed to work with the programme described in this article. These include basic and specific knowledge of anticoagulation. The correct functioning of the service will help provide an optimum control of the INR (International Normalized Ratio and reduce the complications of bleeding, both of which are the main objectives of the nursing care of these patients.
Samuel P. Hammar
Full Text Available We describe a 64-year-old man with extensive diffuse acute lung hemorrhage, presumably as a result of anticoagulation therapy. We evaluated reports in the literature concerning acute exacerbation (acute lung injury of unknown cause in UIP and other forms of fibrotic interstitial pneumonias. We also evaluated autopsy tissue in this case in order to determine the cause of death in this 64-year-old man, who was initially thought to have an asbestos-related disease. Based on the autopsy findings, this man died as a result of anticoagulation therapy; specifically, the use of Xarelto® (rivaroxaban.
Full Text Available Thrombo-embolic disease is a major challenging clinical problem associated with significant mortality and morbidity. Anticoagulation with the existing heparin products and vitamin K antagonist (VKA anticoagulants are still the mainstay of management. However, due to the risk of bleeding and well-documented drawbacks, the quest for a novel oral anticoagulant has led to the clinical development of dabigatran etexilate. Dabigatran etexilate is a direct thrombin (IIa inhibitor which has recently been approved in India for prevention of venous thromboembolic events (VTE in patients who have undergone major orthopaedic (total knee or hip replacement surgery and for prevention of stroke, systemic embolism and reduction of vascular mortality in adult patients with atrial fibrillation. Thus dabigatran etexilate is a promising alternative to the current heparin products and VKAs in patients who require long-term oral anticoagulation. [Int J Basic Clin Pharmacol 2013; 2(5.000: 663-667
Ku, Sae-Kwang; Kim, Tae Hoon; Bae, Jong-Sup
Persicarin and isorhamnetin were isolated from Oenanthe javanica and their anticoagulant activities were examined by monitoring activated partial thromboplastin time (aPTT), prothrombin time (PT), and the activities of cell-based thrombin and activated factor X (FXa). In addition, the effects of persicarin and isorhamnetin on the expressions of plasminogen activator inhibitor type 1 (PAI-1) and tissue-type plasminogen activator (t-PA) were tested in tumor necrosis factor-α (TNF-α) activated human umbilical vein endothelial cells (HUVECs). The data obtained showed that persicarin and isorhamnetin both prolonged aPTT and PT significantly and inhibited the activities of thrombin and FXa. In addition, they both inhibited the generations of thrombin and FXa in HUVECs. In accordance with these anticoagulant activities, persicarin and isorhamnetin prolonged in vivo bleeding time and inhibited TNF-α induced PAI-1 production. Furthermore, PAI-1/t-PA ratio was significantly decreased by persicarin. Interestingly, the anticoagulant and profibrinolytic effects of persicarin were greater than those of isorhamnetin, which suggest that the sulfonate group of persicarin positively regulates its anticoagulatory function. Accordingly, our results suggest that persicarin and isorhamnetin possess antithrombotic activities and that they could provide bases for the development of new anticoagulant agents.
Gadisseur, Alain Peter Anton
Oral anticoagulant therapy has changed little since the development of the coumarin drugs after the Second World War. The basic nature of the therapy, i.e. the balancing between thrombosis and haemorrhage, makes it a therapy difficult to manage. Add to this the many influences from co-morbidity, c
Topping, Christopher John; Elmeros, Morten
Anticoagulant rodenticides (AR) are a widespread and effective method of rodent control but there is concern about the impact these may have on non-target organisms, in particular secondary poisoning of rodent predators. Incidence and concentration of AR in free-living predators in Denmark is ver...
Patel Kinjal B
Full Text Available Thrombin plays a key role in thrombotic events, and therefore thrombin inhibition represents a therapeutic target for numerous thromboembolic diseases. Thrombin is responsible for the conversion of soluble fibrinogen to fibrin; clot stabilization through activation of factor XIII and the formation of cross-linkage among fibrin molecules; and the generation of additional thrombin through activation of factors V, VIII, and XI. Direct thrombin inhibitors are an innovative class of anticoagulants that bind directly to thrombin to inhibit its actions and impede the clotting process. Dabigatran is the first direct thrombin inhibitor, orally available first approval by US Food and Drugs Administration in 2010. Specifically and reversibly inhibits thrombin, so the duration of action is predictable. The anticoagulant effect correlates well with plasma drug concentrations, which implies an effective anticoagulation with low bleeding risk without major problems of interactions with other drugs. The predictable pharmacokinetics and pharmacodynamics characteristics of dabigatran may facilitate dental management of patients who until now have been in treatment with traditional anticoagulants, given that it doesn’t require routine laboratory monitoring in the vast majority of patients treated. They also present a profile of drug interactions very favorable.
Wilts, Ineke Theodora; Bleker, Suzanne Mariella; Van Es, Nick; Buller, Harry Roger; Di Nisio, Marcello; Kamphuisen, Pieter Willem
Introduction: Patients with cancer are at increased risk of (recurrent) venous thronnboembolism. They are also at increased risk of bleeding. This makes treatment of venous thromboembolisms (VTE) in cancer patients challenging. Areas covered: In this review, we will focus on the safety of anticoagul
Vitamin K antagonists have been used as oral anticoagulants (OACs) for over five decades, yet their use in real-world practice is problematic primarily because of their narrow therapeutic window, exacerbated by extensive food and drug interactions, necessitating regular coagulation monitoring and do
Thean, D; Alberghini, M
Several new oral anticoagulants have been studied in the past decade, and have now started to enter the market. These drugs are reported to be as effective as, or more effective than, warfarin. In Australia, the Therapeutic Goods Administration has approved dabigatran, rivaroxaban and apixaban. The use of these newer anticoagulants is likely to increase in time, and it is important for dentists to have a sound understanding of the mechanisms of action, reversal strategies, and management guidelines for patients taking oral anticoagulants. This article discusses the process of coagulation, available anticoagulants and their monitoring and reversal, and provides clinical advice on the management of patients on anticoagulants who require dental treatment.
Satger, Bernadette; Blaise, Sophie; Fontaine, Michèle; Yver, Jacqueline; Allenet, Benoît; Baudrant, Magali; Pernod, Gilles; Bosson, Jean-Luc
The vitamin K antagonists (VKA) remain to this day the only oral form of therapeutic anticoagulation. Approximately 1% of the French population, mainly elderly, is treated with these anticoagulants. Oral anticoagulants have significant risks of iatrogenic complications; indeed they are the leading cause of such drug-induced complications, predominantly hemorrhages. AFSSAPS (French Drug and Medical Products Agency) clinical practice recommendations, repeatedly disseminated, emphasize the education of patients receiving VKAs. Managing oral anticoagulant treatment is challenging, with a significant risk of under- or overdosing and consequently, thrombosis or hemorrhage. The therapeutic window is narrow, multiple drug-interactions are possible, and the specific dose required for a particular individual to achieve appropriate International Normalized Ratio (INR) levels is unpredictable. The literature contains few randomized controlled trials about the efficacy of education for patients treated with oral anticoagulants. These education programs are not standardized and are therefore varied and difficult to compare. Nevertheless, studies demonstrate the importance of patient education programs in reducing the risk of hemorrhage and achieving better treatment stability. The Grenoble region hospital-community network for vascular diseases (GRANTED) has developed an education program for these patients, consisting of individual sessions for the patient and/or a friend or family member (either at a health care facility or at the patient's home), telephone support and group sessions, and using educational tools and supports. There is also a link with the general practitioner who receives a report. This approach makes it possible to adapt the educational message to individual patients and their daily lives, as well as directly involving them in the management of their treatment.
Mukhopadhyay, Suman; Frias, Maria A; Chatterjee, Amrita; Yellen, Paige; Foster, David A
The mTOR pathway is a critical regulator of cell growth, proliferation, metabolism, and survival. Dysregulation of mTOR signaling has been observed in most cancers and, thus, the mTOR pathway has been extensively studied for therapeutic intervention. Rapamycin is a natural product that inhibits mTOR with high specificity. However, its efficacy varies by dose in several contexts. First, different doses of rapamycin are needed to suppress mTOR in different cell lines; second, different doses of rapamycin are needed to suppress the phosphorylation of different mTOR substrates; and third, there is a differential sensitivity of the two mTOR complexes mTORC1 and mTORC2 to rapamycin. Intriguingly, the enigmatic properties of rapamycin dosage can be explained in large part by the competition between rapamycin and phosphatidic acid (PA) for mTOR. Rapamycin and PA have opposite effects on mTOR whereby rapamycin destabilizes and PA stabilizes both mTOR complexes. In this review, we discuss the properties of rapamycin dosage in the context of anticancer therapeutics.
Jensen, A S; Idorn, L; Nørager, B
Adults with congenital heart disease are a growing population. One of the major challenges in the care of these patients is to prevent thromboembolic episodes. Despite relative young age and no typical cardiovascular risk factors, this cohort has a high prevalence of thrombotic events....... It is difficult to use treatment algorithms from the general adult population with acquired heart disease in this heterogeneous population due to special conditions such as myocardial scarring after previous surgery, atypical atrial flutter, prothrombotic conditions and the presence of interatrial shunts....... Furthermore, there is a lack of scientific evidence regarding how to prevent thromboembolic events with anticoagulation in adults with congenital heart disease. The aim of this paper is to review the current literature pertaining to anticoagulation in adults with congenital heart disease and hence enable...
Shapiro, Susie; Laffan, Mike
After 60 years in which warfarin has been the only practical oral anticoagulant, a number of new oral anticoagulants are entering practice. These drugs differ in a several important respects from warfarin; most notably they have a reliable dose-response effect which means they can be given without the need for monitoring. Their simpler metabolism and mode of action also results in fewer interactions with other drugs and with diet. However, some of their other properties such as renal clearance (to varying degrees), short half-life and lack of an available antidote may slow their rate of introduction. Large trials have established their non-inferiority to warfarin in a number of indications and in some cases their superiority. To date they have been licensed for prophylaxis following high risk orthopaedic procedures, non-valvular atrial fibrillation and treatment of venous thromboembolism, but is not clear that they will supplant warfarin in all areas.
Albuquerque, I R L; Queiroz, K C S; Alves, L G; Santos, E A; Leite, E L; Rocha, H A O
Fucan is a term used to denote a family of sulfated L-fucose-rich polysaccharides which are present in the extracellular matrix of brown seaweed and in the egg jelly coat of sea urchins. Plant fucans have several biological activities, including anticoagulant and antithrombotic, related to the structural and chemical composition of polysaccharides. We have extracted sulfated polysaccharides from the brown seaweed Dictyota menstrualis by proteolytic digestion, followed by separation into 5 fractions by sequential acetone precipitation. Gel electrophoresis using 0.05 M 1,3-diaminopropane-acetate buffer, pH 9.0, stained with 0.1% toluidine blue, showed the presence of sulfated polysaccharides in all fractions. The chemical analyses demonstrated that all fractions are composed mainly of fucose, xylose, galactose, uronic acid, and sulfate. The anticoagulant activity of these heterofucans was determined by activated partial thromboplastin time (APTT) using citrate normal human plasma. Only the fucans F1.0v and F1.5v showed anticoagulant activity. To prolong the coagulation time to double the baseline value in the APTT, the required concentration of fucan F1.0v (20 g/ml) was only 4.88-fold higher than that of the low molecular weight heparin Clexane (4.1 g/ml), whereas 80 g/ml fucan 1.5 was needed to obtain the same effect. For both fucans this effect was abolished by desulfation. These polymers are composed of fucose, xylose, uronic acid, galactose, and sulfate at molar ratios of 1.0:0.8:0.7:0.8:0.4 and 1.0:0.3:0.4:1.5:1.3, respectively. This is the fist report indicating the presence of a heterofucan with higher anticoagulant activity from brown seaweed.
Full Text Available Fucan is a term used to denote a family of sulfated L-fucose-rich polysaccharides which are present in the extracellular matrix of brown seaweed and in the egg jelly coat of sea urchins. Plant fucans have several biological activities, including anticoagulant and antithrombotic, related to the structural and chemical composition of polysaccharides. We have extracted sulfated polysaccharides from the brown seaweed Dictyota menstrualis by proteolytic digestion, followed by separation into 5 fractions by sequential acetone precipitation. Gel electrophoresis using 0.05 M 1,3-diaminopropane-acetate buffer, pH 9.0, stained with 0.1% toluidine blue, showed the presence of sulfated polysaccharides in all fractions. The chemical analyses demonstrated that all fractions are composed mainly of fucose, xylose, galactose, uronic acid, and sulfate. The anticoagulant activity of these heterofucans was determined by activated partial thromboplastin time (APTT using citrate normal human plasma. Only the fucans F1.0v and F1.5v showed anticoagulant activity. To prolong the coagulation time to double the baseline value in the APTT, the required concentration of fucan F1.0v (20 µg/ml was only 4.88-fold higher than that of the low molecular weight heparin Clexane® (4.1 µg/ml, whereas 80 µg/ml fucan 1.5 was needed to obtain the same effect. For both fucans this effect was abolished by desulfation. These polymers are composed of fucose, xylose, uronic acid, galactose, and sulfate at molar ratios of 1.0:0.8:0.7:0.8:0.4 and 1.0:0.3:0.4:1.5:1.3, respectively. This is the fist report indicating the presence of a heterofucan with higher anticoagulant activity from brown seaweed.
Patel Kinjal B; Galani Varsha; Patel Paresh B; Mehta Hiren R
Thrombin plays a key role in thrombotic events, and therefore thrombin inhibition represents a therapeutic target for numerous thromboembolic diseases. Thrombin is responsible for the conversion of soluble fibrinogen to fibrin; clot stabilization through activation of factor XIII and the formation of cross-linkage among fibrin molecules; and the generation of additional thrombin through activation of factors V, VIII, and XI. Direct thrombin inhibitors are an innovative class of anticoagulant...
Shaikh, Safiya Imtiaz; Kumari, R. Vasantha; Hegade, Ganapati; Marutheesh, M.
Anticoagulants remain the primary strategy for the prevention and treatment of thrombosis. Unfractionated heparin, low molecular weight heparin (LMWH), fondaparinux, and warfarin have been studied and employed extensively with direct thrombin inhibitors typically reserved for patients with complications or those requiring interventions. Novel oral anticoagulants have emerged from clinical development and are expected to replace older agents with their ease to use and more favorable pharmacodynamic profiles. Increasingly, anesthesiologists are being requested to anesthetize patients who are on some form of anticoagulants and hence it is important to have sound understanding of pharmacology, dosing, monitoring, and toxicity of anticoagulants. We searched the online databases including PubMed Central, Cochrane, and Google Scholar using anticoagulants, perioperative management, anesthetic considerations, and LMWH as keywords for the articles published between 1994 and 2015 while writing this review. In this article, we will review the different classes of anticoagulants and how to manage them in the perioperative settings.
John J. Mondin II
Full Text Available Anticoagulation has proven to be one of the most essential breakthroughs in cardiology in the last 100 years. The first major oral anticoagulant, warfarin, is a 4-hydroxycourmarin first synthesized in the 1940s for use as a rodenticide. It was not until 1954 that warfarin was finally approved by the FDA for use in patients requiring systemic anticoagulation. For over 55 years, warfarin was the only oral anticoagulant available in the United States until the approval of dabigatran in 2010, ushering in the era of the direct oral anticoagulants. This article will review modalities of anticoagulation reversal including activated charcoal, hemodialysis, blood-derived products, and medications currently available as well as in development.
Full Text Available Helia Robert-Ebadi, Grégoire Le Gal, Marc RighiniDivision of Angiology and Hemostasis (HRE, MR, Department of Internal Medicine, Geneva University Hospital and Faculty of Medicine, Geneva, Switzerland, and Department of Internal Medicine and Chest Diseases, EA 3878 (GETBO, Brest University Hospital, Brest, France (GLGAbstract: Elderly people represent a patient population at high thromboembolic risk, but also at high hemorrhagic risk. There is a general tendency among physicians to underuse anticoagulants in the elderly, probably both because of underestimation of thromboembolic risk and overestimation of bleeding risk. The main indications for anticoagulation are venous thromboembolism (VTE prophylaxis in medical and surgical settings, VTE treatment, atrial fibrillation (AF and valvular heart disease. Available anticoagulants for VTE prophylaxis and initial treatment of VTE are low molecular weight heparins (LMWH, unfractionated heparin (UFH or synthetic anti-factor Xa pentasaccharide fondaparinux. For long-term anticoagulation vitamin K antagonists (VKA are the first choice and only available oral anticoagulants nowadays. Assessing the benefit-risk ratio of anticoagulation is one of the most challenging issues in the individual elderly patient, patients at highest hemorrhagic risk often being those who would have the greatest benefit from anticoagulants. Some specific considerations are of utmost importance when using anticoagulants in the elderly to maximize safety of these treatments, including decreased renal function, co-morbidities and risk of falls, altered pharmacodynamics of anticoagulants especially VKAs, association with antiplatelet agents, patient education. Newer anticoagulants that are currently under study could simplify the management and increase the safety of anticoagulation in the future.Keywords: anticoagulation, elderly patients, venous thromboembolism, hemorrhagic risk, atrial fibrillation, thrombin inhibitors, factor Xa
TABUCHI, N; NJO, TL; TIGCHELAAR, [No Value; HUYZEN, RJ; BOONSTRA, PW; VANOEVEREN, W
Since aprotinin has become extensively used during cardiopulmonary bypass the maintenance of safe anticoagulation is a concern. Aprotinin affects anticoagulation measurement by the activated clotting time. Therefore, a reliable new measurement is needed to monitor anticoagulation during cardiopulmon
Full Text Available Tiffany Lee, Erin Davis, Jason Kielly School of Pharmacy, Memorial University, St John's, NL, Canada Background: Anticoagulant therapies provide management options for potentially life-threatening thromboembolic conditions. They also carry significant safety risks, requiring careful consideration of medication dose, close monitoring, and follow-up. Inpatients are particularly at risk, considering the widespread use of anticoagulants in hospitals. This has prompted the introduction of safety goals for anticoagulants in Canada and the USA, which recommend increased pharmacist involvement to reduce patient harm. The goal of this review is to evaluate the efficacy and safety of pharmacist-led inpatient anticoagulation services compared to usual or physician-managed care. Methods: This narrative review includes articles identified through a literature search of PubMed, Embase, and International Pharmaceutical Abstracts databases, as well as hand searches of the references of relevant articles. Full publications of pharmacist-managed inpatient anticoagulation services were eligible if they were published in English and assessed clinical outcomes. Results: Twenty-six studies were included and further divided into two categories: 1 autonomous pharmacist-managed anticoagulation programs (PMAPs and 2 pharmacist recommendation. Pharmacist management of heparin and warfarin appears to result in improvements in some surrogate outcomes (international normalized ratio [INR] stability and time in INR goal range, while results for others are mixed (time to therapeutic INR, length of stay, and activated partial thromboplastin time [aPTT] measures. There is also some indication that PMAPs may be associated with reduced patient mortality. When direct thrombin inhibitors are managed by pharmacists, there seems to be a shorter time to therapeutic aPTT and a greater percentage of time in the therapeutic range, as well as a decrease in the frequency of medication
Testa, Sophie; Paoletti, Oriana; Zimmermann, Anke; Bassi, Laura; Zambelli, Silvia; Cancellieri, Emilia
Anticoagulation Clinics (ACs) are services specialized in management of patients on anticoagulant treatment. At present, ACs manage patients chiefly on antivitamin K antagonists (AVKs), but patient population has already changed in the last few years, because of an increase of treatments with other anticoagulant drugs, which require different management systems. The strong increase in the number of patients at AC, mainly on long-term treatment, has determined the development of web management, through telemedicine systems, improving the quality of life and maintaining the same clinical quality levels. New oral anticoagulants (NOAs) have shown to be as effective as AVK antagonists in stroke prevention in atrial fibrillation and for treatment of venous thromboembolism in addition to VTE prophylaxis in orthopaedic surgery, when administered at a fixed dose, but patient adherence and compliance are crucial for good quality treatment. At present, lacking data from the real world, an oversimplification of treatment with NOAs could cause unjustified risks for patients and also a possible future underuse of good drugs. For these reasons the vigilance must be high and ACs can have a crucial role in defining which is the best management for NOA patients and how to do it, as it happened for AVKs.
Full Text Available Anticoagulation Clinics (ACs are services specialized in management of patients on anticoagulant treatment. At present, ACs manage patients chiefly on antivitamin K antagonists (AVKs, but patient population has already changed in the last few years, because of an increase of treatments with other anticoagulant drugs, which require different management systems. The strong increase in the number of patients at AC, mainly on long-term treatment, has determined the development of web management, through telemedicine systems, improving the quality of life and maintaining the same clinical quality levels. New oral anticoagulants (NOAs have shown to be as effective as AVK antagonists in stroke prevention in atrial fibrillation and for treatment of venous thromboembolism in addition to VTE prophylaxis in orthopaedic surgery, when administered at a fixed dose, but patient adherence and compliance are crucial for good quality treatment. At present, lacking data from the real world, an oversimplification of treatment with NOAs could cause unjustified risks for patients and also a possible future underuse of good drugs. For these reasons the vigilance must be high and ACs can have a crucial role in defining which is the best management for NOA patients and how to do it, as it happened for AVKs.
JIANG Chen-yang(蒋晨阳); ZHAO Li-li(赵莉莉); WANG Jian-an(王建安); SAN Jiang(单江); MOHAMMOD Balgaith
Objective: To investigate if intra-aortic balloon pump(IABP) is contraindicated without anticoagulation therapy. Methods: Some 153 IABP patients in the King Abdulaziz Cardiac Center(KSA) were randomly assigned into two groups. Anticoagulation group(Group A) consisted of 71 patients who were given heparin intravenously with target aPTT 50-70 seconds. Non-anticoagulation group(Group B) consisted of 82 patients without intravenous heparin during balloon pumping. Hematological parameters including platelet count, D-dimer, Plasminogen activator inhibitor-1(PAI-1) and fibrinogen degradation products(FDP) were checked respectively at the point of baseline, 24 hours, 48 hours and 24 hours post IABP counterpulsation. Clot deposits on balloon surface, vascular complications from IABP including bleeding and limb ischemia were recorded. Results: Platelet count and PAI-1 level decreased at 24 hours and 48 hours in both groups (P0.05). Three patients in Group A and 2 patients in Group B developed minor limb ischemia(P>0.05). No major limb ischemia in either group. Two patients in Group A suffered major bleeding and required blood transfusion or surgical intervention, whereas no patient had major bleeding in Group B. Eight patients had minor bleeding in Group A, but only 2 patients in Group B(P<0.05). No clot deposit developed on IABP surface in either group. Conclusion: IABP is safe without routine anticoagulation therapy. Selecting appropriate artery approach and early detection intervention are key methods for preventing complications.
Full Text Available Tiffany Y Hu,1 Vaibhav R Vaidya,2 Samuel J Asirvatham2,31Mayo Medical School, 2Division of Cardiovascular Diseases, Department of Internal Medicine, 3Department of Pediatrics and Adolescent Medicine, Mayo Clinic, Rochester, MN, USAAbstract: Novel oral anticoagulants (NOACs are increasingly used in clinical practice, but lack of commercially available reversal agents is a major barrier for mainstream use of these therapies. Specific antidotes to NOACs are under development. Idarucizumab (aDabi-Fab, BI 655075 is a novel humanized mouse monoclonal antibody that binds dabigatran and reverses its anticoagulant effect. In a recent Phase III study (Reversal Effects of Idarucizumab on Active Dabigatran, a 5 g intravenous infusion of idarucizumab resulted in the normalization of dilute thrombin time in 98% and 93% of the two groups studied, with normalization of ecarin-clotting time in 89% and 88% patients. Two other antidotes, andexanet alfa (PRT064445 and ciraparantag (PER977 are also under development for reversal of NOACs. In this review, we discuss commonly encountered management issues with NOACs such as periprocedural management, laboratory monitoring of anticoagulation, and management of bleeding. We review currently available data regarding specific antidotes to NOACs with respect to pharmacology and clinical trials.Keywords: novel oral anticoagulant, dabigatran, idarucizumab, reversal
Olesen, Jonas Bjerring; Sørensen, Rikke; Hansen, Morten Lock
AIMS: Non-vitamin K antagonist oral anticoagulation (NOAC) agents have been approved for stroke prophylaxis in atrial fibrillation (AF). We investigated 'real-world' information on how these drugs are being adopted. METHODS AND RESULTS: Using Danish nationwide administrative registers, we identif...
蒋晨阳; 赵莉莉; 王建安; 单江; MOHAMMODBalgaith
Objective: To investigate if intra-aortic balloon pump(IABP) is contraindicated without anticoag-ulation therapy. Methods: Some 153 IABP patients in the King Abdulaziz Cardiac Center(KSA) were random-ly assigned into two groups. Anticoagulation group( Group A) consisted of 71 patients who were given heparin intravenously with target aPTT 50 - 70 seconds. Non-anticoagulation group( Group B) consisted of 82 patients without intravenous heparin during balloon pumping. Hematological parameters including platelet count, D-dimer, Plasminogen activator inhibitor-1 (PAI-1) and fibrinogen degradation products(FDP) were checked respectively at the point of baseline, 24 hours, 48 hours and 24 hours post IABP counterpulsation. Clot deposits on balloon surface, vascular complications from IABP including bleeding and limb ischemia were recorded.Results: Platelet count and PAI-1 level decreased at 24 hours and 48 hours in both groups ( P 0.05) . Three patients in Group A and 2 patients in Group B developed minor limb ischemia( P > 0.05). No major limb ischemia in either group. Two patients in Group A suffered major bleeding and required blood transfusion or surgical intervention, whereas no patient had major bleeding in Group B. Eight patients had minor bleeding in Group A, but only 2 patients in Group B ( P <0.05). No clot deposit developed on IABP surface in either group. Conclusion: IABP is safe without routine anticoagulation therapy. Selecting appropriate artery approach and early detection intervention are key methods for preventing complications.
Szakonyi, Gergely; Zelkó, Romána
The present paper summarizes the commonly applied types of drug uptake and the pharmacists' advice concerning a certain dosage form. The manuscript also deals with the modified release dosage forms and their abbreviations in the name of the marketing authorized products.
Stanley M. Gartler
In 1914, H. J. Muller postulated the origin of the Y chromosome as having resulted from restricted recombination between homologous sex chromosomes in the male and the accumulation of deleterious mutations. This evolutionary process leads to dosage compensation. This article lays out a brief history of dosage compensation in genetics.
Full Text Available Carole Decker,1 Linda Garavalia,2 Brian Garavalia,1 Teresa Simon,3 Matthew Loeb,4 John Spertus6, William Daniel51Mid America Heart Institute at Saint Luke's Hospital in Kansas City Missouri, University of Missouri-Kansas City School of Nursing, 2University of Missouri-Kansas City School of Pharmacy, Kansas City, MO, 3Bristol-Myers Squibb, Princeton, NJ, 4Plaza Primary Care and Geriatrics, 5Saint Luke's Cardiovascular Consultants, Kansas City, MO, 6Mid America Heart Institute at Saint Luke's Hospital in Kansas City Missouri, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USABackground: Warfarin, the most commonly used antithrombotic agent for stroke prophylaxis in atrial fibrillation (AF, requires regular monitoring, frequent dosage adjustments, and dietary restrictions. Clinicians' perceptions of barriers to optimal AF management are an important factor in treatment. Anticoagulation management for AF is overseen by both cardiology and internal medicine (IM practices. Thus, gaining the perspective of specialists and generalists is essential in understanding barriers to treatment. We used qualitative research methods to define key issues in the prescription of warfarin therapy for AF by cardiology specialists and IM physicians.Methods and results: Clinicians were interviewed to identify barriers to warfarin treatment in a large Midwestern city. Interviews were conducted until thematic saturation occurred. Content analysis yielded several themes. The most salient theme that emerged from clinician interviews was use of characteristics other than the patient's CHADS2 score to enact a treatment plan, such as the patient's social situation and past medication-taking behavior. Other themes included patient knowledge, real-world problems, breakdown in communication, and clinician reluctance.Conclusion: Warfarin treatment is associated with many challenges. The barriers identified by clinicians highlight the unmet need associated
Markussen, Mette D.; Heiberg, Ann-Charlotte; Nielsen, Robert;
Norway rats, Rattus norvegicus, Denmark, anticoagulant rodenticide resistance, vitamin K requirement......Norway rats, Rattus norvegicus, Denmark, anticoagulant rodenticide resistance, vitamin K requirement...
Pengo, V.; Tripodi, A.; Reber, G.; Rand, J. H.; Ortel, T. L.; Galli, M.; de Groot, P. G.
One of the conclusions of the subcommittee meeting on Lupus Anticoagulant/Phospholipid dependent antibodies, held in Geneva on 2007, was the need to update the guidelines on Lupus Anticoagulant (LA) detection. Particular emphasis was given to several aspects discussed in this official communication.
Herman, W W; Konzelman, J L; Sutley, S H
Despite approximately 40 years of experience with oral anticoagulant drugs, controversy still exists about the safety of dental treatment in a patient receiving this therapy. The authors review the topic in depth and offer detailed recommendations for the dental management of patients receiving coumarin anticoagulant therapy.
L.E. Visser (Loes)
textabstractThis introductory chapter has illustrated that various factors, such as genetic factors, drugs, diet and intercurrent diseases may affect anticoagulation levels. Most of the clinical and pharmacological data related to coumarin anticoagulants have so far been obtained from studying warfa
Atrial fibrillation (AF) increases the risk of stroke.New anticoagulation agents have recently provided alternative and promising approaches.This paper reviews the current state of anticoagulation therapy in AF patients,focusing on various clinical scenarios and on comparisons,where possible,between western and eastern populations.
Albaladejo, Alberto; Alvarado, Alfonso
Background A new group of oral anticoagulants (dabigatran, rivaroxaban, apixaban and edoxaban) with clear advantages over classic dicoumarin oral anticoagulants (warfarin and acenocoumarol) has been developed in recent years. Patients being treated with oral anticoagulants are at higher risk for bleeding when undergoing dental treatments. Material and Methods A literature search was conducted through April 2016 for publications in the ISI Web of Knowledge, PubMed and Cochrane Library using the keywords “dabigatran”, “rivaroxaban”, “apixaban”, “edoxaban”, “new oral anticoagulants”, “novel oral anticoagulants”, “bleeding” and “dental treatment”. Results There is no need for regular coagulation monitoring of patients on dabigatran therapy. Whether or not to temporarily discontinue dabigatran must be assessed according to the bleeding risk involved in the dental procedure to be performed. Conclusions The number of patients under treatment with new oral anticoagulants will increase in the coming years. It is essential to know about the pharmacokinetics and pharmacodynamics of new oral anticoagulants and about their interactions with other drugs. It is necessary to develop clinical guidelines for the perioperative and postoperative management of these new oral anticoagulants in oral surgical procedures, and to carefully evaluate the bleeding risk of dental treatment, as well as the thrombotic risk of suppressing the new oral anticoagulant. Key words:Dabigatran, rivaroxaban, apixaban, edoxaban, novel oral anticoagulants, bleeding. PMID:28210451
Alaali, Yathreb; Barnes, Geoffrey D; Froehlich, James B; Kaatz, Scott
Approximately 4.2 million patients in the United States are taking warfarin, making it the 11th most prescribed drug. Warfarin is primarily used for treatment of venous thromboembolic disease and stroke prevention in patients with atrial fibrillation and mechanical heart valves. Dentists frequently encounter anticoagulated patients and are faced with management decisions in these patients who require dental procedures. Observational studies suggest the risk of thrombosis if anticoagulation is suspended during dental procedures is higher than the risk of bleeding if anticoagulation is not suspended. Several groups now offer guidelines that recommend most minor dental procedures should be performed while on therapeutic warfarin. The recent approval of several new oral anticoagulants has introduced greater complexity to the management of the anticoagulated patient, and this narrative review will discuss current guidelines, the scientific underpinnings of the guidelines, and offer some practical suggestions for patients that are receiving the new agents.
Gary W. Moore
Full Text Available Antiphospholipid syndrome is an autoimmune, acquired thrombophilia diagnosed when vascular thrombosis or pregnancy morbidity are accompanied by persistent antiphospholipid antibodies. Lupus anticoagulants (LA are one of the criteria antibodies but calibration plasmas are unavailable and they are detected by inference based on antibody behaviour in a medley of coagulation-based assays. Elevated screening tests suggest the presence of a LA, which is confirmed with mixing tests to evidence inhibition and confirmatory tests to demonstrate phospholipid-dependence. At least two screening tests of different principle must be used to account for antibody heterogeneity and controversy exists on whether assays, in addition to dilute Russell’s viper venom time and activated partial thromboplastin time, should be employed. A variety of approaches to raw data manipulation and interpretation attract debate, as does inclusion or exclusion of mixing studies in circumstances where the presence of a LA is already evident from other results. Therapeutic anticoagulation compromises coagulation-based assays but careful data interpretation and use of alternative reagents can detect or exclude LA in specific circumstances, and this aspect of LA detection continues to evolve. This review focuses on the main areas of debate in LA detection.
Full Text Available Abstract Background Patient education is an essential component in quality management of the anticoagulated patient. Because it is time consuming for clinicians and overwhelming for patients, education of the anticoagulated patient is often neglected. We surveyed the medical literature in order to identify the best patient education strategies. Methods Study Selection: Two reviewers independently searched the MEDLINE and Google Scholar databases (last search March 2007 using the terms "warfarin" or "anticoagulation", and "patient education". The initial search identified 206 citations, A total of 166 citations were excluded because patients were of pediatric age (4, the article was not related to patient education (48, did not contain original data or inadequate program description (141, was focused solely on patient self-testing (1, was a duplicate citation (3, the article was judged otherwise irrelevant (44, or no abstract was available (25. Data Extraction: Clinical setting, study design, group size, content source, time and personnel involved, educational strategy and domains, measures of knowledge retention. Results Data Synthesis: A total of 32 articles were ultimately used for data extraction. Thirteen articles adequately described features of the educational strategy. Five programs used a nurse or pharmacist, 4 used a physician, and 2 studies used other personnel/vehicles (lay educators (1, videotapes (1. The duration of the educational intervention ranged from 1 to 10 sessions. Patient group size most often averaged 3 to 5 patients but ranged from as low as 1 patient to as much as 11 patients. Although 12 articles offered information about education content, the wording and lack of detail in the description made it too difficult to accurately assign categories of education topics and to compare articles with one another. For the 17 articles that reported measures of patient knowledge, 5 of the 17 sites where the surveys were
Narang, Ajit S; Desai, Divyakant; Badawy, Sherif
Complete characterization and mechanistic understanding of physicochemical interactions in solid dosage forms are not only important for consistent manufacturability, stability, and bioavailability of the drug product, but are also expected under the quality-by-design paradigm of drug development. Lack of this understanding can impact successful and timely development, scale-up, and commercial manufacture of dosage forms. This article highlights the stability and bioavailability implications of physicochemical interactions in dosage forms citing a couple of examples where such interactions necessitated the recall of commercial drug products.
González Bárcenas, Martha L; Pérez Aisa, Ángeles
The development of novel antithrombotic therapy in the past few years and its prescription in patients with cardiovascular and circulatory disease has widened the spectrum of drugs that need to be considered when performing an endoscopic procedure. The balance between the thrombotic risk patients carry due to their medical history and the bleeding risk involved in endoscopic procedures should be thoroughly analyzed by Gastroenterologists. New oral anticoagulants (NOACs) impose an additional task. These agents, that specifically target factor IIa or Xa, do not dispose of an anticoagulation monitoring method nor have an antidote to revert their effect, just as with antiplatelet agents. Understanding the fundamental aspects of these drugs provides the necessary knowledge to determine the ideal period the antithrombotic therapy should be interrupted in order to perform the endoscopic procedure, offering maximum safety for patients and optimal results.
Martha L. González-Bárcenas
Full Text Available The development of novel antithrombotic therapy in the past few years and its prescription in patients with cardiovascular and circulatory disease has widened the spectrum of drugs that need to be considered when performing an endoscopic procedure. The balance between the thrombotic risk patients carry due to their medical history and the bleeding risk involved in endoscopic procedures should be thoroughly analyzed by Gastroenterologists. New oral anticoagulants (NOACs impose an additional task. These agents, that specifically target factor IIa or Xa, do not dispose of an anticoagulation monitoring method nor have an antidote to revert their effect, just as with antiplatelet agents. Understanding the fundamental aspects of these drugs provides the necessary knowledge to determine the ideal period the antithrombotic therapy should be interrupted in order to perform the endoscopic procedure, offering maximum safety for patients and optimal results.
Krueger, Kirsten; Schmutz, Axel; Zieger, Barbara; Kalbhenn, Johannes
patients presented with essential clinical bleeding after 7 days of therapy. No fatal bleeding event and no intracranial hemorrhage was observed. Patients required only a third of blood product transfusion compared to published data. Venovenous ECMO therapy with prophylactic anticoagulation only was feasible in this study. It was not associated with an increased rate of system exchanges compared to regimes with therapeutic anticoagulation in registry data. It provides the potential to relevantly decrease the incidence of severe bleeding events and blood transfusion requirements. The apodictic adherence to anticoagulation in therapeutic dosage should be critically scrutinized in every patient.
E. N. Bochanova
Full Text Available A complex system of hemostasis regulation, insufficient data on drugs pharmacokinetics, multiple factors effecting treatment, including patient’s adherence to therapy, that can lead to the need for the dosage regimen specification are presented.
Dorlo, Thomas P. C.; Kager, Piet A.
Pentamidine has a long history in the treatment of human African trypanosomiasis (HAT) and leishmaniasis. Early guidelines on the dosage of pentamidine were based on the base-moiety of the two different formulations available. Confusion on the dosage of pentamidine arose from a different labelling of the two available products, either based on the salt or base moiety available in the preparation. We provide an overview of the various guidelines concerning HAT and leishmaniasis over the past d...
Full Text Available This review attempts to answer the common questions faced by a clinician regarding thromboembolism and thromboprophylaxis in patients following Fontan surgery. The review is in an easy to understand question and answer format and discusses the currently available literature on the subject in an attempt to arrive at practical clinically relevant solutions. Patients who have undergone the Fontan operation are at a high risk for thromboembolism. Based on available evidence, there is a strong rationale for thromboprophylaxis. However, it is not clear as to which agent should be administered to prevent thromboembolic events. While the available evidence suggests that antiplatelet agents alone may be as good as oral anticoagulants, there is a need for a large multicenter randomized control trial comparing these two common strategies to deliver a clear verdict.
Full Text Available New oral anticoagulants are an effective and safe alternative to vitamin K antagonists in many fields of clinical practice. The use of the direct inhibitors of activated Factor II (dabigatran and activated Factor X (apixaban and rivaroxaban, both in patients with non-valvular atrial fibrillation (NVAF and those with acute venous thromboembolism (VTE, is of great interest for internal medicine physicians. This paper aims to give practical guidance on management (starting therapy, follow up and bleeding complications of patients treated with dabigatran, rivaroxaban or apixaban for NVAF or acute VTE providing practical tables concerning the phases of therapy, management of complications, drug interaction and dose adjustment if renal impairment occurs.
Khorev, N G; Momot, A P; Kon'kova, V O
During the last 10 years, several novel direct oral anticoagulants (NOACs) have entered the clinical arena and were registered in the Russian Federation for use in patients presenting with atrial fibrillation, venous thrombosis, and pulmonary artery thromboembolism. NOACs are classified into two groups: direct thrombin inhibitor (notably dabigatran) and factor Xa inhibitors (including rivaroxaban, apixaban, and edoxaban). Their disadvantage is lack of specific antidotes in case of an emergency situation (injury, infarction, stroke requiring thrombolysis, urgent operation). The review contains the data on the existing therapeutic regimens of treating haemorrhage on the background of taking these coagulants. This is followed by analysing the present-day results of clinical trials aimed at working out pharmaceutical agents (andexanet alpha, idarucizumab, aripazine) being antidotes to direct thrombin inhibitor and the factor Xa inhibitors. Administration of these agents makes it possible to reverse coagulation and minimize the aftermaths of haemorrhage in patients taking these drugs, in emergency situations.
Simeon, L; Nagler, M; Wuillemin, W A
The new oral anticoagulants (NOACs) represent alternative antithrombotic agents for prophylaxis and therapy of thromboembolic diseases. They act either by inhibition of the clotting factor Xa or IIa (thrombin). As a consequence, they influence several coagulation assays (for example prothrombin time, activated partial thromboplastin time). Because of the short half-life of these new agents, these changes show great variations in the course of 24 hours. Furthermore, there are significant differences of laboratory results depending on the used reagents. We explain the influence of apixaban, rivaroxaban (factor Xa inhibitors) and dabigatran (thrombin inhibitor) on the most commonly used coagulation assays. Besides we show that this influence depends on the way of action of the drug as well as on the principle of the coagulation assay. Being aware of this relationships helps to interpret the results of coagulation assays under influence of NOACs correctly.
This review attempts to answer the common questions faced by a clinician regarding thromboembolism and thromboprophylaxis in patients following Fontan surgery. The review is in an easy to understand question and answer format and discusses the currently available literature on the subject in an attempt to arrive at practical clinically relevant solutions. Patients who have undergone the Fontan operation are at a high risk for thromboembolism. Based on available evidence, there is a strong rationale for thromboprophylaxis. However, it is not clear as to which agent should be administered to prevent thromboembolic events. While the available evidence suggests that antiplatelet agents alone may be as good as oral anticoagulants, there is a need for a large multicenter randomized control trial comparing these two common strategies to deliver a clear verdict.
Eusébio, Jorge; Reny, Jean-Luc; Fontana, Pierr; Nendaz, Mathieu
If the benefits of antiplatelet and anticoagulant therapies are well established, bleeding complications appear underestimated in trials in comparison to their real-life incidence. Also, a large number of patients receive various associations of antiplatelet or anticoagulant treatments, while the benefit of some associations is not firmly established and data about their safety are missing. Identifying patients at high risk of bleeding is essential to define appropriate strategies. In this article we discuss the risk-benefit of various antiplatelet and anticoagulant molecules taken individually or in combination. An overview of the main clinical scores available to stratify the risk of bleeding is presented.
Myers, B; Neal, R; Myers, O; Ruparelia, M
Direct oral anticoagulants (DOACs or NOACs -non-vitamin K oral anticoagulants), as the name suggests, are oral anticoagulants with a direct inhibitory action either against factor X or factor II (thrombin). Pregnant women were excluded from participating in all the large trials of the DOACs and they are considered contra-indicated in pregnancy and breast feeding. We present a case of inadvertent exposure to rivaroxaban in a woman who presented at 25 weeks' gestation. The management of her pregnancy and delivery is described, and the previous published case reports are reviewed with a discussion about the use of DOACs in woman of childbearing age.
Scott, Alun; Gibson, John; Crighton, Alexander
Recently, new oral anticoagulants have been introduced as alternatives to warfarin. While national guidelines for treatment of dental patients taking warfarin as an anticoagulant are well-established, no such information is available for these novel therapeutic agents. At present, the local guidance available is contradictory between different health boards/health planning units, and liaison with the medical practitioner managing the individual patient's anticoagulation is imperative if any invasive procedure is proposed. This paper examines the available evidence regarding these drugs and sets out proposals for clinical guidance of dental practitioners treating these patients in primary dental care.
Full Text Available Vitamin K antagonists (VKA are among the most widely prescribed drugs in the industrialized world. In fact, for decades, VKA have been the only orally available anticoagulant for the primary and secondary prevention of venous and arterial thrombotic events. Their efficacy has been widely demonstrated in a series of studies carried out in the 1990s. Since the incidences of atrial fibrillation and venous thromboembolism increase exponentially with age, the number of anticoagulated patients is destined to increase. This paper examines anticoagulation therapy management with particular attention to the use of VKA.
Montes Díaz, R; Nantes, O; Molina, E; Zozaya, J; Hermida, J
The degree of anticoagulation obtained during oral anticoagulation therapy with vitamin K antagonists (VKA) varies among patients due to individual and environmental factors. The rate of anticoagulation influences the hemorrhagic risk. Therefore, it is plausible that patients specially sensitive to oral anticoagulants are at higher hemorrhagic risk, specially during the first weeks. The role of a series of polymorphisms of the enzymes involved in the metabolism of VKA or in the vitamin K cycle are reviewed. Three polymorphisms, two in the cytochrome P450 2C9 and one in the VKORC1 enzyme, are responsible for a high portion of the variability observed in the sensitivity to AVK. Although the available literature suggests that these genetic variants could increase the risk of severe hemorrhage, larger, well designed studies are needed to confirm this notion.
Full Text Available When a patient receiving new oral anticoagulants (NOACs requires an invasive procedure, the consequences of bleeding if anticoagulation is continued and the risk of thrombosis if it is omitted need to be carefully considered. In addition to the bleeding risk of the procedure, it is of paramount importance to evaluate the renal function, especially for dabigatran that is eliminated predominantly via the renal pathway. NOAC therapy should be stopped for at least 24 h before the intervention, and a longer interruption should be considered in cases of high bleeding risk procedures and/or renal failure. A base-line assessment of coagulation should be performed and intervention should be postponed (if possible if high levels of anticoagulation parameters are found. In the post-surgical period, if oral anticoagulant therapy cannot be re-started, patients should temporarily receive low molecular weight heparins and re-start NOACs as soon as possible.
Simon J McRae
Full Text Available Simon J McRae, Jeffrey S GinsbergDepartment of Medicine, McMaster University, Hamilton, ON, CanadaAbstract: Anticoagulant therapy is effective at preventing the development of venous thromboembolism in high-risk patients, and reduces morbidity and mortality in individuals with established thromboembolic disease. Vitamin K antagonists and heparins are currently the most commonly used anticoagulant drugs, but they have practical limitations. Therefore, new antithrombotic agents with predictable dose-responses (thereby decreasing the need for monitoring without compromising efficacy or safety, ideally available in an oral formulation and with a rapidly reversible anticoagulant effect, are needed. New drugs fulfilling some of the above criteria have been developed and have proven to be effective agents for the treatment and prevention of venous thromboembolism.Keywords: venous thromboembolism, anticoagulants, antithrombotic
Rasmussen, Rune Skovgaard; Corell, Pernille; Madsen, Poul
UNLABELLED: BACKGROUND: Computer-assistance and self-monitoring lower the cost and may improve the quality of anticoagulation therapy. The main purpose of this clinical investigation was to use computer-assisted oral anticoagulant therapy to improve the time to reach and the time spent within...... in a computer system by an algorithm specific to each group. The third group received traditional anticoagulation treatment by physicians. The obtained INR values were compared regarding the time to reach, and the time spent within, the therapeutic target range, corresponding to INR values from 2 to 3. RESULTS......: Patients randomized to computer-assisted anticoagulation and the CoaguChek® system reached the therapeutic target range after 8 days compared to 14 days by prescriptions from physicians (p = 0.04). Time spent in the therapeutic target range did not differ between groups. The median INR value measured...
Dorlo, Thomas P C; Kager, Piet A
Pentamidine has a long history in the treatment of human African trypanosomiasis (HAT) and leishmaniasis. Early guidelines on the dosage of pentamidine were based on the base-moiety of the two different formulations available. Confusion on the dosage of pentamidine arose from a different labelling of the two available products, either based on the salt or base moiety available in the preparation. We provide an overview of the various guidelines concerning HAT and leishmaniasis over the past decades and show the confusion in the calculation of the dosage of pentamidine in these guidelines and the subsequent published reports on clinical trials and reviews. At present, only pentamidine isethionate is available, but the advised dosage for HAT and leishmaniasis is (historically) based on the amount of pentamidine base. In the treatment of leishmaniasis this is probably resulting in a subtherapeutic treatment. There is thus a need for a new, more transparent and concise guideline concerning the dosage of pentamidine, at least in the treatment of HAT and leishmaniasis.
Thomas P C Dorlo
Full Text Available Pentamidine has a long history in the treatment of human African trypanosomiasis (HAT and leishmaniasis. Early guidelines on the dosage of pentamidine were based on the base-moiety of the two different formulations available. Confusion on the dosage of pentamidine arose from a different labelling of the two available products, either based on the salt or base moiety available in the preparation. We provide an overview of the various guidelines concerning HAT and leishmaniasis over the past decades and show the confusion in the calculation of the dosage of pentamidine in these guidelines and the subsequent published reports on clinical trials and reviews. At present, only pentamidine isethionate is available, but the advised dosage for HAT and leishmaniasis is (historically based on the amount of pentamidine base. In the treatment of leishmaniasis this is probably resulting in a subtherapeutic treatment. There is thus a need for a new, more transparent and concise guideline concerning the dosage of pentamidine, at least in the treatment of HAT and leishmaniasis.
Wang, Yan-Yun; Chen, Mei; Li, Bin
Dosage compensation mechanism is crucial for the balance expression of X chromosome genes, which ensures the protein or enzyme encoded by the X chromosome to be equal or almost equal expression amounts between males and females. However, different organisms have evolved distinct dosage compensation strategies, and so far three kinds of dosage compensation strategies among organisms have been reported. The first strategy is that the single male X chromosome expression is doubly activated; the second one is to inactivate one female X chromosome by leaving both sexes with one active allele; and the third one is to reduce the expression to half activity in both X chromosomes of the female. The study of dosage compensation will be useful to reveal the mechanism of regulation of X-linked genes as well as the evolution and the differentiation progress of the sex chromosome, and it can also contribute to illustrate mutation and distortion of sex chromosome. Therefore, this paper briefly reviewed and discussed the progresses and prospects of the important mechanism of dosage compensation.
Nowak-Göttl, U; Langer, F; Limperger, V; Mesters, R; Trappe, R U
Oral anticoagulants [Vitamin-K-Antagonists, Dabigatran, Rivaroxaban, Apixaban] or antiplatelet agents [Aspirin, Clopidogrel, Prasugrel, Ticagrelor] are effective in preventing thromboembolic diseases. In case of interventional of surgical procedures patients with indications for chronic anticoagulation [atrial fibrillation, valve prosthesis, venous thromboembolism] or use of antiplatelet agents [cerebrovascular events, cardiovascular events] will require interruption of antithrombotic/antiplatelet therapy with the need of replacement with a short-acting agent. Due to limited data available from randomized studies and meta-analyses the evidence level is low in the majority of recommendations. Therefore for each patient the bleeding and thrombosis risk depending on the individual patient constitution and the planned intervention must be weighted. In patients with an intermediate risk for thrombosis the bleeding risk of the scheduled intervention will influence the bridging recommendation: In patients with a low bleeding risk oral anticoagulation/antiplatelet therapy can be continued or reduced in intensity. In patients with an intermediate or high bleeding risk along with a low thrombosis risk a temporary interruption of the anticoagulation/antiplatelet therapy is feasible. In patients with a high thrombosis and bleeding risk anticoagulation should be bridged with unfractionated heparin [renal insufficiency] or low molecular weight heparin. In the latter risk situation, inhibition of platelet function can be achieved with short-lasting GPIIb-IIIa inhibitors [Eptifibatide, Tirofiban]. Prior to intervention patients treated with the new oral anticoagulants [Dabigatran; Rivaroxaban; Apixaban] are requested to temporary interrupt the anticoagulation depending on the individual drug half-life and their renal function. Bridging therapy with heparin prior to intervention is not necessary with the new oral anticoagulants.
Belmar Vega, Lara; de Francisco, A L M; Bada da Silva, Jairo; Galván Espinoza, Luis; Fernández Fresnedo, Gema
Patients with chronic kidney disease (CKD) develop bleeding and thrombotic tendencies, so the indication of anticoagulation at the onset of atrial fibrillation (AF) is complex. AF is the most common chronic cardiac arrhythmia, and thromboembolism and ischemic stroke in particular are major complications. In recent years, new oral anticoagulant drugs have been developed, and they have shown superiority over the classical AVK in preventing stroke, systemic embolism and bleeding risk, constituting an effective alternative to those resources.
Sosa Rosado, José Manuel; Médico Cardiólogo, Clínica Internacional, Lima, Perú.
Atrial fibrillation is the most frequent cardiac arrhythmia in clinical practice. The value of anticoagulation with vitamin K antagonists like warfarin in the prevention of embolic phenomena is widely demonstrated but managing is difficult because of its known interactions with other drugs and even food. Looking for the ideal anticoagulant in the last years new antithrombotic agents have appeared and others are in advanced phases of investigation. In the current review results of new anticoag...
Feagins, Linda Anne
Colonoscopy frequently is performed for patients who are taking aspirin, NSAIDs, antiplatelet agents and other anticoagulants. These colonoscopies often involve polypectomy, which can be complicated by bleeding. The risks of precipitating thromboembolic complications if anticoagulants are stopped must be weighed against the risk of postpolypectomy bleeding if these agents are continued. This article systematically reviews the management of anticoagulation during elective and emergency colonoscopy. For patients undergoing colonoscopic polypectomy, the overall of risk of postpolypectomy bleeding is less than 0.5%. Risk factors for postpolypectomy bleeding include large polyp size and anticoagulant use, especially warfarin and thienopyridines. For patients who do not stop aspirin or other NSAIDs prior to colonoscopy, the rate of postpolypectomy bleeding is not significantly different than that for patients who do not take those medications. For patients who continue thienopyridines and undergo polypectomy, the risk of delayed postpolypectomy bleeding is approximately 2.4%. Even for patients who interrupt warfarin, the risk of postpolypectomy bleeding is increased. The direct oral anticoagulants (direct thrombin inhibitors and factor Xa inhibitors) have a rapid onset and offset of action, and periprocedural bridging generally is not necessary. For the thienopyridines, warfarin and the direct oral anticoagulants, the decision to interrupt or continue these agents for endoscopy will involve considerable exercise of clinical judgment.
Full Text Available L Bellamy1, N Rosencher1, BI Eriksson21Anaesthesiology Department, Hôpital Cochin (AP-HP, René Descartes University, Paris 75014 France; 2Orthopaedic Department, University Hospital Sahlgrenska/Ostra, Gothenburg, SwedenAbstract: The recent development of new oral anticoagulants, of which dabigatran etexilate is currently at the most advanced stage of development, is the greatest advance in the provision of convenient anticoagulation therapy for many years. A new oral anticoagulation treatment, dabigatran etexilate, is already on the market in Europe. The main interest probably will be to improve the prescription and the adherence to an effective thromboprophylaxis in medical conditions such as atrial fibrillation without bleeding side effects, without the need for monitoring coagulation, and without drug and food interactions such as vitamin K anticoagulant (VKA treatment. Dabigatran is particularly interesting for extended thromboprophylaxis after major orthopedic surgery in order to avoid daily injection for a month. However, oral long-term treatments such as VKA are not systematically associated with a higher compliance level than injected treatments such as low-molecular-weight heparins. Indeed, adherence to an oral treatment, instead of the usual daily injection in major orthopedic surgery, is complex, and based not only on the frequency of dosing but also on patient motivation, understanding, and socio-economic status. New oral anticoagulants may be useful in this way but education and detection of risk factors of nonadherence to treatment are still essential.Keywords: oral anticoagulant, adherence, compliance, education, dabigatran
Olejnik, Anna; Goscianska, Joanna; Nowak, Izabela
The aim of this paper is to review all the aspects of the in vitro release testing (IVRT) from semisolid dosage forms. Although none of the official dissolution methods has been specified for use with semisolid dosage forms, their utility for assessing release rates of drugs from semisolid dosage forms has become a topic of considerable interest. One can expect to overcome such complexity in the future, when the official "Topical and Transdermal Drug Products-Product Performance Tests" will be published in an issue of the Pharmacopeial Forum. Many factors such as type of the dissolution medium, membrane, temperature, and speed have an influence on the mechanism and kinetics of the release testing from gels, creams, and ointments; therefore, those parameters have been widely discussed.
Raparelli, Valeria; Proietti, Marco; Cangemi, Roberto;
and persistence. A multi-level approach, including patients' preferences, factors determining physicians' prescribing habits and healthcare system infrastructure and support, is warranted to improve initiation and adherence of anticoagulants. Adherence to NOACs is paramount to achieve a clinical benefit...
Full Text Available Background/Aim. A single nucleotide polymorphism c.- 1639G>A in the promoter region of vitamin K-epoxide reductase (VKORC1 gene has been found to account for most of the variability in response to oral anticoagulants (OA. The aim of the study was to determine the incidence and the effect of c.-1639G>A polymorphism on the acenocoumarol dosage requirements in the group of patients under stable anticoagulation, and to estimate the variability in response to OA. Methods. Our study included 200 consecutive patients requiring low (n = 43, medium (n = 127 and high (n = 30 acenocoumarol dose. Results. Out of 43 low dose patients, 40 (93 % carried the A allele. The A allele was less frequent in the group of 30 patients requiring high dose: among these patients 13 (43.3% carried the A allele in the heterozygous form and none of them carried AA genotype. The patients with GG genotype required 2.6 times higher dose than the patients carriers of AA genotype (p < 0.0001. In 33 patients (16.5% the overdose occurred during the initiation of anticoagulant therapy and in 11 patients (5.5% it was associated with bleeding. Out of the group of 33 overdosed patients, 27 and 6 patients carried AA and GA genotype, respectively (p < 0.000001. Conclusion. VKORC1 significantly influenced OA dose and predicted individuals predisposed to unstable anticoagulation. The carriers of AA genotype required 2.6 time lower doses of OA than the carriares of GG genotype. Pharmacogenetic testing could predict a high risk of overdose among 28.5 % of our patients - carriers of AA genotype, before anticoagulation therapy initiation.
Gebhart, Johanna; Posch, Florian; Koder, Silvia; Perkmann, Thomas; Quehenberger, Peter; Zoghlami, Claudia; Ay, Cihan; Pabinger, Ingrid
Data on the clinical course of lupus anticoagulant (LA)-positive individuals with or without thrombotic manifestations or pregnancy complications are limited. To investigate mortality rates and factors that might influence mortality, we conducted a prospective observational study of LA-positive individuals. In total, 151 patients (82% female) were followed for a median of 8.2 years; 30 of the patients (20%) developed 32 thromboembolic events (15 arterial and 17 venous events) and 20 patients (13%) died. In univariable analysis, new onset of thrombosis (hazard ratio [HR] = 8.76; 95% confidence interval [CI], 3.46-22.16) was associated with adverse survival. Thrombosis remained a strong adverse prognostic factor after multivariable adjustment for age and hypertension (HR = 5.95; 95% CI, 2.43-14.95). Concomitant autoimmune diseases, anticoagulant treatment at baseline, or positivity for anticardiolipin- or anti-β2-glycoprotein I antibodies were not associated with mortality. In a relative survival analysis, our cohort of LA positives showed a persistently worse survival in comparison with an age-, sex-, and study-inclusion-year-matched Austrian reference population. The cumulative relative survival was 95.0% (95% CI, 88.5-98.8) after 5 years and 87.7% (95% CI, 76.3-95.6) after 10 years. We conclude that occurrence of a thrombotic event is associated with higher mortality in patients with LA. Consequently, the prevention of thromboembolic events in LA positives might improve survival.
Hirudin is the active ingredient of leeches,which has good anticoagulant and antithrombotic function.But because of its short half-life and bleeding risk in clinics, its application effect is not ideal, so some researches in new dosage forms of hirudin have been made.This article reviewed the ways of drug delivery and dosage forms of hirudin based on its pharmacological effects and clinical application,so as to provide a reference for further research and clinical application.%水蛭素是水蛭的活性成分，具有良好的抗凝血和抗血栓作用。但由于临床应用中存在半衰期短、出血危险等不足，实际应用效果并不理想，因此一些水蛭素新剂型的研究也在不断进行。现结合水蛭素的不同药理作用和临床应用对其给药途径及给药剂型进行综述，以期为水蛭素以后的研究和应用提供参考依据。
Fareed, Jawed; Hoppensteadt, Debra A; Fareed, Daniel; Demir, Muzaffer; Wahi, Rakesh; Clarke, Melaine; Adiguzel, Cafer; Bick, Rodger
thrombosis rebound have been reported with their use. For these reasons, the U.S. Food and Drug Administration did not approve the orally active antithrombin agent ximelagatran for several indications. The synthetic pentasaccharide (fondaparinux) has undergone an aggressive clinical development. Unexpectedly, fondaparinux also produced major bleeding problems at minimal dosages. Fondaparinux represents only one of the multiple pharmacologic effects of heparins. Thus, its therapeutic index will be proportionately narrower. The newer antiplatelet drugs have added a new dimension in the management of thrombotic disorders. The favorable clinical outcomes with aspirin and clopidogrel have validated cyclooxygenase (COX)-1 and P2Y (12) receptors as targets for new drug development. Prasugrel, a novel thienopyridine, cangrelor, and AZD 6140 represent newer P2Y (12) antagonists. Cangrelor and AZD 6140 are direct inhibitors, whereas prasugrel requires metabolic activation. Though clinically effective, recent results have prompted a closure of a large clinical trial with prasugrel due to bleeding. The newer anticoagulant and antiplatelet drugs are attractive for several reasons; however, none of these are expected to replace the conventional drugs in polytherapeutic approaches. Heparins, warfarin, and aspirin will continue to play a major role in the management of thrombotic and cardiovascular disorders beyond 2010.
Pandya, Ekta Y; Bajorek, Beata
The role of the direct oral anticoagulants (DOACs) in practice has been given extensive consideration recently, albeit largely from the clinician's perspective. However, the effectiveness and safety of using anticoagulants is highly dependent on the patient's ability to manage and take these complex, high-risk medicines. This structured narrative review explores the published literature to identify the factors underpinning patients' non-adherence to anticoagulants in atrial fibrillation (AF), and subsequently contemplates to what extent the DOACs might overcome the known challenges with traditional warfarin therapy. This review comprised a two-tier search of various databases and search platforms (CINAHL, Cochrane, Current Contents Connect, EMBASE, MEDLINE Ovid, EBSCO, PubMed, Google, Google Scholar) to yield 47 articles reporting patients perspectives on, and patients adherence to, anticoagulant therapy. The findings from the literature were synthesised under five interacting dimensions of adherence: therapy-related factors, patient-related factors, condition-related factors, social-economic factors and health system factors. Factors negatively affecting patients' day-to-day lives (especially regular therapeutic drug monitoring, dose adjustments, dietary considerations) predominantly underpin a patient's reluctance to take warfarin therapy, leading to non-adherence. Other patient-related factors underpinning non-adherence include patients' perceptions and knowledge about the purpose of anticoagulation; understanding of the risks and benefits of therapy; socioeconomic status; and expectations of care from health professionals. In considering these findings, it is apparent that the DOACs may overcome some of the barriers to traditional warfarin therapy at least to an extent, particularly the need for regular monitoring, frequent dose adjustment and dietary considerations. However, their high cost, twice-daily dosing and gastrointestinal adverse effects may present
O'Connell, John Edward; Stassen, Leo F A
Anticoagulation therapy is used in several conditions to prevent or treat thromboembolism. Over the last 40 years, warfarin has been the oral anticoagulant of choice and has been considered the mainstay of treatment. However, its use is limited by a narrow therapeutic index and complex pharmacodynamics, necessitating regular monitoring and dose adjustments. Recently, two new oral anticoagulants--dabigatran etexilate (a direct thrombin inhibitor) and rivaroxiban (a factor Xa inhibitor)--have been approved for use in North America and Europe. Unlike warfarin, dabigatran and rivaroxiban are relatively small molecules that work as anticoagulants by targeting specific single steps of the coagulation cascade. Their advantages, relative to warfarin, include: predictable pharmacokinetics; limited food and drug interactions; rapid onset of action; and, short half-life. They require no monitoring. However, they lack a specific reversal agent. The number of patients taking dabigatran and rivaroxaban is increasing. Therefore, it is inevitable that dentists will be required to perform invasive procedures on this cohort of patients. This paper outlines the various properties of the new oral anticoagulants and the most recent guidelines regarding the management of these dental patients taking these medications.
Full Text Available Due to their mechanism of action, the new oral anticoagulants are named direct oral anticoagulants (DOACs. Dabigatran is a selective, competitive, direct inhibitor of thrombin (Factor IIa while rivaroxaban, apixaban and edoxaban act by directly inhibiting the activated Factor X (FXa in a selective and competitive manner. DOACs have a relatively short half-life and almost immediate anticoagulant activity, and rapidly reach the plasma peak concentration. Therefore, they do not need a phase of overlapping with parenteral anticoagulants. After their withdrawal, their removal is sufficiently rapid, although influenced by renal function. Dabigatran is the only DOACs to be administered as a pro-drug and becomes active after drug metabolization. The route of elimination of dabigatran is primarily renal, whereas FXa inhibitors are mainly eliminated by the biliary-fecal route. The drug interactions of DOACs are mainly limited to drugs that act on P-glycoprotein for dabigatran and on P-glycoprotein and/or cytochrome P3A4 for anti-Xa. DOACs have no interactions with food. Given their linear pharmacodynamics, with a predictable dose/response relationship and anticoagulant effect, DOACs are administered at a fixed dose and do not require routine laboratory monitoring.
Saour, J N; Ali, H A; Mammo, L A; Sieck, J O
Over a 10-year period a uniform management plan for patients receiving long term oral anticoagulation therapy for prosthetic heart valves and needing dental procedures was instituted. Those undergoing dental extraction or gum hygiene in the presence of gross gum pathology (Group A) had their oral anticoagulation discontinued two days prior to the procedure which was carried out only if the INR was 1.5 or less on the day of the procedure. Patients who needed dental fillings or gum hygiene in the absence of gross gum pathology (Group B) continued their anticoagulation therapy and had these procedures completed provided the INR was 3.0 or less. The main outcome measured were valve thrombosis, thromboembolism and excessive bleeding requiring hospitalization and/or blood transfusion. In Group A, 240 procedures were carried out; 212 dental extractions and 28 dental hygiene in the presence of gross gum pathology. They had a brief period of under-anticoagulation (3-7 days) to an INR of 1.5 or less. In Group B, 156 procedures were performed. No patient developed valve thrombosis or thromboembolism. Two patients, both in Group A needed hospitalization for observation but no blood transfusion. This management plan was easy to implement. Patients needed one extra visit to the anticoagulation clinic within one week of the procedure. It was both safe and effective.
Full Text Available Sebastian Luger,1 Carina Hohmann,2 Daniela Niemann,1 Peter Kraft,3 Ignaz Gunreben,3 Tobias Neumann-Haefelin,2 Christoph Kleinschnitz,3 Helmuth Steinmetz,1 Christian Foerch,1 Waltraud Pfeilschifter1 1Department of Neurology, University Hospital Frankfurt, Frankfurt am Main, 2Department of Neurology, Klinikum Fulda gAG, Fulda, 3Department of Neurology, University Hospital Würzburg, Würzburg, Germany Background: Oral anticoagulant therapy (OAT potently prevents strokes in patients with atrial fibrillation. Vitamin K antagonists (VKA have been the standard of care for long-term OAT for decades, but non-VKA oral anticoagulants (NOAC have recently been approved for this indication, and raised many questions, among them their influence on medication adherence. We assessed adherence to VKA and NOAC in secondary stroke prevention. Methods: All patients treated from October 2011 to September 2012 for ischemic stroke or transient ischemic attack with a subsequent indication for OAT, at three academic hospitals were entered into a prospective registry, and baseline data and antithrombotic treatment at discharge were recorded. At the 1-year follow-up, we assessed the adherence to different OAT strategies and patients’ adherence to their respective OAT. We noted OAT changes, reasons to change treatment, and factors that influence persistence to the prescribed OAT. Results: In patients discharged on OAT, we achieved a fatality corrected response rate of 73.3% (n=209. A total of 92% of these patients received OAT at the 1-year follow-up. We observed good adherence to both VKA and NOAC (VKA, 80.9%; NOAC, 74.8%; P=0.243 with a statistically nonsignificant tendency toward a weaker adherence to dabigatran. Disability at 1-year follow-up was an independent predictor of lower adherence to any OAT after multivariate analysis, whereas the choice of OAT did not have a relevant influence. Conclusion: One-year adherence to OAT after stroke is strong (>90% and patients
Full Text Available The new oral direct anticoagulants (DOACs could represent a new frontier for management of thromboembolic diseases. However, the new drugs have limitations that need to be considered. Despite the fact that their efficacy and safety profile are at least not inferior to comparators, bleeding risk represents the most feared complication, as for all the antithrombotic drugs. Bleeding risk increases with conditions that interfere with pharmacokinetics, in addition to the risk strictly linked to patients or their co-morbidities. Since all DOACs are excreted from kidneys (even though at different percentages according to the different molecules, renal impairment represents one of the leading causes of DOACs accumulation and bleeding risk. Moderate renal failure is the main condition in which dose adjustment of DOACs could be required, while severe renal impairment represents an absolute contraindication for their use. Renal function must, therefore, be carefully monitored before prescription and during assumption. The older population is at higher bleeding risk, and dose adjustment of DOACs could be required. Although to a lesser degree than oral anticoagulant vitamin K antagonists, DOACs can have drug interactions, especially with P-glycoprotein and cytochrome P3A4 inducers or inhibitors, and these interactions must be taken into account in real practice to avoid accumulation or under dosage. The concomitant use of other drugs, especially antithrombotics, may expose the patients to bleeding risk by reducing the hemostatic properties.
Bernstein, M L; Salusinsky-Sternbach, M; Bellefleur, M; Esseltine, D W
Endogenous circulating anticoagulants are unusual in children without a congenital factor deficiency. In particular, the lupus anticoagulant has only rarely been reported in children. Despite its functioning in vitro to prolong the partial thromboplastin time, patients more frequently have problems with thrombosis than bleeding, unless there is a coexistent prothrombin deficiency or thrombocytopenia. We report the cases of three children with the lupus anticoagulant. Two children had associated thromboses. One had a thrombosis of the iliofemoral system and the other had a partial Budd-Chiari syndrome, a thrombosis of the deep calf veins and ureteric obstruction. The third child had a concomitant prothrombin deficiency and bleeding after tooth extraction. Associated findings in these patients included a positive antinuclear antibody test in two, a positive anti-DNA antibody test in two, a false-positive VDRL test in two, and an antiphospholipid antibody test in two.
Steinfeldt, Thorsten; Rolfes, Caroline
The decision for an anticoagulant for renal replacement therapy (RRT) in patients with acute renal failure and heparin-induced thrombocytopenia (HIT) has to be made carefully. Based on results from the literature argatroban is favoured in patients without hepatic dysfunction, referring to its short halftime and easy feasable monitoring. In the case of coexsisting hepatic disorder, danaparoid provides a safe alternative therapy. However, long halftime and the difficult elimination of the substance are unfavourable. Lepirudin represents another possible anticoagulant therapy. Bleeding complications and monitoring of the ecarin clotting time imposes limitations. Experiences with bivalirudin, fondaparinux and prostaglandines are limited and future trials will have to determine the significance of their application in RRT in HIT patients. Furthermore it has to be proven whether the combination of alternative anticoagulants with citrate prolongates circuit halftime of CVVH.
Walenga, Jeanine M; Thethi, Indermohan; Lewis, Bruce E
The topic of adverse effects of drugs is now receiving due attention in both the lay and medical communities. For drugs of the coagulation disorder class, such as anticoagulants and antiplatelet agents, the obvious adverse effects are bleeding from a dose too high and thrombosis from a dose too low. However, these drugs have other potential adverse effects that are not directly related to blood coagulation, yet cannot be dismissed due to their medical importance. There has been a recent advancement of several new drugs in this category and this number will soon grow as more drugs are reaching the end of their clinical trials. This article will discuss the nonhemostatic adverse effects of anticoagulants and antiplatelet drugs. As the adverse effects of bleeding and thrombosis will be excluded, this article will be in contrast to the typical discussions on the anticoagulant and antiplatelet drug classes.
Davenport, J; Hart, R G
We retrospectively reviewed the clinical characteristics and outcomes of 61 patients with 62 episodes of prosthetic valve endocarditis, paying particular attention to neurologic complications (stroke). Atypical features of the group included a benign outcome of early postoperative infection (18% mortality) and a high stroke morbidity and mortality rate with Staphylococcus epidermidis infections. Eleven patients (18%) suffered an embolic stroke, most less than or equal to 3 days after diagnosis and before the initiation of antimicrobial therapy; the rate of embolic stroke recurrence was low (9%). The risk of embolic stroke was lower with bioprosthetic than with mechanical valves. No protective effect of anticoagulation therapy with warfarin was observed. Six patients (8%) suffered brain hemorrhage due to septic arteritis, brain infarction, or undetermined causes; no specific risk of hemorrhagic stroke was evident with anticoagulation therapy. Antibiotic treatment appears to be more important than anticoagulation to prevent neurologic complications in patients with prosthetic valve endocarditis.
M. A. Satybaldyeva
Full Text Available The vitamin K antagonist warfarin is an essential medicine from a group of anticoagulants, which is used to treat antiphospholipid syndrome (APS. However, it has a number of disadvantages especially in patients who need longterm and frequently lifetime prevention of thromboses. New oral anticoagulants, such as dabigatran etexilate (Pradaxa®, rivaroxaban (Xarelto®, apixaban (Eliquis and others, have been recently synthesized. Unlike warfarin, they are administered at fixed doses, require neither routine monitoring nor diet, and interact with drugs only in small amounts. The new oral anticoagulants have been approved for certain indications, but the data of performed trials are inapplicable to patients with APS. These medicines are expected to improve quality of life in patients with this condition.
Full Text Available The short-comings of current anticoagulants have led to the development of newer, albeit more expensive, oral alternatives.Objective: To explore the potential impact the new anticoagulants dabigatran and rivaroxaban in the local hospital setting, in terms of utilisation and subsequent costing.Method: A preliminary costing analysis was performed based on a prospective 2-week clinical audit (29th June - 13th July 2009. Data regarding current anticoagulation management were extracted from the medical files of patients admitted to Ryde Hospital. To model potential costing implications of using the newer agents, the reported incidence of VTE/stroke and bleeding events were obtained from key clinical trials.Results: Data were collected for 67 patients treated with either warfarin (n=46 or enoxaparin (n=21 for prophylaxis of VTE/stroke. At least two-thirds of all patients were deemed suitable candidates for the use of newer oral anticoagulants (by current therapy: warfarin: 65.2% (AF, 34.8% (VTE; enoxaparin: 100%, (VTE. The use of dabigatran in VTE/stroke prevention was found to be more cost-effective than warfarin and enoxaparin due to significantly lower costs of therapeutic monitoring and reduced administration costs. Rivaroxaban was more cost-effective than warfarin and enoxaparin for VTE/stroke prevention when supplier-rebates (33% were factored into costing.Conclusion: This study highlights the potential cost-effectiveness of newer anticoagulants, dabigatran and rivaroxaban, compared to warfarin and enoxaparin. These agents may offer economic advantages, as well as clinical benefits, in the hospital-based management of anticoagulated patients.
So, Charlotte H; Eckman, Mark H
The combined use of aspirin and oral anticoagulant therapy in patients with atrial fibrillation (AF) and stable coronary artery disease (CAD) has been questioned due to an increased risk of major bleeding with little to no benefit in preventing ischemic events. (1) To better understand patterns and indications for combined antiplatelet and anticoagulant therapy and identify patients who might reasonably be treated with oral anticoagulant (OAC) therapy alone. (2) To perform an updated literature review regarding the use of combined antiplatelet and OAC therapy in patients with AF and stable CAD. Retrospective review. Patients within the University of Cincinnati Health System with a diagnosis of non-valvular AF, excluding those with acute coronary syndrome or revascularization within the last 12 months. Numbers and indications for combined antiplatelet and anticoagulant therapy and sequence of events leading to the initiation of each. Of 948 patients receiving OAC, 430 (45 %) were receiving concomitant OAC and aspirin. Among patients receiving combined antiplatelet and anticoagulant therapy, 49 and 42 % of patients respectively, had CAD or DM. In a more detailed analysis including chart review of 219 patients receiving combined OAC and aspirin, 27 % had a diagnosis of CAD and 14 % had a diagnosis of DM prior to the development of AF. These patients were initially treated with aspirin. Warfarin was added when they subsequently developed AF but aspirin wasn't discontinued. A surprisingly large proportion of patients (22.8 %) had no obvious indication for dual therapy. Prior myocardial infarction, CAD, vascular disease and DM (among others) increase the likelihood of receiving combined antiplatelet and anticoagulant therapy among patients with AF. A literature review suggests this may lead to increased major bleeding with little benefit in decreasing either AF-related stroke or cardiovascular events.
Allen, Loyd V
The purpose of this article is to provide information on the use of foam dosage forms and pharmacists' ability to extemporaneously compound them. The article provides: (1) a discussion on the rationale and advantages of using foams, (2) a differentiation between the various types and structures of foams, (3) a list of the various types of ingredients and examples of each, and (4) a description of the preparation of pharmaceutical foams.
Tsoumani, Maria E; Tselepis, Alexandros D
Thrombosis is the formation of potentially deadly blood clots in the artery (arterial thrombosis) or vein (venous thrombosis). Since thrombosis is one of the main causes of death worldwide, the development of antithrombotic agents is a global medical priority. They are subdivided into antiplatelet agents and anticoagulants. Antiplatelet agents inhibit clot formation by preventing platelet activation and aggregation, while anticoagulants primarily inhibit the coagulation cascade and fibrin formation. Therapeutics within each category differs with respect to the mechanism of action, time to onset, duration of effect and route of administration. In this review, we critically discuss their main pharmacodynamic and pharmacokinetic characteristics as well as recent advances in daily clinical practice.
Brejcha, M; Gumulec, J; Penka, M; Klodová, D; Wróbel, M; Bogoczová, E
The management of warfarin therapy in patients undergoing surgery or other invasive procedures involves a balance between the risk of hemorrhage, and the risk of thrombosis. Risk of hemorrhage and the trombosis depends on the type of procedure and on pre-existing conditions. Procedures with low risk of hemorrhage (dental, dermatologic or ophtalmologic procedures, endoscopy) can be provided with continuing anticoagulant therapy. Surgery with high hemorrhagic risk need stop warfarin and start bridging anticoagulant therapy, such as unfractionated heparin or low molecular weight heparin, prior and after surgery. In patients requiring emergency surgery, vitamin K, prothrombin complex concentrate or fresh frozen plasma can be used to improve coagulation.
Parekh, Parth J; Merrell, Jonathan; Clary, Meredith; Brush, John E; Johnson, David A
The discovery of the first oral anticoagulant, warfarin, was a milestone in anticoagulation. Warfarin's well-known limitations, however, have led to the recent development of more effective anticoagulants. The rapidly growing list of these drugs, however, presents a challenge to endoscopists who must treat patients on these sundry medications. This review is intended to summarize the pharmacological highlights of new anticoagulants, with particular attention to suggested "best-practice" recommendations for the withholding of these drugs before endoscopic procedures.
D. A. Sychev
Full Text Available The clinical significance of the patient genetic characteristics in the individual pharmacological response to oral anticoagulants is considered. Possible tactics of warfarin dosing and new oral anticoagulants choice on the basis of pharmacogenetic testing as well as indications for this approach in clinical practice are discussed. It should increase efficacy and safety of anticoagulant therapy.
Levi, M.M.; Eerenberg, E.; Löwenberg, E.; Kamphuisen, P.W.
The most important adverse effect of antithrombotic treatment is the occurrence of bleeding. in case of serious or even life-threatening bleeding in a patient who uses anticoagulant agents or when patient on anticoagulants needs to undergo an urgent invasive procedure, anticoagulant treatment can be
Full Text Available Abstract Background The side effects and burden of anticoagulant treatments may contribute to poor compliance and consequently to treatment failure. A specific questionnaire is necessary to assess patients' needs and their perceptions of anticoagulant treatment. Methods A conceptual model of expectation and satisfaction with anticoagulant treatment was designed by an advisory board and used to guide patient (n = 31 and clinician (n = 17 interviews in French, US English and Dutch. Patients had either atrial fibrillation (AF, deep venous thrombosis (DVT, or pulmonary embolism (PE. Following interviews, three PACT-Q language versions were developed simultaneously and further pilot-tested by 19 patients. Linguistic validations were performed for additional language versions. Results Initial concepts were developed to cover three areas of interest: 'Treatment', 'Disease and Complications' and 'Information about disease and anticoagulant treatment'. After clinician and patient interviews, concepts were further refined into four domains and 17 concepts; test versions of the PACT-Q were then created simultaneously in three languages, each containing 27 items grouped into four domains: "Treatment Expectations" (7 items, "Convenience" (11 items, "Burden of Disease and Treatment" (2 items and "Anticoagulant Treatment Satisfaction" (7 items. No item was deleted or added after pilot testing as patients found the PACT-Q easy to understand and appropriate in length in all languages. The PACT-Q was divided into two parts: the first part to measure the expectations and the second to measure the convenience, burden and treatment satisfaction, for evaluation prior to and after anticoagulant treatment, respectively. Eleven additional language versions were linguistically validated. Conclusion The PACT-Q has been rigorously developed and linguistically validated. It is available in 14 languages for use with thromboembolic patients, including AF, PE and DVT patients
... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Levamisole hydrochloride oral dosage forms. 520.1242 Section 520.1242 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.1242 Levamisole hydrochloride oral dosage...
Feher, G; Illes, Z; Hargroves, D
INTRODUCTION: Cerebral venous thrombosis (CVT) is a rare form of venous thromboembolism (VTE). Although anticoagulation is recommended for the initial and long term treatment with regards to thrombotic risks for patients with CVT, the role of anticogalution has not been fully elucidated. The aim...... and the outcome of a second event as good as that of the first one irrespective of underlying risk factors....
Feher, G; Illes, Z; Komoly, S;
Cerebral venous thrombosis (CVT) is an uncommon cause of stroke with extremely diverse clinical features, predisposing factors, brain imaging findings, and outcome. Anticoagulation is the cornerstone of CVT management, however, it is not supported by high-quality evicence. Novel oral anticoagulan...
Verheugt Freek WA
Full Text Available Abstract Thrombosis plays a major role in acute vessel closure both after coronary balloon angioplasty and after stenting. This review will address the role of antiplatelet and anticoagulant therapy in preventing early thrombotic complications after percutaneous coronary intervention. The focus will be on agents that are routinely available and commonly used.
Davis, Christine B; Nowak, Richard M
This is a case of nontraumatic shoulder pain initially diagnosed on x-ray as an anterior dislocation. The patient was on anticoagulants and, in actuality, had severe hemarthrosis that caused the subluxation. Attempts to reduce the dislocation in this situation might have resulted in worsening of the intra-articular bleed. There has been only 1 similar reported case in the European Journal of Emergency Medicine in 2013 of a 53-year-old woman who was thought to have a nontraumatic anterior shoulder dislocation, and attempts were unsuccessful at reduction. Definitive therapy involved hemarthrosis aspiration. Others have reported spontaneous hemarthrosis due to anticoagulants; however, only 1 has reported an initial mistaken joint dislocation diagnosis. Nontraumatic hemarthrosis do occur in patients on anticoagulant therapy, and it is important to recognize that this can be misdiagnosed as a joint dislocation requiring reduction. In a patient who is on anticoagulants presenting with nontraumatic joint pain and anterior shoulder or possibly other dislocations on plain radiographs, it is pertinent to consider hemarthrosis.
Garg, Vaani Panse; Halperin, Jonathan L
This article reviews the pivotal studies of several novel antiplatelet (prasugrel and ticagrelor) and anticoagulant (dabigatran, rivaroxaban, and apixaban) agents. The clinical use of these drugs in cardiac intensive care is discussed, focusing on the management of acute coronary syndromes, ischemic stroke, atrial fibrillation, and venous thromboembolism.
In patients with nonvalvular atrial fibrillation, oral anticoagulation with the vitamin K antagonists acenocoumarol, phenprocoumon and warfarin reduces the risk of stroke by more than 60 %, whereas single or double antiplatelet therapy is much less effective and sometimes associated with a similar b
Coumarin derivatives such as acenocoumarol, phenprocoumon and warfarin are frequently used for the prevention of stroke and systemic embolism in patients with atrial fibrillation or for the treatment of venous thromboembolism. These oral anticoagulants have a narrow therapeutic range and a large var
Eerenberg, E.S.; Kamphuisen, P.W.; Sijpkens, M.K.; Meijers, J.C.; Büller, H.R.; Levi, M.
Background: Rivaroxaban and dabigatran are new oral anticoagulants that both have been licensed worldwide for the treatment of atrial fibrillation and rivaroxaban also for venous thrombosis. Both drugs specifically inhibit one coagulation factor, factor Xa and thrombin, respectively, and both compou
Hall, J G; Pauli, R M; Wilson, K M
Review of published cases of pregnancies in which coumarin derivatives or heparin were administered demonstrates that use of either class of anticoagulant carries substantial risks. Of 418 reported pregnancies in which coumarin derivatives were used, one-sixth resulted in abnormal liveborn infants, one-sixth in abortion or stillbirth and, at most, two-thirds in apparently normal infants. In addition to the expected hemorrhagic complications, fetal effects of coumarin derivative administration include a specific embryopathy and central nervous system abnormalities. All available cases (including unpublished ones) of warfarin embryopathy and central nervous system abnormalities following gestational exposure to coumarin derivatives are reviewed, various complications are tabulated, critical periods of teratogenesis are discussed and possible mechanisms proposed. The use of heparin during gestation does not result in a significantly better outcome of pregnancy. In 135 published cases, the infants in one-eighth were stillborn, in one-fifth premature (a third of whom died) and, again at most, in two-thirds apparently normal. Because of the substantial risks of both clases of anticoagulants, and the inherent risks of pregnancy complicated by the indications for anticoagulation, prevention of pregnancy is usually indicated. If pregnancy occurs, a relatively normal outcome can be anticipated in about two-thirds of the pregnancies regardless of the anticoagulant used. Heparin does not appear to be a clearly superior alternative to coumarin derivatives.
Callonnec, F.; Gerardin, E.; Thiebot, J. [Department of Radiology, Rouen University Hospital, 1 rue de Germont, F-76031 Rouen cedex (France); Marie, J.P.; Andrieu Guitrancourt, J. [Department of Otolaryngology, Rouen University Hospital (France); Marsot-Dupuch, K. [Department of Radiology, St. Antoine, Paris University Hospital (France)
We report a patient who experienced a severe vertiginous episode with bilateral tinnitus and progressive right-sided hearing loss. She had Marfan`s disease and was on anticoagulant treatment. The fluid in the labyrinth gave higher signal than cerebrospinal fluid on T1-weighted images, suggesting haemorrhage. The radiological follow-up is discussed. (orig.) With 2 figs., 11 refs.
Jespersen, Stine Funder; Christensen, Louisa M; Christensen, Anders;
Background. The knowledge is still sparse about patient related factors, influencing oral anticoagulation therapy (OAC) rates, in stroke patients with atrial fibrillation (AF). Aims. To assess the use of OAC in ischemic stroke patients diagnosed with AF and to identify patient related factors...
Rombouts, Eva Karolien
One of the causes of unstable anticoagulation is a variable vitamin K intake. The main objective of this thesis was to test the hypothesis that the INR is particularly sensitive to changes in vitamin K intake when vitamin K status is low, and that patients with a low vitamin K intake would therefore
Holden, Amber; Azimi, Nassir; Forest, Christopher P
Four new oral anticoagulants have been approved for reducing stroke risk in patients with nonvalvular atrial fibrillation. Compared with warfarin, these agents offer a more predictable dose response with fewer food and drug interactions and no regular blood monitoring, although some of the drugs have an increased risk of major gastrointestinal bleeding. This article reviews the new drugs.
Broekema, Ferdinand I.; van Minnen, Baucke; Jansma, Johan; Bos, Rudolf R. M.
To avoid increasing the risk of thromboembolic events, it is recommended that treatment with anticoagulants should be continued during dentoalveolar operations. We have evaluated the incidence of bleeding after dentoalveolar operations in a prospective study of 206 patients, 103 who were, and 103 wh
Hennink, W.E.; Klerx, J.P.A.M.; Dijk, H. van; Feijen, J.
Almost monodisperse heparin fractions (w/n < 1.1) were obtained by gel filtration of a commercial heparin. These fractions were assayed for anticoagulant activity (thrombin times and APTT), chromogenic anti-factor Xa activity, inhibitory activity for the human classical complement pathway, carboxyl
Spyropoulos, Alex C
The management of patients who need temporary interruption of chronic oral anticoagulant (OAC) therapy for an elective surgical or invasive procedure is problematic and complex. Patient and procedural risk factors for thrombosis and bleeding, anticoagulant-related risks of bleeding, and clinical consequences of a thrombotic or bleeding event need to be assessed and properly risk-stratified in the perioperative period. Certain procedures, such as dental, endoscopic, and cutaneous procedures, can be completed without discontinuing OAC, but most procedures with a high bleeding risk (including major surgeries) will necessitate temporary discontinuation of OAC. Bridging therapy with shorter-acting anticoagulants, such as heparin, for patients at intermediate to high risk of thromboembolism represents one strategy to maintain functional anticoagulation during this period. Large, prospective cohort studies and registries of patients on chronic OAC who underwent bridging therapy mostly with low-molecular-weight heparin have been completed recently. This paper reviews these clinical data on bridging therapy and provides an evidence-based perioperative management strategy for the at-risk patient on chronic OAC.
Kelly M. Rudd
Full Text Available Anticoagulation therapy is mandatory in patients with pulmonary embolism to prevent significant morbidity and mortality. The mainstay of therapy has been vitamin-K antagonist therapy bridged with parenteral anticoagulants. The recent approval of new oral anticoagulants (NOACs: apixaban, dabigatran, and rivaroxaban has generated significant interest in their role in managing venous thromboembolism, especially pulmonary embolism due to their improved pharmacokinetic and pharmacodynamic profiles, predictable anticoagulant response, and lack of required efficacy monitoring. This paper addresses the available literature, on-going clinical trials, highlights critical points, and discusses potential advantages and disadvantages of the new oral anticoagulants in patients with pulmonary embolism.
Full Text Available Abstract Background Despite the high frequency with which adverse drug events (ADEs occur in outpatient settings, detailed information regarding these events remains limited. Anticoagulant drugs are associated with increased safety concerns and are commonly involved in outpatient ADEs. We therefore sought to evaluate ambulatory anticoagulation ADEs and the patient population in which they occurred within the Duke University Health System (Durham, NC, USA. Methods A retrospective chart review of ambulatory warfarin-related ADEs was conducted. An automated trigger surveillance system identified eligible events in ambulatory patients admitted with an International Normalized Ratio (INR >3 and administration of vitamin K. Event and patient characteristics were evaluated, and quality/process improvement strategies for ambulatory anticoagulation management are described. Results A total of 169 events in 167 patients were identified from December 1, 2006-June 30, 2008 and included in the study. A median supratherapeutic INR of 6.1 was noted, and roughly half of all events (52.1% were associated with a bleed. Nearly 74% of events resulted in a need for fresh frozen plasma; 64.8% of bleeds were classified as major. A total of 59.2% of events were at least partially responsible for hospital admission. Median patient age was 68 y (range 36-95 y with 24.9% initiating therapy within 3 months prior to the event. Of events with a prior documented patient visit (n = 157, 73.2% were seen at a Duke clinic or hospital within the previous month. Almost 80% of these patients had anticoagulation therapy addressed, but only 60.0% had a follow-up plan documented in the electronic note. Conclusions Ambulatory warfarin-related ADEs have significant patient and healthcare utilization consequences in the form of bleeding events and associated hospital admissions. Recommendations for improvement in anticoagulation management include use of information technology to assist
Mierzynski, Radzisław; Poniedzialek-Czajkowska, Elzbieta; Kimber-Trojnar, Zaneta; Leszczynska-Gorzelak, Bozena; Oleszczuk, Jan
Pregnancy is a specific state of heightened coagulability related to the increase in procoagulant agents and to the reduced fibrinolysis. Pregnancy is associated with a 4-fold increased risk of developing venous thromboembolism (VTE) and this risk still increases to 14-fold during puerperium. A correlation between the metabolic syndrome and development of cardiovascular events and cerebrovascular incidents has been described. Such a relationship is referred to a hypercoagulable state due to increased serum levels of the plasminogen activator inhibitor-1 (PAI-1), fibrinogen, factor (F) VII and VIII, von Willebrand factor and from endothelial activation, caused by increased circulating adhesion molecules. As to the risk of VTE, the probability for its association with cardiovascular incidents is increased by common underlying mechanisms such as the activation of platelets and the blood coagulation. A correlation between idiopathic VTE and the metabolic syndrome has been reported. The anticoagulant therapy may be recommended during the pregnancy for the treatment or the prophylaxis of VTE and, in women with artificial heart valves, for the prevention of the valve thrombosis and systemic embolisation. There are also specific conditions during pregnancy which benefit from anticoagulant use, such as recurrent fetal loss, thrombophilia and assisted reproductive technology. There are no published specific data about using of anticoagulant agents in pregnant patients with the metabolic syndrome except for a few articles addressing reproductive problems. The mechanisms of anticoagulant action were studied with the focus on heparinoids, because of their safety not only for the patient but also for the fetus. The new oral anticoagulants were also shortly described although they have been contraindicated during the pregnancy.
Kulshrestha, Vikas; Kumar, Santhosh
The American College of Chest Physicians (ACCP) recommended routine anticoagulation for thromboprophylaxis in patients undergoing lower limb arthroplasty. We compared results of routine anticoagulation Vs risk stratified approach for Deep Venous Thrombosis (DVT) prophylaxis after TKA in terms of symptomatic DVT and wound complications. Nine hundred TKAs done in 673 patients were randomized after DVT risk screening to routine anticoagulation (n = 450) or to risk stratification (n = 450) and selective anticoagulation. 194 patients in the risk screening group received only Aspirin. Primary outcome was symptomatic DVT and wound complication. This randomized study showed that the symptomatic DVT rates after TKA were similar whether patients were routinely anticoagulated or selectively anticoagulated after risk screening. However there was a significantly higher incidence of wound complications (P < 0.014) after routine anticoagulation.
Oprita, R; Oprita, B; Diaconescu, B; Bratu, MR; Berceanu, D
Anticoagulants are frequently used medications in diverse cardiovascular diseases. Their uses highly increase the risk of bleeding from upper and lower gastrointestinal sources, whether there is a classic vitamin K antagonist or a novel oral anticoagulant. Their interruption can promote procoagulation status with different thromboembolic accidents. Discontinuation of oral anticoagulants before the elective procedures is standardized but there are no guidelines for managing bleeding lesions of upper gastrointestinal tract concomitant with anticoagulation. Also, because some of the anticoagulants are new comers, there is no specific antidote, and so their anticoagulation effect cannot be antagonized fast in order to reduce the bleeding. Therefore, the endoscopic hemostasis must be definitive and efficient. This is a short review of the current management for the bleeding lesions of the upper gastrointestinal tract in patients taking oral anticoagulants. PMID:28255372
Rattner, Barnett A.; Lazarus, Rebecca S.; Eisenreich, Karen M.; Horak, Katherine E.; Volker, Steven F.; Campton, Christopher M.; Eisemann, John D.; Meteyer, Carol U.; Johnson, John J.
New regulatory restrictions have been placed on the use of some second-generation anticoagulant rodenticides in the United States, and in some situations this action may be offset by expanded use of first-generation compounds. We have recently conducted several studies with captive adult American kestrels and eastern screech-owls examining the toxicity of diphacinone (DPN) using both acute oral and short-term dietary exposure regimens. Diphacinone evoked overt signs of intoxication and lethality in these raptors at exposure doses that were 20 to 30 times lower than reported for traditionally used wildlife test species (mallard and northern bobwhite). Sublethal exposure of kestrels and owls resulted in prolonged clotting time, reduced hematocrit, and/or gross and histological evidence of hemorrhage at daily doses as low as 0.16 mg DPN/kg body weight. Findings also demonstrated that DPN was far more potent in short-term 7-day dietary studies than in single-day acute oral exposure studies. Incorporating these kestrel and owl data into deterministic and probabilistic risk assessments indicated that the risks associated with DPN exposure for raptors are far greater than predicted in analyses using data from mallards and bobwhite. These findings can assist natural resource managers in weighing the costs and benefits of anticoagulant rodenticide use in pest control and eradication programs.
Full Text Available Ruxandra Jurcuţ,1 Sebastian Militaru,1 Oliviana Geavlete,1 Nic Drăgotoiu,1 Sergiu Sipoş,1 Răzvan Roşulescu,2 Carmen Ginghină,1 Ciprian Jurcuţ2 1Prof Dr CC Iliescu Emergency Institute for Cardiovascular Diseases, University of Medicine and Pharmacy, 2Dr Carol Davila Central University Emergency Military Hospital, Bucharest, Romania Background: Patient adherence is an essential factor in obtaining efficient oral anticoagulation using vitamin K antagonists (VKAs, a situation with a narrow therapeutic window. Therefore, patient education and awareness are crucial for good management. Auditing the current situation would help to identify the magnitude of the problem and to build tailored education programs for these patients. Methods: This study included 68 hospitalized chronically anticoagulated patients (mean age 62.6±13.1 years; males, 46% who responded to a 26-item questionnaire to assess their knowledge on VKA therapy management. Laboratory and clinical data were used to determine the international normalized ratio (INR at admission, as well as to calculate CHA2DS2-VASC and HAS-BLED scores for patients with atrial fibrillation. Results: The majority of patients (62% were receiving VKA for atrial fibrillation, the others for a mechanical prosthesis and previous thromboembolic disease or stroke. In the atrial fibrillation group, the mean CHA2DS2-VASC score was 3.1±1.5, while the average HAS-BLED score was 1.8±1.2. More than half of the patients (53% had an INR outside of the therapeutic range at admission, with the majority (43% having a low INR. A correct INR value was predicted by education level (higher education and the diagnostic indication (patients with mechanical prosthesis being best managed. Patients presenting with a therapeutic INR had a trend toward longer treatment duration than those outside the therapeutic range (62±72 months versus 36±35 months, respectively, P=0.06. There was no correlation between INR at admission
Waller, E S
Indomethacin, an indole derivative nonsteroidal anti-inflammatory drug, has been available since the early 1960s in gelatin capsules. In 1982, a sustained release product, Indocin SR, was marketed. Awaiting marketing approval is a unique controlled release form of indomethacin, Indos. The disposition of indomethacin includes enterohepatic cycling and extensive metabolism to inactive metabolites. Enterohepatic cycling makes interpretation of bioavailability estimates of indomethacin dosage forms difficult. The relationship of indomethacin plasma concentration to therapeutic effects and side effects is inconclusive. It appears in vivo prostaglandin inhibition occurs at very low plasma concentrations that are achievable with all available dosage forms. Indocin SR is a sustained release capsule of indomethacin designed to deliver 25 mg of drug immediately and 50 mg gradually. Absolute bioavailability of the product is 80%. The plasma concentration-time curves do not show good sustained release characteristics; after four hours plasma concentrations resemble those seen with a single dose of regular capsule. The cost compared with Indocin is competitive. Indos is a zero-order release form of indomethacin. It is a unique drug delivery system that shows good controlled release characteristics. Bioavailability is 85%. Both Indocin SR and Indos are apparently therapeutically equivalent to indomethacin capsules. In elderly patients, Indos has been shown to be associated with fewer side effects than Indocin. Both Indocin SR and Indos have the advantage of once or twice daily dosing.
Full Text Available The objective of pharmaceutical-technological development is to find a procedure of transforming an active substance (a drug into a drug dosage form which is not only acceptable for application, but also enables the active substance to be released following administration, pursuant to therapy objectives. The aim is that the concentration of the active substance in the action location rapidly reaches a therapeutic level and maintains an approximately constant level in the course of a particular time, according to the established therapeutic goal. The primary objective is to present the active ingredient (drug in the form and concentration/quantity that enables the corresponding therapeutic response, i.e. to control the site and rate of medicinal substance release from the drug, as well as the rate at which it reaches the membranes and surfaces to which it is absorbed, while applying a common method of administration. The procedures used to achieve this goal are becoming highly complex and demanding and are aiming at sophisticated drug delivery systems and functional packaging material. Development from the existing drug molecule, through the conventional drug dosage form, to a new system of drug "delivery" (novel delivery system, can improve the drug (active substance characteristics significantly in view of compliance (acceptability by the patient, safety and efficiency. The paper presents an overview of the most important examples of pharmaceutical forms with controlled release and advanced drug "carriers".
Marickar, Y M Fazil; Salim, Abiya
In earlier studies, we have confirmed that in most patients with calcium oxalate stone formation, a combination of allopurinol and pyridoxine is best suited for treatment and prevention of the stone forming process. The objective of this study is to identify the most effective directed medical treatment of urinary stones. The drug dose adjustment was based on clinical, radiological, biochemical, and microscopic parameters. 444 patients with proved calcium oxalate stone disease who were getting a combination of allopurinol and pyridoxine for a minimum period of 36 months were enrolled in this prospective study. The dosage schedule of these patients was recorded. Dosage adjustment was made depending upon the various clinical, biochemical, microscopic, and radiological changes during the study period. The dosage schedules were in six categories, namely very high dose chemotherapy (VHDC), i.e. allopurinol 600 mg/day and pyridoxine 240 mg/day, high-dose chemotherapy (HDC), i.e. allopurinol 300 mg/day and pyridoxine 120 mg/day, moderate dose prophylaxis (MDP), i.e. allopurinol 200 mg/day and pyridoxine 80 mg/day, low-dose prophylaxis (LDP), i.e. allopurinol 100 mg/day and pyridoxine 40 mg/day, and very low-dose prophylaxis (VLDP), i.e. allopurinol 50 mg/day and pyridoxine 20 mg/day and intermittent VLDP, wherein the VLDP was given on alternate months and still later at longer intervals. The temporary risk was assessed at each visit and dosage adjustment was made. The effect of the intervention was assessed during the next visit. All the patients involved in the study needed dose adjustment. The following schedules were initiated: VHDC (12) 3.5%, HDC (103) 23.2%, MDP (78) 17.57%, or LDP (251) 56.53%. Patients who defaulted for more than a month were excluded from the study. During each visit for follow up, all patients were advised change over of dose depending upon the clinical situation at the time of review. Patients on VHDC were advised reduction to lower doses
Shahid S. Chaudhary
Full Text Available Drugs obtained from natural sources are rarely administered or dispensed to patients in their native forms but are formulated into dosage forms. In Unani system of medicine dosage forms are broadly classified into four categories according to their state these are solid dosage forms, semisolid, liquid and gaseous dosage forms. Among them solid dosage forms e.g. Sufoof (powder, Kohal (coryllium, Kushta (calx, Qurs (tablet etc have several advantages over other dosage forms such as higher stability, easy to carry, better patient compliance. The rate of absorption of a formulation depends on the dosage form, route of administration and particle size. Some solid dosage forms like shiyaf (suppository, zarur (dusting powder, noorah (depilatory are used locally to produce their respective actions. But unfortunately some effective and potent dosage forms are neither used nor manufactured and they are near to extinct. Therefore in the present review an effort has been made to summarize the detailed Unani classical literature of solid dosage forms.
Caterina, R. de; Husted, S.; Wallentin, L.; Andreotti, F.; Arnesen, H.; Bachmann, F.; Baigent, C.; Huber, K.; Jespersen, J.; Kristensen, S.D.; Lip, G.Y.; Morais, J.; Rasmussen, L.H.; Siegbahn, A.; Verheugt, F.W.A.; Weitz, J.I.
Until recently, vitamin K antagonists were the only available oral anticoagulants, but with numerous limitations that prompted the introduction of new oral anticoagulants targeting the single coagulation enzymes thrombin (dabigatran) or factor Xa (apixaban, rivaroxaban, and edoxaban) and given in fi
WANG Jing; ZHANG Quanbin; ZHANG Zhongshan; HOU Yun; ZHANG Hong
Fucoidan, a group of sulfated heteropolysaccharides, was extracted from Laminariajaponica,an important economic alga species in China. The anticoagulant activity of fucoidan and its derivatives (including sulfated, phosphorylated, and aminated fucoidan) was examined using in-vitro anticoagulant systems. The correlation between chemical variations within the fucoidan group and anticoagulant activity was determined. The in-vitro anticoagulant properties of fucoidan and its derivatives were determined by measuring activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT).The results indicate anticoagulant activity in all samples using APTT and TT assays; however, only the fucoidan derivatives affected the PT assay. Thus, the fucoidan derivatives were able to inhibit both intrinsic and extrinsic blood coagulants. Fucoidan (FPS) and its derivatives presented better anticoagulant activity than low molecular weight fucoidan (DFPS) and its derivatives, suggesting that molecular weight and proper conformation are contributing factors for anticoagulant activity of polysaccharides. Amino groups have a positive charge and can thus change the charge density of fucoidan. Accordingly, among the tested samples, aminated fucoidan (NF) was the most active reflecting the importance of charge density for anticoagulant activity. Available data obtained using in-vitro models suggest that the sulfate content,sulfate/total-sugar ratio, molecular weight, and the substituted group of fucoidan are important factors for anticoagulant activity but that the influence of sulfate, phosphate and amino groups on anticoagulant activity was different.
Wang, Jing; Zhang, Quanbin; Zhang, Zhongshan; Hou, Yun; Zhang, Hong
Fucoidan, a group of sulfated heteropolysaccharides, was extracted from Laminaria japonica, an important economic alga species in China. The anticoagulant activity of fucoidan and its derivatives (including sulfated, phosphorylated, and aminated fucoidan) was examined using in-vitro anticoagulant systems. The correlation between chemical variations within the fucoidan group and anticoagulant activity was determined. The in-vitro anticoagulant properties of fucoidan and its derivatives were determined by measuring activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT). The results indicate anticoagulant activity in all samples using APTT and TT assays; however, only the fucoidan derivatives affected the PT assay. Thus, the fucoidan derivatives were able to inhibit both intrinsic and extrinsic blood coagulants. Fucoidan (FPS) and its derivatives presented better anticoagulant activity than low molecular weight fucoidan (DFPS) and its derivatives, suggesting that molecular weight and proper conformation are contributing factors for anticoagulant activity of polysaccharides. Amino groups have a positive charge and can thus change the charge density of fucoidan. Accordingly, among the tested samples, aminated fucoidan (NF) was the most active reflecting the importance of charge density for anticoagulant activity. Available data obtained using in-vitro models suggest that the sulfate content, sulfate/total-sugar ratio, molecular weight, and the substituted group of fucoidan are important factors for anticoagulant activity but that the influence of sulfate, phosphate and amino groups on anticoagulant activity was different.
Sodium nitroprusside has proved a useful completion of anaesthesiologist's armament. Nevertheless there still exist some doubts concerning correct dosage. This uncertainity is aggravated by communications in literature about fatal outcomes of hypotensions induced with this drug. For the patient's safety, we recommend not to exceed an infusion rate of 15mcg/kg/minute or a total of 1.5-3mg/kg irrespective of the time of administration. In any case the development of metabolic acidosis or the occurence of tachyphylaxis or resistance should be a strong argument for discontinuing nitroprusside and changing to an other method of hypotensive anaesthesia. A useful aid is the control of infusion rate by the IVAC-531-machine.
Full Text Available Background: Vitamin K antagonist anticoagulants (warfarin/acenocoumarol are commonly used anticoagulants that require careful clinical management to balance the risks of over anticoagulation and bleeding with those of under anticoagulation and clotting. Genetic variants of the enzyme that metabolizes vitamin K antagonist anticoagulant, cytochrome P-450 2C9 (CYP2C9, and of a key pharmacologic target of vitamin K antagonists anticoagulant, vitamin K epoxide reductase (VKORC1, contribute to differences in patients responses to various anticoagulant doses. Methods: In thirty patients on oral vitamin K antagonist anticoagulant therapy, presented with either clotting manifestations (valve thrombosis, pulmonary embolism and DVT or prolonged INR/bleeding manifestations, we assessed CYP2C9 genotypes, VKORC1 haplotypes, clinical characteristics, response to therapy (as determined by the international normalized ratio [INR], and bleeding events. Results: Of the thirty patients, thirteen patients INR was high and four patients presented with major bleeding and four with minor bleeding manifestations. Out of thirteen patients with high INR, ten patients showed CYP2C9 polymorphism ( 1/ 3 and 2/ 3 of poor metabolizer genotype. Most of the high INR patients were recently started on oral vitamin K antagonist anticoagulant. Most patients presented with clotting manifestations with below therapeutic INR are noncompliant with anticoagulants. Conclusions: The results of this study suggest that the CYP2C9 polymorphisms are associated with an increased risk of over anticoagulation and of bleeding events among patients on vitamin K antagonists' anticoagulant setting. Screening for CYP2C9 variants may allow clinicians to develop dosing protocols and surveillance techniques to reduce the risk of adverse drug reactions in patients receiving vitamin K antagonist anticoagulants. However the cost-effectiveness of genotyping of patients must be considered. [Int J Res Med Sci
Cui, Yan-Rui; Guo, Yan; Wu, Qing
Effects of biological activated carbon (BAC) dosage on COD removal in landfill leachate treatment were compared. The COD removal efficiency of reactors with 0, 100 and 300 g activated carbon dosage per litre activated sludge was 12.9%, 19.6% and 27.7%, respectively. The results indicated that BAC improved the refractory organic matter removal efficiency and there was a positive correlation between COD removal efficiency and BAC dosage. The output of carbon dioxide after 8h of aeration in reactors was 109, 193 and 306 mg corresponding to the activated carbon dosages mentioned above, which indicated the amount of biodegradation and BAC dosage also had a positive correlation. The combination of adsorption and bioregeneration of BAC resulted in the positive correlation betweem organic matter removal efficiency and BAC dosage, and bioregeneration was the root cause for the microbial decomposition of refractory organics.
Rastogi, Akriti; Biswas, Sumit; Sarkar, Angshuman; Chakrabarty, Dibakar
Moon jellyfish (Aurelia aurita) tentacle extract was studied for its anticoagulant activity in vitro. The Jellyfish Tentacle Extract (JFTE) showed very strong fibrinogenolytic activity by cleaving Aα and Bβ chain of fibrinogen molecule. The fibrinogenolytic activity was found to be stronger than some snake venom derived anticoagulants. JFTE also completely liquefied fibrin clots in 24 h. JFTE was found to contain both high and low molecular weight proteins/peptides. The fibrinogenolysis appears to be caused by high molecular weight fractions of the extract. It has been also noted that PMSF significantly reduced fibrinogenolytic activity and heating totally abolished it. Autolytic degradation of the high molecular weight protein was also noted. Autolysis slowed down, but did not abolish the fibrinogenolytic activity of the extract.
Lavoignet, Charles-Éric; Le Borgne, Pierrick; Ugé, Sarah; Veneziano, Rinaldo; Brunhuber, Claudia; Kam, Claire; Bilbault, Pascal
Acute renal infarction is an uncommon and often under diagnosed condition mostly because of misleading symptoms. Accurate data regarding clinical presentation, laboratory tests, diagnostic and treatment are lacking. Detection is often delayed or missed because of non-specific clinical presentation. The mechanisms of acute renal infarction are various, mainly embolic or thrombotic. Abdominal CT scan remains the most valuable exam to confirm the diagnosis. Therapeutic guidelines for the treatment of renal embolism have not been well established. The standard treatment strategy includes anticoagulation with or without thrombolysis. Despite the uncertainty regarding management, the renal outcome remains favorable. Some patients do develop some degree of renal insufficiency during the acute episode. We report here the case of a 73-year-old woman with bilateral acute renal infarction after discontinuation of anticoagulant therapy.
Cassinelli, Giuseppe; Naggi, Annamaria
The aim of this chapter is to provide an overview of non-anticoagulant effects of heparins and their potential use in new therapeutic applications. Heparin and heparin derivatives have been tested in inflammatory, pulmonary and reproductive diseases, in cardiovascular, nephro- and neuro-tissue protection and repair, but also as agents against angiogenesis, atheroschlerosis, metastasis, protozoa and viruses. Targeting and inhibition of specific mediators involved in the inflammatory process, promoting some of the above mentioned pathologies, are reported along with recent studies of heparin conjugates and oral delivery systems. Some reports from the institute of the authors, such as those devoted to glycol-split heparins are also included. Among the members and derivatives of this class, several are undergoing clinical trials as antimetastatic and antimalarial agents and for the treatment of labour pain and severe hereditary anaemia. Other heparins, whose therapeutic targets are non-anticoagulant such as nephropathies, retinopathies and cystic fibrosis are also under investigation.
Baron, Todd H; Kamath, Patrick S; McBane, Robert D
A large number of patients worldwide receive anticoagulant and antiplatelet agents, collectively known as antithrombotic agents. Several new anticoagulants and antiplatelet agents recently were approved for use. Gastroenterologists may be unfamiliar with the mechanism of action, indications for use, and pharmacokinetics of these newer drugs. In patients undergoing elective and urgent endoscopic procedures, clinicians must be familiar with these medications to optimize outcomes. When the decision is made to continue the newer antithrombotic agents for elective procedures, the clinician must understand the risk that these agents may impart on procedural-induced bleeding. Finally, it is important to understand how to manage these agents in the presence of acute gastrointestinal bleeding. In this article the use of newer antithrombotic agents is reviewed.
Crowther, Mark; Crowther, Mark A
The direct thrombin inhibitor dabigatran and the anti-Xa agents rivaroxaban, edoxaban, and apixaban are a new generation of oral anticoagulants. Their advantage over the vitamin K antagonists is the lack of the need for monitoring and dose adjustment. Their main disadvantage is currently the absence of a specific reversal agent. Dabigatran's, unlike the anti-Xa agents, absorption can be reduced by activated charcoal if administered shortly after ingestion and it can be removed from the blood with hemodialysis. Prothrombin complex concentrate, activated prothrombin complex concentrate, and recombinant factor VIIa all show some activity in reversing the anticoagulant effect of these drugs but this is based on ex vivo, animal, and volunteer studies. It is unclear, which, if any, of these drugs is the most suitable for emergency reversal. Three novel molecules (idarucizumab, andexanet, and PER977) may provide the most effective and safest way of reversal. These agents are currently in premarketing studies.
Liu, Xiaoqi; Cao, Ye; Zhao, Mengli; Deng, Jianhua; Li, Xifei; Li, Dejun
Graphene may have attractive properties for some biomedical applications, but its potential adverse biological effects, in particular, possible modulation when it comes in contact with blood, require further investigation. Little is known about the influence of exposure to COOH(+)-implanted graphene (COOH(+)/graphene) interacting with red blood cells and platelets. In this paper, COOH(+)/graphene was prepared by modified Hummers' method and implanted by COOH(+) ions. The structure and surface chemical and physical properties of COOH(+)/graphene were characterized by scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), and contact angle measurement. Systematic evaluation of anticoagulation, including in vitro platelet adhesion assays and hemolytic assays, proved that COOH(+)/graphene has significant anticoagulation. In addition, at the dose of 5 × 10(17) ions/cm(2), COOH(+)/graphene responded best on platelet adhesion, aggregation, and platelet activation.
Osoniyi, Omolaja; Onajobi, Funmi
Jatropha curcas Linn. (Euphorbiaceae), a medicinal plant commonly grown in the Tropics, is traditionally used as a haemostatic. Investigation of the coagulant activity of the latex of Jatropha curcas showed that whole latex significantly (Platex, however, prolonged the clotting time: at high dilutions, the blood did not clot at all. This indicates that Jatropha curcas latex possesses both procoagulant and anticoagulant activities. Prothrombin time (PT) and activated partial thromboplastin time (APTT) tests on plasma confirm these observations. Solvent partitioning of the latex with ethyl acetate and butanol led to a partial separation of the two opposing activities: at low concentrations, the ethyl acetate fraction exhibited a procoagulant activity, while the butanol fraction had the highest anticoagulant activity. The residual aqueous fraction had no significant effect on the clotting time of blood and the PT but slightly prolonged the APTT.
Full Text Available In this study, the anticoagulation effect of glycosaminoglycan from Mactra veneriformis was studied. The results showed that glycosaminoglycan mainly exerted anticoagulation via antithrombin III. Glycosaminoglycan could passivate the function of heparin cofactor II inhibiting thrombin activity. Glycosaminoglycan significantly reduced the activities of coagulation factor II, V, VII, X, VIII, IX, XI, XII as well as fibrinogen content in the plasma (p<0.05, p<0.01. Besides, glycosaminoglycan could extend blood recalcification time in rats by shielding Ca2+ in plasma and significantly reduced Ca2+ concentration in rats and mice serum (p<0.05, p<0.01. Glycosaminoglycan reduced the Ca2+ concentration in serum in a more intensive way than that of heparin sodium (p<0.05, p<0.01.
Hellfritzsch, Maja; Rathe, Jette; Stage, Tore Bjerregaard;
PURPOSE: Generic switching of warfarin was recently repealed in Denmark, as adverse drug reaction (ADR) reports suggested risk of excessive anticoagulation following switches from branded to generic warfarin. We investigated this putative association in a formalized pharmacoepidemiological analysis....... METHODS: We conducted a nationwide cohort study based on Danish healthcare registries, including data from the introduction of generic warfarin until the repeal (January 2011-April 2015). We followed Danish warfarin users over time and compared the rate of incident hospitalizations due to excessive...... anticoagulation (i.e. increased INR or any bleeding requiring hospitalization) in periods following a recent switch to generic warfarin to the rate in periods without a recent switch. RESULTS: We included 105 751 warfarin users, filling a total of 1 539 640 prescriptions for warfarin (2.5% for generic warfarin...
Park, Hyun Oh; Moon, Seong Ho; Kim, Jong Woo; Byun, Joung Hun; Kim, Sung Hwan; Yang, Jun Ho; Lee, Chung-Eun; Kim, Jong-Duk
Hypercoagulable states have been associated with aortic thrombosis. Antiphospholipid syndrome (APS) is one of the commonest types of acquired thrombophilia. We report the case of successful anticoagulation management in an APS patient with mobile thrombi within the aorta. A 58-year-old male patient presented to the emergency department (ED) with right-sided hemiparesis. His first symptoms were noted approximately 12–16 hours before presentation to the ED. Magnetic resonance imaging of the brain showed acute embolic infarction of the left frontal and parietotemporal lobes. Transesophageal echocardiography (TEE) and computed tomography angiography (CTA) demonstrated mobile thrombi attached to the wall of the ascending aorta and aortic arch. The patient was diagnosed with APS based on positivity of anti-beta-2 glycoprotein 1 antibodies, and was initiated on anticoagulation therapy. Repeated TEE and CTA revealed complete resolution of the thrombi after 12 days of treatment; the patient was discharged well. PMID:28042559
Cohen, Harold V; Quek, Samuel Y P; Subramanian, Gayathri; Abbas, Ali
A recent occurrence in dental practice is the noting of new "blood thinners" when the clinician is reviewing a patient's medical history and medications. "Doc, I take Pradaxa or Effient or Xarelto" etc. After many years of the widespread use of aspirin and Coumadin there has appeared a new generation of medications focused on reducing thromboembolic events in patients at risk. This trend has been driven by a need for drugs providing better drug efficacy based on patient biologic processing of the medications and the frequency and cost factors associated with the monitoring the degree of anticoagulation. Guidelines for assessing bleeding risk and managing patients on these new medications in dental practice are not yet defined and are empirically based on medical practitioner experience. This paper will review these new medications and will discuss current considerations for dental patient care. (Note that not all new antiplatelet and anticoagulant medications will be reviewed in this paper.)
Francia, Pietro; Adduci, Carmen; Santini, Daria; Musumeci, Beatrice; Tocci, Giuliano
Atrial fibrillation (AF) is associated with an increased risk of embolic stroke. Dose-adjusted vitamin K antagonists (VKAs) to a target international normalized ratio (INR) range of 2.0-3.0 reduce the risk of ischemic stroke and are currently recommended in all patients with AF at moderate-high risk for stroke or systemic embolism. However, VKAs have several drawbacks, including unpredictable anticoagulant response, food and drug interactions, need for regular laboratory monitoring and dose adjustment. These limitations prompted the introduction of new oral anticoagulants (NOA) that target thrombin and factor Xa, key-enzymes in the coagulation pathway. NOA have predictable pharmacodynamics, allowing fixed dosing without the need of laboratory monitoring, and have few drug and food interactions. The present review focuses on pharmacological properties, safety, and appropriate clinical use of dabigatran, rivaroxaban and apixaban.
Renan Domingues; Gustavo Bruniera; Fernando Brunale; Cristóvão Mangueira; Carlos Senne
ABSTRACT The use of anticoagulants and antiplatelet agents has largely increased. Diagnostic lumbar puncture in patients taking these drugs represents a challenge considering the opposing risks of bleeding and thrombotic complications. To date there are no controlled trials, specific guidelines, nor clear recommendations in this area. In the present review we make some recommendations about lumbar puncture in patients using these drugs. Our recommendations take into consideration the pharmaco...
Full Text Available Context: There is limited data regarding the use of activated recombinant factor VII (rFVIIa in anticoagulated patients requiring reversal. Aims: To identify and describe characteristics of subjects who received rFVIIa as part of emergency treatment aimed at improving hemostasis. Settings and Design: Data was obtained from an international peer-reviewed registry haemostasis.com. This registry contains data reported by physicians, who had elected to use rFVIIa to control bleeding in an emergency clinical situation. The contributors′ approval for inclusion in the study was obtained and they were requested to validate and update information. Materials and Methods: Database review of cases receiving rFVIIa to manage bleeding coherent with the use of anticoagulant therapy. Statistical Analysis: The Wilcoxon signed rank test was used to compare requirements for blood products and crystalloids/colloids during the 24h preceding and following rFVIIa administration, as well as changes in the levels of clotting factors during that period. Results: Eighteen patients were treated with rFVIIa (median dose: 87.35 µg/kg; range: 20.0-106.0 µg/kg for bleeding. Anticoagulants requiring reversal included low-molecular-weight heparin (n = 6, unfractionated heparin (n =8, coumarin (n =3 and warfarin (n=1. All patients had failed to respond to traditional antidotes and blood products. Following administration, bleeding stopped in 10, markedly decreased in five and slowed in the remaining three. Amongst 12/16 patients, a response was observed within 2.0 h of first administration. The requirement for blood products and crystalloids/colloids decreased ( P < 0.05 after rFVIIa administration. rFVIIa was well tolerated. Conclusions: rFVIIa may play a role in control of untoward bleeding in subjects receiving anticoagulation therapy.
Knežević Milan; Petrović Dragan; Jović Nebojša; Bosch Carlos
Today there must be established protocol in oral surgery treatment for the patients which are under anticoagulant treatment via oral (ATO). This is due to danger of the possible complications and also for increased demand for hospital treatment of these patients, which can be estimated now days as high as 8%. In the present study, the authors intent to define all the parameters for creation of one acting protocol applicable to this group of patients and concluding that there is no necessary n...
Atrial fibrillation treatment relies on anticoagulation therapy that reduces the risk of stroke. Vitamin K antagonists (VKA) were the only oral anticoagulant drugs for more than 50 years, but they are difficult to manage especially in the elderly. In France, VKA are the main cause of iatrogenic hospitalizations with about 17,000 hospitalizations per year and around 4,000 to 5,000 deaths per year. Pharmacologic properties of VKA, especially the narrow therapeutic margin explain the complexity of their management. Several studies have shown that patients treated with VKA were on average only 50% of the time with an INR in the therapeutic range. In other words, patients are, half of the time, either-under treated or over-treated. Within this framework, development of new oral anticoagulant drugs appeared necessary, in order to obtain drugs with larger therapeutic margin and a better risk/benefit profile than VKA. Three large randomized clinical trials including almost 50,000 patients with 20,000 subjects over 75 years old and 8,000 over 80 years old, show a better risk/benefit profile of the new oral anticoagulants (NOAC) than VKA, characterized by a 50% reduction of cerebral hemorrhages, 22% reduction of stroke and 12% reduction of total mortality. Meanwhile, their renal elimination and the lack of control of the biological efficacy need to be taken into account for their prescription. Renal failure (estimated glomerular filtration rate according to Cockcroft formula < 30 mL/min) contraindicates their use. Their half-life is shorter than that of VKA and the biological monitoring is not available, thus a good adherence to the treatment is important. Studies specifically conducted among geriatric older population with poly-pathologies and frail are therefore needed to evaluate tolerance of NOAC in real life conditions.
Julio Cesar Lazaro
Full Text Available Introduction Electroconvulsive therapy (ECT is considered the most effective treatment for catatonia regardless its underlying condition. The rigid fixed posture and immobility observed in catatonia may lead to several clinical complications, of which, pulmonary embolism (PE is one of the most severe. The rapid improvement of the psychiatric condition in catatonia-related PE is essential, since immobility favors the occurrence of new thromboembolic events and further complications. In that scenario, ECT should be considered, based on a risk-benefit analysis, aiming at the faster resolution of the catatonia. Methods Case report and literature review. Results A 66-years-old woman admitted to the psychiatric ward with catatonia due to a depressive episode presented bilateral PE. Clinically stable, but still severely depressed after a trial of antidepressants, she was treated with ECT in the course of full anticoagulation with enoxaparin. After five ECT sessions, her mood was significantly better and she was walking and eating spontaneously. She did not present complications related either to PE or to anticoagulation. After the eighth ECT session, she evolved with hypomania, which was managed with oral medication adjustments. The patient was completely euthymic at discharge. Conclusion The case we presented provides further evidence to the anecdotal case reports on the safety of ECT in the course of concomitant full anticoagulant therapy after PE, and illustrates how, with the proper precautions, the benefits of ECT in such condition might outweigh its risks.
Full Text Available Valvular heart disease is a major and serious healthcare issue. There is an increasing evidence that Nurse-led anticoagulation clinics may improve patients’ management and care.This is a retrospective comparison study that included the first 94 patients enrolled in the Nurse Led Prosthetic Valve Anticoagulation Clinic (PVATC in King Abdul-Aziz Cardiac Centre between April and June 2013, and received Warfarin by General Cardiology Clinics for one year pre enrollment in PVATC, and one year after. Time in Therapeutic Range (TTR of the International Normalized Ratio (INR was calculated and compared between pre and post PVATC enrolment. Other data including demographics and comorbidities were collected and analyzed. Mean age of patients was 53 ± 12.5 years and males were 56%. Atrial fibrillation was found in 37%, Diabetes Mellitus in 28% and Hypertension in 34%. Mean TTR was 72% pre enrollment in PVATC as compared to 78.9% after (P < 0.006. Median TTR was 75% pre, and 81.5% after attending the PVATC (P < 0.0001. 56% of patients pre enrollment had TTR values above 70% threshold, compared to 75% after enrollment. Nurse-Led PVATC has significant impact on the care provided to patients receiving anticoagulation treatment.
Full Text Available The ideal anticoagulant is oral, has a wide therapeutic range, predictable pharmacokinetics and pharmacodynamics, a rapid onset of action, an available antidote, minimal side effects and minimal interactions with other drugs or food. With the development of the novel direct oral anticoagulants (DOAC, we now have an alternative to the traditional vitamin K antagonists (VKA for the prevention and treatment of thrombosis. DOACs have limited monitoring requirements and very predictable pharmacokinetic profiles. They were shown to be non-inferior or superior to VKA in the prophylaxis or treatment of thromboembolic events. Particularly in terms of safety they were associated with less major bleeding, including intracranial bleeding, thus providing a superior benefit for the prevention of stroke in patients with atrial fibrillation. Despite these advantages, there are remaining limitations with DOACs: their dependence on renal and hepatic function for clearance and the lack of an approved reversal agent, whereas such antidotes are successively being made available. DOACs do not need regular monitoring to assess the treatment effect but, on the other hand, they interact with other drugs and interfere with functional coagulation assays. From a practical point of view, the properties of oral administration, simple dosing without monitoring, a short half-life allowing for the possibility of uncomplicated switching or bridging, and proven safety overwhelm the disadvantages, making them an attractive option for short- or long-term anticoagulation.
Martin, Jennifer A; Parekh, Parag; Kim, Youngmi; Morey, Timothy E; Sefah, Kwame; Gravenstein, Nikolaus; Dennis, Donn M; Tan, Weihong
Adverse drug reactions, including severe patient bleeding, may occur following the administration of anticoagulant drugs. Bivalirudin is a synthetic anticoagulant drug sometimes employed as a substitute for heparin, a commonly used anticoagulant that can cause a condition called heparin-induced thrombocytopenia (HIT). Although bivalrudin has the advantage of not causing HIT, a major concern is lack of an antidote for this drug. In contrast, medical professionals can quickly reverse the effects of heparin using protamine. This report details the selection of an aptamer to bivalirudin that functions as an antidote in buffer. This was accomplished by immobilizing the drug on a monolithic column to partition binding sequences from nonbinding sequences using a low-pressure chromatography system and salt gradient elution. The elution profile of binding sequences was compared to that of a blank column (no drug), and fractions with a chromatographic difference were analyzed via real-time PCR (polymerase chain reaction) and used for further selection. Sequences were identified by 454 sequencing and demonstrated low micromolar dissociation constants through fluorescence anisotropy after only two rounds of selection. One aptamer, JPB5, displayed a dose-dependent reduction of the clotting time in buffer, with a 20 µM aptamer achieving a nearly complete antidote effect. This work is expected to result in a superior safety profile for bivalirudin, resulting in enhanced patient care.
Jennifer A Martin
Full Text Available Adverse drug reactions, including severe patient bleeding, may occur following the administration of anticoagulant drugs. Bivalirudin is a synthetic anticoagulant drug sometimes employed as a substitute for heparin, a commonly used anticoagulant that can cause a condition called heparin-induced thrombocytopenia (HIT. Although bivalrudin has the advantage of not causing HIT, a major concern is lack of an antidote for this drug. In contrast, medical professionals can quickly reverse the effects of heparin using protamine. This report details the selection of an aptamer to bivalirudin that functions as an antidote in buffer. This was accomplished by immobilizing the drug on a monolithic column to partition binding sequences from nonbinding sequences using a low-pressure chromatography system and salt gradient elution. The elution profile of binding sequences was compared to that of a blank column (no drug, and fractions with a chromatographic difference were analyzed via real-time PCR (polymerase chain reaction and used for further selection. Sequences were identified by 454 sequencing and demonstrated low micromolar dissociation constants through fluorescence anisotropy after only two rounds of selection. One aptamer, JPB5, displayed a dose-dependent reduction of the clotting time in buffer, with a 20 µM aptamer achieving a nearly complete antidote effect. This work is expected to result in a superior safety profile for bivalirudin, resulting in enhanced patient care.
Emre Kumral; Tuba Cerraho(g)lu (S)irin
Recent evidence is leading to the replacement of vitamin K antagonists,the efficacy of which in preventing stroke in patients with atrial fibrillation (AF) is well established,with better tolerated and more manageable new anticoagulant drugs,with a lower risk of intracranial bleeding,no clear interactions with food,fewer interactions with medications,and no need for frequent laboratory monitoring and dose adjustments.Among new anticoagulants,dabigatran etexilate is a direct,competitive inhibitor of thrombin.It was evaluated for patients with AF in the RE-LY trial,showing lower rates of stroke and systemic embolism at a dose of 150 mg twice daily with similar rates of major hemorrhage compared with warfarin; and non-inferiority compared with warfarin for the prevention of stroke and systemic embolism at a dose of 110 mg twice daily,with lower rates of major bleeding.Beside dabigatran,oral factor X a inhibitors are also emerging for the prevention of thromboembolic events in AF.Despite the obvious advantages of these new oral anticoagulants over vitamin K antagonists,further information is still needed on how to prioritize the patients deriving the greatest benefit from these novel agents on the basis of patient characteristics or drug pharmacokinetics.There is also a need for assessing their long-term efficacy and safety over decades in the real-world setting.
Fucoidan (FC),an effective anticoagulant constituent extracted from brown algae,was introduced into silk fibroin (SF) for improving its blood compatibility.The SF and SF/FC blend films were characterized by attenuated total reflectance Fourier-transform infrared (ATR-FTIR),X-ray photoelectron spectroscopy (XPS),scanning electron microscopy (SEM) and dynamic contact angle determinator (CA).The in vitro anticoagulant activities of the films were evaluated by activated partial thromboplastin time (APTT),thrombin time (TT) and prothrombin time (PT) measurements.The endothelial cell attachment and proliferation viability on the film were assessed by micropipette aspiration technique and MTT assay,respectively.The testing results indicated that the introduction of FC increased the roughness,hydrophilicity and sulfate component of the film surface without impeding the formation of β-sheet conformation in SF.More important,FC brought excellent anticoagulant activity and better endothelial cell affinity to SF.The SF/FC blend film was hopeful to be used as blood-contacting biomaterials.
Pototski, Mariele; Amenábar, José M
Antiplatelet and anticoagulant agents have been extensively researched and developed as potential therapies in the prevention and management of arterial and venous thrombosis. On the other hand, antiplatelet and anticoagulant drugs have also been associated with an increase in the bleeding time and risk of postoperative hemorrhage. Because of this, some dentists still recommend the patient to stop the therapy for at least 3 days before any oral surgical procedure. However, stopping the use of these drugs exposes the patient to vascular problems, with the potential for significant morbidity. This article reviews the main antiplatelet and anticoagulant drugs in use today and explains the dental management of patients on these drugs, when subjected to minor oral surgery procedures. It can be concluded that the optimal INR value for dental surgical procedures is 2.5 because it minimizes the risk of either hemorrhage or thromboembolism. Nevertheless, minor oral surgical procedures, such as biopsies, tooth extraction and periodontal surgery, can safely be done with an INR lower than 4.0.
Full Text Available Introduction and Objective: Spontaneous pharyngeal-laryngeal hematoma shows the importance of a complete ENT examination in the face of symptoms of banal appearance and a correct history that, in the case reported, unveiled the therapeutic use of anticoagulants. Case description: A 55 year old woman comes to emergency because of unexplained dysphagia. The inspection shows the presence of a hematoma in the pharyngeal-laryngeal region that, after the anticoagulant therapy was reversed, evolved favorably with conservative treatment. Discussion: In this case, apart from medical management performed by the hematology department, we focus our therapeutic approach in the protection of the airway and the prevention of a possible massive bleeding. Determining which patients require endotracheal intubation or tracheostomy and hemostatic surgery is the key to treatment. Conclusions: The anticoagulant therapy involves several complications that ENT specialists must consider in the face of clinical symptoms of dysphagia, dysphonia, dyspnea or signs of bleeding and they must know the possibilities of performance depending on the severity of each case.
Hong, Sung Kuk; Hwang, Sang Mee; Kim, Ji-Eun; Kim, Hyun Kyung
The mixing test is used to determine the presence of inhibitors in laboratory diagnoses of lupus anticoagulant. Updated international guidelines state that an integrated lupus anticoagulant test system does not require the mixing test; an appraisal of the mixing tests in integrated lupus anticoagulant test systems is, therefore, required. We investigated the clinical relevance of mixing tests by using the best cutoff value of the mixing test through thrombotic risk analysis. A retrospective analysis was performed on 525 specimens with positive screening tests by using two integrated lupus anticoagulant tests: diluted Russell's Viper venom (dRVVT) and silica clotting time. The diagnostic performance of two interpretation formulas (percentage correction, Rosner index) was assessed, and the thrombotic risk of a subgroup based on the mixing results was investigated. Finally, the thrombotic risk of lupus anticoagulant positivity based on the integrated lupus anticoagulant test system procedures was assessed for the appraisal of mixing test exclusion in integrated lupus anticoagulant test systems. The best cutoff values of mixing test interpretation methods based on dRVVT were as follows: 60.1% for percentage correction and 15.7 for Rosner index. There was no substantial difference in the thrombotic risk between percentage correction and the Rosner index. The mixing-positive group showed a higher lupus anticoagulant titer and higher thrombotic risk than the mixing-negative group. However, even the mixing-negative group carried a significant risk of thrombosis. Finally, lupus anticoagulant positivity determined by the updated two-step procedure (screening and confirmation tests) showed higher thrombotic risk than that determined by the traditional three-step procedure (screening, mixing, and confirmation tests). Although a positive mixing result can predict a high risk of thrombosis, negative mixing results are also associated with a substantial thrombotic risk. The
Atanaska Dinkova; Donka G. Kirova; Delyan Delev
Dental treatment performed in patients receiving oral anticoagulant drug therapy is becoming increasingly common in dental offices.The aim of oral anticoagulant therapy is to reduce blood coagulability to an optimal therapeutic range within which the patient is provided some degree of protection from thromboembolic events. This is achieved at the cost of a minor risk of haemorrhage. Frequently raised questions concern the safety and efficacy of the various anticoagulation regimens and their a...
Miranda, M; MARTINEZ, L.S.; De Franco, R.; FORTE, V.; BARLATTANI, A.; BOLLERO, P.
The oral anticoagulant therapy is used for the cure and the prevention of thromboembolic diseases. In the last fifty years the warfarin has been considered the oral anticoagulant of choice. However, its use is limited by a narrow therapeutic index and by a complex pharmacodynamics, which requires regular adjustments and monitoring of the dose. Recently, three new oral anticoagulant – dabigatran etexilato (direct thrombin inhibitor), rivaroxaban and apixaban (Xa factor direct inhibitor) – have...
Babilonia, Katrina; Trujillo, Toby
Over the past several years a new era for patients requiring anticoagulation has arrived. The approval of new target specific oral anticoagulants offers practitioners several advantages over traditionally used vitamin K antagonist agents including predictable pharmacokinetics, rapid onset of action, comparable efficacy and safety, all without the need for routine monitoring. Despite these benefits, hemorrhagic complicates are inevitable with any anticoagulation treatment. One of the major disadvantages of the new oral anticoagulants is lack of specific antidotes or reversal agents for patients with serious bleeding or need for urgent surgery. As use of the new target specific oral anticoagulants continues to increase, practitioners will need to understand both the pharmacodynamics and pharmacokinetic properties of the agents, as well as, the available literature with use of non-specific therapies to reverse anticoagulation. Four factor prothrombin complex concentrates have been available for several years in Europe, and recently became available in the United States with approval of Kcentra. These products have shown efficacy in reversing anticoagulation from vitamin K antagonists, however their usefulness with the new target specific oral anticoagulants is poorly understood. This article will review the properties of dabigatran, rivaroxaban and apixaban, as well as the limited literature available on the effectiveness of prothrombin complex concentrates in reversal of their anticoagulant effects. Additional studies are needed to more accurately define the role of prothrombin complex concentrates in patients with life threatening bleeding or who require emergent surgery, as current data is both limited and conflicting.
Son, Kyeong Min; Kim, Ja Kyung; Seo, Young Il; Kim, Hyun Ah
Hemarthrosis can occur in patients with a predisposition to hemorrhage, such as hemophiliacs or patients on anticoagulation therapy. If hemarthrosis recurs after supportive treatment, however, other etiologies such as anatomical abnormalities should be considered. Spontaneous articular pseudoaneurysm associated with anticoagulation treatment has not been reported previously. We describe a patient on anticoagulation therapy with bilateral hemarthrosis due to pseudoaneurysms. After failing to respond to the correction of over-anticoagulation, magnetic resonance imaging led to the diagnosis of articular pseudoaneurysm. The patient was treated successfully by transarterial embolization.
Qin Chuan; Xiao Yingbin
Objective: To evaluate the plasma concentration of thrombus precursor protein (TPP) in patients after mechanical heart valve replacement, and to explore whether it can be used as a marker for monitoring anticoagulation. Methods: Totally 60 patients who took warfarin after mitral valve replacement and 20 control patients with non-valvular heart diseases were subjected in this study. Their plasma TPP concentration and international normalized ratio (INR) were determined, and compared not only between the anticoagulant patients and the control patients, but also between the patients with atrial fibrillaiton (AF, n=37) and the patients with sinus rhythm (SR, n=23) after mechanical valve replacement. The relationship between plasma TPP concentration and INR in the 60 anticoagulant patients was analyzed with linear regression. Results: It was found that the anticoagulant therapy effectively decreased plasma TPP concentration and elevated INR. In the anticoagulant group, the patients with AF had higher plasma TPP concentration than the others with sinus rhythm (P0.05). No significant correlation was found between plasma TPP concentration and INR in the anticoagulant patients (P>0.05). INR did not accord with plasma TPP concentration in several patients. Conclusion: INR can't reflect the coagulation status and guide the anticoagulation correctly sometimes; TPP may be a valuable assistant marker for monitoring anticoagulation in patients with mechanical heart valve prothesis; Patients with AF may require higher density of anticoagulation and TPP is strongly suggested to be monitored in these patients.
Krasny, Marta; Krasny, Kornel; Fiedor, Piotr
Cardiovascular conditions, apart from neoplastic diseases, remain the major cause of death in developed countries; therefore, the number of patients receiving oral anticoagulants is constantly increasing. Anticoagulant therapy considerably reduced mortality in patients with history of myocardial infarction among others. Although many interventions may be performed without withdrawal of the anticoagulant and tooth extraction was qualified as a procedure of low hemorrhage risk, a majority of dentists refer the patient to a cardiologist several days before the elective tooth extraction to withdraw anticoagulants. The aim of the study was to evaluate the efficacy and safety of bone wax used to stop bleeding after dental procedures in a group of patients on chronic anticoagulant therapy and find an answer to a question, whether it is justified to temporarily withdraw anticoagulants for this type of procedures. The study involved 176 patients on chronic anticoagulant therapy undergoing tooth extraction (154 subjects) or surgical extraction of a retained tooth (48 subjects). After the procedure, in each case the alveolus was filled with bone wax to stop bleeding. In all patients involved in the study bleeding from the alveolus was successfully stopped during the procedure. None of the subjects reported increased bleeding from the operational site after coming back home. Bone wax is a good, efficient, and safe material to block bleeding from the alveolus following tooth extractions, also in patients on chronic anticoagulant therapy. The study demonstrated that withdrawal or adjustment of anticoagulant therapy is not necessary before an elective tooth extraction.
Steinberg, M J; Moores, J F
Dental professionals frequently treat patients who are receiving anticoagulation therapy. Proper treatment may require adjustment of the anticoagulant dose usually on the basis of the patient's current prothrombin time. This test has been shown to be less accurate than previously thought. The international normalized ratio is another method that attempts to standardize the degree of anticoagulation and to improve reproducibility of results. This system is slowly being implemented in laboratories in the United States. Practitioners who treat patients taking anticoagulants need to be aware of this system in order to make appropriate management decisions.
Dayse Maria Lourenço
Full Text Available OBJETIVO: Verificar a resposta de 73 pacientes com superdosagem de droga anti-vitamina K (AVK a 3 esquemas de tratamento. MÉTODOS: Os 73 pacientes foram avaliados em 94 ocasiões e divididos em 3 grupos: grupo A (N=32 , suspensão do AVK por 2 dias e introdução de dose menor; grupo B (N=37, suspensão do AVK e reavaliação em 4 dias; grupo C (N=25, vitamina K por via oral. A razão normalizada internacional (RNI final foi considerada adequada quando entre 2,0 e 4,0. RESULTADOS: Não houve diferença entre os tratamentos (chi²=2,352, p=0,671 para 61 pacientes com RNI inicial 8. Cinco dos 7 pacientes do grupo B que continuaram com superdosagem tinham RNI PURPOSE: To evaluate the response of 73 patients with antivitamin K (AVK overdose to 3 different therapeutic regimens. METHODS: Seventy three patients were evaluated in 94 occasions: group A (N=32, consisted of drug withdrawal for 2 days followed by reduced dosage; group B (N=37, drug withdrawal and reassessment within 4 days; group C (N=25, oral administration of vitamin K. Therapeutic range was set between INR-values of 2 and 4. RESULTS: Reversal regimens did not result in differences among 61 patients who had initial INR 4, but 5 of them were bellow 4.5, without increased bleeding risk. There were 10 patients in group C bellow therapeutic range, 6 of them with INR < 1.6, with risk of thromboembolism. Thirteen patients bled, but none required transfusion. CONCLUSION: Reversal of excessive oral anticoagulation can be safely performed by initial withdrawal of the drug, followed by lower doses. Vitamin K administration may lead to INR bellow the therapeutic range. This should be reserved for patients with high INR or in the presence of bleeding.
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Full Text Available Lubrication plays a key role in successful manufacturing of pharmaceutical solid dosage forms; lubricants are essential ingredients in robust formulations to achieve this. Although many failures in pharmaceutical manufacturing operations are caused by issues related to lubrication, in general, lubricants do not gain adequate attention in the development of pharmaceutical formulations. In this paper, the fundamental background on lubrication is introduced, in which the relationships between lubrication and friction/adhesion forces are discussed. Then, the application of lubrication in the development of pharmaceutical products and manufacturing processes is discussed with an emphasis on magnesium stearate. In particular, the effect of its hydration state (anhydrate, monohydrate, dihydrate, and trihydrate and its powder characteristics on lubrication efficiency, as well as product and process performance is summarized. In addition, the impact of lubrication on the dynamics of compaction/compression processes and on the mechanical properties of compacts/tablets is presented. Furthermore, the online monitoring of magnesium stearate in a blending process is briefly mentioned. Finally, the chemical compatibility of active pharmaceutical ingredient (API with magnesium stearate and its reactive impurities is reviewed with examples from the literature illustrating the various reaction mechanisms involved.
Kablitz, Caroline Désirée; Urbanetz, Nora Anne
The dry coating process was evaluated in terms of storage stability investigating drug release and agglomeration tendency of the different coated oral dosage forms; hydroxypropyl methylcellulose acetate succinate (HPMCAS) was used with triethylcitrate (TEC) as plasticizer and acetylated monoglyceride (Myvacet) as wetting agent. Talc or colloidal silicon dioxide (Aerosil) was used as anti-tacking agents. In contrast to coating formulations consisting of HPMCAS and Myvacet all formulations containing TEC showed enteric resistance and no agglomeration tendency after preparation. After storage at 10% RH +/- 5% enteric resistance is increased slightly. This increase is more pronounced at 60% RH +/- 5%. The formulations without anti-tacking agents showed higher drug releases after 12 and 24 months due to the damage of the film's integrity during sample preparation caused by the high tackiness of the film. Tackiness is not affected by storing if samples are stored at low relative humidity. At high relative humidity tackiness increases upon storage especially for formulations without anti-tacking agents. The sieving results of the agglomeration measurements after storage can be confirmed by ring shear measurements performed immediately after preparation and approved to be a tool, which is able to predict the agglomeration during storage.
Mário Augusto Cray da Costa
Full Text Available ABSTRACT Introduction: In patients with mechanical prosthetic heart valves or atrial fibrillation requiring anticoagulation to prevent thromboembolic events, several factors influence adherence and anticoagulation complications. Objective: To evaluate the factors that interfere with the quality and complications of anticoagulation with vitamin K antagonists. Methods: A retrospective cohort study of 100 patients, in the period from 2011 to 2014, was performed. Anticoagulation conditions in the last year, regarding the presence of complications (embolisms/bleeding and inadequate treatment were assessed: achievement of less than 8 annual prothrombin times and International Normalized Ratio outside therapeutic target in more than 40% of prothrombin times. Results: There were 31 complications (22 minor bleeding without hospitalization and 9 major complications: 7 bleeding with hospitalization and two emboli; 70 were with International Normalized Ratio outside the target in more than 40% of the tests and 36 with insufficient number of prothrombin times. Socioeconomic factors, anticoagulant type and anticoagulation reason had no relationship with complications or with inadequate treatment. There were more complications in patients with longer duration of anticoagulation (P=0.001. Women had more International Normalized Ratio outside the target range (OR 2.61, CI:1.0-6.5; P=0.04. Patients with lower number of annual prothrombin times had longer times of anticoagulation (P=0.03, less annual consultations (P=0.02 and less dose adjustments (P=0.003. Patients with longer duration of anticoagulation have more complications (P=0.001. Conclusion: There was a high rate of major complications and International Normalized Ratio was outside the goal. Less annual prothrombin times was related to longer duration of anticoagulation, less annual consultations and less dose adjustments. More major complications occurred in patients with longer duration of
Ratzinger, Franz; Lang, Mona; Belik, Sabine; Jilma-Stohlawetz, Petra; Schmetterer, Klaus G; Haslacher, Helmuth; Perkmann, Thomas; Quehenberger, Peter
Non-vitamin K antagonist oral anticoagulants (NOAC), including rivaroxaban, apixaban or dabigatran, regularly show relevant effects on coagulation tests, making the interpretation of results difficult. The aim of this study was to evaluate possible interferences of NOACs in trough level concentrations in lupus anticoagulant (LA) testing. Citrate plasma specimens of 30 healthy volunteers were spiked with rivaroxaban, apixaban or dabigatran in four plasma concentration levels at or below trough NOAC levels. The NOAC concentration was measured using dedicated surrogate concentration tests and a stepwise diagnostic procedure for LA-testing was applied using screening, mixing and confirmatory testing. Results were compared to NOAC-free specimens. Starting with a plasma concentration of 12.5 ng/ml, dabigatran-spiked specimens showed significant prolongations in the lupus anticoagulant-sensitive activated partial thromboplastin time (aPTT-LA) as well as in the Dilute Russell viper venom time (dRVVT), leading to 43.3 % false positives in confirmatory testing in the dRVVT. In contrast, rivaroxaban, beginning with 7.5 ng/ml, exclusively affected dRVVT-based tests. In confirmatory tests, 30.0 % of rivaroxaban-spiked specimens showed false positive results. Starting with 18.75 ng/ml apixaban, a significant prolongation of the dRVVT and up to 20.7 % false positives in confirmatory tests were found. In contrast to other NOACs tested, apixaban did not present with a dose-dependent increase of the dRVVT ratio. In conclusion, the rate of false positive results in LA-testing is unacceptably high at expected trough levels of NOACs. Even at plasma concentrations below the LLOQ of commercially available surrogate tests, LA testing is best avoided in patients with NOAC therapy.
van der Heide, Astrid; Verduijn, Willem; Haasnoot, Geert W; Drabbels, Jos J M; Lammers, Gert J; Claas, Frans H J
Narcolepsy with cataplexy is a sleep disorder caused by the loss of hypocretin-producing neurons in the hypothalamus. It is tightly associated with a specific human leukocyte antigen (HLA)-allele: HLA-DQB1*06:02. Based on this, an autoimmune process has been hypothesized. A functional HLA-DQ molecule consists of a DQα and a DQβ chain. HLA-DQB1*06:02 (DQβ) has a strong preference for binding to HLA-DQA1*01:02 (DQα), and together they form the functional DQ0602 dimer. A dosage effect would be expected if the HLA-DQ0602 dimer itself is directly involved in the aetiology. An increased expression of the HLA-DQ0602 dimer is expected in individuals homozygous for HLA-DQB1*06:02-DQA1*01:02, but is also hypothesized in individuals heterozygous for HLA-DQB1*06:02 and homozygous for HLA-DQA1*01:02. To study the impact of the expression of the HLA-DQ0602 dimer on narcolepsy susceptibility, 248 Dutch narcolepsy patients and 1272 Dutch control subjects, all of them positive for DQB1*06:02 (heterozygous and homozygous), were HLA-genotyped with attention not only to DQB1 but also to DQA1*01:02. DQB1*06:02-DQA1*01:02 homozygosity was significantly more often seen in patients compared to controls (O.R. 2.29) confirming previous observations. More importantly, a significantly higher prevalence of homozygosity for DQA1*01:02 was found in HLA-DQB1*06:02 heterozygous patients compared to controls (O.R. 2.37, p < 0.001). The latter finding clearly supports a direct role of the HLA-DQ molecule in the development of disease.
Werder, Gabriel M. [William Beaumont Hospital, Department of Radiology, 3600 West Thirteen Mile Road, Royal Oak, MI 48073 (United States); St Christopher Iba Mar Diop College of Medicine, Luton (United Kingdom)], E-mail: email@example.com; Razdan, Rahul S.; Gagliardi, Joseph A.; Chaddha, Shashi K.B. [St Vincent' s Medical Center, Bridgeport, CT (United States)
We present a case of pineal apoplexy in an anticoagulated and hypertensive 56-year-old Hispanic male. At presentation, the patient's international normalized ratio (INR) was 10.51 and his blood pressure was 200/130 mmHg. His presenting symptoms included acute onset of headache, chest pain, nausea, vomiting, vertigo, and visual disturbance. Neuroimaging demonstrated hemorrhage into a morphologically normal pineal gland. Under conservative management, the patient experienced gradual resolution of all symptoms excluding the disturbance of upward gaze.
华法林是临床广泛使用的抗凝药，但其疗效存在明显个体差异，其中基因多态性是导致华法林剂量差异主要影响因素。本文查阅相关文献，综述与华法林剂量相关的基因，为临床华法林个体化应用提供参考。%Warfarin is one of the most frequently prescribed anticoagulant and there is significant indi-vidual variability in dose requirement for the clinical effect. Gene polymorphisms are the important factors that can influence the anticoagulant effect of warfain. Recently, warfarin gene polymorphisms become a re-search topic and a large number of individualized medication algorithms have been established. This article reviews warfarin dosage related gene polymorphisms in order to offer some suggestions for warfarin individ-ualized medication.
The human small intestine, with its enormous absorptive surface area, is invariably the principal site of drug absorption. Hence, the residence time of a dosage form in this part of the gut can have a great influence on the absorption of the contained drug. Various methods have been employed to monitor the gastrointestinal transit of pharmaceutical dosage forms, but the use of gamma-scintigraphy has superceded all the other methods. However, careful consideration of the time interval for image acquisition and proper analysis of the scintigraphic data are important for obtaining reliable results. Most studies reported the mean small intestinal transit time of various dosage forms to be about 3-4h, being closely similar to that of food and water. The value does not appear to be influenced by their physical state nor the presence of food, but the timing of food intake following administration of the dosage forms can influence the small intestinal transit time. While the mean small intestinal transit time is quite consistent among dosage forms and studies, individual values can vary widely. There are differing opinions regarding the effect of density and size of dosage forms on their small intestinal transit properties. Some common excipients employed in pharmaceutical formulations can affect the small intestinal transit and drug absorption. There is currently a lack of studies regarding the effects of excipients, as well as the timing of food intake on the small intestinal transit of dosage forms and drug absorption.
Just, Søren Andreas; Nybo, Mads; Laustrup, Helle;
Inflammation is strongly associated with lupus anticoagulant positivity, indepentent of know autoimmune disease and recent venous or arterial thrombosis......Inflammation is strongly associated with lupus anticoagulant positivity, indepentent of know autoimmune disease and recent venous or arterial thrombosis...
Brouwer, M.A.; Jaspers Focks, J.; Verheugt, F.W.A.
Despite dual antiplatelet therapy (DAPT), one-year event rates after acute coronary syndrome (ACS) vary from 9-12%. The development of novel oral anticoagulants (NOAC) without a need for monitoring has initiated renewed interest for prolonged adjunctive anticoagulation. Importantly, the cornerstone
Schulman, S.; Zondag, M.; Linkins, L.; Pasca, S.; Cheung, Y. W.; De Sancho, M.; Gallus, A.; Lecumberri, R.; Molnar, S.; Ageno, W.; Le Gal, G.; Falanga, A.; Hulegardh, E.; Ranta, S.; Kamphuisen, P.; Debourdeau, P.; Rigamonti, V.; Ortel, T. L.; Lee, A.
BackgroundRecommendations for management of cancer-related venous thromboembolism (VTE) in patients already receiving anticoagulant therapy are based on low-quality evidence. This international registry sought to provide more information on outcomes after a breakthrough VTE in relation to anticoagul
Verheugt, F.W.A.; Granger, C.B.
In patients with non-valvular atrial fibrillation, oral anticoagulation with vitamin K antagonists reduces the risk of stroke by more than 60%. But vitamin K antagonists have limitations, including causing serious bleeding such as intracranial haemorrhage and the need for anticoagulation monitoring.
Rahmat, Nur A; Lip, Gregory Y H
major challenges: the need for reliable laboratory assays to assess their anticoagulation effect, and the lack of approved antidotes to reverse their action. This article provides an overview of monitoring the anticoagulant effect of NOACs and their potential specific antidotes in development....
Numerous factors have been identified as risk factors for instability of oral anticoagulation, including variability in vitamin K intake. However few studies have directly tested the feasibility of manipulating dietary vitamin K to achieve stable oral anticoagulation. Recent findings from a rando...
Hellfritzsch, Maja; Husted, Steen Elkjaer; Grove, Erik Lerkevang;
Patients with atrial fibrillation discontinuing anticoagulant therapy are left unprotected against ischaemic stroke. Further, switching between oral anticoagulants may be associated with a transiently increased risk of bleeding or thromboembolism. However, there is a paucity of real-life data on ...
Isola, G; Matarese, G; Cordasco, G; Rotondo, F; Crupi, A; Ramaglia, L
Patients treated with oral anticoagulant therapy (OAT) represent an issue to the dentist, as an increasing number of people are using anticoagulant drugs for cardiovascular disease. The choice of an eventual suspension or continuation of anticoagulant therapy is important when considering an efficient management of the patient. Patients in anticoagulant therapy and requiring dental procedures sometimes represent therapeutic concerns especially concerning the suspension of the anticoagulant treatment. At the moment there is no consensus among international experts of a possible discontinuation of therapy before invasive dental procedures. In this paper, the authors try to focus on this topic through a critical review of the literature. Most of the studies suggest the continuation of the anticoagulant treatment with heparin before invasive oral surgical interventions. Based on the data of the literature, two rules must be adopted in clinical practice: 1) maintenance of anticoagulation related to the international normalized ratio (INR); 2) local application of antifibrinolytic agents to ensure a proper hemostatic process. Given the widespread use of anticoagulant drugs in cardiovascular disease, dentists must often face the problem of the therapy and, since there is no consensus on the management of these patients, the authors propose, after a thorough critical review of the literature, the implementation of a multiphase protocol of surgical approach to be implemented with safety in daily clinical practice.
Poulsen, Maja Hellfritzsch; Hyllested, Lea Maria Rønneberg; Meegaard, Line
Oral anticoagulants are widely used but information on important aspects in that respect is not available from medical registers or clinical databases. Therefore, we conducted a survey including patients filling a prescription for oral anticoagulants at two large Danish community pharmacies. We...
De Groot, PG; Lutters, B; Derksen, RHWM; Lisman, T; Meijers, JCM; Rosendaal, FR
We have determined lupus anticoagulants, anti-beta(2) glycoprotem I (beta(2)GPI) and antiprothrombin antibodies in the Leiden Thrombophilia Study, a population-based case-control study designed to determine risk factors for deep venous thrombosis (DVT). Lupus anticoagulant (LAC) was measured in 473
Rasmussen, Rasmus V; Snygg-Martin, Ulrika; Olaison, Lars;
OBJECTIVES: To study the impact of anticoagulation on major cerebral events in patients with left-sided Staphylococcus aureus infective endocarditis (IE). METHODS: A prospective cohort study; the use of anticoagulation and the relation to major cerebral events was evaluated separately at onset...
PROOST, JH; MEIJER, DKF
The pharmacokinetic software package MW/Pharm offers an interactive, user-friendly program which gives rapid answers in clinical practice. It comprises a database with pharmacokinetic parameters of 180 drugs, a medication history database, and procedures for an individual drug dosage regimen calcula
Lin, Kevin Y; Lo, Justin H; Consul, Nikita; Kwong, Gabriel A; Bhatia, Sangeeta N
Antithrombotic therapy is a critical portion of the treatment regime for a number of life-threatening conditions, including cardiovascular disease, stroke, and cancer; yet, proper clinical management of anticoagulation remains a challenge because existing agents increase the propensity for bleeding in patients. Here, we describe the development of a bioresponsive peptide-polysaccharide nanocomplex that utilizes a negative feedback mechanism to self-titrate the release of anticoagulant in response to varying levels of coagulation activity. This nanoscale self-titrating activatable therapeutic, or nanoSTAT, consists of a cationic thrombin-cleavable peptide and heparin, an anionic polysaccharide and widely used clinical anticoagulant. Under nonthrombotic conditions, nanoSTATs circulate inactively, neither releasing anticoagulant nor significantly prolonging bleeding time. However, in response to life-threatening pulmonary embolism, nanoSTATs locally release their drug payload and prevent thrombosis. This autonomous negative feedback regulator may improve antithrombotic therapy by increasing the therapeutic window and decreasing the bleeding risk of anticoagulants.
Vinholt, Pernille J; Nybo, Mads
We present a case concerning a patient with splenic marginal zone lymphoma (SMZL) and isolated prolonged activated partial thromboplastin time (aPTT) caused by lupus anticoagulant. Von Willebrand factor (VWF) activity and antigen were immeasurable by latex particle immunoturbidimetric assays......, and several coagulation factor levels were decreased. However, VWF activity and antigen were normal when analyzed by other methods. Also, coagulation factor levels were normal if an aPTT reagent with low lupus anticoagulant sensitivity or a chromogenic method was applied. Altogether, the initial findings were...... because of lupus anticoagulant interference and in fact, the patient had normal VWF activity and coagulation status. Interference of lupus anticoagulant in clot-based assays is well known but has not previously been described in VWF assays. This is furthermore the first report in which lupus anticoagulant...
Desai, Rishi J; Williams, Charlotte E; Greene, Sandra B; Pierson, Stephanie; Hansen, Richard A
Appropriate and safe use of medications is an important aspect of quality of care in nursing home patients. Because of their complex medication use process, anticoagulants are prone to medication errors in the frail elderly. Therefore, we designed this study to characterize anticoagulant medication errors and to evaluate their association with patient harm using individual medication error incidents reported by all North Carolina nursing homes to the Medication Error Quality Initiative (MEQI) during fiscal years 2010-2011. Characteristics, causes, and specific outcomes of harmful anticoagulant medication errors were reported as frequencies and proportions and compared between anticoagulant errors and other medication errors using chi-square tests. A multivariate logistic regression model explored the relationship between anticoagulant medication errors and patient harm, controlling for patient- and error-related factors.
Bidadi, Behzad; Nageswara Rao, Amulya A; Kaur, Dominder; Khan, Shakila P; Rodriguez, Vilmarie
Neonatal renal vein thrombosis (NRVT) is a rare thromboembolic complication in the neonatal period, and sequelae from renal dysfunction can cause significant morbidity. The authors retrospectively reviewed 10 patients with NRVT treated at their institution. The majority of the cohort were male (n = 9), preterm (n = 6), and had unilateral NRVT (n = 6). Six patients received thrombolysis and/or anticoagulation, and 4 patients received supportive care only. Two of the 6 patients treated with anticoagulation who had bilateral NRVT and anuria received thrombolysis with low-dose tissue plasminogen activator. Thrombolysis was not associated with any major adverse events, and both patients had marked improvement of renal function. Eight patients subsequently developed renal atrophy (3 received anticoagulation, 2 received thrombolysis with anticoagulation, and 3 received supportive care). Anticoagulation/thrombolysis did not appear to prevent renal atrophy. The role of thrombolysis needs to be further studied and considered in the setting of bilateral NRVT and acute renal failure.
Full Text Available Whether to resume the anticoagulant or the antiaggregant therapy after an episode of major haemorrhage is a difficult dilemma for the physician. The physician has to take into consideration two major questions: whether the benefits of restarting anticoagulation outweigh the risk, and if so, when and how should anticoagulation be restarted. Although some case reports suggest that anticoagulation can be withheld safely for short periods after ICH, even in patients with mechanical heart valves, it is still not clear if long-term anticoagulation can be safely reinstituted after haemorrhage, for example in patients with atrial fibrillation. In fact, no large and well-conducted randomised clinical trials are available, and there is lack of strong evidence on which guidelines recommendations can be based. The article summarise the available literature findings. Finally, a protocol is suggested which may represent a useful tool for assessing treatment options.
Pelliccia, Francesco; Rollini, Fabiana; Marazzi, Giuseppe; Greco, Cesare; Gaudio, Carlo; Angiolillo, Dominick J; Rosano, Giuseppe
The combination of AF and coronary artery disease not only is a common clinical setting, it is also a complex setting to deal with anticoagulation and antiplatelet therapy, and it is associated with significantly higher mortality rates. Unfortunately, there are no sufficient data available to optimally guide clinical practice in such settings. This review focuses specifically on newer oral anticoagulants (NOACs) associated with dual antiplatelet therapy (DAPT) in patients with coronary artery disease undergoing percutaneous coronary intervention (PCI). There are no randomized studies comparing vitamin K antagonists and NOACs in patients with AF undergoing PCI either for acute coronary syndromes or for stable patients, i.e. those patients who have an indication to receive DAPT. Moreover, new antiplatelet agents such as ticagrelor and prasugrel have entered the market for acute coronary syndromes. So far, there are no large-scale randomized studies published evaluating these newer antiplatelet agents in patients with AF receiving either vitamin K antagonists or NOACs, adding to the uncertainty on how to use these antithrombotics in combination when both coronary artery disease (unstable or stable patients) and AF converge in a given patient. The lack of large outcome trials and the large number of possible combinations are reflected in the wide variety of practices in the real world. To date, given the lack of data, watchfulness when using NOACs as component of DAPT or triple oral antithrombotic therapy is warranted.
Wen-xing FAN; Song-min HUANG; Ping FU; Zheng-xu DENG; Fang LIU; Rong-bo LIU; Ling HE; Bogati AMRIT; Li ZANG; Jing-wen LI; Xian-rong LIU
In this paper,we described the symptoms and treatment of a patient with diabetic nephropathy accompanied by spontaneous retroperitoneal hemorrhage after hemodialysis.An elderly female patient with diabetic nephropathy presented with severe pain,numbness,and an increasing swelling in the left hip and left thigh after six sessions of hemodialysis involving the use of an antiplatelet drug and an anticoagulant agent.Her hemoglobin decreased to 46 g/L.An abdominal ultrasound showed a hematoma in the left retroperitoneal space,and computed tomography (CT) findings revealed a 6 cm×8 cm×10 cm hematoma in the left psoas muscle.After aggressive supportive therapy [the administration of packed red blood cell transfusion,carbazochrome sodium sulfonate injection,and continuous venovenous hemofiltration (CWH)],the patient's vital signs stabilized and her hemoglobin increased to 86 g/L.Repeat CT showed that the hematoma had been partially absorbed after two weeks.Eventually,the patient was discharged with stable vital signs.Physicians should be aware of the possibility of spontaneous retroperitoneal hemorrhage,particularly in patients with diabetic nephropathy undergoing hemodialysis involving the use of anticoagulant agents.
Ellis, Gidon; John Camm, Alan; Datta, Soumendra N
Novel oral anti-coagulants (NOACs) are increasingly being used in clinical practice and are set to almost entirely replace the vitamin K antagonists, such as warfarin, in the near future. Similarly, new antiplatelet agents are now regularly used in place of older agents, such as aspirin and clopidogrel. In an ageing population, with an increasing burden of complex comorbidities, urologists will frequently encounter patients who will be using such agents. Some background knowledge, and an understanding, of these drugs and the issues that surround their usage, is essential. The present article will provide readers with an understanding of these new drugs, including their mechanisms of action, the up-to-date evidence justifying their recent introduction into clinical practice and the appropriate interval for stopping them before surgery. It will also consider the risks of perioperative bleeding for patients taking these drugs and the risks of venous thromboembolism in those in whom they are stopped. Strategies to manage anticoagulant-associated bleeding are discussed.
Vacas, Marta; Lafuente, Pedro José; Unanue, Iciar; Iriarte, José Antonio
Portable prothrombin time (PT) monitors offer the potential for both simplifying and improving oral anticoagulation management. It is necessary to evaluate their concordance and correlation with other PT systems. Our objective was to evaluate the concordance and clinical correlation of two portable PT determination systems, ProTime (ITC) and CoaguChek S (Roche Diagnostics). In all, 20 healthy individuals and 60 anticoagulated patients stabilized over 3 months in a therapeutic International Normalized Ratio (INR) range between 2-3.5 were studied. A drop of capillary blood was obtained simultaneously from two different fingers of each patient and applied to the monitor's application zone. The mean INR of the patients' blood samples of the two monitors differed by 0.01 units (2.32+/-0.63 for Pro Time and 2.33+/-0.68 for CoaguChek). The percentage of simple concordance and the kappa index were 88.3 and 75.9%, respectively. The coefficient of correlation was 0.922. The mean difference (bias) between the monitors was 0.01. The portable PT monitors evaluated presented a high percentage of concordance in INR results.
Jerome D Waye
Full Text Available Colonoscopy was introduced in the 1960s. The facility with which this technique is performed has been enhanced by vast improvements in instrumentation. In spite of this, physician attitudes concerning colonoscopy have changed little over the past several decades. The diet for precolonoscopic preparation has not been altered for 30 years. Colonoscopists have a great reluctance to use a new preparation instead of the 4 L electrolyte solution, perhaps because this was such a significant advance in colonoscopic cleansing, its predecessor being castor oil and enemas. Physicians continue to be wary of the patient who is taking acetylsalicylic acid in the absence of any studies that show that this is detrimental for polypectomy. The management of the patient on warfarin anticoagulation remains a subject for debate. As for antibiotic prophylaxis, most endoscopy units do not have a standardized approach, although there are good guidelines that, if followed, should decrease the risk of infective endocarditis. Sedation for the endoscopic examination is usually administered by the colonoscopist, although anesthesiologists may, in some countries (and in some defined areas of the United States be the primary administrators of sedation and analgesia. The present article is a personal approach to the following issues: the preparation of the colon for an examination, current thoughts about anticoagulation and acetylsalicylic acid, antibiotic prophylaxis for colonoscopy and the technique for sedation out of the hospital.
Elad, S; Marshall, J; Meyerowitz, C; Connolly, G
Currently, 4 novel Direct Oral Anticoagulants (DOACs) were approved by the FDA. This review focuses on these agents and proposes a matrix for the general dentists to assess bleeding risk in dental management of patient on DOACs. The outline covers the pharmacology of DOACs (rivaroxaban, apixaban, edoxaban and dabigatran), bleeding complications, risk associated with discontinuation, monitoring/reversal, and implications for the dental practitioners. A total of 18 randomized controlled trials were identified with mixed results in regards to the risk for bleeding. Considering the pharmacology of DOACs and challenges in monitoring and reversing their effect, the dentist should consider carefully the management of patients on DOACs as it may differ from patients on conventional anticoagulants. Based on the type of dental procedure and the medical risk assessment, several general treatment approaches can be considered: continue DOACs, time dental treatment as late as possible after the last DOACs dose, discontinue DOACs for 24hrs, or discontinue DOACs for 48hrs. Based on the current reported dental literature, limited dental surgery may benefit from the first 2 conservative options. However, this needs to be proven in comparative clinical trials.
Full Text Available In intrauterine life, hemostasis is maintained by the same components as in extrauterine life (blood platelets, coagulation and fibrinolysis systems, involvement of the vascular wall; in the fetus, however, these components show significant differences of a quantitative/qualitative nature. In the present study, we surveyed the literature on the coagulation system in the fetus. We focused on the velocity of development of the coagulation system, being reflected in the increased concentration of all procoagulants and anticoagulants (a rise from approximately 20% in the middle of pregnancy to about 60% or more in the period of labor; exceptions: factors V, VIII and XIII which in the labor period reach the adult level and screening test results (prothrombin time, aPTT - activated prothrombin time, and thrombin time. Reference values were given for the 19-38 weeks of pregnancy and the labor term. Biochemical features of fetal fibrinogen and PIVKA factors were also discussed. The role of activated protein C (APC in the maintenance of balance between procoagulants and anticoagulants was postulated as well as the role of APC in the formation of thrombin activatable fibrinolysis inhibitor (TAFI.
Full Text Available Abstract Background Each day, millions of health consumers seek drug-related information on the Web. Despite some efforts in linking related resources, drug information is largely scattered in a wide variety of websites of different quality and credibility. Methods As a step toward providing users with integrated access to multiple trustworthy drug resources, we aim to develop a method capable of identifying drug's dosage form information in addition to drug name recognition. We developed rules and patterns for identifying dosage forms from different sections of full-text drug monographs, and subsequently normalized them to standardized RxNorm dosage forms. Results Our method represents a significant improvement compared with a baseline lookup approach, achieving overall macro-averaged Precision of 80%, Recall of 98%, and F-Measure of 85%. Conclusions We successfully developed an automatic approach for drug dosage form identification, which is critical for building links between different drug-related resources.
Schillinger, Dean; Machtinger, Edward L; Wang, Frances; Palacios, Jorge; Rodriguez, Maytrella; Bindman, Andrew
Despite the importance of clinician-patient communication, little is known about rates and predictors of medication miscommunication. Measuring rates of miscommunication, as well as differences between verbal and visual modes of assessment, can inform efforts to more effectively communicate about medications. We studied 220 diverse patients in an anticoagulation clinic to assess concordance between patient and clinician reports of warfarin regimens. Bilingual research assistants asked patients to (1) verbalize their prescribed weekly warfarin regimen and (2) identify this regimen from a digitized color menu of warfarin pills. We obtained clinician reports of patient regimens from chart review. Patients were categorized as having regimen concordance if there were no patient-clinician discrepancies in total weekly dosage. We then examined whether verbal and visual concordance rates varied with patient's language and health literacy. Fifty percent of patients achieved verbal concordance and 66% achieved visual concordance with clinicians regarding the weekly warfarin regimen (P visual discordance. Shifting from verbal to visual modes was associated with greater patient-provider concordance across all patient subgroups, but especially for those with communication barriers.Clinician-patient discordance regarding patients' warfarin regimen was common but occurred less frequently when patients used a visual aid. Visual aids may improve the accuracy of medication assessment, especially for patients with communication barriers.
Pessia, Eugénie; Makino, Takashi; Bailly-Bechet, Marc; McLysaght, Aoife; Marais, Gabriel A B
How and why female somatic X-chromosome inactivation (XCI) evolved in mammals remains poorly understood. It has been proposed that XCI is a dosage-compensation mechanism that evolved to equalize expression levels of X-linked genes in females (2X) and males (1X), with a prior twofold increase in expression of X-linked genes in both sexes ("Ohno's hypothesis"). Whereas the parity of X chromosome expression between the sexes has been clearly demonstrated, tests for the doubling of expression levels globally along the X chromosome have returned contradictory results. However, changes in gene dosage during sex-chromosome evolution are not expected to impact on all genes equally, and should have greater consequences for dosage-sensitive genes. We show that, for genes encoding components of large protein complexes (≥ 7 members)--a class of genes that is expected to be dosage-sensitive--expression of X-linked genes is similar to that of autosomal genes within the complex. These data support Ohno's hypothesis that XCI acts as a dosage-compensation mechanism, and allow us to refine Ohno's model of XCI evolution. We also explore the contribution of dosage-sensitive genes to X aneuploidy phenotypes in humans, such as Turner (X0) and Klinefelter (XXY) syndromes. X aneuploidy in humans is common and is known to have mild effects because most of the supernumerary X genes are inactivated and not affected by aneuploidy. Only genes escaping XCI experience dosage changes in X-aneuploidy patients. We combined data on dosage sensitivity and XCI to compute a list of candidate genes for X-aneuploidy syndromes.
Full Text Available The requirements for magnesium (Mg supplementation increase under regional citrate anticoagulation (RCA because citrate acts by chelation of bivalent cations within the blood circuit. The level of magnesium in commercially available fluids for continuous renal replacement therapy (CRRT may not be sufficient to prevent hypomagnesemia.Patients (n = 45 on CRRT (2,000 ml/h, blood flow (Qb 100 ml/min with RCA modality (4% trisodium citrate using calcium free fluid with 0.75 mmol/l of Mg with additional magnesium substitution were observed after switch to the calcium-free fluid with magnesium concentration of 1.50 mmol/l (n = 42 and no extra magnesium replenishment. All patients had renal indications for CRRT, were treated with the same devices, filters and the same postfilter ionized calcium endpoint (<0.4 mmol/l of prefilter citrate dosage. Under the high level Mg fluid the Qb, dosages of citrate and CRRT were consequently escalated in 9h steps to test various settings.Median balance of Mg was -0.91 (-1.18 to -0.53 mmol/h with Mg 0.75 mmol/l and 0.2 (0.06-0.35 mmol/h when fluid with Mg 1.50 mmol/l was used. It was close to zero (0.02 (-0.12-0.18 mmol/h with higher blood flow and dosage of citrate, increased again to 0.15 (-0.11-0.25 mmol/h with 3,000 ml/h of high magnesium containing fluid (p<0.001. The arterial levels of Mg were mildly increased after the change for high level magnesium containing fluid (p<0.01.Compared to ordinary dialysis fluid the mildly hypermagnesemic fluid provided even balances and adequate levels within ordinary configurations of CRRT with RCA and without a need for extra magnesium replenishment.ClinicalTrials.gov Identifier: NCT01361581.
Sam, Tom; Ernest, Terry B; Walsh, Jennifer; Williams, Julie L
The design and selection of new pharmaceutical dosage forms involves the careful consideration and balancing of a quality target product profile against technical challenges and development feasibility. Paediatric dosage forms present particular complexity due to the diverse patient population, patient compliance challenges and safety considerations of this vulnerable population. This paper presents a structured framework for assessing the comparative benefits and risks of different pharmaceutical design options against pre-determined criteria relating to (1) efficacy, (2) safety and (3) patient access. This benefit/risk framework has then been applied to three hypothetical, but realistic, scenarios for paediatric dosage forms in order to explore its utility in guiding dosage form design and formulation selection. The approach allows a rigorous, systematic and qualitative assessment of the merits and disadvantages of each dosage form option and helps identify mitigating strategies to modify risk. The application of a weighting and scoring system to the criteria depending on the specific case could further refine the analysis and aid decision-making. In this paper, one case study is scored for illustrative purposes. However, it is acknowledged that in real development scenarios, the generation of actual data considering the very specific situation for the patient/product/developer would come into play to drive decisions on the most appropriate dosage form strategy.
Byrnes Matthew C
Full Text Available Abstract Introduction Therapeutic anticoagulation is an important treatment of thromboembolic complications, such as DVT, PE, and blunt cerebrovascular injury. Traumatic intracranial hemorrhage has traditionally been considered to be a contraindication to anticoagulation. Hypothesis Therapeutic anticoagulation can be safely accomplished in select patients with traumatic intracranial hemorrhage. Methods Patients who developed thromboembolic complications of DVT, PE, or blunt cerebrovascular injury were stratified according to mode of treatment. Patients who underwent therapeutic anticoagulation with a heparin infusion or enoxaparin (1 mg/kg BID were evaluated for neurologic deterioration or hemorrhage extension by CT scan. Results There were 42 patients with a traumatic intracranial hemorrhage that subsequently developed a thrombotic complication. Thirty-five patients developed a DVT or PE. Blunt cerebrovascular injury was diagnosed in four patients. 26 patients received therapeutic anticoagulation, which was initiated an average of 13 days after injury. 96% of patients had no extension of the hemorrhage after anticoagulation was started. The degree of hemorrhagic extension in the remaining patient was minimal and was not felt to affect the clinical course. Conclusion Therapeutic anticoagulation can be accomplished in select patients with intracranial hemorrhage, although close monitoring with serial CT scans is necessary to demonstrate stability of the hemorrhagic focus.
临床药师参与抗凝管理服务对经皮球囊二尖瓣成形术后心房颤动患者华法林抗凝效果和安全性影响的随机对照试验%A randomized controlled trial of warfarin anti-coagulation efficacy and safety of clinical pharmacist-participated anticoagulation management for patients with atrial fibrillation after percutaneous balloon mitral valvuloplasty
李峥嵘; 王凌; 石增成; 鲍玉琳
Objective To explore the warfarin anti-coagulation effect and safety of clinical pharmacist-participated anticoagulation management service(AMS)on patients with atrial fibrillation after percutaneous balloon mitral valvuloplasty(PBMV). Methods The patients who underwent PBMV were divided into trial group and control group by random number table. The patients in the trial group received the clinical pharmacist-participated AMS. The clinical pharmacist provided adjusted warfarin dosage suggestion to clinician and warfarin anticoagulant education to the patients and their family members. The patients in the control group received warfarin following the visiting doctor's advice. Anticoagulant effect indicators included international normalized ratio( INR)compliance rate,effective anticoagulation rate, anticoagulant deficiency rate and excessive anticoagulation rate. Safety evaluation indicators were embolism and bleeding events during the anticoagulant therapy. Results A total of 131 patients were enrolled in the study. The trial group comprised 68 and the control group 63 patients,respectively. The differences in the patients' age,sex composition,body weight,smoking and drinking habits,degree of mitral stenosis, combined disease,baseline INR,and preliminary warfarin dosage after PBMV were not significant between the 2 groups(all P > 0. 05). The INR compliance rate in the trial group and the control group were 53. 3%(217 / 407)and 41. 8%(155 / 371),respectively(P = 0. 001);effective anticoagulation rates were 55. 9%(38 / 68)and 33. 3%(21 / 63),respectively(P = 0. 016);anticoagulant deficiency rate were 19. 9%(81 /407)and 27. 8%(103 / 371),respectively( P = 0. 003);and the excessive anticoagulation rates were 7. 9%(32 / 407)and 14. 0%(52 / 371),respectively(P = 0. 006). There were 6 and 9 patients developed minor bleeding events and each was one slight embolism in the trial group and the control group, respectively. The incidence rate of adverse reactions in the trial
Domingues, Renan; Bruniera, Gustavo; Brunale, Fernando; Mangueira, Cristóvão; Senne, Carlos
The use of anticoagulants and antiplatelet agents has largely increased. Diagnostic lumbar puncture in patients taking these drugs represents a challenge considering the opposing risks of bleeding and thrombotic complications. To date there are no controlled trials, specific guidelines, nor clear recommendations in this area. In the present review we make some recommendations about lumbar puncture in patients using these drugs. Our recommendations take into consideration the pharmacology of these drugs, the thrombotic risk according to the underlying disease, and the urgency in cerebrospinal fluid analysis. Evaluating such information and a rigorous monitoring of neurological symptoms after lumbar puncture are crucial to minimize the risk of hemorrhage associated neurological deficits. An individualized patient decision-making and an effective communication between the assistant physician and the responsible for conducting the lumbar puncture are essential to minimize potential risks.
Full Text Available ABSTRACT The use of anticoagulants and antiplatelet agents has largely increased. Diagnostic lumbar puncture in patients taking these drugs represents a challenge considering the opposing risks of bleeding and thrombotic complications. To date there are no controlled trials, specific guidelines, nor clear recommendations in this area. In the present review we make some recommendations about lumbar puncture in patients using these drugs. Our recommendations take into consideration the pharmacology of these drugs, the thrombotic risk according to the underlying disease, and the urgency in cerebrospinal fluid analysis. Evaluating such information and a rigorous monitoring of neurological symptoms after lumbar puncture are crucial to minimize the risk of hemorrhage associated neurological deficits. An individualized patient decision-making and an effective communication between the assistant physician and the responsible for conducting the lumbar puncture are essential to minimize potential risks.
Nilsson, Hanna; Grove, E; Larsen, Torben Bjerregaard
of Cardiology, Aarhus University Hospital, Aarhus; 3Department of Cardiology, Aalborg Hospital & Department of Health Science and Technology, Aalborg University, Aalborg, Denmark firstname.lastname@example.org Objectives: Patient-self-management (PSM) of oral anticoagulant therapy with vitamin K antagonists have...... demonstrated efficacy in randomized clinical trials. An important question remains about its clinical effectiveness. We hypothesized that implementation of PSM in everyday clinical practice could improve the quality of treatment. The aim of this study was to evaluate the effectiveness of PSM in everyday...... clinical practice. Materials and methods: A case-series study including all patients who had passed an exam in PSM in the period 1995-2012 at Aarhus University Hospital or Aalborg University Hospital, including 2200 patients and 11000 patient-years in total. The effectiveness was measured using...
Full Text Available Thyroid storm is a life-threatening condition that occurs secondary to an uncontrolled hyperthyroid state. Atrial fibrillation is a cardiovascular complication occurring in up to 15% of patients experiencing thyroid storm, and if left untreated this condition could have up to a 25% mortality rate. Thyroid storm with stroke is a rare presentation. This case report details a left middle cerebral artery (MCA stroke with global aphasia and thyroid storm in a 53-year-old Hispanic male patient. Although uncommon, this combination has been reported in multiple case series. Although it is well documented that dysfunctional thyroid levels promote a hypercoagulable state, available guidelines from multiple entities are unclear on whether anticoagulation therapy is appropriate in this situation.
Blus, L.J.; Henny, C.J.; Grove, R.A.
A moribund, emaciated California quail (Callipepla californica) that was found in an orchard in the state of Washington had an impacted crop and gizzard. Pellets containing the anticoagulant chlorophacinone (Rozol, RO) were in the crop; the gizzard contents consisted of a pink mass of paraffin that was selectively accumulated from the paraffinized pellets. The plasma prothrombin time of 28 sec was near that determined for control quail. The signs of RO intoxication seen in the moribund wild quail were duplicated in captive quail given ad libitum diets of either RO or another paraffinized chlorophacinone pellet (Mr. Rat Guard II, MRG). This left little doubt that paraffin impaction of the gizzard was the primary problem. All captive quail fed RO or MRG pellets showed no increases in prothrombin times compared to control values, died in an emaciated condition, and had gizzards impacted with paraffin.
Full Text Available Abstract Background The prevention of venous thromboembolism has been identified as a leading priority in hospital safety. Recommended parenteral anticoagulant agents with different indications for the prevention and treatment of venous thromboembolism include unfractionated heparin, low-molecular-weight heparins and fondaparinux. Prescribing decisions in venous thromboembolism management may seem complex due to the large range of clinical indications and patient types, and the range of anticoagulants available. Methods MEDLINE and EMBASE databases were searched to identify relevant original articles. Results Low-molecular-weight heparins have nearly replaced unfractionated heparin as the gold standard antithrombotic agent. Low-molecular-weight heparins currently available in the US are enoxaparin, dalteparin, and tinzaparin. Each low-molecular-weight heparin is a distinct pharmacological entity with different licensed indications and available clinical evidence. Enoxaparin is the only low-molecular-weight heparin that is licensed for both venous thromboembolism prophylaxis and treatment. Enoxaparin also has the largest body of clinical evidence supporting its use across the spectrum of venous thromboembolism management and has been used as the reference standard comparator anticoagulant in trials of new anticoagulants. As well as novel oral anticoagulant agents, biosimilar and/or generic low-molecular-weight heparins are now commercially available. Despite similar anticoagulant properties, studies report differences between the branded and biosimilar and/or generic agents and further clinical studies are required to support the use of biosimilar low-molecular-weight heparins. The newer parenteral anticoagulant, fondaparinux, is now also licensed for venous thromboembolism prophylaxis in surgical patients and the treatment of acute deep-vein thrombosis; clinical experience with this anticoagulant is expanding. Conclusions Parenteral
Pauline E Jullien
Full Text Available In mammals and in plants, parental genome dosage imbalance deregulates embryo growth and might be involved in reproductive isolation between emerging new species. Increased dosage of maternal genomes represses growth while an increased dosage of paternal genomes has the opposite effect. These observations led to the discovery of imprinted genes, which are expressed by a single parental allele. It was further proposed in the frame of the parental conflict theory that parental genome imbalances are directly mirrored by antagonistic regulations of imprinted genes encoding maternal growth inhibitors and paternal growth enhancers. However these hypotheses were never tested directly. Here, we investigated the effect of parental genome imbalance on the expression of Arabidopsis imprinted genes FERTILIZATION INDEPENDENT SEED2 (FIS2 and FLOWERING WAGENINGEN (FWA controlled by DNA methylation, and MEDEA (MEA and PHERES1 (PHE1 controlled by histone methylation. Genome dosage imbalance deregulated the expression of FIS2 and PHE1 in an antagonistic manner. In addition increased dosage of inactive alleles caused a loss of imprinting of FIS2 and MEA. Although FIS2 controls histone methylation, which represses MEA and PHE1 expression, the changes of PHE1 and MEA expression could not be fully accounted for by the corresponding fluctuations of FIS2 expression. Our results show that parental genome dosage imbalance deregulates imprinting using mechanisms, which are independent from known regulators of imprinting. The complexity of the network of regulations between expressed and silenced alleles of imprinted genes activated in response to parental dosage imbalance does not support simple models derived from the parental conflict hypothesis.
Barroso, Edjane M A; Costa, Leandro S; Medeiros, Valquíria P; Cordeiro, Sara L; Costa, Mariana S S P; Franco, Célia R C; Nader, Helena B; Leite, Edda L; Rocha, Hugo A O
Fucan is a term used to denominate a family of sulfated L-fucose-rich polysaccharides. The brown alga Spatoglossum schröederi (Dictyotaceae) has three heterofucans namely fucan A, B and C. The 21 kDa fucan A is composed of a core of a beta (1-3) glucuronic acid-containing oligosaccharide of 4.5 kDa with branches at C4 of the fucose chains alpha (1-3) linked. The fucose is mostly substituted at C4 with a sulfate group and at C2 with chains of beta (1-4) xylose. This fucan has neither anticoagulant (from from 0.1 to 100 microg) nor hemorrhagic activities (from 50 to 800 microg/mL). The antithrombotic test in vivo showed that fucan A has no activity in any of the concentrations (from 0.2 to 20 microg/g/day) tested 1 h after polysaccharide administration. However, when fucan A was injected endovenously 24 h before the ligature of the venae cavae, we observed a dose-dependent effect, reaching saturation at around 20 microg/g of rat weight. In addition, this effect is also time-dependent, reaching saturation around 16 h after fucan administration. In addition, regardless of the administration route, fucan A displayed antithrombotic activity. The exception was the oral pathway. Of particular importance was the finding that fucan A stimulates the synthesis of an antithrombotic heparan sulfate from endothelial cells like heparin. The hypothesis has been raised that the in vivo antithrombotic activity of fucan A is related to the increased production of this heparan. Taken together with the fact that the compound is practically devoid of anticoagulant and hemorrhagic activity, the data suggest that it may be an ideal antithrombotic agent in vivo.
WANG Jian-qi; SHI Xu-bo; YANG Jin-gang; HU Da-yi
Background Although low-molecular-weight heparin has replaced unfractionated heparin to become the primary anticoagulation drug for treatment of acute coronary syndrome, there is no convenient bedside monitoring method. We explored the best laboratory monitoring method of low-molecular-weight heparins (enoxapadn, dalteparin, and nadroparin) by use of the Sonoclot coagulation analyzer to monitor the activated clotting time.Methods Atotal of 20 healthy volunteers were selected and 15 ml of fasting venous blood samples were collected and incubated. Four coagulants, kaolin, diatomite, glass bead, and magnetic stick, were used to determine the activated clotting time of the low-molecular-weight heparins at different in vitro anti-Xa factor concentrations. A correlation analysis was made to obtain the regression equation. The activated clotting time of the different low-molecular-weight heparins with the same anti-Xa factor concentration was monitored when the coagulant glass beads were applied. Results The activated clotting time measured using the glass beads, diatomite, kaolin, and magnetic stick showed a linear correlation with the concentration of nadroparin (r= 0.964, 0.966, 0.970, and 0.947, respectively). The regression equation showed that the linear slopes of different coagulants were significantly different (glass beads 230.03 s/IU,diatomite 89.91 s/IU, kaolin 50.87 s/IU, magnetic stick could not be calculated). When the concentration of the anti-Xa factor was the same for different low-molecular-weight heparins, the measured activated clotting time was different after the application of the glass bead coagulant.Conclusions The glass bead coagulant is most feasible for monitoring the in vitro anticoagulation activity of nadroparin.The different effects of different low-molecular-weight heparins on the activated clotting time may be related to the different anti-Ila activities.
Estol, Conrado J.; Kase, Carlos S.
One of the unsolved dilemmas in cerebrovascular disease is the ideal timing to restart anticoagulant therapy (ACT) safely in patients who have suffered an intracranial hemorrhage and have an indication to continue ACT. No randomized studies with evidence-based data are available to settle this issue. Only a few reports have been published; their shortcomings include small numbers of patients evaluated retrospectively, a broad spectrum of indications for ACT, different types of hemorrhage, and variable methods of reversing and restarting ACT. Despite this variability, most reports agree that 1) ACT has to be immediately reversed to decrease the risk of hemorrhage progression; 2) a period between 1 and 2 weeks appears sufficient to allow for management and monitoring of the hemorrhage off ACT; and 3) ACT can be safely restarted after the period off of treatment. A physician confronting a patient with intracranial hemorrhage and the need for ACT faces a situation of individually focused clinical decision making. The problem rests in balancing the risks of a worsening or recurring hemorrhage on one side, and the risk of thromboembolism on the other. From available information and personal experience, an unvalidated risk stratification can be proposed to categorize patients in low- and high-risk groups for hemorrhagic complications and embolic phenomena, assigning them to 5 or 15 days off ACT, respectively. Intermediate-risk patients can have ACT restarted in 5 to 15 days from the onset of the intracranial hemorrhage. Anticoagulation should be immediately reversed. Fresh frozen plasma is the standard treatment in most institutions. Prothrombin complex concentrate is an alternative, but issues of availability make its use impractical. The use of recombinant factor VIIa is an attractive new option.
Khamar Jenil C.
Full Text Available The present manuscript describe simple, sensitive, rapid, accurate, precise and cost effective Second derivative spectrophotometric zero crossing point method for the simultaneous determination of Rifampicin and Piperine in combined capsule dosage form. The utility of Second derivative data processing program is its ability to calculate unknown concentration of components of interest in a mixture containing an interfering component. The Second order derivative absorption at 341 nm (zero cross point for Piperine was used for Rifampicin and 241 nm (zero cross point for Rifampicin was used for Piperine. The linearity was obtained in the concentration range of 10-60 μg/ml for Rifampicin and 2-20 μg/ml for Piperine. The method was successfully applied to pharmaceutical dosage form because no interference from the capsule excipients was found. The suitability of these methods for the quantitative determination of Rifampicin and Piperine was proved by validation. The proposed methods were found to be simple and sensitive for the routine quality control application of Rifampicin and Piperine in pharmaceutical capsule dosage form. The results of analysis have been validated statistically and by recovery studies.
Feng-Di Liu; Rong Zhao; Xue-Mei Wang; Shuo Wang; Xiao-Lei Shen; Xiao-Xiao Tao; Bo Zheng
Objective:To summarize the use rate,safety,efficacy of antithrombotics in stroke/transient ischemic attack (TIA) prevention,and reasons for not using dabigatran etexilate (DE) in Shanghai,China.Methods:Non-valvular atrial fibrillation (NVAF)-associated stroke patients were prospectively registered as an electronic database.Use rate of antithrombofics and reasons for not using DE were extracted during follow-up.Patients' baseline characteristics,recurrent ischemic stroke/TIA events and bleeding complications were analyzed.Patients:From April 2012 to August 2014,110 inpatients with NVAF-associated stroke were studied in our hospital.NVAF was diagnosed by 12-lead electrocardiogram,24 h Holter and echocardiography.Results:Before introduction of DE (April 2013),use rates of warfarin and antiplatelets were 28.9％ (11/38) and 60.5％ (23/38)respectively; after that,use rates of warfarin,DE,and antiplatelets were 20.8％ (15/72),12.5％ (9/72),and 43.1％ (31/72).The DE did not improve use of anticoagulants (P =0.639).There were 19 (17.3％) recurrent ischemic stroke events up to October 2015; two (9.5％) in the non-user group,10 (18.5％) in the antiplatelet group,and seven (20.0％) in the anticoagulants group (P =0.570).Furthermore,recurrence rates were similar between the DE group (20.0％) and the Warfarin group (20.0％,P =1.000).The most common reason for not using DE was financial concerns (61.0％),followed by inconvenience to purchase (14.0％) and hemorrhage concerns (11.0％).Two patients using warfarin found fecal occult blood so they stopped warfarin and began to use antiplatelet drugs.No bleeding event occurred in the other groups.Only one patient had side effects (dyspepsia and gastroesophageal reflux)from DE.Conclusion:The use rate of either DE or warfarin in Shanghai was low; DE had not improved anticoagulation therapy for NVAF patients in Shanghai mainly because DE had not been covered by health insurance.
Galland, Joris; Mohamed, Shirine; Revuz, Sabine; de Maistre, Emmanuel; de Laat, Bas; Marie, Pierre-Yves; Zuily, Stéphane; Lévy, Bruno; Regnault, Véronique; Wahl, Denis
Lupus anticoagulant-hypoprothrombinemia syndrome is a rare condition characterized by the association of acquired factor II deficiency and lupus anticoagulant. Contrary to classical antiphospholipid syndrome, it may cause severe life-threatening bleeding (89% of published cases). We report a patient, positive for antidomain I antibodies, with initially primary lupus anticoagulant-hypoprothrombinemia syndrome without previous clinical manifestation or underlying systemic disease. Five years later, he experienced the first systemic lupus erythematous flare. Within a few days, catastrophic antiphospholipid syndrome was diagnosed with heart, liver and kidney involvement. The patient recovered under pulse steroids, intravenous heparin and intravenous immunoglobulins.
Ohno, Norioki; Kobayashi, Masao; Hayakawa, Seiichi; Utsunomiya, Akari; Karakawa, Shuhei
EDTA-dependent pseudothrombocytopenia (PTCP) is characterised by a low platelet count caused by autoantibodies in the serum reacting with EDTA-anticoagulated blood. EDTA-dependent PTCP is caused by a factor that retains EDTA anticoagulation activity in the serum. We report here that a neonate from a mother with PTCP presented with transient low platelet counts when EDTA was used as an anticoagulant. To confirm the transmission of a maternal serum factor to the neonate, we examined to add the maternal serum into the normal blood. Platelet count decreased significantly after adding maternal serum. Clumped platelets were also observed in the smears of mixed samples.
confluent SMV (n=12; type III (n=1 resulted from a primary end-to-end anastomosis above confluent and PTFE graph was used for reconstruction for type IV (n=2. Curative anticoagulant treatment was always indicated after type IV (n=2 resection, and after resection of type II when the length of venous resection was longer than ≥2 cm. Results. Venous thrombosis rate reached: 0%, 41%, and 100% for type I, II, IV resections, respectively. Among them four patients received curative anticoagulant treatment. Conclusion. After a portal vein resection was achieved in the course of a PD, curative postoperative anticoagulation does not prevent efficiently the onset of thrombosis.
刘心; 张梅; 刘陕西; 祈光裕; 刘亚民
Objective: To explore the effect of thrombolysis with anticoagulation treatment for early stage of deep vein thrombosis of lower extremity. Methods: The clinical data of 106 patients at the early stage of deep vein thrombosis (DVT) in the lower extremities treated by thrombolysis with anticoagulation and dispersion drugs were analyzed retrospectively. Results: The thrombolytic effect was significant. After treatment, the deep veins were recanalized without regurgitation in 75.3% of the patients. The total effective rate was 100%. Only three patients had hemorrhagic complication, but none of the patients died. Conclusion: Thrombolysis with anticoagulation treatment is an effective and safe method for DVT at the early stage.
Full Text Available Abstract Background In animals with heteromorphic sex chromosomes, dosage compensation of sex-chromosome genes is thought to be critical for species survival. Diverse molecular mechanisms have evolved to effectively balance the expressed dose of X-linked genes between XX and XY animals, and to balance expression of X and autosomal genes. Dosage compensation is not understood in birds, in which females (ZW and males (ZZ differ in the number of Z chromosomes. Results Using microarray analysis, we compared the male:female ratio of expression of sets of Z-linked and autosomal genes in two bird species, zebra finch and chicken, and in two mammalian species, mouse and human. Male:female ratios of expression were significantly higher for Z genes than for autosomal genes in several finch and chicken tissues. In contrast, in mouse and human the male:female ratio of expression of X-linked genes is quite similar to that of autosomal genes, indicating effective dosage compensation even in humans, in which a significant percentage of genes escape X-inactivation. Conclusion Birds represent an unprecedented case in which genes on one sex chromosome are expressed on average at constitutively higher levels in one sex compared with the other. Sex-chromosome dosage compensation is surprisingly ineffective in birds, suggesting that some genomes can do without effective sex-specific sex-chromosome dosage compensation mechanisms.
Full Text Available The Curve Fitting and Interpolation Model are applied in Nonel dosage detection in this paper firstly, and the gray of continuous explosive in the Nonel has been forecasted. Although the traditional infrared equipment establishes the relationship of explosive dosage and light intensity, but the forecast accuracy is very low. Therefore, gray prediction models based on curve fitting and interpolation are framed separately, and the deviations from the different models are compared. Simultaneously, combining on the sample library features, the cubic polynomial fitting curve of the higher precision is used to predict grays, and 5mg-28mg Nonel gray values are calculated by MATLAB. Through the predictive values, the dosage detection operations are simplified, and the defect missing rate of the Nonel are reduced. Finally, the quality of Nonel is improved.
Full Text Available Vitamin K antagonists, such as warfarin, used in oral anticoagulation therapy currently represent the standard drugs for the primary and secondary prevention of stroke in non-valvular atrial fibrillation (AF, with a relative risk reduction close to 70%. Newer oral anticoagulants, such as direct thrombin inhibitors (i.e., dabigatran and direct factor Xa inhibitors (i.e., apixaban and rivaroxaban have been recently compared with warfarin in large randomized trials for stroke prevention in AF. The new oral anticoagulants showed, compared with warfarin, no statistically significant difference in the rate of stroke or systemic embolism in secondary prevention (patients with previous transient ischemic attack or stroke subgroups. With regard to safety, the risk of intracranial bleeding was reduced with new anticoagulants compared with warfarin. Indirect treatment comparisons of clinical trials on secondary prevention cohorts showed no significant difference in efficacy among apixaban, rivaroxaban, and dabigatran; but dabigatran 110 mg was associated with less intracranial bleedings than rivaroxaban.
Interpretation & conclusions: It may be concluded that stable therapeutic INR is difficult to maintain in neurological patients. Optimal modification of diet, drug and dose of oral anticoagulant may help in stabilization of INR.
Ami M Karkar
Full Text Available Thromboembolism continues to be a major concern in patients with mechanical heart valves, especially in those with unsatisfactory anticoagulation levels. The new On-X valve (On-X Life Technologies, Austin, TX, USA has been reported as having unique structural characteristics that offer lower thrombogenicity to the valve. We report a case where the patient received no or minimal systemic anticoagulation after placement of On-X mitral and aortic valves due to development of severe mucosal arterio-venous malformations yet did not show any evidence of thromboembolism. This case report reinforces the findings of recent studies that lower anticoagulation levels may be acceptable in patients with On-X valves and suggests this valve may be particularly useful in those in whom therapeutic levels of anticoagulation cannot be achieved due to increased risk of bleeding.
Nielsen, Henriette Svarre; Christiansen, Ole Bjarne
BACKGROUND: Anticardiolipin antibodies (ACA) are found with increased prevalence in women with unexplained recurrent miscarriage (RM) but their impact on future pregnancy outcome in lupus anticoagulant (LAC) negative patients needs better quantification. METHODS: The impact of a repeatedly positive...
Kovac, Mirjana; Mikovic, Zeljko; Mitic, Gorana; Djordjevic, Valentina; Mandic, Vesna; Rakicevic, Ljiljana; Radojkovic, Dragica
The study was conducted to evaluate the effect of anticoagulant therapy in women with thrombophilia and to detect the possible differences among carriers of mutations (factor V [FV] Leiden and FIIG20210) and those with natural anticoagulant deficiency. The 4-year prospective investigation included 85 pregnant women, with a history of recurrent fetal loss (RFL). They were treated with prophylactic doses of low-molecular-weight heparin (nadroparin) starting from 6 to 8 weeks of gestation. Pregnancy outcomes were evaluated based on the thrombophilia type. Carriers of thrombophilic mutations had a live birth rate of 93%, compared to 41.6% for women with natural anticoagulant deficiencies. Significant differences between the groups were also observed for intrauterine fetal death, intrauterine growth restriction, and postpartum thrombosis. The optimal therapy for women with natural anticoagulant deficiency and RFL remains unclear and future prospective study with a large number of patients is required to determine the best treatment for these severe thrombophilic conditions.
Although therapeutic anticoagulation improves early (within 1 month) outcomes after ischemic stroke in hospital-admitted patients with atrial fibrillation, no information exists on late outcomes in unselected population-based studies, including patients with all stroke (ischemic and hemorrhagic).
Spivak, Inna E
Anticoagulation is an important strategy for the prevention of stroke associated with atrial fibrillation. Development of new oral agents has created a need to educate nurses to administer these medications and provide patient education.
Vogt, M; Derendorf, H; Krämer, J; Junginger, H E; Midha, K K; Shah, V P; Stavchansky, S; Dressman, J B; Barends, D M
Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing prednisolone are reviewed. Data on its solubility, oral absorption, and permeability are not totally conclusive, but strongly suggest a BCS Class 1 classification. Prednisolone's therapeutic indications and therapeutic index, pharmacokinetics, and the possibility of excipient interactions were also taken into consideration. Available evidence indicates that a biowaiver for IR solid oral dosage forms formulated with the excipients tabulated in this article would be unlikely to expose patients to undue risks.
Objective To study the solute clearance effect of the new concentrated anticoagulation hemodialysate of citrate for hemodialysis in patients with high risk of bleeding. Methods Forty-two kidney failure patients with high risk of bleeding were divided into two groups (Group A and Group B) according to their hemodialysis manners. Patients in Group A were hemodialyzed with bicarbonate hemodialysate with low-molecular-weight heparin (dalteparin) anticoagulation and those in Group B with the new citrate anticoag...
Lin, Kevin Y.; Lo, Justin H.; Consul, Nikita; Kwong, Gabriel A.; Bhatia, Sangeeta N.
Antithrombotic therapy is a critical portion of the treatment regime for a number of life-threatening conditions, including cardiovascular disease, stroke, and cancer; yet, proper clinical management of anticoagulation remains a challenge because existing agents increase the propensity for bleeding in patients. Here, we describe the development of a bioresponsive peptide–polysaccharide nanocomplex that utilizes a negative feedback mechanism to self-titrate the release of anticoagulant in resp...
Aspegren, Oskar P.; Åstrand, Ramona; Lundgren, Maria I.
Chronic subdural hematoma (CSDH) is a common disease among the elderly and with increasing incidence we have chosen to focus on associations between development and recurrence of CSDH and anticoagulation and/or antiplatelet agent therapy.......Chronic subdural hematoma (CSDH) is a common disease among the elderly and with increasing incidence we have chosen to focus on associations between development and recurrence of CSDH and anticoagulation and/or antiplatelet agent therapy....
Abdelhafez, Omaima M; Amin, Kamelia M; Batran, Rasha Z; Maher, Timothy J; Nada, Somaia A; Sethumadhavan, Shalini
The action of the coumarin-type drugs and related compounds is reviewed to their VKOR antagonistic effects. In our study, twenty 3-pyridinyl, pyrimidinyl and pyrazolyl-4-hydroxycoumarin derivatives were synthesized. A comparative in vivo (CT, PT determination) and in vitro (measurement of PIVKA-II levels) anticoagulant study with respect to warfarin showed that the synthesized compounds have different anticoagulant activities, the most prospective compounds were the 3-pyrazolyl-4-hydroxycoumarin derivatives.
Christensen, Thomas D; Attermann, Jørn; Hjortdal, Vibeke E.;
Objective: The concept of self – management of oral anticoagulation has been shown to entail better quality of treatment than conventional management when assessed in selected adults. We have extended the concept of self – management to include children with congenital cardiac disease...... complications requiring doctoral intervention. All the patients and their parents expressed full satisfaction with the treatment. Conclusion: Selfmanagement of oral anticoagulation provides a good quality of treatment, which is feasible and safe in selected children with congenital cardiac disease....
Objective(s): Snake venoms contain complex mixture of proteins with biological activities. Some of these proteins affect blood coagulation and platelet function in different ways. Snake venom toxin may serve as a starting material for drug design to combat several pathophysiological problems such as cardiovascular disorders. In the present study, purification of anticoagulation factor from venom of snake (Echis carinatus) was studied. Materials and Methods: Anticoagulation activity of crude v...
Vitor Hugo Pomin; Paulo Antonio De Souza Mourão
Based on considered achievements of the last 25 years, specific combinations of sulfation patterns and glycosylation types have been proved to be key structural players for the anticoagulant activity of certain marine glycans. These conclusions were obtained from comparative and systematic analyses on the structure-anticoagulation relationships of chemically well-defined sulfated polysaccharides of marine invertebrates and red algae. These sulfated polysaccharides are known as sulfated fucans...
Pomin, Vitor H.; Mourão, Paulo A. S.
Based on considered achievements of the last 25 years, specific combinations of sulfation patterns and glycosylation types have been proved to be key structural players for the anticoagulant activity of certain marine glycans. These conclusions were obtained from comparative and systematic analyses on the structure-anticoagulation relationships of chemically well-defined sulfated polysaccharides of marine invertebrates and red algae. These sulfated polysaccharides are known as sulfated fucans...
Rattner, Barnett A.; Horak, Katherine E.; Lazarus, Rebecca; Schultz, Sandra; Knowles, Susan N.; Abbo, B.G.; Volker, Steven F.
with exposure to environmentally realistic concentrations of CPN could compromise survival of free-ranging raptors, and should be considered in weighing the costs and benefits of anticoagulant rodenticide use in pest control and eradication programs.
López Castañón, Lorena
This case report describes an 83 year-old immobilised patient with multiple diseases and on polypharmacy. Nursing care is developed at home. The patient is included in patient care programs for the anticoagulated and polymedicated patient. Nursing assessments were made using the Marjory Gordon functional health patterns, by which we identified, among others, problems related to non-compliance with the pharmacological treatment. The Nurse's Diagnosis was: Ineffective Management of own health. With the support of NANDA, NOC and NIC taxonomy we determined the nursing objectives and interventions. The expected results of the Care Plan were achieved. Polypharmacy in the elderly can lead to treatment problems, increasing hospital admissions, morbidity and mortality and health expenditure Nursing care at home is a continuous development process and is increasing due to aging of the population, the prevalence of chronic diseases, as well as the increased life expectancy. It is estimated that in 2030, 24% of the Spanish population will be over 64 years. The physical, sensory, cognitive and chronic disabilities of aging make this type of care necessary. It is a major element in the comprehensive care of these patients, by checking the correct use of medication, symptom control, helping them to be autonomous in managing their disease and establishing a fluid relationship between the patients and their family.
Hanslik, Thomas; Prinseau, Jacques
Anticoagulation with antivitamin K (AVK) is very effective for primary and secondary prevention of thromboembolic events. However, questions persist about the risks and management of over-anticoagulation. For reversal of excessive anticoagulation by warfarin, AVK withdrawal, oral or parenteral vitamin K administration, prothrombin complex or fresh frozen plasma may be used, depending on the excess of anticoagulation, the existence and site of active bleeding, patient characteristics and the indication for AVK. In over-anticoagulated patients, vitamin K aims at rapid lowering of the international normalized ratio (INR) into a safe range to reduce the risk of major bleeding and therefore improving patient outcome without exposing the patient to the risk of thromboembolism due to overcorrection, resistance to AVK, or an allergic reaction to the medication. The risk of bleeding increases dramatically when the INR exceeds 4.0-6.0, although the absolute risk of bleeding remains fairly low, 10.0, a dose of 5mg may be more appropriate. Overcorrection of the INR or resistance to warfarin is unlikely if the above doses of vitamin K are used. Vitamin K is less effective for over-anticoagulation after treatment with acenocoumarol or phenprocoumon than after treatment with warfarin.
T. Djumhana Atmakusuma
Full Text Available Aim: to assess the current use of anticoagulants and implementation of International Guidelines in venous thromboembolism (VTE prophylaxis in hospitalized patients with acute medical illnesses in Jakarta, Indonesia. Methods: a multicenter, prospective, disease registry, recruiting patients diagnosed as acutely ill medical diseases and other medical conditions at risk of VTE, with in-hospital immobilization for at least 3 days. Results: of 401 patients, 46.9% received anticoagulants which included unfractionated heparin (64.4%, fondaparinux (11.7%, enoxaparin (9.6%, warfarin (3.7%, and combination of anticoagulants (10.6%. VTE prophylaxis using physical and mechanical method was used in 81.3% of patients, either as a single modality or in combination with anticoagulants. During hospitalization, VTE were found in 3.2% patients; 10 patients (2.5% had lower limb events and 3 patients (0.75% had a suspected pulmonary embolism. The main reference international guidelines used were AHA/ASA 2007 (47.4%, followed by ACCP 2008 (21.7%. Conclusion: the study showed underutilization of prophylaxis anticoagulants in which mechanical thromboprophylaxis either alone or combination with anticoagulants was the most commonly used. Unfractionated heparin was the preferable choice. The most commonly used guideline was AHA/ASA 2007. VTE thromboprophylaxis in medically ill patients needs to be encouraged. Key words: venous thromboembolism (VTE, prophylaxis, registry, non-surgery hospitalization.
Levi, M M; Eerenberg, E; Löwenberg, E; Kamphuisen, P W
The most important adverse effect of antithrombotic treatment is the occurrence of bleeding. In case of serious or even life-threatening bleeding in a patient who uses anticoagulant agents or when patient on anticoagulants needs to undergo an urgent invasive procedure, anticoagulant treatment can be reversed by various specific strategies. Heparin and heparin derivatives can be counteracted by protamine sulphate, whereas the anticoagulant effect of vitamin K antagonists may be neutralised by administration of vitamin K or prothrombin complex concentrates. The antihaemostatic effect of aspirin and other antiplatelet strategies can be corrected by the administration of platelet concentrate and/or desmopressin, if needed. Recently, a new generation of anticoagulants with a greater specificity towards activated coagulation factors has been introduced and most of these agents are currently being evaluated in clinical studies, showing promising results. The new-generation anticoagulants include specific inhibitors of factor IIa or factor Xa (including pentasaccharides) and antiplatelet agents belonging to the class of thienopyridine derivatives. A limitation of the new class of anti-IIa and anti-Xa agents may be the lack of an appropriate strategy to reverse the effect if a bleeding event occurs, although in some cases the administration of recombinant factor VIIa may be an option.
Schuff-Werner, Peter; Steiner, Michael; Fenger, Sebastian; Gross, Hans-Jürgen; Bierlich, Alexa; Dreissiger, Katrin; Mannuß, Steffen; Siegert, Gabriele; Bachem, Maximilian; Kohlschein, Peter
Pseudothrombocytopenia remains a challenge in the haematological laboratory. The pre-analytical problem that platelets tend to easily aggregate in vitro, giving rise to lower platelet counts, has been known since ethylenediamine-tetra acetic acid EDTA and automated platelet counting procedures were introduced in the haematological laboratory. Different approaches to avoid the time and temperature dependent in vitro aggregation of platelets in the presence of EDTA were tested, but none of them proved optimal for routine purposes. Patients with unexpectedly low platelet counts or flagged for suspected aggregates, were selected and smears were examined for platelet aggregates. In these cases patients were asked to consent to the drawing of an additional sample of blood anti-coagulated with a magnesium additive. Magnesium was used in the beginning of the last century as anticoagulant for microscopic platelet counts. Using this approach, we documented 44 patients with pseudothrombocytopenia. In all cases, platelet counts were markedly higher in samples anti-coagulated with the magnesium containing anticoagulant when compared to EDTA-anticoagulated blood samples. We conclude that in patients with known or suspected pseudothrombocytopenia the magnesium-anticoagulant blood samples may be recommended for platelet counting.
Fenger-Eriksen, C; Münster, A-M; Grove, E L
New oral anticoagulants like the direct thrombin inhibitor, dabigatran (Pradaxa®), and factor Xa-inhibitors, rivaroxaban (Xarelto®) and apixaban (Eliquis®) are available for prophylaxis and treatment of thromboembolic disease. They are emerging alternatives to warfarin and provide equal or better clinical outcome together with reduced need for routine monitoring. Methods for measuring drug concentrations are available, although a correlation between plasma drug concentrations and the risk of bleeding has not been firmly established. Standard laboratory measures like prothrombin time and activated partial thromboplastin time are not sensitive enough to detect thrombin or factor Xa inhibition provided by new oral anticoagulants. Thus, these standard tests may only be used as a crude estimation of the actual anticoagulation status. Further challenges regarding patients receiving new oral anticoagulants who presents with major bleeding or need for emergency surgery pose a unique problem. No established agents are clinically available to reverse the anticoagulant effect, although preclinical data report prothrombin complex concentrate as more efficient than fresh frozen plasma or other prohaemostatic agents. This review summaries current knowledge on approved new oral anticoagulants and discusses clinical aspects of monitoring, with particular focus on the management of the bleeding patient.
Miranda, M; Martinez, L S; Franco, R; Forte, V; Barlattani, A; Bollero, P
The oral anticoagulant therapy is used for the cure and the prevention of thromboembolic diseases. In the last fifty years the warfarin has been considered the oral anticoagulant of choice. However, its use is limited by a narrow therapeutic index and by a complex pharmacodynamics, which requires regular adjustments and monitoring of the dose. Recently, three new oral anticoagulant - dabigatran etexilato (direct thrombin inhibitor), rivaroxaban and apixaban (Xa factor direct inhibitor) - have been approved for use in europe. Increasing the number of patients taking these drugs, it is important that the dentist knows these new oral anticoagulants, their indications and methods of action, in particular for the management of patients, who require invasive treatments. With regard to the management of the patient threated with the new oral anticoagulants (NAO), there have been new significant changes in the procedure compared to the one followed by patients treated with warfarin. This led to the development of new guidelines that the dentist has to follow in order to ensure a safe and appropriate dental treatment and reduce any postoperative complications. The aim of this work is to evaluate the effectiveness of the new oral anticoagulants compared to warfarin, especially in terms of risks of bleeding events and intra and postoperative complications, in patients requiring multiple dental extractions.
Full Text Available Several studies have reported underprescription of anticoagulants in atrial fibrillation (AF. We conducted an observational study on 142 out of a total of 995 consecutive ≥75 years old patients presenting AF (14% when admitted in an emergency unit of a general hospital, in search of geriatric characteristics that might be associated with the underprescription of anticoagulation therapy (mostly antivitamin K at the time of the study. The following data was collected from patients presenting AF: medical history including treatment and comorbidities, CHADS2 score, ISAR scale (frailty, Lawton’s scale (ADL, GDS scale (mood status, MUST (nutrition, and blood analysis (INR, kidney function, and albumin. Among those patients for who anticoagulation treatment was recommended (73%, only 61% were treated with it. In the group with anticoagulation therapy, the following characteristics were observed more often than in the group without such therapy: a recent (≤6 months hospitalization and medical treatment including digoxin or based on >3 different drugs. Neither the value of the CHADS2 score, nor the geriatric characteristics could be correlated with the presence or the absence of an anticoagulation therapy. More research is thus required to identify and clarify the relative importance of patient-, physician-, and health care system-related hurdles for the prescription of oral anticoagulation therapy in older patients with AF.
Full Text Available Anticoagulant therapy is essential for the prevention of risks associated with the formation of thrombus in patients after surgery, especially in orthopedics. Recently, new oral anticoagulants were introduced in the therapeutic arsenal. This fact is important, because the current drug of choice in clinical practice is enoxaparin, a low molecular weight heparin. As all injecting drugs, enoxaparin may reduce patients' adherence to treatment by dissatisfaction with and resistance to the administration. This article reviews the available literature on the overall utility of these innovative medicines, approaching the pharmacology, the compared efficacy in relation to current agents, and the potential targets for new agents, as well as points to new trends in research and development. The article also contributes with a practical guide for use and recommendations to health professionals, especially focusing on the reversibility of hemorrhagic events, and discusses the importance of convenience/satisfaction of use, the cost of treatment, and the risk-benefit profile for patients.A terapia anticoagulante é fundamental para a prevenção de riscos associados à formação de trombos em pacientes pós-cirúrgicos, principalmente em ortopedia. Recentemente, novos anticoagulantes orais foram introduzidos no arsenal terapêutico. Tal fato é importantíssimo, visto que o atual medicamento de primeira escolha na prática clínica é a enoxaparina, uma heparina de baixo peso molecular. Por ser de uso injetável, a enoxaparina pode diminuir a adesão do paciente ao tratamento, devido à insatisfação e à resistência quanto à via de administração. Este artigo revisa a literatura disponível sobre a utilidade total desses medicamentos inovadores ao abordar a farmacologia, a eficácia em comparação com os agentes atuais e os alvos potenciais para novos agentes, bem como aponta as novas tendências em pesquisa e desenvolvimento. O artigo também contribui
... HUMAN SERVICES Food and Drug Administration 21 CFR Part 520 Oral Dosage Form New Animal Drugs; Estriol AGENCY: Food and Drug Administration, HHS. ACTION: Final rule. SUMMARY: The Food and Drug Administration (FDA) is amending the animal drug regulations to reflect approval of an original new animal...
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... HUMAN SERVICES Food and Drug Administration 21 CFR Part 520 Oral Dosage Form New Animal Drugs; Tylosin... drug application (ANADA) filed by Huvepharma AD. The ANADA provides for use of tylosin tartrate soluble... for use of PHARMASIN (tylosin tartrate) Soluble in medicated drinking water for chickens,...
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Conclusions: Within the range of total energy examined, there is a positive correlation between total energy used and amount of pressure reduction achieved at up to 3 years of follow-up. This may be useful in determining the optimal energy dosage for maximum effect for patients receiving SLT.
Hoffman, LaVae M.
This article expands on the work of S. F. Warren, M. E. Fey, and P. J. Yoder (2007) by applying their suggested intervention-intensity parameters to narrative language intervention with school-aged children. These pharmacologically based dosage concepts are examined from two perspectives: oral narrative skills as the target of language therapy and…
Koeppe, Marcelle O; Cristofoletti, Rodrigo; Fernandes, Eduardo F; Storpirtis, Silvia; Junginger, Hans E; Kopp, Sabine; Midha, Kamal K; Shah, Vinod P; Stavchansky, Salomon; Dressman, Jennifer B; Barends, Dirk M
Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing levofloxacin as the only active pharmaceutical ingredient (API) are reviewed. According to the current Biopharmaceutics Classification System, levofloxacin can be assigned to Class I. No problems with BE of IR levofloxacin formulations containing different excipients and produced by different manufacturing methods have been reported and hence the risk of bioinequivalence caused by these factors appears to be low. In addition, levofloxacin has a wide therapeutic index. On the basis of this evidence, a biowaiver is recommended for IR solid oral dosage forms containing levofloxacin as the single API provided that (a) the test product contains only excipients present in IR levofloxacin drug products that have been approved in International Conference on Harmonization (ICH) or associated countries and which have the same dosage form; (b) both the test and comparator dosage form are "very rapidly dissolving" or "rapidly dissolving" with similarity of the dissolution profiles demonstrated at pH 1.2, 4.5, and 6.8; and (c) if the test product contains polysorbates, it should be both qualitatively and quantitatively identical to its comparator in terms of polysorbate content.
Vogt, M; Derendorf, H; Krämer, J; Junginger, H E; Midha, K K; Shah, V P; Stavchansky, S; Dressman, J B; Barends, D M
Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing prednisolone are reviewed. Data on its solubility, oral absorption, and permeability are not totally conclusive, but strongl
Jantratid, E; Prakongpan, S; Dressman, J B; Amidon, G L; Junginger, H E; Midha, K K; Barends, D M
Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing cimetidine are reviewed. According to the current Biopharmaceutics Classification System (BCS), cimetidine would be assigned
... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Monensin oral dosage forms. 520.1448 Section 520.1448 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... starting line). The loss on drying is not more than 10 percent when dried in vacuum at 60 °C for 2 hours....
Ghiadoni, Lorenzo; Taddei, Stefano; Virdis, Agostino
Hypertension and atrial fibrillation are the most common cardiovascular risk factors and clinically significant arrhythmia, respectively. These conditions frequently coexist and their prevalence increases rapidly with aging. Despite several different risk factors and clinical conditions predisposing to hypertension for its high prevalence in the population is still the main risk factor for the development of atrial fibrillation. Several pathophysiologic mechanisms (such as structural changes at the level of left ventricle and or atrium, neurohormonal activation, arterial stiffness, etc.) can contribute to the onset of atrial fibrillation. Some antihypertensive treatments have been shown to contribute to reduce the risk of new-onset atrial fibrillation. Atrial fibrillation is a major risk factor for stroke, which is further increased in the presence of hypertension. For this reason, hypertension is included as a major risk factor in the available models for the risk stratification and the prevention of thromboembolism in patients with atrial fibrillation. In this article we will review the relationship between atrial fibrillation and hypertension, looking at the possible specific indications of the antithrombotic treatment with new classes of anticoagulants in the prevention of thromboembolic events in hypertensive patients with atrial fibrillation.
Full Text Available Piperlonguminine (PL, an important component of Piperlongum fruits, is known to exhibit anti-hyperlipidemic, antiplateletand anti-melanogenic activities. Here, the anticoagulantactivities of PL were examined by monitoring activatedpartial-thromboplastin-time (aPTT, prothrombin-time (PT, andthe activities of thrombin and activated factor X (FXa. Theeffects of PL on the expressions of plasminogen activatorinhibitor type 1 (PAI-1 and tissue-type plasminogen activator(t-PA were also tested in tumor necrosis factor-α (TNF-αactivated HUVECs. The results showed that PL prolonged aPTTand PT significantly and inhibited the activities of thrombin andFXa. PL inhibited the generation of thrombin and FXa inHUVECs. In accordance with these anticoagulant activities, PLprolonged in vivo bleeding time and inhibited TNF-α inducedPAI-1 production. Furthermore, PAI-1/t-PA ratio was significantlydecreased by PL. Collectively, our results suggest that PLpossesses antithrombotic activities and that the current studycould provide bases for the development of new anticoagulantagents. [BMB Reports 2013; 46(10: 484-489
Matsumoto, T; Sagawa, N; Ihara, Y; Kobayashi, F; Itoh, H; Mori, T
Lupus anticoagulant (LAC), a serum antiphospholipid autoantibody, is believed to be one of the causes of infertility or fetal loss. The purpose of the present study was to evaluate the role of LAC in the pathogenesis of hypertension during pregnancy. In this study, 20 pregnant women with hypertension were classified into two groups: 14 patients who did not have hypertension before the pregnancy but developed it during the pregnancy (pregnancy-induced hypertension; Group A) and 6 patients who had hypertensive or renal disease before the pregnancy, and developed further hypertension during the pregnancy (pregnancy-aggravated hypertension; Group B). A LAC coagulation assay was performed, and the presence of LAC in each group was compared. All 14 patients in group A were LAC-negative. In contrast, 3 of the 6 patients in group B were LAC-positive, and had clinical autoimmune diseases. The incidence of pregnancy-induced hypertension was also examined in 15 pregnancies from 9 LAC-positive women who had a history of repeated fetal loss but no systemic autoimmune disease (Group C). None of these 15 pregnancies had hypertensive complications, even when they reached term. In the placentas of LAC-positive women, no characteristic changes other than fibrinoid degeneration and microscopic infarction were observed upon histological examination. These results suggest that LAC does not relate with the onset of hypertension during pregnancy.
Vitor Hugo Pomin
Full Text Available Marine sulfated polysaccharides (MSP, such as sulfated fucans (SF, sulfated galactans (SG and glycosaminoglycans (GAG isolated from either algae or invertebrate animals, are highly anionic polysaccharides capable of interacting with certain cationic proteins, such as (co-factors of the coagulation cascade during clotting-inhibition processes. These molecular complexes between MSP and coagulation-related proteins might, at first glance, be assumed to be driven mostly by electrostatic interactions. However, a systematic comparison using several novel sulfated polysaccharides composed of repetitive oligosaccharides with clear sulfation patterns has shown that these molecular interactions are regulated essentially by the stereochemistry of the glycans (which depends on a conjunction of anomericity, monosaccharide, conformational preference, and glycosylation and sulfation sites, rather than just a simple consequence of their negative charge density (mainly the number of sulfate groups. Here, we present an overview of the structure-function relationships of MSP, correlating their structures with their potential anticoagulant and antithrombotic actions, since pathologies related to the cardiovascular system are one of the major causes of illness and mortality in the world.
1例46岁男性患者，既往有房颤及脑梗塞病史，二尖瓣机械瓣膜置换术后予以华法林抗凝治疗。根据药物基因检测及合并用药情况，初始给予华法林2.5 mg po qd，监测INR值偏低，华法林调整至3.75 mg po qd后出院，一月后复查INR 1.64。在随访过程中，临床药师发现该患者出院后自2014年10月至2015年1月，华法林剂量上调，但抗凝效果不佳，有栓塞风险。经详细了解后，考虑与患者服药依从性差相关，建议家属严格监督患者每日按时按量服用华法林，在饮食上避免长期摄入大量含有维生素K的食物并戒酒，一周后复查INR为1.46，接近合适范围。%A 46-year-old male patient, who has a history of atrial fibrillation and cerebral infarction, has taken warfarin-anticoagulant therapy after mechanical heart valve replacement. According to the results of drug genetic testing and drug combination, an abnormal low international standardization ration (INR) was observed when the initial warfarin dosage was 2.5 mg po qd, which indicated the risk of thrombosis. The warfarin dosage was adjusted to 3.75 mg po qd as the patient left hospital and then INR was 1.64 when rechecked one month later. At follow-up, with the increasing dosage of warfarin, the anticoagulant effect was not satisfactory from October 2014 to January 2015. After the detailed investigation, the clinical pharmacists considered the unsatisfactory anticoagulant effect was related to the poor compliance of the patient. The family dependents of the patient were advised to strictly supervise the patient to take warfarin timely and quantitatively and the patient was exhorted to avoid long-term foods with large amounts of vitamin K and forbear from alcohols. INR was 1.46 when rechecked one week later, which was close to the target range.
Full Text Available Background: Anticoagulation patient self-testing (PST represents an alternative approach to warfarin monitoring by enabling patients to use coagulometers to test their international normalized ratio (INR values. PST offers several advantages that potentially improve warfarin management. Objective: To describe implementation and associated performance of a PST demonstration program at an Indian Health Service (IHS facility. Methods: A non-consecutive case series analysis of patients from a pharmacy-managed PST demonstration program was performed at an IHS facility in Oklahoma between July 2008 and February 2009.Results: Mean time in therapeutic range (TTR for the seven patients showed a small, absolute increase during the twelve weeks of PST compared to the twelve weeks prior to PST. Four of the seven patients had an increase in TTR during the twelve week course of PST compared to their baseline TTR. Three of four patients with increased TTR in the final eight week period of PST achieved a TTR of 100%. Of the three patients who experienced a decrease in TTR after initiating self-testing, two initially presented with a TTR of 100% prior to PST and one patient had a TTR of 100% for the final eight weeks of PST. The two patients not achieving a TTR of 100% during the twelve week PST period demonstrated an increase in TTR following the first four weeks of PST. Conclusion: Although anticoagulation guidelines now emphasize patient self-management (PSM only, optimal PST remains an integral process in PSM delivery. In the patients studied, the results of this analysis suggest that PST at the IHS facility provided a convenient, alternative method for management of chronic warfarin therapy for qualified patients. More than half of the patients demonstrated improvement in TTR. Although there is a learning curve immediately following PST initiation, the mean TTR for the entire PST period increased modestly when compared to the time period prior to PST.
Williams, Brett; Davis, Samantha
A student's accuracy on drug calculation tests may be influenced by maths anxiety, which can impede one's ability to understand and complete mathematic problems. It is important for healthcare students to overcome this barrier when calculating drug dosages in order to avoid administering the incorrect dose to a patient when in the clinical setting. The aim of this study was to examine the effects of maths anxiety on healthcare students' ability to accurately calculate drug dosages by performing a scoping review of the existing literature. This review utilised a six-stage methodology using the following databases; CINAHL, Embase, Medline, Scopus, PsycINFO, Google Scholar, Trip database (http://www.tripdatabase.com/) and Grey Literature report (http://www.greylit.org/). After an initial title/abstract review of relevant papers, and then full text review of the remaining papers, six articles were selected for inclusion in this study. Of the six articles included, there were three experimental studies, two quantitative studies and one mixed method study. All studies addressed nursing students and the presence of maths anxiety. No relevant studies from other disciplines were identified in the existing literature. Three studies took place in the U.S, the remainder in Canada, Australia and United Kingdom. Upon analysis of these studies, four factors including maths anxiety were identified as having an influence on a student's drug dosage calculation abilities. Ultimately, the results from this review suggest more research is required in nursing and other relevant healthcare disciplines regarding the effects of maths anxiety on drug dosage calculations. This additional knowledge will be important to further inform development of strategies to decrease the potentially serious effects of errors in drug dosage calculation to patient safety.
Gouda, P; Ezekowitz, J A
Patients with atrial fibrillation (AF) and heart failure (HF) are at risk for stroke, and progress in anticoagulation has led to new options for these patients. Patients in sinus rhythm may benefit from antiplatelet agents or anticoagulants, but much work remains to establish efficacy and safety. Additional progress is needed, including better tools for risk stratification and clarity regarding the need for antiplatelet agents in combination with anticoagulants for those with other vascular diseases.
Dewilde, Willem J. M.; Janssen, Paul W.; Kelder, Johannes C.; Verheugt, Freek W. A.; De Smet, Bart J. G. L.; Adriaenssens, Tom; Vrolix, Mathias; Brueren, Guus B.; Vandendriessche, Tom; Van Mieghem, Carlos; Cornelis, Kristoff; Vos, Jeroen; Breet, Nicoline J.; ten Berg, Jurrien M.
Aims: To investigate the optimal periprocedural antithrombotic strategy in patients on long-term oral anticoagulation (OAC) who require percutaneous coronary intervention with stenting. Methods and results: The WOEST study was a randomised controlled trial which recruited 573 patients on long-term O
Pasquale De Bonis
Full Text Available BACKGROUND AND PURPOSE: In the last decade there has been an increasing use of antiplatelet/anticoagulant agents in the elderly. The aim of the study was to evaluate the association between exposure to anticoagulant/antiplatelet therapy and chronic subdural haematoma-CSDH. METHODS: Single institution case-control study involving 138786 patients older than 60 years who visited our academic tertiary care Emergency Department from January 1st 2001 to December 31st 2010. 345 patients with CSDH (cases were identified by review of ICD-9 codes 432.1 and 852.2x. Case and controls were matched with a 1:3 ratio for gender, age (± 5 years, year of admission and recent trauma. A conditional logistic model was built. A stratified analysis was performed with respect to the presence (842 patients or absence (536 patients of recent trauma. RESULTS: There were 345 cases and 1035 controls. Both anticoagulant and antiplatelet agents were associated with an increased risk of CSDH with an OR of 2.46 (CI 95% 1.66-3.64 and 1.42 (CI 95% 1.07-1.89, respectively. OR was 2.70 (CI 95% 1.75-4.15, 1.90 (CI 95% 1.13-3.20, and 1.37(CI 95% 0.99-1.90 for patients receiving oral anticoagulants, ADP-antagonists, or Cox-inhibitors, respectively. History of recent trauma was an effect modifier of the association between anticoagulants and CSDH, with an OR 1.71 (CI 95% 0.99-2.96 for patients with history of trauma and 4.30 (CI 95% 2.23-8.32 for patients without history of trauma. CONCLUSIONS: Anticoagulant and antiplatelet therapy have a significant association with an increased risk of CSDH. This association, for patients under anticoagulant therapy, appears even stronger in those patients who develop a CSDH in the absence of a recent trauma.
Wei Lai; Shi-Chun Lu; Guan-Yin Li; Chuan-Yun Li; Ju-Shan Wu; Qing-Liang Guo; Meng-Long Wang; Ning Li
AIM:To compare the incidence of early portal or splenic vein thrombosis (PSVT) in patients treated with irregular and regular anticoagulantion alter splenectomy with gastroesophageal devascularization.METHODS:We retrospectively analyzed 301 patients who underwent splenectomy with gastroesophageal devascularization for portal hypertension due to cirrhosis between April 2004 and July 2010.Patients were categorized into group A with irregular anticoagulation and group B with regular anticoagulation,respectively.Group A (153 patients) received anticoagulant monotherapy for an undesignated time period or with aspirin or warfarin without low-molecular-weight heparin (LMWH) irregularly.Group B (148 patients) received subcutaneous injection of LMWH routinely within the first 5 d after surgery,followed by oral warfarin and aspirin for one month regularly.The target prothrombin time/international normalized ratio (PT/INR) was 1.25-1.50.Platelet and PT/INR were monitored.Color Doppler imaging was performed to monitor PSVT as well as the effectiveness of thrombolytic therapy.RESULTS:The patients' data were collected and analyzed retrospectively.Among the patients,94 developed early postoperative mural PSVT,including 63patients in group A (63/153,41.17％) and 31 patients in group B (31/148,20.94％).There were 50 (32.67％)patients in group A and 27 (18.24％) in group B with mural PSVT in the main trunk of portal vein.After the administration of thrombolytic,anticoagulant and antiaggregation therapy,complete or partial thrombus dissolution achieved in 50 (79.37％) in group A and 26 (83.87％) in group B.CONCLUSION:Regular anticoagulation therapy can reduce the incidence of PSVT in patients who undergo splenectomy with gastroesophageal devascularization,and regular anticoagulant therapy is safer and more effective than irregular anticoagulant therapy.Early and timely thrombolytic therapy is imperative and feasible for the prevention of PSVT.
Soule, Erin E; Bompiani, Kristin M; Woodruff, Rebecca S; Sullenger, Bruce A
Potent and rapid-onset anticoagulation is required for several clinical settings, including cardiopulmonary bypass surgery. In addition, because anticoagulation is associated with increased bleeding following surgery, the ability to rapidly reverse such robust anticoagulation is also important. Previously, we observed that no single aptamer was as potent as heparin for anticoagulating blood. However, we discovered that combinations of two aptamers were as potent as heparin. Herein, we sought to combine two individual anticoagulant aptamers into a single bivalent RNA molecule in an effort to generate a single molecule that retained the potent anticoagulant activity of the combination of individual aptamers. We created four bivalent aptamers that can inhibit Factor X/Xa and prothrombin/thrombin and anticoagulate plasma, as well as the combination of individual aptamers. Detailed characterization of the shortest bivalent aptamer indicates that each aptamer retains full binding and functional activity when presented in the bivalent context. Finally, reversal of this bivalent aptamer with a single antidote was explored, and anticoagulant activity could be rapidly turned off in a dose-dependent manner. These studies demonstrate that bivalent anticoagulant aptamers represent a novel and potent approach to actively and reversibly control coagulation.
Firriolo, F John; Hupp, Wendy S
Warfarin has been the primary anticoagulant drug used in the USA for more than 50 years. However, 2 novel types of oral anticoagulants have recently been approved for use in the USA. These are direct thrombin inhibitors (e.g., dabigatran etexilate) and factor Xa inhibitors (e.g., rivaroxaban). Dental health care providers may soon encounter patients who are being prescribed these medications. This article describes the pharmacologic properties and medical uses of these new oral anticoagulants. Also discussed are implications for the management of dental patients being treated with these new oral anticoagulants, including potential interactions with drugs commonly used or prescribed in the course of dental treatment.
Başaran, Özcan; Dogan, Volkan; Beton, Osman; Tekinalp, Mehmet; Aykan, Ahmet Cağri; Kalaycioğlu, Ezgi; Bolat, Ismail; Taşar, Onur; Şafak, Özgen; Kalcik, Macit; Yaman, Mehmet; İnci, Sinan; Altintaş, Bernas; Kalkan, Sedat; Kirma, Cevat; Biteker, Murat
Abstract This study aimed to investigate the potential misuse of novel oral anticoagulants (NOACs) and the physicians’ adherence to current European guideline recommendations in real-world using a large dataset from Real-life Multicenter Survey Evaluating Stroke Prevention Strategies in Turkey (RAMSES Study). RAMSES study is a prospective, multicenter, nationwide registry (ClinicalTrials.gov identifier NCT02344901). In this subgroup analysis of RAMSES study, patients who were on NOACs were classified as appropriately treated (AT), undertreated (UT), and overtreated (OT) according to the European Society of Cardiology (ESC) guidelines. The independent predictors of UT and OT were determined by multivariate logistic regression. Of the 2086 eligible patients, 1247 (59.8%) received adequate treatment. However, off-label use was detected in 839 (40.2%) patients; 634 (30.4%) patients received UT and 205 (9.8%) received OT. Independent predictors of UT included >65 years of age, creatinine clearance ≥50 mL/min, urban living, existing dabigatran treatment, and HAS-BLED score of <3, whereas that of OT were creatinine clearance <50 mL/min, ongoing rivaroxaban treatment, and HAS-BLED score of ≥3. The suboptimal use of NOACs is common because of physicians’ poor compliance to the guideline recommendations in patients with nonvalvular atrial fibrillation (NVAF). Older patients who were on dabigatran treatment with good renal functions and low risk of bleeding were at risk of UT, whereas patients who were on rivaroxaban treatment with renal impairment and high risk of bleeding were at risk of OT. Therefore, a greater emphasis should be given to prescribe the recommended dose for the specified patients. PMID:27583892
Czepluch, F S; Hasenfuß, G; Jacobshagen, C
Three innovative pharmaceuticals which might play an important role in the field of cardiology in the near future were recently tested in large clinical studies. Serelaxin, a vasoactive hormone peptide that is produced during pregnancy, reduces vessel resistance, increases cardiac output, and improves renal function. Lately, it was demonstrated that serelaxin significantly reduces congestion symptoms in patients with acute heart failure. As a secondary endpoint the mortality at day 180 was reduced. Therefore, serelaxin seems to be a promising new drug for the treatment of acute heart failure which might have a prognostic impact. Edoxaban is a selective factor Xa inhibitor, which inhibits thrombin production and thrombus formation. Two recently published studies reported that edoxaban is at least as effective as the vitamin K antagonist warfarin in prevention and treatment of venous thromboembolism and in the prevention of stroke and systemic embolism due to nonvalvular atrial fibrillation. Compared to warfarin, edoxaban significantly exhibited less frequent severe bleeding complications. Edoxaban will probably soon be the fourth new oral anticoagulant available for patients. The serine protease proprotein convertase subtilisin/kexin 9 (PCSK9) reduces the ability of the liver to bind low-density lipoprotein cholesterol (LDL-C) and to remove it from the circulation. Recently, a monoclonal antibody for PCSK9 was developed which induces a LDL-C plasma level reduction up to 73 % and also decreases lipoprotein(a) and apolipoprotein B. PCSK9 inhibition is a promising new mechanism for LDL-C reduction and the corresponding drug will be presumably approved soon by the regulatory authorities.
Alizadeh, Moein [Department of Radiation Oncology, Centre Hospitalier de l' Universite de Montreal, Montreal, Quebec (Canada); Sylvestre, Marie-Pierre [Research Center, Department of Statistics, University of Montreal, Montreal, Quebec (Canada); Zilli, Thomas; Van Nguyen, Thu; Guay, Jean-Pierre; Bahary, Jean-Paul [Department of Radiation Oncology, Centre Hospitalier de l' Universite de Montreal, Montreal, Quebec (Canada); Taussky, Daniel, E-mail: email@example.com [Department of Radiation Oncology, Centre Hospitalier de l' Universite de Montreal, Montreal, Quebec (Canada)
Purpose: Statins and anticoagulants (ACs) have both been associated with a less-aggressive prostate cancer (PCa) and a better outcome after treatment of localized PCa. The results of these studies might have been confounded because patients might often take both medications. We examined their respective influence on PCa aggressiveness at initial diagnosis. Materials and Methods: We analyzed 381 patients treated with either external beam radiotherapy or brachytherapy for low-risk (n = 152), intermediate-risk (n = 142), or high-risk (n = 87) localized PCa. Univariate and multivariate logistic regression analyses were used to investigate an association between these drug classes and prostate cancer aggressiveness. We tested whether the concomitant use of statins and ACs had a different effect than that of either AC or statin use alone. Results: Of the 381 patients, 172 (45.1%) were taking statins and 141 (37.0%) ACs; 105 patients (27.6%) used both. On univariate analysis, the statin and AC users were associated with the prostate-specific antigen (PSA) level (p = .017) and National Comprehensive Cancer Network risk group (p = .0022). On multivariate analysis, statin use was associated with a PSA level <10 ng/mL (odds ratio, 2.9; 95% confidence interval, 1.3-6.8; p = .012) and a PSA level >20 ng/mL (odds ratio, 0.29; 95% confidence interval, 0.08-0.83; p = .03). The use of ACs was associated with a PSA level >20 ng/mL (odds ratio, 0.13; 95% confidence interval, 0.02-0.59, p = .02). Conclusion: Both AC and statins have an effect on PCa aggressiveness, with statins having a more stringent relationship with the PSA level, highlighting the importance of considering statin use in studies of PCa aggressiveness.
Pomin, Vitor H.; Mourão, Paulo A. S.
Based on considered achievements of the last 25 years, specific combinations of sulfation patterns and glycosylation types have been proved to be key structural players for the anticoagulant activity of certain marine glycans. These conclusions were obtained from comparative and systematic analyses on the structure-anticoagulation relationships of chemically well-defined sulfated polysaccharides of marine invertebrates and red algae. These sulfated polysaccharides are known as sulfated fucans (SFs), sulfated galactans (SGs) and glycosaminoglycans (GAGs). The structural combinations necessary for the anticoagulant activities are the 2-sulfation in α-L-SGs, the 2,4-di-sulfation in α-L-fucopyranosyl units found as composing units of certain sea-urchin and sea-cucumber linear SFs, or as branching units of the fucosylated chondroitin sulfate, a unique GAG from sea-cucumbers. Another unique GAG type from marine organisms is the dermatan sulfate isolated from ascidians. The high levels of 4-sulfation at the galactosamine units combined with certain levels of 2-sulfation at the iduronic acid units is the anticoagulant structural requirements of these GAGs. When the backbones of red algal SGs are homogeneous, the anticoagulation is proportionally dependent of their sulfation content. Finally, 4-sulfation was observed to be the structural motif required to enhance the inhibition of thrombin via heparin cofactor-II by invertebrate SFs. PMID:24639954
Full Text Available The use of non-vitamin K antagonist oral anticoagulants (NOACs has become a breakthrough in anticoagulant treatment and it is expected to rise significantly in upcoming years. The use of conventional anticoagulants have several limitations: subcutaneous administration of heparin, or close monitoring of INR during application of vitamin K antagonists. In the last decade, target-specific oral anticoagulants (TSOAC including dabigatran, rivaroxaban, apixaban, edoxaban have been marketed for prophylaxis and treatment. Therefore, it is crucial to understand the potential uses, side effects, and management of these agents in routine practice. NOACs have major pharmacologic advantages, including a rapid onset and offset of action, fewer drug interactions than conventional anticoagulants, and predictable pharmacokinetics. These agents are gaining popularity among both physicians and patients because of their easiness of administration and the eliminating the requirement for regular coagulation monitoring. In this review, we focus on discussing practical recommendations for the use of NOACs and the risks and benefits of incorporating them into routine practice.
Levi, M; Eerenberg, E; Kamphuisen, P W
The most important adverse effect of antithrombotic treatment is the occurrence of bleeding. In the case of severe bleeding in a patient who uses anticoagulant agents or when a patient on anticoagulants needs to undergo an urgent invasive procedure, it may be useful to reverse anticoagulant treatment. Conventional anticoagulants such as vitamin K antagonists may be neutralized by administration of vitamin K or prothrombin complex concentrates, whereas heparin and heparin derivatives can be counteracted by protamine sulphate. The anti-hemostatic effect of aspirin and other antiplatelet strategies can be corrected by the administration of platelet concentrate and/or desmopressin, if needed. Recently, a new generation of anticoagulants with a greater specificity towards activated coagulation factors as well as new antiplatelet agents have been introduced and these drugs show promising results in clinical studies. A limitation of these new agents may be the lack of an appropriate strategy to reverse the effect if a bleeding event occurs, although experimental studies show hopeful results for some of these agents.
Full Text Available Physiological hemostatic balance is a coordinated outcome of counteracting coagulation and fibrinolytic systems. An imbalance of procoagulant and anticoagulant factors may result in life threatening thromboembolism. Presently, anticoagulant administration is the first line of therapy for the treatment of these conditions and several anticoagulants have been approved, including various forms of heparin. However, the polyanionic nature and multispecificity of heparin pose several complications. Generally, the polysulfated compounds with antithrombotic potential are thought to have feasible synthetic procedures with much less bleeding, thus having favourable safety profiles. Here we report the synthesis of a novel compound, trehalose octasulfate and the assessment of its anticoagulation potential. Molecular docking of trehalose and trehalose octasulfate with antithrombin showed a specificity switch in binding affinity on sulfation, where trehalose octasulfate interacts with critical residues of AT that are either directly involved in heparin binding or in the conformational rearrangement of AT on heparin binding. An in vitro analysis of trehalose octasulfate demonstrated prolonged clotting time. Lead compound when intravenously injected in occlusion induced thrombotic rats showed remarkable reduction in the size and weight of the clot at a low dose. Delay in coagulation time was observed by analysing blood plasma isolated from rats preinjected with trehalose octasulfate. A decrease in Adenosine 5′-Diphosphate (ADP induced platelet aggregation indicated a probable dual anticoagulant and antiplatelet mechanism of action. To summarize, this study presents trehalose octasulfate as a novel, effective, dual acting antithrombotic agent.
Smythe, Maureen A; Priziola, Jennifer; Dobesh, Paul P; Wirth, Diane; Cuker, Adam; Wittkowsky, Ann K
Venous thromboembolism (VTE) is a serious and often fatal medical condition with an increasing incidence. Despite the changing landscape of VTE treatment with the introduction of the new direct oral anticoagulants many uncertainties remain regarding the optimal use of traditional parenteral agents. This manuscript, initiated by the Anticoagulation Forum, provides clinical guidance based on existing guidelines and consensus expert opinion where guidelines are lacking. This specific chapter addresses the practical management of heparins including low molecular weight heparins and fondaparinux. For each anticoagulant a list of the most common practice related questions were created. Each question was addressed using a brief focused literature review followed by a multidisciplinary consensus guidance recommendation. Issues addressed included initial anticoagulant dosing recommendations, recommended baseline laboratory monitoring, managing dose adjustments, evidence to support a relationship between laboratory tests and meaningful clinical outcomes, special patient populations including extremes of weight and renal impairment, duration of necessary parenteral therapy during the transition to oral therapy, candidates for outpatient treatment where appropriate and management of over-anticoagulation and adverse effects including bleeding and heparin induced thrombocytopenia. This article concludes with a concise table of clinical management questions and guidance recommendations to provide a quick reference for the practical management of heparin, low molecular weight heparin and fondaparinux.
Abdou, John K; Auyeung, Vivian; Patel, Jignesh P; Arya, Roopen
Adherence to medication, commonly reported as being 50% in chronic diseases, is of great concern in healthcare. Medication non-adherence is particularly apparent in chronic diseases, where treatment is often preventative and may provide little or no symptomatic relief or feedback for the patient. A lot of research has been undertaken to describe the extent of non-adherence to long-term anticoagulation therapy, particularly with vitamin K antagonists and more recently with direct oral anticoagulants. However, the literature is scarce with respect to describing adherence to anticoagulation in terms of the behavioural aspects that influence medicine use. Utilizing the COM-B (capability, opportunity, motivation and behaviour) psychological model of non-adherence, we present the available evidence, not only in terms of describing the extent of the non-adherence problem, but also describing why patients do not adhere, offering theory-driven and evidence-based solutions to improve long-term adherence to chronic anticoagulation therapy. Lessons learned are not only applicable within the field of anticoagulation but throughout haematology.
Lisa M. Baumann Kreuziger
Full Text Available Ease of dosing and simplicity of monitoring make new oral anticoagulants an attractive therapy in a growing range of clinical conditions. However, newer oral anticoagulants interact with the coagulation cascade in different ways than traditional warfarin therapy. Replacement of clotting factors will not reverse the effects of dabigatran, rivaroxaban, or apixaban. Currently, antidotes for these drugs are not widely available. Fortunately, withholding the anticoagulant and dialysis are freqnently effective treatments, particularly with rivaroxaban and dabigatran. Emergent bleeding, however, requires utilization of Prothrombin Complex Concentrates (PCCs. PCCs, in addition to recombinant factor VIIa, are used to activate the clotting system to reverse the effects of the new oral anticoagulants. In cases of refractory or emergent bleeding, the recommended factor concentrate in our protocols differs between the new oral anticoagulants. In patients taking dabigatran, we administer an activated PCC (aPCC [FELBA] due to reported benefit in human in vitro studies. Based on human clinical trial evidence, the 4-factor PCC (Kcentra is suggested for patients with refractory rivaroxaban- or apixaban-associated hemorrhage. If bleeding continues, recombinant factor VIIa may be employed. With all of these new procoagulant agents, the risk of thrombosis associated with administration of factor concentrates must be weighed against the relative risk of hemorrhage.
Full Text Available Jeffrey Steven Habert Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada Abstract: Many primary care physicians are wary about using direct oral anticoagulants (DOACs in patients with nonvalvular atrial fibrillation (AF. Factors such as comorbidities, concomitant medications, and alcohol misuse increase concerns over bleeding risk, especially in elderly and frail patients with AF. This article discusses strategies to minimize the risk of major bleeding events in patients with AF who may benefit from oral anticoagulant therapy for stroke prevention. The potential benefits of the DOACs compared with vitamin K antagonists, in terms of a lower risk of intracranial hemorrhage, are discussed, together with the identification of reversible risk factors for bleeding and correct dose selection of the DOACs based on a patient’s characteristics and concomitant medications. Current bleeding management strategies, including the new reversal agents for the DOACs and the prevention of bleeding during preoperative anticoagulation treatment, in addition to health care resource use associated with anticoagulation treatment and bleeding, are also discussed. Implementing a structured approach at an individual patient level will minimize the overall risk of bleeding and should increase physician confidence in using the DOACs for stroke prevention in their patients with nonvalvular AF. Keywords: anticoagulants, atrial fibrillation, bleeding, primary care
Romero Guardeño, Araceli; Pérez Lucena, Dolores Amalia
A significant increase during recent years in the number of patients who need Oral Anticoagulant Treatment has meant a greater role for nurses, especially in Primary Health Care Centers, since nurses, along with doctors, are the professionals responsible for treating those patients. This control is carried out by measuring the levels of anticoagulants in the blood, regulating the anticoagulant medicine doses, and providing patients with the essential health education so patients participate in the treatment of their illness. To a large degree, the preponderance of Primary Health Care Centers in the aforementioned control has developed hand-in-hand with the availability of portable, simple and low cost coagulation measuring systems which permit a direct reading of a patient's anticoagulation level with one drop of capillary blood. The objective of this article is introduce the reader to a measuring system appropriate for outpatient clinic control of anticoagulant levels in blood by mans of the CoaguChek XS System, which is described. The authors specify the sample extraction procedure, how to measure coagulant levels, and recommendations to keep in mind while carrying out this procedure. The authors sketch the importance of health education and finally, they describe some advantages and inconveniences this system has.
Cortez-Dias, Nuno; Correia, Maria José; Coutinho, Ana; Fernandes, Catarina; Diogo, A Nunes; Lopes, Mário G
Inter- and intra-individual variability of response to warfarin means that its anticoagulant effect must be monitored, given the risk of thromboembolic complications and bleeding. This variability is influenced by gender, age, body mass index, smoking, diet, comorbid conditions, drug interactions and genetic factors. Pharmacogenetics refers to the study of genetic background to predict drug response, effectiveness and risk of adverse effects in a given patient. The authors illustrate its relevance in two case reports. A 40-year-old woman admitted for massive pulmonary thromboembolism underwent anticoagulant and fibrinolytic therapy, following which warfarin was needed in unusually high doses to achieve effective anticoagulation. The genetic variants c.430CC and c.1075AA of the CYP2C9 gene were identified, predisposing to rapid warfarin metabolism, as well as the c.-1639GG variant of the VKORC1 gene, associated with low sensitivity to the drug. Together, these variants give high resistance to warfarin. In the second case, a 76-year-old man with permanent atrial fibrillation developed excessive prolongation of prothrombin time after being treated with 5 mg/day warfarin for 5 days. The genetic variants c.430CC and c.1075AC of the CYP2C9 gene and 1639AA of the VKORC1 gene were identified. Together, these polymorphisms confer high sensitivity to warfarin, necessitating smaller doses to maintain therapeutic anticoagulation levels. The authors review the relevance of the study of genetic polymorphisms related to anticoagulant therapy and discuss its potential usefulness in clinical practice.
Full Text Available In order to search for sulfated polysaccharides in different invertebrate connective tissues and to examine their biological activities, we have isolated three types of polysaccharides from the body wall of the three sea cucumbers Holothuria edulis, Apostichopus japonicas and Holothuria nobilis. The physicochemical properties and anticoagulant activities of these polysaccharides were examined and compared. The chemical composition analysis and nuclear magnetic resonance (NMR analysis indicate that two types of polysaccharides, sulfated fucan and fucosylated chondroitin sulfate (FuCS, were found in all of the three species and in addition a neutral glycan was observed in H. edulis. The neutral α-glucan was firstly obtained from sea cucumber. The same type of polysaccharides from different species of sea cucumbers have similar physicochemical properties and anticoagulant activities, but those of different types of glycans are significantly different, possibly due to their different monosaccharide compositions, electric charges and average molecular weights. The FuCSs have stronger anticoagulant activities than the sulfated fucans, although the molecular sizes of the FuCSs are lower than those of the sulfated fucans, whereas the neutral glucan has no activity, as expected from the absence of sulfate. Thus, anticoagulant activities of the different type of polysaccharides are likely to relate to monosaccharide composition and sulfate content. Preliminary analysis suggests that the sulfation patterns of the FuCSs may result in the difference in anticoagulant activities. Our data could help elucidate the structure-activity relationship of the sea cucumber polysaccharides.
Vitor Hugo Pomin
Full Text Available Based on considered achievements of the last 25 years, specific combinations of sulfation patterns and glycosylation types have been proved to be key structural players for the anticoagulant activity of certain marine glycans. These conclusions were obtained from comparative and systematic analyses on the structure-anticoagulation relationships of chemically well-defined sulfated polysaccharides of marine invertebrates and red algae. These sulfated polysaccharides are known as sulfated fucans (SFs, sulfated galactans (SGs and glycosaminoglycans (GAGs. The structural combinations necessary for the anticoagulant activities are the 2-sulfation in α-L-SGs, the 2,4-di-sulfation in α-L-fucopyranosyl units found as composing units of certain sea-urchin and sea-cucumber linear SFs, or as branching units of the fucosylated chondroitin sulfate, a unique GAG from sea-cucumbers. Another unique GAG type from marine organisms is the dermatan sulfate isolated from ascidians. The high levels of 4-sulfation at the galactosamine units combined with certain levels of 2-sulfation at the iduronic acid units is the anticoagulant structural requirements of these GAGs. When the backbones of red algal SGs are homogeneous, the anticoagulation is proportionally dependent of their sulfation content. Finally, 4-sulfation was observed to be the structural motif required to enhance the inhibition of thrombin via heparin cofactor-II by invertebrate SFs.
Pomin, Vitor H; Mourão, Paulo A S
Based on considered achievements of the last 25 years, specific combinations of sulfation patterns and glycosylation types have been proved to be key structural players for the anticoagulant activity of certain marine glycans. These conclusions were obtained from comparative and systematic analyses on the structure-anticoagulation relationships of chemically well-defined sulfated polysaccharides of marine invertebrates and red algae. These sulfated polysaccharides are known as sulfated fucans (SFs), sulfated galactans (SGs) and glycosaminoglycans (GAGs). The structural combinations necessary for the anticoagulant activities are the 2-sulfation in α-L-SGs, the 2,4-di-sulfation in α-L-fucopyranosyl units found as composing units of certain sea-urchin and sea-cucumber linear SFs, or as branching units of the fucosylated chondroitin sulfate, a unique GAG from sea-cucumbers. Another unique GAG type from marine organisms is the dermatan sulfate isolated from ascidians. The high levels of 4-sulfation at the galactosamine units combined with certain levels of 2-sulfation at the iduronic acid units is the anticoagulant structural requirements of these GAGs. When the backbones of red algal SGs are homogeneous, the anticoagulation is proportionally dependent of their sulfation content. Finally, 4-sulfation was observed to be the structural motif required to enhance the inhibition of thrombin via heparin cofactor-II by invertebrate SFs.
Luo, Lan; Wu, Mingyi; Xu, Li; Lian, Wu; Xiang, Jingying; Lu, Feng; Gao, Na; Xiao, Chuang; Wang, Shengmin; Zhao, Jinhua
In order to search for sulfated polysaccharides in different invertebrate connective tissues and to examine their biological activities, we have isolated three types of polysaccharides from the body wall of the three sea cucumbers Holothuria edulis, Apostichopus japonicas and Holothuria nobilis. The physicochemical properties and anticoagulant activities of these polysaccharides were examined and compared. The chemical composition analysis and nuclear magnetic resonance (NMR) analysis indicate that two types of polysaccharides, sulfated fucan and fucosylated chondroitin sulfate (FuCS), were found in all of the three species and in addition a neutral glycan was observed in H. edulis. The neutral α-glucan was firstly obtained from sea cucumber. The same type of polysaccharides from different species of sea cucumbers have similar physicochemical properties and anticoagulant activities, but those of different types of glycans are significantly different, possibly due to their different monosaccharide compositions, electric charges and average molecular weights. The FuCSs have stronger anticoagulant activities than the sulfated fucans, although the molecular sizes of the FuCSs are lower than those of the sulfated fucans, whereas the neutral glucan has no activity, as expected from the absence of sulfate. Thus, anticoagulant activities of the different type of polysaccharides are likely to relate to monosaccharide composition and sulfate content. Preliminary analysis suggests that the sulfation patterns of the FuCSs may result in the difference in anticoagulant activities. Our data could help elucidate the structure-activity relationship of the sea cucumber polysaccharides.
Full Text Available In pharmaceutical organizations, validation is a fundamental segment that supports a company commitment to quality assurance. Validation is a tool of quality assurance which provides confirmation of the quality in equipment systems, manufacturing processes, software and testing methods. Validation assures that products with pre-determined quality characteristics and attributes can be reproduced consistently/reproducibly within the established limits of the manufacturing process operation at the manufacturing site. Validation of the individual steps of the manufacturing processes is called the process validation. Different dosage forms have different validation protocols. Here this article concentrates on the process validation of tablet dosage form, protocol preparation and regulatory basis for process validation in industry. It gives in detail the validation of each step of the manufacturing process of tablets through wet granulation.
Larsson, Jan; Meller, Victoria H
Over the past 100 years Drosophila has been developed into an outstanding model system for the study of evolutionary processes. A fascinating aspect of evolution is the differentiation of sex chromosomes. Organisms with highly differentiated sex chromosomes, such as the mammalian X and Y, must compensate for the imbalance in gene dosage that this creates. The need to adjust the expression of sex-linked genes is a potent force driving the rise of regulatory mechanisms that act on an entire chromosome. This review will contrast the process of dosage compensation in Drosophila with the divergent strategies adopted by other model organisms. While the machinery of sex chromosome compensation is different in each instance, all share the ability to direct chromatin modifications to an entire chromosome. This review will also explore the idea that chromosome-targeting systems are sometimes adapted for other purposes. This appears the likely source of a chromosome-wide targeting system displayed by the Drosophila fourth chromosome.
Full Text Available A simple and sensitive spectrophotometric method has been developed for determination of azithromycin in its pharmaceutical dosage forms. In the proposed method, azithromycin is oxidized with potassium permanganate to liberate formaldehyde, which is determined in situ using acetyl acetone, in the presence of ammonium acetate. A yellow coloured chromogen was obtained, having an absorption maxima at 412 nm. The method is found to be linear in the concentration range of 10-75 µg/ml, with regression coefficient of 0.9978. Various reaction parameters such as concentration of potassium permanganate and reagent, time required for oxidation, and maximum colour intensity were optimized. The method was validated, and can be used successfully to assay azithromycin in its pharmaceutical dosage forms viz. tablets, capsules, and injections.
Disteche, Christine M
Males are XY and females are XX in most mammalian species. Other species such as birds have a different sex chromosome make-up: ZZ in males and ZW in females. In both types of organisms one of the sex chromosomes, Y or W, has degenerated due to lack of recombination with its respective homolog X or Z. Since autosomes are present in two copies in diploid organisms the heterogametic sex has become a natural "aneuploid" with haploinsufficiency for X- or Z-linked genes. Specific mechanisms have evolved to restore a balance between critical gene products throughout the genome and between males and females. Some of these mechanisms were co-opted from and/or added to compensatory processes that alleviate autosomal aneuploidy. Surprisingly, several modes of dosage compensation have evolved. In this review we will consider the evidence for dosage compensation and the molecular mechanisms implicated.
Vogt, M; Derendorf, H; Krämer, J; Junginger, H E; Midha, K K; Shah, V P; Stavchansky, S; Dressman, J B; Barends, D M
Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing prednisone are reviewed. Due to insufficient data prednisone cannot be definitively classified according to the current Biopharmaceutics Classification System (BCS) criteria as both the solubility and the permeability of prednisone are on the borderline of the present criteria of BCS Class I. Prednisone's therapeutic indications and therapeutic index, pharmacokinetics and the possibility of excipient interactions were also taken into consideration. Available evidence indicates that a biowaiver for IR solid oral dosage forms formulated with the excipients tabulated in this article would be unlikely to expose patients to undue risks.
Full Text Available Nateglinide (NTG is available as tablet dosage form in 60 mg and 120 mg strength. In the present study, two simple, reproducible and efficient UV spectrophotometric methods for the estimation of this drug in bulk and pharmaceutical dosage forms have been developed. In method I, methanol-AR was used as solvent, while in method II, Methanol-AR + 10% V/V 3N NaOH was used as reference solvent. In method I, nateglinide shows λmax at 216 nm, which is then shifted to 225.4 nm on increasing the basicity of the reference solvent in method II. The linearity for nateglinide was observed to be statistically in the range of 10-100 μg/ml in method I and 100-1000 μg/ml in method II. Both the methods were validated using ANOVA. The recovery studies confirmed the accuracy of the proposed methods.
Huang, Haiyu; Zhao, Peisen; Chen, Pai-Yen; Ren, Yong; Liu, Xuewu; Ferrari, Mauro; Hu, Ye; Akinwande, Deji
Miniaturized helix antennas are integrated with drug reservoirs to function as RFID wireless tag sensors for real-time drug dosage monitoring. The general design procedure of this type of biomedical antenna sensors is proposed based on electromagnetic theory and finite element simulation. A cost effective fabrication process is utilized to encapsulate the antenna sensor within a biocompatible package layer using PDMS material, and at the same time form a drug storage or drug delivery unit inside the sensor. The in vitro experiment on two prototypes of antenna sensor-drug reservoir assembly have shown the ability to monitor the drug dosage by tracking antenna resonant frequency shift from 2.4-2.5-GHz ISM band with realized sensitivity of 1.27 [Formula: see text] for transdermal drug delivery monitoring and 2.76-[Formula: see text] sensitivity for implanted drug delivery monitoring.
Isabelle M Henry
Full Text Available Aneuploidy, the relative excess or deficiency of specific chromosome types, results in gene dosage imbalance. Plants can produce viable and fertile aneuploid individuals, while most animal aneuploids are inviable or developmentally abnormal. The swarms of aneuploid progeny produced by Arabidopsis triploids constitute an excellent model to investigate the mechanisms governing dosage sensitivity and aneuploid syndromes. Indeed, genotype alters the frequency of aneuploid types within these swarms. Recombinant inbred lines that were derived from a triploid hybrid segregated into diploid and tetraploid individuals. In these recombinant inbred lines, a single locus, which we call SENSITIVE TO DOSAGE IMBALANCE (SDI, exhibited segregation distortion in the tetraploid subpopulation only. Recent progress in quantitative genotyping now allows molecular karyotyping and genetic analysis of aneuploid populations. In this study, we investigated the causes of the ploidy-specific distortion at SDI. Allele frequency was distorted in the aneuploid swarms produced by the triploid hybrid. We developed a simple quantitative measure for aneuploidy lethality and using this measure demonstrated that distortion was greatest in the aneuploids facing the strongest viability selection. When triploids were crossed to euploids, the progeny, which lack severe aneuploids, exhibited no distortion at SDI. Genetic characterization of SDI in the aneuploid swarm identified a mechanism governing aneuploid survival, perhaps by buffering the effects of dosage imbalance. As such, SDI could increase the likelihood of retaining genomic rearrangements such as segmental duplications. Additionally, in species where triploids are fertile, aneuploid survival would facilitate gene flow between diploid and tetraploid populations via a triploid bridge and prevent polyploid speciation. Our results demonstrate that positional cloning of loci affecting traits in populations containing ploidy and
Vogt, M.; Derendorf, H; Krämer, J.; Junginger, H E; Midha, K.K.; Shah, V. P.; Stavchansky, S; Dressman, J B; Barends, D M
Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing prednisolone are reviewed. Data on its solubility, oral absorption, and permeability are not totally conclusive, but strongly suggest a BCS Class 1 classification. Prednisolone's therapeutic indications and therapeutic index, pharmacokinetics, and the possibility of excipient interactions were also taken into considerat...
Jantratid, E; Prakongpan, S.; Dressman, J B; Amidon, G L; Junginger, H E; Midha, K.K.; Barends, D M
Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing cimetidine are reviewed. According to the current Biopharmaceutics Classification System (BCS), cimetidine would be assigned to Class III. Cimetidine's therapeutic use and therapeutic index, its pharmacokinetic properties, data related to the possibility of excipient interactions, and reported BE/bioavailability (BA) pr...
Ka, Sojeong; Ahn, Hyeonju; Seo, Minseok; Kim, Heebal; Kim, Jin Nam; Lee, Hyun-Jeong
Dosage compensation system with X chromosome upregulation and inactivation have evolved to overcome the genetic imbalance between sex chromosomes in both male and female of mammals. Although recent development of chromosome-wide technologies has allowed us to test X upregulation, discrete data processing and analysis methods draw disparate conclusions. A series of expression studies revealed status of dosage compensation in some species belonging to monotremes, marsupials, rodents and primates. However, X upregulation in the Artiodactyla order including cattle have not been studied yet. In this study, we surveyed the genome-wide transcriptional upregulation in X chromosome in cattle RNA-seq data using different gene filtration methods. Overall examination of RNA-seq data revealed that X chromosome in the pituitary gland expressed more genes than in other peripheral tissues, which was consistent with the previous results observed in human and mouse. When analyzed with globally expressed genes, a median X:A expression ratio was 0.94. The ratio of 1-to-1 ortholog genes between chicken and mammals, however, showed considerable reduction to 0.68. These results indicate that status of dosage compensation for cattle is not deviated from those found in rodents and primate, and this is consistent with the evolutionary history of cattle.
Becker, C; Dressman, J B; Junginger, H E; Kopp, S; Midha, K K; Shah, V P; Stavchansky, S; Barends, D M
Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of new multisource and reformulated immediate release (IR) solid oral dosage forms containing rifampicin as the only Active Pharmaceutical Ingredient (API) are reviewed. Rifampicin's solubility and permeability, its therapeutic use and index, pharmacokinetics, excipient interactions and reported BE/bioavailability (BA) problems were taken into consideration. Solubility and absolute BA data indicate that rifampicin is a BCS Class II drug. Of special concern for biowaiving is that many reports of failure of IR solid oral dosage forms of rifampicin to meet BE have been published and the reasons for these failures are yet insufficiently understood. Moreover, no reports were identified in which in vitro dissolution was shown to be predictive of nonequivalence among products. Therefore, a biowaiver based approval of rifampicin containing IR solid oral dosage forms cannot be recommended for either new multisource drug products or for major scale-up and postapproval changes (variations) to existing drug products.
Petruševska, Marija; Berglez, Sandra; Krisch, Igor; Legen, Igor; Megušar, Klara; Peternel, Luka; Abrahamsson, Bertil; Cristofoletti, Rodrigo; Groot, D W; Kopp, Sabine; Langguth, Peter; Mehta, Mehul; Polli, James E; Shah, Vinod P; Dressman, Jennifer
Literature and experimental data relevant for the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing levetiracetam are reviewed. Data on solubility and permeability suggest that levetiracetam belongs to class I of the biopharmaceutical classification system (BCS). Levetiracetam's therapeutic use, its wide therapeutic index, and its favorable pharmacokinetic properties make levetiracetam a valid candidate for the BCS-based biowaiver approach. Further, no BE studies with levetiracetam IR formulations in which the test formulation failed to show BE with the comparator have been reported in the open literature. On the basis of the overall evidence, it appears unlikely that a BCS-based biowaiver approach for levetiracetam IR solid oral dosage forms formulated with established excipients would expose patients to undue risks. Thus, the BCS-based biowaiver approach procedure is recommended for IR solid oral dosage form containing levetiracetam, provided the excipients in the formulation are also present in products that have been approved in countries belonging to or associated with the International Committee on Harmonization and are used in their usual quantities, and provided the dissolution profiles of the test and reference product comply with the current requirements for BCS-based biowaivers.
Becker, C; Dressman, J B; Amidon, G L; Junginger, H E; Kopp, S; Midha, K K; Shah, V P; Stavchansky, S; Barends, D M
Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing pyrazinamide as the only active pharmaceutical ingredient (API) are reviewed. Pyrazinamide is BCS Class III, with linear absorption over a wide dosing range. The risk of bioinequivalence is estimated to be low. Depending on the definition used, pyrazinamide can be classified as a narrow therapeutic index (NTI) drug, which is usually a caveat to biowaiving but may be deemed acceptable if the Summary of Product Characteristics (SmPCs) of the test product stipulates the need for regular monitoring of liver function. It is concluded that a biowaiver can be recommended for IR solid oral dosage only when the test product (a) contains only excipients present in pyrazinamide IR solid oral drug products approved in ICH or associated countries, (b) these excipients are present in amounts normally used in IR solid oral dosage forms, (c) the test product is very rapidly dissolving, (d) the SmPC of the test product indicates the need for monitoring of the patient's liver function.
Malayandi, Rajkumar; Kondamudi, Phani Krishna; Ruby, P K; Aggarwal, Deepika
Colon targeted dosage forms have been extensively studied for the localized treatment of inflammatory bowel disease. These dosage forms not only improve the therapeutic efficacy but also reduce the incidence of adverse drug reactions and hence improve the patient compliance. However, complex and highly variable gastro intestinal physiology limits the clinical success of these dosage forms. Biopharmaceutical characteristics of these dosage forms play a key role in rapid formulation development and ensure the clinical success. The complexity in product development and clinical success of colon targeted dosage forms are based on the biopharmaceutical characteristics such as physicochemical properties of drug substances, pharmaceutical characteristics of dosage form, physiological conditions and pharmacokinetic properties of drug substances as well as drug products. Various in vitro and in vivo techniques have been employed in past to characterize the biopharmaceutical properties of colon targeted dosage forms. This review focuses on the factors influencing the biopharmaceutical performances of the dosage forms, in vitro characterization techniques and in vivo studies.
Full Text Available We present the case of an aphasic 77-year-old stroke patient with left distal M1 occlusion who received rt-PA for thrombolysis while on oral anticoagulant treatment with dabigatran (150 mg b.i.d.. Coagulation parameters were normal (thrombin time 20 s, aPTT 20 s, INR 1.08 and the patient improved from an NIHSS of 15 to 5 within 24 h with sonographic evidence of M1 recanalization. She did not develop intracranial bleeding complications but showed unusually large diffuse skin ecchymoses. In our report, we give an overview of all reported cases of thrombolysis under dabigatran anticoagulation and discuss the questions of medication adherence under novel oral anticoagulants (NOA and the safety of NOA in terms of secondary intracerebral hemorrhage after stroke.
Pottegård, Anton; Meegaard, P. M.; Holck, L. H.;
OBJECTIVES: The objective was to assess whether the concurrent use of tramadol and vitamin K antagonists (VKAs) leads to an increased risk of excessive anticoagulation. DESIGN: The study was designed as a case-control study, nested within users of VKA and with tramadol use as our main exposure. We...... anticoagulation attributable to the use of tramadol. RESULTS: A total of 178 patients were included, 30 of which were exposed to tramadol, along with 2643 controls, 114 of which were exposed to tramadol. The adjusted odds-ratio for experiencing excessive anticoagulation during use of tramadol was 3.1 (1.......9-5.2). This corresponds to, on average, one excess case per 250 treatment years (CI 125-584). The result is potentially confounded by concomitant paracetamol use and the presence of acute illness. CONCLUSION: Caution is advised when using tramadol in patients using VKA, and if possible, an alternative pain...
Lindvall, Peter; Koskinen, Lars-Owe D
Seventy-one patients from northern Sweden were diagnosed with chronic subdural haematomas (CSDH) and treated at the Department of Neurosurgery at Umeå University Hospital over 12 months. Fifty-four patients with CSDH had a history of head trauma (trauma group), while 17 patients had no previous head trauma (non-trauma group). In the non-trauma group 71% of patients were treated with anticoagulants or antiplatelet aggregation agents (AAA) compared to 18% in the trauma group. Considering only AAA, 59% of the non-trauma patients were treated with these drugs versus 17% of patients in the trauma group. The recurrence rate for all patients was 17%. These findings confirm that the use of anticoagulants and AAA is over-represented in patients with non-traumatic CSDH. In our study, recurrence was not associated with previous use of anticoagulants or AAA.
Park, In-Chul; Baek, Yang-Hyun; Han, Sang-Young; Lee, Sung-Wook; Chung, Won-Tae; Lee, Sung-Won; Kang, Sang-Hyeon; Cho, Duk-Song
Warfarin is a widely used anticoagulant. Interindividual differences in drug response, a narrow therapeutic range and the risk of bleeding render warfarin difficult to use clinically. An 18-year-old woman with antiphospholipid syndrome received long-term warfarin therapy for a recurrent deep vein thrombosis. Six years later, she developed right flank pain. We diagnosed intrahepatic and subgaleal hemorrhages secondary to anticoagulation therapy. After stopping oral anticoagulation, a follow-up computed tomography showed improvement in the hemorrhage. After restarting warfarin because of a recurrent thrombosis, the intrahepatic hemorrhage recurred. We decided to start clopidogrel and hydroxychloroquine instead of warfarin. The patient has not developed further recurrent thrombotic or bleeding episodes. Intrahepatic hemorrhage is a very rare complication of warfarin, and our patient experienced intrahepatic and subgaleal hemorrhage although she did not have any risk factors for bleeding or instability of the international normalized ratio control.
Jensen, A S; Idorn, L; Nørager, B; Vejlstrup, N; Sondergaard, L
Adults with congenital heart disease are a growing population. One of the major challenges in the care of these patients is to prevent thromboembolic episodes. Despite relative young age and no typical cardiovascular risk factors, this cohort has a high prevalence of thrombotic events. It is difficult to use treatment algorithms from the general adult population with acquired heart disease in this heterogeneous population due to special conditions such as myocardial scarring after previous surgery, atypical atrial flutter, prothrombotic conditions and the presence of interatrial shunts. Furthermore, there is a lack of scientific evidence regarding how to prevent thromboembolic events with anticoagulation in adults with congenital heart disease. The aim of this paper is to review the current literature pertaining to anticoagulation in adults with congenital heart disease and hence enable recommendations for which patients are likely to benefit from which anticoagulation treatments, when they should be considered and how these would be carried out.
Full Text Available Acute airway compromise due to hemorrhage in of thyroid gland is a rare life-hreating condition. The increasing use of anticoagulants for various reasons is likely increased the occurrence of this this complication. We describe an elderly patient on anticoagulation for atrial fibrillation, which developed swelling on the right side of neck causing acute airway obstruction requiring emergency intubation for airway protection. Computed tomographic scan showed massive intrathyroid hemorrhage along with substernal extension. She had supratherapeutic INR which was appropriately corrected emergently. She underwent resection of the thyroid gland which showed multinodular goiter without any evidence of malignancy. Our case illustrates the rare but lethal bleeding complication of anticoagulants in critical anatomical area and we request physicians should be wary of similar conditions.
Objective: Molluscs are highly delicious seafood and they are also very good source for biomedically imported products. Among the molluscs some have pronounced pharmacological activities or other properties which are useful in biomedical area. Methods: In the present study GAGs was isolated from the bivalve such as Donax incarnates. Results: The isolated GAGs were quantified in crude samples and they were estimated as 6.84 gm/kg crude GAGs in Donax incarnates. The bivalve showed the anticoagulant activity of the crude samples 124.53 USP units/mg in Donax incarnates. FTIR analysis reveals the presence of anticoagulant substance signals at different ranges. Conclusions: The determined in this research show that gastropod Donax incarnates tissue is value medicinal due to high quality of anticoagulant compounds.
Full Text Available Acute cardiac tamponade requires urgent diagnosis andtreatment. We report a case of a 43-year-old man whowas receiving warfarin treatment for 8 months followingmitral valve replacement. The patient had complaint ofdyspnea and fatigue for a few days. Cardiac tamponadewas diagnosed, and the INR at that time was 10.4. Urgentpericardiocentesis were undertaken and 1400 ml of pericardialblood was drained. Following surgery the patient’srecovery was uneventful. An intravenous vitamin K injectionand fresh frozen plasma transfusion were administeredto reverse the patient’s over-anticoagulated state.The final pathology revealed chronic inflammation andthere was no malignancy, and no bacteria or mycobacteriumwere seen. Emergency physicians should rememberthat over-anticoagulation with warfarin may contribute tocertain complications, including hemopericardium, andthat strict control of target INR should be the goal for patientswho require continuous warfarin treatment. J ClinExp Invest 2013; 4 (2: 229-233Key words: Hemopericardium, tamponade, oral anticoagulation,warfarin, echocardiography
Mörsdorf, S; Leipnitz, G; Pindur, G; Schenk, J F; Erdlenbruch, W; Krischek, B; Wenzel, E
In contrast to other European countries, in Germany more than 90% of oral anticoagulated patients are controlled by general practitioners. The International Normalized Ratio (INR) system in laboratory control is not in widespread use, often leading to misinterpretations of prothrombin time (PT) measurements. To improve the management of anticoagulated patients, a model was developed, consisting of different questionnaires and on the base of the INR system. Since 1993, 60 patients in our Department's outpatient anticoagulant clinic and since 1996 16 patients in the office of a general practitioner were followed for 146.32 patient years. There were no thromboembolic events and no major bleedings during follow-up. A total of 126 minor bleedings occurred in 30 patients. There were no significant differences in INR values and stable phases between the two centers; however, significantly shorter stable phases in patients with bleeding episodes were noted. Thus, this model seems to be useful also in general practitioners' hands.
Arnesen, H; Smith, P
To evaluate the effect of PIVKA (Proteins Induced by Vitamin K Absence or Antagonism) on the bleeding tendency during oral anticoagulation, we studied consecutive patients intensively treated with warfarin (INR greater than 4.8). The level of anticoagulation was measured with the PIVKA-insensitive Normotest (NT) as well as with the PIVKA-sensitive Thrombotest (TT), and the results are expressed as per cent coagulant activity. The NT/TT ratio was determined. Twenty patients with bleeding episodes had a mean NT/TT ratio of 2.06 as compared to 2.20 in 143 patients without bleeding episodes (p = 0.08). As the NT/TT ratio was not higher in patients with bleedings, we conclude that PIVKA are of no importance for bleeding during anticoagulation with vitamin K antagonists.
Murray, Maureen; Tseng, Florina
Anticoagulant rodenticides inhibit the activation of vitamin K-ependent clotting factors, resulting in fatal hemorrhage. Nontarget species are exposed to these rodenticides primarily by direct consumption of baits or secondarily by consumption of poisoned prey. The diagnosis of anticoagulant rodenticide toxicosis is more challenging in birds than in mammals because of the limited availability of laboratory tests to evaluate avian coagulation. In addition, the presenting signs in birds may differ from those commonly seen in mammals. Treatment for acute blood loss and therapy with vitamin K1 can result in a favorable outcome in birds. This report describes the presenting signs, diagnosis, and successful treatment of a red-tailed hawk (Buteo jamaicensis) with secondary anticoagulant rodenticide toxicosis.
Han, S K; Lee, B I; Kim, W K
Adequate venous repair is not always possible in fingertip replantation. We have used topical and systemic anticoagulation for fingertip replantation to overcome venous congestion in cases without venous repair or in cases in which there is obstruction of a repaired vein. Our technique consists of continuous external bleeding via a stab incision on the paraungal area and dripping heparinized saline solution at the incision site to maintain external bleeding. From July 1985 to December 1993, 157 fingers in 140 patients with complete amputation of the fingertip were replanted at Korea University Guro Hospital. Of these, 74 fingers in 68 patients were managed by topical and systemic anticoagulation due to the impossibility of repair or obstruction of a repaired vein. The overall survival rate of the fingertip replantations was 76%; that of the topical and systemic anticoagulation group was 64%.
Maas, Angela H E M; Euler, Mia von; Bongers, Marlies Y; Rolden, Herbert J A; Grutters, Janneke P C; Ulrich, Lian; Schenck-Gustafsson, Karin
A growing number of premenopausal women are currently using antithrombotic and/or (dual) antiplatelet therapy for various cardiovascular indications. These may induce or exacerbate abnormal uterine bleeding and more awareness and knowledge among prescribers is required. Heavy and irregular menstrual bleeding is common in women in their forties and may have a variety of underlying causes that require different treatment options. Thus using anticoagulants in premenopausal women demands specific expertise and close collaboration between cardiovascular physicians and gynecologists. In this article we summarize the scope of the problem and provide practical recommendations for the care for young women taking anticoagulants and/or (dual) antiplatelet therapy. We also recommend that more safety data on uterine bleeding with novel anticoagulants in premenopausal women should be obtained.
José Antonio Morales-Molina
Full Text Available Pulmonary arterial hypertension is an infrequent but nevertheless serious life-threatening severe complication of HIV infection. It can be treated with bosentan and oral anticoagulants. Bosentan could induce the acenocoumarol metabolism and it increases the INR values. Until now, no study of interaction between bosentan and oral anticoagulants in HIV patients has reported. So we present a case of this interaction between these drugs and we reviewed MEDLINE to identify all the papers published so far. In our case, several weeks after increasing dose of bosentan acenocoumarol dose had to be progressively increased to 70 mg/week (+33% without obtaining an adequate INR level (2.0-3.0. Forty-nine days later, we achieved a therapeutic INR with 90 mg/week of warfarin. The use of bosentan and oral anticoagulants together in these patients require a closer monitoring during first weeks of treatment, after increasing the bosentan dose and even during longer periods of time.
Nadia Cristine Weinert
Full Text Available Clinical hematology facilitates the diagnosis of disease and can act as a prognostic indicator of pathological conditions in fish. The aim of the present study was to evaluate hematological parameters of Nile tilapia (Oreochromis niloticus subjected to different anesthetics and anticoagulants. Thirty apparently healthy fishes (average weight of 473 ± 35. 50 g and mean total length of 29. 33 ± 0. 37 cm, were selected from the local commercial fish farm in the Lages municipality (Santa Catarina, Brazil. The animals were randomly divided into three groups of 10. In two groups, anesthesia was induced with eugenol (70 mg·L- 1 (EG and Benzocaine hydrochloride (100 mg·L-1 (BG, respectively. Anesthesia was not administered to fish of the third group (CG/control group. Blood samples were obtained by venipuncture of the caudal vessels and placed into microtubes containing sodium heparin or Na2EDTA for further analysis. The results were analyzed by Sigma Stat for Windows, the paired t-test for significant differences between anticoagulants of the same group, and analysis of variance followed by the Tukey test for comparison of means between groups (p ? 0. 05. Most of the observed changes in the erythrogram were significantly higher for the anticoagulant heparin and benzocaine group in comparison to the control group. However, the values obtained for the leukogram were significantly higher for all groups subjected to the Na2EDTA anticoagulant, suggesting that heparin may cause cell clumping. The results suggest that the anesthetics under investigation effectively minimizes the effects of stress caused by handling and invasive procedures, and that the anticoagulant heparin causes less hemolysis in comparison to Na2EDTA for Nile tilapia. Thus, the hematological variations attributed to different anesthetic protocols and/or different anticoagulants should be considered for the species Oreochromis niloticus.
Full Text Available Objectives: Bee venom (BV is a complex mixture of proteins and contains proteins such as phospholipase and melittin, which have an effect on blood clotting and blood clots. The mechanism of action of honey bee venom (HBV, Apis mellifera on human plasma proteins and its anti-thrombotic effect were studied. The purpose of this study was to investigate the anti-coagulation effect of BV and its effects on blood coagulation and purification. Methods: Crude venom obtained from Apis mellifera was selected. The anti-coagulation factor of the crude venom from this species was purified by using gel filtration chromatography (sephadex G-50, and the molecular weights of the anti-coagulants in this venom estimated by using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE. Blood samples were obtained from 10 rabbits, and the prothrombin time (PT and the partial thromboplastin time (PTT tests were conducted. The approximate lethal dose (LD values of BV were determined. Results: Crude BV increased the blood clotting time. For BV concentrations from 1 to 4 mg/mL, clotting was not observed even at more than 300 seconds, standard deviations (SDs = ± 0.71; however, clotting was observed in the control group 13.8 s, SDs = ± 0.52. Thus, BV can be considered as containing anti-coagulation factors. Crude BV is composed 4 protein bands with molecular weights of 3, 15, 20 and 41 kilodalton (kDa, respectively. The LD50 of the crude BV was found to be 177.8 μg/mouse. Conclusion: BV contains anti-coagulation factors. The fraction extracted from the Iranian bees contains proteins that are similar to anti-coagulation proteins, such as phospholipase A2 (PLA2 and melittin, and that can increase the blood clotting times in vitro.
Full Text Available Raj Patel Department of Haematological Medicine, King's Thrombosis Centre, King's College Hospital, London, UK Abstract: Anticoagulation therapy is essential for the effective treatment and secondary prevention of venous thromboembolism (VTE. For many years, anticoagulation for acute VTE was limited to the use of initial parenteral heparin, overlapping with and followed by a vitamin K antagonist. Although highly effective, this regimen has several limitations and is particularly challenging when given in an ambulatory setting. Current treatment pathways for most patients with deep-vein thrombosis typically involve initial hospital or community-based ambulatory care with subsequent follow-up in a secondary care setting. With the introduction of non-vitamin K antagonist oral anticoagulants (NOACs into routine clinical practice, it is now possible for the initial acute management of patients with deep-vein thrombosis to be undertaken by primary care. As hospital admissions associated with VTE become shorter, primary care will play an increasingly important role in the long-term management of these patients. Although the NOACs can potentially simplify patient management and improve clinical outcomes, primary care physicians may be less familiar with these new treatments compared with traditional therapy. To assist primary care physicians in further understanding the role of the NOACs, this article outlines the main differences between NOACs and traditional anticoagulation therapy and discusses the benefit–risk profile of the different NOACs in the treatment and secondary prevention of recurrent VTE. Key considerations for the use of NOACs in the primary care setting are highlighted, including dose transition, risk assessment and follow-up, duration of anticoagulant therapy, how to minimize bleeding risks, and the importance of patient education and counseling. Keywords: venous thromboembolism, oral anticoagulant, prevention, treatment, primary
Gomez-Outes, Antonio; Suarez-Gea, M L; Lecumberri, Ramon; Terleira-Fernandez, Ana I; Vargas-Castrillon, Emilio
In the last decade, several direct oral anticoagulants (DOAC; dabigatran, rivaroxaban, apixaban, edoxaban) have been marketed for prophylaxis and/or treatment of thromboembolism without having specific antidotes available for their reversal. Current management of bleeding associated to DOAC includes the removal of all antithrombotic medications and supportive care. Non-specific procoagulant agents (prothrombin complex concentrates and activated factor VIIa) have been used in case of serious bleeding. Currently, some specific antidotes for the DOAC are under development. Idarucizumab (BI 655075; Boehringer Ingelheim) is a fragment of an antibody (Fab), which is a specific antidote to the oral direct thrombin inhibitor dabigatran. Andexanet alfa (r-Antidote, PRT064445; Portola Pharmaceuticals) is a truncated form of enzymatically inactive factor Xa, which binds and reverses the anticoagulant action of the factor Xa inhibitors (e.g.: rivaroxaban, apixaban and edoxaban). Aripazine (PER-977, ciraparantag; Perosphere Inc.) is a synthetic small molecule (~500 Da) that reverses oral dabigatran, apixaban, rivaroxaban, as well as subcutaneous fondaparinux and LMWH in vivo. These antidotes could provide an alternative for management of life-threatening bleeding events occurring with the above-mentioned anticoagulants. In addition, the specific antidote anivamersen (RB007; Regado Biosciences Inc.) is an RNA aptamer in clinical development to reverse the anticoagulant effect of the parenteral factor IXa inhibitor pegnivacogin, which is also in development. This anticoagulant-antidote pair may provide an alternative in situations in which a fast onset and offset of anticoagulation is needed, like in patients undergoing cardiac surgery with extracorporeal circulation, as an alternative to the heparin/protamine pair. This patent review includes a description of the pharmacological characteristics of the novel specific antidotes, the available results from completed non
Chan, Noel C; Siegal, Deborah; Lauw, Mandy N; Ginsberg, Jeffrey S; Eikelboom, John W; Guyatt, Gordon H; Hirsh, Jack
In the last decade, major advances in venous thromboembolism (VTE) prophylaxis in orthopaedic surgery have included the development of new anticoagulants that are poised to replace low molecular weight heparins (LMWHs) and improvements in operative and perioperative care that have likely led to a decline in the rates of symptomatic VTE and mortality independent of anticoagulant use. A systematic review of the literature was performed to identify phase III randomized controlled trials of VTE prevention that compared new anticoagulants (fondaparinux, rivaroxaban, dabigatran, apixaban) with LMWH (enoxaparin) in major elective orthopaedic surgery. Our aims were to obtain best estimates of the rates of patient important events (symptomatic VTE, mortality, and bleeding) in contemporary trials of VTE prevention, and to consider the implications of these contemporary rates for clinical practice and future research. Fourteen studies, which enrolled 40,285 patients, were included in the analyses. The combined median rates (ranges) for all five anticoagulants for symptomatic VTE and mortality to the end of follow-up were 0.99 % (0.15-2.58 %) and 0.26 % (0-0.92 %) respectively, whereas the median rate (range) of clinically important bleeding was 3.44 % (2.25-7.74 %). In contemporary trials of anticoagulants, the rates of symptomatic VTE and mortality are low, but the rates of clinically important post-operative bleeding remain relatively high. Based on these results, we propose that approaches that minimize bleeding without substantially reducing efficacy merit investigation, particularly if improvement in surgical and perioperative care have also resulted in falling baseline patient important VTE rates independent of anticoagulant use.
Markussen, Mette D K; Heiberg, Ann-Charlotte; Fredholm, Merete;
BACKGROUND: Anticoagulant resistance in Norway rats, Rattus norvegicus (Berk.), has been suggested to be conferred by mutations in the VKORC1 gene, encoding the target protein of anticoagulant rodenticides. Other factors, e.g. pharmacokinetics, may also contribute to resistance, however. To exa...
Markussen, Mette Drude; Heiberg, Ann-Charlotte; Fredholm, Merete;
Anticoagulant resistance in Norway rats (Rattus norvegicus) has been suggested to be due to mutations in the VKORC1 gene, encoding the target protein of anticoagulant rodenticides such as warfarin and bromadiolone. Other factors, e.g. pharmacokinetics, may however also contribute to resistance. W...
Mahmoud, Wafeya; Redfern, R.
The response of Acomys cahirinus to three anticoagulant rodenticides was investigated in the laboratory. In contrast to the other commensal rodents Rattus rattus and R. norvegicus, this species appears to be naturally very resistant to warfarin, difenacoum and brodifacoum. It is considered unlikely that anticoagulant poisons would be effective in the field for the control of A. cahirinus. PMID:7240734
Objective To observe the application of continuous renal replacement therapy(CRRT) and heparin anticoagulation in patients with HFRS, and to explore a more suitable anticoagulant strategy. MethodsEighty-five severe-type patients (severe group) and 71 critical-type patients (critical group) were enrolled in this study. The frequency of CRRT was compared between the two groups; the frequency of CRRT treated with and without heparin anticoagulation and the frequency of hemorrhage and channel blood clotting induced by the two anticoagulant strategies were observed. ResultsThe frequency of CRRT in the critical group was higher than thatin the severe group (P<0.001). The frequency of CRRT initiated during the overlapping phases in the critical group was signiifcantly higher than that of the severe group (P=0.032). The total times of CRRT was 103, and 70 of them were treated with heparin anticoagulation. The frequencies of hemorrhage induced by heparin anticoagulation and no heparinization were 16 and 0, respectively, and the frequencies of channel blood clotting were 2 and 4, respectively. Conclusions CRRT has been used extensively in the critical-type patients with HFRS. The heparin anticoagulation and no anticoagulant strategies should be used more rationally in patients treated with CRRT, according to the clinical characteristics of the disease.
Bublis, V. V.; Zabrodina, L. V.; Platonova, A. T.; Meyerova, Y. A.
The data which have been obtained on the influence of magnetic bracelets on the coagulation and anticoagulation systems of the blood indicate that the wearing of magnetic bracelets results in a decrease in the coagulation activity of the blood and an increase in the activity of the anticoagulation system. These changes must be viewed as favorable for patients with cardiovascular pathology.
Sarah M. Alyousif
Conclusion: Quality of anticoagulation in patients with AF receiving medical care in a tertiary care hospital was suboptimal, with nearly 40% of the time spent outside the therapeutic range. Methods to improve anticoagulation control among patients with AF should be implemented.
Hohwy, Thomas; Jensen, Martin Glümer; Tøttrup, Anders;
and the presence of lupus anticoagulant, but no anti-cardiolipin antibodies. The patient was treated with narrow-band ultraviolet (UV)B, prednisolone and, later, aspirin, pentoxifyllin and warfarin. Despite this very intensive anticoagulant and anti-platelet therapy, the treatment had no effect on the skin lesions...
Christopher John Topping
Full Text Available Anticoagulant rodenticides (AR are a widespread and effective method of rodent control but there is concern about the impact these may have on non-target organisms, in particular secondary poisoning of rodent predators. Incidence and concentration of AR in free-living predators in Denmark is very high. We postulate that this is caused by widespread exposure due to widespread use of AR in Denmark in and around buildings. To investigate this theory a spatio-temporal model of AR use and mammalian predator distribution was created. This model was supported by data from an experimental study of mice as vectors of AR, and was used to evaluate likely impacts of restrictions imposed on AR use in Denmark banning the use of rodenticides for plant protection in woodlands and tree-crops. The model uses input based on frequencies and timings of baiting for rodent control for urban, rural and woodland locations and creates an exposure map based on spatio-temporal modelling of movement of mice-vectored AR (based on Apodemus flavicollis. Simulated predator territories are super-imposed over this exposure map to create an exposure index. Predictions from the model concur with field studies of AR prevalence both before and after the change in AR use. In most cases incidence of exposure to AR is predicted to be greater than 90%, although cessation of use in woodlots and Christmas tree plantations should reduce mean exposure concentrations. Model results suggest that the driver of high AR incidence in non-target small mammal predators is likely to be the pattern of use and not the distance AR is vectored. Reducing baiting frequency by 75% had different effects depending on the landscape simulated, but having a maximum of 12% reduction in exposure incidence, and in one landscape a maximum reduction of <2%. We discuss sources of uncertainty in the model and directions for future development of predictive models for environmental impact assessment of rodenticides. The
James, Robert F; Palys, Viktoras; Lomboy, Jason R; Lamm, J Richard; Simon, Scott D
New anticoagulant and antiplatelet medications have been approved and are prescribed with increased frequency. Intracranial hemorrhage is associated with the use of these medications. Therefore, neurosurgeons need to be aware of these new medications, how they are different from their predecessors, and the strategies for the urgent reversal of their effects. Utilization of intraluminal stents by endovascular neurosurgeons has resulted in the need to have a thorough understanding of antiplatelet agents. Increased use of dabigatran, rivaroxaban, and apixaban as oral anticoagulants for the treatment of atrial fibrillation and acute deep venous thrombosis has increased despite the lack of known antidotes to these medications.
Rentea, Rebecca M.; Fehring, Charles H.
Causes of colonic and recto-sigmoid hematomas are multifactorial. Patients can present with a combination of dropping hemoglobin, bowel obstruction and perforation. Computed tomography imaging can provide clues to a diagnosis of intramural hematoma. We present a case of rectal hematoma and a review of current management literature. A 72-year-old male on therapeutic anticoagulation for a pulmonary embolism, was administered an enema resulting in severe abdominal pain unresponsive to blood transfusion. A sigmoid colectomy with end colostomy was performed. Although rare, colonic and recto-sigmoid hematomas should be considered as a possible diagnosis for adults with abdominal pain on anticoagulant therapy. PMID:28108634
Demet Funda Baş
Full Text Available Atrial fibrillation is an independent, powerful risk factor for stroke. Until recently, acetyl salicylic acid (aspirin and warfarin were the only approved treatment options for stroke prophylaxis. Although warfarin provides a significantly better risk reduction in stroke compared to placebo and aspirin, its usage difficulties entailed investigation of new treatment alternatives. Studies showed that new oral anticoagulants (such as dabigatran, apixaban and rivaroxaban are as efficient and safe as warfarin. New anticoagulants seem appealing by their rapid onset of action and low drug and diet interactions, together with not necessitating any routine monitoring; however lack of specific antidotes constitute a disadvantage at the moment.
Full Text Available A group of oral anticoagulant-treated patients affected by permanent atrial fibrillation was evaluated after their access to the emergency room as a result of a traumatic accident. In these patients, the re-evaluation of their risk of thromboembolism and bleeding was performed together with the evaluation of their risk of falling and institutionalization. Results show that the emergency department identifies a cohort of very elderly frail patients, who should be carefully reconsidered for anticoagulant therapy after a traumatic event.
Wang, Xiaomei; Zhang, Zhongshan; Yao, Zhiyun; Zhao, Mingxing; Qi, Huimin
Sulfated polysaccharides exerted potent biological property which was relative to degree of sulfation, molecular weight, substitution position and chain conformation. In present study, the polysaccharide with low molecular weight (LEP) from Enteromorpha linza was sulfated with chlorosulfuric acid in formamide. The obtained polysaccharide sulfate was selected to evaluate their antioxidant activities and the anticoagulant activity in the coagulation assays, activated partial thromboplastin time (APTT), thrombin time (TT) and prothrombin time (PT). The data obtained in vitro models indicated that high DS and moderate Mw showed the best anticoagulant and antioxidant activities.
Arihiro, Shoji; Todo, Kenichi; Yamagami, Hiroshi; Kimura, Kazumi; Furui, Eisuke; Terasaki, Tadashi; Shiokawa, Yoshiaki; Kamiyama, Kenji; Takizawa, Shunya; Okuda, Satoshi; Okada, Yasushi; Kameda, Tomoaki; Nagakane, Yoshinari; Hasegawa, Yasuhiro; Mochizuki, Hiroshi; Ito, Yasuhiro; Nakashima, Takahiro; Takamatsu, Kazuhiro; Nishiyama, Kazutoshi; Kario, Kazuomi; Sato, Shoichiro; Koga, Masatoshi; Nagatsuka, K; Minematsu, K; Nakagawara, J; Akiyama, H; Shibazaki, K; Maeda, K; Shibuya, S; Yoshimura, S; Endo, K; Miyagi, T; Osaki, M; Kobayashi, J; Okata, T; Tanaka, E; Sakamoto, Y; Takizawa, H; Takasugi, J; Tokunaga, K; Homma, K; Kinoshita, N; Matsuki, T; Higashida, K; Shiozawa, M; Kanai, H; Uehara, S
Background Large clinical trials are lack of data on non‐vitamin K antagonist oral anticoagulants for acute stroke patients. Aim To evaluate the choice of oral anticoagulants at acute hospital discharge in stroke patients with nonvalvular atrial fibrillation and clarify the underlying characteristics potentially affecting that choice using the multicenter Stroke Acute Management with Urgent Risk‐factor Assessment and Improvement‐NVAF registry (ClinicalTrials.gov NCT01581502). Method The study included 1192 acute ischemic stroke/transient ischemic attack patients with nonvalvular atrial fibrillation (527 women, 77·7 ± 9·9 years old) between September 2011 and March 2014, during which three nonvitamin K antagonist oral anticoagulant oral anticoagulants were approved for clinical use. Oral anticoagulant choice at hospital discharge (median 23‐day stay) was assessed. Results Warfarin was chosen for 650 patients, dabigatran for 203, rivaroxaban for 238, and apixaban for 25. Over the three 10‐month observation periods, patients taking warfarin gradually decreased to 46·5% and those taking nonvitamin K antagonist oral anticoagulants increased to 48·0%. As compared with warfarin users, patients taking nonvitamin K antagonist oral anticoagulants included more men, were younger, more frequently had small infarcts, and had lower scores for poststroke CHADS 2, CHA 2 DS 2‐VASc, and HAS‐BLED, admission National Institutes of Health stroke scale, and discharge modified Rankin Scale. Nonvitamin K antagonist oral anticoagulants were started at a median of four‐days after stroke onset without early intracranial hemorrhage. Patients starting nonvitamin K antagonist oral anticoagulants earlier had smaller infarcts and lower scores for the admission National Institutes of Health stroke scale and the discharge modified Rankin Scale than those starting later. Choice of nonvitamin K antagonist oral anticoagulants was independently associated with 20‐day or
Full Text Available Mohit K Turagam, Poonam Velagapudi, Greg C FlakerDivision of Cardiovascular Medicine, University of Missouri School of Medicine, Columbia, MO, USAAbstract: Stroke prevention in elderly atrial fibrillation patients remains a challenge. There is a high risk of stroke and systemic thromboembolism but also a high risk of bleeding if anticoagulants are prescribed. The elderly have increased chronic kidney disease, coronary artery disease, polypharmacy, and overall frailty. For all these reasons, anticoagulant use is underutilized in the elderly. In this manuscript, the benefits of non-vitamin K antagonist oral anticoagulants compared with warfarin in the elderly patient population with multiple comorbid conditions are reviewed.Keywords: non-vitamin K antagonist oral anticoagulants, novel oral anticoagulants, warfarin, dabigatran, rivaroxaban, apixaban, edoxaban
Robert, A; Eschwège, V; Hameg, H; Drouet, L; Aillaud, M F
As specific assays used to identify defects in the protein C (PC) anticoagulant pathway are laborious and expensive, we describe here a global test to screen for these defects. This assay is expressed as the ratio of two activated partial thromboplastin times, one in the absence and one in the presence of 0,125 U/ml of the PC activator of Agkistrodon contortrix venom (ACV). Eight of the 168 healthy volunteers of the control group exhibited an ACV ratio below the lower normal limit of 3.37 [6 subjects with the mutation Arg 506 to Gln in their factor V gene (FV R506Q) and one with PS deficiency]. 128 patients who have had at least one episode of deep-vein thrombosis were retrospectively studied. All patients carrying FV Q506R (n = 48), PC deficiency (n = 14) or combined defects, i.e. FV Q506R and PC deficiency (n = 4) or FV Q506R and PS deficiency (n = 3), had ACV ratios ACV ratios which overlapped normal range. ACV ratios of one out of seven patients with antithrombin deficiency, and 10% of patients without identified defect in the PC anticoagulant pathway (n = 30) were ACV ratio raised to 3.70 could lead to a test identifying all patients with a defect in the PC anticoagulant pathway.
Full Text Available As a result of sex chromosome differentiation from ancestral autosomes, male mammalian cells only contain one X chromosome. It has long been hypothesized that X-linked gene expression levels have become doubled in males to restore the original transcriptional output, and that the resulting X overexpression in females then drove the evolution of X inactivation (XCI. However, this model has never been directly tested and patterns and mechanisms of dosage compensation across different mammals and birds generally remain little understood. Here we trace the evolution of dosage compensation using extensive transcriptome data from males and females representing all major mammalian lineages and birds. Our analyses suggest that the X has become globally upregulated in marsupials, whereas we do not detect a global upregulation of this chromosome in placental mammals. However, we find that a subset of autosomal genes interacting with X-linked genes have become downregulated in placentals upon the emergence of sex chromosomes. Thus, different driving forces may underlie the evolution of XCI and the highly efficient equilibration of X expression levels between the sexes observed for both of these lineages. In the egg-laying monotremes and birds, which have partially homologous sex chromosome systems, partial upregulation of the X (Z in birds evolved but is largely restricted to the heterogametic sex, which provides an explanation for the partially sex-biased X (Z expression and lack of global inactivation mechanisms in these lineages. Our findings suggest that dosage reductions imposed by sex chromosome differentiation events in amniotes were resolved in strikingly different ways.
Full Text Available How allopolyploids are able not only to cope but profit from their condition is a question that remains elusive, but is of great importance within the context of successful allopolyploid evolution. One outstanding example of successful allopolyploidy is the endemic Iberian cyprinid Squalius alburnoides. Previously, based on the evaluation of a few genes, it was reported that the transcription levels between diploid and triploid S. alburnoides were similar. If this phenomenon occurs on a full genomic scale, a wide functional ''diploidization'' could be related to the success of these polyploids. We generated RNA-seq data from whole juvenile fish and from adult livers, to perform the first comparative quantitative transcriptomic analysis between diploid and triploid individuals of a vertebrate allopolyploid. Together with an assay to estimate relative expression per cell, it was possible to infer the relative sizes of transcriptomes. This showed that diploid and triploid S. alburnoides hybrids have similar liver transcriptome sizes. This in turn made it valid to directly compare the S. alburnoides RNA-seq transcript data sets and obtain a profile of dosage responses across the S. alburnoides transcriptome. We found that 64% of transcripts in juveniles' samples and 44% in liver samples differed less than twofold between diploid and triploid hybrids (similar expression. Yet, respectively 29% and 15% of transcripts presented accurate dosage compensation (PAA/PA expression ratio of 1 instead of 1.5. Therefore, an exact functional diploidization of the triploid genome does not occur, but a significant down regulation of gene expression in triploids was observed. However, for those genes with similar expression levels between diploids and triploids, expression is not globally strictly proportional to gene dosage nor is it set to a perfect diploid level. This quantitative expression flexibility may be a strong contributor to overcome the genomic shock
Periáñez-Párraga, Leonor; Martínez-López, Iciar; Ventayol-Bosch, Pere; Puigventós-Latorre, Francesc; Delgado-Sánchez, Olga
Chronic liver diseases (CLD) alter the kinetics of drugs. Despite dosage adjustment is based on Child-Pugh scores, there are no available recommendations and/or algorithms of reference to facilitate dosage regimens. A literature review about dose adjustment of the drugs from the hospital guide -which are included in the list of the WHO recommended drugs to be avoided or used with caution in patients with liver disease- was carried out. The therapeutic novelties from the last few years were also included. In order to do so, the summary of product characteristics (SPC), the database DrugDex-Micromedex, the WHO recommendations and the review articles from the last 10 years in Medline were reviewed. Moreover, the kinetic parameters of each drug were calculated with the aim of establishing a theoretical recommendation based on the proposal of Delcò and Huet. Recommendations for 186 drugs are presented according to the SPC (49.5%), DrugDex-Micromedex (26.3%) and WHO (18.8%) indications; six recommendations were based on specific publications; the theoretical recommendation based on pharmacokinetic parameters was proposed in four drugs. The final recommendations for clinical management were: dosage modification (26.9%), hepatic/analytical monitoring of the patient (8.6%), contraindication (18.8%), use with caution (19.3%) and no adjustment required (26.3%). In this review, specific recommendations for the practical management of patients with chronic liver disease are presented. It has been elaborated through a synthesis of the published bibliography and completed by following a theoretical methodology.
Haseeb, Muhammad; Azam, Shumaila; Bhatti, A I; Azam, Rizwan; Ullah, Mukhtar; Fazal, Sahar
We propose a new paradigm in the drug design for the revival of the p53 pathway in cancer cells. It is shown that the current strategy of using small molecule based Mdm2 inhibitors is not enough to adequately revive p53 in cancerous cells, especially when it comes to the extracting pulsating behavior of p53. This fact has come to notice when a novel method for the drug dosage design is introduced using system oriented concepts. As a test case, small molecule drug Mdm2 repressor Nutlin 3a is considered. The proposed method determines the dose of Nutlin to revive p53 pathway functionality. For this purpose, PBK dynamics of Nutlin have also been integrated with p53 pathway model. The p53 pathway is the focus of researchers for the last thirty years for its pivotal role as a frontline cancer suppressant protein due to its effect on cell cycle checkpoints and cell apoptosis in response to a DNA strand break. That is the reason for finding p53 being absent in more than 50% of tumor cancers. Various drugs have been proposed to revive p53 in cancer cells. Small molecule based drugs are at the foremost and are the subject of advanced clinical trials. The dosage design of these drugs is an important issue. We use control systems concepts to develop the drug dosage so that the cancer cells can be treated in appropriate time. We investigate by using a computational model how p53 protein responds to drug Nutlin 3a, an agent that interferes with the MDM2-mediated p53 regulation. The proposed integrated model describes in some detail the regulation network of p53 including the negative feedback loop mediated by MDM2 and the positive feedback loop mediated by Mdm2 mRNA as well as the reversible represses of MDM2 caused by Nutlin. The reported PBK dynamics of Nutlin 3a are also incorporated to see the full effect. It has been reported that p53 response to stresses in two ways. Either it has a sustained (constant) p53 response, or there are oscillations in p53 concentration. The
Fehrmann, Rudolf S. N.; Karjalainen, Juha M.; Krajewska, Malgorzata;
expression. We reanalyzed 77,840 expression profiles and observed a limited set of 'transcriptional components' that describe well-known biology, explain the vast majority of variation in gene expression and enable us to predict the biological function of genes. On correcting expression profiles...... for these components, we observed that the residual expression levels (in 'functional genomic mRNA' profiling) correlated strongly with copy number. DNA copy number correlated positively with expression levels for 99% of all abundantly expressed human genes, indicating global gene dosage sensitivity. By applying...
Pereira, Mariana S; Vilela-Silva, Ana-Cristina E S; Valente, Ana-Paula; Mourão, Paulo A S
Marine alga is an abundant source of sulfated polysaccharides with potent anticoagulant activity. However, several attempts to identify the specific structural features in these compounds, which confer the biological activity, failed due to their complex, heterogeneous structure. We isolated and characterized several sulfated alpha-L-galactans and sulfated alpha-L-fucans from marine invertebrates. In contrast to the algal fucans and galactans, these invertebrate polysaccharides have a simple structure, composed of well-defined units of oligosaccharides. We employed two of these compounds to elucidate their structure-anticoagulant action relationship. Our results indicate that a 2-sulfated, 3-linked alpha-L-galactan, but not an alpha-L-fucan, is a potent thrombin inhibitor mediated by antithrombin or heparin cofactor II. The difference between the activities of these two polysaccharides is not very pronounced when factor Xa replaces thrombin. Thus, the anticoagulant activity of sulfated galactan and sulfated fucan is not merely a consequence of their charge density. The interaction of these polysaccharides with coagulation cofactors and their target proteases are specific. Identification of specific structural requirements in sulfated galactans and sulfated fucans necessary for interaction with coagulation cofactors is an essential step for a more rational approach to develop new anticoagulant and antithrombotic drugs.
Fábio Wildson Gurgel Costa
Full Text Available PURPOSE: To conduct a systematized review of the literature about the main local hemostatic measures to control postoperative bleeding in anticoagulated patients. METHODS: A systematized review of literature was performed in the electronic database Medline (PubMed without restriction of the publication date. The eligibility criteria were studies involving maintenance of the anticoagulant therapy, prospective studies, retrospective studies, randomized clinical trials, controlled clinical studies, comparative studies, multicentric studies or case-control studies. Studies discontinuing anticoagulant therapy, case reports, literature reviews, in vitro studies, animal experiments and articles written in language not compatible with the search strategy adopted in this work were excluded. RESULTS: Twenty-four articles that met the adopted eligibility criteria were selected, enrolling 3891 subjects under anticoagulant therapy. A total of 171 cases of hemorrhage was observed. Tranexamic acid was the main local hemostatic measure used to controlling of postoperative bleeding. CONCLUSION: The local hemostatic measures proved to be effective according to previously published studies. Nevertheless, further clinical studies should be conducted to confirm this effectiveness.
Christensen, Henry; Lauterlein, Jens-Jacob; Sørensen, Patricia D
We have developed an expert computer system for the control of oral anticoagulation therapy, accessible by the patients via their own computer. To investigate if the weekly measurement and dosing of international normalized ratio (INR) at home using the online Internet-based system was superior...
Swadzba, J.; Iwaniec, T.; Pulka, M.; De Laat, B.; De Groot, P. G.; Musial, J.
Objectives: Lupus anticoagulant (LA) is clinically the most relevant among all antiphospholipid antibody tests. Recently, new guidelines for LA detection were published. The objective of this retrospective cohort study was to compare tests recommended under these guidelines with other methods used f
Pieper, P. G.
In pregnant women with a mechanical valve prosthesis, anticoagulation therapy is challenging because of the risk of embryopathy with vitamin K antagonists (VKA's), while unfractioned heparin and low molecular weight heparin (LMWH) are associated with a higher risk of valve thrombosis . The presen
Li, Na; Liu, Xue; He, Xiaoxi; Wang, Shuyao; Cao, Sujian; Xia, Zheng; Xian, Huali; Qin, Ling; Mao, Wenjun
An anticoagulant-active polysaccharide PF2 was extracted with boiling water from the green seaweed Monostroma angicava, further purified by anion-exchange and size-exclusion chromatography. PF2 was a rhamnan-type sulfated polysaccharide with molecular weight of about 88.1kDa. Results of chemical and spectroscopic analyses demonstrated that PF2 consisted of→3)-α-l-Rhap-(1→ and →2)-α-l-Rhap-(1→residues, with partially branches at C-2 of→3)-α-l-Rhap-(1→residues. Sulfate groups were substituted at C-3 of →2)-α-l-Rhap-(1→ residues. The sulfated polysaccharide PF2 had a high anticoagulant action, and the mechanism of anticoagulant activity mediated by PF2 was mainly attributed to strong potentiation thrombin by heparin cofactor II. PF2 also exhibited weak effect on antithrombin-dependent thrombin or factor Xa inhibition. The fibrin(ogen)olytic activity and thrombolytic activity of PF2 were also evaluated. The investigation revealed that PF2 was a novel sulfated rhamnan differing from previously described sulfated polysaccharides from green seaweed and could be a potential anticoagulant polysaccharide.
Z. M. Safiullina
Full Text Available Studies data on new anticoagulants, direct oral thrombin inhibitor (dabigatran and direct inhibitors of coagulation factor Xa (rivaroxaban, apixaban, in the treatment of nonvalvular atrial fibrillation are presented. Effects of these drugs on cardiovascular events in atrial fibrillation are analyzed based on the results of various studies. Prospects for further research are discussed.
Objective To evaluate the safety and efficacy of regional citrate anticoagulation in sustained low efficiency dialysis (SLED) .Methods A total of 45 patients with acute kidney injury (AKI) or end stage renal disease (ESRD) admitted in our hospital from August 2011 to
Kaliyamoorthy Kalidasan; Velayudham Ravi; Sunil Kumar Sahu; Murugan Lakshmi Maheshwaran; Kathiresan Kandasamy
Objective:To study the spine structure of stingray Himantura imbricata (H. imbricata) and to evaluate the anticoagulant properties of the spine extract obtained through various solvents extracts followed by antibacterial activity against human pathogens. Methods:Spines of H. imbricata were collected from Nagappattinam coast, Tamil Nadu, India and their spines were observed under the light microscope. The grounded spines were subjected to extraction of metabolites using methanol, ethanol, chloroform and acetone. Antibacterial activity was evaluated by disc diffusion technique against 10 human pathogens. Similarly, anticoagulant activity was also assessed by following United States Pharmacopeia method. Results:Light microscopic observation of spine revealed that the venom apparatus of the stingray H. imbricata consisted of two to three spines, glandular tissue and a sheath. The spine extract showed potent antibacterial activity against all tested pathogen. Maximum activity (14 mm) was found against Staphylococcus aureus. Crude extract showed 91.50 USP units/mg of anticoagulant activity. Conclusions: Microscopic observations gave new insight about the spine structure of the stingray. The spine extracts of H. imbricate showed potent activity against human pathogens revealed by the good zone of inhibition. Chloroform extracts conferred the most prominent antibacterial activity. The anticoagulant activity was also comparable with that of standard heparin.
Full Text Available Objective: To study the spine structure of stingray Himantura imbricata (H. imbricata and to evaluate the anticoagulant properties of the spine extract obtained through various solvents extracts followed by antibacterial activity against human pathogens. Methods: Spines of H. imbricata were collected from Nagappattinam coast, Tamil Nadu, India and their spines were observed under the light microscope. The grounded spines were subjected to extraction of metabolites using methanol, ethanol, chloroform and acetone. Antibacterial activity was evaluated by disc diffusion technique against 10 human pathogens. Similarly, anticoagulant activity was also assessed by following United States Pharmacopeia method. Results: Light microscopic observation of spine revealed that the venom apparatus of the stingray H. imbricata consisted of two to three spines, glandular tissue and a sheath. The spine extract showed potent antibacterial activity against all tested pathogen. Maximum activity (14 mm was found against Staphylococcus aureus. Crude extract showed 91.50 USP units/mg of anticoagulant activity. Conclusions: Microscopic observations gave new insight about the spine structure of the stingray. The spine extracts of H. imbricate showed potent activity against human pathogens revealed by the good zone of inhibition. Chloroform extracts conferred the most prominent antibacterial activity. The anticoagulant activity was also comparable with that of standard heparin.
Lutz, Jens; Jurk, Kerstin
Progressive impairment of renal function can lead to uremia, which is associated with thus increasing the risk of bleeding as well as thrombosis. Furthermore, many patients with chronic kidney disease (CKD) have an indication for an anticoagulation or antiplatelet therapy due to atrial fibrillation, coronary artery disease, thromboembolic disease, or peripheral artery disease. The treatment usually includes vitamin-K antagonists (VKAs) and/or platelet aggregation inhibitors. The direct oral anticoagulants (DOACs) inhibiting factor Xa or thrombin activity represent an alternative for heparins and VKAs. However, DOACs can further aggravate the bleeding risk in CKD patients. This is related to a combination of an accumulation of the substance due to the reduced renal clearance, an inhibition of thrombin-mediated platelet activation, and uremia associated factors such as impaired coagulation, platelet function, and platelet-vessel wall. Furthermore, platelet aggregation inhibitors can also influence the bleeding risk, particularly if they are administered in combination with anticoagulants in patients with advanced CKD. In this review we discuss the different mechanisms leading to the increased risk of bleeding and thrombosis as well as the different options and problems related to an antiplatelet or anticoagulation therapy in CKD patients.
Full Text Available Dental treatment performed in patients receiving oral anticoagulant drug therapy is becoming increasingly common in dental offices.The aim of oral anticoagulant therapy is to reduce blood coagulability to an optimal therapeutic range within which the patient is provided some degree of protection from thromboembolic events. This is achieved at the cost of a minor risk of haemorrhage. Frequently raised questions concern the safety and efficacy of the various anticoagulation regimens and their accompanying thromboembolic and bleeding risks relative to invasive dental procedures.The aim of this literature review is to evaluate the available evidence on the impact of anticoagulant medications on dental treatment and highlight certain patient management issues closely interrelated to various aspects of dental treatment. For that purpose literature search in the electronic database of Medscape, Pubmed-Medline, Science Direct, and EBSCO host, in the data base of Medical University Plovdiv and specialised published books in general medicine and dentistry was made.A total of 33 publications between 1995 and 2013 were identified: 12 review articles, 11 randomized controlled and non-randomised studies, 6 guidelines and practical guides, 1 meta-analysis and 3 specialised books.
BACKGROUND: The majority of rat problems in cities are thought to be related to defective sewers, and the use of anticoagulant rodenticides in such places is often implemented as part of regular urban rodent control. Knowledge pertaining to the resistance status of sewer rat populations is non-ex...
The European Food Safety Authority (EFSA) asked the Panel on Dietetic Products, Nutrition and Allergies to provide a scientific statement on the safety of glucosamine for patients receiving coumarin anticoagulants. More than 40 case reports have been collected by drug-monitoring agencies that sho......The European Food Safety Authority (EFSA) asked the Panel on Dietetic Products, Nutrition and Allergies to provide a scientific statement on the safety of glucosamine for patients receiving coumarin anticoagulants. More than 40 case reports have been collected by drug-monitoring agencies...... that showed in some patients being prescribed coumarin anticoagulants, especially warfarin, that the International Normalised Ratio (INR) increased after they began taking glucosamine, which indicated an increase in the coagulation time. In most cases the increased INR values were symptomless but in some...... cases haemorrhage occurred in a variety of organs, and in one case this resulted in a persistent vegetative state. The evidence for an interaction between glucosamine and coumarin anticoagulants is strengthened by the observation that in the majority of cases the INR began to fall to normal values when...
Kersbergen, Karina J.; de Vries, Linda S.; van Straaten, H. L. M. (Irma); Benders, Manon J. N. L.; Nievelstein, Ruter A. J.; Groenendaal, Floris
Background and Purpose-Cerebral sinovenous thrombosis is a rare disorder with a high risk of an adverse neurodevelopmental outcome. Until now, anticoagulation therapy has been restricted to neonates without an associated parenchymal hemorrhage. In this study, we describe sequential neuroimaging find
Heiberg, A.C.; Leirs, H.; Siegismund, Hans Redlef
Resistance to anticoagulant rodenticides in Norway rats (Rattus norvegicus) is documented to be associated with pleiotropic effects, notably with an increased dietary vitamin K requirement. The aim of this study was to quantify these effects in small populations of Norway rat in Denmark and to se...
Dowding, Claire V., E-mail: firstname.lastname@example.org [School of Biological Sciences, University of Bristol, Woodland Road, Bristol BS8 1UG (United Kingdom); Shore, Richard F.; Worgan, Andrew [NERC Centre for Ecology and Hydrology, Lancaster Environment Centre, Library Avenue, Bailrigg, Lancaster LA1 4AP (United Kingdom); Baker, Philip J.; Harris, Stephen [School of Biological Sciences, University of Bristol, Woodland Road, Bristol BS8 1UG (United Kingdom)
Studies on exposure of non-targets to anticoagulant rodenticides have largely focussed on predatory birds and mammals; insectivores have rarely been studied. We investigated the exposure of 120 European hedgehogs (Erinaceus europaeus) from throughout Britain to first- and second-generation anticoagulant rodenticides (FGARs and SGARs) using high performance liquid chromatography coupled with fluorescence detection (HPLC) and liquid-chromatography mass spectrometry (LCMS). The proportion of hedgehogs with liver SGAR concentrations detected by HPLC was 3-13% per compound, 23% overall. LCMS identified much higher prevalence for difenacoum and bromadiolone, mainly because of greater ability to detect low-level contamination. The overall proportion of hedgehogs with LCMS-detected residues was 57.5% (SGARs alone) and 66.7% (FGARs and SGARs combined); 27 (22.5%) hedgehogs contained >1 rodenticide. Exposure of insectivores and predators to anticoagulant rodenticides appears to be similar. The greater sensitivity of LCMS suggests that hitherto exposure of non-targets is likely to have been under-estimated using HPLC techniques. - Exposure of insectivorous hedgehogs to anticoagulant rodenticides in Britain is similar to predatory birds and mammals that specialise in eating small mammals, and hitherto exposure levels have been under-estimated using HPLC techniques.
Nigel P. Murray
Full Text Available Hypernephroma can present as a variety of paraneoplastic, nonmetastatic conditions, including vasculitis, and rarely a lupus-type anticoagulant. Nephrectomy leads to the resolution of the systemic complaints. Malignancy, in this case hypernephroma, can present as an immune-mediated paraneoplastic syndrome which resolves after removal of the underlying tumor.
桂保松; 高卫华; 桂琳; 吕星; 王亮琪; 郭蕊军
Objective To observe the hemodialysis effect of t he new type of concentrated anticoagulant hemodialysate of citrate. Methods Ten dogs were given intermittent hemodialysis and were divided into 3 groups according to hemodialysis manners. Group 1 was saline-flush hemodialysed with bicarbonate hemodialysate; Group 2 was hemodialysed with citrate hemodialysis without any anticoagulant; Group 3 wa s hemodialysed with bicarbonate hemodialysate and heparin .ACT, Ca2+, BUN, Cr,ALT, AST, TBIL, DBIL, Na+, Cl-, HCO3- and venous pressure were monitored in the animals of each group during hemodialysis. Results During the hemodialysis in Group 1,venous pressure increased lastingly, resulting in t he failure of hemodialysis for 2 hours. Hemodialysis for 2 hours in Group 2 were all finished successfully. ACT was extended and Ca2+ decreased obviously in the venous end during hemodialysis.And ALT、AST、Ca2+、K+、Na+、Cl -、HCO3- after the hemodialysis in Group 2 were not changed(P>0.05).Moreover, the clearance rat e of the dialyzers with citrate dialysate increased significantly compared with those of saline-flush and heparin anticoagulation.Conclusion The anticoagulant and dialytic effects of the new t ype citrate hemodialysis are satisfactory and better than that of saline-flush ..
Objective:To observe the hemodialysis effcet of the new type of concentrated anticoagulant hemodialysate of citrate.Methods:Ten dogs were given intermittent hemodialysis and were divided into 3 groups according to hemodialysis manners.Group 1 was saline-flush hemodialysed with bicarbonate hemodialysate;Group 2 was hemodialysed with citrate hemodialysis without any anticoagulant;Group 3 was hemodialysed with bicarbonate hemodlalysate and heparin,ACT,Ca2+,BUN,Cr,ALT,AST,TBIL,BDIL,Na+,Cl-,HCO3- and venous pressure were monitored in the animals of each group during hemodialysis.Results:During the hemodialysis in Group 1,venous pressure increased lastingly,resulting in the failure of hemodialysis for 2 hours.Hemodialysis for 2 hours in Group 2 were all finished successfully.ACT was extended and Ca2+ decreased obviously in the venous end during hemodialysis,And ALT,AST,Ca2+,K+,Na+,Cl-,HCO3- after the hemodialysis in Group 2 were not changed(P>0.05).Moreover,the clearance rate of the dialyzers with citrate dialysate increased significantly compared with those of saline-flush and heparin anticoagulation.Conclusion:The anticoagulant and dialytic effects of the new type citrate hemodialysis are satisfactory and better than that of saline-flush.
Habert, Jeffrey Steven
Many primary care physicians are wary about using direct oral anticoagulants (DOACs) in patients with nonvalvular atrial fibrillation (AF). Factors such as comorbidities, concomitant medications, and alcohol misuse increase concerns over bleeding risk, especially in elderly and frail patients with AF. This article discusses strategies to minimize the risk of major bleeding events in patients with AF who may benefit from oral anticoagulant therapy for stroke prevention. The potential benefits of the DOACs compared with vitamin K antagonists, in terms of a lower risk of intracranial hemorrhage, are discussed, together with the identification of reversible risk factors for bleeding and correct dose selection of the DOACs based on a patient’s characteristics and concomitant medications. Current bleeding management strategies, including the new reversal agents for the DOACs and the prevention of bleeding during preoperative anticoagulation treatment, in addition to health care resource use associated with anticoagulation treatment and bleeding, are also discussed. Implementing a structured approach at an individual patient level will minimize the overall risk of bleeding and should increase physician confidence in using the DOACs for stroke prevention in their patients with nonvalvular AF.
Solbeck, Sacha; Meyer, Martin A S; Johansson, Pär I;
may not sufficiently display the effect. Furthermore, no antidote exists and reversal of the anticoagulant effect is impossible or difficult. The present study investigated the in vitro effect of dabigatran on whole blood thromboelastography (TEG) and its reversal by recombinant activated factor VII...
Sarah T.B.G. Loubele
Full Text Available Renal ischemia/reperfusion (I/R injury is the main cause of acute renal failure. The severity of injury is determined by endothelial damage as well as inflammatory and apoptotic processes. The anticoagulants active site inhibited factor VIIa (ASIS and activated protein C (APC are besides their anticoagulant function also known for their cytoprotective properties. In this study the effect of ASIS and APC was assessed on renal I/R injury and this in relation to inflammation and apoptosis. Our results showed no effect of ASIS or APC on renal injury as determined by histopathological scoring as well as by blood urea nitrogen (BUN and creatinine levels. Furthermore, no effect on fibrin staining was detected but ASIS did reduce tissue factor activity levels after a 2-hr reperfusion period. Neither ASIS nor APC administration influenced overall inflammation markers, although some inflammatory effects of ASIS on interleukin (IL-1β and tumor necrosis factor (TNF-α were detectable after 2 hr of reperfusion. Finally, neither APC nor ASIS had an influence on cell signaling pathways or on the number of apoptotic cells within the kidneys. From this study we can conclude that the anticoagulants ASIS and APC do not have protective effects in renal I/R injury in the experimental setup as used in this study which is in contrast to the protective effects of these anticoagulants in other models of I/R.
Staerk, Laila; Fosbøl, Emil Loldrup; Gadsbøll, Kasper;
Among atrial fibrillation (AF) patients, Danish nationwide registries (2011-2015) were used to examine temporal trends of initiation patterns of oral anticoagulation (OAC) treatment according to age. Overall, 43,299 AF patients initiating vitamin K antagonists (VKA) (42%), dabigatran (29...
Den Exter, P.L.; Van Es, J.; Kroft, L.J.M.; Erkens, P.G.M.; Douma, Renee; Jonkers, G.; Ten Cate, H.; Beenen, L.; Kamphuisen, P.W.; Huisman, M.V.
Background: In patients with acute pulmonary embolism (PE), systematic assessment of residual thrombotic obstruction after long-term anticoagulation has been understudied. This information may be of clinical importance for diagnostic baseline imaging, in case of clinically suspected recurrent PE or
Verhoef, Talitha I.; Redekop, William K.; Daly, Ann K.; Van Schie, Rianne M F; De Boer, Anthonius; Maitland-Van Der Zee, Anke Hilse
Coumarin derivatives, such as warfarin, acenocoumarol and phenprocoumon are frequently prescribed oral anticoagulants to treat and prevent thromboembolism. Because there is a large inter-individual and intra-individual variability in dose-response and a small therapeutic window, treatment with couma
Laith G. Alsayegh
Full Text Available Novel oral anticoagulants (NOACs are becoming popular management options for stroke prophylaxis in nonvalvular atrial fibrillation as well as deep vein thrombosis and pulmonary embolism treatment and prophylaxis. NOACs have similar efficacy to warfarin along with noninferior safety profiles. Patient comorbidities, size, renal and hepatic function, and concomitant drug regimen play a role in which NOAC a physician may choose.
Full Text Available Background: To analyze the characteristics of the patients with diagnosis of spontaneous retroperitoneal hematoma associated with anticoagulation therapy and antiplatet therapy. Methods: From January 2006 to March 2013, 9 patients (6 from Haseki Training and Research Hospital - Urology Department and 3 from Istanbul Medical Faculty - Gynecology and Obstetric Department were included in the study. Patients charts including sex, age, comorbidities, main complaint, and medication intake were examined. Also initial hemoglobin level, initial International Normalized Ratio level, red blood cells and fresh frozen plasma units transfused were evaluated. Results: Median age was 60 year-old. Abdominal pain and flank pain were common symptoms. Eight patients were taking only anticoagulation therapy, 2 only antiplatet therapy and 1 both anticoagulation and antiplatet therapy. Median initial hemoglobin value was 9,0 g/dL and median International Normalized Ratio level was 3.2 Patients were evaluated by abdominal ultrasonography or abdominal computer tomography. Seven patients were treated conservatively. Only one patient died because of septic shock with a mortality ratio of 11%. Conclusion: Despite benefits of anticoagulation and antiplatet theraphy these agents have serious side-affects as retroperitoneal hemorrhage in elderly patients taking multi-drug medication.
Full Text Available Background: Dried Whitmania pigra is used for the treatment of cardiovascular and cerebrovascular diseases in traditional Chinese medicine and hot water and alcohol extracts also have anticogulant activity. However, a lower molecular weight and more stable anticogulant is needed. Objective: The objective of the following study is to purify and characterize of an anticoagulant oligopeptide from Hirudo (Whitmania pigra Whitman. Materials and Methods: Gel filtration on Sephadex G 50, ion exchange on diethylaminoethyl cellulose, and semi prepared high performance liquid chromatography were used to purify Hirudo. Automated coagulation analyzer was used for evaluating anticoagulant activity. Molecular weight was measured by Matrix assisted laser desorption ionization time of flight mass spectrometry. Amino acid sequence of the oligopeptide was measured by amino acid sequence analyzer. Results: A new anticoagulant, named whitide, isolated from Hirudo was purified, with a molecular weight 1997.1 Da. Amino acid sequence of the oligopeptide was identified as Gly-Pro-ALa-Gly-Hyp-Val-Gly-Ala-Hyp-Gly-Gly-Hyp-Gly-Val-Arg-Gly-Leu-Hyp-Gly-Asp-Arg-Gly. The results revealed that its amino acid sequence had strong homology to various types of collagen. Conclusion: Whitide might be an orally anticoagulant for its hot and trypsin stable.
van den Bemt, PMLA; Joosten, P; Risselada, A; van den Boogaart, MHA; Egberts, ACG; Brouwers, JRBJ
The initiation and stabilization of oral anticoagulant therapy in hospitalized patients in a setting without specialized medical or pharmaceutical advice, was studied. In addition, potential risk factors for lack of stabilization were studied. All patients from three wards (orthopaedic surgery, gene
Willems, H.P.J.; Heijer, M. den; Gerrits, W.B.J.; Schurgers, L.J.; Havekes, M.; Blom, H.J.; Bos, G.M.
BACKGROUND: High circulating levels of homocysteine are a risk factor for arterial and venous thrombosis. This association has been established in numerous case-control studies. In some of these studies, patients were treated with anticoagulants at the time of venapuncture. It is not clear whether h
Won-Seok Park; Hyeong-Il Kim; Byung-Jun Jeon; Seong-Hun Kim; Seung-Ok Lee
Venous complications in patients with acute pancreatitis typically occur as a form of splenic,portal,or superior mesenteric vein thrombosis and have been detected more frequently in recent reports.Although a well-organized protocol for the treatment of venous thrombosis has not been established,anticoagulation therapy is commonly recommended.A 73-year-old man was diagnosed with acute progressive portal vein thrombosis associated with acute pancreatitis.After one month of anticoagulation therapy,the patient developed severe hematemesis.With endoscopy and an abdominal computed tomography scan,hemorrhages in the pancreatic pseudocyst,which was ruptured into the duodenal bulb,were confirmed.After conservative treatment,the patient was stabilized.While the rupture of a pseudocyst into the surrounding viscera is a well-known phenomenon,spontaneous rupture into the duodenum is rare.Moreover,no reports of upper gastrointestinal bleeding caused by pseudocyst rupture in patients under anticoagulation therapy for venous thrombosis associated with acute pancreatitis have been published.Herein,we report a unique case of massive upper gastrointestinal bleeding due to pancreatic pseudocyst rupture into the duodenum,which developed during anticoagulation therapy for portal vein thrombosis associated with acute pancreatitis.
Elham Amrollahi Byoki
Full Text Available Objective(s: Snake venoms contain complex mixture of proteins with biological activities. Some of these proteins affect blood coagulation and platelet function in different ways. Snake venom toxin may serve as a starting material for drug design to combat several pathophysiological problems such as cardiovascular disorders. In the present study, purification of anticoagulation factor from venom of snake (Echis carinatus was studied. Anticoagulation activity of crude venom, fractions and purified peptide were determined by using prothrombin time (PT and thrombin time (TT. Three fractions were partially purified from the venom of E. Carinatus by gel filtration on sephadex G-75 and final purification was performed by high-performance liquid chromatography (HPLC with C18 column. A purified anticoagulant factor was derived which showed a single protein band in SDS-PAGE electrophoresis under reducing condition. Results of PT and TT tests for purified peptide (EC217 were found to be 102±4.242 and < 5 min. respectively. Determination of molecular weight revealed that the active purified peptide (EC217 was about 30 KD. In conclusion, the present study showed that the venom of E. carinatus contains at least one anticoagulant factor.
Full Text Available Background. Warfarin reduces the incidence of thromboembolism but increases the risk of gastrointestinal bleeding (GIB. GIB during warfarin anticoagulation is rarely evaluated in Asian patients. Aims. This study aimed at investigating the incidence, risk factors, management, and outcome of GIB in Taiwanese patients treated with warfarin. Methods. We analyzed a cohort of warfarin anticoagulated patients between July 1993 and May 2012. Clinical data were retrieved in a chart-reviewing manner. Results. A total of 401 warfarin anticoagulated patients were enrolled. The incidence of GIB was 3.9% per patient-years. Multivariate analysis with Cox regression showed that age >65 years old (RR: 2.5, 95% CI: 1.2–5.5, a mean international normalized ratio >2.1 (RR: 2.1, 95% CI: 1.0–4.2, a history of GIB (RR: 5.1, 95% CI: 1.9–13.5, and cirrhosis (RR: 6.9, 95% CI: 2.0–24.5 were independent factors predicting GIB. 27.3% of the GIB patients had rebleeding after restarting warfarin while thromboembolic events were found in 16.7% of the patients discontinuing warfarin therapy. Conclusions. Warfarin was associated with a significant incidence of GIB in Taiwanese patients. The intensity of anticoagulation should be monitored closely during warfarin therapy, especially in patients with risk factors of GIB.
van den Bemt, PMLA; Geven, LM; Kuitert, NA; Risselada, A; Brouwers, JRBJ
Objective: The drug-drug interaction between oral anticoagulants (especially warfarin) and acetaminophen has been described, but evidence is conflicting and evidence for a similar interaction between acenocoumarol or phenprocoumon and acetaminophen is limited. Therefore, a study was performed to det
Simmelink, MJA; Derksen, RHWM; Arnout, J; De Groot, PG
Lupus anticoagulants (LAC) are a heterogeneous group of autoantibodies that prolong phospholipid-dependent clotting assays. The autoantibodies that cause LAC activity are predominantly directed against beta(2)-glycoprotein I (beta(2)GPI) or prothrombin. In the present study, we describe a method to
de Araújo, Cristiano A; Noseda, Miguel D; Cipriani, Thales R; Gonçalves, Alan G; Duarte, Maria Eugênia R; Ducatti, Diogo R B
Sulfated polysaccharides are recognized for their broad range of biological activities, including anticoagulant properties. The positions occupied by the sulfate groups are often related to the level of the inherent biological activity. Herein the naturally sulfated galactans, kappa-, iota- and theta-carrageenan, were additionally sulfated by regioselective means. The anticoagulant activity of the resulting samples was then studied using the aPTT in vitro assay. The influence of sulfate regiochemistry on the anticoagulant activity was evaluated. From kappa-carrageenan three rare polysaccharides were synthesized, one of them involved a synthetic route with an amphiphilic polysaccharide intermediate containing pivaloyl groups. Iota- and theta-carrageenan were utilized in a selective C6 sulfation at β-D-Galp units to produce different structures comprising trisulfated diads. All the samples were characterized by NMR (1D and 2D). The resulting aPPT measurements suggested that sulfation at C2 of 3,6-anhydro-α-D-Galp and C6 of β-D-Galp increased the anticoagulant activity.
de Oliveira Barddal, Helyn Priscila; Gracher, Ana Helena Pereira; Simas-Tosin, Fernanda Fogagnoli; Iacomini, Marcello; Cipriani, Thales Ricardo
Heparin has great clinical importance as anticoagulant and antithrombotic agent. However, because of its risks of causing bleeding and contamination by animal pathogens, several studies aim to obtain alternatives to heparin. In the search for anticoagulant and antithrombotic agents from a non-animal source, a glycoglucuronomannan from the gum exudate of the plant Vochysia thyrsoidea was partially hydrolyzed, and both native and partially degraded polysaccharides were chemically sulfated, yielding VThS and Ph-VThS respectively. Methylation analysis indicated that sulfation occurred preferentially at the O-5 position of arabinose units in the VThS and at the O-6 position of mannose units in Ph-VThS. In vitro aPTT assay showed that VThS and Ph-VThS have anticoagulant activity, which could be controlled by protamine, and ex vivo aPTT assay demonstrated that Ph-VThS is absorbed by subcutaneous route. Like heparin, they were able to inhibit α-thrombin and factor Xa by a serpin-dependent mechanism. In vivo, VThS and Ph-VThS reduced thrombus formation by approximately 50% at a dose of 40 IU/kg, similarly to heparin. The results demonstrated that the chemically sulfated polysaccharides are promising anticoagulant and antithrombotic agents.
Full Text Available Abstract Background The 'Perception of Anti-Coagulant Treatment Questionnaire' (PACT-Q was developed to assess patients' expectations of, and satisfaction with their anticoagulant treatment. This questionnaire needs to be finalised and psychometrically validated. Methods The PACT-Q was included in the United States, the Netherlands and France into three phase III multinational clinical trials conducted to evaluate efficacy and safety of a new long-acting anticoagulant drug (idraparinux compared to vitamin K antagonist (VKA. PACT-Q was administered to patients with deep venous thrombosis (DVT, atrial fibrillation (AF or pulmonary embolism (PE at Day 1, to assess patients' expectations, and at 3 and 6 months to assess patients' satisfaction and treatment convenience and burden. The final structure of the PACT-Q (Principal Component Analysis – PCA – with Varimax Rotation was first determined and its psychometric properties were then measured with validity of the structure (Multitrait analysis, internal consistency reliability (Cronbach's alpha coefficients and known-group validity. Results PCA and multitrait analyses showed the multidimensionality of the "Treatment Expectations" dimension, comprising 7 items that had to be scored independently. The "Convenience" and "Burden of Disease and Treatment" dimensions of the hypothesised original structure of the questionnaire were combined, thus resulting in 13 items grouped into the single dimension "Convenience". The "Anticoagulant Treatment Satisfaction" dimension remained unchanged and included 7 items. All items of the "Convenience" and "Anticoagulant Treatment Satisfaction" dimensions displayed good convergent and discriminant validity. The internal consistency reliability was good, with a Cronbach's alpha of 0.84 for the "Convenience" dimension, and 0.76 for the "Anticoagulant Treatment Satisfaction" dimension. Known-group validity was good, especially with regard to occurrence of
Dua, Kamal; Pabreja, Kavita; Ramana, Malipeddi Venkata
Aceclofenac is a new generation non-steroidal anti-inflammatory drug showing effective anti-inflammatory and analgesic properties. It is available in the form of tablets of 100 mg. Importance of aceclofenac as a NSAID has inspired development of topical dosage forms. This mode of administration may help avoid typical side effects associated with oral administration of NSAIDs, which have led to its withdrawal. Furthermore, aceclofenac topical dosage forms can be used as a supplement to oral therapy for better treatment of conditions such as arthritis. Ointments, creams, and gels containing 1% (m/m) aceclofenac have been prepared. They were tested for physical appearance, pH, spreadability, extrudability, drug content uniformity, in vitro diffusion and in vitro permeation. Gels prepared using Carbopol 940 (AF2, AF3) and macrogol bases (AF7) were selected after the analysis of the results. They were evaluated for acute skin irritancy, anti-inflammatory and analgesic effects using the carrageenan-induced thermal hyperalgesia and paw edema method. AF2 was shown to be significantly (p < 0.05) more effective in inhibiting hyperalgesia associated with inflammation, compared to AF3 and AF7. Hence, AF2 may be suggested as an alternative to oral preparations.
Patra, Biranchi; Kon, Yoshiko; Yadav, Gitanjali; Sevold, Anthony W.; Frumkin, Jesse P.; Vallabhajosyula, Ravishankar R.; Hintze, Arend; Østman, Bjørn; Schossau, Jory; Bhan, Ashish; Marzolf, Bruz; Tamashiro, Jenna K.; Kaur, Amardeep; Baliga, Nitin S.; Grayhack, Elizabeth J.; Adami, Christoph; Galas, David J.; Raval, Alpan; Phizicky, Eric M.; Ray, Animesh
Genomic robustness is the extent to which an organism has evolved to withstand the effects of deleterious mutations. We explored the extent of genomic robustness in budding yeast by genome wide dosage suppressor analysis of 53 conditional lethal mutations in cell division cycle and RNA synthesis related genes, revealing 660 suppressor interactions of which 642 are novel. This collection has several distinctive features, including high co-occurrence of mutant-suppressor pairs within protein modules, highly correlated functions between the pairs and higher diversity of functions among the co-suppressors than previously observed. Dosage suppression of essential genes encoding RNA polymerase subunits and chromosome cohesion complex suggests a surprising degree of functional plasticity of macromolecular complexes, and the existence of numerous degenerate pathways for circumventing the effects of potentially lethal mutations. These results imply that organisms and cancer are likely able to exploit the genomic robustness properties, due the persistence of cryptic gene and pathway functions, to generate variation and adapt to selective pressures. PMID:27899637
Cristofoletti, Rodrigo; Nair, Anita; Abrahamsson, Bertil; Groot, D W; Kopp, Sabine; Langguth, Peter; Polli, James E; Shah, Vinod P; Dressman, Jennifer B
Literature data pertaining to the decision to allow a waiver of in vivo bioequivalence testing for the approval of immediate-release (IR) solid oral dosage forms containing efavirenz as the only active pharmaceutical ingredient (API) are reviewed. Because of lack of conclusive data about efavirenz's permeability and its failure to comply with the "high solubility" criteria according to the Biopharmaceutics Classification System (BCS), the API can be classified as BCS Class II/IV. In line with the solubility characteristics, the innovator product does not meet the dissolution criteria for a "rapidly dissolving product." Furthermore, product variations containing commonly used excipients or in the manufacturing process have been reported to impact the rate and extent of efavirenz absorption. Despite its wide therapeutic index, subtherapeutic levels of efavirenz can lead to treatment failure and also facilitate the emergence of efavirenz-resistant mutants. For all these reasons, a biowaiver for IR solid oral dosage forms containing efavirenz as the sole API is not scientifically justified for reformulated or multisource drug products.
Rediguieri, Camila F; Porta, Valentina; G Nunes, Diana S; Nunes, Taina M; Junginger, Hans E; Kopp, Sabine; Midha, Kamal K; Shah, Vinod P; Stavchansky, Salomon; Dressman, Jennifer B; Barends, Dirk M
Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing metronidazole are reviewed. Metronidazole can be assigned to Biopharmaceutics Classification System Class I. Most BE studies that were identified reported the investigated formulations to be bioequivalent, indicating the risk of bioinequivalence to be low. Formulations showing differences in bioavailability showed dissimilarities in in vitro dissolution profiles. Furthermore, metronidazole has a wide therapeutic index. It is concluded that a biowaiver for solid IR formulations is justified, provided: (a) the test product and its comparator are both rapidly dissolving; (b) meet similarity of the dissolution profiles at pH 1.2, 4.5, and 6.8; (c) the test product contains only excipients present in IR drug products approved in International Conference on Harmonisation (ICH) or associated countries in the same dosage form; and (d) if the test product contains sorbitol, sodium laurilsulfate, or propylene glycol, the test product needs to be qualitatively and quantitatively identical to its comparator with respect to these excipients [corrected]..
Alhnan, Mohamed A; Okwuosa, Tochukwu C; Sadia, Muzna; Wan, Ka-Wai; Ahmed, Waqar; Arafat, Basel
The recent introduction of the first FDA approved 3D-printed drug has fuelled interest in 3D printing technology, which is set to revolutionize healthcare. Since its initial use, this rapid prototyping (RP) technology has evolved to such an extent that it is currently being used in a wide range of applications including in tissue engineering, dentistry, construction, automotive and aerospace. However, in the pharmaceutical industry this technology is still in its infancy and its potential yet to be fully explored. This paper presents various 3D printing technologies such as stereolithographic, powder based, selective laser sintering, fused deposition modelling and semi-solid extrusion 3D printing. It also provides a comprehensive review of previous attempts at using 3D printing technologies on the manufacturing dosage forms with a particular focus on oral tablets. Their advantages particularly with adaptability in the pharmaceutical field have been highlighted, which enables the preparation of dosage forms with complex designs and geometries, multiple actives and tailored release profiles. An insight into the technical challenges facing the different 3D printing technologies such as the formulation and processing parameters is provided. Light is also shed on the different regulatory challenges that need to be overcome for 3D printing to fulfil its real potential in the pharmaceutical industry.
Nie, Haichen; Byrn, Stephen R; Zhou, Qi Tony
Using pharmaceutical salts in solid dosage forms can raise stability concerns, especially salt dissociation which can adversely affect the product performance. Therefore, a thorough understanding of the salt instability encountered in solid state formulations is imperative to ensure the product quality. The present article uses the fundamental theory of acid base, ionic equilibrium, relationship of pH and solubility as a starting point to illustrate and interpret the salt formation and salt disproportionation in pharmaceutical systems. The criteria of selecting the optimal salt form and the underlying theory of salt formation and disproportionation are reviewed in detail. Factors influencing salt stability in solid dosage forms are scrutinized and discussed with the case studies. In addition, both commonly used and innovative strategies for preventing salt dissociations in formulation, on storage, and during manufacturing will be suggested herein. This article will provide formulation scientists and manufacturing engineers an insight into the mechanisms of salt disproportionation and salt formation, which can help them avoid and solve the instability issues of pharmaceutical salts in the product design.
Full Text Available Life-threatening bleeding in anticoagulation with Warfarin is an emergency challenging issue. Several approaches are available to treat bleeding in either over-anticoagulation or propeanticoagulation, including vitamin K, fresh frozen plasma and prothrombin complex concentrates (PCC administration. In coexisting trauma-induced bleeding and anticoagulation, reversal of anticoagulation must be a rapid and highly effective procedure. Furthermore the appropriate treatment must be directly available in each shock rooms to guarantee the rapid management of the emergency. PCC require a simple storage, rapid accessibility, fast administration procedures and high effectiveness. Here we report the utility of PCC in management of a craniofacial trauma in proper-anticoagulation.
Tatarunas, Vacis; Lesauskaite, Vaiva; Veikutiene, Audrone; Grybauskas, Pranas; Jakuska, Povilas; Jankauskiene, Laima; Bartuseviciute, Ruta; Benetis, Rimantas
The dosage of warfarin is restricted due to its narrow therapeutic index, so, the required dose must be adapted individually to each patient. Variations in warfarin dosage are influenced by genetic factors, the changes in patient diet, anthropometric and clinical parameters. To determine whether VKORC1 G3730A and CYP4F2 G1347A genotypes contribute to warfarin dosage in patients during initiation and long-term anticoagulation treatment after heart valve surgery. From totally 307 patients, who underwent heart valve surgery, 189 patients (62 %) who had been treated with warfarin more than 3 months, were included into the study. A hierarchical stepwise multivariate linear regression model showed, that during initiation clinical factors can explain 17 % of the warfarin dose variation. The addition of CYP2C9 and VKORC1 G-1639A genotype raises the accuracy about twice-to 32 %. The CYP4F2 G1347A genotype can add again about 2-34 %. During long-term treatment clinical factors explain about 26 % of warfarin dose variation. If the CYP2C9 *2, *3, VKORC1*2 alleles are detected, model can explain about 49 % in dose variation. The *3 allele of VKORC1 raises the accuracy by 1-50 %. The carriers of CYP4F2 A1347A genotype required higher daily warfarin doses during initiation of warfarin therapy after heart valve surgery than comparing to G/G and G/A carriers, but during the longer periods of warfarin use, the dosage of warfarin depended significantly on VKORC1 *3 allele (G3730A polymorphism) and on the thyroid stimulating hormone level in the blood plasma.
Park, Jin Woo; Jeon, Ok Cheol; Kim, Sang Kyoon; Al-Hilal, Taslim Ahmed; Jin, Shun Ji; Moon, Hyun Tae; Yang, Victor C; Kim, Sang Yoon; Byun, Youngro
Heparin, an anticoagulant that is widely used clinically, is also known to bind to several kinds of proteins through electrostatic interactions because of its polyanionic character. These interactions are mediated by the physicochemical properties of heparin such as sequence composition, sulfation patterns, charge distribution, overall charge density, and molecular size. Although this electrostatic character mediates its binding to many proteins related with tumor progression, thereby providing its antiangiogenic property, the administration of heparin for treating cancer is limited in clinical applications due to several drawbacks, such as its low oral absorption, unsatisfactory therapeutic effects, and strong anticoagulant activity which induces hemorrhaging. Here, we evaluated novel, orally active, low molecular weight heparin (LMWH) derivatives (LHD) conjugated with deoxycholic acid (DOCA) that show reduced anticoagulant activity and enhanced antiangiogenic activity. The chemical conjugate of LMWH and DOCA was synthesized by conjugating the amine group of N-deoxycholylethylamine (EtDOCA) with the carboxylic groups of heparin at various DOCA conjugation ratios. The LMWH-DOCA conjugate series (LHD1, LHD1.5, LHD2, and LHD4) were further formulated with poloxamer 407 as a solubilizer for oral administration. An in vitro endothelial tubular formation and in vivo Matrigel plug assay were performed to verify the antiangiogenic potential of LHD. Finally, we evaluated tumor growth inhibition of oral LHD administration in a SCC7 model as well as in A549 human cancer cell lines in a mouse xenograft model. Increasing DOCA conjugation ratios showed decreased anticoagulant activity, eventually to zero. LHD could block angiogenesis in the tubular formation assay and the Matrigel plug assay. In particular, oral administration of LHD4, which has 4 molecules of DOCA per mole of LMWH, inhibited tumor growth in SCC7 mice model as well as A549 mice xenograft model. LHD4 was orally
Anticoagulation plays an important role in the prevention and treatment of thromboembolism. Heparin and warfarin are the two most common anticoagulants. The development of new anticoagulants advanced rapidly over recent years. The advantages of novel anticoagulants were: (1) They are used either intravenously with rapid onset of action or orally with improved patient convenience. (2) May be used for patients with renal insufficiency. (3) The doses are stable, do not need laboratory monitoring. (4) Less bleeding, less adverse reactions. AVE5026, idrabiotaparinux, otamixaban, RB006, dabigatran etexilate, AZD0837, rivaroxaban, apixaban and edoxaban are new anticoagulants which are used widely in clinic and research work currently.%抗凝治疗在预防和治疗血栓栓塞性疾病中发挥重要作用.肝素和华法林是最经典的抗凝药物.近年来新的抗凝药物进展很快.新的抗凝药物的优点是:(1)有的经静脉应用,起效快;有的口服,使用方便.(2)可用于肾功能不全患者.(3)使用剂量较稳定,不需实验室监测.(4)出血不良反应小.AVE5026、艾比肝素、奥米沙班、RB006、达比加群酯、AZD0837、利伐沙班、阿哌沙班、依度沙班等为目前研究和临床应用较多的新的抗凝药物.
Full Text Available Background: The marine environment is anexceptional reservoir of bioactive natural products, many of them exhibit structural/chemical features that not found in terrestrial natural products.Glycosaminoglycans are one of this various bioactive compounds. Heparin, as a well known glycosaminoglycan, is a sulfated glycosaminoglycan that has natural anticoagulant properties. Heparin and heparin-like compounds are used as anticoagulants in many aspects of medicine. However, for two main reasons: 1. Contamination in heparin samples obtained from pig intestine or bovine lung pathogens and other pathogens, 2 .resource for use of heparin is limited and there are a lot of requirements for new compounds from natural resources. According to GAGs importance and widespread using of heparin in medicine, in the present study, GAGs compounds extracted from sea anemones and anticoagulant properties of the human blood is investigated. Materials and Methods: GAGs compound was extracted by using cetylpyridinium chloride. Anticoagulation activity of extracted GAGs (the extracted tentacle was tested in human blood plasma, using manual procedures, and assay system, prothrombin time (PT and activated partial thromboplastin time (APTT. Results: In this study the amount of the crude GAGs was 24 mg per gram of tentacle dry weight. The results ofanticoagulant activity extracted on human blood plasma showed that these compounds prolonged clotting time compared to the control. In APTT and PT assay of the extracted GAGs from the sea anemone also clotting time prolonged in compared to the control. Conclusion: The results demonstrated that anticoagulant compounds existed in the tentacle of the sea anemone, and although their effects is weaker than the heparin, but they can be substituted for heparin, at least in laboratory conditions.
López-Lacomba, Daniel; Roa-López, Antonio; González-Jaranay, Maximino; Gómez-Moreno, Gerardo
Background The aim is to evaluate periodontal alteration and biochemical markers associated with bone turnover in chronic oral with dicoumarins anticoagulant treatment patients. Material and Methods 80 patients treated with oral anticoagulants were divided into 2 cohort: Group A (n=36) 6 month to 1 year with anticoagulant treatment and Group B (n=44) > 2 years with anticoagulant treatment. Clinical evaluation included: Clinical attachment level (CAL), plaque index (PI) and gingival index (GI). Analytically biochemical parameters of bone remodeling (calcium and phosphorus), formation (total acid phosphatase, alkaline phosphatase and osteocalcin) and resorption (tartrate-resistant acid phosphatase and beta-crosslaps) were evaluated. Results High values of PI (67-100%) especially in men and in Group B were observed. Men with anticoagulation treatment length showed an increased GI (49.167 vs 78.083) while Group B women showed a decreased GI in comparison with Group A (59.389 vs 42.120). Women presented a greater average CAL than men as well as Group B vs Group A but without statistical significance. All biochemical markers were decreased respect to values of general population. Osteocalcin in GroupB women showed a statistically significant outcome vs GroupA (p=0.004). Acid phosphatase (total and tartrate-resistant) has a slight increase in Group B women versus Group A, and Beta-crosslap showed lower values in Group A men than Group B and slightly lower in Group A women versus Group B, without statistical significance. Conclusions Patients showed a slight to moderate degree of periodontal affectation, especially gingivitis related to bacterial plaque. Periodontal disorders tended to be more severe in Group B. While bone remodeling showed an overall decrease with greater affectation of bone neoformation phenomena, bone destruction tended to recover and normalize in time. Key words:Periodontal disease, dicoumarin, biochemical markers, bone remodeling. PMID:28160591
Gómez-Outes, Antonio; Suárez-Gea, M Luisa; Lecumberri, Ramón; Terleira-Fernández, Ana Isabel; Vargas-Castrillón, Emilio; Rocha, Eduardo
Venous thromboembolism (VTE), encompassing deep vein thrombosis and pulmonary embolism, represents a major cause of morbidity and mortality in patients with cancer. Low molecular weight heparins are the preferred option for anticoagulation in cancer patients according to current clinical practice guidelines. Fondaparinux may also have a place in prevention of VTE in hospitalized cancer patients with additional risk factors and for initial treatment of VTE. Although low molecular weight heparins and fondaparinux are effective and safe, they require daily subcutaneous administration, which may be problematic for many patients, particularly if long-term treatment is needed. Studying anticoagulant therapy in oncology patients is challenging because this patient group has an increased risk of VTE and bleeding during anticoagulant therapy compared with the population without cancer. Risk factors for increased VTE and bleeding risk in these patients include concomitant treatments (surgery, chemotherapy, placement of central venous catheters, radiotherapy, hormonal therapy, angiogenesis inhibitors, antiplatelet drugs), supportive therapies (ie, steroids, blood transfusion, white blood cell growth factors, and erythropoiesis-stimulating agents), and tumor-related factors (local vessel damage and invasion, abnormalities in platelet function, and number). New anticoagulants in development for prophylaxis and treatment of VTE include parenteral compounds for once-daily administration (ie, semuloparin) or once-weekly dosing (ie, idraparinux and idrabiotaparinux), as well as orally active compounds (ie, dabigatran, rivaroxaban, apixaban, edoxaban, betrixaban). In the present review, we discuss the pharmacology of the new anticoagulants, the results of clinical trials testing these new compounds in VTE, with special emphasis on studies that included cancer patients, and their potential advantages and drawbacks compared with existing therapies.
Subhalaxmi Borah; Ashok Naglot; Sewali Goswami; Imtiaz Rahman; Manab Deka
Objective: To study the morphology of the salivary gland of the female blackfly of the speciesSimulium indicum gland extract.Methods:(S. indicum) along with protein profile and anticoagulant activity of the salivary protein profile of the salivary gland extract (SGE) and anticoagulant activities against thrombin, and the extrinsic and intrinsic coagulation pathways were found in S. indicum SGE in the TT, PT and APTT assays, respectively.Results:Sodium dodecyl sulphate polyacrylamide gel electrophoresis was used to analyze the and a more or less spherical reservoir. The protein contents of whole salivary glands were also quantified and the amount of salivary gland proteins in the adult female S. indicum was found out to be approximately 1.12±0.13 µg/female. At least 16 major and several minor protein bands Results revealed that each gland consisted of a cylindrical U-shaped secretory lobe were detected in the female salivary glands. The molecular masses of these major protein bands were estimated at 69, 65, 61, 58, 44, 42, 39, 33, 30, 28, 27, 26, 23, 21, 18 and 16 kDa, consecutively. Anticoagulant activities were found in S. indicum SGE in all the assays. It was found that SGE prolonged human plasma clotting time in a dose-dependent manner. Factor Xa inhibition was shown by the SGE of S. indicum. Percent inhibition value was 93.8. A positive correlation (r=0.89) was observed between total protein and percent inhibition of factor Xa. Conclusions: The present study demonstrated that the mode of action of the anticoagulant(s) is mainly on the inhibition of thrombin and factor Xa along with other target factors of the coagulation cascade.
Full Text Available Abstract Aim In order to avoid the complications associated with thromboembolic disease, patients with this condition typically are placed on long-term anticoagulant therapy. This report compares bleeding complications in this patient population by level of achieved INR. Materials and Methods During the 6-year period between January 1997 and January 2003, 386 patients with venous thromboembolism of the lower extremities were admitted to the Cardiovascular Surgery Outpatient Clinic of Alsancak State Hospital. Of the 386 patients, 198 (51.2% were women, and the average age was 52.3 years. All diagnoses of venous thromboembolism were confirmed by means of Doppler ultrasonography. Further investigation showed occult neoplasms in 22 (5.6% of the cases. We excluded the patients with occult disease, and the remaining 364 constituted our study population. Results Oral anticoagulation was standardized at 6 months' duration in all cases. We divided the patients into two groups. Group I consisted of 192 patients (52.7% with INR values between 1.9 and 2.5; Group II comprised 172 patients with INR values between 2.6 and 3.5. Complications in each group were assessed and compared. The minor hemorrhage rate was 1.04% in Group I and 4.06% in Group II. The major hemorrhage rate was also 1.04% in Group I and was 6.3% in Group II. We determined that the complication rates for both minor and major hemorrhage were significant in patients with INR values above 2.5. Conclusion Oral anticoagulation must be followed closely in patients with venous thromboembolism. Higher INR levels are associated with significant increases in hemorrhage and associated complications. INR values of 2.0 to 2.5 are sufficient for long-term anticoagulant therapy, ensuring ideal anticoagulation levels and minimizing the complication rate.
Lippi, Giuseppe; Favaloro, Emmanuel J; Mattiuzzi, Camilla
The recent development and marketing of novel direct oral anticoagulants (DOACs) represents a paradigm shift in the management of patients requiring long-term anticoagulation. The advantages of these compounds over traditional therapy with vitamin K antagonists include a reportedly lower risk of severe hemorrhages and the limited need for laboratory measurements. However, there are several scenarios in which testing should be applied. The potential for drug-to-drug interaction is one plausible but currently underrecognized indication for laboratory assessment of the anticoagulant effect of DOACs. In particular, substantial concern has been raised during Phase I studies regarding the potential interaction of these drugs with some antibiotics, especially those that interplay with permeability glycoprotein (P-gp) and cytochrome 3A4 (CYP3A4). A specific electronic search on clinical trials published so far confirms that clarithromycin and rifampicin significantly impair the bioavailability of dabigatran, whereas clarithromycin, erythromycin, fluconazole, and ketoconazole alter the metabolism of rivaroxaban in vivo. Because of their more recent development, no published data were found for apixaban and edoxaban, or for potential interactions of DOACs with other and widely used antibiotics. It is noteworthy, however, that an online resource based on Food and Drug Administration and social media information, reports several hemorrhagic and thrombotic events in patients simultaneously taking dabigatran and some commonly used antibiotics such as amoxicillin, cephalosporin, and metronidazole. According to these reports, the administration of antibiotics in patients undergoing therapy with DOACs would seem to require accurate evaluation as to whether dose adjustments (personalized or antibiotic class driven) of the anticoagulant drug may be advisable. This might be facilitated by direct laboratory assessments of their anticoagulant effect ex vivo.
T.K. Mohammed Rayees
Full Text Available In the prophylaxis of stroke in Non valvular Atrial Fibrillation (NVAF as well as Deep Vein Thrombosis (DVT and Pulmonary Embolism (PE treatment, the Novel Oral Anticoagulants are becoming popular management option. These NOACs have efficacy similar to that of Warfarin along with non inferior safety profiles. Though Warfarin has been widely used because of its anticoagulant effect and also has a probable reversibility in terms of bleeding, it may also be disadvantageous sometimes in few cases such as food interactions, drug and drug interaction, having a poor and unpredictable therapeutic response. The use of Novel Oral Anticoagulants (NOACs, approved by U.S Food and Drug Administration (FDA rendered a new hope in patients who needed anticoagulant therapy. There are about four Novel Oral Anticoagulants approved by FDA, which includes Dabigatran (direct thrombin inhibitor, Rivaroxaban, Apixaban and Edoxaban (selective factor Xa Inhibitors. The predictable pharmacokinetics and minimal drug interactions of apixaban should allow for safe anticoagulation in the majority of patients, including temporary interruption for elective procedures. The main aim is to provide better treatment and prophylaxis of stroke, venous thromboembolism and Pulmonary Embolism using Novel Oral Anticoagulants (NOACs as they exhibit minimal adverse effects when compared to Warfarin.
Zanon, Ezio; Martinelli, Franco; Bacci, Christian; Cordioli, GianPiero; Girolami, Antonio
We found no prospective studies on dental extraction in anticoagulated patients in the literature, even though most authors suggest that there is no need to change anticoagulant treatment and to utilize a local haemostatic measure after extraction. In the present study, we have verified the incidence of bleeding complications after dental extraction in a group of 250 consecutive anticoagulated patients. Two hundred and fifty non-anticoagulated subjects requiring dental extraction represented the control group. In all patients, anticoagulant treatment was not changed (International Normalized Ratio, 1.8-4) and local haemostatic measures (fibrin sponge, silk suture and a gauze saturated with tranexamic acid) were used. All procedures were performed in an outpatient clinic setting. We registered four bleeding complications in the group of anticoagulated patients and three in the control group. The difference of bleeding complications in the two groups was not statistically different (relative risk, 1.14; 95% confidence interval, 0.29-6.04; P = 0.7). None of the post-operative late bleeding required hospitalization and/or blood transfusions, and further local measures were sufficient to stop the bleeding. The protocol proposed in the present study makes dental extractions in anticoagulated patients possible on an outpatient basis with a cost reduction for the community and minor discomfort for the patients.
Konstantinos C Thomopoulos; Konstantinos P Mimidis; George J Theocharis; Anthie G Gatopoulou; Georgios N Kartalis; Vassiliki N Nikolopoulou
AIM: Acute gastrointestinal bleeding is a severe complication in patients receiving long-term oral anticoagulant therapy.The purpose of this study was to describe the causes and clinical outcome of these patients.METHODS: From January 1999 to October 2003, 111patients with acute upper gastrointestinal bleeding (AUGIB)were hospitalized while on oral anticoagulants. The causes and clinical outcome of these patients were compared with those of 604 patients hospitalized during 2000-2001with AUGIB who were not taking warfarin.RESULTS: The most common cause of bleeding was peptic ulcer in 51 patients (45%) receiving anticoagulants compared to 359/604 (59.4%) patients not receiving warfarin (P＜0.05). No identifiable source of bleeding could be found in 33 patients (29.7%) compared to 31/604(5.1%) patients not receiving anticoagulants (P= 0.0001).The majority of patients with concurrent use of non-steroidal anti-inflammatory drugs (NSATDs) (26/35, 74.3%) had a peptic ulcer as a cause of bleeding while 32/76 (40.8%)patients not taking a great dose of NSATDs had a negative upper and lower gastrointestinal endoscopy. Endoscopic hemostasis was applied and no complication was reported.Six patients (5.4%) were operated due to continuing or recurrent hemorrhage, compared to 23/604 (3.8%) patients not receiving anticoagulants. Four patients died, the overall mortality was 3.6% in patients with AUGIB due to anticoagulants, which was not different from that in patients not receiving anticoagulant therapy.CONCLUSION: Patients with AUGIB while on long-term anticoagulant therapy had a clinical outcome, which is not different from that of patients not taking anticoagulants.Early endoscopy is important for the management of these patients and endoscopic hemostasis can be safely applied.
Sangrithi, Mahesh N; Royo, Helene; Mahadevaiah, Shantha K; Ojarikre, Obah; Bhaw, Leena; Sesay, Abdul; Peters, Antoine H F M; Stadler, Michael; Turner, James M A
Somatic X dosage compensation requires two mechanisms: X inactivation balances X gene output between males (XY) and females (XX), while X upregulation, hypothesized by Ohno and documented in vivo, balances X gene with autosomal gene output. Whether X dosage compensation occurs in germ cells is unclear. We show that mouse and human germ cells exhibit non-canonical X dosage states that differ from the soma and between the sexes. Prior to genome-wide reprogramming, X upregulation is present, consistent with Ohno's hypothesis. Subsequently, however, it is erased. In females, erasure follows loss of X inactivation, causing X dosage excess. Conversely, in males, erasure leads to permanent X dosage decompensation. Sex chromosomally abnormal models exhibit a "sex-reversed" X dosage state: XX males, like XX females, develop X dosage excess, while XO females, like XY males, develop X dosage decompensation. Thus, germline X dosage compensation states are determined by X chromosome number, not phenotypic sex. These unexpected differences in X dosage compensation states between germline and soma offer unique perspectives on sex chromosome infertility.
Stigendal, L; André, U; Christenson, B
As long-term anticoagulant treatment, with warfarin for instance, is associated with a risk of both thrombotic and thrombolytic complications, blood testing for dose regulation is necessary at 3-8-week intervals, which is expensive and inconvenient for patients who must take time off work and travel to and fro. A new technique, using small portable monitors designed for home use by patients, makes self-management of anticoagulant treatment possible. In Germany, over 25,000 patients had their own monitor by the end of 1998. After appropriate instruction, the German patients are able to monitor their prothrombin time and adjust their anticoagulant treatment accordingly. In case of problems they contact their GP. In a two-year pilot study conducted at the Anticoagulation Clinic of Sahlgrenska University Hospital, Gothenburg, in 1996-98, where 51 patients on long-term anticoagulant treatment were trained in self-management, the results of over 1,000 patient-hours of treatment showed self-management to be at least as safe as management by the clinic. The level of patient satisfaction is high, in terms of safety and freedom from regular hospital attendance during working hours, and the convenience of self-monitoring on holiday or business trips. As the patients do their testing once a week, the risk of complications is also reduced.
Chen Muyan; Yang Hongsheng; Shi Fangfang
Mixtures of hemolymph from Chlamys farreri with three different anticoagulant solutions were incubated for an hour in vitro , then the ultrastructural alterations of hemocytes were observed , and the aggregation rate was analyzed by using transmission electron microscropy and flow cytometry respectively. The results showed that Formula 3 (glucose 20. 8 g L-1; EDTA 20mM ; sodium chloride 20 g L-1 ; Tris-HCl 0.05M;pH 7. 4) was the desirable anticoagulant solution for C . Farreri hemocytes. Further phagocytosis assay showed that no obvious negative effect was given to the hemocyte phagocytic activity when using Formula 3 as the anticoagulant solution.
Full Text Available Two simple, rapid, and precise methods - linear regression equation (LRE and standard absorptivity - were developed and validated for the estimation of pioglitazone hydrochloride in tablet dosage form. The maximum absorbance (lmax of pioglitazone hydrochloride was found to be 269.8 nm in methanol:water:hydrochloric acid (250:250:1. Beer-Lambert law was obeyed in the concentration range of 10-50 µg/ml, and the standard absorptivity was found to be 253.97 dl/g/cm. Both the methods were validated for linearity, accuracy, precision (days, analysts, and instrument variation, and robustness (solvent composition. The numerical values for all parameters lie within the acceptable limits. Pioglitazone hydrochloride was estimated in the range of 99.58-99.97% by LRE method and 100.25-100.75% by standard absorptivity method. At 99% confidence limit, the F-test value for the methods was found to be 1.8767.
Satinder Kakar; Ramandeep Singh; Alok Semwal
Area of drug delivery is vast, and various advances have been made in the medical field. Besides the versatility in the dosage forms, various orders for the drug release are known, which includes zero order, first order, Higuchi model, Hixon Crowell model and Korsmeyer Peppas model. In vitro dissolution is recognized as an important element in the development of drug. The nature of the drug such as its shape, crystallinity, particle size and solubility reflects the kinetics of the drug. Various models are used to study the dissolution profiles of the new drug substances. Qualitative and quantitative changes in the drug alters the drug release and performance that is action of drug in the body, which is in vivo performance. Various model dependent methods and model independent methods have been taken into consideration for studying the drug release kinetics.
Peng, Weilin; Song, Ruijie; Acar, Murat
Genetic noise together with genome duplication and volume changes during cell cycle are significant contributors to cell-to-cell heterogeneity. How can cells buffer the effects of these unavoidable epigenetic and genetic variations on phenotypes that are sensitive to such variations? Here we show that a simple network motif that is essential for network-dosage compensation can reduce the effects of extrinsic noise on the network output. Using natural and synthetic gene networks with and without the network motif, we measure gene network activity in single yeast cells and find that the activity of the compensated network is significantly lower in noise compared with the non-compensated network. A mathematical analysis provides intuitive insights into these results and a novel stochastic model tracking cell-volume and cell-cycle predicts the experimental results. Our work implies that noise is a selectable trait tunable by evolution. PMID:27694830
Jantratid, E; Prakongpan, S; Dressman, J B; Amidon, G L; Junginger, H E; Midha, K K; Barends, D M
Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing cimetidine are reviewed. According to the current Biopharmaceutics Classification System (BCS), cimetidine would be assigned to Class III. Cimetidine's therapeutic use and therapeutic index, its pharmacokinetic properties, data related to the possibility of excipient interactions, and reported BE/bioavailability (BA) problems were also taken into consideration. On the basis of the overall evidence, a biowaiver can be recommended for cimetidine IR products, provided that the test product contains only those excipients reported in this paper in their usual amounts, and that the test and the comparator drug products both are "rapidly dissolving" as per BCS.
Granero, G E; Longhi, M R; Mora, M J; Junginger, H E; Midha, K K; Shah, V P; Stavchansky, S; Dressman, J B; Barends, D M
Literature and new experimental data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing furosemide are reviewed. The available data on solubility, oral absorption, and permeability are sufficiently conclusive to classify furosemide into Class IV of the Biopharmaceutics Classification System (BCS). Furosemide's therapeutic use and therapeutic index, its pharmacokinetic properties, data related to the possibility of excipient interactions and reported BE/bioavailability (BA) problems are also taken into consideration. In view of the data available, it is concluded that the biowaiver procedure cannot be justified for either the registration of new multisource drug products or major postapproval changes (variations) to existing drug products.
Potthast, H; Dressman, J B; Junginger, H E; Midha, K K; Oeser, H; Shah, V P; Vogelpoel, H; Barends, D M
Literature data are reviewed on the properties of ibuprofen related to the biopharmaceutics classification system (BCS). Ibuprofen was assessed to be a BCS class II drug. Differences in composition and/or manufacturing procedures were reported to have an effect on the rate, but not the extent of absorption; such differences are likely to be detectable by comparative in vitro dissolution tests. Also in view of its therapeutic use, its wide therapeutic index and uncomplicated pharmacokinetic properties, a biowaiver for immediate release (IR) ibuprofen solid oral drug products is scientifically justified, provided that the test product contains only those excipients reported in this paper in their usual amounts, the dosage form is rapidly dissolving (85% in 30 min or less) in buffer pH 6.8 and the test product also exhibits similar dissolution profiles to the reference product in buffer pH 1.2, 4.5, and 6.8.
Granero, G E; Longhi, M R; Becker, C; Junginger, H E; Kopp, S; Midha, K K; Shah, V P; Stavchansky, S; Dressman, J B; Barends, D M
Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing acetazolamide are reviewed. Acetazolamide's solubility and permeability characteristics according to the Biopharmaceutics Classification System (BCS), as well as its therapeutic use and therapeutic index, its pharmacokinetic properties, data related to the possibility of excipient interactions and reported BE/bioavailability (BA) problems are taken into consideration. The available data on solubility, on oral absorption and permeability are not sufficiently conclusive to classify acetazolamide with certainty. Taking a conservative approach, no biowaiver is considered justified for the registration of new multisource drug products. However, SUPAC level 1 and level 2 postapproval changes and most EU Type I variations can be approved waiving in vivo BE studies.
Full Text Available The aim of this work was to investigate the suitability of electrospinning for biodrug delivery and to develop an electrospinning-based method to produce vaginal drug delivery systems. Lactobacillus acidophilus bacteria were encapsulated into nanofibers of three different polymers (polyvinyl alcohol and polyvinylpyrrolidone with two different molar masses. Shelf life of the bacteria could be enhanced by the exclusion of water and by preparing a solid dosage form, which is an advantageous and patient-friendly way of administration. The formulations were stored at –20, 7 and 25°C, respectively. Viability testing showed that the nanofibers can provide long term stability for huge amounts of living bacteria if they are kept at (or below 7°C. Furthermore, all kinds of nanowebs prepared in this work dissolved instantly when they got in contact with water, thus the developed biohybrid nanowebs can provide new potential ways for curing bacterial vaginosis.
FELICIA G. GLIGOR
Full Text Available Several tablet formulations containing silymarin were developed, in order to meet the requirements of different markets. Milk thistle - Silybum marianum (L. Gaertn – standardized extracts have proven their positive effect on liver functionality plus other health benefits. Lactose is a widely used excipient for the production of oral solid dosage forms. One important inconvenient of lactose is related to the lactose intolerant potential customers. Cellulose, isomalt and dicalcium phosphate have been selected as alternative possible tablet binders and diluents. Laboratory and pilot batches were studied for each excipient. The pharmacotechnical properties and silybin content of the tablets were measured and recorded in accordance to the European Pharmacopoeia. All pilot batches had results in the desired range of values in order to permit large scale compacting and blistering of the tablets. Currently the formulations containing isomalt and dicalcium phosphate that made the subject of this study are being produced on industrial scale.
Full Text Available Laura A Michielsen,1 Frank MMA van der Heijden,1 Paddy KC Janssen,2 Harold JH Kuijpers11Vincent van Gogh Institute for Psychiatry, Venlo, the Netherlands; 2Department of Pharmacy, VieCuri Medical Centre, Venlo, the NetherlandsBackground: The aim of this retrospective study was to explore the relationship between psychotropic medication dosage and birth outcomes.Methods: A total of 136 women were enrolled, who had an active mental disorder, were taking medication to prevent a relapse, or had a history of postpartum depression or psychosis. Medication use was evaluated for the three trimesters and during labor. Based on the defined daily dose, medication use was classified into three groups. Primary outcome variables included the infant gestational age at birth, birth weight, and Apgar scores at one and 5 minutes.Results: Our study showed a significantly higher incidence of Apgar score ≤7 at 5 minutes in women taking psychotropic drugs as compared with the group taking no medication, respectively (16.3% versus 0.0%, P=0.01. There was no significant difference between the two groups in Apgar score at one minute or in gestational age and birth weight. The results showed no significant differences in gestational age, birth weight, or Apgar scores for a low–intermediate or high dose of a selective serotonin reuptake inhibitor and for a low or intermediate dose of an antipsychotic.Conclusion: This study does not indicate a relationship between doses of selective serotonin reuptake inhibitors and antipsychotics and adverse neonatal outcomes.Keywords: pregnancy, psychotropic medication, dosage, birth outcomes
Hug, Alexandra; Udert, Kai M
When magnesium is added to source-separated urine, struvite (MgNH(4)PO(4)·6H(2)O) precipitates and phosphorus can be recovered. Up to now, magnesium salts have been used as the main source of magnesium. Struvite precipitation with these salts works well but is challenging in decentralized reactors, where high automation of the dosage and small reactor sizes are required. In this study, we investigated a novel approach for magnesium dosage: magnesium was electrochemically dissolved from a sacrificial magnesium electrode. We demonstrated that this process is technically simple and economically feasible and thus interesting for decentralized reactors. Linear voltammetry and batch experiments at different anode potentials revealed that the anode potential must be higher than -0.9 V vs. NHE (normal hydrogen electrode) to overcome the strong passivation of the anode. An anode potential of -0.6 V vs. NHE seemed to be suitable for active magnesium dissolution. For 13 subsequent cycles at this potential, we achieved an average phosphate removal rate of 3.7 mg P cm(-2) h(-1), a current density of 5.5 mA cm(-2) and a current efficiency of 118%. Some magnesium carbonate (nesquehonite) accumulated on the anode surface; as a consequence, the current density decreased slightly, but the current efficiency was not affected. The energy consumption for these experiments was 1.7 W h g P(-1). A cost comparison showed that sacrificial magnesium electrodes are competitive with easily soluble magnesium salts such as MgCl(2) and MgSO(4), but are more expensive than dosing with MgO. Energy costs for the electrochemical process were insignificant. Dosing magnesium electrochemically could thus be a worthwhile alternative to dosing magnesium salts. Due to the simple reactor and handling of magnesium, this may well be a particularly interesting approach for decentralized urine treatment.
Shohin, Igor E; Kulinich, Julia I; Ramenskaya, Galina V; Abrahamsson, Bertil; Kopp, Sabine; Langguth, Peter; Polli, James E; Shah, Vinod P; Groot, D W; Barends, Dirk M; Dressman, Jennifer B
Literature and experimental data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing piroxicam in the free acid form are reviewed. Piroxicam solubility and permeability, its therapeutic use and therapeutic index, pharmacokinetic properties, data related to the possibility of excipient interactions and reported BE/bioavailability (BA), and corresponding dissolution data are taken into consideration. The available data suggest that according to the current biopharmaceutics classification system (BCS) and all current guidances, piroxicam would be assigned to BCS Class II. The extent of piroxicam absorption seems not to depend on manufacturing conditions or excipients, so the risk of bioinequivalence in terms of area under the curve (AUC) is very low, but the rate of absorption (i.e., BE in terms of Cmax ) can be affected by the formulation. Current in vitro dissolution methods may not always reflect differences in terms of Cmax for BCS Class II weak acids; however, minor differences in absorption rate of piroxicam would not subject the patient to unacceptable risks: as piroxicam products may be taken before or after meals, the rate of absorption cannot be considered crucial to drug action. Therefore, a biowaiver for IR piroxicam solid oral dosage form is considered feasible, provided that (a) the test product contains only excipients, which are also present in IR solid oral drug products containing piroxicam, which have been approved in ICH or associated countries, for instance, those presented in Table 3 of this paper; (b) both the test and comparator drug products dissolve 85% in 30 min or less at pH 1.2, 4.5, and 6.8; and (c) the test product and comparator show dissolution profile similarity in pH 1.2, 4.5, and 6.8. When not all of these conditions can be fulfilled, BE of the products should be established in vivo.
Full Text Available Objectives: To evaluate the effects of folic acid supplementation on isolated oral cleft recurrence and fetal growth. Patients and Methods: The study included 2,508 women who were at-risk for oral cleft recurrence and randomized into two folic acid supplementation groups: 0.4 and 4 mg per day before pregnancy and throughout the first trimester. The infant outcome data were based on 234 live births. In addition to oral cleft recurrence, several secondary outcomes were compared between the two folic acid groups. Cleft recurrence rates were also compared to historic recurrence rates. Results: The oral cleft recurrence rates were 2.9% and 2.5% in the 0.4 and 4 mg groups, respectively. The recurrence rates in the two folic acid groups both separately and combined were significantly different from the 6.3% historic recurrence rate post the folic acid fortification program for this population (p = 0.0009 when combining the two folic acid groups. The rate of cleft lip with palate recurrence was 2.9% in the 0.4 mg group and 0.8% in the 4 mg group. There were no elevated fetal growth complications in the 4 mg group compared to the 0.4 mg group. Conclusions: The study is the first double-blinded randomized clinical trial (RCT to study the effect of high dosage folic acid supplementation on isolated oral cleft recurrence. The recurrence rates were similar between the two folic acid groups. However, the results are suggestive of a decrease in oral cleft recurrence compared to the historic recurrence rate. A RCT is still needed to identify the effect of folic acid on oral cleft recurrence given these suggestive results and the supportive results from previous interventional and observational studies, and the study offers suggestions for such future studies. The results also suggest that high dosage folic acid does not compromise fetal growth.
Full Text Available Antonio Gómez-Outes,1 M Luisa Suárez-Gea,1 Ramón Lecumberri,2 Ana Isabel Terleira-Fernández,3,4 Emilio Vargas-Castrillón,3,4 Eduardo Rocha51Division of Pharmacology and Clinical Evaluation, Medicines for Human Use, Spanish Agency for Medicines and Medical Devices, Madrid, 2Department of Hematology, University Clinic of Navarra, Pamplona, 3Department of Clinical Pharmacology, Hospital Clínico, Madrid, 4Department of Pharmacology, Universidad Complutense, Madrid, 5Department of Hematology, School of Medicine, University of Navarra, Pamplona, SpainAbstract: Venous thromboembolism (VTE, encompassing deep vein thrombosis and pulmonary embolism, represents a major cause of morbidity and mortality in patients with cancer. Low molecular weight heparins are the preferred option for anticoagulation in cancer patients according to current clinical practice guidelines. Fondaparinux may also have a place in prevention of VTE in hospitalized cancer patients with additional risk factors and for initial treatment of VTE. Although low molecular weight heparins and fondaparinux are effective and safe, they require daily subcutaneous administration, which may be problematic for many patients, particularly if long-term treatment is needed. Studying anticoagulant therapy in oncology patients is challenging because this patient group has an increased risk of VTE and bleeding during anticoagulant therapy compared with the population without cancer. Risk factors for increased VTE and bleeding risk in these patients include concomitant treatments (surgery, chemotherapy, placement of central venous catheters, radiotherapy, hormonal therapy, angiogenesis inhibitors, antiplatelet drugs, supportive therapies (ie, steroids, blood transfusion, white blood cell growth factors, and erythropoiesis-stimulating agents, and tumor-related factors (local vessel damage and invasion, abnormalities in platelet function, and number. New anticoagulants in development for prophylaxis
Phillips, R; Plaa, G L
The biliary excretion of diazepam metabolites was found in rats. Equivalent dosages of diazepam were administered orally and intraperitoneally. The biliary excretion was dose-dependent and was greater following intraperitoneal administration. After intravenous administration, a greater percentage of the diazepam dosage administered was excreted into the bile. Repetitive intravenous administrations yielded results which approached those observed after intraperitoneally administered dosages given as a bolus.
Odineila Martins Monteiro
Full Text Available This study aimed to determine the more efficient and economically viable dosage of chemical insecticide to control Quesada gigas (Hemiptera: Cicadidae nymphs in parica plantations. Three dosages of three products (carbofuran, imidacloprid and thiamethoxam were tested based on the maximum recommended dosage for the control of cicadas in coffee plants and applied in total area. The dosage of one kilogram of a commercial product based in thiamethoxam per hectare was more efficient economically and environmentally to control nymphs of Q. gigas in parica plantations.
Vanhille, Derek L; Nussenzveig, Roberto H; Glezos, Christopher; Perkins, Sherrie; Agarwal, Archana M
The HEMOX Analyzer (TCS Scientific) has been used to measure the full oxygen-dissociation curve (ODC) and to calculate P(50) and the Hill coefficient. The effects of different anticoagulants on sample stability and P(50) values have not been evaluated extensively for this instrument. We characterized an artificial hemoglobin (Equil QC463) for quality control (QC) and compared P(50) values for blood samples drawn into 3 different anticoagulants (acid citrate dextrose [ACD], heparin, and EDTA). P(50) values were not stable in ACD but were stable in heparin and EDTA anticoagulants for up to 4 days. Tests with Equil QC463 showed that P(50) values were quite sensitive to small variations in buffer pH. Use of the correct anticoagulant and strict control of buffer pH are 2 parameters that need to be accounted for in best-practices use of this hemoximeter and before determining P(50).
Verhoef, Talitha I; Redekop, William K; Hasrat, Fazila; de Boer, Anthonius; Maitland-van der Zee, Anke Hilse
OBJECTIVES: Our objectives were to investigate the cost effectiveness of apixaban, rivaroxaban, and dabigatran compared with coumarin derivatives for stroke prevention in patients with atrial fibrillation in a country with specialized anticoagulation clinics (the Netherlands) and in a country withou
Deitch, Edwin A; Qin, Xiaofa; Sheth, Sharvil U; Tiesi, Gregory; Palange, David; Dong, Wei; Lu, Qi; Xu, Dazhong; Feketeova, Eleonora; Feinman, Rena
Many models of trauma-hemorrhagic shock (T/HS) involve the reinfusion of anticoagulated shed blood. Our recent observation that the anticoagulant heparin induces increased mesenteric lymph lipase activity and consequent in vitro endothelial cell cytotoxicity prompted us to investigate the effect of heparin-induced lipase activity on organ injury in vivo as well as the effects of other anticoagulants on mesenteric lymph bioactivity in vitro and in vivo. To investigate this issue, rats subjected to trauma-hemorrhage had their shed blood anticoagulated with heparin, the synthetic anticoagulant arixtra (fondaparinux sodium), or citrate. Arixtra, in contrast to heparin, did not increase lymph lipase activity or result in high levels of endothelial cytotoxicity. Yet, the arixtra-treated rats subjected to T/HS still manifested lung injury, neutrophil priming, and red blood cell dysfunction, which was totally abrogated by lymph duct ligation. Furthermore, the injection of T/HS mesenteric lymph, but not sham-shock lymph, collected from the arixtra rats into control mice recreated the pattern of lung injury, polymorphonucleocyte (PMN) priming, and red blood cell dysfunction observed after actual shock. Consistent with these observations, citrate-anticoagulated rats subjected to T/HS developed lung injury, and the injection of mesenteric lymph from the citrate-anticoagulated T/HS rats into control mice also resulted in lung injury. Based on these results, several conclusions can be drawn. First, heparin-induced increased mesenteric lymph lipase activity is not responsible for the in vivo effects of T/HS mesenteric lymph. Second, heparin should be avoided as an anticoagulant when studying the biology or composition of mesenteric lymph because of its ability to cause increases in lymph lipase activity that increase the in vitro cytotoxicity of these lymph samples.
A. A. Rumyantsev
Full Text Available Despite large number of known risk factors of venous thromboembolism (VTE in cancer patients existing prediction models do not allow definite identification of cancer patients that have indications for anticoagulant prevention. Besides, heparin and warfarin use for VTE prevention in cancer is accompanied by some problems. New oral anticoagulants (NOAC are promising drugs for use in oncology practice; however their use is complicated by the lack of data on efficacy and safety in these patients, potential drug interactions and the possibility of unpredictable changes in effect during chemotherapy. Widespread use of NOAC for the prevention and treatment of tumor-associated VTE prior to phase III trials is not recommended. However, the criteria for selection of patients for whom the study of the efficacy and safety of NOAC is a priority can now be developed.
Full Text Available Non-neoplastic portal vein thrombosis (PVT is an increasingly recognized complication of liver cirrhosis. It is often diagnosed fortuitously and can be either partial or complete. The clinical significance of PVT is not obvious except in some situations such as when patients are on the waiting list for liver transplantation. The only known therapy is anticoagulation which has been shown to permit the disappearance of thrombosis and to prevent further extension. Anticoagulation is a challenging therapy in individuals with liver cirrhosis because of the well-recognized coagulation abnormalities observed in that setting and because of the increased risk of bleeding, especially from gastrointestinal tract caused by portal hypertension. We herein review the current knowledge on that topic in order to highlight the advantages and disadvantages of the currently proposed therapeutic attitudes in face of the diagnosis of PVT in individuals with cirrhosis.
Lamberts, Morten; Gislason, Gunnar H.; Lip, Gregory Y. H.
Background The optimal long-term antithrombotic treatment of patients with coexisting atrial fibrillation and stable coronary artery disease is unresolved, and commonly, a single antiplatelet agent is added to oral anticoagulation. We investigated the effectiveness and safety of adding antiplatelet...... or thromboembolism, whereas risk of bleeding is increased significantly. The common practice of adding antiplatelet therapy to oral VKA anticoagulation in patients with atrial fibrillation and stable coronary artery disease warrants reassessment........23-1.82]) or clopidogrel (hazard ratio, 1.84 [95% confidence interval, 1.11-3.06]) was added to VKA. Conclusions In atrial fibrillation patients with stable coronary artery disease, the addition of antiplatelet therapy to VKA therapy is not associated with a reduction in risk of recurrent coronary events...
Divchev, D; Nienaber, C; Ince, H
There is ongoing development of new therapeutic regimens in the use of antithrombotic agents and anticoagulants focussing on acute coronary syndrome (ACS) with an increasing impact on current guidelines over the last years. This was especially accompanied by an increase in innovative percutaneous coronary interventional (PCI) methods in patients with ACS, non-ST-segment elevation myocardial infarction (NSTEMI) or ST-segment elevation myocardial infarction (STEMI) with a need for therapeutics with more sufficient and effective antiplatelet action. On the other hand, newer direct and indirect thrombin inhibitors with primary use in prevention and therapy of thromboembolic events have been shown to have beneficial and even superior effects in ACS with or without PCI. The current review aims to report on the evidence-based use of approved antithrombotic agents and anticoagulants in ACS with special focus on PCI according to the actualized European guidelines.
Full Text Available Dabigatran etexilate (DE, rivaroxaban, and apixaban are nonvitamin K antagonist oral anticoagulants (NOACs that have been compared in clinical trials with existing anticoagulants (warfarin and enoxaparin in several indications for the prevention and treatment of thrombotic events. All NOACs presented bleeding events despite a careful selection and control of patients. Compared with warfarin, NOACs had a decreased risk of intracranial hemorrhage, and apixaban and DE (110 mg BID had a decreased risk of major bleeding from any site. Rivaroxaban and DE showed an increased risk of major gastrointestinal bleeding compared with warfarin. Developing strategies to minimize the risk of bleeding is essential, as major bleedings are reported in clinical practice and specific antidotes are currently not available. In this paper, the following preventive approaches are reviewed: improvement of appropriate prescription, identification of modifiable bleeding risk factors, tailoring NOAC’s dose, dealing with a missed dose as well as adhesion to switching, bridging and anesthetic procedures.