The History of Antithrombotic Therapy: The Discovery of Heparin, the Vitamin K Antagonists, and the Utility of Aspirin.

PubMed

Handin, Robert I

2016-10-01

The administration of intravenous heparin to postoperative patients by Barritt and Jordan reduced the incidence of fatal and nonfatal pulmonary embolism and established heparin as the standard for parenteral anticoagulation. The coumarin family of vitamin K antagonists quickly became the standard for long-term oral anticoagulation. Aspirin became a widely used antithrombotic agent after the discovery that chronic oral administration reduced the incidence of secondary strokes and myocardial infarction. This article gives a brief history of antithrombotic therapy, including the discovery of heparin, the vitamin k antagonists, and the utility of aspirin. Copyright © 2016 Elsevier Inc. All rights reserved.

Effect of lysine clonixinate on the pharmacokinetics and anticoagulant activity of phenprocoumon.

PubMed

Russmann, S; Dilger, K; Trenk, D; Nagyivanyi, P; Jähnchen, E

2001-11-01

The effect of the non-steroidal anti-inflammatory drug lysine clonixinate ([2-(3-chloro-o-toluidino)nicotinic acid]-L-lysinate, CAS 55837-30-4) on the pharmacokinetics and anticoagulant activity of phenprocoumon (4-hydroxy-3-(1-phenylpropyl)-coumarin, CAS 435-97-2) was investigated in an open, randomised, two-fold, cross-over study in 12 healthy male volunteers. These subjects received a single dose of 18 mg phenprocoumon without or with concomitant treatment with lysine clonixinate (125 mg five times a day for 3 days before and 13 days after ingestion of a single dose of phenprocoumon). Pharmacokinetic parameters of phenprocoumon following oral administration were: CL/f: 0.779 +/- 0.157 ml/min, half-life of elimination: 147.2 +/- 19.9 h; free fraction in serum: 0.51 +/- 0.20%. These parameters were not significantly altered by concomitant treatment with lysine clonixinate. Prothrombin time increased from 13.3 +/- 1.3 s (at time 0) to 17.7 +/- 2.7 s following phenprocoumon and from 13.3 +/- 1.2 s to 18.0 +/- 2.2 s following combined administration. Prothrombin time returned to the pretreatment values 240 h after administration of phenprocoumon. The integrated effect (AUEC0-288 h) was identical following both treatments (4.303 +/- 461 and 4.303 +/- 312 s x h for phenprocoumon alone and phenprocoumon with lysine clonixinate, respectively). Thus, lysine clonixinate administered in therapeutic doses does not affect the pharmacokinetics and anticoagulant activity of phenproxoumon.

21 CFR 189.130 - Coumarin.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Coumarin. 189.130 Section 189.130 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) SUBSTANCES PROHIBITED FROM USE IN HUMAN FOOD Substances Generally Prohibited From Direct Addition or Use as Human Food § 189...

Evaluation in vitro and in vivo of dimethicone transdermal therapeutic systems. Influence of propylene glycol on drug release.

PubMed

Ritschel, W A; Nayak, P M

1987-03-01

Coumarin-containing transdermal drug delivery systems were studied in vitro for drug release and in vivo in rats for drug absorption. The matrix of the transdermal delivery system, dimethicone, was a commercially available silicone elastomer. The devices containing 1, 3 and 5% coumarin released in vitro 8.8 (87.4%), 23.4 (74.5%) and 31.6 mg (63.3%) of drug within 24 h. The device containing 5% coumarin was selected for further studies in which 5, 10, 20, 30, 50 and 70% propylene glycol was added. Up to 20% propylene glycol content did not change the amount released. The preparations with 30, 50 and 70% propylene glycol released 69.3, 73.6 and 87.9%, respectively. The 50 and 70% preparations were physically not acceptable. Only the preparations containing 5% coumarin without propylene glycol and 5% coumarin and 30% propylene glycol in the elastomer were evaluated in vivo. The area under the blood level-time curve of the propylene glycol-containing system was twice that of the device without propylene glycol. Blood levels were maintained between about 2 micrograms/ml and 5 micrograms/ml during the time the device was kept on the skin (24 h).

[Pulmonary embolism following percutaneous vertebroplasty].

PubMed

Bedini, Marianela Patricia; Albertini, Ricarso Arturo; Orozco, Santiago

2013-01-01

Vertebroplasty is a minimally invasive technique for the treatment of osteoporotic fractures. Within its complications is pulmonary embolism, which can be asymptomatic or with respiratory distress and may be notes by radiography or computed tomography. At present there is no guide to indicate the routine performance of imaging techniques after treatment, and all agreed on the need to start anticoagulant therapy for 3 months or so with coumarin in symptomatic or asymptomatic central emboli.

A Self-Assembled Coumarin-Anchored Dendrimer for Efficient Gene Delivery and Light-Responsive Drug Delivery.

PubMed

Wang, Hui; Miao, Wujun; Wang, Fei; Cheng, Yiyun

2018-06-11

The assembly of low molecular weight polymers into highly efficient and nontoxic nanostructures has broad applicability in gene delivery. In this study, we reported the assembly of coumarin-anchored low generation dendrimers in aqueous solution via hydrophobic interactions. The synthesized material showed significantly improved DNA binding and gene delivery, and minimal toxicity on the transfected cells. Moreover, the coumarin moieties in the assembled nanostructures endow the materials with light-responsive drug delivery behaviors. The coumarin substitutes in the assembled nanostructures were cross-linked with each other upon irradiation at 365 nm, and the cross-linked assemblies were degraded upon further irradiation at 254 nm. As a result, the drug-loaded nanoparticle showed a light-responsive drug release behavior and light-enhanced anticancer activity. The assembled nanoparticle also exhibited a complementary anticancer activity through the codelivery of 5-fluorouracil and a therapeutic gene encoding tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). This study provided a facile strategy to develop light-responsive polymers for the codelivery of therapeutic genes and anticancer drugs.

New anticoagulants for the prevention of stroke in atrial fibrillation.

PubMed

Höchtl, Thomas; Huber, Kurt

2012-02-01

Oral anticoagulation in atrial fibrillation is obligatory to lower the risk of spontaneous cerebrovascular and systemic thromboembolism. For this purpose, vitamin K antagonists (coumarins) have been recommended as the most effective drugs for a long time. However, problems with the practical use of these agents, e.g. the need for frequent and regular coagulation controls, the inter-individual differences in maintaining a stable therapeutic range, as well as drug or food interactions, have led to the search and investigation of alternative compounds characterized by a more simple use (e.g. without regular controls of therapeutic levels), high efficacy, as well as low risk of bleeding. The direct thrombin inhibitor dabigatran and the direct factor Xa inhibitors rivaroxaban and apixaban have recently been investigated to prove whether they fulfill the high expectancy of an ideal anticoagulant with respect to a more favorable efficacy/safety profile and without the need for coagulation controls, thereby improving quality of life. Dabigatran (RE-LY) achieved an impressive reduction in stroke and non-central nervous system (non-CNS) embolism (110 mg: 1.5%/year; 150 mg: 1.1%/year) in contrast to warfarin (1.7%/year; P = 0.34 and P < 0.001) with a favorable action on bleeding hazards. The results of rivaroxaban which were obtained in the ROCKET AF study (on treatment analysis: stroke and non-CNS embolism: 1.7%/year vs. 2.15%/year with warfarin; P = 0.015; primary safety endpoint major and minor bleeding: 14.91 vs. 14.52%; P = 0.442) point in the same direction. And finally, compared to aspirin, apixaban reduced the combined primary efficacy endpoint by 52% with comparable rates of bleeding (AVERROES). This review gives a summary of the current knowledge about these agents and their potential future importance. © 2011 The Authors Fundamental and Clinical Pharmacology © 2011 Société Française de Pharmacologie et de Thérapeutique.

Anticoagulant Medicine: Potential for Drug-Food Interactions

MedlinePlus

... Medications Anticoagulants and Drug-Food Interactions Anticoagulants and Drug-Food Interactions Make an Appointment Ask a Question ... care provider before making the change. Anticoagulants and Medicine There are many medicines that can interact with ...

Recent developments of coumarin-containing derivatives and their anti-tubercular activity.

PubMed

Hu, Yuan-Qiang; Xu, Zhi; Zhang, Shu; Wu, Xiang; Ding, Jun-Wei; Lv, Zao-Sheng; Feng, Lian-Shun

2017-08-18

Tuberculosis (TB) is a lift-threatening chronic deadliest infectious disease caused predominantly by Mycobacterium tuberculosis (MTB) which affects primarily the lungs (pulmonary TB) apart from other vital organs. The emergence of drug-resistant TB (DR-TB), multidrug-resistant TB (MDR-TB), extensively drug-resistant TB (XDR-TB) and the recently cases of totally drug resistant (TDR) towards currently accessible standard drugs was increased up to alarming level in the recent decades. In pursuit of searching new anti-TB agents, numerous of derivatives have been synthesized and screened for their anti-TB activity. Coumarins are one of the most important classes of natural products that exhibited various biological activities, and their derivatives regarded as a new class of effective anti-TB candidates owing to their potential anti-TB activity. Thus, coumarin skeleton has attracted great interest in the development of new anti-TB agents. This review outlines the advances in the application of coumarin-containing derivatives as anti-TB agents and the critical aspects of design and structure-activity relationship of these derivatives. Published by Elsevier Masson SAS.

Oral Anticoagulant Use After Bariatric Surgery: A Literature Review and Clinical Guidance.

PubMed

Martin, Karlyn A; Lee, Craig R; Farrell, Timothy M; Moll, Stephan

2017-05-01

Bariatric surgery may alter the absorption, distribution, metabolism, or elimination (disposition) of orally administered drugs via changes to the gastrointestinal tract anatomy, body weight, and adipose tissue composition. As some patients who have undergone bariatric surgery will need therapeutic anticoagulation for various indications, appropriate knowledge is needed regarding anticoagulant drug disposition and resulting efficacy and safety in this population. We review general considerations about oral drug disposition in patients after bariatric surgery, as well as existing literature on oral anticoagulation after bariatric surgery. Overall, available evidence on therapeutic anticoagulation is very limited, and individual drug studies are necessary to learn how to safely and effectively use the direct oral anticoagulants. Given the sparsity of currently available data, it appears most prudent to use warfarin with international normalized ratio monitoring, and not direct oral anticoagulants, when full-dose anticoagulation is needed after bariatric surgery. Copyright © 2017 Elsevier Inc. All rights reserved.

Mechanism of action of coumarin and silver(I)-coumarin complexes against the pathogenic yeast Candida albicans.

PubMed

Thati, Bhumika; Noble, Andy; Rowan, Raymond; Creaven, Bernadette S; Walsh, Maureen; McCann, Malachy; Egan, Denise; Kavanagh, Kevin

2007-08-01

The anti-fungal activity and mode of action of a range of silver(I)-coumarin complexes was examined. The most potent silver(I)-coumarin complexes, namely 7-hydroxycoumarin-3-carboxylatosilver(I), 6-hydroxycoumarin-3-carboxylatosilver(I) and 4-oxy-3-nitrocoumarinbis(1,10-phenanthroline)silver(I), had MIC80 values of between 69.1 and 4.6 microM against the pathogenic yeast Candida albicans. These compounds also reduced respiration, lowered the ergosterol content of cells and increased the trans-membrane leakage of amino acids. A number of the complexes disrupted cytochrome synthesis in the cell and induced the appearance of morphological features consistent with cell death by apoptosis. These compounds appear to act by disrupting the synthesis of cytochromes which directly affects the cell's ability to respire. A reduction in respiration leads to a depletion in ergosterol biosynthesis and a consequent disruption of the integrity of the cell membrane. Disruption of cytochrome biosynthesis may induce the onset of apoptosis which has been shown previously to be triggered by alteration in the location of cytochrome c. Silver(I)-coumarin complexes demonstrate good anti-fungal activity and manifest a mode of action distinct to that of the conventional azole and polyene drugs thus raising the possibility of their use when resistance to conventional drug has emerged or in combination with such drugs.

Recent progress and market analysis of anticoagulant drugs

PubMed Central

Fan, Ping; Gao, Yangyang; Zheng, Minglin; Xu, Ting; Schoenhagen, Paul

2018-01-01

This review describes epidemiology of thromboembolic disease in China and abroad, evaluates trends in the development of anticoagulant drugs, and analyzes the market situation based on large amounts of accumulated data. Specifically, we describe advances in clinical application of anticoagulants and analyze the most commonly used anticoagulants in the market systematically.

Anticoagulant and antithrombotic drugs in pregnancy: what are the anesthetic implications for labor and cesarean delivery?

PubMed

Butwick, A J; Carvalho, B

2011-02-01

Neuraxial anesthetic techniques are commonly used during the peripartum period to provide effective pain relief for labor and anesthesia during cesarean delivery. Major neurologic complications are rare after neuraxial anesthesia; however, spinal hematoma is associated with catastrophic neurologic outcomes (including lower-limb paralysis). Anticoagulant and antithrombotic drugs can increase the risk of spinal hematoma after neuraxial anesthesia, and better understanding of the pharmacokinetics and pharmacodynamics of anticoagulants has led to greater appreciation for withholding anticoagulation before and after neuraxial anesthesia. A number of national anesthetic societies have produced guidelines for performing neuraxial anesthesia in patients receiving anticoagulation. However, there is limited information about anesthetic implications of anticoagulation during the peripartum period. This article will review the risks of spinal hematoma after neuraxial anesthesia in pregnant patients; current guidelines for neuraxial anesthesia for anticoagulated patients; and relevant pharmacological data of specific anticoagulant and antithrombotic drugs in pregnancy.

Anti-mitotic potential of 7-diethylamino-3(2 Prime -benzoxazolyl)-coumarin in 5-fluorouracil-resistant human gastric cancer cell line SNU620/5-FU

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Nam Hyun; Kim, Su-Nam; Oh, Joa Sub

2012-02-24

Highlights: Black-Right-Pointing-Pointer DBC exerts antiproliferative potential against 5FU-resistant human gastric cancer cells. Black-Right-Pointing-Pointer This effect is mediated by destabilization of microtubules and subsequent mitotic arrest. Black-Right-Pointing-Pointer DBC enhances apoptosis via caspase activation and downregulation of antiapoptotic genes. -- Abstract: In this study, we investigate an anti-mitotic potential of the novel synthetic coumarin-based compound, 7-diethylamino-3(2 Prime -benzoxazolyl)-coumarin, in 5-fluorouracil-resistant human gastric cancer cell line SNU-620-5FU and its parental cell SNU-620. It exerts the anti-proliferative effects with similar potencies against both cancer cells, which is mediated by destabilization of microtubules and subsequent mitotic arrest. Furthermore, this compound enhances caspase-dependent apoptotic cell deathmore » via decreased expression of anti-apoptotic genes. Taken together, our data strongly support anti-mitotic potential of 7-diethylamino-3(2 Prime -benzoxazolyl)-coumarin against drug-resistant cancer cells which will prompt us to further develop as a novel microtubule inhibitor for drug-resistant cancer chemotherapy.« less

Synergism of coumarins from the Chinese drug Zanthoxylum nitidum with antibacterial agents against methicillin-resistant Staphylococcus aureus (MRSA).

PubMed

Zuo, Guo-Ying; Wang, Chun-Juan; Han, Jun; Li, Yu-Qing; Wang, Gen-Chun

2016-12-15

Methicillin-resistant Staphylococcus aureus (MRSA) poses a serious therapeutic challenge in current clinic and new drug development. Natural coumarins have diverse bioactivities and the potential of resistance modifying effects. This study is to present in-depth evaluations of in vitro antimicrobial activities of four natural coumarins 5-geranyloxy-7-methoxycoumarin (Gm, 1), (5,7-dimethoxy-8-prenyloxycoumarin (artanin, Ar, 2)), isopimpinellin (Is, 3) and phellopterin (Ph, 4) from Zanthoxylum nitidum (Roxb.) DC. (Rutaceae) extracts, focusing on their potential restoration the activity of conventional antibacterial agents against clinical MRSA strains. Bioactivity-guided fractionation and spectral analyses were used to isolate the coumarins and identify the structures, respectively. The double broth microdilution method was used to assay the coumarins' alone activity. The classic checkerboard microdilution and dynamic time-killing methods were used to evaluate combinatory effects. The four plant coumarins Gm (1), Ar (2), Is (3) and Ph (4) were isolated and identified from Z. nitidum extracts. Coumarins 1-4 displayed promising inhibition against both MSSA and MRSA with minimal inhibitory concentrations (MICs) of 8-64µg/ml, but very weak against Gram-negative pathogen and yeast with MICs of 256 to ≥1024µg/ml. The geranyloxy and prenyloxy substitutions showed to be more active than the methoxy substitution on the coumarin skeletons. 1-4 also showing different extent of synergism with a total of eight conventional antibacterial agents, i.e. chloramphenicol (CL), gentamicin (CN), fosfomycin (FF), levofloxacin (LE), minocycline (MI), piperacillin/tazobactam (P/T), teicoplanin (TE) and vancomycin (VA) against ten clinical MRSA strains. Four to ten of the tested MRSA strains showed bacteriostatic synergy in the eleven combinations. The anti-MRSA modifying effects were related to different arrangement in the combinations with fractional inhibitory concentration indices (FICIs) from 0.187 to 1.125 and the three combinations CN (Is), CL (Ph) and MI (Gm) were the best ones. The enhancement of activity was also shown by 2-64 of dose reduction indices (DRIs) of the combined MICs, with VA (Ph) combination resulted the biggest DRI. The resistance of MRSA to antibacterial agents could be reversed in the combinations of CL (Gm or Ph), LE (Ph) and MI (Is) following the Clinical and Laboratory Standards Institute (CLSI) criteria. Six combinations P/T (Gm), TE (Ar), CN (Is), VA (Ph) and CL (Gm or Ph) also showed bactericidal synergy with Δlog 10 CFU/ml >2 at 24h incubation. The coumarins showed high potentiating effects of the antibacterial agents against multi-drug resistant SA. The resistance reversal effect of CL, LE and MI warrants further pharmacological investigation on combinatory therapy for the sake of fighting against MRSA infections. Copyright © 2016 Elsevier GmbH. All rights reserved.

Tailored on demand anti-coagulant dosing: an in vitro and in vivo evaluation of 3D printed purpose-designed oral dosage forms.

PubMed

Arafat, Basel; Qinna, Nidal; Cieszynska, Milena; Forbes, Robert T; Alhnan, Mohamed A

2018-04-16

Coumarin therapy has been associated with high levels of inter- and intra-individual variation in the required dose to reach a therapeutic anticoagulation outcome. Therefore, a dynamic system that is able to achieve accurate delivery of a warfarin dose is of significant importance. Here we assess, the ability of 3D printing to fabricate and deliver tailored individualised precision dosing using an in-vitro model. Sodium warfarin loaded filaments were compounded using hot melt extrusion (HME) and further fabricated via fused deposition modelling (FDM) 3D printing to produce capsular-ovoid-shaped dosage forms loaded at 200 and 400 µg dose. The solid dosage forms and comparator warfarin aqueous solutions were administered by oral gavage to Sprague-Dawley rats. In vitro, warfarin release was faster at pH 1.2 in comparison to pH 2. A novel UV imaging approach indicated that the erosion of the methacrylate matrix was at a rate of 16.4 and 15.2 µm/min for horizontal and vertical planes respectively. In vivo, 3D printed forms were as proportionately effective as their comparative solution form in doubling plasma exposure following a doubling of warfarin dose (184% versus 192% respectively). The 3D printed ovoids showed a lower C max of warfarin (1.51 and 3.33 mg/mL versus 2.5 and 6.44 mg/mL) and a longer T max (6 and 3.7 versus 4 and 1.5 h) in comparison to liquid formulation. This work demonstrates for the first time in vivo, the potential of FDM 3D printing to produce a tailored specific dosage form and to accurately titrate coumarin dose response to an individual patient. Copyright © 2018. Published by Elsevier B.V.

[New oral anticoagulant drugs].

PubMed

Berkovits, Alejandro; Aizman, Andrés; Zúñiga, Pamela; Pereira, Jaime; Mezzano, Diego

2011-10-01

Thromboembolic disease (TED) is the leading cause of morbidity and mortality worldwide. The hallmark of oral long-term anticoagulant therapy has been the use of vitamin K antagonists, whose anticoagulant effect is exerted inhibiting vitamin K epoxide reductase. Warfarin and acenocoumarol are the most commonly used. In the last five years several new drugs for long term anticoagulation have been developed, which can inhibit single clotting factors with the purpose of improving drug therapeutic range and, ideally, minimizing bleeding risks. This review addresses the state of the art on the clinical use of inhibitors of activated factor X and thrombin.

Melanogenesis stimulation in murine b16 melanoma cells by umberiferae plant extracts and their coumarin constituents.

PubMed

Matsuda, Hideaki; Hirata, Noriko; Kawaguchi, Yoshiko; Yamazaki, Miho; Naruto, Shunsuke; Shibano, Makio; Taniguchi, Masahiko; Baba, Kimiye; Kubo, Michinori

2005-07-01

Melanogenesis stimulation activities of seven ethanolic extracts obtained from Umbelliferae plants used as Chinese crude drugs, namely the roots of Angelica dahurica BENTH. et HOOK., A. biserrata SHEN et YUAN, Notopterygium incisum TING, Heracleum lanatum MICHX., and H. candicans WALL., and the fruits of Cinidium monnieri (L.) CUSSON and C. formosanum YABE, were examined by using cultured murine B16 melanoma cells. Among them, the extract (5, 25 microg/ml) of H. lanatum showed a potent stimulatory effect on melanogenesis with significant enhancement of cell proliferation in a dose-dependent manner. The melanogenesis stimulatory effects of sixteen coumarins (1-16) isolated from the seven Umbelliferae crude drugs were also examined. Among them, linear-furocoumarins [psoralen (1), xanthotoxin (2), bergapten (3), and isopimpinellin (4)] and angular-furocoumarin [sphondin (13)] exhibited potent melanogenesis stimulation activity. From the view point of structure-activity relationships, it may be assumed that a linear-furocoumarin ring having a hydrogen and/or methoxyl group at 5 and 8 positions such as 1, 2, 3 and 4 was preferable for the melanogenesis stimulation activity. The introduction of a prenyl group into the furocoumarin ring was disadvantageous. Coumarin derivatives having a simple coumarin ring were inactive.

Under-prescribing of Prevention Drugs and Primary Prevention of Stroke and Transient Ischaemic Attack in UK General Practice: A Retrospective Analysis.

PubMed

Turner, Grace M; Calvert, Melanie; Feltham, Max G; Ryan, Ronan; Fitzmaurice, David; Cheng, K K; Marshall, Tom

2016-11-01

Stroke is a leading cause of death and disability; worldwide it is estimated that 16.9 million people have a first stroke each year. Lipid-lowering, anticoagulant, and antihypertensive drugs can prevent strokes, but may be underused. We analysed anonymised electronic primary care records from a United Kingdom (UK) primary care database that covers approximately 6% of the UK population. Patients with first-ever stroke/transient ischaemic attack (TIA), ≥18 y, with diagnosis between 1 January 2009 and 31 December 2013, were included. Drugs were considered under-prescribed when lipid-lowering, anticoagulant, or antihypertensive drugs were clinically indicated but were not prescribed prior to the time of stroke or TIA. The proportions of strokes or TIAs with prevention drugs under-prescribed, when clinically indicated, were calculated. In all, 29,043 stroke/TIA patients met the inclusion criteria; 17,680 had ≥1 prevention drug clinically indicated: 16,028 had lipid-lowering drugs indicated, 3,194 anticoagulant drugs, and 7,008 antihypertensive drugs. At least one prevention drug was not prescribed when clinically indicated in 54% (9,579/17,680) of stroke/TIA patients: 49% (7,836/16,028) were not prescribed lipid-lowering drugs, 52% (1,647/3,194) were not prescribed anticoagulant drugs, and 25% (1,740/7,008) were not prescribed antihypertensive drugs. The limitations of our study are that our definition of under-prescribing of drugs for stroke/TIA prevention did not address patients' adherence to medication or medication targets, such as blood pressure levels. In our study, over half of people eligible for lipid-lowering, anticoagulant, or antihypertensive drugs were not prescribed them prior to first stroke/TIA. We estimate that approximately 12,000 first strokes could potentially be prevented annually in the UK through optimal prescribing of these drugs. Improving prescription of lipid-lowering, anticoagulant, and antihypertensive drugs is important to reduce the incidence and burden of stroke and TIA.

Pharmacological and Nutritional Effects of Natural Coumarins and Their Structure-Activity Relationships.

PubMed

Zhu, Jing-Jing; Jiang, Jian-Guo

2018-05-11

Coumarins are fused benzene and pyrone ring systems with a wide spectrum of bioactivities including anti-tumor, anti-inflammation, antiviral and antibacterial effects. In this paper, the current development of coumarins-based drugs is introduced, and their structure-activity relationship is discussed by reviewing the relevant literatures published in the past twenty years. Coumarin molecules can be customized by the target site to prevent systemic side effects by virtue of structural modification. The ortho-phenolic hydroxyl on the benzene ring had remarkable antioxidant and anti-tumor activities. Coumarins with aryl groups at the C-4 position have good activities in anti-HIV, anti-tumor, anti-inflammation and analgesia. C-3 phenylcoumarins have strong anti-HIV and antioxidant effects. Tetracycline pyranocoumarins can significantly inhibit the HIV, osthol structural analogues have antimicrobial activity. Praeruptorin C and its derivatives play an important role in lowering blood pressure and dilating coronary arteries, and khellactone derivatives have significant inhibitory effects on AIDS, cancer and cardiovascular diseases. It is concluded that the specific site on the core structure of coumarin exhibits one or more activities due to the electronic or steric effects of the substituents. This review is designed to be conducive to rational design and development of more active and less toxic agents with a coumarin scaffold. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

PEG-coumarin based biocompatible self-assembled fluorescent nanoaggregates synthesized via click reactions and studies of aggregation behavior.

PubMed

Behl, Gautam; Sikka, Manisha; Chhikara, Aruna; Chopra, Madhu

2014-02-15

Click chemistry has found wide application in drug discovery, bioconjugation reactions, polymer chemistry and synthesis of amphiphilic materials with pharmaceutical and biomedical applications. Triazole substitution via a click reaction alters photophysical properties of coumarin. Both coumarin and triazole moieties participate in π-π stacking interactions. Hence it should be possible to prepare fluorescent self-assembly systems by conjugation of coumarin to poly (ethylene glycol) (PEG) via click reactions exhibiting hydrophilic, hydrophobic and π-π stacking interactions. Moreover, the materials can be suitable platforms to assess fluorescence modulation effect of triazole substitution on coumarins. PEG supported coumarin conjugates were synthesized and the fluorescence modulation effect of the formation of triazole on coumarin was assessed. Their aggregation properties were studied by surface tension measurements, dynamic light scattering (DLS), transmission electron microscopy (TEM), fluorescence and (1)H NMR spectroscopy. The conjugates were found to form nanoaggregates in the size range of 100-120 nm with a negative free energy of micellization (~-27 kJ mol(-1)) confirming aggregation and self-assembly. The Quantum yield of 4-methyl-7-propargylcoumarin (7P4MC) was enhanced after triazole formation with azide functionalized PEG (methoxy-PEG350 azide). The conjugates were found to exhibit π-π stacking interactions in addition to hydrophilic and hydrophobic interactions. They were found to be biocompatible with human pancreatic cancer cells. Copyright © 2013 Elsevier Inc. All rights reserved.

Effect of anticoagulants on the protein corona-induced reduced drug carrier adhesion efficiency in human blood flow.

PubMed

Sobczynski, Daniel J; Eniola-Adefeso, Omolola

2017-01-15

Plasma proteins rapidly coat the surfaces of particulate drug carriers to form a protein corona upon their injection into the bloodstream. The high presence of immunoglobulins in the corona formed on poly(lactic-co-glycolic acid) (PLGA) vascular-targeted carrier (VTC) surfaces was recently shown to negatively impact their adhesion to activated endothelial cells (aECs) in vitro. Here, we characterized the influence of anticoagulants, or their absence, on the binding efficiency of VTCs of various materials via modulation of their protein corona. Specifically, we evaluated the adhesion of PLGA, poly(lactic acid) (PLA), polycaprolactone (PCL), silica, and polystyrene VTCs to aECs in heparinized, citrated, and non-anticoagulated (serum and whole) blood flows relative to buffer control. Particle adhesion is substantially reduced in non-anticoagulated blood flows regardless of the material type while only moderate to minimal reduction is observed for VTCs in anticoagulant-containing blood flow depending on the anticoagulant and material type. The substantial reduction in VTC adhesion in blood flows was linked to a high presence of immunoglobulin-sized proteins in the VTC corona via SDS-PAGE analysis. Of all the materials evaluated, PLGA was the most sensitive to plasma protein effects while PCL was the most resistant, suggesting particle hydrophobicity is a critical component of the observed negative plasma protein effects. Overall, this work demonstrates that anticoagulant positively alters the effect of plasma proteins in prescribing VTC adhesion to aECs in human blood flow, which has implication in the use of in vitro blood flow assays for functional evaluation of VTCs for in vivo use. This study addresses the impact of anticoagulant on altering the extent of the previously observed protein corona-induced adhesion reduction of vascular-targeted drug carriers in human blood flows. Specifically, serum blood flow (no anticoagulant) magnifies the negative effect of the plasma protein corona on drug carrier adhesion relative to citrated or heparinized blood flows. Overall, the results from this work suggest that serum better predicts targeted drug carrier adhesion efficiency in vivo compared to anticoagulant containing plasma. Furthermore, this study offers critical insight into the importance of how the choice of anticoagulant can greatly affect drug delivery-related processes in vitro. Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Anticoagulant management in the cardiovascular setting.

PubMed

Verheugt, Freek W A

2012-02-01

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 dose adjustment. Around half of patients receiving warfarin are within the therapeutic range, exposing them to the dangers of under-anticoagulation (i.e. thrombosis formation) or over-anticoagulation (i.e. bleeding). A new generation of OACs with improved pharmacology promises to revolutionize antithrombotic management. Rivaroxaban, apixaban (both oral direct Factor Xa inhibitors) and dabigatran (a direct thrombin inhibitor) all exhibit predictable anticoagulant responses and few drug-drug interactions and do not require routine coagulation monitoring. © 2011 The Author Fundamental and Clinical Pharmacology © 2011 Société Française de Pharmacologie et de Thérapeutique.

Oral Anticoagulant Therapy

PubMed Central

Gallus, Alexander S.; Wittkowsky, Ann; Crowther, Mark; Hylek, Elaine M.; Palareti, Gualtiero

2012-01-01

Background: The objective of this article is to summarize the published literature concerning the pharmacokinetics and pharmacodynamics of oral anticoagulant drugs that are currently available for clinical use and other aspects related to their management. Methods: We carried out a standard review of published articles focusing on the laboratory and clinical characteristics of the vitamin K antagonists; the direct thrombin inhibitor, dabigatran etexilate; and the direct factor Xa inhibitor, rivaroxaban Results: The antithrombotic effect of each oral anticoagulant drug, the interactions, and the monitoring of anticoagulation intensity are described in detail and discussed without providing specific recommendations. Moreover, we describe and discuss the clinical applications and optimal dosages of oral anticoagulant therapies, practical issues related to their initiation and monitoring, adverse events such as bleeding and other potential side effects, and available strategies for reversal. Conclusions: There is a large amount of evidence on laboratory and clinical characteristics of vitamin K antagonists. A growing body of evidence is becoming available on the first new oral anticoagulant drugs available for clinical use, dabigatran and rivaroxaban. PMID:22315269

Quantitation in chiral capillary electrophoresis: theoretical and practical considerations.

PubMed

D'Hulst, A; Verbeke, N

1994-06-01

Capillary electrophoresis (CE) represents a decisive step forward in stereoselective analysis. The present paper deals with the theoretical aspects of the quantitation of peak separation in chiral CE. Because peak shape is very different in CE with respect to high performance liquid chromatography (HPLC), the resolution factor Rs, commonly used to describe the extent of separation between enantiomers as well as unrelated compounds, is demonstrated to be of limited value for the assessment of chiral separations in CE. Instead, the conjunct use of a relative chiral separation factor (RCS) and the percent chiral separation (% CS) is advocated. An array of examples is given to illustrate this. The practical aspects of method development using maltodextrins--which have been proposed previously as a major innovation in chiral selectors applicable in CE--are documented with the stereoselective analysis of coumarinic anticoagulant drugs. The possibilities of quantitation using CE were explored under two extreme conditions. Using ibuprofen, it has been demonstrated that enantiomeric excess determinations are possible down to a 1% level of optical contamination and stereoselective determinations are still possible with a good precision near the detection limit, increasing sample load by very long injection times. The theoretical aspects of this possibility are addressed in the discussion.

Fever as a risk factor for increased response to vitamin K antagonists: a review of the evidence and potential mechanisms.

PubMed

Self, Timothy H; Oliphant, Carrie S; Reaves, Anne B; Richardson, Amy M; Sands, Christopher W

2015-01-01

Numerous factors affect the response to vitamin K antagonists (VKA) including age, dietary vitamin K, other drugs, pharmacogenetics, and disease states. In antithrombotic guidelines, fever is mentioned as a factor that may increase response to VKA. The purpose of this article is to review the available evidence regarding the effect of fever on response to VKA, and to discuss possible mechanisms of this effect. We performed a search of the English literature from 1943 to June 2014, using the key words fever AND warfarin, acenocoumarol, phenprocoumon, coumarin anticoagulants and VKA; fever AND vitamin K dependent clotting factors II, VII, IX, and X. One animal investigation and 6 studies in humans suggest fever increases response to VKA, but one study did not find a significant effect. The magnitude of this effect is variable. Possible mechanisms for the increased effect of VKA associated with fever are increased catabolism of vitamin K dependent clotting factors, decreased vitamin K intake, and inhibition of VKA metabolism. More rigorous studies are needed to confirm that fever increases response to warfarin and other VKA. Copyright © 2014 Elsevier Ltd. All rights reserved.

Coumarins as cholinesterase inhibitors: A review.

PubMed

de Souza, Luana G; Rennã, Magdalena N; Figueroa-Villar, Jose D

2016-07-25

The first report in literature of the isolation of coumarin was in the year 1820. After this report, other papers were published demonstrating the isolation and synthesis of coumarin and analogues. These compounds have been studying along the years for several different pathologies. One of these pathologies was Alzheimer's disease (AD), being the main cause of dementia in the contemporary world. There are two hypotheses to explain the pathogenesis mechanism and disease symptoms, then having the "amyloid hypothesis" and the "cholinergic hypothesis". Some drugs for AD are based on the theory of "cholinergic hypothesis", which objective is to increase the concentration of ACh in the synaptic cleft by the inhibition of cholinesterases. Over the last twenty years, many studies with coumarins compounds were reported as cholinesterases inhibitors. The aim of the present review is to discuss the studies and development of new compounds for AD treatment. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Determination of coumarin in seasonal bakery products using QuEChERS and GC-MS.

PubMed

Vetter, F; Müller, C; Stöckelhuber, M; Bracher, F

2017-06-01

Cinnamon is a traditional herbal drug, but more importantly, it is used as a flavor compound in the production of foodstuff. Due to the content of significant concentrations of coumarin in Cassia cinnamon, effective control of the coumarin content in seasonal bakery products like ginger bread and cinnamon biscuits is urgently needed. Here we present a novel, fast and fully validated protocol for the determination of coumarin in marketed bakery products using the QuEChERS sample preparation technique in combination with GC-MS analysis. Ten grams of homogenized sample was mixed with 20 mL acetonitrile/water (1:1) and 5 g magnesium sulfate/sodium chloride mixture (4:1). The organic phase was cleaned by dSPE with 25 mg magnesium sulfate/PSA (5:1). The LOD was 0.15 μg/mL and the LOQ 0.50 μg/mL. We detected a mean coumarin content of 19.5 μg/kg in 9 out of 14 seasonal food products (ranging from 1.45 to 39.4 mg/kg). No coumarin was detected in five cinnamon containing products. With this investigation we demonstrate that the QuEChERS sample preparation, previously applied mainly to the analysis of pesticides in vegetables, is also suitable for other complex matrices.

Under-prescribing of Prevention Drugs and Primary Prevention of Stroke and Transient Ischaemic Attack in UK General Practice: A Retrospective Analysis

PubMed Central

Fitzmaurice, David; Cheng, K. K.; Marshall, Tom

2016-01-01

Background Stroke is a leading cause of death and disability; worldwide it is estimated that 16.9 million people have a first stroke each year. Lipid-lowering, anticoagulant, and antihypertensive drugs can prevent strokes, but may be underused. Methods and Findings We analysed anonymised electronic primary care records from a United Kingdom (UK) primary care database that covers approximately 6% of the UK population. Patients with first-ever stroke/transient ischaemic attack (TIA), ≥18 y, with diagnosis between 1 January 2009 and 31 December 2013, were included. Drugs were considered under-prescribed when lipid-lowering, anticoagulant, or antihypertensive drugs were clinically indicated but were not prescribed prior to the time of stroke or TIA. The proportions of strokes or TIAs with prevention drugs under-prescribed, when clinically indicated, were calculated. In all, 29,043 stroke/TIA patients met the inclusion criteria; 17,680 had ≥1 prevention drug clinically indicated: 16,028 had lipid-lowering drugs indicated, 3,194 anticoagulant drugs, and 7,008 antihypertensive drugs. At least one prevention drug was not prescribed when clinically indicated in 54% (9,579/17,680) of stroke/TIA patients: 49% (7,836/16,028) were not prescribed lipid-lowering drugs, 52% (1,647/3,194) were not prescribed anticoagulant drugs, and 25% (1,740/7,008) were not prescribed antihypertensive drugs. The limitations of our study are that our definition of under-prescribing of drugs for stroke/TIA prevention did not address patients’ adherence to medication or medication targets, such as blood pressure levels. Conclusions In our study, over half of people eligible for lipid-lowering, anticoagulant, or antihypertensive drugs were not prescribed them prior to first stroke/TIA. We estimate that approximately 12,000 first strokes could potentially be prevented annually in the UK through optimal prescribing of these drugs. Improving prescription of lipid-lowering, anticoagulant, and antihypertensive drugs is important to reduce the incidence and burden of stroke and TIA. PMID:27846215

[Drug compliance of patients on anticoagulant treatment].

PubMed

Gadó, Klára; Kocsis, Eszter; Zelkó, Romána; Hankó, Balázs; Kovácsné Balogh, Judit; Forczig, Mónika; Domján, Gyula

2015-08-09

Despite several therapeutic possibilities the morbidity and mortality of thromboembolic disorders remain high. Improving drug compliance - i. e. keeping up the doctor's prescriptions - may be an effective tool to reach better results. To improve patients' compliance, the risk factors of non-compliance should be recognized. Among these patients' fear of adverse effects of drugs, their lack of knowledge about their illness and medication, forgetfulness, and other social, economic factors may be the most important. Furthermore, adherence may be worsened when the patient feels that the decision has been made over his/her head. Sustained medical adherence is important because anticoagulation may be a life-long treatment. The new oral anticoagulants make the matter of compliance to be current. These new type of drugs do not need regular laboratory monitoring and, therefore, compliance cannot be strictly followed. There are several studies concerning drug compliance to anticoagulant medications. Improvement of adherence is based on regular patient education after reviewing the factors of non-compliance, which needs teamwork with important roles of doctors, pharmacists, dietetics and nurses. Careful and accurate work of the participants of primary care might be complemented by the activity of anticoagulant clinics.

Anticoagulation beyond direct thrombin and factor Xa inhibitors: indications for targeting the intrinsic pathway?

PubMed

van Montfoort, Maurits L; Meijers, Joost C M

2013-08-01

Antithrombotic drugs like vitamin K antagonists and heparin have been the gold standard for the treatment and prevention of thromboembolic disease for many years. Unfortunately, there are several disadvantages of these antithrombotic drugs: they are accompanied by serious bleeding problems, it is necessary to monitor the therapeutic window, and there are various interactions with food and other drugs. This has led to the development of new oral anticoagulants, specifically inhibiting either thrombin or factor Xa. In terms of effectiveness, these drugs are comparable to the currently available anticoagulants; however, they are still associated with issues such as bleeding, reversal of the drug and complicated laboratory monitoring. Vitamin K antagonists, heparin, direct thrombin and factor Xa inhibitors have in common that they target key proteins of the haemostatic system. In an attempt to overcome these difficulties we investigated whether the intrinsic coagulation factors (VIII, IX, XI, XII, prekallikrein and high-molecular-weight kininogen) are superior targets for anticoagulation. We analysed epidemiological data concerning thrombosis and bleeding in patients deficient in one of the intrinsic pathway proteins. Furthermore, we discuss several thrombotic models in intrinsic coagulation factor-deficient animals. The combined results suggest that intrinsic coagulation factors could be suitable targets for anticoagulant drugs.

[A 50-year history of new drugs in Japan-the development and trends of hemostatics and antithrombotic drugs].

PubMed

Ozawa, Hikaru; Abiko, Yasushi; Akimoto, Takeshi

2003-01-01

The developments and trends of hemostatic and antithrombotic drugs in Japan were investigated chronologically for the last 50 years after the 2nd World War. 1. Hemostatic drugs are classified into three groups ; capillary stabilizers, blood coagulants and antifibrinolytics. l) As to capillary stabilizers, flavonoid (rutin, 1949), adrenochrome derivative (carbazochrome, 1954) and conjugated estrogen (Premarin, 1964) were introduced therapeutically. Especially, the soluble types of adrenochrome compounds (Adona 1956, S-Adchnon, 1962) were devised and used widely in Japan. 2) Drugs concerning blood coagulation, thrombin, introduced in 1953, and hemocoagulase, a snake venom introduced in 1966, were used clinically. V.K. groups producing various coagulation factors were introduced as V.K1 (Phytonadione, 1962) and V.K2 (rnenatetrenone,1972), and they were admitted in "The Japanese Pharmacopoeia"editions 8 and 14, respectively). 3) Regarding antifibrinolytic drugs, Japanese researchers have made remarkable contributions. e-Aminocapronic acid (Ipsilon, 1962) and tranexamic acid (Transamin, 1965) were developed and used for various abnormal bleedings or hemorrhage associated with plasmin over-activation. tranexamic acid also proved to suppress inflammations of the throat such as tonsillitis, pharyngitis or laryngitis. 2. Antithrombotic drugs are also divided into three groups; anticoagulants, antiplatelet drugs and fibrinolytics.1) The anticoagulants used therapeutically by injection are heparins (Na-salt, 1951; Ca-salt, 1962) and low-molecular-weight heparins such as dalteparin (1992), parnaparin (1994) and reviparin (1999). The low molecule compounds are superior to the original heparins in reducing the risk of bleeding. As oral anticoagulants, coumarin derivatives, dicumarol (1950), ethylbiscoumacetate (1954), phenylindandione (1956) and warfarin (1962) are known. Warfarin potassium is the main drug for oral therapy of thromboembolism lately. Gabexate mesilate (1989) and nafamostat mesilate (1989) were developed in Japan and used for DIC and acute pancreatitis to inhibit protease enzymes. Argatroban is a unique antithrombin product developed by Japanese researchers in 1990, and is used for vascular or cerebral thrombosis. After noticing in 1968 that aspirin inhibits platelet aggregation and prevents myocardial infraction, projects for developing antiplatelet drugs were initiated worldwide. Ticlopidine, originally developed in France, was introduced in 1981 and prevailed widely in Japan for reducing the risk of thrombotic stroke. Aspirin itself was recognized by the FDA (USA) as an antithrombotic drug in 1988, and was also approved by Japanese authorities in 2000. PGE1 clathrate compounds have also been developed as antiplatelet drugs; alprostadil alfadex for injection (1979), and limaprost alfadex for oral use (1988). The PGI2 product, beraprost sodium, for oral use followed them in 1992. Other antiplatelet drugs with unique mechanisms explored in Japan: Ozagrel (1988), which inhibits TXA2 synthetase, cilostazol (1988), which inhibits cAMP phosphodiesterase, and sarpogrelate (1993), which blocks 5HT in platelets, are the notable drugs in this field. Ethyl icosapentate, from fish oil, is available for antiplatelet therapy. Concerning the fibrinolytic system, plasminogen activators are useful for thromboembolism. The streptokinase from bacterial origin developed in the USA and Europe was not introduced, and urokinase (1965) was the first plasminogen activator developed in Japan. Then tissue plasminogen activators (t-PA) tisokinase (cell culture, 1991), alteplase (genetical recombination, 1991), nateplase (genetical recombination, 1996), monteplase (1998) and pamiteplase (1998) were developed and approved for acute myocardial infarction. Nasaruplase (prourokinase, cell culture,1991) was also approved for the same indication. While the development of the hemostatic drugs ceased in the 1960s, avid project studies for antithrombotic drugs including fibrinolytics began in the 1980s and are progressing now towards new molecular targets. This may be due to the increasing tendency of cardiovascular thromboembolic diathesis in Japan. (The figures in parentheses are the years approved by the Japanese Ministry of Health, Labor and Welfare.)

Novel anticoagulants for stroke prevention in patients with atrial fibrillation.

PubMed

Jalota, A; Scarabelli, T M; Saravolatz, L; Bakhsh, M U; Agrawal, P; Jalota, R; Chen-Scarabelli, C; Fuster, V; Halperin, J

2014-06-01

Atrial fibrillation (AF) is the most common cardiac arrhythmia that can potentially result in stroke. Vitamin K antagonists (VKA) like warfarin were for many decades the only oral anticoagulants available for stroke prevention in patients with non-valvular atrial fibrillation (AF) at high risk of stroke. Recently, new oral anticoagulants (NOACS) have been introduced that act via direct inhibition of thrombin (dabigatran) or activated factor X (edoxaban, rivaroxaban and apixaban). Unlike VKAs, these anticoagulants do not require routine INR monitoring and posses favorable pharmacological properties. NOACs act rapidly, and have a stable and predictable dose-related anticoagulant effect with few clinically relevant drug-drug interactions. Phase III trials comparing these agents to warfarin for stroke prevention in patients with non-valvular AF demonstrated that they are at least as efficacious and safe as warfarin. Evolution of clinical guidelines to incorporate the new anticoagulants for stroke prevention in non-valvular AF may result in a reduction in the incidence of AF-related strokes. Safe and effective use of these new drugs in clinical practice requires understanding of their distinct pharmacological properties.

PEG-coumarin nanoaggregates as π-π stacking derived small molecule lipophile containing self-assemblies for anti-tumour drug delivery.

PubMed

Behl, Gautam; Kumar, Parveen; Sikka, Manisha; Fitzhenry, Laurence; Chhikara, Aruna

2018-03-01

Polymeric self-assemblies formed by non-covalent interactions such as hydrophobic interactions, hydrogen bonding, π-π stacking, host-guest and electrostatic interactions have been utilised widely and exhibit controlled release of encapsulated drug. Beside carrier-carrier interactions, small molecule amphiphiles exhibiting carrier-drug interactions have recently been an area of interest for cancer drug delivery, as most of the hydrophobic anti-tumour drugs are aromatic and exhibit π-π conjugated structure. In the present study PEG-coumarin (PC) conjugates forming self-assembled nanoaggregates were synthesised with PEG (polyethylene glycol) as hydrophilic block and coumarin as small molecule lipophilic segment. Curcumin (CUR) as model conjugated aromatic drug was loaded in to the nanoaggregates via dual hydrophobic and π-π stacking interactions. The interactions between the conjugates and CUR, drug release profile and in vitro anti-tumour efficacy were investigated in detail. CUR-loaded nanoaggregate self-assembly was driven by π-π interactions and a maximum loading level of about 18 wt.% (~60 % encapsulation efficiency) was achieved. The average hydrodynamic diameter (D av ) was in the range of 120-160 nm and a spherical morphology was observed by transmission electron microscopy (TEM). A sustained release of CUR was observed for 90 h. Cytotoxicity evaluation of CUR-loaded nanoaggregates on pancreatic cancer cell lines indicated higher efficacy, IC 50 ~11 and ~15 μM as compared to free CUR, IC 50 ~14 and ~20 μM on human pancreatic carcinoma (MIA PaCa-2) and human pancreatic duct epithelioid carcinoma (PANC-1) cell lines respectively. PC conjugates provided a new strategy of fabricating nanoparticles for drug delivery and may form the basis for the development of advanced biomaterials in near future.

Stroke prophylaxis with warfarin or dabigatran for patients with non-valvular atrial fibrillation-cost analysis.

PubMed

Ali, Ali; Bailey, Claire; Abdelhafiz, Ahmed H

2012-09-01

cost of anticoagulation with dabigatran is largely based on estimation of complication rates derived from clinical trials. to investigate cost of anticoagulation with dabigatran in comparison with warfarin in clinical practice. a prospective observational study of patients with non-vavular atrial fibrillation (NVAF) referred to anticoagulation clinic. Patients were interviewed (4-6 weekly by telephone) about bleeding events. Costs of anticoagulation were calculated as: (i) drug cost, (ii) international normalised ratio (INR) monitoring cost and (iii) bleeding cost. For cost calculation of dabigatran, INR monitoring cost was omitted. a total of 402 patients were included and followed up for a mean (SD) of 19 (8.1) months. Annual cost of anticoagulation was £207.3 and £1,573.5 per patient for warfarin and dabigatran, respectively. Drug price constituted 13.6% of the total cost for warfarin and 94% for dabigatran. Total cost of anticoagulation to prevent one stroke per year was £6,219, £28,086.5 and £25,181 for warfarin, dabigatran 110 and 150 mg, respectively. cost of anticoagulation is mainly driven by drug price for dabigatran and quality of INR control for warfarin. Until the price of dabigatran is reviewed, warfarin remains suitable for the majority of patients with NVAF.

[Case report. Phenprocoumon (Marcumar, Falithrom) as an unusual reason for coumarin poisoning in a dog].

PubMed

Lutze, G; Römhild, W; Elwert, J; Leppelt, J; Kutschmann, K

2003-01-01

Coumarin poisoning in dogs is not unusual and is in most cases caused by warfarin, a coumarin derivative which is used as a rodenticide. Competitive inhibition of vitamin K with an incomplete synthesis of the coagulation factors II, VII, IX and X can lead to a significant bleeding tendency. We observed a 3-year old male West Highland White Terrier with a reduced general condition and dyspnoea together with a massive haemothorax. Administration of vitamin K1 (3 mg/kg) led to a rapid improvement of the condition. Coagulation analysis revealed a prolonged activated recalcification time (ARCT), prothrombin time (PT) and aPTT with uncharacteristic thrombin time (TT); factor II, VII and X activities were reduced while factor V activity was normal, all of which are characteristic for coumarin poisoning. HPLC did not reveal the presence of warfarin but of phenoprocoumon, a drug used for thromboembolic prophylaxis in humans. This observation has not been described for dogs to date.

Combination of aptamer and drug for reversible anticoagulation in cardiopulmonary bypass.

PubMed

Gunaratne, Ruwan; Kumar, Shekhar; Frederiksen, James W; Stayrook, Steven; Lohrmann, Jens L; Perry, Kay; Bompiani, Kristin M; Chabata, Charlene V; Thalji, Nabil K; Ho, Michelle D; Arepally, Gowthami; Camire, Rodney M; Krishnaswamy, Sriram; Sullenger, Bruce A

2018-06-04

Unfractionated heparin (UFH), the standard anticoagulant for cardiopulmonary bypass (CPB) surgery, carries a risk of post-operative bleeding and is potentially harmful in patients with heparin-induced thrombocytopenia-associated antibodies. To improve the activity of an alternative anticoagulant, the RNA aptamer 11F7t, we solved X-ray crystal structures of the aptamer bound to factor Xa (FXa). The finding that 11F7t did not bind the catalytic site suggested that it could complement small-molecule FXa inhibitors. We demonstrate that combinations of 11F7t and catalytic-site FXa inhibitors enhance anticoagulation in purified reaction mixtures and plasma. Aptamer-drug combinations prevented clot formation as effectively as UFH in human blood circulated in an extracorporeal oxygenator circuit that mimicked CPB, while avoiding side effects of UFH. An antidote could promptly neutralize the anticoagulant effects of both FXa inhibitors. Our results suggest that drugs and aptamers with shared targets can be combined to exert more specific and potent effects than either agent alone.

[Vitamin K antagonists overdose].

PubMed

Groszek, Barbara; Piszczek, Paweł

2015-01-01

Nowadays, anticoagulant therapy belongs to the most commonly used forms of pharmacotherapy in modern medicine. The most important representatives of anticoagulants are heparins (unfractionated heparin and low-molecular-weight heparin) and coumarin derivatives (vitamin K antagonists--VKA). Next to the many advantages of traditional oral anticoagulants may also have disadvantages. In Poland most often used two VKA: acenocoumarol and warfarin. The aim of the work is the analysis of the causes of the occurrence of bleeding disorders and symptoms of overdose VKA in patients to be hospitalized. In the years 2012 to 2014 were hospitalized 62 patients with overdose VKA (40 women and 22 men). The average age of patients was 75.3 years) and clotting disturbances and/or bleeding. At the time of the admission in all patients a significant increase in the value of the INR was stated, in 22 patients INR result was " no clot detected", on the remaining value of the INR were in the range of 7 to 13.1. On 51 patients observed different severe symptoms of bleeding (hematuria, bleeding from mucous membranes of the nose or gums ecchymoses on the extremities, bleeding from the gastrointestinal tract--as in 5 patients has led to significant anemia and transfusion of concentrated red blood cells. Up on 33 patients kidney function disorder were found--exacerbated chronic renal failure and urinary tract infection. 8 diagnosed inflammatory changes in the airways. On 13 patients, it was found a significant degree of neuropsychiatric disorders (dementia, cognitive impairment), which made impossible the understanding the sense of treatment and cooperation with the patient. In 6 patients the symptoms of overdose were probably dependent on the interaction with the congestants at the same time (change the preparation of anticoagulant, NSAIDs, antibiotics). In 2 cases, the overdose was a suicide attempt in nature. In addition to the above mentioned disorders, on two of those patients diagnosed with a malignant disease. Two patients died, the other has been improving and anticoagulant therapy with VKA was continued, in 4 VKA were changed to low-molecular-weight heparin, and on 4 commissioned new generation anticoagulant (rivaroxaban).

Utility of Von Pechman synthesis of coumarin reaction for development of spectrofluorimetric method for quantitation of salmeterol xinafoate in pharmaceutical preparations and human plasma.

PubMed

Awad, Mohamed; Hammad, Mohamed A; Abdel-Megied, Ahmed M; Omar, Mahmoud A

2018-04-30

Simple, precise and selective spectrofluorimetric technique was evolved for quantitation of selective β 2 agonist drug namely salmeterol xinafoate (SAL). Utilizing its phenolic nature, a method was described based on the reaction of the studied drug with ethyl acetoacetate (EAA) to yield extremely fluorescent coumarin product which can be detected at 480 nm (λ ex  = 420 nm). The procedure obeys Beer's law with a correlation coefficient of r = 0.9999 in the concentration range between 500 and 5000 ng ml -1 with and 177 ng ml -1 for limit of detection (LOD) and limit of quantification (LOQ), respectively. Diverse reaction variables influencing the firmness and formation of the coumarin product were accurately examined and modified to ensure greatest sensitivity of the procedure. The proposed technique was performed and examined according to the US Food and Drug Administration (FDA) guidelines for bio-analytical methods and was efficiently applied for quantitation of SAL in both pharmaceutical preparations (% recovery = 100.06 ± 1.07) and spiked human plasma (% recovery = 96.64-97.14 ± 1.01-1.52). Copyright © 2018 John Wiley & Sons, Ltd.

Risk of upper and lower gastrointestinal bleeding in patients taking nonsteroidal anti-inflammatory drugs, antiplatelet agents, or anticoagulants.

PubMed

Lanas, Ángel; Carrera-Lasfuentes, Patricia; Arguedas, Yolanda; García, Santiago; Bujanda, Luis; Calvet, Xavier; Ponce, Julio; Perez-Aísa, Ángeles; Castro, Manuel; Muñoz, Maria; Sostres, Carlos; García-Rodríguez, Luis A

2015-05-01

Treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) or low-dose aspirin is associated with increased risk of upper gastrointestinal bleeding. There is little evidence on the risk of lower gastrointestinal bleeding with NSAIDs, antiplatelet agents (APAs), or anticoagulants. We aimed to quantify the relative risk (RR) of upper and lower gastrointestinal bleeding associated with use of NSAIDs, APAs, or anticoagulants. We performed a case-control study that used data collected from consecutive patients hospitalized for gastrointestinal bleeding (563 upper, mean age, 63.6 ± 16.7 years and 415 lower, mean age, 70.8 ± 13.8 years), confirmed by endoscopy or other diagnostic procedures. Unhospitalized patients were used as controls (n = 1008) and matched for age, hospital, and month of admission. Drug use was considered current when taken within 7 days or less before hospitalization. RRs and 95% confidence intervals (CIs) were estimated by unconditional logistic regression analysis. Use of anticoagulants, low-dose aspirin, and other drugs (non-aspirin-APA, 82.3% thienopiridines) was associated with upper and lower gastrointestinal bleeding; the risk was 2-fold higher for anticoagulants (RR, 4.2; 95% CI, 2.9-6.2) than for low-dose aspirin (RR, 2.1; 95% CI, 1.4-3.3) or other non-aspirin-APA drugs (RR, 2.0; 95% CI, 1.6-2.6). NSAID use was also associated with increased risk of gastrointestinal bleeding and greater for upper (RR, 2.6; 95% CI, 2.0-3.5) than lower gastrointestinal bleeding (RR, 1.4; 95% CI, 1.0-1.9). Use of proton pump inhibitors was associated with reduced risk of upper, but not lower, gastrointestinal bleeding. Anticoagulants, low-dose aspirin, NSAIDs, and other non-aspirin-APA drugs are associated with increased risk of upper and lower gastrointestinal bleeding. Use of anticoagulants appears to be the strongest risk factor for gastrointestinal bleeding. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.

Coumarin versus Chromone Monoamine Oxidase B Inhibitors: Quo Vadis?

PubMed

Fonseca, André; Reis, Joana; Silva, Tiago; Matos, Maria João; Bagetta, Donatella; Ortuso, Francesco; Alcaro, Stefano; Uriarte, Eugenio; Borges, Fernanda

2017-08-24

Because of the lack of significant disease-modifying drugs for neurodegenerative disorders, a pressing need for new chemical entities endowed with IMAO-B still exists. Within this framework, and for the first time, a study was performed to compare coumarin- and chomone-3-phenylcarboxamide scaffolds. Compounds 10a and 10b were the most potent, selective, and reversible noncompetitive IMAO-B. The benzopyrone sp 2 oxygen atom was found to be position independent and a productive contributor for the ligand-enzyme complex stability.

[Treatment with inhibitors of new oral direct anticoagulants in patients with severe bleedings or urgent surgical procedures. The new dabigatran antidote: the place of idarucizumab in clinical practice].

PubMed

Boda, Zoltán

2016-03-20

Only vitamin K antagonists could be applied as oral anticoagulants over the past six decades. Coumarols have narrow therapeutic range, and unpredictable anticoagulant effects are resulted by multiple drug interactions. Therefore, regular routine monitoring of the international normalized ratio is necessary. There are two groups of factor-specific anticoagulants: molecules with anti-FIIa (dabigatran) and anti-FXa (rivaroxaban, apixaban and edoxaban) effect. Author summarizes the most important clinical features of the new oral anticoagulants, their indications and the possibilities of laboratory controls. Bleedings are the most important side effects of anticoagulants. This review summarizes the current published evidences for new oral anticoagulants reversal (non-specific and specific) agents, especially in cases with severe acute bleedings or urgent surgery procedures. It reports on how to use inhibitors, the recommended doses and the most important clinical results. The review focuses on idarucizumab - already approved by the U.S. Food and Drug Administration and the European Medicines Agency - which has a key role as the first specific inhibitor of dabigatran.

Switching, Adverse Effects and Use of Over-the-Counter Analgesics among Users of Oral Anticoagulants: A Pharmacy-based Survey.

PubMed

Hellfritzsch, Maja; Hyllested, Lea Maria Rønneberg; Meegaard, Line; Wiberg-Hansen, Alexander; Grove, Erik Lerkevang; Pottegård, Anton

2017-07-01

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 collected information concerning the patients' knowledge of their anticoagulant treatment including prior drug switching. Further, patients were asked about use of over-the-counter analgesics, adverse effects and how the treatment affected their everyday life. Among 335 eligible patients, 301 (90%) agreed to participate. Atrial fibrillation was the most common indication (65%), and most patients filled a prescription for a non-vitamin K antagonist oral anticoagulant (NOAC) (58%). Among the 12% (n = 35) of participants who had switched oral anticoagulant treatment, 69% had switched from a vitamin K antagonist (VKA) to a NOAC. Switching was most frequently caused by inconvenience (34%) and adverse effects (23%). Although half of all patients had recently bought over-the-counter analgesics, purchase of ibuprofen and aspirin was rare (6%). More VKA users than NOAC users felt limited in their everyday life because of anticoagulant treatment (18% versus 9%). Among non-incident NOAC users, 21% had experienced adverse effects during their current treatment. Based on first-hand information from a large sample of anticoagulant users, we conclude that the main drug-related issues leading to anticoagulant switching and perceived limitations in everyday life were inconvenience and adverse effects. This varied between drug groups. Further, use of NSAIDs obtained over the counter was rare. © 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Dabigatran and kidney disease: a bad combination.

PubMed

Knauf, Felix; Chaknos, C Michael; Berns, Jeffrey S; Perazella, Mark A

2013-09-01

Dabigatran is an oral direct thrombin inhibitor widely used to prevent and treat various thromboembolic complications. An advantage of this agent over other anticoagulants is that routine laboratory monitoring and related dose adjustments are considered unnecessary. A major disadvantage is the absence of a reliable means of reversing its anticoagulant effect. After U.S. Food and Drug Administration approval, recently emerged data suggest a higher bleeding risk with dabigatran, especially in the elderly. Clinicians are thus faced with caring for patients with serious bleeding events without readily available tests to measure drug levels or the anticoagulant effects of dabigatran and without effective antidotes to rapidly reverse the anticoagulant effect. On the basis of dabigatran's pharmacokinetic profile, hemodialysis and continuous renal replacement therapy have been used to remove dabigatran with the hope, still unproven, that this would rapidly reverse the anticoagulant effect and reduce bleeding in patients with normal and those with reduced kidney function. However, the best clinical approach to the patient with serious bleeding is not known, and the risks of placing a hemodialysis catheter in an anticoagulated patient can be substantial. This article reviews this issue, addressing clinical indications, drug pharmacokinetics, clinical and laboratory monitoring tests, and dialytic and nondialytic approaches to reduce bleeding in dabigatran-treated patients.

Combined administration of antibiotics and direct oral anticoagulants: a renewed indication for laboratory monitoring?

PubMed

Lippi, Giuseppe; Favaloro, Emmanuel J; Mattiuzzi, Camilla

2014-10-01

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. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Drug Interactions of Direct-Acting Oral Anticoagulants.

PubMed

Fitzgerald, John Leonard; Howes, Laurence Guy

2016-09-01

In recent years, new direct-acting oral anticoagulants (DOACs) have been introduced into clinical practice that specifically inhibit either factor Ia or Xa. These drugs have, to a large extent, replaced warfarin for the treatment of venous thrombosis, pulmonary embolism, and non-valvular atrial fibrillation. They have potential advantages over warfarin in providing more stable anticoagulation and the lack of a need for regular venesection to monitor activity. They also have the promise of less drug and food interactions. All of these drugs are substrates for the permeability glycoprotein (P-gp) excretion system, and several are metabolised, in part, by cytochrome P450 (CYP) 3A4. This current article assesses the interactions that do or may occur with the DOACs, particularly with respect to the P-gp and CYP3A4 systems.

Association between payments from manufacturers of pharmaceuticals to physicians and regional prescribing: cross sectional ecological study.

PubMed

Fleischman, William; Agrawal, Shantanu; King, Marissa; Venkatesh, Arjun K; Krumholz, Harlan M; McKee, Douglas; Brown, Douglas; Ross, Joseph S

2016-08-18

 To examine the association between payments made by the manufacturers of pharmaceuticals to physicians and prescribing by physicians within hospital referral regions.  Cross sectional analysis of 2013 and 2014 Open Payments and Medicare Part D prescribing data for two classes of commonly prescribed, commonly marketed drugs: oral anticoagulants and non-insulin diabetes drugs, overall and stratified by physician and payment type.  306 hospital referral regions, United States.  45 949 454 Medicare Part D prescriptions written by 623 886 physicians to 10 513 173 patients for two drug classes: oral anticoagulants and non-insulin diabetes drugs.  Proportion, or market share, of marketed oral anticoagulants and non-insulin diabetes drugs prescribed by physicians among all drugs in each class and within hospital referral regions.  Among 306 hospital referral regions, there were 977 407 payments to physicians totaling $61 026 140 (£46 174 600; €54 632 500) related to oral anticoagulants, and 1 787 884 payments totaling $108 417 616 related to non-insulin diabetes drugs. The median market share of the hospital referral regions was 21.6% for marketed oral anticoagulants and 12.6% for marketed non-insulin diabetes drugs. Among hospital referral regions, one additional payment (median value $13, interquartile range, $10-$18) was associated with 94 (95% confidence interval 76 to 112) additional days filled of marketed oral anticoagulants and 107 (89 to 125) additional days filled of marketed non-insulin diabetes drugs (P<0.001). Payments to specialists were associated with greater prescribing of marketed drugs than payments to non-specialists (212 v 100 additional days filled per payment of marketed oral anticoagulants, 331 v 114 for marketed non-insulin diabetes drugs, P<0.001). Payments for speaker and consulting fees for non-insulin diabetes drugs were associated with greater prescribing of marketed drugs than payments for food and beverages or educational materials (484 v 110, P<0.001).  Payments by the manufacturers of pharmaceuticals to physicians were associated with greater regional prescribing of marketed drugs among Medicare Part D beneficiaries. Payments to specialists and payments for speaker and consulting fees were predominantly associated with greater regional prescribing of marketed drugs than payments to non-specialists or payments for food and beverages, gifts, or educational materials. As a cross sectional, ecological study, we cannot prove causation between payments to physicians and increased prescribing. Furthermore, our findings should be interpreted only at the regional level. Our study is limited to prescribing by physicians and the two drug classes studied. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Oral Anticoagulation in Chronic Kidney Disease and Atrial Fibrillation.

PubMed

Heine, Gunnar H; Brandenburg, Vincent; Schirmer, Stephan H

2018-04-27

Cardiological societies recommend, in their guidelines, that patients with atrial fibrillation and an intermediate (or higher) risk of stroke and systemic embolization should be treated with oral anticoagulant drugs. For patients who do not have mitral valve stenosis or a mechanical valve prosthesis, non-vitamin-K dependent oral anticoagulants (NOAC) are preferred over vitamin K antagonists (VKA) for this purpose. It is unclear, however, whether patients with chronic kidney disease and atrial fibrillation benefit from oral anticoagulation to the same extent as those with normal kidney function. It is also unclear which of the two types of anti - coagulant drug is preferable for patients with chronic kidney disease; NOAC are, in part, renally eliminated. This review is based on pertinent publications retrieved by a selective literature search, and on international guidelines. Current evidence suggests that patients with atrial fibrillation who have chronic kidney disease with a glomerular filtration rate (GFR) above 15 mL/ min/1.73 m² should be treated with an oral anticoagulant drug if they have an at least intermediate risk of embolization, as assessed with the CHA2DS2-VASc score. For patients with advanced chronic kidney disease (GFR from 15 to 29 mL/ min/1.73 m²), however, this recommendation is based only on registry studies. For dialysis patients with atrial fibrillation, decisions whether to give oral anticoagulant drugs should be taken on an individual basis, in view of the elevated risk of hemorrhage and the unclear efficacy of such drugs in these patients. The subgroup analyses of the NOAC approval studies show that, for patients with atrial fibrillation and chronic kidney disease with a creatinine clearance of >25-30 mL/min, NOAC should be given in preference to VKA, as long as the patient does not have mitral valve stenosis or a mechanical valve prosthesis. For those whose creatinine clearance is less than 25 mL/min, the relative merits of NOAC versus VKA are still debated. The cardiological societies' recommendation that patients with atrial fibrillation should be given oral anticoagulant drugs applies to the majority of such patients who also have chronic kidney disease.

New oral anticoagulants--a review.

PubMed

Ghanima, Waleed; Atar, Dan; Sandset, Per Morten

2013-10-01

Dabigatran, rivaroxaban and apixaban are three new oral anticoagulants that have recently been approved in Norway. The aim of this article is to provide an overview of the mechanisms of action, the most important indications and practical advice on the use of these drugs. The review is based on published phase 3 studies, a literature search in PubMed and the authors' clinical experience. Indications for use of the new anticoagulants include thromboprophylaxis after total hip and knee replacement surgery (all three), prevention of stroke and systemic embolism in non-valvular atrial fibrillation (all three), treatment of acute venous thrombosis and secondary prophylaxis after venous thrombosis (currently only rivaroxaban). For the aforementioned indications, these drugs have proven to be non-inferior to standard established anticoagulation therapy. For atrial fibrillation, all three drugs have also shown a lower incidence of intracranial bleeding compared with standard treatment. It is important to limit the use of these drugs to approved indications, to select patients who show good compliance, to rule out contraindications and to identify drug interactions. Monitoring of coagulation is not required, but patients should be followed up regularly to detect conditions that may lead to changes in the expected efficacy or safety.

Antiplatelet and Anticoagulant Drugs in Interventional Radiology

DOE Office of Scientific and Technical Information (OSTI.GOV)

Altenburg, Alexander; Haage, Patrick, E-mail: patrick.haage@helios-kliniken.de

In treating peripheral arterial disease, a profound knowledge of antiplatelet and anticoagulative drug therapy is helpful to assure a positive clinical outcome and to anticipate and avoid complications. Side effects and drug interactions may have fatal consequences for the patient, so interventionalists should be aware of these risks and able to control them. Aspirin remains the first-line agent for antiplatelet monotherapy, with clopidogrel added where dual antiplatelet therapy is required. In case of suspected antiplatelet drug resistance, the dose of clopidogrel may be doubled; prasugrel or ticagrelor may be used alternatively. Glycoprotein IIb/IIIa inhibitors (abciximab or eptifibatide) may help inmore » cases of hypercoagulability or acute embolic complications. Desmopressin, tranexamic acid, or platelet infusions may be used to decrease antiplatelet drug effects in case of bleeding. Intraprocedurally, anticoagulant therapy treatment with unfractionated heparin (UFH) still is the means of choice, although low molecular-weight heparins (LMWH) are suitable, particularly for postinterventional treatment. Adaption of LMWH dose is often required in renal insufficiency, which is frequently found in elderly patients. Protamine sulphate is an effective antagonist for UFH; however, this effect is less for LMWH. Newer antithrombotic drugs, such as direct thrombin inhibitors or factor X inhibitors, have limited importance in periprocedural treatment, with the exception of treating patients with heparin-induced thrombocytopenia (HIT). Nevertheless, knowing pharmacologic properties of the newer drugs facilitate correct bridging of patients treated with such drugs. This article provides a comprehensive overview of antiplatelet and anticoagulant drugs for use before, during, and after interventional radiological procedures.« less

Risk assessment of Soulatrolide and Mammea (A/BA+A/BB) coumarins from Calophyllum brasiliense by a toxicogenomic and toxicological approach.

PubMed

Gomez-Verjan, J C; Estrella-Parra, E; Vazquez-Martinez, E R; Gonzalez-Sanchez, I; Guerrero-Magos, G; Mendoza-Villanueva, D; Isus, L; Alfaro, A; Cerbón-Cervantes, M; Aloy, P; Reyes-Chilpa, R

2016-05-01

Calophyllum brasiliense (Calophyllaceae) is a tropical rain forest tree distributed in Central and South America. It is an important source of tetracyclic dipyrano coumarins (Soulatrolide) and Mammea type coumarins. Soulatrolide is a potent inhibitor of HIV-1 reverse transcriptase and displays activity against Mycobacterium tuberculosis. Meanwhile, Mammea A/BA and A/BB, pure or as a mixture, are highly active against several human leukemia cell lines, Trypanosoma cruzi and Leishmania amazonensis. Nevertheless, there are few studies evaluating their safety profile. In the present work we performed toxicogenomic and toxicological analysis for both type of compounds. Soulatrolide, and the Mammea A/BA + A/BB mixture (2.1) were slightly toxic accordingly to Lorke assay classification (DL50 > 3000 mg/kg). After a short-term administration (100 mg/kg/daily, orally, 1 week) liver toxicogenomic analysis revealed 46 up and 72 downregulated genes for Mammea coumarins, and 665 up and 1077 downregulated genes for Soulatrolide. Gene enrichment analysis identified transcripts involved in drug metabolism for both compounds. In addition, network analysis through protein-protein interactions, tissue evaluation by TUNEL assay, and histological examination revealed no tissue damage on liver, kidney and spleen after treatments. Our results indicate that both type of coumarins displayed a safety profile, supporting their use in further preclinical studies to determine its therapeutic potential. Copyright © 2016 Elsevier Ltd. All rights reserved.

Selection of an Aptamer Antidote to the Anticoagulant Drug Bivalirudin

PubMed Central

Martin, Jennifer A.; Parekh, Parag; Kim, Youngmi; Morey, Timothy E.; Sefah, Kwame; Gravenstein, Nikolaus; Dennis, Donn M.; Tan, Weihong

2013-01-01

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. PMID:23483901

Convergence of Free Energy Profile of Coumarin in Lipid Bilayer

PubMed Central

2012-01-01

Atomistic molecular dynamics (MD) simulations of druglike molecules embedded in lipid bilayers are of considerable interest as models for drug penetration and positioning in biological membranes. Here we analyze partitioning of coumarin in dioleoylphosphatidylcholine (DOPC) bilayer, based on both multiple, unbiased 3 μs MD simulations (total length) and free energy profiles along the bilayer normal calculated by biased MD simulations (∼7 μs in total). The convergences in time of free energy profiles calculated by both umbrella sampling and z-constraint techniques are thoroughly analyzed. Two sets of starting structures are also considered, one from unbiased MD simulation and the other from “pulling” coumarin along the bilayer normal. The structures obtained by pulling simulation contain water defects on the lipid bilayer surface, while those acquired from unbiased simulation have no membrane defects. The free energy profiles converge more rapidly when starting frames from unbiased simulations are used. In addition, z-constraint simulation leads to more rapid convergence than umbrella sampling, due to quicker relaxation of membrane defects. Furthermore, we show that the choice of RESP, PRODRG, or Mulliken charges considerably affects the resulting free energy profile of our model drug along the bilayer normal. We recommend using z-constraint biased MD simulations based on starting geometries acquired from unbiased MD simulations for efficient calculation of convergent free energy profiles of druglike molecules along bilayer normals. The calculation of free energy profile should start with an unbiased simulation, though the polar molecules might need a slow pulling afterward. Results obtained with the recommended simulation protocol agree well with available experimental data for two coumarin derivatives. PMID:22545027

Convergence of Free Energy Profile of Coumarin in Lipid Bilayer.

PubMed

Paloncýová, Markéta; Berka, Karel; Otyepka, Michal

2012-04-10

Atomistic molecular dynamics (MD) simulations of druglike molecules embedded in lipid bilayers are of considerable interest as models for drug penetration and positioning in biological membranes. Here we analyze partitioning of coumarin in dioleoylphosphatidylcholine (DOPC) bilayer, based on both multiple, unbiased 3 μs MD simulations (total length) and free energy profiles along the bilayer normal calculated by biased MD simulations (∼7 μs in total). The convergences in time of free energy profiles calculated by both umbrella sampling and z-constraint techniques are thoroughly analyzed. Two sets of starting structures are also considered, one from unbiased MD simulation and the other from "pulling" coumarin along the bilayer normal. The structures obtained by pulling simulation contain water defects on the lipid bilayer surface, while those acquired from unbiased simulation have no membrane defects. The free energy profiles converge more rapidly when starting frames from unbiased simulations are used. In addition, z-constraint simulation leads to more rapid convergence than umbrella sampling, due to quicker relaxation of membrane defects. Furthermore, we show that the choice of RESP, PRODRG, or Mulliken charges considerably affects the resulting free energy profile of our model drug along the bilayer normal. We recommend using z-constraint biased MD simulations based on starting geometries acquired from unbiased MD simulations for efficient calculation of convergent free energy profiles of druglike molecules along bilayer normals. The calculation of free energy profile should start with an unbiased simulation, though the polar molecules might need a slow pulling afterward. Results obtained with the recommended simulation protocol agree well with available experimental data for two coumarin derivatives.

Influence of novel oral anticoagulants on anticoagulation care management.

PubMed

Janzic, Andrej; Kos, Mitja

2017-09-01

Anticoagulation treatment was recently improved by the introduction of novel oral anticoagulants (NOACs). Using a combination of qualitative and quantitative methods, this study explores the effects of the introduction of NOACs on anticoagulation care in Slovenia. Face-to-face interviews with key stakeholders revealed evolvement and challenges of anticoagulation care from different perspectives. Obtained information was further explored through the analysis of nationwide data of drug prescriptions and realization of health care services. Simplified management of anticoagulation treatment with NOACs and their high penetration expanded the capacity of anticoagulation clinics, and consequentially the treated population increased by more than 50 % in the last 5 years. The main challenge concerned the expenditures for medicines, which increased approximately 10 times in just a few years. At the same time, the anticoagulation clinics and their core organisation were not affected, which is not expected to change, since they are vital in delivering high-quality care.

Exploring Cancer Therapeutics with Natural Products from African Medicinal Plants, Part I: Xanthones, Quinones, Steroids, Coumarins, Phenolics and other Classes of Compounds.

PubMed

Simoben, Conrad V; Ibezim, Akachukwu; Ntie-Kang, Fidele; Nwodo, Justina N; Lifongo, Lydia L

2015-01-01

Cancer is known to be the second most common disease-related cause of death among humans. In drug discovery programs anti-cancer chemotherapy remains quite challenging due to issues related to resistance. Plants used in traditional medicine are known to contribute significantly within a large proportion of the African population. A survey of the literature has led to the identification of ~400 compounds from African medicinal plants, which have shown anti-cancer, anti-proliferation, anti-tumor and/or cytotoxic activities, tested by in vitro and in vivo assays (from mildly active to very active), mainly alkaloids, terpenoids, flavonoids, coumarins, phenolics, polyacetylates, xanthones, quinones, steroids and lignans. The first part of this review series focuses on xanthones, quinones, steroids, coumarins, phenolics and other compound classes, while part II is focused on alkaloids, terpenoids, flavonoids.

Battle of oral anticoagulants in the field of atrial fibrillation scrutinized from a clinical practice (the real world) perspective

PubMed Central

2011-01-01

Warfarin has a long history of benefit and has become the gold standard medication for the prevention of ischemic stroke in patients with atrial fibrillation. Nevertheless, it is far from perfect and there is no doubt that new drugs must be found to replace warfarin. The new oral anticoagulants that are on the market or awaiting approval or under research offer some benefits but not enough to replace warfarin until results of additional studies can show an adequate balance between effectiveness/safety and cost/benefit. There are several issues concerning the new oral anticoagulants. It is essential that the effect of any anticoagulant can be measured in plasma. But to date, there is no test to assess the effect or therapeutic range for the new oral anticoagulants. There is no antidote to neutralize the action of the new drugs in cases of bleeding or when acute surgical intervention is necessary. Dabigatran requires dose adjustment in patients with moderate renal impairment and is contraindicated in patients with severe renal failure. Rivaroxaban should be used with caution in patients with severe renal impairment. Apixaban excretion is also partly dependent on renal function, although the impact of renal insufficiency has not yet been determined. How anticoagulant bridging can be done before surgery has not yet been established. In conclusion, although thousands of patients have been treated in phase III studies, additional data are necessary before conclusions can be drawn on the potential for these new anticoagulant drugs to replace warfarin in patients with atrial fibrillation. PMID:21794130

Syntheses of coumarin-tacrine hybrids as dual-site acetylcholinesterase inhibitors and their activity against butylcholinesterase, Aβ aggregation, and β-secretase.

PubMed

Sun, Qi; Peng, Da-Yong; Yang, Sheng-Gang; Zhu, Xiao-Lei; Yang, Wen-Chao; Yang, Guang-Fu

2014-09-01

Exploring small-molecule acetylcholinesterase (AChE) inhibitors to slow the breakdown of acetylcholine (Ach) represents the mainstream direction for Alzheimer's disease (AD) therapy. As the first acetylcholinesterase inhibitor approved for the clinical treatment of AD, tacrine has been widely used as a pharmacophore to design hybrid compounds in order to combine its potent AChE inhibition with other multi-target profiles. In present study, a series of novel tacrine-coumarin hybrids were designed, synthesized and evaluated as potent dual-site AChE inhibitors. Moreover, compound 1g was identified as the most potent candidate with about 2-fold higher potency (Ki=16.7nM) against human AChE and about 2-fold lower potency (Ki=16.1nM) against BChE than tacrine (Ki=35.7nM for AChE, Ki=8.7nM for BChE), respectively. In addition, some of the tacrine-coumarin hybrids showed simultaneous inhibitory effects against both Aβ aggregation and β-secretase. We therefore conclude that tacrine-coumarin hybrid is an interesting multifunctional lead for the AD drug discovery. Copyright © 2014 Elsevier Ltd. All rights reserved.

Health care expenditures and therapeutic outcomes of a pharmacist-managed anticoagulation service versus usual medical care.

PubMed

Hall, Deanne; Buchanan, Julianne; Helms, Bethany; Eberts, Matthew; Mark, Scott; Manolis, Chronis; Peele, Pamela; Docimo, Anne

2011-07-01

To evaluate the differences in health care expenditures and therapeutic outcomes of patients receiving warfarin therapy management by a pharmacist-managed anticoagulation service compared with those receiving warfarin management by usual medical care. Retrospective, matched-cohort study. University of Pittsburgh Medical Center (UPMC) and UPMC Health Plan. Three hundred fifty adults who received warfarin therapy; 175 were managed by the pharmacist-managed anticoagulation service for at least 2 months between October 1, 2007, and September 30, 2008, (case patients) and 175 received usual care (matched comparison group). Medical claims data compared were direct anticoagulation cost and overall medical care costs, anticoagulation-related adverse events, hospitalizations and emergency department visits, frequency of international normalized ratio (INR) testing, and quantity of warfarin refills. Operational costs of the anticoagulation service were also calculated. The INR values and time within therapeutic range were assessed through anticoagulation service reports and laboratory results. The direct anticoagulation care cost was $35,465 versus $111,586 and the overall medical care cost was $754,191 versus $1,480,661 for the anticoagulation service group versus the usual care group. Accounting for operational and drug expenditure costs, the cost savings was $647,024 for the anticoagulation service group. The anticoagulation service group had significantly fewer anticoagulation-related adverse events (14 vs 41, p<0.0001), hospital admissions (3 vs 14, p<0.00001), and emergency department visits (58 vs 134, p<0.00001). The percentage of INR values in range and the percentage of time the INR values were in range were significantly higher in the anticoagulation service group (67.2% vs 54.6%, p<0.0001, and 73.7% vs 61.3%, p<0.0001, respectively). Compared with the usual care group, the anticoagulation service group had significantly more INR tests performed but demonstrated no significant difference in the quantity of drug refills. After accounting for operational costs, pharmacist-managed anticoagulation leads to reduced health care expenditure while improving therapeutic outcomes compared with usual medical care.

[Inhibitory effects of 11 coumarin compounds against growth of human bladder carcinoma cell line E-J in vitro].

PubMed

Yang, Xiu-wei; Xu, Bo; Ran, Fu-xiang; Wang, Rui-qing; Wu, Jun; Cui, Jing-rong

2007-01-01

To screen antitumor active compounds, drug-like or leading compounds from Chinese traditional and herbal drugs. Eleven coumarin compounds isolated from the Chinese traditional and herbal drugs were studied for their antitumor activities in vitro by determining the inhibition rates against growth of human bladder carcinoma cell line E-J. It showed that umbelliferone, scoparone, demethylfuropinarine, isopimpinellin, forbesoside, columbianadin, decursin and glycycoumarin inhibited the growth of human bladder carcinoma cell line E-J in vitro and their activities showed a concentration-effect relationship. The inhibitory effects of forbesoside, columbianadin, decursin and umbelliferone, with IC50 values of 7.50x10(-7), 2.30x10(-6), 6.00x10(-6) and 1.30x10(-6) mol/L, respectively, were stronger than those of the other tested compounds. However, xanthotoxin, esculin and sphondin did not inhibit the growth of human bladder carcinoma cell line E-J in this assay condition. These findings indicate that forbesoside, columbianadin, esculin, decursin and umbelliferone would be effective or regarded as potent drug-like or leading compounds against human bladder carcinoma.

Amelioration of L-thyroxine-induced hyperthyroidism by coumarin (1,2-benzopyrone) in female rats.

PubMed

Panda, Sunanda; Kar, Anand

2007-11-01

1. The efficacy of coumarin (1,2-benzopyrone) was examined for the regulation of hyperthyroidism in female rats. 2. Coumarin was administered (10 mg/kg per day for 15 days) to l-thyroxine (L-T(4))-induced hyperthyroid as well as to euthyroid rats and changes in serum concentrations of thyroid hormones and in associated parameters, such as serum cholesterol, activity of hepatic 5'-monodeiodinase (5'DI) and glucose-6-phosphatase (G-6-Pase), glycogen content, bodyweight and daily food consumption, were analysed. Simultaneously, changes in hepatic lipid peroxidation (LPO), reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) were also investigated. 3. Although L-T(4) administration increased serum levels of thyroid hormones, the activity of hepatic 5'DI, G-6-Pase and LPO and daily food consumption, it decreased the level of serum cholesterol, hepatic glycogen content and the activities of anti-oxidant enzymes, such as SOD, CAT and GSH. 4. However, simultaneous administration of coumarin for 15 days to a group of hyperthyroid animals reversed most of the aforementioned changes, indicating its potential to ameliorate hyperthyroidism. Moreover, the drug did not increase, but rather decreased, hepatic LPO, suggesting its safe nature. 5. The present findings reveal a positive role for coumarin in the regulation of hyperthyroidism without any hepatotoxicity. It also appears that the test compound inhibits thyroid function at both a glandular level and at the level of peripheral conversion of T(4) to tri-iodothyronine.

Anticoagulant Preferences and Concerns among Venous Thromboembolism Patients.

PubMed

Lutsey, Pamela L; Horvath, Keith J; Fullam, Lisa; Moll, Stephan; Rooney, Mary R; Cushman, Mary; Zakai, Neil A

2018-03-01

 Warfarin and direct oral anticoagulants (DOACs) are used for the initial treatment and secondary prevention of venous thromboembolism (VTE), and have similar efficacy. Patient concerns and preferences are important considerations when selecting an anticoagulant, yet these are not well studied.  VTE patients ( n  = 519) were surveyed from online sources (clotconnect.org, stoptheclot.org and National Blood Clot Alliance Facebook followers [ n  = 495]) and a haematology clinic in Vermont ( n  = 24).  Patients were 83% females and on average (±standard deviation [SD]) 45.7 ± 13.1 years; 65% self-reported warfarin as their initial VTE treatment and 35% a DOAC. Proportions reporting being extremely concerned about the following outcomes were as follows: recurrent VTE 33%, major bleeding 21%, moderate bleeding 16% and all-cause death 29%. When asked about oral anticoagulant characteristics, patients strongly preferred anticoagulants that are reversible (53%), and for which blood drug levels can be monitored (30%). Lower proportions agreed with statements that regular blood testing is inconvenient (18%), that they are comfortable using the newest drug versus an established drug (15%) and that it is difficult to change their diet to accommodate their anticoagulant (17%). In multivariable-adjusted models, patients tended to have had as their initial treatment, and to currently be taking, the oral anticoagulant option they personally preferred.  Patients held the greatest concern for recurrent VTE and mortality, regardless of which treatment they were prescribed. Potential weaknesses of warfarin (e.g., dietary restrictions, regular monitoring) were generally not considered onerous, while warfarin's advantages (e.g., ability to monitor) were viewed favourably. Schattauer GmbH Stuttgart.

Modulation of chaperone function and cochaperone interaction by novobiocin in the C-terminal domain of Hsp90: evidence that coumarin antibiotics disrupt Hsp90 dimerization.

PubMed

Allan, Rudi K; Mok, Danny; Ward, Bryan K; Ratajczak, Thomas

2006-03-17

The C-terminal domain of Hsp90 displays independent chaperone activity, mediates dimerization, and contains the MEEVD motif essential for interaction with tetratricopeptide repeat-containing immunophilin cochaperones assembled in mature steroid receptor complexes. An alpha-helical region, upstream of the MEEVD peptide, helps form the dimerization interface and includes a hydrophobic microdomain that contributes to the Hsp90 interaction with the immunophilin cochaperones and corresponds to the binding site for novobiocin, a coumarin-related Hsp90 inhibitor. Mutation of selected residues within the hydrophobic microdomain significantly impacted the chaperone function of a recombinant C-terminal Hsp90 fragment and novobiocin inhibited wild-type chaperone activity. Prior incubation of the Hsp90 fragment with novobiocin led to a direct blockade of immunophilin cochaperone binding. However, the drug had little influence on the pre-formed Hsp90-immunophilin complex, suggesting that bound cochaperones mask the novobiocin-binding site. We observed a differential effect of the drug on Hsp90-immunophilin interaction, suggesting that the immunophilins make distinct contacts within the C-terminal domain to specifically modulate Hsp90 function. Novobiocin also precluded the interaction of full-length Hsp90 with the p50(cdc37) cochaperone, which targets the N-terminal nucleotide-binding domain, and is prevalent in Hsp90 complexes with protein kinase substrates. Novobiocin therefore acts locally and allosterically to induce conformational changes within multiple regions of the Hsp90 protein. We provide evidence that coumermycin A1, a coumarin structurally related to novobiocin, interferes with dimerization of the Hsp90 C-terminal domain. Coumarin-based inhibitors then may antagonize Hsp90 function by inducing a conformation favoring separation of the C-terminal domains and release of substrate.

Managing bleeding and emergency reversal of newer oral anticoagulants: a review for primary care providers.

PubMed

Peacock, W Frank

2014-10-01

The therapeutic landscape for anticoagulation management is undergoing a shift from the use of traditional anticlotting agents such as heparins and warfarin as the only options to the growing adoption of newer target-specific oral anticoagulants (TSOACs) with novel mechanisms of action. Dabigatran, the first TSOAC approved for use in the United States, is a direct competitive inhibitor of thrombin. It has predictable kinetics, with an elimination half-life of 12 to 17 hours in healthy volunteers. Apixaban and rivaroxaban are selective inhibitors of factor Xa, and also display first-order kinetics. In younger healthy individuals, apixaban has an apparent half-life of approximately 12 hours, whereas rivaroxaban has an elimination half-life of 5 to 9 hours. Understanding the pharmacologic properties of these newer drugs can lead to better insights regarding their respective safety and efficacy profiles and their application in clinical practice. Laboratory assessments have been developed to measure the anticoagulant efficacy of these newer agents. However, the results of these tests can be highly variable, and are therefore not always useful for monitoring the anticoagulation effects of these agents. In addition, several strategies have been documented for the potential reversal of the anticoagulant effects of these drugs, from the temporary discontinuation of an agent before elective surgery to suggested emergency procedures in the case of major bleeding events. New, specific reversal agents for dabigatran, apixaban, and rivaroxaban are currently being developed, and dabigatran has received fast-track designation from the US Food and Drug Administration. Until comprehensive clinical guidelines are developed, institutions involved in emergency care should establish their own procedures for the management of patients undergoing anticoagulation who require emergency treatment. These protocols should include appropriate laboratory testing to assess anticoagulant activity as part of the inpatient workup if time allows, and the potential use of hemodialysis, prohemostatic agents, and reversal agents when available.

Laboratory Assessment of the Anticoagulant Activity of Direct Oral Anticoagulants: A Systematic Review.

PubMed

Samuelson, Bethany T; Cuker, Adam; Siegal, Deborah M; Crowther, Mark; Garcia, David A

2017-01-01

Direct oral anticoagulants (DOACs) are the treatment of choice for most patients with atrial fibrillation and/or noncancer-associated venous thromboembolic disease. Although routine monitoring of these agents is not required, assessment of anticoagulant effect may be desirable in special situations. The objective of this review was to summarize systematically evidence regarding laboratory assessment of the anticoagulant effects of dabigatran, rivaroxaban, apixaban, and edoxaban. PubMed, Embase, and Web of Science were searched for studies reporting relationships between drug levels and coagulation assay results. We identified 109 eligible studies: 35 for dabigatran, 50 for rivaroxaban, 11 for apixaban, and 13 for edoxaban. The performance of standard anticoagulation tests varied across DOACs and reagents; most assays, showed insufficient correlation to provide a reliable assessment of DOAC effects. Dilute thrombin time (TT) assays demonstrated linear correlation (r 2  = 0.67-0.99) across a range of expected concentrations of dabigatran, as did ecarin-based assays. Calibrated anti-Xa assays demonstrated linear correlation (r 2  = 0.78-1.00) across a wide range of concentrations for rivaroxaban, apixaban, and edoxaban. An ideal test, offering both accuracy and precision for measurement of any DOAC is not widely available. We recommend a dilute TT or ecarin-based assay for assessment of the anticoagulant effect of dabigatran and anti-Xa assays with drug-specific calibrators for direct Xa inhibitors. In the absence of these tests, TT or APTT is recommended over PT/INR for assessment of dabigatran, and PT/INR is recommended over APTT for detection of factor Xa inhibitors. Time since last dose, the presence or absence of drug interactions, and renal and hepatic function should impact clinical estimates of anticoagulant effect in a patient for whom laboratory test results are not available. Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

New strategies for the treatment of acute venous thromboembolism.

PubMed

Prandoni, Paolo; Lensing, Anthonie W A; Pesavento, Raffaele

2006-11-01

In recent years, new opportunities have emerged that have the potential to change rapidly the therapeutic scenario of patients with acute venous thromboembolism (VTE). Selected patients with deep vein thrombosis (DVT) can be treated effectively and safely at home with fixed doses of low molecular weight heparins. The prompt administration of compression elastic stockings in addition to anticoagulant drugs in patients with acute DVT has the potential to halve the rate of late postthrombotic sequelae. The long-term use of low molecular weight heparins is likely to be more effective than oral anticoagulants for the secondary prevention of VTE in patients with advanced malignancy. Patients with pulmonary embolism and right ventricular dysfunction might benefit from the early administration of thrombolytic drugs in combination with heparin to a greater extent than from heparin alone. Despite an impressive amount of clinical information on the proper duration of oral anticoagulants in patients with unprovoked VTE, the optimal long-term treatment of these patients remains undefined. Finally, new categories of drugs are emerging that have the potential to replace conventional anticoagulants in the near future. They include compounds that inhibit factor Xa or thrombin.

US Emergency Department Visits for Outpatient Adverse Drug Events, 2013-2014.

PubMed

Shehab, Nadine; Lovegrove, Maribeth C; Geller, Andrew I; Rose, Kathleen O; Weidle, Nina J; Budnitz, Daniel S

2016-11-22

The Patient Protection and Affordable Care Act of 2010 brought attention to adverse drug events in national patient safety efforts. Updated, detailed, nationally representative data describing adverse drug events can help focus these efforts. To describe the characteristics of emergency department (ED) visits for adverse drug events in the United States in 2013-2014 and describe changes in ED visits for adverse drug events since 2005-2006. Active, nationally representative, public health surveillance in 58 EDs located in the United States and participating in the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance project. Drugs implicated in ED visits. National weighted estimates of ED visits and subsequent hospitalizations for adverse drug events. Based on data from 42 585 cases, an estimated 4.0 (95% CI, 3.1-5.0) ED visits for adverse drug events occurred per 1000 individuals annually in 2013 and 2014 and 27.3% (95% CI, 22.2%-32.4%) of ED visits for adverse drug events resulted in hospitalization. An estimated 34.5% (95% CI, 30.3%-38.8%) of ED visits for adverse drug events occurred among adults aged 65 years or older in 2013-2014 compared with an estimated 25.6% (95% CI, 21.1%-30.0%) in 2005-2006; older adults experienced the highest hospitalization rates (43.6%; 95% CI, 36.6%-50.5%). Anticoagulants, antibiotics, and diabetes agents were implicated in an estimated 46.9% (95% CI, 44.2%-49.7%) of ED visits for adverse drug events, which included clinically significant adverse events, such as hemorrhage (anticoagulants), moderate to severe allergic reactions (antibiotics), and hypoglycemia with moderate to severe neurological effects (diabetes agents). Since 2005-2006, the proportions of ED visits for adverse drug events from anticoagulants and diabetes agents have increased, whereas the proportion from antibiotics has decreased. Among children aged 5 years or younger, antibiotics were the most common drug class implicated (56.4%; 95% CI, 51.8%-61.0%). Among children and adolescents aged 6 to 19 years, antibiotics also were the most common drug class implicated (31.8%; 95% CI, 28.7%-34.9%) in ED visits for adverse drug events, followed by antipsychotics (4.5%; 95% CI, 3.3%-5.6%). Among older adults (aged ≥65 years), 3 drug classes (anticoagulants, diabetes agents, and opioid analgesics) were implicated in an estimated 59.9% (95% CI, 56.8%-62.9%) of ED visits for adverse drug events; 4 anticoagulants (warfarin, rivaroxaban, dabigatran, and enoxaparin) and 5 diabetes agents (insulin and 4 oral agents) were among the 15 most common drugs implicated. Medications to always avoid in older adults according to Beers criteria were implicated in 1.8% (95% CI, 1.5%-2.1%) of ED visits for adverse drug events. The prevalence of emergency department visits for adverse drug events in the United States was estimated to be 4 per 1000 individuals in 2013 and 2014. The most common drug classes implicated were anticoagulants, antibiotics, diabetes agents, and opioid analgesics.

Laboratory measurement of the anticoagulant activity of the non-vitamin K oral anticoagulants.

PubMed

Cuker, Adam; Siegal, Deborah M; Crowther, Mark A; Garcia, David A

2014-09-16

Non-vitamin K oral anticoagulants (NOACs) do not require routine laboratory monitoring. However, laboratory measurement may be desirable in special situations and populations. This study's objective was to systematically review and summarize current evidence regarding laboratory measurement of the anticoagulant activity of dabigatran, rivaroxaban, and apixaban. We searched PubMed and Web of Science for studies that reported a relationship between drug levels of dabigatran, rivaroxaban, and apixaban and coagulation assay results. Study quality was evaluated using QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2). We identified 17 eligible studies for dabigatran, 15 for rivaroxaban, and 4 for apixaban. For dabigatran, a normal thrombin time excludes clinically relevant drug concentrations. The activated partial thromboplastin time (APTT) and prothrombin time (PT) are less sensitive and may be normal at trough drug levels. The dilute thrombin time (R(2) = 0.92 to 0.99) and ecarin-based assays (R(2) = 0.92 to 1.00) show excellent linearity across on-therapy drug concentrations and may be used for drug quantification. For rivaroxaban and apixaban, anti-Xa activity is linear (R(2) = 0.89 to 1.00) over a wide range of drug levels and may be used for drug quantification. Undetectable anti-Xa activity likely excludes clinically relevant drug concentrations. The PT is less sensitive (especially for apixaban); a normal PT may not exclude clinically relevant levels. The APTT demonstrates insufficient sensitivity and linearity for quantification. Dabigatran, rivaroxaban, and apixaban exhibit variable effects on coagulation assays. Understanding these effects facilitates interpretation of test results in NOAC-treated patients. More information on the relationship between drug levels and clinical outcomes is needed. Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Dental management of patients receiving anticoagulant and/or antiplatelet treatment

PubMed Central

Chaveli-López, Begonya; Gavaldá-Esteve, Carmen

2014-01-01

Introduction: Adequate hemostasis is crucial for the success of invasive dental treatment, since bleeding problems can give rise to complications associated with important morbidity-mortality. The dental treatment of patients who tend to an increased risk of bleeding due to the use of anticoagulant and/or antiplatelet drugs raises a challenge in the daily practice of dental professionals. Adequate knowledge of the mechanisms underlying hemostasis, and the optimized management of such patients, are therefore very important issues. Objectives: A study is made of the anticoagulant / antiplatelet drugs currently available on the market, with evaluation of the risks and benefits of suspending such drugs prior to invasive dental treatment. In addition, a review is made of the current management protocols used in these patients. Material and Methods: A literature search was made in the PubMed, Cochrane Library and Scopus databases, covering all studies published in the last 5 years in English and Spanish. Studies conducted in humans and with scientific evidence levels 1 and 2 (metaanalyses, systematic reviews, randomized phase 1 and 2 trials, cohort studies and case-control studies) were considered. The keywords used for the search were: tooth extraction, oral surgery, hemostasis, platelet aggregation inhibitors, antiplatelet drugs, anticoagulants, warfarin, acenocoumarol. Results and Conclusions: Many management protocols have been developed, though in all cases a full clinical history is required, together with complementary hemostatic tests to minimize any risks derived from dental treatment. Many authors consider that patient medication indicated for the treatment of background disease should not be altered or suspended unless so indicated by the prescribing physician. Local hemostatic measures have been shown to suffice for controlling possible bleeding problems resulting from dental treatment. Key words:Tooth extraction, oral surgery, hemostasis, platelet aggregation inhibitors, antiplatelet drugs, anticoagulants, warfarin, acenocoumarol. PMID:24790716

Patient preferences and willingness to pay for different options of anticoagulant therapy.

PubMed

Moia, Marco; Mantovani, Lorenzo Giovanni; Carpenedo, Monica; Scalone, Luciana; Monzini, Mara Silvia; Cesana, Giancarlo; Mannucci, Pier Mannuccio

2013-04-01

New anticoagulant drugs alternative to vitamin K antagonists are currently under clinical evaluation. Patient's preferences should be considered in the development of new therapeutic strategies. Our study aim was to elicit patient preferences, and estimate their willingness to pay for the different treatment options. A Discrete Choice Experiment was administered to patients consecutively attending an anticoagulation clinic, either on stable oral anticoagulant therapy, or during their first visit at the time of starting therapy. Six treatment characteristics were analysed: route and number of medication administrations, frequency of monitoring, risk of some minor bleeding, the amount of attention required for drug/food interactions, requirement for dose adjustment, and out-of-pocket treatment cost. Relationships between patient's preferences and their characteristics were analysed. 255 patients participated (55 % men, with a mean age 64 years; 35.7 % on stable therapy). A statistically significant importance was attributed to all but two characteristics (the amount of attention required for interaction with other drugs/food and for dose adjustment.) Monthly patient willingness to pay was 79 for tablets versus injections; 41 for once-daily versus twice-daily tablets, 25 for drugs without risk of minor bleeding events and 20 for once-monthly versus twice-monthly monitoring. Patients on stable therapy considered more important the amount of attention required for drug/food interactions than did the starters. Younger or working patients considered the reduction of monitoring frequency more important than did the older or not working patients (retired, housewives). This study elicited preferences from patients on oral anticoagulant therapy with a simple and well established method, which allows to obtain information warranted for planning optimal healthcare.

An in vivo strategy to counteract post-administration anticoagulant activity of azido-Warfarin

NASA Astrophysics Data System (ADS)

Ursuegui, Sylvain; Recher, Marion; Krężel, Wojciech; Wagner, Alain

2017-05-01

Drugs, usually long acting and metabolically stable molecules, might be the source of adverse effects triggered by complex drug interactions, anaphylaxis and drug-induced coagulopathy. To circumvent this growing drug safety issue, we herein investigate the opportunity offered by bio-orthogonal chemistry for in vivo drug neutralization. We design a small-molecule anticoagulant drug (Warfarin) containing an azide group that acts as a safety pin. It allows drug deactivation and restoration of physiological coagulation via in vivo click reaction with a suitable cyclooctyne-based neutralizing agent. In this strategy, the new molecule formed by reaction of the drug and the antidote is deprived of biological activity and prone to fast renal clearance. This `Click & Clear' approach lays ground for new strategies in designing drugs with switchable biophysical properties.

Novel oral anticoagulants for stroke prevention in patients with atrial fibrillation: dawn of a new era.

PubMed

Contractor, Tahmeed; Levin, Vadim; Martinez, Matthew W; Marchlinski, Francis E

2013-01-01

Atrial fibrillation (AF) is an important cause of ischemic stroke and is the underlying cause of > 20% of all strokes, with increasing age being a risk factor. Until recently, warfarin was the only available oral anticoagulant used to decrease this risk in patients with AF. However, there are several disadvantages of warfarin use, such as the requirement for monitoring the international normalized ratio, its wide range of drug-food interactions, and its narrow therapeutic index. Thus, there has been a strong impetus for the development of newer oral anticoagulants with predictable pharmacokinetics that obviate the need for monitoring the international normalized ratio. The US Food and Drug Administration has approved a direct thrombin inhibitor (dabigatran) and 2 factor Xa inhibitors (rivaroxaban and apixaban) for stroke prevention in patients with nonvalvular AF. There are several other new oral anticoagulant agents on the horizon, including the factor Xa inhibitor edoxaban. This review article discusses the pharmacological properties, clinical trial data, and practical issues associated with the use of these novel oral anticoagulants.

Chemistry and biological activity of coumarins at molecular level.

PubMed

Garro, Hugo A; García, Celina; Martín, Víctor S; Tonn, Carlos E; Pungitore, Carlos R

2014-08-01

Synthetic coumarins were prepared in high yields using ionic liquids as an environmental friendly alternative. 3,4-Dimethyl-7-hydroxycoumarin (3ab) and 3-isopropyl-4-methyl-5,7-dihydroxycoumarin (3bc) showed interesting activity against Taq DNA polymerase with IC50 values of 115.7 microM and 82.2 microM, respectively. Also, 4-methyl-7-hydroxycoumarin (3aa) and 4-methyl-5,7-dihydroxycoumarin (3ba) exhibited inhibitory activity against MMLV-RT with IC50 values of 23.5 microM and 18.3 microM, respectively. These inhibitors could have importance as antiretroviral chemotherapeutic agents and also for the development of antitumor drugs.

Impact of genetic factors (VKORC1, CYP2C9, CYP4F2 and EPHX1) on the anticoagulation response to fluindione

PubMed Central

Lacut, Karine; Ayme-Dietrich, Estelle; Gourhant, Lenaick; Poulhazan, Elise; Andro, Marion; Becquemont, Laurent; Mottier, Dominique; Le Gal, Gregoire; Verstuyft, Celine

2012-01-01

AIM Genetic variants of the enzyme that metabolizes warfarin, cytochrome P-450 2C9 (CYP2C9) and of a key pharmacologic target of vitamin K antagonists, vitamin K epoxide reductase (VKORC1), contribute to differences in patients' responses to coumarin derivatives. The role of these variants in fluindione response is unknown. Our aim was to assess whether genetic factors contribute to the variability in the response to fluindione. METHODS Four hundred sixty-five patients with a venous thromboembolic event treated by fluindione for at least 3 months with a target international normalized ratio (INR) of 2.0 to 3.0 were studied. VKORC1, CYP2C9, CYP4F2 and EPHX1 genotypes were assessed. INR checks, fluindione doses and bleeding events were collected. RESULTS VKORC1 genotype had a significant impact on early anticoagulation (INR value ≥2 after the first two intakes) (P < 0.0001), on the time required to reach a first INR within the therapeutic range (P < 0.0001) and on the time to obtain a first INR value > 4 (P = 0.0002). The average daily dose of fluindione during the first period of stability was significantly associated with the VKORC1 genotype: 19.8 mg (±5.5) for VKORC1 CC, 14.7 mg (±6.2) for VKORC1 CT and 8.2 mg (±2.5) for VKORC1 TT (P < 0.0001). CYP2C9, CYP4F2 and EPHX1 genotypes did not significantly influence the response to fluindione. CONCLUSIONS VKORC1 genotype strongly affected anticoagulation induced by fluindione whereas CYP2C9, CYP4F2 and EPHX1 genotypes seemed less determining. PMID:21883387

Acute management of bleeding in patients on novel oral anticoagulants.

PubMed

Siegal, Deborah M; Crowther, Mark A

2013-02-01

Novel oral anticoagulants that directly inhibit thrombin (dabigatran) or factor Xa (rivaroxaban, apixaban) are currently available for prevention of venous thromboembolism (VTE) after orthopaedic surgery, treatment of acute VTE, and prevention of arterial thromboembolism in non-valvular atrial fibrillation. These agents offer advantages over VKAs, including rapid onset, shorter half-lives, fewer drug interactions, and lack of need for routine monitoring. However, there are no established agents to reverse their anticoagulant effect. We review the risk of bleeding with the novel oral anticoagulants and the limitations of conventional coagulation assays for measuring anticoagulant effect. We provide an approach to the management of patients with bleeding complications with evidence for various interventions for reversal, where available.

Suspected adverse drug reaction reports with oral anticoagulants in Portugal: a pharmacovigilance study.

PubMed

Caldeira, Daniel; Rodrigues, Raquel; Abreu, Daisy; Anes, Ana Marta; Rosa, Mário M; Ferreira, Joaquim J

2018-04-01

In this pharmacovigilance study, we aimed to determine the incidence of spontaneously reported suspected adverse drug reactions (ADRs) related to oral anticoagulants: non-vitamin K antagonist oral anticoagulants (NOACs; apixaban, dabigatran, edoxaban, rivaroxaban) and vitamin K antagonists (VKA) Research design and methods: In this retrospective observational study, we extracted all the individual case safety reports related to oral anticoagulants recorded in the Portuguese Pharmacovigilance Database (January 2010 to April 2015). The annual incidence of suspected ADRs was estimated using drug exposure data. Disproportionality of reporting ADR was addressed through reporting odds ratio (ROR) and 99% confidence intervals. We appraised 794 suspected ADR (78% related to NOACs). The annual number of ADRs increased overtime with 9 ADRs/million Defined Daily Dose (DDD) at the end of 2014. The incidence of NOACs ADRs decreased from 2012 onwards. VKA showed a disproportion in 'Investigation' (ROR 0.10, 99%CI 0.05-0.22) and 'Injury, poisoning and procedural complications' (ROR 0.36, 99%CI 0.19-0.69) ADRs compared with NOACs. NOACs had a higher significant disproportion of 'Nervous system disorders' related ADRs (ROR 3.98, 99%CI 1.50-10.53). Reporting of ADRs associated with oral anticoagulants (mainly NOACs), is increasing. Exploratory disproportion analyses showed an increase of reports of nervous system ADRs with NOACs, and INR-related ADRs with VKA.

[Factors influencing activity of oral anticoagulants. Interactions with drugs and food].

PubMed

Sawicka-Powierza, Jolanta; Rogowska-Szadkowska, Dorota; Ołtarzewska, Alicja Małgorzata; Chlabicz, Sławomir

2008-05-01

Oral anticoagulants (OAC) are commonly used as a life-long therapy in prevention of systemic embolism in patients with atrial fibrillation, valvular heart disease and prosthetic hart valves and in the primary and secondary prevention of venous thromboembolism. They are also used for the prevention of thromboembolic events in patients with acute myocardial infarction and with angina pectoris, in patients with biological hart valves and after some types of orthopaedics surgery. The International Normalized Ratio (INR) is used to evaluate the efficacy of anti-coagulant therapy. The risk of thromboembolic and haemorrhagic complications increases when the INR is out of the therapeutic range. The aim of this study was to present information about the factors influencing activity of oral anticoagulants and interactions between oral anticoagulants and drugs or food. The effect of oral anticoagulants is influenced by genetic and environmental factors such as: medicines, food, diseases and pre-existing conditions. A common mutation in the gene coding for the cytochrome P450 (CYP2C9), with one or more combinations of its polymorphisms, is responsible for the reduced warfarin requirements or for the resistance to warfarin. A mutation in the factor IX is responsible for the risk of bleeding during OAC therapy without excessive prolongation of the prothrombin time (PT). Drugs, herbs and multivitamin supplements can alter the absorption, pharmacokinetics or pharmakodynamics of OAC. Nonsteroid anti-inflammatory drugs and paracetamol in combination with OAC seem to be the most dangerous because they are available without prescription and are used without medical consultation. Patients on OAC therapy are sensitive to changing dietary intake of vitamin K, which is supplied from phylloquinones in plants or from vitamin K-containing medicines. The effect of OAC can be influenced by other existing factors like: fever, diarrhoea, alcohol abuse or physical hyperactivity. Some malignancies or other diseases like cardiac insufficiency, hyperthyroidism and hypothyroidism or hepatic dysfunction may also affect OAC therapy. This treatment requires patients and doctors to be knowledgeable about factors influencing the activity of oral anticoagulants. For this reason educational programme on OAC therapy should be conducted among patients and doctors.

Comparing new anticoagulants.

PubMed

Wooten, James M

2012-12-01

For years, the pharmaceutical industry has been trying to find a safe and effective drug to replace warfarin. Although warfarin is an effective anticoagulant, its pharmacology, adverse effects, and risk profiles dictate that patients taking this medication must be monitored judiciously. The US Food and Drug Administration has approved two drugs for commercial use, dabigatran and rivaroxaban, that will compete directly with warfarin for use in specific indications. Because of direct marketing to patients, physicians are being asked to comment on these new medications. This brief review illustrates the data available for the two new drugs when compared to warfarin for the specified indications. For some patients, these drugs may be highly beneficial and offer an excellent alternative to warfarin. For others, warfarin may still be the preferred drug.

[Pharmacokinetics of α-asarone after intranasal and intravenous administration with PLA-α-asarone nanoparticles].

PubMed

Lu, Jin; Guo, Li-Wei; Fu, Ting-Ming; Zhu, Guo-Long; Dai, Zhen-Nan; Zhan, Guan-Jun; Chen, Li-Li

2017-06-01

PLA-α-asarone nanoparticles were prepared by using organic solvent evaporation method, and their in vivo distribution and brain targeting after intranasal administration were studied as compared with intravenous administration. The results showed that brain targeting coefficient of PLA-α-asarone nanoparticles after intranasal and intravenous administration was 1.65 and 1.16 respectively. The absolute bioavailability, brain-targeting efficiency and the percentage of nasal-brain delivery of PLA-α-asarone nanoparticles were 74.2%, 142.24 and 29.83%, respectively after intranasal administration. The results of fluorescence labeling showed that the fluorescent intensity of coumarin-6 in the brain tissue was the highest after intranasal administration of PLA-α-asarone fluorescent nanoparticles, achieving the purpose of brain-targeted drug delivery. The fluorescent intensity of coumarin-6 in liver tissue after intravenous administration of PLA-α-asarone nanoparticles was much higher than that after intranasal administration, indicating that intranasal administration of PLA-α-asarone nanoparticles could decrease drug-induced hepatotoxicity. In addition, the fluorescent intensity of coumarin-6 in lung tissue was weaker after intranasal administration, which solved the shortcomings of intranasal administration of α-asarone dry powder prepared by airflow pulverization method. In vivo studies indicated that PLA-α-asarone nanoparticles after intranasal administration had a stronger brain targeting as compared with intravenous administration. Copyright© by the Chinese Pharmaceutical Association.

Delivery of optimized inpatient anticoagulation therapy: consensus statement from the anticoagulation forum.

PubMed

Nutescu, Edith A; Wittkowsky, Ann K; Burnett, Allison; Merli, Geno J; Ansell, Jack E; Garcia, David A

2013-05-01

To provide recommendations for optimized anticoagulant therapy in the inpatient setting and outline broad elements that need to be in place for effective management of anticoagulant therapy in hospitalized patients; the guidelines are designed to promote optimization of patient clinical outcomes while minimizing the risks for potential anticoagulation-related errors and adverse events. The medical literature was reviewed using MEDLINE (1946-January 2013), EMBASE (1980-January 2013), and PubMed (1947-January 2013) for topics and key words including, but not limited to, standards of practice, national guidelines, patient safety initiatives, and regulatory requirements pertaining to anticoagulant use in the inpatient setting. Non-English-language publications were excluded. Specific MeSH terms used include algorithms, anticoagulants/administration and dosage/adverse effects/therapeutic use, clinical protocols/standards, decision support systems, drug monitoring/methods, humans, inpatients, efficiency/ organizational, outcome and process assessment (health care), patient care team/organization and administration, program development/standards, quality improvement/organization and administration, thrombosis/ drug therapy, thrombosis/prevention and control, risk assessment/standards, patient safety/standards, and risk management/methods. Because of this document's scope, the medical literature was searched using a variety of strategies. When possible, recommendations are supported by available evidence; however, because this paper deals with processes and systems of care, high-quality evidence (eg, controlled trials) is unavailable. In these cases, recommendations represent the consensus opinion of all authors and are endorsed by the Board of Directors of the Anticoagulation Forum, an organization dedicated to optimizing anticoagulation care. The board is composed of physicians, pharmacists, and nurses with demonstrated expertise and experience in the management of patients receiving anticoagulation therapy. Recommendations for delivering optimized inpatient anticoagulation therapy were developed collaboratively by the authors and are summarized in 8 key areas: (1) process, (2) accountability, (3) integration, (4) standards of practice, (5) provider education and competency, (6) patient education, (7) care transitions, and (8) outcomes. Recommendations are intended to inform the development of coordinated care systems containing elements with demonstrated benefit in improvement of anticoagulation therapy outcomes. Recommendations for delivering optimized inpatient anticoagulation therapy are intended to apply to all clinicians involved in the care of hospitalized patients receiving anticoagulation therapy. Anticoagulants are high-risk medications associated with a significant rate of medication errors among hospitalized patients. Several national organizations have introduced initiatives to reduce the likelihood of patient harm associated with the use of anticoagulants. Health care organizations are under increasing pressure to develop systems to ensure the safe and effective use of anticoagulants in the inpatient setting. This document provides consensus guidelines for anticoagulant therapy in the inpatient setting and serves as a companion document to prior guidelines relevant for outpatients.

Direct oral anticoagulants: An update.

PubMed

Franco Moreno, Ana Isabel; Martín Díaz, Rosa María; García Navarro, María José

2017-12-30

Vitamin K antagonists were the only choice for chronic oral anticoagulation for more than half a century. Over the past few years, direct oral anticoagulants have emerged, including one direct thrombin inhibitor (dabigatran etexilate) and three factor Xa inhibitors (apixaban, edoxaban and rivaroxaban). In randomised controlled trials comparing direct oral anticoagulants with traditional vitamin K antagonists, the direct oral anticoagulants all showed a favourable benefit-risk balance in their safety and efficacy profile, in prevention of thromboembolic events in patients with atrial fibrillation and in the prevention and treatment of venous thromboembolism and acute coronary syndrome. In 2008, dabigatran was the first direct oral anticoagulant approved by the European Medicine Agency. Subsequently, rivaroxaban, apixaban and edoxaban were also authorised. This article reviews the evidence related to the use of these drugs. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

Adherence and Coagulation Assays in Dabigatran-treated Patients With Atrial Fibrillation

ClinicalTrials.gov

2017-09-12

Atrial Fibrillation; Medication Adherence; Blood Coagulation Tests; Anticoagulants; Circulating, Hemorrhagic Disorder; Drug Effect; Drug Use; Drug Toxicity; Drug Intolerance; Blood Clot; Blood Coagulation Disorder; Laboratory Problem; Bleeding; Thrombosis

Think of HIT.

PubMed

Warkentin, Theodore E

2006-01-01

Heparin-induced thrombocytopenia, or HIT, can present in many ways, ranging from common-isolated thrombocytopenia, venous thromboembolism, acute limb ischemia-to less common but specific presentations-necrotizing skin lesions at heparin injection sites, post-bolus acute systemic reactions, and adrenal hemorrhagic necrosis (secondary to adrenal vein thrombosis). Many patients with HIT have mild or moderate thrombocytopenia: the median platelet count nadir is 60 x 10(9)/L, and ranges from 15 to 150 x 10(9)/L in 90% of patients, most of whom evince a 50% or greater fall in the platelet count. HIT that begins after stopping heparin ("delayed-onset HIT") is increasingly recognized. Factors influencing risk of HIT include type of heparin (unfractionated heparin > low-molecular-weight heparin), type of patient (surgical > medical), and gender (female > male). Since timely diagnosis and treatment of HIT may reduce the risk of adverse outcomes, this review focuses on those clinical circumstances that should prompt the clinician to "think of HIT." Coumarin anticoagulants such as warfarin are ineffective in acute HIT and can even be deleterious by predisposing to micro-thrombosis via protein C depletion (venous limb gangrene and skin necrosis syndromes). Thus, it is important to avoid or postpone coumarin while managing HIT hypercoagulability, focusing on agents that inhibit thrombin directly (lepirudin, argatroban) or that inhibit its generation (danaparoid, fondaparinux). Post-marketing experience suggests that standard dosing of lepirudin is too high; current recommendations are to avoid the initial lepirudin bolus and to begin with lower infusion rates, even in patients without overt renal dysfunction.

Cytochrome P450-mediated warfarin metabolic ability is not a critical determinant of warfarin sensitivity in avian species: In vitro assays in several birds and in vivo assays in chicken.

PubMed

Watanabe, Kensuke P; Kawata, Minami; Ikenaka, Yoshinori; Nakayama, Shouta M M; Ishii, Chihiro; Darwish, Wageh Sobhi; Saengtienchai, Aksorn; Mizukawa, Hazuki; Ishizuka, Mayumi

2015-10-01

Coumarin-derivative anticoagulant rodenticides used for rodent control are posing a serious risk to wild bird populations. For warfarin, a classic coumarin derivative, chickens have a high median lethal dose (LD50), whereas mammalian species generally have much lower LD50. Large interspecies differences in sensitivity to warfarin are to be expected. The authors previously reported substantial differences in warfarin metabolism among avian species; however, the actual in vivo pharmacokinetics have yet to be elucidated, even in the chicken. In the present study, the authors sought to provide an in-depth characterization of warfarin metabolism in birds using in vivo and in vitro approaches. A kinetic analysis of warfarin metabolism was performed using liver microsomes of 4 avian species, and the metabolic abilities of the chicken and crow were much higher in comparison with those of the mallard and ostrich. Analysis of in vivo metabolites from chickens showed that excretions predominantly consisted of 4'-hydroxywarfarin, which was consistent with the in vitro results. Pharmacokinetic analysis suggested that chickens have an unexpectedly long half-life despite showing high metabolic ability in vitro. The results suggest that the half-life of warfarin in other bird species could be longer than that in the chicken and that warfarin metabolism may not be a critical determinant of species differences with respect to warfarin sensitivity. © 2015 SETAC.

Cost-Effectiveness of Oral Anticoagulants for Ischemic Stroke Prophylaxis Among Nonvalvular Atrial Fibrillation Patients.

PubMed

Shah, Anuj; Shewale, Anand; Hayes, Corey J; Martin, Bradley C

2016-06-01

The objective of the study is to compare the cost-effectiveness of oral anticoagulants among atrial fibrillation patients at an increased stroke risk. A Markov model was constructed to project the lifetime costs and quality-adjusted survival (QALYs) of oral anticoagulants using a private payer's perspective. The distribution of stroke risk (CHADS2 score: congestive heart failure, hypertension, advanced age, diabetes mellitus, stroke) and age of the modeled population was derived from a cohort of commercially insured patients with new-onset atrial fibrillation. Probabilities of treatment specific events were derived from published clinical trials. Event and downstream costs were determined from the cost of illness studies. Drug costs were obtained from 2015 National Average Drug Acquisition Cost data. In the base case analysis, warfarin was the least costly ($46 241; 95% CI, 44 499-47 874) and apixaban had the highest QALYs (9.38; 95% CI, 9.24-9.48 QALYs). Apixaban was found to be a cost-effective strategy over warfarin (incremental cost-effectiveness ratio=$25 816) and dominated other anticoagulants. Probabilistic sensitivity analysis showed that apixaban had at least a 61% chance of being the most cost-effective strategy at willingness to pay value of $100 000 per QALY. Among patients with CHADS2 ≥3, dabigatran was the dominant strategy. The model was sensitive to efficacy estimates of apixaban, dabigatran, and edoxaban and the cost of these drugs. All the newer oral anticoagulants compared were more effective than adjusted dosed warfarin. Our model showed that apixaban was the most effective anticoagulant in a general atrial fibrillation population and has an incremental cost-effectiveness ratio <$50 000/QALY. For those with higher stroke risk (CHADS2≥3), dabigatran was the most cost-effective treatment option. © 2016 American Heart Association, Inc.

Clinical events after interruption of anticoagulation in patients with atrial fibrillation: An analysis from the ENGAGE AF-TIMI 48 trial.

PubMed

Cavallari, Ilaria; Ruff, Christian T; Nordio, Francesco; Deenadayalu, Naveen; Shi, Minggao; Lanz, Hans; Rutman, Howard; Mercuri, Michele F; Antman, Elliott M; Braunwald, Eugene; Giugliano, Robert P

2018-04-15

Patients with atrial fibrillation (AF) who interrupt anticoagulation are at high risk of thromboembolism and death. Patients enrolled in the ENGAGE AF-TIMI 48 trial (randomized comparison of edoxaban vs. warfarin) who interrupted study anticoagulant for >3 days were identified. Clinical events (ischemic stroke/systemic embolism, major cardiac and cerebrovascular events [MACCE]) were analyzed from day 4 after interruption until day 34 or study drug resumption. During 2.8 years median follow-up, 13,311 (63%) patients interrupted study drug for >3 days. After excluding those who received open-label anticoagulation during the at-risk window, the population for analysis included 9148 patients. The rates of ischemic stroke/systemic embolism and MACCE post interruption were substantially greater than in patients who never interrupted (15.42 vs. 0.26 and 60.82 vs. 0.36 per 100 patient-years, respectively, p adj  < .001). Patients who interrupted study drug for an adverse event (44.1% of the cohort), compared to those who interrupted for other reasons, had an increased risk of MACCE (HR adj 2.75; 95% CI 2.02-3.74, p < .0001), but similar rates of ischemic stroke/systemic embolism. Rates of clinical events after interruption of warfarin and edoxaban were similar. Interruption of study drug was frequent in patients with AF and was associated with a substantial risk of major cardiac and cerebrovascular events over the ensuing 30 days. This risk was particularly high in patients who interrupted as a result of an adverse event; these patients deserve close monitoring and resumption of anticoagulation as soon as it is safe to do so. Copyright © 2018 Elsevier B.V. All rights reserved.

Novel coumarin derivatives bearing N-benzyl pyridinium moiety: potent and dual binding site acetylcholinesterase inhibitors.

PubMed

Alipour, Masoumeh; Khoobi, Mehdi; Foroumadi, Alireza; Nadri, Hamid; Moradi, Alireza; Sakhteman, Amirhossein; Ghandi, Mehdi; Shafiee, Abbas

2012-12-15

A novel series of coumarin derivatives linked to benzyl pyridinium group were synthesized and biologically evaluated as inhibitors of both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The enzyme inhibitory activity of synthesized compounds was measured using colorimetric Ellman's method. It was revealed that compounds 3e, 3h, 3l, 3r and 3s have shown higher activity compared with donepezil hydrochloride as standard drug. Most of the compounds in these series had nanomolar range IC(50) in which compound 3r (IC(50) = 0.11 nM) was the most active compound against acetylcholinesterase enzyme. Copyright © 2012 Elsevier Ltd. All rights reserved.

Cholesterol embolisms as possible adverse drug reaction of direct oral anticoagulants.

PubMed

Muller-Hansma, A H G; Daemen-Gubbels, C R G M; Schut, N H

2018-04-01

The Netherlands Pharmacovigilance Centre Lareb has received two reports of cholesterol crystal embolisms associated with the use of a direct oral anticoagulant (DOAC). The European pharmacovigilance database contains several other cases concerning this association, and one report was published in the scientific literature. Cholesterol crystal embolisms were described in association with the use of several other antithrombotic drugs, although the role as an independent risk factor is not conclusive. The case series described in this article, indicates the possibility of an adverse drug reaction when a patient develops cholesterol crystal embolisms while using a DOAC.

Heparin increases food intake through AgRP neurons

USDA-ARS?s Scientific Manuscript database

Although the widely used anticoagulant drug heparin has been shown to have many other biological functions independent of its anticoagulant role, its effects on energy homeostasis are unknown. Here, we demonstrate that heparin level is negatively associated with nutritional states and that heparin t...

Super-Anticoagulant Heparin-Mimicking Hydrogel Thin Film Attached Substrate Surfaces to Improve Hemocompatibility.

PubMed

He, Min; Cui, Xiaofei; Jiang, Huiyi; Huang, Xuelian; Zhao, Weifeng; Zhao, Changsheng

2017-02-01

In this study, heparin-mimicking hydrogel thin films are covalently attached onto poly(ether sulfone) membrane surfaces to improve anticoagulant property. The hydrogel films display honeycomb-like porous structure with well controlled thickness and show long-term stability. After immobilizing the hydrogel films, the membranes show excellent anticoagulant property confirmed by the activated partial thromboplastin time values exceeding 600 s. Meanwhile, the thrombin time values increase from 20 to 61 s as the sodium allysulfonate proportions increase from 0 to 80 mol%. In vitro investigations of protein adsorption and blood-related complement activation also confirm that the membranes exhibit super-anticoagulant property. Furthermore, gentamycin sulfate is loaded into the hydrogel films, and the released drug shows significant inhibition toward E. coli bacteria. It is believed that the surface attached heparin-mimicking hydrogel thin films may show high potential for the applications in various biological fields, such as blood contacting materials and drug loading materials. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Catheter-related thrombosis: biological and clinical evidence for risk with currently available anticoagulants.

PubMed

Montalescot, Gilles; Walenga, Jeanine M

2009-01-01

Anticoagulants used during percutaneous coronary intervention (PCI) should not only prevent coronary events, but also minimize the risk of periprocedural complications. Current anticoagulation therapies for PCI include unfractionated heparin (UFH), enoxaparin, fondaparinux, and bivalirudin. UFH and enoxaparin have good efficacy and safety profiles in PCI; furthermore, associated periprocedural complications such as catheter thrombosis are rare. Although newer anticoagulants seem safe and effective in patients with acute coronary syndrome, clinical trial data suggest that some pure factor Xa (FXa) inhibitors are associated with increased rates of catheter thrombosis, compared with heparin-based agents. Experimental systems show that polytherapeutic agents, including UFH and enoxaparin, are more effective anticoagulants than certain single-target agents. More studies are needed to assess whether catheter thrombosis is a class-, drug-, or dose-related effect, and how best to prevent it. Future trials should report the rates of periprocedural complications when assessing the safety of novel anticoagulation therapies in PCI.

Synthesis and biological evaluation of coumarin derivatives containing imidazole skeleton as potential antibacterial agents.

PubMed

Hu, Yang; Shen, Yufeng; Wu, Xiaohu; Tu, Xiao; Wang, Gao-Xue

2018-01-01

Emergence of multidrug-resistant bacteria causes an urgent need for new generation of antibiotics, which may have a different mechanism of inhibition or killing action from the existing. Here, we report on the design, synthesis, and biological evaluation of thirty-nine coumarin derivatives in order to solve the antibacterial resistance by targeting at the inhibition of biosynthesis pathway of fatty acids. Their antibacterial activities against Escherichia coli, Staphylococcus aureus, Streptococcus agalactiae, and Flavobacterium cloumnare are tested and action mechanism against the key enzyme in bacterial fatty acid synthesis pathway are studied. The results show that compounds 13 and 18 have potent and broad spectrum antimicrobial activity. In addition, 9, 14 and 19 show eminent antimicrobial efficacy toward S. aureus, S. agalactiae, and F. cloumnare. Mechanistically, coumarin derivatives display the antibacterial activity via the control of FabI and FabK function. The structure-activity relationship analysis indicate that the length of linker and imidazole substitute group could significantly influence the antimicrobial activity, as well as the inhibitory activity against FabI and FabK. The structural optimization analysis of coumarin suggest that derivatives 9, 13, 14, 18 and 19 could be a viable way of preventing and controlling bacteria and considered as promising lead compounds for the development of commercial drugs. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Bleeding risk of patients with acute venous thromboembolism taking nonsteroidal anti-inflammatory drugs or aspirin.

PubMed

Davidson, Bruce L; Verheijen, Sara; Lensing, Anthonie W A; Gebel, Martin; Brighton, Timothy A; Lyons, Roger M; Rehm, Jeffrey; Prins, Martin H

2014-06-01

Combined anticoagulant and aspirin therapy is associated with increased bleeding risk in patients with atrial fibrillation, but the bleeding risk of combined use of anticoagulant and nonsteroidal anti-inflammatory drugs (NSAIDs) is poorly documented. To estimate the bleeding risk of combined anticoagulant (rivaroxaban or enoxaparin-vitamin K antagonist [VKA]) and NSAID or aspirin therapy in patients with venous thromboembolism. Prospective analysis of observational data from the EINSTEIN deep vein thrombosis and pulmonary embolism clinical trials comparing rivaroxaban with enoxaparin-VKA treatment, trials performed in hospitals and clinics in 8246 patients enrolled from 2007 to 2009. Bleeding event rates during exposure to NSAID and aspirin therapy were compared to time without exposure. Days of NSAID or aspirin use and nonuse, clinically relevant bleeding event and major bleeding event rates by patient-years, and hazard ratios. During NSAID-anticoagulant concomitant treatment, clinically relevant bleeding occurred with an event rate of 37.5 per 100 patient-years vs 16.6 per 100 patient-years during anticoagulant use only (hazard ratio [HR], 1.77 [95% CI, 1.46-2.14]). Major bleeding during NSAID-anticoagulant treatment occurred with an event rate of 6.5 per 100 patient-years, compared to 2.0 per 100 patient-years during nonuse (HR, 2.37 [95% CI, 1.51-3.75]). For aspirin-anticoagulant concomitant treatment, clinically relevant bleeding occurred with an event rate of 36.6 per 100 patient-years, compared to 16.9 per 100 patient-years during aspirin nonuse (HR, 1.70 [95% CI, 1.38-2.11]). Major bleeding in aspirin-anticoagulant-treated patients occurred with an event rate of 4.8 per 100 patient-years, compared to 2.2 per 100 patient-years during aspirin nonuse (HR, 1.50 [95% CI, 0.86-2.62]). Increases in risk for clinically relevant and major bleeding were similar for rivaroxaban and enoxaparin-VKA anticoagulation regimens. Among patients with venous thromboembolism receiving anticoagulant therapy, concomitant use of an NSAID or aspirin is associated with an increased risk of clinically relevant and major bleeding.

Quality of Vitamin K Antagonist Anticoagulation in Spain: Prevalence of Poor Control and Associated Factors.

PubMed

Anguita Sánchez, Manuel; Bertomeu Martínez, Vicente; Cequier Fillat, Ángel

2015-09-01

To study the prevalence of poorly controlled vitamin K antagonist anticoagulation in Spain in patients with nonvalvular atrial fibrillation, and to identify associated factors. We studied 1056 consecutive patients seen at 120 cardiology clinics in Spain between November 2013 and March 2014. We analyzed the international normalized ratio from the 6 months prior to the patient's visit, calculating the prevalence of poorly controlled anticoagulation, defined as < 65% time in therapeutic range using the Rosendaal method. Mean age was 73.6 years (standard deviation, 9.8 years); women accounted for 42% of patients. The prevalence of poorly controlled anticoagulation was 47.3%. Mean time in therapeutic range was 63.8% (25.9%). The following factors were independently associated with poorly controlled anticoagulation: kidney disease (odds ratio = 1.53; 95% confidence interval, 1.08-2.18; P = .018), routine nonsteroidal anti-inflammatory drugs (odds ratio = 1.79; 95% confidence interval, 1.20-2.79; P = .004), antiplatelet therapy (odds ratio = 2.16; 95% confidence interval, 1.49-3.12; P < .0001) and absence of angiotensin receptor blockers (odds ratio = 1.39; 95% confidence interval, 1.08-1.79; P = .011). There is a high prevalence of poorly controlled vitamin K antagonist anticoagulation in Spain. Factors associated with poor control are kidney disease, routine nonsteroidal anti-inflammatory drugs, antiplatelet use, and absence of angiotensin receptor blockers. Copyright © 2014 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

New horizons in anticoagulation: Direct oral anticoagulants and their implications in oral surgery

PubMed Central

Ripollés-de Ramón, Jorge; Collado-Yurrita, Luis; Vaello-Checa, Iris; Colmenero-Ruiz, Constantino; Helm, Alexandra; Ciudad-Cabañas, Maria-José; Serrano-Cuenca, Victoriano

2017-01-01

Background Thrombotic disorders remain a leading cause of death in the Western World. For decades, vitamin K antagonists used in the prevention of this pathology, such as warfarin or sintrom, were the only oral agents available for long-term anticoagulation, in spite of their disadvantages. Material and Methods An electronic database search was carried out on MedLine and The Cochrane Library Plus, without restrictions on the type of study nor dates, in English and Spanish. Abstracts were reviewed, and complete articles if necessary, considering all articles that included recommendations on DOACs and oral surgery. Results In recent years, the so-called “new oral anticoagulants” have been introduced in clinical practice to treat those patients whose medical conditions require long-term anticoagulant treatment, replacing traditional oral anticoagulants. Conclusions The new oral anticoagulants represent new therapeutic options, with a number of advantages such as poor interaction with food, minor drug interactions, and do not require periodic dose adjustments or routine controls. The purpose of this review is to establish an update on the new oral anticoagulants: Dabigatran, Rivarozaban, Apixaban and Edoxaban. Key words:Novel oral anticoagulants, Dabigatran, Rivaroxaban, Apixaban, Edoxaban, bleeding management, oral surgery, Anti-IIa, Anti Xa. PMID:28809374

[Clinical spectrum of patients with spontaneous retroperitoneal hematomas].

PubMed

Sánchez-González, Amada; Riancho-Zarrabeitia, Leyre; Salmón-González, Zaida; Riancho, José Antonio; Valero, Carmen

2015-10-05

Spontaneous retroperitoneal hematoma (SRH) is a potentially fatal clinical entity requiring immediate recognition and intervention. The clinical records of 18-year-old and older patients admitted to the University Hospital Marqués de Valdecilla from 2003 to 2013 were reviewed. "Spontaneous" was defined as unrelated to trauma, invasive procedures or bleeding due to aortic aneurysm rupture. Thirty-four patients with SRH (44% were on anticoagulant drugs). One-third of cases had chronic renal insufficiency. Abdominal pain was the most common symptom both in anticoagulated and non-anticoagulated patients (80% in anticoagulated and 89% in non-anticoagulated patients). About one half of the patients developed shock. A CT scan was the most commonly performed diagnostic test, followed by abdominal ultrasound. Most cases were managed conservatively (80%). More than half of the patients (66%) restarted anticoagulation therapy after the acute event with a mean delay of 19 days (range 2-90 days). None of them suffered a new bleeding episode. Restarting the anticoagulation treatment after hematoma resolution seems to be a safe practice. There is an increasing frequency of SRH in non-anticoagulated patients. Copyright © 2015 Elsevier España, S.L.U. All rights reserved.

Practical considerations in emergency management of bleeding in the setting of target-specific oral anticoagulants.

PubMed

Miller, Michael P; Trujillo, Toby C; Nordenholz, Kristen E

2014-04-01

The recent arrival of the target-specific oral anticoagulants (TSOACs) offers potential advantages in the field of anticoagulation. However, there are no rapid and accurate and routinely available laboratory assays to evaluate their contribution to clinical bleeding. With the expanding clinical indications for the TSOACs, and the arrival of newer reversal agents on the market, the emergency clinician will need to be familiar with drug specifics as well as methods for anticoagulation reversal. This review offers a summary of the literature and some practical strategies for the approach to the patient taking TSOACs and the management of bleeding in these cases. Copyright © 2014 Elsevier Inc. All rights reserved.

[Management of new oral anticoagulants in gastrointestinal bleeding and endoscopy].

PubMed

del Molino, Fátima; Gonzalez, Isabel; Saperas, Esteve

2015-10-01

New oral direct anticoagulants agents are alternatives to warfarin for long-term anticoagulation in a growing number of patients that require long-term anticoagulation for atrial fibrillation, deep venous thrombosis and pulmonary embolism. These new agents with predictable pharmacokinetic and pharmacodynamics profiles offer a favorable global safety profile, but increased gastrointestinal bleeding compared to the vitamin K antagonists. Many gastroenterologists are unfamiliar and may be wary of these newer drugs, since Clinical experience is limited and no specific antidote is available to reverse their anticoagulant effect. In this article the risk of these new agents and, how to manage these agents in both the presence of acute gastrointestinal bleeding and in patients undergoing endoscopic procedures is reviewed. Copyright © 2014 Elsevier España, S.L.U. and AEEH y AEG. All rights reserved.

Athletes and blood clots: individualized, intermittent anticoagulation management.

PubMed

Berkowitz, J N; Moll, S

2017-06-01

Essentials Athletes on anticoagulants are typically prohibited from participation in contact sports. Short-acting anticoagulants allow for reconsideration of this precedent. An individualized pharmacokinetic/pharmacodynamics study can aid patient-specific management. Many challenges and unresolved issues exist regarding such tailored intermittent dosing. Athletes with venous thromboembolism (VTE) are typically prohibited from participating in contact sports during anticoagulation therapy, but such mandatory removal from competition can cause psychological and financial detriments for athletes and overlooks patient autonomy. The precedent of compulsory removal developed when options for anticoagulation therapy were more limited, but medical advances now allow for rethinking of the management of athletes with VTE. We propose a novel therapeutic approach to the treatment of athletes who participate in contact sports and require anticoagulation. A personalized pharmacokinetic/pharmacodynamics study of a direct oral anticoagulant can be performed for an athlete, which can inform the timing of medication dosing. Managed carefully, this can allow athletic participation when plasma drug concentration is minimal (minimizing bleeding risk) and prompt resumption of treatment after the risk of bleeding sufficiently normalizes (maximizing therapeutic time). © 2017 International Society on Thrombosis and Haemostasis.

Pathology consultation on anticoagulation monitoring: factor X-related assays.

PubMed

Wool, Geoffrey D; Lu, Chuanyi M

2013-11-01

To review various anticoagulation therapies and related laboratory monitoring issues, with a focus on factor X-related chromogenic assays. A case-based approach is used to review pertinent published literatures and product inserts of anticoagulation drugs and to look back on clinical use of factor X-related chromogenic assays. The number of anticoagulants available to clinicians has increased greatly in the past decade. Whether and how these anticoagulants should be monitored are areas of uncertainty for clinicians, which can lead to misuse of laboratory assays and suboptimal patient management. Factor X-related assays are of particular concern because of the similar and often confusing test names. Based on a common clinical case scenario and literature review regarding anticoagulant monitoring, an up-to-date discussion and review of the various factor X-related assays are provided, focusing on the differences in test designs and clinical utilities between the chromogenic anti-Xa and chromogenic factor X activity assays. Anticoagulation therapy and related laboratory monitoring are rapidly evolving areas of clinical practices. A good knowledge of relevant laboratory assays and their clinical applications is necessary to help optimize patient care.

Transition of patients from blinded study drug to open-label anticoagulation: the ENGAGE AF-TIMI 48 trial.

PubMed

Ruff, Christian T; Giugliano, Robert P; Braunwald, Eugene; Mercuri, Michele; Curt, Valentin; Betcher, Joshua; Grip, Laura; Cange, Abby L; Crompton, Andrea E; Murphy, Sabina A; Deenadayalu, Naveen; Antman, Elliott M

2014-08-12

At the end of 2 previous trials, an excess of stroke and bleeding was observed in patients with AF randomized to a new oral anticoagulant (NOAC) who transitioned to a vitamin K antagonist (VKA). The ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) trial compared once-daily edoxaban to warfarin for stroke prevention in patients with AF. An end-of-trial transition plan was developed to minimize the risks of stroke due to inadequate anticoagulation and bleeding from excessive anticoagulation during this critical period. All patients on the blinded study drug at the trial's conclusion were included in this analysis. In pre-specified analyses, stroke, bleeding, and death that occurred through 30 days after the end-of-trial visit were stratified by randomized treatment allocation and open-label anticoagulant selected post-trial. Of the 13,642 patients taking the blinded study drug at the end of the trial, 9,304 (68.2%) were transitioned to open-label VKA and 4,258 patients (31.2%) to an NOAC. There were 21 strokes evenly distributed across the 3 randomized treatment arms: warfarin 7 (1.90%/year), edoxaban high dose 7 (1.89%/year), edoxaban low dose 7 (1.85%/year). Major bleeding was also similar across the 3 treatment arms: warfarin 11 (2.98%/year), edoxaban high dose 10 (2.69%/year), edoxaban low dose 18 (4.76%/year). In patients transitioned to VKA, 85% of patients had at least 1 INR ≥ 2 by day 14 after the transition and 99% by day 30. The ENGAGE AF-TIMI 48 transition plan protected patients from an excess of thrombotic and bleeding events and should be helpful in clinical practice when patients are transitioned between oral anticoagulants. (Global Study to Assess the Safety and Effectiveness of Edoxaban [DU-176b] vs Standard Practice of Dosing With Warfarin in Patients With Atrial Fibrillation [EngageAFTIMI48]; NCT00781391). Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

[Effects of sub-micro emulsion composition on cellular disposition of incorporated lipophilic drug].

PubMed

Sun, Xiao-Yi; Xiang, Zhi-Qiang; Wu, Shuo; Lv, Yuan-Yuan; Liang, Wen-Quan

2013-09-01

To investigate the effects of sub-micro emulsion composition on cellular uptake and disposition of incorporated lipophilic drug. Sub-micro emulsions containing 10 % oil, 1.2 % lecithin and 2.25 % glycerol were prepared, and the fluorescent agent coumarin 6 was used as a model drug. The effects of oil types, co-surfactants and cationic lipid on uptake and elimination kinetics of 6-coumarin in HeLa cells were studied. The uptake mechanism of sub-micro emulsions was further investigated. Oil type and Tweens had no influence on the cellular uptake. Modifications of surfactants with Span series increased the cellular influx, among which Span 20 with hydrophilic-lipophilic balance (HLB) value of 8.6 was the best enhancer. The intracellular drug level reached up to (46.09 ± 1.98)ng/μg protein which had significant difference with control group [(38.54 ± 0.34)ng/μg protein]. The positively charged emulsions significantly increased the uptake rate constant and elimination rate constant which were 4 times and 1.5 times of those in anionic groups, respectively. The uptake enhancement was also observed in cationic emulsions, cellular concentrations at plateau were (42.73 ± 0.84)ng/μg protein, which was about 3 times of that in anionic emulsions [(15.71 ± 0.74)ng/μg protein], when extracellular drug concentration kept at 100 ng/ml. Cationic emulsions delivered the payload mainly by direct drug transfer to contacted cells, while the negative ones depended on both drug passive diffusion and clathrin-mediated endocytosis of drug containing oil droplets which accounted for 20% of the intracellular drug. Interfacial characteristic of sub-micro emulsions such as co-surfactants HLB as well as zeta potentials can influence lipophilic drug both in cellular uptake and elimination.

[Reviews on antiviral activity of chemical constituents from plants].

PubMed

Yang, Xian-Feng; Wang, Yu-Li; Xu, Wei-Ren

2008-01-01

This paper reviewed the progress in researches on antiviral activity of chemical constituents from plants in recent years, the antiviral activity and mechanism of action of flavonoids, alkaloids, terpenoids, coumarins and polysaccharoses were sammarszed, provided new leading compound for antivirus new drugs from the plares in prospect.

A network-based multi-target computational estimation scheme for anticoagulant activities of compounds.

PubMed

Li, Qian; Li, Xudong; Li, Canghai; Chen, Lirong; Song, Jun; Tang, Yalin; Xu, Xiaojie

2011-03-22

Traditional virtual screening method pays more attention on predicted binding affinity between drug molecule and target related to a certain disease instead of phenotypic data of drug molecule against disease system, as is often less effective on discovery of the drug which is used to treat many types of complex diseases. Virtual screening against a complex disease by general network estimation has become feasible with the development of network biology and system biology. More effective methods of computational estimation for the whole efficacy of a compound in a complex disease system are needed, given the distinct weightiness of the different target in a biological process and the standpoint that partial inhibition of several targets can be more efficient than the complete inhibition of a single target. We developed a novel approach by integrating the affinity predictions from multi-target docking studies with biological network efficiency analysis to estimate the anticoagulant activities of compounds. From results of network efficiency calculation for human clotting cascade, factor Xa and thrombin were identified as the two most fragile enzymes, while the catalytic reaction mediated by complex IXa:VIIIa and the formation of the complex VIIIa:IXa were recognized as the two most fragile biological matter in the human clotting cascade system. Furthermore, the method which combined network efficiency with molecular docking scores was applied to estimate the anticoagulant activities of a serial of argatroban intermediates and eight natural products respectively. The better correlation (r = 0.671) between the experimental data and the decrease of the network deficiency suggests that the approach could be a promising computational systems biology tool to aid identification of anticoagulant activities of compounds in drug discovery. This article proposes a network-based multi-target computational estimation method for anticoagulant activities of compounds by combining network efficiency analysis with scoring function from molecular docking.

A Network-Based Multi-Target Computational Estimation Scheme for Anticoagulant Activities of Compounds

PubMed Central

Li, Canghai; Chen, Lirong; Song, Jun; Tang, Yalin; Xu, Xiaojie

2011-01-01

Background Traditional virtual screening method pays more attention on predicted binding affinity between drug molecule and target related to a certain disease instead of phenotypic data of drug molecule against disease system, as is often less effective on discovery of the drug which is used to treat many types of complex diseases. Virtual screening against a complex disease by general network estimation has become feasible with the development of network biology and system biology. More effective methods of computational estimation for the whole efficacy of a compound in a complex disease system are needed, given the distinct weightiness of the different target in a biological process and the standpoint that partial inhibition of several targets can be more efficient than the complete inhibition of a single target. Methodology We developed a novel approach by integrating the affinity predictions from multi-target docking studies with biological network efficiency analysis to estimate the anticoagulant activities of compounds. From results of network efficiency calculation for human clotting cascade, factor Xa and thrombin were identified as the two most fragile enzymes, while the catalytic reaction mediated by complex IXa:VIIIa and the formation of the complex VIIIa:IXa were recognized as the two most fragile biological matter in the human clotting cascade system. Furthermore, the method which combined network efficiency with molecular docking scores was applied to estimate the anticoagulant activities of a serial of argatroban intermediates and eight natural products respectively. The better correlation (r = 0.671) between the experimental data and the decrease of the network deficiency suggests that the approach could be a promising computational systems biology tool to aid identification of anticoagulant activities of compounds in drug discovery. Conclusions This article proposes a network-based multi-target computational estimation method for anticoagulant activities of compounds by combining network efficiency analysis with scoring function from molecular docking. PMID:21445339

Novel oral anticoagulants for atrial fibrillation.

PubMed

How, Choon How

2015-12-01

Anticoagulation therapy is effective in preventing primary and secondary thromboembolic events due to atrial fibrillation. Warfarin, which was approved by the United States in 1954, was the only long-term oral anticoagulation therapy till the approval of dabigatran in 2010, and of rivaroxaban and other direct factor Xa inhibitors from 2011, forming a group known as novel oral anticoagulants (NOAC). NOAC have fewer food and drug interactions compared to warfarin; hence, the patient will require fewer clinic visits. However, the short half-life of NOAC means that twice-a-day dosing is needed and there is higher risk of a prothrombotic state when doses are missed. Other disadvantages are the lack of long-term data on NOAC, their high cost and the current lack of locally available antidotes.

Appropriateness of Oral Anticoagulants for the Long-Term Treatment of Atrial Fibrillation in Older People: Results of an Evidence-Based Review and International Consensus Validation Process (OAC-FORTA 2016).

PubMed

Wehling, Martin; Collins, Ronan; Gil, Victor M; Hanon, Olivier; Hardt, Roland; Hoffmeister, Martin; Monteiro, Pedro; Quinn, Terence J; Ropers, Dieter; Sergi, Giuseppe; Verheugt, Freek W A

2017-07-01

Age appropriateness of anticoagulants for stroke prevention in atrial fibrillation is uncertain. To review oral anticoagulants for the treatment of atrial fibrillation in older (age >65 years) people and to classify appropriate and inappropriate drugs based on efficacy, safety and tolerability using the Fit-fOR-The-Aged (FORTA) classification. We performed a structured comprehensive review of controlled clinical trials and summaries of individual product characteristics to assess study and total patient numbers, quality of major outcome data and data of geriatric relevance. The resulting evidence was discussed in a round table with an interdisciplinary panel of ten European experts. Decisions on age appropriateness were made using a Delphi process. For the eight drugs included, 380 citations were identified. The primary outcome results were reported in 32 clinical trials with explicit and relevant data on older people. Though over 24,000 patients aged >75/80 years were studied for warfarin, data on geriatric syndromes were rare (two studies reporting on frailty/falls/mental status) and missing for all other compounds. Apixaban was rated FORTA-A (highly beneficial). Other non-vitamin K antagonist oral anticoagulants (including low/high-intensity dabigatran and high-intensity edoxaban) and warfarin were assigned to FORTA-B (beneficial). Phenprocoumon, acenocoumarol and fluindione were rated FORTA-C (questionable), mainly reflecting the absence of data. All non-vitamin K antagonist oral anticoagulants and warfarin were classified as beneficial or very beneficial in older persons (FORTA-A or -B), underlining the overall positive assessment of the risk/benefit ratio for these drugs. For other vitamin-K antagonists regionally used in Europe, the lack of evidence should challenge current practice.

The role of oral anticoagulants in epistaxis.

PubMed

Buchberger, A M S; Baumann, A; Johnson, F; Peters, N; Piontek, G; Storck, K; Pickhard, A

2018-06-23

The purpose of this retrospective study was to identify the impact of oral anticoagulants on epistaxis with the focus on new oral anticoagulants. The study was conducted at the Department  for Ear- Nose- and Throat (ENT), Head and Neck Surgery, Technical University Munich, Germany. All patients presenting in 2014 with the diagnosis of epistaxis to a specialized ENT accident and emergency department were identified and analyzed in clinical data and medication. 600 adult cases, with a median age of 66.6 years were identified with active bleeding. 66.8% of all cases were anticoagulated. Classic oral anticoagulants (COAC) were three times more common in patients than new-generation oral anticoagulants (NOAC). Recurrent bleeding was significantly associated with oral anticoagulants (OAC) (p = 0.014) and bleeding location was most often anterior (p = 0.006). In contrast, severe cases, which required surgery or embolization were significantly more likely in non-anticoagulated middle-aged patients with posterior bleedings (p < 0.05). In our epistaxis cohort, OAC were highly overrepresented (40%) when compared to the general German population (1%) but COAC as well as NOAC played only a minor role in severe courses of epistaxis. Oral anticoagulation, especially with new-generation drugs, is not associated with more complicated and severe courses of epistaxis, but rather with recurrent bleeding. One should keep this information in mind when triaging the patient in the emergency room and when planning further procedures.

Benefit, risk and cost of new oral anticoagulants and warfarin in atrial fibrillation; A multicriteria decision analysis.

PubMed

Mendoza-Sanchez, Jose; Silva, Federico; Rangel, Lady; Jaramillo, Linda; Mendoza, Leidy; Garzon, Jenny; Quiroga, Andrea

2018-01-01

Warfarin and new oral anticoagulants are effective in reducing stroke in atrial fibrillation; however, the benefits and risks rates in clinical trials show heterogeneity for each anticoagulant, and is unknown the cost influence on a model considering most of the treatment consequences. We designed a benefit-risk and cost assessment of oral anticoagulants. We followed the roadmap proposed by IMI-PROTECT and the considerations of emerged good practice to perform Multi-Criteria Decision Analysis (MCDA). The roadmap defines the following steps: (1) planning, (2) evidence gathering and data preparation, (3) analyses, (4) explorations, and (5) conclusions. We defined two reference points (0-100) to allocate numerical values for scores and weights, and used an analogue numeric scale to assess physicians' preferences. As benefits of the anticoagulant therapy, we included reductions in stroke and all-cause mortality; intracranial haemorrhage, gastrointestinal haemorrhage, minor bleeding and myocardial infarction were considered risks. We also made an estimation of the annual drug cost per person. The scores were: Apixaban 33, Dabigatrán 25, warfarin 18 and Rivaroxaban 14 this score reveals the most preferred up to the less preferred option, considering the benefit-risk ratio and drug costs altogether. The relative model weights were: 51.1% for risks, 40.4% for benefits and 8.5% for cost. The sensitivity analysis confirms the model robustness. From this analysis, apixaban should be considered as the preferred anticoagulant option -due to a better benefit-risk balance and a minor cost influence- followed by dabigatran, warfarin and rivaroxaban.

Using Artificial Intelligence to Reduce the Risk of Nonadherence in Patients on Anticoagulation Therapy.

PubMed

Labovitz, Daniel L; Shafner, Laura; Reyes Gil, Morayma; Virmani, Deepti; Hanina, Adam

2017-05-01

This study evaluated the use of an artificial intelligence platform on mobile devices in measuring and increasing medication adherence in stroke patients on anticoagulation therapy. The introduction of direct oral anticoagulants, while reducing the need for monitoring, have also placed pressure on patients to self-manage. Suboptimal adherence goes undetected as routine laboratory tests are not reliable indicators of adherence, placing patients at increased risk of stroke and bleeding. A randomized, parallel-group, 12-week study was conducted in adults (n=28) with recently diagnosed ischemic stroke receiving any anticoagulation. Patients were randomized to daily monitoring by the artificial intelligence platform (intervention) or to no daily monitoring (control). The artificial intelligence application visually identified the patient, the medication, and the confirmed ingestion. Adherence was measured by pill counts and plasma sampling in both groups. For all patients (n=28), mean (SD) age was 57 years (13.2 years) and 53.6% were women. Mean (SD) cumulative adherence based on the artificial intelligence platform was 90.5% (7.5%). Plasma drug concentration levels indicated that adherence was 100% (15 of 15) and 50% (6 of 12) in the intervention and control groups, respectively. Patients, some with little experience using a smartphone, successfully used the technology and demonstrated a 50% improvement in adherence based on plasma drug concentration levels. For patients receiving direct oral anticoagulants, absolute improvement increased to 67%. Real-time monitoring has the potential to increase adherence and change behavior, particularly in patients on direct oral anticoagulant therapy. URL: http://www.clinicaltrials.gov. Unique identifier: NCT02599259. © 2017 American Heart Association, Inc.

Direct oral anticoagulants and its implications in dentistry. A review of literature.

PubMed

Lanau, Neus; Mareque, Javier; Giner, Lluis; Zabalza, Michel

2017-11-01

Four novel direct oral anticoagulants (DOACs) named dabigatran, rivaroxaban, edoxaban and apixaban have been recently introduced to overcome some of the drawbacks of existing anticoagulants. They have less interactions and do not require routine monitoring. However, there is not enough scientific data about the protocol to apply in these patients on DOACs undergoing dental treatment. Thus is necessary to evaluate the potential bleeding risk of these drugs, the possibility of thromboembolic events occurring if they are withdrawn or the need to change to heparin previously. A comprehensive search of the PubMed, Scopus and ISI Web of Science databases was conducted to identify studies that evaluated the relationship between direct oral anticoagulants and dental procedures. The quality of the reported information was assessed following the PRISMA statement. Eleven studies that met the inclusion criteria were included in the review: 2 randomized clinical trials, 3 prospective studies, 3 retrospective studies, 2 case series and 1 case report. DOACs are safe drugs in terms of bleeding. The possible postoperative bleeding complications are manageable with conventional haemostasis measurements. The bridging approach with heparin does not seem to be recommended. Consensus among the professionals involved in the management of the patient is fundamental in invasive dental treatments and in complex patients. Key words: Oral anticoagulants, DOAC, NOAC, dabigatran, rivaroxaban, apixaban, edoxaban, bleeding, oral surgery.

Contribution of Helicobacter pylori infection to the risk of peptic ulcer bleeding in patients on nonsteroidal anti-inflammatory drugs, antiplatelet agents, anticoagulants, corticosteroids and selective serotonin reuptake inhibitors.

PubMed

Venerito, M; Schneider, C; Costanzo, R; Breja, R; Röhl, F-W; Malfertheiner, P

2018-06-01

Nonsteroidal anti-inflammatory drugs, low-dose aspirin, non-aspirin antiplatelet agents, anticoagulants, selective serotonin reuptake inhibitors and corticosteroids increase the risk of gastroduodenal bleeding. To determine in a retrospective cohort study the contribution of Helicobacter pylori infection to the risk of peptic ulcer bleeding in patients taking these drugs. Among patients with peptic ulcer disease diagnosed by endoscopy from 01/2004 to 12/2014 (N = 1719, 60% males, age 65.8 ± 14.5), 56.9% had peptic ulcer bleeding (cases) and 43.1% uncomplicated peptic ulcer disease (controls). Demographics, intake of nonsteroidal anti-inflammatory drugs, aspirin, non-aspirin antiplatelet agents, anticoagulants, selective serotonin reuptake inhibitors, proton pump inhibitors and corticosteroids were documented. H. pylori status was determined by histology, rapid urease test or serology. Adjusted odds ratios (OR) were estimated by logistic regression analysis. Helicobacter pylori infection increased the risk of peptic ulcer bleeding in nonsteroidal anti-inflammatory drug and aspirin users (OR = 2.91, 95% CI = 1.71-4.98 and OR = 2.23, 95% CI = 1.52-3.28, respectively), but not in patients on anticoagulants, selective serotonin reuptake inhibitor or corticosteroid therapy. H. pylori-positive status substantially increased the risk of peptic ulcer bleeding in patients on non-aspirin antiplatelet agents (OR = 4.37, 95% CI = 1.28-14.99), concomitant aspirin/nonsteroidal anti-inflammatory drug intake (OR = 5.85, 95% CI = 1.68-20.36) and combined antiplatelet therapy (OR = 8.43, 95% CI = 1.09-65.17). After further adjustment for proton pump inhibitor intake, H. pylori infection was still a risk factor for peptic ulcer bleeding in nonsteroidal anti-inflammatory drug and aspirin users. Helicobacter pylori infection increases the risk of peptic ulcer bleeding in peptic ulcer disease patients on nonsteroidal anti-inflammatory drugs, aspirin and non-aspirin antiplatelet agents. H. pylori-positive patients on combined antiplatelet therapy carry the highest risk for peptic ulcer bleeding. © 2018 John Wiley & Sons Ltd.

Antioxidant and intestinal anti-inflammatory effects of plant-derived coumarin derivatives.

PubMed

Witaicenis, Aline; Seito, Leonardo Noboru; da Silveira Chagas, Alexandre; de Almeida, Luiz Domingues; Luchini, Ana Carolina; Rodrigues-Orsi, Patrícia; Cestari, Silvia Helena; Di Stasi, Luiz Claudio

2014-02-15

Coumarins, also known as benzopyrones, are plant-derived products with several pharmacological properties, including antioxidant and anti-inflammatory activities. Based on the wide distribution of coumarin derivatives in plant-based foods and beverages in the human diet, our objective was to evaluate both the antioxidant and intestinal anti-inflammatory activities of six coumarin derivatives of plant origin (scopoletin, scoparone, fraxetin, 4-methyl-umbeliferone, esculin and daphnetin) to verify if potential intestinal anti-inflammatory activity was related to antioxidant properties. Intestinal inflammation was induced by intracolonic instillation of TNBS in rats. The animals were treated with coumarins by oral route. The animals were killed 48 h after colitis induction. The colonic segments were obtained after laparotomy and macroscopic and biochemical parameters (determination of glutathione level and myeloperoxidase and alkaline phosphatase activities) were evaluated. The antioxidant properties of these coumarins were examined by lipid peroxidation and DPPH assays. Treatment with esculin, scoparone and daphnetin produced the best protective effects. All coumarin derivatives showed antioxidant activity in the DPPH assay, while daphnetin and fraxetin also showed antioxidant activity by inhibiting lipid peroxidation. Coumarins, except 4-methyl-umbeliferone, also showed antioxidant activity through the counteraction of glutathione levels or through the inhibition of myeloperoxidase activity. The intestinal anti-inflammatory activity of coumarin derivatives were related to their antioxidant properties, suggesting that consumption of coumarins and/or foods rich in coumarin derivatives, particularly daphnetin, esculin and scoparone, could prevent intestinal inflammatory disease. Copyright © 2013 Elsevier GmbH. All rights reserved.

Anticoagulant treatment of medical patients with complex clinical conditions.

PubMed

Ruiz-Ruiz, F; Medrano, F J; Santos-Lozano, J M; Rodríguez-Torres, P; Navarro-Puerto, A; Calderón, E J

2018-06-12

There is scarce available information on the treatment or prophylaxis with anticoagulant drugs of outpatients with medical diseases and complex clinical conditions. There are no clinical practice guidelines and/or specific recommendations for this patient subgroup, which are frequently treated by internists. Complex clinical conditions are those in which, due to comorbidity, age, vital prognosis or multiple treatment with drugs, a clinical situation arises of disease-disease, disease-drug or drug-drug interactions that is not included within the scenarios that commonly generate the scientific evidence. The objective of this narrative review is collecting and adapting of the clinical guidelines recommendations and systematic reviews to complex clinical conditions, in which the direct application of recommendations based on studies that do not include patients with this complexity and comorbidity could be problematic. Copyright © 2018 Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI). All rights reserved.

Prevention of thromboembolic events in patients with atrial fibrillation - new anticoagulants.

PubMed

Campos, Alexandre Holthausen; Cirenza, Cláudio

2011-09-01

The authors present alternatives for the treatment of cardiac arrhythmias. Its detection is based on the use of different methods that record the cardiac electrical activity. The treatment involves intervening in the underlying disorder, antiarrhythmic drugs, stimulation and cardiac defibrillation devices, and, less often, surgery. The technological advances in the last two decades have provided greater efficiency in diagnoses and therapy. Atrial fibrilation patients will benefit from a new set of anticoagulant drugs tested in the past three years. The potential advantages include greater safety and efficacy, as well as convenience for not requiring frequent laboratory controls.

Pharmacogenomics of Anti-platelet and Anti-coagulation Therapy

PubMed Central

Fisch, Adam S.; Perry, Christina G.; Stephens, Sarah H.; Horenstein, Richard B.; Shuldiner, Alan R.

2013-01-01

Arterial thrombosis is a major component of vascular disease, especially myocardial infarction (MI) and stroke. Current anti-thrombotic therapies such as warfarin and clopidogrel are effective in inhibiting cardiovascular events; however, there is great inter-individual variability in response to these medications. In recent years, it has been recognized that genetic factors play a significant role in drug response, and, subsequently, common variants in genes responsible for metabolism and drug action have been identified. These discoveries along with the new diagnostic targets and therapeutic strategies on the horizon hold promise for more effective individualized anti-coagulation and anti-platelet therapy. PMID:23797323

Direct anticoagulants and nursing: an approach from patient's safety.

PubMed

Romero Ruiz, Adolfo; Romero-Arana, Adolfo; Gómez-Salgado, Juan

In recent years, a new line of treatment for the prevention of stroke in non-valvular atrial fibrillation, the so-called direct anticoagulants or new anticoagulants has appeared. The proper management and follow-up of these patients is essential to minimize their side effects and ensure patient safety. In this article, a description of these drugs is given, analyzing their characteristics, functioning and interactions together with the most habitual nursing interventions, as well as a reflection on the implications for the practice. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

Antithrombotic treatment in elderly patients with atrial fibrillation: a practical approach.

PubMed

Suárez Fernández, Carmen; Fernández, Suárez; Formiga, Francesc; Camafort, Miguel; Cepeda Rodrigo, María; Rodrigo, Jose Cepeda; Díez-Manglano, Jesús; Pose Reino, Antonio; Reino, Pose; Tiberio, Gregorio; Mostaza, Jose María

2015-11-04

Atrial fibrillation (AF) in the elderly is a complex condition. It has a direct impact on the underuse of antithrombotic therapy reported in this population. All patients aged ≥75 years with AF have an individual yearly risk of stroke >4 %. However, the risk of hemorrhage is also increased. Moreover, in this population it is common the presence of other comorbidities, cognitive disorders, risk of falls and polymedication. This may lead to an underuse of anticoagulant therapy. Direct oral anticoagulants (DOACs) are at least as effective as conventional therapy, but with lesser risk of intracranial hemorrhage. The simplification of treatment with these drugs may be an advantage in patients with cognitive impairment. The great majority of elderly patients with AF should receive anticoagulant therapy, unless an unequivocal contraindication. DOACs may be the drugs of choice in many elderly patients with AF. In this manuscript, the available evidence about the management of anticoagulation in elderly patients with AF is reviewed. In addition, specific practical recommendations about different controversial issues (i.e. patients with anemia, thrombocytopenia, risk of gastrointestinal bleeding, renal dysfunction, cognitive impairment, risk of falls, polymedication, frailty, etc.) are provided.

Low doping concentration studies of doped PVA-Coumarin nanocomposite films

NASA Astrophysics Data System (ADS)

Tripathi, J.; Tripathi, S.; Bisen, R.; Sharma, A.; Choudhary, A.; Shripathi, T.

2016-05-01

The observations of combination of Poly (vinyl) alcohol and Coumarin properties in nanocmposite films are reported. The X-ray diffraction measurements reveal nanocrystalline nature of PVA film, which remains nanocrystalline after doping Coumarin but along with PVA peaks, additional peak due to dopant crystallinity is seen. The absorption edge shows a double edge feature, where distinct bandgaps for PVA host and dopant Coumarin are obtained. However at a higher doping wt % of 1 and 2, the absorption is mainly dominated by Coumarin and single absorption edge is observed giving a bandgap equal to that of bulk Coumarin (3.3 eV). The composite formation affects the bonding of host drastically and is seen through the bond modification in FTIR spectra. The results suggest that doping below 2 wt% is advantageous as combination of PVA and Coumarin properties are obtained but at 2 wt %, the properties are dominated by mainly Coumarin and the signature of PVA from optical properties is completely lost.

Low doping concentration studies of doped PVA-Coumarin nanocomposite films

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tripathi, J., E-mail: jtripathi00@rediffmail.com; Bisen, R.; Choudhary, A.

2016-05-23

The observations of combination of Poly (vinyl) alcohol and Coumarin properties in nanocmposite films are reported. The X-ray diffraction measurements reveal nanocrystalline nature of PVA film, which remains nanocrystalline after doping Coumarin but along with PVA peaks, additional peak due to dopant crystallinity is seen. The absorption edge shows a double edge feature, where distinct bandgaps for PVA host and dopant Coumarin are obtained. However at a higher doping wt % of 1 and 2, the absorption is mainly dominated by Coumarin and single absorption edge is observed giving a bandgap equal to that of bulk Coumarin (3.3 eV). Themore » composite formation affects the bonding of host drastically and is seen through the bond modification in FTIR spectra. The results suggest that doping below 2 wt% is advantageous as combination of PVA and Coumarin properties are obtained but at 2 wt %, the properties are dominated by mainly Coumarin and the signature of PVA from optical properties is completely lost.« less

Venous thromboembolism: role of pharmacists and managed care considerations.

PubMed

Horner, Tuesdy; Mahan, Charles E

2017-12-01

Venous thromboembolism (VTE) includes deep vein thrombosis and pulmonary embolism. Anticoagulation is used in patients with VTE to reduce the risk of recurrent VTE and VTE-related death. The overall incidence of VTE is 1 to 2 per 1000 person-years. Long-term mortality for patients with VTE is poor, with 25% of patients not surviving 7 days and nearly 40% not surviving the first year. Coagulation disorders demand effective anticoagulant therapy to avoid complications, especially recurrent VTE and VTE-related death. For more than 60 years, warfarin has been the cornerstone of therapy for patients requiring anticoagulation and was the sole oral anticoagulant available in the United States until 2010. Since then, the FDA has approved 5 direct-acting oral anticoagulants (DOACs) that inhibit single coagulation factors (factor Xa and thrombin). DOACs provide predictable anticoagulation with fixed dosing, easier perioperative management, no routine laboratory monitoring, and fewer food-drug interactions. However, when choosing DOACs, clinicians must consider several issues in addition to efficacy and safety before employing these therapies, including patient-specific factors, adherence and persistence with therapy, and their cost-effectiveness for clinical use.

Clinical considerations on the posology of direct oral anticoagulants.

PubMed

Sáez-Peñataro, J; Avendaño-Solá, C; González-Juanatey, J R

2016-10-01

The efficacy of dicoumarin anticoagulants has been shown in patients with nonvalvular atrial fibrillation. However, they have drawbacks such as the need to adjust the dosage and the interaction with drugs and food. Direct oral anticoagulants are an effective and safe alternative and have a less complicated clinical management. There is considerable debate on the selection criteria for the posology regimens of direct oral anticoagulants. The differences among them and their administration regimens have raised questions about the clinical, pharmacokinetic and pharmacodynamic selection criteria that support the posology. This review critically analyses the available evidence and its impact on the final selection of the dosage regimen. Copyright © 2016 Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI). All rights reserved.

Novel oral anticoagulants for atrial fibrillation

PubMed Central

How, Choon How

2015-01-01

Anticoagulation therapy is effective in preventing primary and secondary thromboembolic events due to atrial fibrillation. Warfarin, which was approved by the United States in 1954, was the only long-term oral anticoagulation therapy till the approval of dabigatran in 2010, and of rivaroxaban and other direct factor Xa inhibitors from 2011, forming a group known as novel oral anticoagulants (NOAC). NOAC have fewer food and drug interactions compared to warfarin; hence, the patient will require fewer clinic visits. However, the short half-life of NOAC means that twice-a-day dosing is needed and there is higher risk of a prothrombotic state when doses are missed. Other disadvantages are the lack of long-term data on NOAC, their high cost and the current lack of locally available antidotes. PMID:26702159

Evaluation of bleeding in patients receiving direct oral anticoagulants

PubMed Central

Hellenbart, Erika L; Faulkenberg, Kathleen D; Finks, Shannon W

2017-01-01

Direct oral anticoagulants (DOACs) are recognized by evidence-based treatment guidelines as the first-line option for the treatment of venous thromboembolism and prevention of stroke and systemic embolism in nonvalvular atrial fibrillation. As use of these anticoagulants has become favored over the past several years, reported bleeding-related adverse drug events with these agents has increased. In randomized clinical trials, all DOACs have a reduced risk for intracranial hemorrhage, while major and other bleeding results have varied among the agents compared to vitamin K antagonists. We have reviewed the bleeding incidence and severity from randomized and real-world data in patients receiving DOACs in an effort to provide the clinician with a critical review of bleeding and offer practical considerations for avoiding adverse events with these anticoagulants. PMID:28860793

Considerations for long-term anticoagulant therapy in patients with venous thromboembolism in the novel oral anticoagulant era.

PubMed

Toth, Peter P

2016-01-01

Patients who have had a venous thromboembolic event are generally advised to receive anticoagulant treatment for 3 months or longer to prevent a recurrent episode. Current guidelines recommend initial heparin and an oral vitamin K antagonist (VKA) for long-term anticoagulation. However, because of the well-described disadvantages of VKAs, including extensive food and drug interactions and the need for regular anticoagulation monitoring, novel oral anticoagulants (NOACs) have become an attractive option in recent years. These agents are given at fixed doses and do not require routine coagulation-time monitoring. The NOACs are discussed in this review with regard to the needs of patients on long-term anticoagulation. Current guidelines from Europe and North America that refer to the treatment of deep vein thrombosis and/or pulmonary embolism are included, as well as published randomized Phase III clinical trials of NOACs. PubMed searches were used for sourcing case studies of long-term anticoagulant treatment, and results were filtered for human application and screened for relevance. NOAC-based therapy showed a similar efficacy and safety profile to heparins/VKAs but without the need for regular anticoagulation monitoring or dietary adjustments, and can be taken as a fixed-dose regimen once or twice daily. This represents a significant step forward in facilitating the management of long-term anticoagulation therapy. Furthermore, in the EINSTEIN studies, improved patient satisfaction was documented with the NOAC rivaroxaban, which may result in better adherence to therapy and an overall reduction in the incidence of recurrent venous thromboembolism.

The Best Anticoagulation Therapy in Multiple-Trauma Patients with Mechanical Heart Valves: Evaluation of Latest Guidelines and Studies.

PubMed

Moeinipour, Aliasghar; Zarifian, Ahmadreza; Sheikh Andalibi, Mohammad Sobhan; Shamloo, Alireza Sepehri; Ahmadabadi, Ali; Amouzeshi, Ahmad; Hoseinikhah, Hamid

2015-12-22

It is common practice for patients with prosthetic cardiac devices, especially heart valve prosthesis, arterial stents, defibrillators, and pacemaker devices, to use anticoagulation treatment. When these patients suffer from multiple trauma after motor vehicle accidents, the best medical management for this challenging position is mandatory. This strategy should include a rapid diagnosis of all possible multiple organ injuries, with special attention to anticoagulation therapy so as to minimize the risk of thromboembolism complication in prosthetic devices. In this review, we describe the best medical management for patients with multiple trauma who use anticoagulants after heart valve replacement. We searched electronic databases PubMed/Medline, Scopus, Embase, and Google Scholar using the following terms: anticoagulant, warfarin, heparin, and multiple trauma. Also, similar studies suggested by the databases were included. Non-English articles were excluded from the review. For patients who use anticoagulation therapy, teamwork between cardiac surgeons, general surgeons, anesthesiologists, and cardiologists is essential. For optimal medical management, multiple consults between members of this team is mandatory for rapid diagnosis of all possible damaged organs, with special attention to the central nervous system, chest, and abdominal traumas. With this strategy, it is important to take note of anticoagulation drugs to minimize the risk of thromboembolism complications in cardiac devices. The best anticoagulant agents for emergency operations in patients with multiple trauma who are using an anticoagulant after heart valve replacement are fresh frozen plasma (FFP) and prothrombin complex concentrates (PCC).

Spectral and quantum-mechanical characterizations of 7-amino-4-trifluoromethyl coumarin

NASA Astrophysics Data System (ADS)

Benchea, Andreea Celia; Gaina, Marius; Dorohoi, Dana Ortansa

2017-01-01

Coumarins are crystalline compounds utilized in pharmaceutical, food and cosmetic industries. Our study refers to quantum-mechanical and spectral characterization of 7-amino-4-trifluoromethyl coumarin (7-NH2-4-CF3-coumarin or coumarin 151) in order to estimate its stability, reactivity and biological activity. The contribution of different types of interactions to the spectral shifts in homogeneous solutions and the limits in which the excited state dipole moment of the studied molecule can vary are established by solvatochromic study.

Risk of gastrointestinal bleeding with direct oral anticoagulants: a systematic review and network meta-analysis.

PubMed

Burr, Nick; Lummis, Katie; Sood, Ruchit; Kane, John Samuel; Corp, Aaron; Subramanian, Venkataraman

2017-02-01

Direct oral anticoagulants are increasingly used for a wide range of indications. However, data are conflicting about the risk of major gastrointestinal bleeding with these drugs. We compared the risk of gastrointestinal bleeding with direct oral anticoagulants, warfarin, and low-molecular-weight heparin. For this systematic review and meta-analysis, we searched MEDLINE and Embase from database inception to April 1, 2016, for prospective and retrospective studies that reported the risk of gastrointestinal bleeding with use of a direct oral anticoagulant compared with warfarin or low-molecular-weight heparin for all indications. We also searched the Cochrane Library for systematic reviews and assessment evaluations, the National Health Service (UK) Economic Evaluation Database, and ISI Web of Science for conference abstracts and proceedings (up to April 1, 2016). The primary outcome was the incidence of major gastrointestinal bleeding, with all gastrointestinal bleeding as a secondary outcome. We did a Bayesian network meta-analysis to produce incidence rate ratios (IRRs) with 95% credible intervals (CrIs). We identified 38 eligible articles, of which 31 were included in the primary analysis, including 287 692 patients exposed to 230 090 years of anticoagulant drugs. The risk of major gastrointestinal bleeding with direct oral anticoagulants did not differ from that with warfarin or low-molecular-weight heparin (factor Xa vs warfarin IRR 0·78 [95% CrI 0·47-1·08]; warfarin vs dabigatran 0·88 [0·59-1·36]; factor Xa vs low-molecular-weight heparin 1·02 [0·42-2·70]; and low-molecular-weight heparin vs dabigatran 0·67 [0·20-1·82]). In the secondary analysis, factor Xa inhibitors were associated with a reduced risk of all severities of gastrointestinal bleeding compared with warfarin (0·25 [0.07-0.76]) or dabigatran (0.24 [0.07-0.77]). Our findings show no increase in risk of major gastrointestinal bleeding with direct oral anticoagulants compared with warfarin or low-molecular-weight heparin. These findings support the continued use of direct oral anticoagulants. Leeds Teaching Hospitals Charitable Foundation. Copyright © 2017 Elsevier Ltd. All rights reserved.

To Bleed or Not to Bleed: That is the Question. The Side Effects of Apixaban.

PubMed

Ciccone, Marco Matteo; Zito, Annapaola; Devito, Fiorella; Maiello, Maria; Palmiero, Pasquale

2018-01-01

Apixaban is a new oral anticoagulant (NOACs: Novel Oral Anticoagulant), like dabigatran, rivaroxaban, and edoxaban. All of them are prescribed to patients with non valvular atrial fibrillation or venous thromboembolism, to replace warfarin, because of the lower probability of bleeding, however they can cause bleeding by themselves. Bleeding is an adverse event in patients taking anticoagulants. It is associated with a significant increase of morbidity and risk of death. However, these drugs should be used only for the time when anticoagulation is strictly required, especially when used for preventing deep vein thrombosis. Prolonged use increases the risk of bleeding. In the ARISTOTLE Trial Apixaban, compared with warfarin, was associated with a lower rate of intracranial hemorrhages and less adverse consequences following extracranial hemorrhage. Many physicians still have limited experience with new oral anticoagulants and about bleeding risk managment. We reviewed the available literature on extracranial and intracranial bleeding concerning apixaban. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

The efficacy and safety of novel oral anticoagulants for the preventive treatment in atrial fibrillation patients: a systematic review and meta-analysis.

PubMed

Liu, Guang Jian; Wang, Yun Fu; Chen, Ping You; Chang, Wei; Tu, Ming Li; Chang, Li Ying; Cheng, Ping; Luo, Jie

2014-09-01

Novel oral anticoagulants, including direct factor Xa inhibitors and direct factor IIa inhibitors, have been used to prevent stroke in patients with atrial fibrillation (AF) for a decade. In this study, the efficacy and safety of the novel oral anticoagulants were assessed in AF patients. No language restrictions were applied. Study selection and data extraction were carried out by searching PubMed, EMBASE, OVID, the BIOSIS, the Web of Science, Clinical Trials Registers, Cochrane Central Register of Controlled Trials and the China Academic Library and Information System. Each database was searched from its inception date to June 2013. Using odds ratio (OR) as an indicator, we systematically evaluated the primary efficacy endpoints and safety endpoints, as well as 10 secondary endpoints. Compared to the control drugs, the novel oral anticoagulants showed an OR decreased by 26% (OR: 0.74, 95% confidence interval (CI): 0.62-0.88) for stroke or systemic embolism, decreased by 24% (OR: 0.76, 95% CI: 0.64-0.90) for major bleeding, decreased by 10% (OR: 0.90, 95% CI: 0.84-0.95) for death from any cause, decreased by 27% for disabling or fatal stroke (OR: 0.73, 95% CI: 0.54-0.97), decreased by 31% (OR: 0.69, 95% CI: 0.60-0.8) for fatal bleeding, and decreased by 8% (OR: 0.92, 95% CI: 0.88-0.95) for serious adverse events. However, there was no significant difference in acute myocardial infarction, systemic embolism, major bleeding or clinically relevant non-major, all bleeding events, all adverse events and liver function disorder, between the novel oral anticoagulants and control drugs (p > 0.05). Compared to the control drugs, the novel oral anticoagulants showed higher efficiency and safety in patients with AF, as evidenced by their superior performance not only in reducing the risk of stroke or systemic embolism with a lower risk of major bleeding but also in decreasing the incidence of death from any cause, disabling or fatal stroke, serious adverse events and fatal bleeding.

Dabigatran etexilate versus warfarin as the oral anticoagulant of choice? A review of clinical data.

PubMed

Ma, Terry K W; Yan, Bryan P; Lam, Yat-Yin

2011-02-01

For many years, warfarin was the only effective oral anticoagulant to prevent and treat thromboembolism. Nevertheless, its clinical use is limited by a narrow therapeutic window, extensive drug interactions, need of strict dietary control and frequent monitoring. The pharmacological response is also unpredictable and highly variable among patients. Suboptimal anticoagulation can lead to detrimental thromboembolic events or life-threatening bleeding. Direct thrombin inhibitor (DTI) activity represents a new class of anticoagulant activity that was intended to replace warfarin. Ximelagatran was the first DTI shown to have similar efficacy to warfarin, but failed to replace it because of a high incidence of liver toxicity. Dabigatran etexilate is another novel DTI with a more predictable pharmacokinetic profile and fewer drug interactions compared with warfarin. Recent large-scaled, randomized studies have shown that it does not share ximelagatran's hepatotoxicity, and is as effective as conventional anticoagulants for venous thromboembolism (VTE) and prophylaxis in atrial fibrillation (AF). These findings led to the approval of dabigatran etexilate for thromboprophylaxis following hip or knee replacement surgery in Europe, Canada and the United Kingdom. Here we summarize the latest evidence concerning the use of dabigatran etexilate in VTE (BISTRO, RE-MODEL, RE-NOVATE, RE-MOBILIZE and RECOVER) and AF (PETRO and RELY). Potential problems related to dabigatran use are also discussed to examine whether it can truly replace warfarin as the gold standard. Copyright © 2010 Elsevier Inc. All rights reserved.

Rivaroxaban in the cardiovascular world: a direct anticoagulant useful to prevent stroke and venous and arterial thromboembolism.

PubMed

Seoane, Leonardo; Cortés, Marcia; Aris Cancela, María Esther; Furmento, Juan; Baranchuk, Adrián; Conde, Diego

2018-06-14

Until recently, vitamin K antagonists (VKA) were the only drugs available for long-term anticoagulation. The use of these drugs is laborious due to their variable pharmacokinetics and pharmacodynamics. The advent of direct oral anticoagulants has produced a paradigm shift due to their low incidence of drug interactions, their stable plasma levels, and their lack of monitoring. Rivaroxaban, a factor Xa inhibitor, has been tested in different clinical scenarios and has proved to be effective and safe, even increasing the scope of the old VKA. Areas covered: A non-systematic review of the literature was conducted using the PubMed and Cochrane databases, focusing on randomized clinical trials and real-world observational studies that evaluated rivaroxaban in patients with atrial fibrillation, venous thromboembolism, and atherosclerotic coronary and peripheral vascular disease. Expert commentary: The role of rivaroxaban keeps expanding into areas that were unimaginable few years ago, in the light of solid evidence that has eliminated old strict paradigms. Nonetheless, it will be necessary to adjust costs and better understand the perceived barriers to its widespread implementation, to get fully acceptation of rivaroxaban for the different clinical conditions that have been suggested.

ANMCO Position Paper: the use of non-vitamin K dependent new oral anticoagulant(s) in pulmonary embolism therapy and prevention

PubMed Central

Roncon, Loris; Azzarito, Michele; Becattini, Cecilia; Bongarzoni, Amedeo; Casazza, Franco; Cuccia, Claudio; D’Agostino, Carlo; Rugolotto, Matteo; Vatrano, Marco; Vinci, Eugenio; Fenaroli, Paride; Formigli, Dario; Silvestri, Paolo; Nardi, Federico; Vedovati, Maria Cristina; Scherillo, Marino

2017-01-01

Abstract The new oral anticoagulants (NOACs) have radically changed the approach to the treatment and prevention of thromboembolic pulmonary embolism. The authors of this position paper face, in succession, issues concerning NOACs, including (i) their mechanism of action, pharmacodynamics, and pharmacokinetics; (ii) the use in the acute phase with the ‘double drug single dose’ approach or with ‘single drug double dose’; (iii) the use in the extended phase with demonstrated efficacy and with low incidence of bleeding events; (iv) the encouraging use of NOACs in particular subgroups of patients such as those with cancer, the ones under- or overweight, with renal insufficiency (creatinine clearance > 30 mL/min), the elderly (>75 years); (v) they propose a possible laboratory clinical pathway for follow-up; and (vi) carry out an examination on the main drug interactions, their potential bleeding risk, and the way to deal with some bleeding complications. The authors conclude that the use of NOACs both in the acute phase and in the extended phase is equally effective to conventional therapy and associated with fewer major bleeding events, which make their use in patients at higher risk of recurrences safer. PMID:28751847

The ineffectiveness of coumarin treatment on thermal oedema of macrophage-free rats.

PubMed Central

Piller, N. B.

1976-01-01

The administration of silica prevents coumarin-stimulated lysis of accumulated abnormal protein. This impairs the resolution of thermal oedema which is normally increased with coumarin administration. Evidence suggests that there is a rapid differentiation and infiltration of monocytes into the tissues and that these are selectively retained. This is aided by coumarin which increases tissue permeability. Coumarin also injures the vascular endothelium of some vessels, allowing extra protein and fluid into the tissues. Death of recently differentiated macrophages and subsequent release of their lysosomal contents into the extra-cellular spaces may be responsible for the changes in serum enzyme levels. It would seem that macrophages are the only cells in which coumarin stimulates increased phagocytosis, enzyme production and proteolysis. PMID:178336

RGD-modified pH-sensitive liposomes for docetaxel tumor targeting.

PubMed

Chang, Minglu; Lu, Shanshan; Zhang, Fang; Zuo, Tiantian; Guan, Yuanyuan; Wei, Ting; Shao, Wei; Lin, Guimei

2015-05-01

Phosphatidylethanolamine-based pH-sensitive liposomes of various compositions have been described as efficient systems for delivery of therapeutic molecules into tumor cells. The aim of this work was to develop a drug delivery system based on pH-sensitive liposomes (PLPs) that were modified with arginine-glycine-aspartic acid (RGD) peptide to enhance the effectiveness of docetaxel treatment. Docetaxel/coumarin-6 loaded PLPs were prepared by the thin-film dispersion method and characterized in detail, including by particle size, polydispersity, zeta potential and drug encapsulation efficiency. In vitro studies using MCF-7, HepG2and A549 cells were employed to investigate cytotoxicity and cellular uptake of the drug solution or docetaxel/coumarin-6 loaded PLPs. The accumulation of 7-nitro-2-1,3-benzoxadiazol-4-yl (NBD)-labeled liposomes in vivo was studied through tumor section imaging of xenograft mouse models of MCF-7 24h after intravenous administration. The particle size of the non-coated or RGD modified PLPs ranged between 146 and 129nm. Drug release in vitro was modestly prolonged and had good pH sensitivity. In the in vitro study, RGD-coated PLPs showed higher cytotoxicity and cellular uptake relative to non-coated ones. The results of the in vivo study showed that RGD-coated PLPs had higher fluorescence, which suggested a more efficient accumulation than normal PLPs in tumors. In conclusion, these results confirmed RGD-modified PLPs as a potential drug delivery system to achieve controlled release and tumor targeting. Copyright © 2015 Elsevier B.V. All rights reserved.

Optical profiling of anticoagulation status (Conference Presentation)

NASA Astrophysics Data System (ADS)

Tshikudi, Diane M.; Tripathi, Markandey M.; Hajjarian, Zeinab; Nadkarni, Seemantini K.

2016-02-01

Defective blood coagulation resulting from excessive procoagulant activity often leads to thrombotic disorders such as stroke and myocardial infarction. A variety of oral and injectable anticoagulant drugs are prescribed to prevent or treat life-threatening thrombosis. However, due to bleeding complications often associated with anticoagulant treatment, routine monitoring and accurate dosing of anticoagulant therapy is imperative. We have developed Optical thromboelastography (OTEG), a non-contact approach that utilizes a drop of whole blood to measure blood coagulation status in patients. Here, we demonstrate the capability of OTEG for rapidly monitoring anticoagulation in whole blood samples. OTEG monitors coagulation status by assessing changes in blood viscosity from temporal intensity fluctuations of laser speckle patterns during clotting. In OTEG a blood drop is illuminated with coherent light and the blood viscosity is measured from the speckle intensity autocorrelation curve, g2 (t). The metrics, clotting time (R+k), clot progression (angle) and maximum clot stiffness (MA) are then extracted. The aim of the current study was to evaluate the accuracy of OTEG in assessing anticoagulation status of common anticoagulants including heparin, argatroban and rivaroxaban status. A dose-dependent prolongation of R+k was observed in anticoagulated blood, which closely corresponded with standard-reference Thromboelastography (TEG) (r 0.87-0.99, P>0.01 for all cases). OTEG angle was unaltered by anticoagulation whereas TEG angle presented a dose-dependent diminution probably linked to clot rupture. In both OTEG and TEG, MA was unaffected by heparin, argatroban or rivaroxaban. We conclude that OTEG can accurately monitor anticoagulation status following treatment, potentially providing a powerful tool for routine monitoring of patients in the doctor's office or in the home setting.

Antagonists for the orphan G-protein-coupled receptor GPR55 based on a coumarin scaffold.

PubMed

Rempel, Viktor; Volz, Nicole; Gläser, Franziska; Nieger, Martin; Bräse, Stefan; Müller, Christa E

2013-06-13

The orphan G-protein-coupled receptor GPR55, which is activated by 1-lysophosphatidylinositol and interacts with cannabinoid (CB) receptor ligands, has been proposed as a new potential drug target for the treatment of diabetes, Parkinson's disease, neuropathic pain, and cancer. We applied β-arrestin assays to identify 3-substituted coumarins as a novel class of antagonists and performed an extensive structure-activity relationship study for GPR55. Selectivity versus the related receptors CB1, CB2, and GPR18 was assessed. Among the 7-unsubstituted coumarins selective, competitive GPR55 antagonists were identified, such as 3-(2-hydroxybenzyl)-5-isopropyl-8-methyl-2H-chromen-2-one (12, PSB-SB-489, IC50 = 1.77 μM, pA2 = 0.547 μM). Derivatives with long alkyl chains in position 7 were potent, possibly allosteric GPR55 antagonists which showed ancillary CB receptor affinity. 7-(1,1-Dimethyloctyl)-5-hydroxy-3-(2-hydroxybenzyl)-2H-chromen-2-one (69, PSB-SB-487, IC50 = 0.113 μM, KB = 0.561 μM) and 7-(1,1-dimethylheptyl)-5-hydroxy-3-(2-hydroxybenzyl)-2H-chromen-2-one (67, PSB-SB-1203, IC50 = 0.261 μM) were the most potent GPR55 antagonists of the present series.

[Renal impairment in patients with thromboembolic event: prevalence and clinical implications. A systematic review of the literature].

PubMed

Wilke, Thomas; Wehling, Martin; Amann, Steffen; Bauersachs, Rupert M; Böttger, Björn

2015-08-01

The assessment of the renal function of patients with a deep vein thrombosis/pulmonary embolism (VTE patients) is of utmost importance for the selection/dosage of an agent in the initial anticoagulation management of these patients because the majority of available anticoagulants are cleared renally. Specifically, there is a high risk of drug accumulation and subsequent bleedings in patients with severe renal insufficiency. Consequently, specific recommendations have been made for the initial anticoagulation management of these patients in both product labels and AWMF treatment recommendations: some drugs should not be used in these patients, for other drugs a careful use, intensified screening (anti-Xa), or, in the case of enoxaparin, a dose-adjustment are recommended.This literature review aimed to answer the following questions: · What is the prevalence of renal insufficiency in VTE patients?. · Which data are available with regard to the real-world initial anticoagulation management and corresponding clinical outcomes (recurrent VTE events, bleedings, mortality) of these patients? We did a systematic review of existing publications in german or english published in 2004-2014. Only quantitative analyses have been included in the review. We identified 1,135 publications, 37 of them were included in our review. The prevalence of renal insufficiency in VTE patients, defined as CrCl < 60 ml / min, was reported to be 12.3 %-71.9 % related to all VTE patients. The prevalence of severe renal insufficiency, defined as CrCl < 30 ml / min, was reported to be 3,3 %-13,6 %. The substantial ranges in reported prevalences are mainly due to differences in the characteristics of patients addressed in the different publications.A CrCl < 30 ml / min is an independent predictor for both mortality and lethal recurrent pulmonary embolism, possibly also for severe bleedings in VTE patients. In addition to that, a severe renal insufficiency may also be a predictor for the probability that a first VTE event occurs.Several anticoagulants approved for the initial anticoagulation management of VTE patients face the risk of drug accumulation in renally insufficent patients. So, for example, a standard enoxaparin dosage was shown to be associated with elevated bleeding risk compared to adjusted enoxaparin dosage in renally insufficient patients. However, similar data do not exist for other low molecular weight heparins (LMWHs) or unfractioned heparins (UFHs). Only for two LMWHs, Certoparin and Tinzaparin, safety data with regard to renally insufficient patients have been published so far.None of the included studies showed advantages of UFH therapy in comparison to LMWH therapy in initial anticoagulation management of VTE patients. In contrast to that, available evidence shows disadvantageous efficacy/safety of UFH in comparison to LMWH treatment. However, this evidence is not based on head-to-head comparisons but is derived from registry and observational study data only. A detailed knowledge of product labels is of utmost importance in the inital anticoagulation treatment of VTE patients because several agents may not be used in the addressed patients with severe renal insufficiency at all while others may be used based on specific dosage/surveillance schemes only. We also recommend to critically appraise the current AWMF treatment guideline because it still recommends initial anticoagulation management with UFHs in VTE patients with severe renal insufficiency. Available data do not support that recommendation. © Georg Thieme Verlag KG Stuttgart · New York.

Advances in Inhibitors of FXa.

PubMed

Guo, Liwei; Ma, Shutao

2015-01-01

Thromboembolic diseases such as deep vein thrombosis (DVT), pulmonary embolism (PE), myocardial infarction (MI) and ischemic strokes are mainly responsible for people's morbidity and mortality and have severely affected the people's quality of life all over the world. According to WHO statistics, an average of 17 million people are killed by the thromboembolic diseases each year globally. Therefore, the prevention and treatment of thromboembolic diseases have received widespread attention in recent years. Based on thrombotic mechanism, anti-thrombotic drugs are mainly divided into anticoagulants, antiplatelet agents and direct thrombolytic drugs. In particular, anticoagulants such as vitamin K antagonists (VKAs), unfractionated heparin (UFH), and low-molecular-weight heparins (LMWHs) have become the main therapies for pre-treatment of thromboembolic disorders. However, the limitations of traditional anticoagulants such as slow onset of action, dose-adjusted requirement, drug-drug and drug-food interactions have restricted their improvement in the clinical treatment. The mechanism of the thromboembolic disorders has indicated that coagulation factor Xa (fXa) plays a pivotal role in the blood coagulation cascade. Thus, selective inhibition of fXa by diminishing the amplified generation of thrombin without affecting the pre-existing thrombin levels can provide better antithrombotic effect, thereby causing less impairment of primary hemostasis. In this paper, we mainly introduce the recent advances of fXa inhibitors, with focus on their biological activity and structure-activity relationship (SAR) information. In particular, the inspirations from the structures of the fXa inhibitors and their future direction are highlighted.

3D QSAR studies on binding affinities of coumarin natural products for glycosomal GAPDH of Trypanosoma cruzi

NASA Astrophysics Data System (ADS)

Menezes, Irwin R. A.; Lopes, Julio C. D.; Montanari, Carlos A.; Oliva, Glaucius; Pavão, Fernando; Castilho, Marcelo S.; Vieira, Paulo C.; Pupo, M.^onica T.

2003-05-01

Drug design strategies based on Comparative Molecular Field Analysis (CoMFA) have been used to predict the activity of new compounds. The major advantage of this approach is that it permits the analysis of a large number of quantitative descriptors and uses chemometric methods such as partial least squares (PLS) to correlate changes in bioactivity with changes in chemical structure. Because it is often difficult to rationalize all variables affecting the binding affinity of compounds using CoMFA solely, the program GRID was used to describe ligands in terms of their molecular interaction fields, MIFs. The program VolSurf that is able to compress the relevant information present in 3D maps into a few descriptors can treat these GRID fields. The binding affinities of a new set of compounds consisting of 13 coumarins, for one of which the three-dimensional ligand-enzyme bound structure is known, were studied. A final model based on the mentioned programs was independently validated by synthesizing and testing new coumarin derivatives. By relying on our knowledge of the real physical data (i.e., combining crystallographic and binding affinity results), it is also shown that ligand-based design agrees with structure-based design. The compound with the highest binding affinity was the coumarin chalepin, isolated from Rutaceae species, with an IC50 value of 55.5 μM towards the enzyme glyceraldehyde-3-phosphate dehydrogenase (gGAPDH) from glycosomes of the parasite Trypanosoma cruzi, the causative agent of Chagas' disease. The proposed models from GRID MIFs have revealed the importance of lipophilic interactions in modulating the inhibition, but without excluding the dependence on stereo-electronic properties as found from CoMFA fields.

AD6 (8-monochloro-3-beta-diethylamino-ethyl-4-methyl-7-ethoxycarbonyl-meth oxy coumarin) inhibits the release of arachidonic acid in human platelets stimulated by thrombin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Porcellati, S.; Costantini, V.; Prosdocimi, M.

1987-07-01

The coumarin derivative AD6 is known to inhibit platelet aggregation and release and it possesses vasodilatory properties on coronary arteries of laboratory animals. Furthermore, the inhibition of the production of TxB2 from endogenous substrates after stimulation of human platelets with collagen has been demonstrated. The present report demonstrates that AD6 inhibits the production of labeled arachidonic acid and diglycerides from phospholipids of platelets stimulated with thrombin. This effect is dose-dependent and is already evident at a concentration of the drug (25 microM) which is unable to prevent the aggregation. Apparently, AD6 inhibits the release of arachidonic acid from phosphatidylinositol andmore » choline phosphoglycerides which are the main sources of the substrate for the synthesis of prostaglandins and thromboxanes.« less

Recent developments in separation of low molecular weight heparin anticoagulants.

PubMed

Sadowski, Radosław; Gadzała-Kopciuch, Renata; Buszewski, Bogusław

2017-10-05

The general function of anticoagulants is to prevent blood clotting and growing of the existing clots in blood vessels. In recent years, there has been a significant improvement in developing methods of prevention as well as pharmacologic and surgical treatment of thrombosis. For over the last two decades, low molecular weight heparins (LMWHs) have found their application in the antithrombotic diseases treatment. These types of drugs are widely used in clinical therapy. Despite the biological and medical importance of LMWHs, they have not been completely characterized in terms of their chemical structure. Due to both, the structural complexity of these anticoagulants and the presence of impurities, their structural characterization requires the employment of advanced analytical techniques. Since separation techniques play the key role in these endeavors, this review will focus on the presentation of recent developments in the separation of LMWH anticoagulants. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Healthcare resources and needs in anticoagulant therapy for patients with nonvalvular atrial fibrillation. SAMOA Study.

PubMed

Barrios, V; Egocheaga-Cabello, M I; Gállego-Culleré, J; Ignacio-García, E; Manzano-Espinosa, L; Martín-Martínez, A; Mateo-Arranz, J; Polo-García, J; Vargas-Ortega, D

2017-05-01

To determine, in the various medical specialties, the healthcare process for anticoagulated patients with nonvalvular atrial fibrillation, to determine the available and necessary resources and to identify potential areas of improvement in the care of these patients. We performed a cross-sectional survey of primary care and specialised physicians involved in the care of anticoagulated patients. The questionnaires referred to the healthcare process, the indication and prescription of anticoagulant therapy and the barriers and deficiencies present for these patients. A total of 893 physicians participated in the study, 437 of whom worked in primary care and 456 of whom were specialists (mostly cardiologists). Forty-two percent of the family doctors indicated that they assessed and prescribed anticoagulant therapy, and 66% performed the regular follow-up of these patients. In both healthcare settings, the physicians noted the lack of standardised protocols. There was also a lack of quality control in the treatment. The role of primary care in managing anticoagulated patients has grown compared with previous reports. The responses of the participating physicians suggest marked gaps in the standardisation of the healthcare process and several areas for improvement in these patients' follow-up. The promotion of training in direct-acting anticoagulant drugs remains pivotal. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI). All rights reserved.

Powder diffraction and crystal structure prediction identify four new coumarin polymorphs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shtukenberg, Alexander G.; Zhu, Qiang; Carter, Damien J.

Coumarin, a simple, commodity chemical isolated from beans in 1820, has, to date, only yielded one solid state structure. Here, we report a rich polymorphism of coumarin grown from the melt. Four new metastable forms were identified and their crystal structures were solved using a combination of computational crystal structure prediction algorithms and X-ray powder diffraction. With five crystal structures, coumarin has become one of the few rigid molecules showing extensive polymorphism at ambient conditions. We demonstrate the crucial role of advanced electronic structure calculations including many-body dispersion effects for accurate ranking of the stability of coumarin polymorphs and themore » need to account for anharmonic vibrational contributions to their free energy. As such, coumarin is a model system for studying weak intermolecular interactions, crystallization mechanisms, and kinetic effects.« less

Powder diffraction and crystal structure prediction identify four new coumarin polymorphs

DOE PAGES

Shtukenberg, Alexander G.; Zhu, Qiang; Carter, Damien J.; ...

2017-05-15

Coumarin, a simple, commodity chemical isolated from beans in 1820, has, to date, only yielded one solid state structure. Here, we report a rich polymorphism of coumarin grown from the melt. Four new metastable forms were identified and their crystal structures were solved using a combination of computational crystal structure prediction algorithms and X-ray powder diffraction. With five crystal structures, coumarin has become one of the few rigid molecules showing extensive polymorphism at ambient conditions. We demonstrate the crucial role of advanced electronic structure calculations including many-body dispersion effects for accurate ranking of the stability of coumarin polymorphs and themore » need to account for anharmonic vibrational contributions to their free energy. As such, coumarin is a model system for studying weak intermolecular interactions, crystallization mechanisms, and kinetic effects.« less

[Advances in the pharmacological study of Morus alba L].

PubMed

Yang, Shuang; Wang, Bao-Lian; Li, Yan

2014-06-01

Morus alba L. (mulberry) is a well-known deciduous tree, belonging to the genus of Morus of Moraceae famlily. Its leaves, twigs, roots (bark) and fruits are widely used in the traditional Chinese medicine. The active constituents of mulberry contained flavonoids, alkaloids, steroids, coumarins, with the significant hypoglycemic, hypolipidemic, antihypertension, anti-oxidation, anti-inflammatory, anti-bacterial, anti-tumor and immunomodulatory activities. This review summarized the research progress of the major pharmacological activity, pharmacokinetics and drug-drug interaction based on CYPs and transporters of mulberry and its active constituents.

Preparation of nanobubbles for ultrasound imaging and intracelluar drug delivery.

PubMed

Wang, Ye; Li, Xiang; Zhou, Yan; Huang, Pengyu; Xu, Yuhong

2010-01-15

Echogenic bubble formulations have wide applications in both disease diagnosis and therapy. In the current study, nanobubbles were prepared and the contrast agent function was evaluated in order to study the nanosized bubble's property for ultrasonic imaging. Coumarin-6 as a model drug was loaded into nanobubbles to investigate the drug delivery potential to cells. The results showed that the nanobubbles composed of 1% of Tween 80, and 3 mg/ml of lipid worked well as an ultrasonic contrast agent by presenting a contrast effect in the liver region in vivo. The drug-loaded nanobubbles could enhance drug delivery to cells significantly, and the process was analyzed by sigmoidally fitting the pharmacokinetic curve. It can be concluded that the nanobubble formulation is a promising approach for both ultrasound imaging and drug delivery enhancing.

[Clinical scores for the risk of bleeding with or without anticoagulation].

PubMed

Junod, Alain

2016-09-14

The assessment of hemorragic risk related to therapeutic anticoagulation is made difficult because of the variety of existing drugs, the heterogeneity of treatment strategies and their duration. Six prognostic scores have been analyzed. For three of them, external validations have revealed a marked decrease in the discrimination power. One British study, Qbleed, based on the data of more than 1 million of ambulatory patients, has repeatedly satisfied quality criteria. Two scores have also studied the bleeding risk during hospital admission for acute medical disease. The development of new and effective anticoagulants with fewer side-effects is more likely to solve this problem than the production of new clinical scores.

Response to warfarin and other oral anticoagulants: effects of disease states.

PubMed

Demirkan, K; Stephens, M A; Newman, K P; Self, T H

2000-05-01

Warfarin is associated with numerous drug and food interactions, and much attention has been appropriately focused on this subject. Because several disease states may also affect response to oral anticoagulants, we present a summary of the literature. We searched MEDLINE for original articles on the effect of disease states on response to warfarin. Liver disease and thyroid dysfunction are well-documented as affecting warfarin response. Further study is needed to establish whether febrile illness, congestive heart failure, and other disease states enhance the effect of warfarin in some patients. Careful monitoring of anticoagulant therapy in patients with diseases that have the potential to affect warfarin response could increase safety and efficacy of this important agent.

Factor XI as a target for antithrombotic therapy

PubMed Central

Bane, Charles E.; Gailani, David

2014-01-01

Anticoagulants currently used in clinical practice to treat thromboembolic disorders are effective but increase the risk of severe bleeding because they target proteins that are essential for normal coagulation (hemostasis). Drugs with better safety profiles are required for prevention and treatment of thromboembolic disease. Coagulation factor XIa has emerged as a novel target for safer anticoagulant therapy because of its role in thrombosis and its relatively small contribution to hemostasis. PMID:24886766

Prescribing Warfarin Appropriately to Meet Patient Safety Goals

PubMed Central

Dharmarajan, Lekshmi; Dharmarajan, T.S.

2008-01-01

The anticoagulant warfarin is increasingly used in a variety of disorders associated with risk of thromboembolism. The drug is undoubtedly effective but is linked to numerous nutrient, disease, and drug interactions; safe use of warfarin therefore necessitates close patient monitoring, using the international normalized ratio. The predominant adverse effect is bleeding, and individuals respond to warfarin in different ways. Both high and subtherapeutic international normalized ratios warrant attention, whereas a high international normalized ratio, with or without bleeding, mandates prompt patient evaluation. The 2008 National Patient Safety Goals require medical institutions to develop processes to ensure the safe use and monitoring of anticoagulant use. Last August, the US Food and Drug Administration revised the prescribing information for warfarin to include genetic testing before initiating therapy, although this is still not covered by most health plans. PMID:25126243

Severe glomerulonephritis complicated by coagulopathy: treatment with anticoaguland and immunosuppresive drugs.

PubMed

Robson, A M; Cole, B R; Kienstra, R A; Kissane, J M; Alkjaersig, N; Fletcher, A P

1977-06-01

Serial determinations, using plasma fibrinogen gel chromatography as well as standard methodology, demonstrated that six children with severe glomerulonephritis, characterized on renal biopsy by glomerular necrosis and crescent formation, had persistent evidence of intravascular coagulation. Based on these observations, therapy with anticoagulants and azathicoagulants and azathioprine was instituted for one year; treatment with anticoagulants was continued for a second year. Anticoagulant therapy was initiated with heparin, followed by oral anticoagulation with phenindione and dipyridamole. In contrast to our earlier experience with similar patients, each of the present patients improved. Urinalyses returned to normal and glomerular filtration rates to near normal values in all patients at the end of the treatment period and have remained so for up to 3.9 years since treatment has been completed. Post-treatment biopsies showed remarkable improvement, with virtually no glomerulosclerosis even in patients who had had a high incidence of glomerular crescents before treatment. It is suggested that the therapeutic regimen favorably influenced the natural history of disease and that plasma fibrinogen chromatographic findings may be helpful in selecting patients likely to benefit from the use of anticoagulant therapy.

Diet as prophylaxis and treatment for venous thromboembolism?

PubMed Central

2010-01-01

Background Both prophylaxis and treatment of venous thromboembolism (VTE: deep venous thrombosis (DVT) and pulmonary emboli (PE)) with anticoagulants are associated with significant risks of major and fatal hemorrhage. Anticoagulation treatment of VTE has been the standard of care in the USA since before 1962 when the U.S. Food and Drug Administration began requiring randomized controlled clinical trials (RCTs) showing efficacy, so efficacy trials were never required for FDA approval. In clinical trials of 'high VTE risk' surgical patients before the 1980s, anticoagulant prophylaxis was clearly beneficial (fatal pulmonary emboli (FPE) without anticoagulants = 0.99%, FPE with anticoagulants = 0.31%). However, observational studies and RCTs of 'high VTE risk' surgical patients from the 1980s until 2010 show that FPE deaths without anticoagulants are about one-fourth the rate that occurs during prophylaxis with anticoagulants (FPE without anticoagulants = 0.023%, FPE while receiving anticoagulant prophylaxis = 0.10%). Additionally, an FPE rate of about 0.012% (35/28,400) in patients receiving prophylactic anticoagulants can be attributed to 'rebound hypercoagulation' in the two months after stopping anticoagulants. Alternatives to anticoagulant prophylaxis should be explored. Methods and Findings The literature concerning dietary influences on VTE incidence was reviewed. Hypotheses concerning the etiology of VTE were critiqued in relationship to the rationale for dietary versus anticoagulant approaches to prophylaxis and treatment. Epidemiological evidence suggests that a diet with ample fruits and vegetables and little meat may substantially reduce the risk of VTE; vegetarian, vegan, or Mediterranean diets favorably affect serum markers of hemostasis and inflammation. The valve cusp hypoxia hypothesis of DVT/VTE etiology is consistent with the development of VTE being affected directly or indirectly by diet. However, it is less consistent with the rationale of using anticoagulants as VTE prophylaxis. For both prophylaxis and treatment of VTE, we propose RCTs comparing standard anticoagulation with low VTE risk diets, and we discuss the statistical considerations for an example of such a trial. Conclusions Because of (a) the risks of biochemical anticoagulation as anti-VTE prophylaxis or treatment, (b) the lack of placebo-controlled efficacy data supporting anticoagulant treatment of VTE, (c) dramatically reduced hospital-acquired FPE incidence in surgical patients without anticoagulant prophylaxis from 1980 - 2010 relative to the 1960s and 1970s, and (d) evidence that VTE incidence and outcomes may be influenced by diet, randomized controlled non-inferiority clinical trials are proposed to compare standard anticoagulant treatment with potentially low VTE risk diets. We call upon the U. S. National Institutes of Health and the U.K. National Institute for Health and Clinical Excellence to design and fund those trials. PMID:20701748

Anticoagulant and Antiplatelet Prescribing Patterns for Patients with Atrial Fibrillation after Percutaneous Coronary Intervention.

PubMed

Woods, Erin A; Ackman, Margaret L; Graham, Michelle M; Koshman, Sheri L; Boswell, Rosaleen M; Barry, Arden R

2016-01-01

Current guidelines recommend triple antithrombotic therapy (TAT), defined as acetylsalicylic acid (ASA), clopidogrel, and warfarin, for patients with nonvalvular atrial fibrillation who have undergone percutaneous coronary intervention with stent implantation. The choice of anticoagulant/antiplatelet therapy in this population is ambiguous and complex, and prescribing patterns are not well documented. To characterize local prescribing patterns for anticoagulant/antiplatelet therapy after percutaneous coronary intervention in patients with nonvalvular atrial fibrillation. A chart review was conducted at a single quaternary cardiology centre. Patients with nonvalvular atrial fibrillation were identified via medical records, and those who underwent percutaneous coronary intervention were identified using a local clinical patient registry. Adult inpatients with nonvalvular atrial fibrillation and a CHADS2 score (based on congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, prior stroke) of 1 or higher who underwent percutaneous coronary intervention from 2011 to 2013 were included. Patients undergoing cardiovascular surgery or transcatheter aortic valve replacement, those with mechanical devices requiring anticoagulation, and those with an allergy to any component of TAT were excluded. Seventy patients were included. The median age was 75 years, and 52 (74%) were men. At discharge, 30 (43%) were receiving TAT and 27 (39%) were receiving dual antiplatelet therapy (clopidogrel and ASA). No patients received the combination of warfarin and clopidogrel. Among those who received TAT, 90% (19 of 21) who received a bare metal stent had a recommended duration of 1 month, and 75% (6 of 8) who received a drug-eluting stent had a recommended duration of 1 year. Direct-acting oral anticoagulants with 2 antiplatelet drugs were prescribed for 9% (6 of 70) of the patients, and 10% (7 of 70) received ticagrelor and ASA with or without warfarin. Overall, the combination of ASA, oral anticoagulant, and P2Y12 inhibitor was used for 54% (38/70) of the patients. Fewer than half of the patients in this study received TAT, and almost 20% received non-evidence-based therapy with a direct-acting oral anticoagulant or ticagrelor, alone or in combination. Despite current guideline recommendations, the rate of TAT utilization was lower than rates reported in the literature.

Clinical and Demographic Characteristics Associated With Suboptimal Primary Stroke and Transient Ischemic Attack Prevention: Retrospective Analysis.

PubMed

Turner, Grace M; Calvert, Melanie; Feltham, Max G; Ryan, Ronan; Finnikin, Samuel; Marshall, Tom

2018-03-01

Primary prevention of stroke and transient ischemic attack (TIA) is important to reduce the burden of these conditions; however, prescribing of prevention drugs is suboptimal. We aimed to identify individual clinical and demographic characteristics associated with potential missed opportunities for prevention therapy with lipid-lowering, anticoagulant, or antihypertensive drugs before stroke/TIA. We analyzed anonymized electronic primary care records from a UK primary care database that covers 561 family practices. Patients with first-ever stroke/TIA, ≥18 years, with diagnosis between January 1, 2009, and December 31, 2013, were included. Missed opportunities for prevention were defined as people with clinical indications for lipid-lowering, anticoagulant, or antihypertensive drugs but not prescribed these drugs before their stroke/TIA. Mixed-effect logistic regression models evaluated the relationship between missed opportunities and individual clinical/demographic characteristics. The inclusion criteria were met by 29 043 people with stroke/TIA. Patients with coronary heart disease, chronic kidney disease, peripheral arterial disease, or diabetes mellitus were at less risk of a missed opportunity for prescription of lipid-lowering and antihypertensive drugs. However, patients with a 10-year cardiovascular disease risk ≥20% but without these diagnoses had increased risk of having a missed opportunity for prescription of lipid-lowering drugs or antihypertensive drugs. Women were less likely to be prescribed anticoagulants but more likely to be prescribed antihypertensive drugs. The elderly (≥85 years of age) were less likely to be prescribed all 3 prevention drugs, compared with people aged 75 to 79 years. Knowing the patient characteristics predictive of missed opportunities for stroke prevention may help primary care identify and appropriately manage these patients. Improving the management of these groups may reduce their risk and potentially prevent large number of future strokes and TIAs in the population. © 2018 American Heart Association, Inc.

Fungi as a source of natural coumarins production.

PubMed

Costa, Tania Maria; Tavares, Lorena Benathar Ballod; de Oliveira, Débora

2016-08-01

Natural coumarins and derivatives are compounds that occur naturally in several organisms (plant, bacteria, and fungi) consisting of fused benzene and α-pyrone rings. These compounds show high technological potential applications in agrochemical, food, pharmaceuticals, and cosmetics industries. Therefore, the need for bulk production of coumarins and the advancement of the chemical and pharmaceutical industries led to the development of synthetic coumarin. However, biotransformation process, synthetic bioengineering, metabolic engineering, and bioinformatics have proven effective in the production of natural products. Today, these biological systems are recognized as green chemistry innovation and business strategy. This review article aims to report the potential of fungi for synthesis of coumarin. These microorganisms are described as a source of natural products capable of synthesizing many bioactive metabolites. The features, classification, properties, and industrial applications of natural coumarins as well as new molecules obtained by basidiomycetes and ascomycetes fungi are reported in order to explore a topic not yet discussed in the scientific literature.

Synthesis and characterization of tunable coumarin- linked glasses as new class of organic/inorganic phosphors

NASA Astrophysics Data System (ADS)

Luridiana, Alberto; Pretta, Gianluca; Secci, Francesco; Frongia, Angelo; Chiriu, Daniele; Carbonaro, Carlo Maria; Corpino, Riccardo; Ricci, Pier Carlo

2014-10-01

It is well known that stilbene with a trans conformation is highly fluorescent. From the viewpoint of molecular structure, coumarins bear a carbon-carbon double bond which is fixed as trans conformation as in trans-stilbene through a lactone structure. This can help to avoid the trans-cis transformation of the double bond under ultraviolet (UV) irradiation as observed in stilbene compounds and results in strong fluorescence and high fluorescence quantum yield and photostability in most of coumarin derivatives. Herein we report some preliminary results about the synthesis and spectroscopic characterization of tunable coumarins and the development of a new linkage protocol for the obtainment of monolayer coumarin-covalently linked glasses. The resulting organic/inorganic coumarin/silica based Self-Assembled Monolayer (SMA) film is proposed as new phosphors for the substituting of critical raw materials, like rare earths, in photonics applications.

Synthesis and characterization of tunable coumarin- linked glasses as new class of organic/inorganic phosphors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Luridiana, Alberto; Pretta, Gianluca; Secci, Francesco

2014-10-21

It is well known that stilbene with a trans conformation is highly fluorescent. From the viewpoint of molecular structure, coumarins bear a carbon-carbon double bond which is fixed as trans conformation as in trans-stilbene through a lactone structure. This can help to avoid the trans-cis transformation of the double bond under ultraviolet (UV) irradiation as observed in stilbene compounds and results in strong fluorescence and high fluorescence quantum yield and photostability in most of coumarin derivatives. Herein we report some preliminary results about the synthesis and spectroscopic characterization of tunable coumarins and the development of a new linkage protocol formore » the obtainment of monolayer coumarin-covalently linked glasses. The resulting organic/inorganic coumarin/silica based Self-Assembled Monolayer (SMA) film is proposed as new phosphors for the substituting of critical raw materials, like rare earths, in photonics applications.« less

Luminescent lanthanide chelates and methods of use

DOEpatents

Selvin, Paul R.; Hearst, John

1997-01-01

The invention provides lanthanide chelates capable of intense luminescence. The celates comprise a lanthanide chelator covalently joined to a coumarin-like or quinolone-like sensitizer. Exemplary sensitzers include 2- or 4-quinolones, 2- or 4-coumarins, or derivatives thereof e.g. carbostyril 124 (7-amino-4-methyl-2-quinolone), coumarin 120 (7-amino-4-methyl-2-coumarin), coumarin 124 (7-amino-4-(trifluoromethyl)-2-coumarin), aminomethyltrimethylpsoralen, etc. The chelates form high affinity complexes with lanthanides, such as terbium or europium, through chelator groups, such as DTPA. The chelates may be coupled to a wide variety of compounds to create specific labels, probes, diagnostic and/or therapeutic reagents, etc. The chelates find particular use in resonance energy transfer between chelate-lanthanide complexes and another luminescent agent, often a fluorescent non-metal based resonance energy acceptor. The methods provide useful information about the structure, conformation, relative location and/or interactions of macromolecules.

Italian intersociety consensus on DOAC use in internal medicine.

PubMed

Prisco, Domenico; Ageno, Walter; Becattini, Cecilia; D'Angelo, Armando; Davì, Giovanni; De Cristofaro, Raimondo; Dentali, Francesco; Di Minno, Giovanni; Falanga, Anna; Gussoni, Gualberto; Masotti, Luca; Palareti, Gualtiero; Pignatelli, Pasquale; Santi, Roberto M; Santilli, Francesca; Silingardi, Mauro; Tufano, Antonella; Violi, Francesco

2017-04-01

The direct oral anticoagulants (DOACs) are drugs used in clinical practice since 2009 for the prevention of stroke or systemic embolism in non-valvular atrial fibrillation, and for the treatment and secondary prevention of venous thromboembolism. The four DOACs, including the three factor Xa inhibitors (rivaroxaban, apixaban and edoxaban) and one direct thrombin inhibitor (dabigatran) provide oral anticoagulation therapy alternatives to Vitamin K antagonists (VKAs). Despite their clear advantages, the DOACs require on the part of the internist a thorough knowledge of their pharmacokinetic and pharmacodynamic characteristics to ensure their correct use, laboratory monitoring and the appropriate management of adverse events. This document represents a consensus paper on the use of DOACs by representatives of three Italian scientific societies: the Italian Society of Internal Medicine (SIMI), the Federation of the Associations of Hospital Managers (FADOI), and the Society for the Study of Haemostasis and Thrombosis (SISET). This document formulates expert opinion guidance for pragmatic managing, monitoring and reversing the anticoagulant effect of DOACs in both chronic and emergency settings. This practical guidance may help the internist to create adequate protocols for patients hospitalized ion internal medicine wards, where patients are often elderly subjects affected by poly-morbidities and renal insufficiency, and, thus, require particular attention to drug-drug interactions and peri-procedural protocols.

Direct-Acting Oral Anticoagulants: Practical Considerations for Emergency Medicine Physicians

PubMed Central

Peacock, W. Frank; Rafique, Zubaid; Singer, Adam J.

2016-01-01

Nonvalvular atrial fibrillation- (NVAF-) related stroke and venous thromboembolism (VTE) are cardiovascular diseases associated with significant morbidity and economic burden. The historical standard treatment of VTE has been the administration of parenteral heparinoid until oral warfarin therapy attains a therapeutic international normalized ratio. Warfarin has been the most common medication for stroke prevention in NVAF. Warfarin use is complicated by a narrow therapeutic window, unpredictable dose response, numerous food and drug interactions, and requirements for frequent monitoring. To overcome these disadvantages, direct-acting oral anticoagulants (DOACs)—dabigatran, rivaroxaban, apixaban, and edoxaban—have been developed for the prevention of stroke or systemic embolic events (SEE) in patients with NVAF and for the treatment of VTE. Advantages of DOACs include predictable pharmacokinetics, few drug-drug interactions, and low monitoring requirements. In clinical studies, DOACs are noninferior to warfarin for the prevention of NVAF-related stroke and the treatment and prevention of VTE as well as postoperative knee and hip surgery VTE prophylaxis, with decreased bleeding risks. This review addresses the practical considerations for the emergency physician in DOAC use, including dosing recommendations, laboratory monitoring, anticoagulation reversal, and cost-effectiveness. The challenges of DOACs, such as the lack of specific laboratory measurements and antidotes, are also discussed. PMID:27293895

Release profile of synthesized coumarin derivatives as a novel antibacterial agent from glass ionomer cement (GIC)

NASA Astrophysics Data System (ADS)

Rahman, Fatimah Suhaily Abdul; Osman, Hasnah; Mohamad, Dasmawati

2017-12-01

Glass ionomer cements (GIC) are widely used as dental restorative materials due to their aesthetics features and fluoride content. However, a capability of fluoride content in GIC to inhibit bacteria growth in an oral environment was insufficient for a long term which may lead to secondary caries. Therefore, two types of synthesized coumarin derivatives were incorporated with GIC to act as new antibacterial agent. However prior to the antibacterial evaluation, this study investigated the release profile of GIC incorporated with 3-Acetylcoumarin (GIC-1) and hydrazinyl thiosemicarbazide of coumarin derivatives (GIC-2) at three different concentrations of 0.5, 1.0 and 1.5 wt% up to 30 days. At early incubation period, GIC-1 revealed a higher release profile at 0.5 % fabrication that reached almost 45 % of cumulative release for 8 hours observational. Meanwhile, a slightly different output was obtained for GIC-2 in which 1.0 % fabrication of coumarin gave a better release in the initial hour. However, the pattern was replaced by 0.5 % substitution after 4 hours incubation time. A substitution of 1.5 % coumarin seems to be low in releasing activity for all materials. Conversely, in a longer period 1.0 % fabrication was discovered to be the highest coumarin release among others fabrications for both materials. Filler particle size and porosity of the materials were considered to be the main factor that may affect the coumarin release. Nonetheless, both synthesized coumarin derivatives can be incorporated with GIC as their release profile look very promising. Ultimately, the coumarin derivatives could improve the properties of GIC.

Reduced Anticoagulant Effect of Dabigatran in a Patient Receiving Concomitant Phenytoin.

PubMed

Wiggins, Barbara S; Northup, Amanda; Johnson, Dominic; Senfield, Jeffrey

2016-02-01

Dabigatran, a direct thrombin inhibitor, is an oral anticoagulant indicated for the prevention of stroke in patients with atrial fibrillation (AF) and for the treatment and prevention of deep vein thrombosis and pulmonary embolism. Dabigatran, as well as the other new anticoagulants-rivaroxaban, apixaban, and edoxaban-are substrates for P-glycoprotein (P-gp). Although the U.S. labeling for rivaroxaban and apixaban states to avoid concomitant use with phenytoin, a known P-gp inducer, the U.S. labeling for dabigatran and edoxaban are less clear. We describe the first case report, to our knowledge, documenting a drug interaction between phenytoin and dabigatran by using laboratory measurements of dabigatran serum concentrations. A 45-year-old African-American man was admitted to the inpatient cardiology service following defibrillations from his implantable cardioverter defibrillator. The patient was evaluated and received appropriate antitachycardia pacing for atrial tachyarrhythmias for an episode of ventricular tachycardia (VT), and antiarrhythmic therapy with sotalol was initiated to reduce both his AF and VT burden. On review of the patient's medications for potential interactions, it was discovered that the patient was taking both dabigatran and phenytoin. To determine the magnitude of this drug interaction prior to making a change in his anticoagulation regimen, a dabigatran serum concentration was measured. This concentration was undetectable, indicating that phenytoin had a significant influence on dabigatran's metabolism and that this patient was at high risk for stroke. Clinicians should be aware of this interaction between phenytoin and dabigatran as well as with all other new oral anticoagulants. In patients taking phenytoin who require an anticoagulant, only warfarin should be prescribed to minimize the risk of stroke. In addition, the prescribing information for dabigatran should be updated to include other medications that result in a significant reduction in dabigatran serum concentrations, such as phenytoin. © 2016 Pharmacotherapy Publications, Inc.

Photodimerisation of a coumarin-dipeptide gelator.

PubMed

Draper, Emily R; McDonald, Tom O; Adams, Dave J

2015-08-18

Here we report a coumarin based hydrogelator that can form bulk gels, or homogeneous thin gels via an electrochemical pH drop. The gel can then be strengthened by post-gelation photodimerisation of the coumarin groups by irradiating with UV light.

New oral anticoagulants: their advantages and disadvantages compared with vitamin K antagonists in the prevention and treatment of patients with thromboembolic events.

PubMed

Mekaj, Ymer H; Mekaj, Agon Y; Duci, Shkelzen B; Miftari, Ermira I

2015-01-01

Despite the discovery and application of many parenteral (unfractionated and low-molecular-weight heparins) and oral anticoagulant vitamin K antagonist (VKA) drugs, the prevention and treatment of venous and arterial thrombotic phenomena remain major medical challenges. Furthermore, VKAs are the only oral anticoagulants used during the past 60 years. The main objective of this study is to present recent data on non-vitamin K antagonist oral anticoagulants (NOACs) and to analyze their advantages and disadvantages compared with those of VKAs based on a large number of recent studies. NOACs are novel direct-acting medications that are selective for one specific coagulation factor, either thrombin (IIa) or activated factor X (Xa). Several NOACs, such as dabigatran (a direct inhibitor of FIIa) and rivaroxaban, apixaban and edoxaban (direct inhibitors of factor Xa), have been used for at least 5 years but possibly 10 years. Unlike traditional VKAs, which prevent the coagulation process by suppressing the synthesis of vitamin K-dependent factors, NOACs directly inhibit key proteases (factors IIa and Xa). The important indications of these drugs are the prevention and treatment of deep vein thrombosis and pulmonary embolisms, and the prevention of atherothrombotic events in the heart and brain of patients with acute coronary syndrome and atrial fibrillation. They are not fixed, and dose-various strengths are available. Most studies have reported that more advantages than disadvantages for NOACs when compared with VKAs, with the most important advantages of NOACs including safety issues (ie, a lower incidence of major bleeding), convenience of use, minor drug and food interactions, a wide therapeutic window, and no need for laboratory monitoring. Nonetheless, there are some conditions for which VKAs remain the drug of choice. Based on the available data, we can conclude that NOACs have greater advantages and fewer disadvantages compared with VKAs. New studies are required to further assess the efficacy of NOACs.

New oral anticoagulants: their advantages and disadvantages compared with vitamin K antagonists in the prevention and treatment of patients with thromboembolic events

PubMed Central

Mekaj, Ymer H; Mekaj, Agon Y; Duci, Shkelzen B; Miftari, Ermira I

2015-01-01

Despite the discovery and application of many parenteral (unfractionated and low-molecular-weight heparins) and oral anticoagulant vitamin K antagonist (VKA) drugs, the prevention and treatment of venous and arterial thrombotic phenomena remain major medical challenges. Furthermore, VKAs are the only oral anticoagulants used during the past 60 years. The main objective of this study is to present recent data on non-vitamin K antagonist oral anticoagulants (NOACs) and to analyze their advantages and disadvantages compared with those of VKAs based on a large number of recent studies. NOACs are novel direct-acting medications that are selective for one specific coagulation factor, either thrombin (IIa) or activated factor X (Xa). Several NOACs, such as dabigatran (a direct inhibitor of FIIa) and rivaroxaban, apixaban and edoxaban (direct inhibitors of factor Xa), have been used for at least 5 years but possibly 10 years. Unlike traditional VKAs, which prevent the coagulation process by suppressing the synthesis of vitamin K-dependent factors, NOACs directly inhibit key proteases (factors IIa and Xa). The important indications of these drugs are the prevention and treatment of deep vein thrombosis and pulmonary embolisms, and the prevention of atherothrombotic events in the heart and brain of patients with acute coronary syndrome and atrial fibrillation. They are not fixed, and dose-various strengths are available. Most studies have reported that more advantages than disadvantages for NOACs when compared with VKAs, with the most important advantages of NOACs including safety issues (ie, a lower incidence of major bleeding), convenience of use, minor drug and food interactions, a wide therapeutic window, and no need for laboratory monitoring. Nonetheless, there are some conditions for which VKAs remain the drug of choice. Based on the available data, we can conclude that NOACs have greater advantages and fewer disadvantages compared with VKAs. New studies are required to further assess the efficacy of NOACs. PMID:26150723

Highlighting the effects of coumarin on adult plants of Arabidopsis thaliana (L.) Heynh. by an integrated -omic approach.

PubMed

Araniti, Fabrizio; Scognamiglio, Monica; Chambery, Angela; Russo, Rosita; Esposito, Assunta; D'Abrosca, Brigida; Fiorentino, Antonio; Lupini, Antonio; Sunseri, Francesco; Abenavoli, Maria Rosa

2017-06-01

In this study, the effects of the allelochemical coumarin through a metabolomic, proteomic and morpho-physiological approach in Arabidopsis adult plants (25days old) were investigated. Metabolomic analysis evidenced an increment of amino acids and a high accumulation of soluble sugars, after 6days of coumarin treatment. This effect was accompanied by a strong decrease on plant fresh and dry weights, as well as on total protein content. On the contrary, coumarin did not affect leaf number but caused a reduction in leaf area. An alteration of water status was confirmed by a reduction of relative water content and an increase in leaf osmotic potential. Moreover, coumarin impaired plant bio-membranes through an increase of lipid peroxidation and H 2 O 2 content suggesting that coumarin treatment might induce oxidative stress. Coumarin reduced the effective quantum yield of the photosystem II, the energy dissipation in the form of heat, the maximum PSII efficiency, the coefficient of the photochemical quenching and the estimated electron transport rate, while it significantly stimulated the fluorescence emission and the coefficient of the non photochemical quenching. Finally, the proteomic characterization of coumarin-treated plants revealed a down-regulation of the ROS detoxifying proteins, responsible of oxidative damage and consequently of physiological cascade effects. Copyright © 2017 Elsevier GmbH. All rights reserved.

[Prevention and treatment of venous thromboembolism: the place of new oral anticoagulants].

PubMed

Reis, Abílio

2012-04-01

Venous thromboembolism (VTE) is still an important problem of Public Health, due to its impact in terms of morbidity, mortality, resource allocation and associated costs. In the prevention and treatment of VTE, pharmacological therapy is well defined and efficacious but has some inconveniences that leave space for improvement. Several new oral anticoagulants are being developed and tested for the prevention and treatment of VTE. The better studied are the selective Factor Xa inhibitors apixaban, rivaroxaban and edoxaban, and the thrombin antagonist dabigatran. They all are orally administrated, don't have important interactions with food or other drugs, have a convenient fixed-dose regimen and a predictable action, and dispense routine monitoring of their anticoagulant effect. The major part of them has phase III studies concluded and published. Some of them are already approved by de European Medicines Agency (EMA) and the Food and Drug Administration (FDA) and recommended by the international guidelines. Rivaroxaban is approved by the EMA for the treatment of deep venous thrombosis (DVT) and for the prevention of recurrences of DVT and pulmonary embolism. In this article the available evidences are reviewed, the place of the new oral anticoagulants is discussed and future perspectives regarding the prevention and treatment of VTE are outlined. Copyright © 2012 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.

Interaction of cruciferin-based nanoparticles with Caco-2 cells and Caco-2/HT29-MTX co-cultures.

PubMed

Akbari, Ali; Lavasanifar, Afsaneh; Wu, Jianping

2017-12-01

The objective of this work was to assess the potential of Cruciferin/Calcium (Cru/Ca) and Cruciferin/Chitosan (Cru/Cs) nanoparticles for oral drug delivery. For this purpose, Cru/Ca and Cru/Cs nanoparticles were developed through cold gelation of Cruciferin, a major canola protein, and in interaction with calcium and chitosan, respectively. The extent and rate of particle uptake in Caco-2 cells and Caco-2/HT29 co-culture was then evaluated by fluorescence spectroscopy as well as flow cytometry. Through pre-incubation of Caco-2 cell monolayer with specific endocytosis inhibitors, the mechanism of cell uptake was investigated. Our results showed that the uptake of negatively-charged Cru/Ca particles to be ∼3 times higher than positively-charged Cru/Cs ones by Caco-2 cells. Presence of mucus secreted by HT29 cells in their co-culture with Caco-2 had negligible influence on the uptake and transport of both particles. In contrast to Cru/Ca particles which were dissociated in the simulated gastrointestinal conditions, digestion of Cru/Cs particles resulted in 6- and 2-fold increase in the cellular uptake and transport of encapsulated coumarin in the latter particles, respectively. While the presence of mucus in Caco-2/HT29 co-culture caused 40-50% decrease of cellular uptake and transport for coumarin encapsulated in digested Cru/Cs particles, it had no significant effect on the cell uptake and transport of coumarin associated with Cru/Ca particles after digestion. Energy-dependent mechanisms were the dominant mechanism for uptake of both undigested and digested particles. Therefore, in Caco-2/HT29 co-culture which closely simulated intestinal epithelial cells, undigested Cru/Ca and Cru/Cs particles had the ability to penetrate mucus layers, while digested Cru/Cs particles showed mucoadhesive property, and digested Cru/Ca particles were dissociated. Our results points to a potential for cruciferin based nanoparticles for oral drug delivery. The long-term objective of this research is to investigate the potential of edible and safe biopolymer in enhanced oral delivery of drugs and/or vaccines. Here, we investigated the potential application of nanoparticles based on a protein extracted from Canola seeds, i.e., cruciferin, for oral delivery of a model small molecule, i.e., coumarin, through cells representing gastrointestinal epithelium, Caco-2 and Caco-2/HT29 cell monolayer. This study was completed for intact cruciferin nanoparticles and cruciferin coated chitosan nanoparticles, before and after digestion with gastric or intestine simulating fluids. This comparison was useful to understand the fate the cruciferin based particles in digestive mucosal tissues and their potential mucoadhesive and/or mucus-penetrating property. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Rivaroxaban in the treatment of venous thromboembolism and the prevention of recurrences: a practical approach.

PubMed

Arcelus, Juan I; Domènech, Pere; Fernández-Capitan, Ma Del Carmen; Guijarro, Ricardo; Jiménez, David; Jiménez, Sonia; Lozano, Francisco S; Monreal, Manel; Nieto, José A; Páramo, José A

2015-05-01

Anticoagulation therapy is the standard treatment of patients with symptomatic venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism. Until recently, treatment of VTE was based on parenteral or low-molecular-weight heparin for initial therapy (5-10 days) and oral vitamin K antagonists for long-term therapy. Those treatments have some limitations, including parenteral administration (heparins), the need for frequent monitoring and dose adjustments, interactions with several medications, and dietary restrictions (vitamin K antagonists). Rivaroxaban is a new oral direct factor Xa inhibitor with a wide therapeutic window, predictable anticoagulant effect, no food interactions, and few drug interactions. Consequently, no periodic monitoring of anticoagulation is needed, and fixed doses can be prescribed. EINSTEIN program demonstrated that rivaroxaban was as effective as and significantly safer than standard therapy for treatment of VTE. Rivaroxaban was recently authorized so doubts exist about how to use it in daily clinical practice. This document aims to clarify common questions formulated by clinicians regarding the use of this new drug. © The Author(s) 2014.

Assessment of healthcare professionals' knowledge about warfarin-vitamin K drug-nutrient interactions.

PubMed

Couris, R R; Tataronis, G R; Dallal, G E; Blumberg, J B; Dwyer, J T

2000-08-01

Dietary vitamin K can interact with oral anticoagulant drugs and interfere with their therapeutic safety and efficacy. Therefore, knowledge about drug-nutrient interactions involving vitamin K possessed by physicians, pharmacists, dietitians and nurses practicing anticoagulant therapy was assessed. Healthcare practitioners were surveyed using a 30-question, 98-item questionnaire on the most common and/or important food interactions with warfarin, drug interactions with warfarin and general drug-nutrient interactions involving vitamin K. The study sample included 160 randomly selected healthcare providers (40 physicians, pharmacists, dietitians and nurses) from 10 hospitals with 200 to 1000 beds from six Massachusetts regions. Random selection was conducted from a pool of selected healthcare providers practicing anticoagulant therapy who counsel patients receiving warfarin. All surveys were completed within three months of the start of the study, and all participants provided usable data for statistical analysis. The mean scores (+/- SD) on the overall test were 72.5+/-9.0 for pharmacists, 62.51+/-10.6 for physicians, 56.9+/-8.8 for dietitians and 50.2+/-9.3 for nurses, with 100 being a perfect score. Pharmacists scored significantly higher in the area of drug interactions (75.9+/-11.3, p<0.05). Dietitians scored higher in the area of food interactions (73.0+/-10.3). No significant differences between physicians and pharmacists were evident on general drug-nutrient interactions. While over 87% of the healthcare professionals correctly identified some common foods containing large amounts of vitamin K, such as broccoli and spinach, fewer than 25% were able to identify others such as pea soup, coleslaw and dill pickles. Although the healthcare professionals surveyed in this study appear to have demonstrated some proficiency in their respective areas of expertise, they exhibited less knowledge in others. Therefore, additional training and integration of knowledge and expertise about drug-nutrient interactions among healthcare professionals are essential to provide appropriate patient counseling and optimal therapeutic outcomes.

Simple and rapid assay for effect of the new oral anticoagulant (NOAC) rivaroxaban: preliminary results support further tests with all NOACs

PubMed Central

2014-01-01

Background New oral anticoagulant (NOAC) drugs are known to influence the results of some routine hemostasis tests. Further data are needed to enable routine assessment of the effects of NOAC on clotting parameters in some special circumstances. Methods Following administration of rivaroxaban to patients, at the likely peak and trough activity times, we assessed the effects on prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), and clotting time using Russell’s viper venom, and in the presence of phospholipids and calcium reagent available as DVVreagent® and DVVconfirm®. The data were used to determine an adequate NOAC plasma level based on anticoagulant activities expressed as a ratio (patients/normal, R-C). Results DVVconfirm as R-C could be rapidly performed, and the results were reasonably sensitive for rivaroxaban and probably for other FX inhibitors. This assay is not influenced by lupus anticoagulant and heparin, does not require purified NOAC as control, and will measure whole-plasma clotting activity. Conclusions We propose a cut-off R-C value of 4.52 ± 0.33 for safety, but clinical studies are needed to establish whether this cut-off is useful for identifying patients at increased risk of hemorrhage or exhibiting low anticoagulation effect. It also seems possible that normal R-C could indicate an absence of anticoagulant activity when rivaroxaban is discontinued due to episodes of uncontrolled bleeding during anticoagulation or for emergency surgery. PMID:24656069

Direct Oral Anticoagulants: An Overview for the Interventional Radiologist

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kumar, Pradesh, E-mail: pradeshkumar@doctors.org.uk; Ravi, Rajeev, E-mail: rajeev.ravi@aintree.nhs.uk; Sundar, Gaurav, E-mail: gaurav.sundar@aintree.nhs.uk

The direct oral anticoagulants (DOACs) have emerged as a good alternative for the treatment of thromboembolic diseases, and their use in clinical practice is increasing rapidly. The DOACs act by blocking the activity of one single step in the coagulation cascade. These drugs act downstream in the common pathway of the coagulation cascade by directly antagonising the action of thrombin or factor Xa. The development of DOACs represents a paradigm shift from the oral vitamin K antagonists such as warfarin. This article aims to describe the properties of the currently available DOACs including pharmacology and dosing. We also address themore » strategies for periprocedural management and reversal of anticoagulation of patients treated with these agents.« less

Role of Pharmacogenomics in the Management of Traditional and Novel Oral Anticoagulants

PubMed Central

Cavallari, Larisa H.; Shin, Jaekyu; Perera, Minoli A.

2013-01-01

Warfarin is the most commonly prescribed oral anticoagulant. However, it remains a difficult drug to manage mostly because of its narrow therapeutic index and wide interpatient variability in anticoagulant effects. Over the past decade, there has been substantial progress in our understanding of genetic contributions to variable warfarin response, particularly with regard to warfarin dose requirements. The genes encoding for cytochrome P450 (CYP) 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) are the major genetic determinants of warfarin pharmacokinetics and pharmacodynamics, respectively. Numerous studies have demonstrated significant contributions of these genes to warfarin dose requirements. The CYP2C9 gene has also been associated with bleeding risk with warfarin. The CYP4F2 gene influences vitamin K availability and makes minor contributions to warfarin dose requirements. Less is known about genes influencing warfarin response in African-American patients compared with other racial groups, but this is the focus of ongoing research. Several warfarin pharmacogenetic dosing algorithms and United States Food and Drug Administration–cleared genotyping tests are available for clinical use. Clinical trials are ongoing to determine the clinical utility and cost-effectiveness of genotype-guided warfarin dosing. Results from these trials will likely influence clinical uptake and third party payer reimbursement for genotype-guided warfarin therapy. There is still a lack of pharmacogenetic data for the newly approved oral anticoagulants, dabigatran and rivaroxaban, and with other oral anticoagulants in the research and development pipeline. These data, once known, could be of great importance as routine monitoring parameters for these agents are not available. PMID:22122181

[Consensus statement: Management of oral anticoagulation for stroke prevention in patients with nonvalvular atrial fibrillation].

PubMed

Helms, Thomas Maria; Silber, Sigmund; Schäfer, Andreas; Masuhr, Florian; Palm, Frederick; Darius, Harald; Schrör, Karsten; Bänsch, Dietmar; Bramlage, Peter; Hankowitz, Johannes; Karle, Christoph A; Stargardt, Tom; Weil, Joachim; Geller, Johann Christoph

2016-09-01

With the introduction of edoxaban last year in Germany, four nonvitamin K antagonist oral anticoagulants are now available for stroke prevention in patients with nonvalvular atrial fibrillation. These novel oral anticoagulants (NOAC) represent an attractive new option compared to vitamin K antagonists (e.g., warfarin or phenprocoumon) due to simple use and fewer interactions with other drugs or food. Therefore, no INR monitoring and dosage adjustments are required for NOAC. The compelling clinical advantage of NOAC is the dramatic risk reduction of hemorhagic stroke and intracranial bleeding compared to current standard. In addition, total mortality is significantly reduced by 10 %. These effects are demonstrated for all four NOAC (dabigatran, rivaroxaban, apixaban and edoxaban). Therefore, current national and international guidelines recommend NOAC as the preferred option or at least as an attractive alternative compared to the former standard of vitamin K antagonists. The economic impact and reimbursement by Statutory Health Insurance (GKV) is of major importance for treatment in an outpatient setting. For apixaban and edoxaban, an additional benefit was granted by the institution of G‑BA and IQWiG in this clinical setting, whereas dabigatran and rivaroxaban were not assessed due to market entrance prior to 2011 before the AMNOG procedure was initiated. The members of this consensus paper recommend NOAC as the preferred option for patients with nonvalvular atrial fibrillation who are currently not treated with anticoagulant drugs in spite of clear indication for anticoagulation. For new patients with nonvalvular fibrillation, it should be decided on an individual basis which treatment option is adequate for the patient with their respective comorbidities.

Assessment of anticoagulation treatments in non-valvular atrial fibrillation patients diagnosed in a basic health area.

PubMed

Aguilera Alcaraz, Beatriz M; Abellán Huerta, José; Carbayo Herencia, Julio Antonio; Ariza Copado, Consuelo; Hernández Menárguez, Fernando; Abellán Alemán, José

Atrial fibrillation (AF) is the most common cardiac arrhythmia. To assess the need for anticoagulation is essential for its management. Our objective was to investigate whether the indication of anticoagulation was adequate in patients diagnosed with non-valvular AF, given the CHA2-DS2-VASc scale, measuring the International Normalizad Ratio range (INR) in patients treated with anti-vitamin K drugs. This is an observational and cross sectional study. 232 patients with atrial fibrillation were included. We analyzed demographic, the CHA2-DS2-VASc and HAS-BLED variables, the treatment and INR values for 6 consequentive months. The confrontation of variables was performed using chi-square and Mantel-Haenzel test. The prevalence of AF was 1.05%. The 88.4% had CHA2-DS2-VASc ≥ 2. The 71.1% were taking anticoagulants, of which 58.2% were under antivitamin k. The 46.7% of patients taking antivitamin K, presented inadequate range of INR. There was a greater prescription of antivitamin k in patients with persistent or permanent AF compared to the paroxysmal form (62.8 vs. 37.2% p<.001). The use of drugs that increase bleeding was associated with a worse control of INR after adjustment for the main variables of clinical relevance (odds ratio 2.17 [1.02-4.59], p=.043). The level of anticoagulation with antivitamin K was inadequate in our sample, despite a proper follow up and adherence to treatment. Patients with paroxysmal AF received less antivitamin K than those with persistent/permanent AF. Copyright © 2017 Sociedad Española de Arteriosclerosis. Publicado por Elsevier España, S.L.U. All rights reserved.

Two new coumarins from Micromelum falcatum with cytotoxicity and brine shrimp larvae toxicity.

PubMed

Luo, Xiongming; He, Weihong; Yin, Hao; Li, Qingxin; Liu, Qiao; Huang, Yongzhong; Zhang, Si

2012-06-06

Two new coumarins, 7-methoxy-8-(2-hydroxmethyl-1-O-isovaleryl-4-butenyl)-coumarin (1) and 7-methoxy-8-(1-hydroxy-2-O-β-glucopyranosyl-3-methyl-4-butene-1-yl)coumarin (2), and twelve known coumarins 3-14 were isolated from the stem bark of Micromelum falcatum. The structures of compounds 1-14 were elucidated by extensive spectroscopic data analyses. The toxicity of compounds 1-14 was tested using a brine shrimp assay and in vitro antiproliferative assay against mammary cancer (F10) and lung cancer (HvEvc) cell lines by the MTT method. Some compounds had moderate activities. All compounds were also tested against the microorganisms Bacillus subtilis, Bacillus thuringiensis and Escherichia coli, but no activity was observed.

Extraction and quantitation of coumarin from cinnamon and its effect on enzymatic browning in fresh apple juice: a bioinformatics approach to illuminate its antibrowning activity.

PubMed

Thada, Rajarajeshwari; Chockalingam, Shivashri; Dhandapani, Ramesh Kumar; Panchamoorthy, Rajasekar

2013-06-05

Enzymatic browning by polyphenoloxidase (PPO) affects food quality and taste in fruits and vegetables. Thus, the study was designed to reduce browning in apple juice by coumarin. The ethanolic extract of cinnamon was prepared and its coumarin content was quantitated by HPLC, using authentic coumarin (AC) as standard. The effect of cinnamon extract (CE) and AC on enzymatic browning, its time dependent effects, and the specific activity of PPO and peroxidase (POD) were studied in apple juice. The docking of coumarin with PPO and POD was also performed to elucidate its antibrowning mechanism. The CE (73%) and AC (82%) showed better reduction in browning, maintained its antibrowning effect at all time points, and significantly (p < 0.05) reduced the specific activity of PPO and POD when compared with controls. Coumarin showed strong interaction with binding pockets of PPO and POD, suggesting its potential use as inhibitor to enzyme mediated browning in apple juice.

Novel coumarins and related copper complexes with biological activity: DNA binding, molecular docking and in vitro antiproliferative activity.

PubMed

Pivetta, Tiziana; Valletta, Elisa; Ferino, Giulio; Isaia, Francesco; Pani, Alessandra; Vascellari, Sarah; Castellano, Carlo; Demartin, Francesco; Cabiddu, Maria Grazia; Cadoni, Enzo

2017-12-01

Coumarins show biological activity and are widely exploited for their therapeutic effects. Although a great number of coumarins substituted by heterocyclic moieties have been prepared, few studies have been carried out on coumarins containing pyridine heterocycle, which is known to modulate their physiological activities. We prepared and characterized three novel 3-(pyridin-2-yl)coumarins and their corresponding copper(II) complexes. We extended our investigations also to three known similar coumarins, since no data about their biochemical activity was previously been reported. The antiproliferative activity of the studied compounds was tested against human derived tumor cell lines and one human normal cell line. The DNA binding constants were determined and docking studies with DNA carried out. Selected Quantitative Structure-Activity Relationship (QSAR) descriptors were calculated in order to relate a set of structural and topological descriptors of the studied compounds to their DNA interaction and cytotoxic activity. Copyright © 2017 Elsevier Inc. All rights reserved.

Solvatochromic benzo[h] coumarins: Synthesis, solvatochromism, NLO and DFT study

NASA Astrophysics Data System (ADS)

Warde, Umesh; Sekar, Nagaiyan

2017-10-01

Three benzo[h] coumarins were synthesized and analyzed for their potential NLOphoric properties. Coumarins were synthesized using Knoevenagel condensation method by reacting hydroxyl-naphthalene aldehyde with cyano-methylelene-benzazoles containing NH, O and S elements respectively as the active methylene compounds. The absorption maxima for the coumarins are not affected by the solvent polarity but emission maxima does. Emission solvatochromism was analyzed using various solvent polarity functions which highlights the polarity dependency of the emission profile. Coumarins showed satisfactory values for first and second hyperpolarizability which are comparable using solvatochromism and DFT. NLO properties are also compared with the limits of hyperpolarizability calculated using sum rule of quantum mechanics. Results show that the NLO properties predicted by DFT are close to the upper limits of hyperpolarizability. The functional CAM-B3LYP is proven to be suitable for predicting NLO properties for these coumarins compared to functional B3LYP. The present study highlights the importance of such molecules for incorporating in advanced NLOphores.

A comparison of US and Norwegian regulation of coumarin in tobacco products

PubMed Central

Givel, M

2003-01-01

Objective: This paper examines policy processes regarding why the USA and Norway have not regulated coumarin in tobacco. Design: A qualitative analysis of all tobacco industry documents regarding coumarin since the 1950s from the 1998 US Master Settlement Agreement and subsequent legal settlements. Additional data were collected from newspaper reports, general internet search engines, journal articles, scholarly reports, court cases, statutes, regulations, and informal correspondence with tobacco control experts in Norway. Main outcome measure: An overview, summary, and analysis of all documents related to coumarin. Results: In the USA from 1954 until 1985 when coumarin was reportedly removed from domestic cigarettes, but not from pipe tobacco until 1996, and not at all from imported Indian bidi cigarettes, regulatory efforts were stymied. In Norway, from 1973 to the present, the tobacco industry has never disclosed whether its tobacco products contain coumarin. In both the USA and Norway, the extreme delay and lack of vigorous evidence gathering and significant remedies were caused by tobacco industry assertions that revealing tobacco additives was a violation of trade secrets, and by weak regulatory authority and efforts to regulate coumarin. Conclusion: Vigorous and expeditious regulatory investigations and remedies for harmful additives in tobacco, such as coumarin, can protect the public health. Astute insider and outsider political advocacy by health advocates is required to hold elected officials and civil servants publicly accountable for failing to enact disclosure laws and to engage in effective regulatory efforts. PMID:14660776

Preparation of magnetic and pH-responsive chitosan microcapsules via sonochemical method.

PubMed

Xu, Fengzhi; Zhao, Tianqi; Wang, Shurong; Liu, Songfeng; Yang, Ting; Li, Zhanfeng; Wang, Hongyan; Cui, Xuejun

2016-01-01

Magnetic and pH-responsive chitosan microcapsules (MPRCMCs) were prepared by a simple sonochemical method. Superparamagnetic oleic acid modified Fe3O4 nanoparticles (OA-Fe3O4 NPs) and hydrophobic drugs could be directly loaded into MPRCMCs during sonication. The obtained microcapsules had a well-defined spherical morphology with the average size of 2 μm. The microcapsules showed an excellent magnetic property. In addition, the pH-responsive controlled release of coumarin 6 (C6) from MPRCMCs indicated that the developed microcapsules could be a promising candidate for drugs carriers.

Cardiac arrest due to left circumflex coronary artery embolism as a complication of subtherapeutic oral anticoagulation in a patient with mitral and aortic mechanical valve prostheses

PubMed Central

Protasiewicz, Marcin; Gajek, Jacek; Mysiak, Andrzej

2013-01-01

We report a case of a 65-year-old female patient after replacement of aortic and mitral valve with mechanical prostheses and implantation of a pacemaker hospitalized in our clinic due to acute coronary syndrome complicated with cardiac arrest due to ventricular fibrillation. The electrocardiogram performed on admission showed signs of myocardial infarction with concomitant ventricular pacing. After successful resuscitation the coronary angiography was performed, which showed occlusion of the left circumflex artery (LCx) by thrombus. On the basis of intravascular ultrasound imaging the presence of vulnerable plaque, parietal thrombus and dissection of LCx were excluded. It suggested that occlusion of the LCx resulted from its embolism by left-sided heart thrombus due to subtherapeutic oral anticoagulation. In this case suboptimal anticoagulation was partially iatrogenic. Two weeks before the patient had been given vitamin K intravenously due to indeterminable international normalized ratio (INR) level, which caused transient resistance to oral anticoagulants. This case report illustrates tragic difficulties in the treatment with vitamin K antagonists, which concern as many as 2/3 of anticoagulated patients. These troubles contributed to the search for new, more efficient and safer anticoagulants. There are two classes of new oral anticoagulant drugs, which do not require monitoring of coagulation: direct thrombin inhibitors (e.g. dabigatran) and factor Xa inhibitors (e.g. rivaroxaban). In spite of their proven efficacy in the prevention of ischaemic stroke related to atrial fibrillation and prevention or treatment of deep vein thrombosis and pulmonary embolism, the use of new oral anticoagulants for the treatment of patients with mechanical valve prostheses needs further research. PMID:24570697

Cardiac arrest due to left circumflex coronary artery embolism as a complication of subtherapeutic oral anticoagulation in a patient with mitral and aortic mechanical valve prostheses.

PubMed

Protasiewicz, Marcin; Rojek, Aleksandra; Gajek, Jacek; Mysiak, Andrzej

2013-01-01

We report a case of a 65-year-old female patient after replacement of aortic and mitral valve with mechanical prostheses and implantation of a pacemaker hospitalized in our clinic due to acute coronary syndrome complicated with cardiac arrest due to ventricular fibrillation. The electrocardiogram performed on admission showed signs of myocardial infarction with concomitant ventricular pacing. After successful resuscitation the coronary angiography was performed, which showed occlusion of the left circumflex artery (LCx) by thrombus. On the basis of intravascular ultrasound imaging the presence of vulnerable plaque, parietal thrombus and dissection of LCx were excluded. It suggested that occlusion of the LCx resulted from its embolism by left-sided heart thrombus due to subtherapeutic oral anticoagulation. In this case suboptimal anticoagulation was partially iatrogenic. Two weeks before the patient had been given vitamin K intravenously due to indeterminable international normalized ratio (INR) level, which caused transient resistance to oral anticoagulants. This case report illustrates tragic difficulties in the treatment with vitamin K antagonists, which concern as many as 2/3 of anticoagulated patients. These troubles contributed to the search for new, more efficient and safer anticoagulants. There are two classes of new oral anticoagulant drugs, which do not require monitoring of coagulation: direct thrombin inhibitors (e.g. dabigatran) and factor Xa inhibitors (e.g. rivaroxaban). In spite of their proven efficacy in the prevention of ischaemic stroke related to atrial fibrillation and prevention or treatment of deep vein thrombosis and pulmonary embolism, the use of new oral anticoagulants for the treatment of patients with mechanical valve prostheses needs further research.

Aspirin in stroke prevention in nonvalvular atrial fibrillation and stable vascular disease: an era of new anticoagulants.

PubMed

Turagam, Mohit K; Velagapudi, Poonam; Leal, Miguel A; Kocheril, Abraham G

2012-04-01

Atrial fibrillation (AF) is a major cause of ischemic stroke, especially in the elderly. There are currently enough data to support the notion that anticoagulation with warfarin or dabigatran is far superior to aspirin in the prevention of stroke or systemic embolism in AF. Aspirin is the preferred modality in patients who are either not candidates for anticoagulation, such as patients with increased risk for bleeding, low-risk patients based on the CHADS2 score or patients who have difficulty in maintaining a therapeutic international normalized ratio. There is no dispute on the recommendations regarding stroke prevention in high-risk patients (CHADS2 risk score of 2 and beyond) with AF. However, there is some controversy regarding the appropriate strategy (anticoagulation vs aspirin) for stroke prevention in low-risk patients (CHA2DS2-VASc score of 0-1). Novel oral anticoagulant drugs (direct thrombin inhibitors and Factor Xa inhibitors) might further diminish the role of aspirin for stroke prevention in AF due to their superior efficacy, lack of need for monitoring of therapeutic effects and lower bleeding risk when compared with warfarin, especially in patients with stable vascular disease.

Purification, structural characterization and anticoagulant properties of fucosylated chondroitin sulfate isolated from Holothuria mexicana.

PubMed

Mou, Jiaojiao; Wang, Cong; Li, Wenjing; Yang, Jie

2017-05-01

A novel fucosylated chondroitin sulfate (HmG) was isolated from sea cucumber Holothuria mexicana, the structure of which was characterized by monosaccharide composition, disaccharide composition, IR, 1 H and 13 C NMR spectrum, additionally with two dimensional NMR spectrum of degraded HmG (DHmG). The backbone of HmG was identified as chondroitin 6-O sulfate, while the major O-4 sulfated fucose branches linked to O-3 position of glucuronic acid in almost every disaccharide unit. The anticoagulant activities of HmG and DHmG were assessed and compared with heparin and low molecular weight heparin. The results indicated that HmG and DHmG both could significantly prolong the activated partial thrombo-plastin time, and the properties were well related to its molecular weight. DHmG showed similar anticoagulant properties to low molecular weight heparin with less bleeding risks, making it a safer anticoagulant drug. Copyright © 2017 Elsevier B.V. All rights reserved.

Target specific oral anticoagulants in the management of thromboembolic disease in the elderly.

PubMed

Maddula, Surekha; Ansell, Jack

2013-08-01

The elderly population represents a population at highest risk of thromboembolism, but also the most vulnerable to hemorrhage. In the community setting there is a general tendency to under- treat this patient group. Specific consideration must be taken with elderly patients because they have reduced renal function, co-morbidities and risk of falls, altered pharmacodynamics, and challenges with adherence. Vitamin K antagonists, most often warfarin, have been the first line choice of therapy for long-term anticoagulation and enjoyed an unopposed position in the market for the last 70 years. Recently several new oral anticoagulants have been developed and found to be equally effective as warfarin in phase III studies and may provide an optimal treatment option in the elderly population. In this review we explore the target-specific oral anticoagulants and the pharmacological differences between them with a focus on the elderly population in whom these new drugs would constitute a possible alternative to warfarin therapy.

[Antithrombotic therapy and nonvariceal upper gastrointestinal bleeding].

PubMed

Belanová, Veronika; Gřiva, Martin

2015-12-01

The incidence of acute upper gastrointestinal bleeding is about 85-108/100,000 inhabitants per year, nonvariceal bleeding accounts for 80-90%. Antiplatelet and anticoagulation treatment are the significant risk factors for upper gastrointestinal bleeding. To evaluate the occurrence of upper gastrointestinal bleeding in the general community of patients in a county hospital. And to compare the role played by antiplatelet and anticoagulation drugs and other risk medication. Retrospective analysis of patients over 18 years of age who underwent endoscopy for acute upper gastrointestinal bleeding or anaemia (haemoglobin<100 g/l) with proved source of blood losses in upper gastrointestinal tract during a hospital stay in 2013 (from January to June). We included 111 patients of average age 69±15 years, men 60%. Nonvariceal bleeding accounted for 90% of the cases. None of the patients with variceal bleeding (10% of patients) took antiplatelet or anticoagulation therapy. There were 100 patients with nonvariceal bleeding of average age 70±15, 61% men. With the symptoms of acute bleeding (hematemesis, melena) presented in 73% of patients. The most frequent cause of bleeding was gastric and duodenal ulcer (54%). 32% of patients with nonvariceal bleeding had antiplatelets, 19% anticoagulants and 10% used nonsteroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors or corticosteroids. 30-days mortality of patients with nonvariceal bleeding was 11%, annual mortality was 23%. There was no significant difference in mortality, blood transfusion requirements or surgical intervention between the patients with antithrombotic agents and without them. 25% of patients (8 patients) using acetylsalicylic acid did not fulfil the indication for this treatment. Among the patients examined by endoscopy for symptomatic nonvariceal bleeding and/or anaemia (haemoglobin<100 g/l) significantly higher portions of patients are taking antiplatelet rather than anticoagulation therapy. This may be caused by greater use of these drugs in the population, but on the other hand it may reflect an association with greater risk of gastrointestinal bleeding. With regard to that, it is alarming, that there still exists a nonnegligible percentage of patients taking acetylsalicylic acid even though they do not meet the indication for the prescription according to the guidelines.

Natural products as sources of new lead compounds for the treatment of Alzheimer's disease.

PubMed

Huang, Ling; Su, Tao; Li, Xingshu

2013-01-01

Alzheimer's disease (AD) is the most prevalent form of dementia and affects approximately 24 million people worldwide. One possible approach for the treatment of this disease is the restoration of the level of acetylcholine (ACh) through the inhibition of acetylcholinesterase (AChE) with reversible inhibitors. Naturally occurring alkaloids are an important source of AChE inhibitors. Galantamine and huperzine A have been used for the clinical treatment of AD patients. In this review, we summarise the natural products and their derivatives that were reported to act as AChE inhibitors for the treatment of AD in 2010-2013. Several characteristics were summarised from the literature results: 1) Amongst all of the natural products with AChE inhibitory activity, alkaloids appear to be the most promising compound class. 2) Coumarins, flavonoids, stilbenes, and other natural products are also important AChE inhibitors from natural products. Among these inhibitors, 146 (IC50 = 0.573 µM) was identified as the most potent AChE inhibitor. 3) A coumarin derivative (117, IC50 = 0.11 nM) exhibited more than 100-fold superior activity compared with the reference drug donepezil hydrochloride (IC50 = 14 nM). In conclusion, natural products and their derivatives are promising leads for the development of new drugs for the future treatment of AD.

Effect of coumarins on HL-60 cell differentiation.

PubMed

Kawaii, S; Tomono, Y; Katase, E; Ogawa, K; Yano, M

2000-01-01

Twenty-eight coumarins, including 7 furocoumarins, were examined for their activity of induction of terminal differentiation of human promyelocytic leukemia cells (HL-60) by nitro blue tetrazolium (NBT) reducing, nonspecific esterase, specific esterase and phagocytic activities. Esculetin, nordalbergin, 6,7-dihydroxy-4-methylcoumarin and imperatorin had strong activity among the coumarins examined. HL-60 cells treated with these coumarins differentiated into mature monocyte/macrophage. The structure-activity relationship established from the results revealed that 6,7-dihydroxy moiety had an important role in the induction of differentiation of HL-60.

New coumarin carboxylates having trifluoromethyl, diethylamino and morpholino terminal groups: Synthesis and mesomorphic characterisations

NASA Astrophysics Data System (ADS)

Srinivasa, Hosapalya Thimmaiah; Harishkumar, Hosanagara Narayana; Palakshamurthy, Bandrehalli Siddagangappa

2017-03-01

New set of trifluromethyl, diethylamino and morpholino derived coumarin compounds were prepared by reacting various coumarin 3-carboxylic acids with various phenyl esters with peripheral alkyl, ester and polar cyano moieties in the presence of EDC.HCl/DMAP as esterification agent. The chemical structures of new coumarin derivatives were confirmed by standard spectroscopic techniques and mesomorphic behaviours were established by polarised optical microscopy (POM) and differential scanning calorimetry (DSC). Trifluoromethane and morpholino derivatives show SmA/Nematic phase, while diethylamino derivatives did not show liquid crystalline property.

13C CP MAS NMR and GIAO-CHF calculations of coumarins.

PubMed

Zolek, Teresa; Paradowska, Katarzyna; Wawer, Iwona

2003-01-01

13C cross-polarization magic-angle spinning NMR spectra were recorded for a series of solid coumarins. Ab initio calculations of shielding constants were performed with the use of GIAO-CHF method. The combined CPMAS NMR and theoretical approach was successful in characterizing solid-state conformations of coumarins; a relationship sigma (ppm) = -1.032 xdelta + 205.28 (R(2) = 0.9845) can be used to obtain structural information for coumarins, for which solid-state NMR or crystal structure data are not available. Copyright 2002 Elsevier Science (USA)

Broadband Light-Harvesting Molecular Triads with High FRET Efficiency Based on the Coumarin-Rhodamine-BODIPY Platform.

PubMed

He, Longwei; Zhu, Sasa; Liu, Yong; Xie, Yinan; Xu, Qiuyan; Wei, Haipeng; Lin, Weiying

2015-08-17

Broadband capturing and FRET-based light-harvesting molecular triads, CRBs, based on the coumarin-rhodamine-BODIPY platform were rationally designed and synthesized. The absorption band of CRBs starts from blue-green to yellow-orange regions (330-610 nm), covering the strong radiation scope of sunlight. The peripheral coumarin and BODIPY chromophore energy could transfer to the central acceptor rhodamine by a one-step direct way. The energy of the coumarin moiety could also transfer to the BODIPY unit, subsequently transferring to the rhodamine core by two-step sequential ways. Both the efficiencies of the coumarin moiety and the BODIPY unit to the rhodamine core in CRBs, determined by two different ways, are very high. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Anti-angiogenic activity and antitumor efficacy of amphiphilic twin drug from ursolic acid and low molecular weight heparin

NASA Astrophysics Data System (ADS)

Cheng, Wenming; Zohra Dahmani, Fatima; Zhang, Juan; Xiong, Hui; Wu, Yuanyuan; Yin, Lifang; Zhou, Jianping; Yao, Jing

2017-02-01

Heparin, a potential blood anti-coagulant, is also known for its binding ability to several angiogenic factors through electrostatic interactions due to its polyanionic character. However, the clinical application of heparin for cancer treatment is limited by several drawbacks, such as unsatisfactory therapeutic effects and severe anticoagulant activity that could induce hemorrhaging. Herein, low molecular weight heparin (LMWH) was conjugated to ursolic acid (UA), which is also an angiogenesis inhibitor, by binding the amine group of aminoethyl-UA (UA-NH2) with the carboxylic groups of LMWH. The resulting LMWH-UA conjugate as an amphiphilic twin drug showed reduced anticoagulant activity and could also self-assemble into nanomicelles with a mean particle size ranging from 200-250 nm. An in vitro endothelial tubular formation assay and an in vivo Matrigel plug assay were performed to verify the anti-angiogenic potential of LMWH-UA. Meanwhile, the in vivo antitumor effect of LMWH-UA was also evaluated using a B16F10 mouse melanoma model. LMWH-UA nanomicelles were shown to inhibit angiogenesis both in vitro and in vivo. In addition, the i.v. administration of LMWH-UA to the B16F10 tumor-bearing mice resulted in a significant inhibition of tumor growth as compared to the free drug solutions. These findings demonstrate the therapeutic potential of LMWH-UA as a new therapeutic remedy for cancer therapy.

COMMUNICATION: Drug loading of nanoporous TiO2 films

NASA Astrophysics Data System (ADS)

Ayon, Arturo A.; Cantu, Michael; Chava, Kalpana; Mauli Agrawal, C.; Feldman, Marc D.; Johnson, Dave; Patel, Devang; Marton, Denes; Shi, Emily

2006-12-01

The loading of therapeutic amounts of drug on a nanoporous TiO2 surface is described. This novel drug-loading scheme on a biocompatible surface, when employed on medical implants, will benefit patients who require the deployment of drug-eluting implants. Anticoagulants, analgesics and antibiotics can be considered on the associated implants for drug delivery during the time of maximal pain or risk for patients undergoing orthopedic procedures. Therefore, this scheme will maximize the chances of patient recovery.

Coagulation management in patients undergoing neurosurgical procedures.

PubMed

Robba, Chiara; Bertuetti, Rita; Rasulo, Frank; Bertuccio, Alessando; Matta, Basil

2017-10-01

Management of coagulation in neurosurgical procedures is challenging. In this contest, it is imperative to avoid further intracranial bleeding. Perioperative bleeding can be associated with a number of factors, including anticoagulant drugs and coagulation status but is also linked to the characteristic and the site of the intracranial disorder. The aim of this review will be to focus primarily on the new evidence regarding the management of coagulation in patients undergoing craniotomy for neurosurgical procedures. Antihemostatic and anticoagulant drugs have shown to be associated with perioperative bleeding. On the other hand, an increased risk of venous thromboembolism and hypercoagulative state after elective and emergency neurosurgery, in particular after brain tumor surgery, has been described in several patients. To balance the risk between thrombosis and bleeding, it is important to be familiar with the perioperative changes in coagulation and with the recent management guidelines for anticoagulated patients undergoing neurosurgical procedures, in particular for those taking new direct anticoagulants. We have considered the current clinical trials and literature regarding both safety and efficacy of deep venous thrombosis prophylaxis in the neurosurgical population. These were mainly trials concerning both elective surgical and intensive care patients with a poor grade intracranial bleed or multiple traumas with an associated severe traumatic brain injury (TBI). Coagulation management remains a major issue in patients undergoing neurosurgical procedures. However, in this field of research, literature quality is poor and further studies are necessary to identify the best strategies to minimize risks in this group of patients.

Management of antithrombotic therapy during cardiac implantable device surgery.

PubMed

AlTurki, Ahmed; Proietti, Riccardo; Birnie, David H; Essebag, Vidal

2016-06-01

Anticoagulants are commonly used drugs that are frequently encountered during device placement. Deciding when to halt or continue the use of anticoagulants is a balance between the risks of thromboembolism versus bleeding. Patients taking warfarin with a high risk of thromboembolism should continue to take their warfarin without interruption during device placement while ensuring their international normalized ratio remains below 3. For patients who are taking warfarin and have low risk of thromboembolism, either interrupted or continued warfarin may be used, with no evidence to clearly support either strategy. There is little evidence to support continuing direct acting oral anticoagulants (DOACs) for device implantation. The timing of halting these medications depends largely on renal function. If bleeding occurs, warfarin׳s anticoagulation effect is reversible with vitamin K and activated prothrombin complex concentrate. There are no DOAC reversal agents currently available, but some are under development. Regarding antiplatelet agents, aspirin alone can be safely continued while clopidogrel alone may also be continued, but with a slightly higher bleeding risk. Dual antiplatelet therapy for bare-metal stent/drug-eluting stent implanted within 4 weeks/6 months, respectively, should be continued due to high risk of stent thrombosis; however, if they are implanted after this period, then clopidogrel can be halted 5 days before the procedure and resumed soon after, while aspirin is continued. If the patient is taking both aspirin and warfarin, aspirin should be halted 5 days prior to the procedure, while warfarin is continued.

Hydroxychloroquine protects the annexin A5 anticoagulant shield from disruption by antiphospholipid antibodies: evidence for a novel effect for an old antimalarial drug.

PubMed

Rand, Jacob H; Wu, Xiao-Xuan; Quinn, Anthony S; Ashton, Anthony W; Chen, Pojen P; Hathcock, James J; Andree, Harry A M; Taatjes, Douglas J

2010-03-18

Annexin A5 (AnxA5) is a potent anticoagulant protein that crystallizes over phospholipid bilayers (PLBs), blocking their availability for coagulation reactions. Antiphospholipid antibodies disrupt AnxA5 binding, thereby accelerating coagulation reactions. This disruption may contribute to thrombosis and miscarriages in the antiphospholipid syndrome (APS). We investigated whether the antimalarial drug, hydroxychloroquine (HCQ), might affect this prothrombotic mechanism. Binding of AnxA5 to PLBs was measured with labeled AnxA5 and also imaged with atomic force microscopy. Immunoglobulin G levels, AnxA5, and plasma coagulation times were measured on cultured human umbilical vein endothelial cells and a syncytialized trophoblast cell line. AnxA5 anticoagulant activities of APS patient plasmas were also determined. HCQ reversed the effect of antiphospholipid antibodies on AnxA5 and restored AnxA5 binding to PLBs, an effect corroborated by atomic force microscopy. Similar reversals of antiphospholipid-induced abnormalities were measured on the surfaces of human umbilical vein endothelial cells and syncytialized trophoblast cell lines, wherein HCQ reduced the binding of antiphospholipid antibodies, increased cell-surface AnxA5 concentrations, and prolonged plasma coagulation to control levels. In addition, HCQ increased the AnxA5 anticoagulant activities of APS patient plasmas. In conclusion, HCQ reversed antiphospholipid-mediated disruptions of AnxA5 on PLBs and cultured cells, and in APS patient plasmas. These results support the concept of novel therapeutic approaches that address specific APS disease mechanisms.

Computational Study on New Natural Compound Inhibitors of Pyruvate Dehydrogenase Kinases

PubMed Central

Zhou, Xiaoli; Yu, Shanshan; Su, Jing; Sun, Liankun

2016-01-01

Pyruvate dehydrogenase kinases (PDKs) are key enzymes in glucose metabolism, negatively regulating pyruvate dehyrogenase complex (PDC) activity through phosphorylation. Inhibiting PDKs could upregulate PDC activity and drive cells into more aerobic metabolism. Therefore, PDKs are potential targets for metabolism related diseases, such as cancers and diabetes. In this study, a series of computer-aided virtual screening techniques were utilized to discover potential inhibitors of PDKs. Structure-based screening using Libdock was carried out following by ADME (adsorption, distribution, metabolism, excretion) and toxicity prediction. Molecular docking was used to analyze the binding mechanism between these compounds and PDKs. Molecular dynamic simulation was utilized to confirm the stability of potential compound binding. From the computational results, two novel natural coumarins compounds (ZINC12296427 and ZINC12389251) from the ZINC database were found binding to PDKs with favorable interaction energy and predicted to be non-toxic. Our study provide valuable information of PDK-coumarins binding mechanisms in PDK inhibitor-based drug discovery. PMID:26959013

Computational Study on New Natural Compound Inhibitors of Pyruvate Dehydrogenase Kinases.

PubMed

Zhou, Xiaoli; Yu, Shanshan; Su, Jing; Sun, Liankun

2016-03-04

Pyruvate dehydrogenase kinases (PDKs) are key enzymes in glucose metabolism, negatively regulating pyruvate dehyrogenase complex (PDC) activity through phosphorylation. Inhibiting PDKs could upregulate PDC activity and drive cells into more aerobic metabolism. Therefore, PDKs are potential targets for metabolism related diseases, such as cancers and diabetes. In this study, a series of computer-aided virtual screening techniques were utilized to discover potential inhibitors of PDKs. Structure-based screening using Libdock was carried out following by ADME (adsorption, distribution, metabolism, excretion) and toxicity prediction. Molecular docking was used to analyze the binding mechanism between these compounds and PDKs. Molecular dynamic simulation was utilized to confirm the stability of potential compound binding. From the computational results, two novel natural coumarins compounds (ZINC12296427 and ZINC12389251) from the ZINC database were found binding to PDKs with favorable interaction energy and predicted to be non-toxic. Our study provide valuable information of PDK-coumarins binding mechanisms in PDK inhibitor-based drug discovery.

From evidence based medicine to mechanism based medicine. Reviewing the role of pharmacogenetics.

PubMed

Wilffert, Bob; Swen, Jesse; Mulder, Hans; Touw, Daan; Maitland-Van der Zee, Anke-Hilse; Deneer, Vera

2013-06-01

The translation of evidence based medicine to a specific patient presents a considerable challenge. We present by means of the examples nortriptyline, tramadol, clopidogrel, coumarins, abacavir and antipsychotics the discrepancy between available pharmacogenetic information and its implementation in daily clinical practice. Literature review. A mechanism based approach may be helpful to personalize medicine for the individual patient to which pharmacogenetics may contribute significantly. The lack of consistency in what we accept in bioequivalence and in pharmacogenetics of drug metabolising enzymes is discussed and illustrated with the example of nortriptyline. The impact of pharmacogenetics on examples like tramadol, clopidogrel, coumarins and abacavir is described. Also the present status of the polymorphisms of 5-HT2A and C receptors in antipsychotic-induced weight gain is presented as a pharmacodynamic example with until now a greater distance to clinical implementation. The contribution of pharmacogenetics to tailor-made pharmacotherapy, which especially might be of value for patients deviating from the average, has not yet reached the position it seems to deserve.

Novel push-pull fluorescent dyes - 7-(diethylamino)furo- and thieno[3,2-c]coumarins derivatives: structure, electronic spectra and TD-DFT study

NASA Astrophysics Data System (ADS)

Akchurin, Igor O.; Yakhutina, Anna I.; Bochkov, Andrei Y.; Solovjova, Natalya P.; Medvedev, Michael G.; Traven, Valerii F.

2018-05-01

Novel push-pull fluorescent dyes - 7-(diethylamino)furo- and 7-(diethylamino)thieno[3,2-c]coumarins derivatives have been synthesized using formyl derivatives of furo- and thieno[3,2-c]coumarins as starting materials. Electron absorption and fluorescent spectra of the dyes have been recorded in different solvents. Structure and solvent effects on the dyes spectral characteristics were analyzed. The fusion of five-membered heterocycle to coumarin provides a definite increase of Stokes shifts in all solvents and results in higher quantum yields of fluorescence. The absorption and emission bands of thieno[3,2-c] coumarin derivatives are definitely shifted to the red region (3-30 nm) compared to similar derivatives of furo[3,2-c]coumarin. TD-DFT calculations of some of the studied compounds have shown that hybrid DFT functionals and adequate representation of molecular environment are essential for obtaining accurate UV-Vis absorption spectra for the dyes with extended π-system. The longest-wave electron transitions in the studied compounds were computationally shown to be of push-pull nature.

Effect of solvent polarity levels on separation of xanthone and coumarin from Calophyllum inophyllum leaves extract

NASA Astrophysics Data System (ADS)

Susanto, D. F.; Hapsari, S.; Trilutfiani, Z.; Borhet, A.; Aparamarta, H. W.; Widjaja, A.; Gunawan, S.

2018-03-01

Calophyllum inophyllum has various benefits that can be utilized from root, stem, leaf, until seed. C. inophyllum leaves contain many bioactive compounds, such as xanthone and coumarin which are useful as antioxidant, and inhibitors of enzyme activity from HIV virus. The aim of this research was to investigate the effect of solvent polarity levels on the separation of xanthone and coumarin compounds contained in the crude extract of C. inophyllum leaves. Crude leaves extract was obtained by percolation method. Moreover, Liquid Liquid Extraction (LLE) was used for separating xanthone and coumarin compounds. It was performed by methanol (polar solvent) and hexane (non-polar solvent) with solvent ratio of 1. Methanol concentration in water used were 20%, 50%, 80%, and 100%. Each fraction obtained was tested qualitatively using Thin Layer Chromatography (TLC) and quantitatively using Gas Chromatography (GC) to analyze xanthone and coumarin. The best separation result was obtained by using 50% methanol. In this results, coumarin and xanthones were separated in methanol fraction (81.18% recovery) and in hexane fraction (81.91% recovery), respectively.

Preclinical and clinical data for factor Xa and “universal” reversal agents☆,☆☆,★

PubMed Central

Milling, Truman J.; Kaatz, Scott

2017-01-01

Oral Factor Xa (FXa) inhibitors, a growing class of direct-acting anticoagulants, are frequently used to prevent stroke and systemic embolism in patients with atrial fibrillation and to prevent and treat venous thromboembolism. These drugs reduce the risk of clotting at the expense of increasing the risk of bleeding, and currently they have no specific reversal agent. However, andexanet alfa, a recombinant modified FXa decoymolecule, is in a late-phase clinical trial in bleeding patients, and ciraparantag, a small molecule that appears to reverse many anticoagulants including the FXa inhibitors, is in development. This review summarizes the published data to date on both drugs, which have the potential to change the management approach to patients with FXa inhibitoreassociated major hemorrhage. PMID:27697443

Preclinical and Clinical Data for Factor Xa and “Universal” Reversal Agents

PubMed Central

Milling, Truman J.; Kaatz, Scott

2017-01-01

Oral Factor Xa (FXa) inhibitors, a growing class of direct-acting anticoagulants, are frequently used to prevent stroke and systemic embolism in patients with atrial fibrillation and to prevent and treat venous thromboembolism. These drugs reduce the risk of clotting at the expense of increasing the risk of bleeding, and currently they have no specific reversal agent. However, andexanet alfa, a recombinant modified FXa decoy molecule, is in a late-phase clinical trial in bleeding patients, and ciraparantag, a small molecule that appears to reverse many anticoagulants including the FXa inhibitors, is in development. This review summarizes the published data to date on both drugs, which have the potential to change the management approach to patients with FXa inhibitor–associated major hemorrhage. PMID:27575436

Tagging RDT&E Volume 2--Appendices A-G

DTIC Science & Technology

1994-03-01

significantly from the index matched case. C - 20 S• nj= 1.4 0 a nj= 1.5 o nj= 1.6 C • ni= 1.64 10 S15 *% 0 -0.0 0.5 1.0 1.5 2.0 Fiber-Dump Separation...index matching fluid, dump fiber characteristics, laser fluence, and laser wavelength. C -30 * Coumarin 460 o Coumarin 500 * Rhodamine 590a A Kiton Red...Splice • IE-5 o Coumarin 460 * Coumarin 500 T Rhodamine 590 A Kitton Red 620 * DCM 0 LDS 698 OEO0 450 500 550 600 650 700 Wavelength (rim) Figure C -21

Solvatochromic studies on 4-Bromomethyl-7-methyl coumarins

NASA Astrophysics Data System (ADS)

Khanapurmath, Netravati; Kulkarni, Manohar V.; Pallavi, L.; Yenagi, Jayashree; Tonannavar, Jagdish

2018-05-01

Non- and dinitro 4-bromomethyl-7-methyl coumarins and new mono- and trinitro 4-bromomethyl-7-methyl coumarins have been synthesized. Effect of nitro groups on the photophysical properties of the parent 4-bromomethyl-7-methyl coumarin has been reported. Their ground and excited state dipole moments have been estimated by solvatochromic method using nine solvents. A reasonable agreement has been observed between calculated and observed dipole moments. Reduction in dipole moment has been observed for mono- and dinitro compounds where as the trinitro compound was found to have higher dipole moment in the excited state.

[Simultaneous analysis of aromatic aldehydes and coumarins with high pressure liquid chromatography. Application to wines and brandies stored in oak barrels].

PubMed

Salagoity-Auguste, M H; Tricard, C; Sudraud, P

1987-04-17

Aromatic aldehydes (vanillin, syringaldehyde, coniferaldehyde and sinapaldehyde) and coumarins (esculetin, umbelliferone, scopoletin and methylumbelliferone) are natural wood compounds. Storage of wines and brandies in oak barrels increases notably aldehydes and coumarins (particularly scopoletin) concentrations. These compounds were separated by high-performance liquid chromatography, on hydrocarbon bonded reversed-phase packings, with a water-acetonitrile elution gradient. They were first extracted from wines and brandies by diethyl ether and then injected on chromatographic column. A double detection was used to determine simultaneously aromatic aldehydes and coumarins by UV absorption and fluorescence respectively.

Percutaneous left atrial appendage occlusion for stroke prevention in patients with atrial fibrillation and contraindication for anticoagulation.

PubMed

Grosset-Janin, D; Barth, E; Bertrand, B; Detante, O

2015-05-01

Stroke, as the third cause of death in developed countries, is a public health issue. Atrial fibrillation is an important cause of ischemic stroke and its prevention is efficient with oral anticoagulation. However, oral anticoagulation can be contraindicated because of hemorrhagic risk related to these treatments. Percutaneous left atrial appendage occlusion is a new alternative of oral anticoagulation for patients with atrial fibrillation and high risk of cardio-embolic stroke but contraindicated for oral anticoagulation. We describe in this paper the procedure of left atrial appendage occlusion with the Amplatzer cardiac plug device, used in our center in Grenoble university hospital, for the first three patients who have been treated with this device. These three patients (one man and two women) have all atrial fibrillation with neurological complication of this arrhythmia, as ischemic stroke. Oral anticoagulation is indicated to prevent another ischemic stroke. However, they all have a high risk of cerebral bleeding for different reasons (cavernomatosis, history of intracerebral hemorrhage and aneurysm of the polygon of Willis). Consequently, they have a high risk of cardio-embolic complication but contraindication for oral anticoagulation. They have been treated by left atrial appendage occlusion with Amplatzer cardiac plug device by percutaneous and trans-septal access. Then, they have been followed by neurologist and cardiologist, with clinical and paraclinical evaluation by echocardiography. Our three first patients have been successfully implanted, without periprocedural complication. No latest adverse event was observed, and particularly no cardiac or neurologic adverse event. The technique of left atrial appendage occlusion is a very interesting and promising technique for ischemic stroke prevention in patient with high risk of cardio-embolic complication because of atrial fibrillation, but high risk of bleeding and contraindication for oral anticoagulation. Because of frequency of both atrial fibrillation and contraindication for oral anticoagulation, occlusion of the left atrial appendage should become an interesting alternative for many patients. However, it remains an invasive procedure and efficacy and indications need to be evaluated in further clinical trials. Risk/benefit ratio must be carefully assessed and compared to that of the new anticoagulant drugs. Copyright © 2015. Published by Elsevier Masson SAS.

Molecular Mechanisms of Prostate Cancer Progression

DTIC Science & Technology

2003-01-01

other drugs ( novobiocin and related hsp90 inhibitors have been shown to bind to the N-ter- coumarins) that are reported to target hsp90 are now be...undesirable for an indirect method of telomerase inhibition (data not shown). However, radicicol, which binds in the ATP- binding pocket of hsp90 and...compounds (e.g. novobiocin ) to block chaperone function using a totally different mechanism of hsp90 inhbition, as well as innovative genetic approaches

Determination of non-Vitamin K oral anticoagulant (NOAC) effects using a new-generation thrombelastography TEG 6s system.

PubMed

Bliden, Kevin P; Chaudhary, Rahul; Mohammed, Nafees; Muresan, Adina A; Lopez-Espina, Carlos G; Cohen, Eli; Raviv, Gabriel; Doubleday, Marc; Zaman, Fowzia; Mathew, Blessy; Tantry, Udaya S; Gurbel, Paul A

2017-05-01

Non vitamin K oral anticoagulants (NOACs) do not require regular monitoring but information about their pharmacodynamic effect may be importantin situations like trauma, stroke oremergent surgery. Currently, no standardized point-of-care test is available to evaluate the anticoagulant effects of NOACs. We evaluated the anticoagulant effect of NOACs with the next generation point-of-care TEG assay (TEG® 6S) based on a fully-automated thrombelastography system. We used two TEG® 6S assays, the DTI assay and Anti-Factor Xa (AFXa) assay, to detect anticoagulant effects and classify NOACs. Blood from healthy volunteers (n = 26) was used to obtain a baseline reference range. Data derived from patients on factor Xa inhibitors (FXi) (rivaroxaban and apixaban) (n = 39), and direct thrombin inhibitors (DTIs) (dabigatran) (n = 25) were compared against the reference range for detection of drug effect and drug classification. TEG®6s R-time highly correlated to each NOAC. Presence of NOACs caused elongation of R-time on the AFXa assay compared to the reference range (4.3 ± 1.7 vs. 1.3 ± 0.3 min. for FXi, p < 0.001 and 3.5 ± 1.2 vs. 1.3 ± 0.3 min. for DTI, p < 0.001). R-time on the DTI assay was elongated only in presence of a DTI (3.4 ± 1.0 vs. 1.5 ± 0.2 min, p < 0.001). The cutoff for detection of a DTI effect was an R time of 1.9 min and for anti-Xa effect was 1.95 min. For detection of NOAC therapy, there was ≥92% sensitivity and ≥95% specificity. The automated TEG®6s NOAC assay may be an effective tool to identify an anticoagulant effect from NOAC therapy and facilitate care of patients with bleeding or at risk of bleeding in the event of needing emergency surgery.

Ratiometric fluorescence sensing of mercuric ion based on dye-doped lanthanide coordination polymer particles.

PubMed

Zhang, Zhenzhen; Wu, Yongmei; He, Shizhen; Xu, Yuanyuan; Li, Gaiping; Ye, Baoxian

2018-07-19

This work focused on the development of a novel ratiometric fluorescence sensor for detection of Hg 2+ by using dye-doped lanthanide infinite coordination polymer (Ln-ICP) particles. The dye-doped Ln-ICP used herein was prepared by self-assemble of adenosine monophosphate (AMP) with Ce 3+ and Tb 3+ (Ce/Tb-AMP) through self-adaptive chemistry, in which the fluorescent dye coumarin was encapsulated during the assembly process as a guest molecule. Under 310 nm irradiation, the obtained coumarin@Ce/Tb-AMP itself emitted characteristic green luminescence of Tb 3+ , accompanied with a weak fluorescence at 445 nm originated from coumarin encapsulated in the Ce/Tb-AMP networks. The fluorescence emission of coumarin became strong when it was released to the solution. In the presence of Hg 2+ , the coumarin@Ce/Tb-AMP was destroyed due to the specific coordination interaction between AMP and Hg 2+ , which leaded to the release of coumarin to the solution meanwhile. Consequently, the fluorescence of Ce/Tb-AMP was quenched, while that of coumarin enhanced. On the basis of this strategy, we developed a novel ratiometric fluorescent sensor for the detection of Hg 2+ by measuring the ratio of fluorescent intensity of the coumarin@Ce/Tb-AMP suspension, which showed a wide linear range from 0.08 to 1000 nM and detection limit of 0.03 nM with high selectivity and sensitivity. Furthermore, the constructed ratiometric fluorescent sensor was successfully applied in detecting Hg 2+ in drinking water and human blood serum (HBS) with satisfactory results. Copyright © 2018 Elsevier B.V. All rights reserved.

Effects of anti-aggregant, anti-inflammatory and anti-coagulant drug consumption on the preparation and therapeutic potential of plasma rich in growth factors (PRGF).

PubMed

Anitua, Eduardo; Troya, María; Zalduendo, Mar; Orive, Gorka

2015-02-01

The prevalence and incidence of trauma-related injuries, coronary heart disease and other chronic diseases increase dramatically with age. This population sector is therefore a regular consumer of different types of drugs that may affect platelet aggregation and the coagulation cascade. We have evaluated whether the consumption of acetylsalicylic acid, acenocoumarol, glucosamine sulfate and chondroitin sulfate, and therefore their presence in blood, could interfere with the preparation and biological outcomes of plasma rich in growth factors (PRGF). Clotting time, clot retraction and platelet activation of PRGF was evaluated. PRGF growth factor content and the release of different biomolecules by tendon fibroblasts were also quantified, as well as cell proliferation and cell migration. The preparation and biological potential of PRGF is not affected by the intake of the evaluated drugs, and solely its angiogenic potential and its capacity to induce HA and fibronectin synthesis, is reduced in patients taking anti-coagulants.

Stability-indicating spectrophotometric methods for determination of the anticoagulant drug apixaban in the presence of its hydrolytic degradation product

NASA Astrophysics Data System (ADS)

Tantawy, Mahmoud A.; El-Ragehy, Nariman A.; Hassan, Nagiba Y.; Abdelkawy, Mohamed

2016-04-01

Apixaban (a novel anticoagulant agent) was subjected to a stress stability study including acid, alkali, oxidative, photolytic, and thermal degradation. The drug was found to be only liable to acidic and alkaline hydrolysis. The degradation product was then isolated and identified by IR and GC-mass spectrometry. Four spectrophotometric methods, namely; first derivative (D1), derivative ratio (DR), ratio difference (RD) and mean centering of ratio spectra (MCR), have been suggested for the determination of apixaban in presence of its hydrolytic degradation product. The proposed methods do not require any preliminary separation step. The accuracy, precision and linearity ranges of the proposed methods were determined, and the methods were validated as per ICH guidelines and the specificity was assessed by analyzing synthetic mixtures containing different percentages of the degradation product with the drug. The developed methods were successfully applied for the determination of apixaban in bulk powder and its tablet dosage form.

Stability-indicating spectrophotometric methods for determination of the anticoagulant drug apixaban in the presence of its hydrolytic degradation product.

PubMed

Tantawy, Mahmoud A; El-Ragehy, Nariman A; Hassan, Nagiba Y; Abdelkawy, Mohamed

2016-04-15

Apixaban (a novel anticoagulant agent) was subjected to a stress stability study including acid, alkali, oxidative, photolytic, and thermal degradation. The drug was found to be only liable to acidic and alkaline hydrolysis. The degradation product was then isolated and identified by IR and GC-mass spectrometry. Four spectrophotometric methods, namely; first derivative (D(1)), derivative ratio (DR), ratio difference (RD) and mean centering of ratio spectra (MCR), have been suggested for the determination of apixaban in presence of its hydrolytic degradation product. The proposed methods do not require any preliminary separation step. The accuracy, precision and linearity ranges of the proposed methods were determined, and the methods were validated as per ICH guidelines and the specificity was assessed by analyzing synthetic mixtures containing different percentages of the degradation product with the drug. The developed methods were successfully applied for the determination of apixaban in bulk powder and its tablet dosage form. Copyright © 2016 Elsevier B.V. All rights reserved.

Effects of oversulfated and fucosylated chondroitin sulfates on coagulation. Challenges for the study of anticoagulant polysaccharides.

PubMed

Fonseca, Roberto J C; Oliveira, Stephan-Nicollas M C G; Pomin, Vitor H; Mecawi, André S; Araujo, Iracema G; Mourão, Paulo A S

2010-05-01

We report the effects of a chemically oversulfated chondroitin sulfate and a naturally fucosylated chondroitin sulfate on the coagulation system. The former has been recently identified as a contaminant of heparin preparations and the latter has been proposed as an alternative anticoagulant. The mechanism of action of these polymers on coagulation is complex and target different components of the coagulation system. They have serpin-independent anticoagulant activity, which preponderates in plasma. They also have serpin-dependent anticoagulant activity but differ significantly in the target coagulation protease and preferential serpin. Their anticoagulant effects differ even more markedly when tested as inhibitors of coagulation proteases using plasma as a source of serpins. It is possible that the difference is due to the high availability of fucosylated chondroitin sulfate whereas oversulfated chondroitin sulfate has strong unspecific binding to plasma protein and low availability for the binding to serpins. When tested using a venous thrombosis experimental model, oversulfated chondroitin sulfate is less potent as an antithrombotic agent than fucosylated chondroitin sulfate. These highly sulfated chondroitin sulfates activate factor XII in in vitro assays, based on kallikrein release. However, only fucosylated chondroitin sulfate induces hypotension when intravenously injected into rats. In conclusion, the complexity of the regulatory mechanisms involved in the action of highly sulfated polysaccharides in coagulation requires their analysis by a combination of in vitro and in vivo assays. Our results are relevant due to the urgent need for new anticoagulant drugs or alternative sources of heparin.

Gastrointestinal bleeding risk of non-vitamin K oral anticoagulants is similar to warfarin - a Japanese retrospective cohort study
.

PubMed

Shirai, Tsuguru; Yamamoto, Takatsugu; Kawasugi, Kazuo; Kuyama, Yasushi; Kita, Hiroto

2016-11-01

Although several non-vitamin K oral anticoagulants have been developed to prevent cardiogenic thrombosis, the status of hemorrhagic complications in the clinical setting among Asian populations, including Japan, remains unclear. We conducted this retrospective cohort study to clarify the current status of hemorrhagic events during antithrombotic therapy with non-vitamin K oral anticoagulants, with particular focus on gastrointestinal bleeding. Medical charts of 475 patients prescribed dabigatran, rivaroxaban, or apixaban between April 2011 and September 2014 were reviewed to examine whether any hemorrhagic events occurred, compared with 135 patients who received warfarin between April 2009 and March 2011. Incidences of total and actionable hemorrhage in patient taking non-vitamin K oral anticoagulants were 13.8% per year and 4.6% per year, respectively, showing no significant differences from those in warfarin users (9.3% per year and 5.0% per year, respectively). In addition, actionable gastrointestinal hemorrhage occurred at similar rates in non-vitamin K oral anticoagulants users (2.1% per year) and warfarin users (1.5% per year). Most hemorrhages were from the lower gastrointestinal tract, and considerable events involved perianal bleeding. Multiple regression analysis showed that age, concomitant dual antiplatelet therapy, and concomitant nonsteroidal anti-inflammatory drug therapy were significant factors related to actionable gastrointestinal bleeding. Risk of gastrointestinal hemorrhage in patients taking non-vitamin K oral anticoagulants was similar to that in patients taking warfarin. The dominant bleeding site was the lower gastrointestinal tract.
.

Photochemical synthesis and photophysical properties of coumarins bearing extended polyaromatic rings studied by emission and transient absorption measurements.

PubMed

Yamaji, Minoru; Hakoda, Yuma; Okamoto, Hideki; Tani, Fumito

2017-04-12

We prepared a variety of coumarin derivatives having expanded π-electron systems along the direction crossing the C 3 -C 4 bond of the coumarin skeleton via a photochemical cyclization process and investigated their photophysical features as a function of the number (n) of the added benzene rings based on emission and transient absorption measurements. Upon increasing n, the fluorescence quantum yields of the π-extended coumarins increased. Expanding the π-electron system on the C 3 -C 4 bond of the coumarin skeleton was found to be efficient for increasing the fluorescence ability more than that on the C 7 -C 8 bond. Introducing the methoxy group at the 7-position was also efficient for enhancing the fluorescence quantum yield and rate of the expanded coumarins. The non-radiative process from the fluorescence state was not substantially influenced by the expanded π-electron system. The competitive process with the fluorescence was found to be intersystem crossing to the triplet state based on the observations of the triplet-triplet absorption. The effects of the expanded π-electron systems on the fluorescence ability were investigated with the aid of TD-DFT calculations.

Chirality transfer effects in proline-substituted coumarin compounds.

PubMed

Park, Eun-Kyung; Park, Bongjeong; Choi, Jun-Ho; Choi, Kihang; Cho, Minhaeng

2009-08-13

Conformations of proline-substituted chromophores are determined by using circular dichroism (CD) spectroscopy and quantum chemistry calculation method. Coumarin is chosen for the optical chromophore and proline amino acid is attached to its C7 position. The coumarin-proline conjugate considered contains both fluorophore and peptide linker where any polypeptides or biomolecules can be additionally connected to the free carboxyl group of the proline. Thus, the coumarin-proline is a potentially useful composite chirality-probe system for studies of protein dynamics in solution. However, detailed conformation of coumarin ring with respect to the proline ring has to be determined first. We found that there are two possible conformers, which differ from each other by the relative orientation of the coumarin ring. Comparing the measured CD spectra with the calculated ones, we directly show that only one of the two conformers is dominant in polar solvents except for water. The present study suggests that the local structure around an optical chromophore, when it is introduced to polypeptides or other biomolecules, can be studied by examining the electronic optical activity of the probe chromophore, as long as the chirality transfer from the attached amino acid to the chromophore is significantly large.

Point-of-Care Coagulation Tests Monitoring of Direct Oral Anticoagulants and Their Reversal Therapy: State of the Art.

PubMed

Iapichino, Giacomo E; Bianchi, Paolo; Ranucci, Marco; Baryshnikova, Ekaterina

2017-06-01

Direct oral anticoagulants (DOACs) exert similar anticoagulant effects to vitamin K antagonists and are increasingly used worldwide. Nevertheless, an evidence-based approach to patients receiving DOACs when any unplanned urgent surgery or bleeding (either spontaneous or traumatic) occurs is still missing. In this review, we investigate the role of point-of-care coagulation tests when other, more specific tests are not available. Indeed, thromboelastography and activated clotting time can detect dabigatran-induced coagulopathy, while their accuracy is limited for apixaban and rivaroxaban, mostly in cases of low drug plasma concentrations. These tests can also be used to guide the reversal of DOAC-induced coagulopathy providing a quick, before-and-after picture in case of therapeutic use of hemostatic compounds. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Warfarin interaction with erythromycin.

PubMed

Sato, R I; Gray, D R; Brown, S E

1984-12-01

The drug interaction between warfarin and erythromycin is not well known. We report a case in which erythromycin was observed to markedly potentiate warfarin anticoagulation, resulting in hemorrhage in a patient treated for Legionella pneumonia. The morbidity of this drug interaction is enhanced in elderly patients who have infection accompanied by anorexia and/or fever and who are receiving intravenous erythromycin. The well-documented, temporal relationship established erythromycin as the interacting drug.

The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) : Exploring the changes in anticoagulant practice in patients with non-valvular atrial fibrillation in the Netherlands.

PubMed

Ten Cate, V; Ten Cate, H; Verheugt, F W A

2016-10-01

There are over 385,000 cases of atrial fibrillation (AF) in the Netherlands, with over 45,000 new cases each year. Among other things, AF patients are at high risk of stroke. Patients are often prescribed oral anticoagulation, such as vitamin K antagonists (VKA), to mitigate these risks. A recently introduced class of oral anticoagulants, non-vitamin K antagonists (NOAC), is quickly gaining currency in global clinical practice. This study provides insight into the changes these new drugs will bring about in Dutch clinical practice.GARFIELD-AF is a large-scale observational AF patient registry initiated in 2009 to track the evolution of global anticoagulation practice, and to study the impact of NOAC therapy in AF in particular. The registry includes a wide array of baseline characteristics and has a particular focus on: (1) bleeding and thromboembolic events; (2) international normalised ratio fluctuations; and (3) therapy compliance and persistence patterns. The results in this paper provide the baseline characteristics of the first cohorts of Dutch participants in this registry and discuss some of the consequences of the changes in anticoagulation practice.Although VKA therapy remains overwhelmingly favoured by Dutch practitioners, NOACs are clearly gaining in popularity. Between 2011 and 2014, NOACs constituted an increasingly large proportion of prescriptions for oral anticoagulants.The insights provided by the GARFIELD-AF registry can be used by healthcare systems to inform better budgetary strategies, by practitioners to better tailor treatment pathways to patients, and finally to promote awareness of the various available treatment options and their associated risks and benefits for patients.

Potential use of NOACs in developing countries: pros and cons.

PubMed

Bista, Durga; Chalmers, Leanne; Bereznicki, Luke; Peterson, Gregory

2014-07-01

Although vitamin K antagonists (VKAs) are effective for long-term thromboprophylaxis in atrial fibrillation (AF), their limitations have led to widespread underutilisation, especially in the developing world. Novel oral anticoagulants (NOACs) have emerged as promising alternatives to VKAs, although there are some particular considerations and challenges to their introduction in developing countries. This review summarises the current state of antithrombotic management of AF in the developing world, explores the early evidence for the NOACs and describes some of the special considerations that must be taken into account when considering the role of the NOACs within developing countries' health care systems. A literature search was conducted via PubMed and Google Scholar to find articles published in English between the years 2000 to 2014. Search terms used were "atrial fibrillation", "oral anticoagulants", "warfarin", "NOACs", "dabigatran", "rivaroxaban", "apixaban", "edoxaban", "time in therapeutic range", "International Normalized Ratio" "cost-effectiveness", "stroke", "adverse-drug reactions" and "drug-drug interactions", together with the individual names of developing countries as listed by the World Bank. We reviewed the results of randomized clinical trials, relevant retrospective and prospective studies, case-studies and review articles. Many developing countries lack or have sporadic data on the quality of AF management, making it difficult to anticipate the potential impact of NOACs in these settings. The utilisation of anticoagulants for AF appears highly variable in developing countries. Given the issues associated with VKA therapy in many developing countries, NOACs offer some potential advantages; however, there is insufficient evidence to advocate the widespread replacement of warfarin at present. VKAs may continue to have a role in selected patients or countries, especially if alternative monitoring strategies can be utilised. The evaluation of the introduction of NOACs should consider safety, budget concerns and the quality of oral anticoagulation care achieved by each country. Prospective registries will be important in developing countries to better elucidate the comparative safety, efficacy and cost-effectiveness of NOACs and VKAs as NOACs are introduced into practice.

A Method for LC-MS/MS Profiling of Coumarins in Zanthoxylum zanthoxyloides (Lam.) B. Zepernich and Timler Extracts and Essential Oils.

PubMed

Tine, Yoro; Renucci, Franck; Costa, Jean; Wélé, Alassane; Paolini, Julien

2017-01-22

The metabolites from the coumarin class, present in tissues of plants belonging mainly to the Rutaceae and Apiaceae families, included compounds with high chemical diversity such as simple coumarins and furocoumarins. These health-promoting components are recognized for their valuable biological activities in herbal preparations but also for their phototoxic effects. In this work, a targeted liquid chromatography (LC) coupled with tandem mass spectrometry (MS²) was developed for the screening of 39 reference standards of coumarins and furocoumarins in essential oils and plant extracts. Chromatographic separation was accomplished on reversed phase column using water/acetonitrile as the mobile phase and detection was performed on a hybrid QqQ/linear ion trap spectrometer fitted with an atmospheric pressure chemical ionization (APCI) source operating in positive ion mode. This analytical approach was applied to investigate the coumarin compositions of fruit essential oils and methanolic extracts obtained from separated parts (fruit, leaf, stem, trunk, and root) of Zanthoxylum zanthoxyloides . Ten coumarins and six furanocoumarins were reported in this species and data analyses were used to assess the suitability of these compounds to the metabolomics-based differentiation of plant organs. The quantification criteria of the metabolites in extract samples included linearity, limit of quantification, limit of detection, and matrix effect were validated. As reported for other species of the Rutaceae family, the concentration of coumarins was drastically higher in Z. zanthoxyloides fruits than in other plant organs.

Magnetic Resonance Imaging Findings Predict the Recurrence of Chronic Subdural Hematoma

PubMed Central

GOTO, Haruo; ISHIKAWA, Osamu; NOMURA, Masashi; TANAKA, Kentaro; NOMURA, Seiji; MAEDA, Keiichiro

2015-01-01

The exact predictive factors for postoperative recurrence of chronic subdural hematoma (CSDH) are still unknown. Based on the preoperative magnetic resonance imaging (MRI), low recurrence rate of T1-hyperintensity hematoma was previously reported. We investigated the other types of radiological findings which are related to the recurrence rate of CSDH in large number of patients analyzed by multivariate logistic regression model. Preoperative MRI and postoperative computed tomography (CT) were performed and the influence of the preoperative use of antiplatelet or anticoagulant drugs was also studied. The overall recurrence rate was 9.3% (47 of 505 hematomas). The MRI T1-iso/hypointensity group showed a significantly higher recurrence rate (18.2%, 29 of 159) compared to the other groups (5.2%, 18 of 346; p < 0.001). Multivariate logistic regression analysis showed T1 classification was the solo significant prognostic predictor among various factors such as bilateral hematoma, antiplatelet or anticoagulant drug usage, residual hematoma on postoperative CT, and MRI classification (p < 0.001): adjusted odds ratio for the recurrence in T1-iso/hypointensity group relative to the T1-hyperintensity group was 5.58 [95% confidence interval (CI), 2.09–14.86] (p = 0.001). Postoperative residual hematoma and antiplatelet or anticoagulant drug usage did not increase the recurrence risk. The preoperative MRI findings, especially T1WI findings, have predictive value for postoperative recurrence of CSDH and the T1-iso/hypointensity group can be assumed to be a high recurrence risk group. PMID:25746312

Cardioembolic Stroke

PubMed Central

Kamel, Hooman; Healey, Jeff S.

2017-01-01

Cardiac embolism accounts for an increasing proportion of ischemic strokes, and might multiply several-fold over the next decades. However, research points to several potential strategies to stem this expected rise in cardioembolic stroke. First, although one-third of strokes are of unclear cause, it is increasingly accepted that many of these cryptogenic strokes arise from a distant embolism rather than in-situ cerebrovascular disease, leading to the recent formulation of “embolic stroke of undetermined source” (ESUS) as a distinct target for investigation. Second, recent clinical trials have indicated that ESUS may often stem from subclinical atrial fibrillation (AF) which can be diagnosed with prolonged heart-rhythm monitoring. Third, emerging evidence indicates that a thrombogenic atrial substrate can lead to atrial thromboembolism even in the absence of AF. Such an atrial cardiopathy may explain many cases of ESUS, and oral anticoagulant drugs may prove to reduce stroke risk from atrial cardiopathy given its parallels to AF. Non-vitamin K antagonist oral anticoagulant (NOAC) drugs have recently expanded therapeutic options for preventing cardioembolic stroke and are currently being tested for stroke prevention in patients with ESUS, including specifically those with atrial cardiopathy. Fourth, increasing appreciation of thrombogenic atrial substrate and the common co-existence of cardiac and extra-cardiac stroke risk factors suggests benefits from global vascular risk factor management in addition to anticoagulation. Finally, improved imaging of ventricular thrombus plus the availability of NOAC drugs may lead to better prevention of stroke from acute myocardial infarction and heart failure. PMID:28154101

Trends in initiation of direct oral anticoagulant therapies for atrial fibrillation in a national population-based cross-sectional study in the French health insurance databases

PubMed Central

Huiart, Laetitia; Ferdynus, Cyril; Renoux, Christel; Beaugrand, Amélie; Lafarge, Sophie; Bruneau, Léa; Suissa, Samy; Maillard, Olivier; Ranouil, Xavier

2018-01-01

Objective Unlike several other national health agencies, French health authorities recommended that the newer direct oral anticoagulant (DOAC) agents only be prescribed as second choice for the treatment of newly diagnosed non-valvular atrial fibrillation (NVAF), with vitamin K antagonists (VKA) remaining the first choice. We investigated the patterns of use of DOACs versus VKA in the treatment of NVAF in France over the first 5 years of DOAC availability. We also identified the changes in patient characteristics of those who initiated DOAC treatment over this time period. Methods Based on the French National Health Administrative Database, we constituted a population-based cohort of all patients who were newly treated for NVAF between January 2011 and December 2015. Trends in drug use were described as the percentage of patients initiating each drug at the time of treatment initiation. A multivariate analysis using logistic regression model was performed to identify independent sociodemographic and clinical predictors of initial anticoagulant choice. Results The cohort comprised 814 446 patients who had received a new anticoagulant treatment for NVAF. The proportion of patients using DOACs as initial anticoagulant therapy reached 54% 3 months after the Health Ministry approved the reimbursement of dabigatran for NVAF, and 61% by the end of 2015, versus VKA use. In the multivariate analysis, we found that DOAC initiators were younger and healthier overall than VKA initiators, and this tendency was reinforced over the 2011–2014 period. DOACs were more frequently prescribed by cardiologists in 2012 and after (adjusted OR in 2012: 2.47; 95% CI 2.40 to 2.54). Conclusion Despite recommendations from health authorities, DOACs have been rapidly and massively adopted as initial therapy for NVAF in France. Observational studies should account for the fact that patients selected to initiate DOAC treatment are healthier overall, as failure to do so may bias the risk–benefit assessment of DOACs. PMID:29602837

Setting priorities in the health care sector - the case of oral anticoagulants in nonvalvular atrial fibrillation in Denmark.

PubMed

Poulsen, Peter Bo; Johnsen, Søren Paaske; Hansen, Morten Lock; Brandes, Axel; Husted, Steen; Harboe, Louise; Dybro, Lars

2017-01-01

Resources devoted to health care are limited, therefore setting priorities is required. It differs between countries whether decision-making concerning health care technologies focus on broad economic perspectives or whether focus is narrow on single budgets ("silo mentality"). The cost perspective as one part of the full health economic analysis is important for decision-making. With the case of oral anticoagulants in patients with nonvalvular atrial fibrillation (NVAF), the aim is to discuss the implication of the use of different cost perspectives for decision-making and priority setting. In a cost analysis, the annual average total costs of five oral anticoagulants (warfarin and non-vitamin K oral anticoagulants [NOACs; dabigatran, rivaroxaban, apixaban, and edoxaban]) used in daily clinical practice in Denmark for the prevention of stroke in NVAF patients are analyzed. This is done in pairwise comparisons between warfarin and each NOAC based on five potential cost perspectives, from a "drug cost only" perspective up to a "societal" perspective. All comparisons of warfarin and NOACs show that the cost perspective based on all relevant costs, ie, total costs perspective, is essential for the choice of therapy. Focusing on the reimbursement costs of the drugs only, warfarin is the least costly option. However, with the aim of therapy to prevent strokes and limit bleedings, including the economic impact of this, all NOACs, except rivaroxaban, result in slightly lower health care costs compared with warfarin. The same picture was found applying the societal perspective. Many broad cost-effectiveness analyses of NOACs exist. However, in countries with budget focus in decision-making this information does not apply. The present study's case of oral anticoagulants has shown that decision-making should be based on health care or societal cost perspectives for optimal use of limited resources. Otherwise, the risk is that suboptimal decisions will be likely.

Using Artificial Intelligence to Reduce the Risk of Nonadherence in Patients on Anticoagulation Therapy

PubMed Central

Labovitz, Daniel L.; Shafner, Laura; Gil, Morayma Reyes; Virmani, Deepti; Hanina, Adam

2017-01-01

Background and Purpose This study evaluated the use of an artificial intelligence (AI) platform on mobile devices in measuring and increasing medication adherence in stroke patients on anticoagulation therapy. The introduction of direct oral anticoagulants (DOACs), while reducing the need for monitoring, have also placed pressure on patients to self-manage. Suboptimal adherence goes undetected as routine laboratory tests are not reliable indicators of adherence, placing patients at increased risk of stroke and bleeding. Methods A randomized, parallel-group, 12-week study was conducted in adults (n = 28) with recently diagnosed ischemic stroke receiving any anticoagulation. Patients were randomized to daily monitoring by the AI Platform (intervention) or to no daily monitoring (control). The AI application visually identified the patient, the medication and confirmed ingestion. Adherence was measured by pill counts and plasma sampling in both groups. Results For all patients (n = 28), mean (standard deviation [SD]) age was 57 (13.2) years and 53.6% were female. Mean (SD) cumulative adherence based on the AI Platform was 90.5% (7.5%). Plasma drug concentration levels indicated that adherence was 100% (15 of 15) and 50% (6 of 12) in the intervention and control groups, respectively. Conclusions Patients, some with little experience using a smartphone, successfully used the technology and demonstrated a 50% improvement in adherence based on plasma drug concentration levels. For patients receiving DOACs, absolute improvement increased to 67%. Real-time monitoring has the potential to increase adherence and change behavior, particularly in patients on DOAC therapy. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT02599259. PMID:28386037

Choosing a particular oral anticoagulant and dose for stroke prevention in individual patients with non-valvular atrial fibrillation: part 1

PubMed Central

Diener, Hans-Christoph; Aisenberg, James; Ansell, Jack; Atar, Dan; Breithardt, Günter; Eikelboom, John; Ezekowitz, Michael D.; Granger, Christopher B.; Halperin, Jonathan L.; Hohnloser, Stefan H.; Hylek, Elaine M.; Kirchhof, Paulus; Lane, Deirdre A.; Verheugt, Freek W.A.; Veltkamp, Roland; Lip, Gregory Y.H.

2017-01-01

Patients with atrial fibrillation (AF) have a high risk of stroke and mortality, which can be considerably reduced by oral anticoagulants (OAC). Recently, four non-vitamin-K oral anticoagulants (NOACs) were compared with warfarin in large randomized trials for the prevention of stroke and systemic embolism. Today's clinician is faced with the difficult task of selecting a suitable OAC for a patient with a particular clinical profile or a particular pattern of risk factors and concomitant diseases. We reviewed analyses of subgroups of patients from trials of vitamin K antagonists vs. NOACs for stroke prevention in AF with the aim to identify patient groups who might benefit from a particular OAC more than from another. In the first of a two-part review, we discuss the choice of NOAC for stroke prevention in the following subgroups of patients with AF: (i) stable coronary artery disease or peripheral artery disease, including percutaneous coronary intervention with stenting and triple therapy; (ii) cardioversion, ablation and anti-arrhythmic drug therapy; (iii) mechanical valves and rheumatic valve disease, (iv) patients with time in therapeutic range of >70% on warfarin; (v) patients with a single stroke risk factor (CHA2DS2VASc score of 1 in males, 2 in females); and (vi) patients with a single first episode of paroxysmal AF. Although there are no major differences in terms of efficacy and safety between the NOACs for some clinical scenarios, in others we are able to suggest that particular drugs and/or doses be prioritized for anticoagulation. PMID:26848149

Efficiency and effectiveness of the use of an acenocoumarol pharmacogenetic dosing algorithm versus usual care in patients with venous thromboembolic disease initiating oral anticoagulation: study protocol for a randomized controlled trial

PubMed Central

2012-01-01

Background Hemorrhagic events are frequent in patients on treatment with antivitamin-K oral anticoagulants due to their narrow therapeutic margin. Studies performed with acenocoumarol have shown the relationship between demographic, clinical and genotypic variants and the response to these drugs. Once the influence of these genetic and clinical factors on the dose of acenocoumarol needed to maintain a stable international normalized ratio (INR) has been demonstrated, new strategies need to be developed to predict the appropriate doses of this drug. Several pharmacogenetic algorithms have been developed for warfarin, but only three have been developed for acenocoumarol. After the development of a pharmacogenetic algorithm, the obvious next step is to demonstrate its effectiveness and utility by means of a randomized controlled trial. The aim of this study is to evaluate the effectiveness and efficiency of an acenocoumarol dosing algorithm developed by our group which includes demographic, clinical and pharmacogenetic variables (VKORC1, CYP2C9, CYP4F2 and ApoE) in patients with venous thromboembolism (VTE). Methods and design This is a multicenter, single blind, randomized controlled clinical trial. The protocol has been approved by La Paz University Hospital Research Ethics Committee and by the Spanish Drug Agency. Two hundred and forty patients with VTE in which oral anticoagulant therapy is indicated will be included. Randomization (case/control 1:1) will be stratified by center. Acenocoumarol dose in the control group will be scheduled and adjusted following common clinical practice; in the experimental arm dosing will be following an individualized algorithm developed and validated by our group. Patients will be followed for three months. The main endpoints are: 1) Percentage of patients with INR within the therapeutic range on day seven after initiation of oral anticoagulant therapy; 2) Time from the start of oral anticoagulant treatment to achievement of a stable INR within the therapeutic range; 3) Number of INR determinations within the therapeutic range in the first six weeks of treatment. Discussion To date, there are no clinical trials comparing pharmacogenetic acenocoumarol dosing algorithm versus routine clinical practice in VTE. Implementation of this pharmacogenetic algorithm in the clinical practice routine could reduce side effects and improve patient safety. Trial registration Eudra CT. Identifier: 2009-016643-18. PMID:23237631

Dissociation between the pharmacokinetics and pharmacodynamics of once-daily rivaroxaban and twice-daily apixaban: a randomized crossover study.

PubMed

Kreutz, R; Persson, P B; Kubitza, D; Thelen, K; Heitmeier, S; Schwers, S; Becka, M; Hemmrich, M

2017-10-01

Essentials In this crossover study the anticoagulant effects of rivaroxaban and apixaban were compared. Healthy volunteers received rivaroxaban 20 mg once daily or apixaban 5 mg twice daily. Rivaroxaban was associated with more prolonged inhibition of thrombin generation than apixaban. Rivaroxaban induced a clear prolongation of prothrombin time and activated partial thromboplastin time. Background The anticoagulant actions of the oral direct activated factor Xa inhibitors, rivaroxaban and apixaban, have not previously been directly compared. Objectives To compare directly the steady-state pharmacokinetics and anticoagulant effects of rivaroxaban and apixaban at doses approved for stroke prevention in patients with non-valvular atrial fibrillation. Methods Twenty-four healthy Caucasian male volunteers were included in this open-label, two-period crossover, phase 1 study (EudraCT number: 2015-002612-32). Volunteers were randomized to receive rivaroxaban 20 mg once daily or apixaban 5 mg twice daily for 7 days, followed by a washout period of at least 7 days before they received the other treatment. Plasma concentrations and anticoagulant effects were measured at steady state and after drug discontinuation. Results Overall exposure was similar for both drugs: the geometric mean area under the plasma concentration-time curve for the 0-24-h interval was 1830 μg h L -1 for rivaroxaban and 1860 μg h L -1 for apixaban. Rivaroxaban was associated with greater inhibition of endogenous thrombin potential (geometric mean area under the curve relative to baseline during the 0-24-h interval: 15.5 h versus 17.5 h) and a more pronounced maximal prolongation relative to baseline of prothrombin time (PT) (1.66-fold versus 1.14-fold) and activated partial thromboplastin time (APTT) (1.43-fold versus 1.16-fold) at steady state than apixaban. Conclusions Despite similar exposure to both drugs, rivaroxaban 20 mg once daily was associated with greater and more sustained inhibition of thrombin generation than apixaban 5 mg twice daily. Sensitive PT and APTT assays can be used to estimate the anticoagulant effects of rivaroxaban. © 2017 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.

NPC1L1 is a key regulator of intestinal vitamin K absorption and a modulator of warfarin therapy.

PubMed

Takada, Tappei; Yamanashi, Yoshihide; Konishi, Kentaro; Yamamoto, Takehito; Toyoda, Yu; Masuo, Yusuke; Yamamoto, Hideaki; Suzuki, Hiroshi

2015-02-18

Vitamin K (VK) is a micronutrient that facilitates blood coagulation. VK antagonists, such as warfarin, are used in the clinic to prevent thromboembolism. Because VK is not synthesized in the body, its intestinal absorption is crucial for maintaining whole-body VK levels. However, the molecular mechanism of this absorption is unclear. We demonstrate that Niemann-Pick C1-like 1 (NPC1L1) protein, a cholesterol transporter, plays a central role in intestinal VK uptake and modulates the anticoagulant effect of warfarin. In vitro studies using NPC1L1-overexpressing intestinal cells and in vivo studies with Npc1l1-knockout mice revealed that intestinal VK absorption is NPC1L1-dependent and inhibited by ezetimibe, an NPC1L1-selective inhibitor clinically used for dyslipidemia. In addition, in vivo pharmacological studies demonstrated that the coadministration of ezetimibe and warfarin caused a reduction in hepatic VK levels and enhanced the pharmacological effect of warfarin. Adverse events caused by the coadministration of ezetimibe and warfarin were rescued by oral VK supplementation, suggesting that the drug-drug interaction effects observed were the consequence of ezetimibe-mediated VK malabsorption. This mechanism was supported by a retrospective evaluation of clinical data showing that, in more than 85% of warfarin-treated patients, the anticoagulant activity was enhanced by cotreatment with ezetimibe. Our findings provide insight into the molecular mechanism of VK absorption. This new drug-drug interaction mechanism between ezetimibe (a cholesterol transport inhibitor) and warfarin (a VK antagonist and anticoagulant) could inform clinical care of patients on these medications, such as by altering the kinetics of essential, fat-soluble vitamins. Copyright © 2015, American Association for the Advancement of Science.

Safety profile of the direct oral anticoagulants: an analysis of the WHO database of adverse drug reactions.

PubMed

Monaco, Luca; Biagi, Chiara; Conti, Valentino; Melis, Mauro; Donati, Monia; Venegoni, Mauro; Vaccheri, Alberto; Motola, Domenico

2017-07-01

Direct oral anticoagulants (DOACs) have shown noninferiority to warfarin for stroke prevention in nonvalvular atrial fibrillation (AF) and a more promising safety profile. Unanswered safety aspects remain to be addressed and available evidence on the risk associated with these drugs are conflicting. In order to contribute to the debate on their safety profile, we conducted a comparative analysis of the reports of suspected adverse drug reactions (ADRs) associated with DOACs in VigiBase. Study based on reports of suspected ADRs held in VigiBase as at December 2014, in which a DOAC or warfarin were administered in patients with nonvalvular AF and listed as suspected/interacting drugs. Medical Dictionary for Regulatory Activities was used to classify ADRs. Reporting odds ratio (ROR) with 95% confidence interval were calculated. Results with P ≤ 0.05 were statistically significant. We retrieved 32 972 reports. We identified 204 ADRs with a ROR >1 (P ≤ 0.05) and we focused on 105 reactions. Positive ROR emerged for DOACs and gastrointestinal haemorrhage compared with warfarin [(1.6 (1.47-1.75)], but no disproportionality with cerebral haemorrhage was found [0.31 (0.28-0.34)]. We identified other potential signals that have not been associated with DOACs previously. As well as premarketing authorization clinical trial studies, we found a reduced risk of intracranial haemorrhage, but an increased risk of gastrointestinal haemorrhage in patients treated with DOACs compared to warfarin. We provide new data and we highlight several differences between the three novel oral anticoagulants, in the rate and type of ADRs occurred. © 2017 The British Pharmacological Society.

[Appropriateness of the prescriptions of conventional versus new oral anticoagulants at discharge from a department of internal medicine].

PubMed

Bochatay, L; Beney, J; Jordan-von Gunten, V; Petignat, P A; Roulet, L

2016-09-01

The recently introduced oral direct anticoagulants (ODAs), presumably safer, and with comparable efficacy to the vitamin K antagonists (VKAs), may reshape the world of anticoagulation medicine. This study aimed to assess the prescription appropriateness of ODAs and VKAs at discharge from hospital. We performed a one year retrospective study between August 2012 and July 2013 in the department of internal medicine of a regional hospital (HVs Sion) using Electronic Medical Records. All patients receiving an ODA were included and matched to a patient treated with a VKA. The appropriateness of prescription at discharge was defined by an adequate indication and dosing, the absence of contraindication, a minimal risk of drug-drug interactions and no major bleeding or venous thromboembolism during the hospitalization. The bleeding risk was evaluated with the HAS-BLED score when the indication was atrial fibrillation (AF). Out of the 44patients included (22 with an ODA and 22 with a VKA), 38 received an appropriate prescription according to all criteria. Two patients had an inadequate dosing. A potential drug-drug interaction was detected in 3patients receiving a VKA and in 1patient receiving an ODA. No major contraindication was found, but a relative contraindication was discussed in 3cases. The majority of patients receiving an ODA for an AF had a minor bleeding risk. No significant difference was ascertained between the two groups regarding the appropriateness of prescription. Our results suggest that ODAs were cautiously used in our setting. Copyright © 2015 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier SAS. All rights reserved.

The Effect of Millisecond Pulsed Electric Fields (msPEF) on Intracellular Drug Transport with Negatively Charged Large Nanocarriers Made of Solid Lipid Nanoparticles (SLN): In Vitro Study.

PubMed

Kulbacka, Julita; Pucek, Agata; Wilk, Kazimiera Anna; Dubińska-Magiera, Magda; Rossowska, Joanna; Kulbacki, Marek; Kotulska, Małgorzata

2016-10-01

Drug delivery technology is still a dynamically developing field of medicine. The main direction in nanotechnology research (nanocarriers, nanovehicles, etc.) is efficient drug delivery to target cells with simultaneous drug reduction concentration. However, nanotechnology trends in reducing the carrier sizes to several nanometers limit the volume of the loaded substance and may pose a danger of uncontrolled access into the cells. On the other hand, nanoparticles larger than 200 nm in diameter have difficulties to undergo rapid diffusional transport through cell membranes. The main advantage of large nanoparticles is higher drug encapsulation efficiency and the ability to deliver a wider array of drugs. Our present study contributes a new approach with large Tween 80 solid lipid nanoparticles SLN (i.e., hydrodynamic GM-SLN-glycerol monostearate, GM, as the lipid and ATO5-SLNs-glyceryl palmitostearate, ATO5, as the lipid) with diameters DH of 379.4 nm and 547 nm, respectively. They are used as drug carriers alone and in combination with electroporation (EP) induced by millisecond pulsed electric fields. We evaluate if EP can support the transport of large nanocarriers into cells. The study was performed with two cell lines: human colon adenocarcinoma LoVo and hamster ovarian fibroblastoid CHO-K1 with coumarin 6 (C6) as a fluorescent marker for encapsulation. The biological safety of the potential treatment procedure was evaluated with cell viability after their exposure to nanoparticles and EP. The EP efficacy was evaluated by FACS method. The impact on intracellular structure organization of cytoskeleton was visualized by CLSM method with alpha-actin and beta-tubulin. The obtained results indicate low cytotoxicity of both carrier types, free and loaded with C6. The evaluation of cytoskeleton proteins indicated no intracellular structure damage. The intracellular uptake and accumulation show that SLNs do not support transport of C6 coumarin. Only application of electroporation improved the transport of encapsulated and free C6 into both treated cell lines.

Comparative evaluation of flavone from Mucuna pruriens and coumarin from Ionidium suffruticosum for hypolipidemic activity in rats fed with high fat diet.

PubMed

Dharmarajan, Satheesh Kumar; Arumugam, Kottai Muthu

2012-10-02

The objective of the study is a comparative evaluation of flavone isolated from Mucuna pruriens and coumarin isolated from Ionidium suffruticosum was assessed for the hypolipidemic activity in rats fed with high fat diet. The acute toxicity study was found that flavone (M.pruriens) and coumarin (I.suffruticosum) are safe up to 100 mg/kg, so one tenth of this dose (10 mg/kg) was consider as a evaluation dose. High fat diet group of rats showed significant (p<0.001) elevation in plasma total and LDL-cholesterol, triglycerides and phospholipids. Administration of flavone (M. pruriens) and coumarin isolated from (I.suffruticosum) at the dose of 10mg/kg b.wt/day along with high fat diet significantly (p<0.001) prevented the rise in the plasma total and LDL-cholesterol, triglycerides and phospholipids than that of other extracts. However, treatment of coumarin isolated from (I.suffruticosum) had showed more cardio protective effect against hyperlipidemia than that of flavone (M.pruriens).

Intra-arterial thrombolysis of digital artery occlusions in a patient with polycythemia vera.

PubMed

Jud, Philipp; Hafner, Franz; Gary, Thomas; Ghanim, Leyla; Lipp, Rainer; Brodmann, Marianne

2017-01-01

There are limited therapeutic options for the resolution of digital artery occlusions. Intra-arterial thrombolysis with anticoagulative and thrombolytic drugs successfully restored the blood flow in the affected digital arteries.

Esculetin and esculin (esculetin 6-O-glucoside) occur as inclusions and are differentially distributed in the vacuole of palisade cells in Fraxinus ornus leaves: a fluorescence microscopy analysis.

PubMed

Tattini, Massimiliano; Di Ferdinando, Martina; Brunetti, Cecilia; Goti, Andrea; Pollastri, Susanna; Bellasio, Chandra; Giordano, Cristiana; Fini, Alessio; Agati, Giovanni

2014-11-01

The location of individual coumarins in leaves of Fraxinus ornus acclimated at full solar irradiance was estimated using their specific UV- and fluorescence spectral features. Using a combination of UV-induced fluorescence and blue light-induced fluorescence of tissues stained with diphenylborinic acid 2-amino-ethylester, in wide field or confocal laser scanning microscopy, we were able to visualize the distribution of esculetin and esculetin 6-O-glucoside (esculin) in palisade cells. Coumarins are not uniformly distributed in the cell vacuole, but accumulate mostly in the adaxial portion of palisade cells. Our study indeed shows, for the first time, that coumarins in palisade cells accumulate as vacuolar inclusions, as previously reported in the pertinent literature only for anthocyanins. Furthermore, esculetin and esculin have a different vacuolar distribution: esculetin largely predominates in the first 15 μm from the adaxial epidermis. This leads to hypothesize for esculetin and esculin different transport mechanisms from the endoplasmic reticulum to the vacuole as well as potentially different roles in photoprotection. Our study open to new experiments aimed at exploring the mechanisms that deliver coumarins to the vacuole using different fluorescence signatures of coumarin aglycones and coumarin glycosides. Copyright © 2014 Elsevier B.V. All rights reserved.

Ultrafast Electron Transfer across a Nanocapsular Wall: Coumarins as Donors, Viologen as Acceptor, and Octa Acid Capsule as the Mediator.

PubMed

Chuang, Chi-Hung; Porel, Mintu; Choudhury, Rajib; Burda, Clemens; Ramamurthy, V

2018-01-11

Results of our study on ultrafast electron transfer (eT) dynamics from coumarins (coumarin-1, coumarin-480, and coumarin-153) incarcerated within octa acid (OA) capsules as electron donors to methyl viologen dissolved in water as acceptor are presented. Upon photoexcitation, coumarin inside the OA capsule transfers an electron to the acceptor electrostatically attached to the capsule leading to a long-lived radical-ion pair separated by the OA capsular wall. This charge-separated state returns to the neutral ground state via back electron transfer on the nanosecond time scale. This system allows for ultrafast electron transfer processes through a molecular wall from the apolar capsular interior to the highly polar (aqueous) environment on the femtosecond time scale. Employing femtosecond transient absorption spectroscopy, distinct rates of both forward (1-25 ps) and backward eT (700-1200 ps) processes were measured. Further understanding of the energetics is provided using Rehm-Weller analysis for the investigated photoinduced eT reactions. The results provide the rates of the eT across a molecular wall, akin to an isotropic solution, depending on the standard free energy of the reaction. The insights from this work could be utilized in the future design of efficient electron transfer processes across interfaces separating apolar and polar environments.

The influence of naphthaleneacetic acid (NAA) and coumarin on flavonoid production by fungus Phellinus sp.: modeling of production kinetic profiles.

PubMed

Ma, Xiao-Kui; Li, Le; Peterson, Eric Charles; Ruan, Tingting; Duan, Xiaoyi

2015-11-01

For the purpose of improving the fungal production of flavonoids, the influence of naphthaleneacetic acid (NAA) and coumarin on flavonoid production by fungus Phellinus sp. P0988 was investigated by developing the corresponding kinetics of flavonoid production in a 7-L bioreactor. Phellinus sp. was confirmed to form flavonoids in pellets and broth when cultivated in basic medium, and the optimum concentration of NAA and coumarin in medium for flavonoid production were determined to be 0.03 and 0.02 g/L, respectively. The developed unstructured mathematical models were in good agreement with the experimental results with respect to flavonoid production kinetic profiles with NAA and coumarin supplementation at optimum levels and revealed significant accuracy in terms of statistical consistency and robustness. Analysis of these kinetic processes indicated that NAA and coumarin supplementations imposed a stronger positive influence on flavonoid production and substrate consumption compared to their effects on cell growth. The separate addition of NAA and coumarin resulted in enhancements in final product accumulation and productivity, achieving final flavonoid concentrations of 3.60 and 2.75 g/L, respectively, and glucose consumption showed a significant decrease compared to the non-supplemented control as well. Also, the separate presence of NAA and coumarin respectively decreased maintenance coefficients (M s) from 2.48 in the control to 1.39 and 0.22, representing decreases of 43.9 and 91.1 %, respectively. The current study is the first known application of mathematical kinetic models to explore the influence of medium components adding on flavonoid production by fungi.

The Distribution of Coumarins and Furanocoumarins in Citrus Species Closely Matches Citrus Phylogeny and Reflects the Organization of Biosynthetic Pathways

PubMed Central

Dugrand-Judek, Audray; Olry, Alexandre; Hehn, Alain; Costantino, Gilles; Ollitrault, Patrick; Froelicher, Yann; Bourgaud, Frédéric

2015-01-01

Citrus plants are able to produce defense compounds such as coumarins and furanocoumarins to cope with herbivorous insects and pathogens. In humans, these chemical compounds are strong photosensitizers and can interact with medications, leading to the “grapefruit juice effect”. Removing coumarins and furanocoumarins from food and cosmetics imply additional costs and might alter product quality. Thus, the selection of Citrus cultivars displaying low coumarin and furanocoumarin contents constitutes a valuable alternative. In this study, we performed ultra-performance liquid chromatography coupled with mass spectrometry analyses to determine the contents of these compounds within the peel and the pulp of 61 Citrus species representative of the genetic diversity all Citrus. Generally, Citrus peel contains larger diversity and higher concentrations of coumarin/furanocoumarin than the pulp of the same fruits. According to the chemotypes found in the peel, Citrus species can be separated into 4 groups that correspond to the 4 ancestral taxa (pummelos, mandarins, citrons and papedas) and extended with their respective secondary species descendants. Three of the 4 ancestral taxa (pummelos, citrons and papedas) synthesize high amounts of these compounds, whereas mandarins appear practically devoid of them. Additionally, all ancestral taxa and their hybrids are logically organized according to the coumarin and furanocoumarin pathways described in the literature. This organization allows hypotheses to be drawn regarding the biosynthetic origin of compounds for which the biogenesis remains unresolved. Determining coumarin and furanocoumarin contents is also helpful for hypothesizing the origin of Citrus species for which the phylogeny is presently not firmly established. Finally, this work also notes favorable hybridization schemes that will lead to low coumarin and furanocoumarin contents, and we propose to select mandarins and Ichang papeda as Citrus varieties for use in creating species devoid of these toxic compounds in future breeding programs. PMID:26558757

Acute Pulmonary Embolism in Emergency Department Patients Despite Therapeutic Anticoagulation.

PubMed

Liu, Michelle Y; Ballard, Dustin W; Huang, Jie; Rauchwerger, Adina S; Reed, Mary E; Bouvet, Sean C; Vinson, David R

2018-05-01

Emergency department (ED) patients with acute pulmonary embolism (PE) despite therapeutic anticoagulation at the time of diagnosis are uncommonly encountered and present a diagnostic and management challenge. Their characterization and outcomes are poorly described. We sought to describe the prevalence and characteristics of therapeutically anticoagulated patients among a population of patients with acute PE in a community setting and to describe treatment changes and 30-day outcomes. From a large retrospective cohort of adults with acute, objectively-confirmed PE across 21 EDs between 01/2013 and 04/2015, we identified patients who arrived on direct oral or injectable anticoagulants, or warfarin with an initial ED international normalized ratio (INR) value ≥2.0. Patients were excluded from the larger cohort if they had received a diagnosis of venous thromboembolism (VTE) in the prior 30 days. We gathered demographic and clinical variables from electronic health records and structured manual chart review. We report discharge anticoagulation regimens and major 30-day adverse outcomes. Among 2,996 PE patients, 36 (1.2%) met study criteria. Mean age was 63 years. Eleven patients (31%) had active cancer and 25 (69%) were high risk on the PE Severity Index (Classes III-V), comparable to the larger cohort (p>0.1). Reasons for pre-arrival anticoagulation were VTE treatment or prevention (n=21), and atrial fibrillation or flutter (n=15). All patients arrived on warfarin and one was also on enoxaparin: 32 had a therapeutic INR (2.0-3.0) and four had a supratherapeutic INR (>3.0). Fifteen patients (42%) had at least one subtherapeutic INR (<2.0) in the 14 days preceding their diagnostic visit. Two patients died during hospitalization. Of the 34 ultimately discharged, 22 underwent a change in anticoagulation drug or dosing, 19 of whom received injectables, either to replace or to supplement warfarin. Four patients also received inferior vena cava filters. Thirty-day outcomes included one major hemorrhage and one additional death. No patients experienced recurrent or worsening VTE. We found a low prevalence of therapeutic anticoagulation at the time of acute PE diagnosis. Most patients with breakthrough PE underwent a change in therapy, though management varied widely. Subtherapeutic anticoagulation levels in the preceding weeks were common and support the importance of anticoagulation adherence.

Acute Pulmonary Embolism in Emergency Department Patients Despite Therapeutic Anticoagulation

PubMed Central

Liu, Michelle Y.; Ballard, Dustin W.; Huang, Jie; Rauchwerger, Adina S.; Reed, Mary E.; Bouvet, Sean C.

2018-01-01

Introduction Emergency department (ED) patients with acute pulmonary embolism (PE) despite therapeutic anticoagulation at the time of diagnosis are uncommonly encountered and present a diagnostic and management challenge. Their characterization and outcomes are poorly described. We sought to describe the prevalence and characteristics of therapeutically anticoagulated patients among a population of patients with acute PE in a community setting and to describe treatment changes and 30-day outcomes. Methods From a large retrospective cohort of adults with acute, objectively-confirmed PE across 21 EDs between 01/2013 and 04/2015, we identified patients who arrived on direct oral or injectable anticoagulants, or warfarin with an initial ED international normalized ratio (INR) value ≥2.0. Patients were excluded from the larger cohort if they had received a diagnosis of venous thromboembolism (VTE) in the prior 30 days. We gathered demographic and clinical variables from electronic health records and structured manual chart review. We report discharge anticoagulation regimens and major 30-day adverse outcomes. Results Among 2,996 PE patients, 36 (1.2%) met study criteria. Mean age was 63 years. Eleven patients (31%) had active cancer and 25 (69%) were high risk on the PE Severity Index (Classes III–V), comparable to the larger cohort (p>0.1). Reasons for pre-arrival anticoagulation were VTE treatment or prevention (n=21), and atrial fibrillation or flutter (n=15). All patients arrived on warfarin and one was also on enoxaparin: 32 had a therapeutic INR (2.0–3.0) and four had a supratherapeutic INR (>3.0). Fifteen patients (42%) had at least one subtherapeutic INR (<2.0) in the 14 days preceding their diagnostic visit. Two patients died during hospitalization. Of the 34 ultimately discharged, 22 underwent a change in anticoagulation drug or dosing, 19 of whom received injectables, either to replace or to supplement warfarin. Four patients also received inferior vena cava filters. Thirty-day outcomes included one major hemorrhage and one additional death. No patients experienced recurrent or worsening VTE. Conclusion We found a low prevalence of therapeutic anticoagulation at the time of acute PE diagnosis. Most patients with breakthrough PE underwent a change in therapy, though management varied widely. Subtherapeutic anticoagulation levels in the preceding weeks were common and support the importance of anticoagulation adherence. PMID:29760849

Challenges of stroke prevention in patients with atrial fibrillation in clinical practice.

PubMed

Hobbs, F D Richard; Leach, I

2011-09-01

Strokes and transient ischaemic attacks in patients with atrial fibrillation (AF) can be largely prevented. Risk stratification and appropriate prophylactic regimens help to alleviate the burden of AF-related thromboembolism. Guidelines recommend routine anticoagulation with oral vitamin K antagonists (VKAs) for patients at moderate-to-high risk of stroke, and acetylsalicylic acid (ASA) for those at low risk of stroke. ASA is less effective at reducing the risk of stroke than VKAs; however, ASA does not require monitoring or dose adjustment. Trials of anticoagulants show consistent benefits of oral VKAs for primary and secondary stroke prevention in patients with AF. Nevertheless, VKAs do require frequent coagulation monitoring and dose adjustment because of their variable dose-response profile, narrow therapeutic window, increased risk for bleeding complications and numerous food and drug interactions. This review aims to provide an overview of the clinical challenges of anticoagulant therapy for the prevention of stroke in patients with AF.

Identification of potent orally active factor Xa inhibitors based on conjugation strategy and application of predictable fragment recommender system.

PubMed

Ishihara, Tsukasa; Koga, Yuji; Iwatsuki, Yoshiyuki; Hirayama, Fukushi

2015-01-15

Anticoagulant agents have emerged as a promising class of therapeutic drugs for the treatment and prevention of arterial and venous thrombosis. We investigated a series of novel orally active factor Xa inhibitors designed using our previously reported conjugation strategy to boost oral anticoagulant effect. Structural optimization of anthranilamide derivative 3 as a lead compound with installation of phenolic hydroxyl group and extensive exploration of the P1 binding element led to the identification of 5-chloro-N-(5-chloro-2-pyridyl)-3-hydroxy-2-{[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]amino}benzamide (33, AS1468240) as a potent factor Xa inhibitor with significant oral anticoagulant activity. We also reported a newly developed Free-Wilson-like fragment recommender system based on the integration of R-group decomposition with collaborative filtering for the structural optimization process. Copyright © 2014 Elsevier Ltd. All rights reserved.

Clinical utility of apixaban in the prevention and treatment of venous thromboembolism: current evidence

PubMed Central

Zalpour, Ali; Oo, Thein Hlaing

2014-01-01

Anticoagulation with heparin and vitamin K antagonist has been the mainstay of prevention and treatment of venous thromboembolism (VTE) for many years. In recent years, novel oral anticoagulants such as dabigatran etexilate (a direct thrombin inhibitor) and rivaroxaban, apixaban, and edoxaban (a direct factor Xa inhibitor) have emerged for the prevention and treatment of VTE. Novel oral anticoagulants have been shown to be noninferior to vitamin K antagonist or heparin in the prevention and treatment of VTE. This review specifically examines the role of apixaban in the prevention and treatment of VTE based on the available literature. The management of apixaban in the perioperative setting is also explored because some patients on apixaban may require surgical intervention. Finally, we discuss the management of apixaban-induced major bleeding complications, the relevance of drug–drug interactions, and patient education. PMID:25395835

Comparing thrombin generation in patients with hemophilia A and patients on vitamin K antagonists.

PubMed

de Koning, M L Y; Fischer, K; de Laat, B; Huisman, A; Ninivaggi, M; Schutgens, R E G

2017-05-01

Essentials It is unknown if hemophilia patients with atrial fibrillation need anticoagulation. Endogenous thrombin potentials (ETP) in hemophilia patients and patients on coumarins were compared. Severe hemophilia patients had comparable ETP to therapeutic international normalized ratio (INR). In non-severe hemophilia, 33% had higher ETP than therapeutic INR and may need anticoagulation. Click to hear Dr Negrier's perspective on global assays for assessing coagulation SUMMARY: Background It is unknown whether patients with hemophilia A with atrial fibrillation require treatment with vitamin K antagonists (VKAs) to the same extent as the normal population. Objective To compare hemostatic potential in hemophilia patients and patients on VKAs using thrombin generation (TG). Methods In this cross-sectional study, TG, initiated with 1pM tissue factor, was measured in 133 patients with severe (FVIII < 1%, n = 15) and non-severe (FVIII 1-50%, n = 118) hemophilia A, 97 patients on a VKA with an international normalized ratio (INR) ≥ 1.5 and healthy controls. Endogenous thrombin potential (ETP) (nm*min) was compared according to FVIII level (< 1%, 1-19% and 20-50%) with healthy controls and patients with sub-therapeutic INR (1.5-1.9) and therapeutic INR (≥ 2.0). Medians and interquartile ranges (IQRs) were calculated. Results Compared with healthy controls (898 [IQR 803-1004]), both hemophilia patients and patients on VKAs had lower median ETPs at 304 (196-449) and 176 (100-250), respectively. ETP was quite similar in severe hemophilia patients (185 [116-307]) and patients with a therapeutic INR (156 [90-225]). Compared with patients with therapeutic INR, ETP in patients with FVIII 1-19% and patients with FVIII 20-50% was higher at 296 (203-430) and 397 (219-632), respectively. All patients with therapeutic INR had an ETP < 400. Considering this threshold, 93% of severe hemophilia patients, 70% of patients with FVIII 1-19% and 52% of patients with FVIII 20-50% had an ETP < 400. Conclusion In severe hemophilia patients, TG was comparable to that in patients with a therapeutic INR. In one-third of non-severe hemophilia patients, TG was higher. These results suggest that anticoagulation therapy should be considered in a substantial proportion of non-severe hemophilia patients. © 2017 International Society on Thrombosis and Haemostasis.

Severe jaundice due to intrahepatic cholestasis after initiating anticoagulation with rivaroxaban.

PubMed

Aslan, Abdullah N; Sari, Cenk; Baştuğ, Serdal; Sari, Sevil Ö; Akçay, Murat; Durmaz, Tahir; Bozkurt, Engin

2016-03-01

Rivaroxaban, a highly selective direct factor Xa inhibitor, is a new oral anticoagulant approved by the US Food and Drug Administration in November 2011 for stroke prophylaxis in patients with nonvalvular atrial fibrillation. Because of its efficacy and once-a-day dosing, it is commonly preferred in patients with nonvalvular atrial fibrillation and intolerance to warfarin in clinical practice. However, it can result in some adverse effects such as bleeding, rashes and liver injury. Here, we described a very rare adverse reaction of rivaroxaban, jaundice due to intrahepatic cholestasis, appeared in a 71-year-old male patient after taking rivaroxaban.

Development of Interstitial Lung Disease after Initiation of Apixaban Anticoagulation Therapy.

PubMed

Tomari, Shinya; Homma, Kazunari; Noguchi, Teruo; Aiba, Takeshi; Matsuki, Takayuki; Suzuki, Rieko; Koga, Masatoshi; Takigami, Masao; Tagawa, Hiroshi; Hashimoto, Taisuke; Toyoda, Kazunori

2016-07-01

Nonvitamin K antagonist oral anticoagulants may cause interstitial lung disease (ILD) similar to that seen for other cardiovascular drugs. The aim of this study was to determine trends and medical conditions associated with ILD in patients taking apixaban. A single-center observational survey conducted between February 2013 and May 2015 examined patients who developed ILD after initiation of apixaban administration. Chest computed tomography showed that 4 (~.45%) out of approximately 870 apixaban users developed ILD. All patients were elderly Japanese men with decreased creatinine clearance who had nonvalvular atrial fibrillation. Three of the four were confirmed smokers, whereas three had a history of lung disease. Dyspnea occurred during the initial week after starting apixaban administration in 3 patients and at 90 days in 1 patient. All patients underwent methylprednisolone pulse therapy, with three requiring mechanical ventilation. Although 2 patients recovered, the other two died of respiratory failure. Development of ILD during anticoagulation with apixaban is not rare. When apixaban is administered in elderly high-risk patients, subjects need to be carefully monitored for respiratory symptoms. As drug-induced ILD is often reported in Japan, further studies that clarify if these types of cases are common in countries other than Japan will also need to be undertaken. Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Multipurpose HTS Coagulation Analysis: Assay Development and Assessment of Coagulopathic Snake Venoms

PubMed Central

Still, Kristina B. M.; Nandlal, Randjana S. S.; Slagboom, Julien; Somsen, Govert W.; Kool, Jeroen

2017-01-01

Coagulation assays currently employed are often low throughput, require specialized equipment and/or require large blood/plasma samples. This study describes the development, optimization and early application of a generic low-volume and high-throughput screening (HTS) assay for coagulation activity. The assay is a time-course spectrophotometric measurement which kinetically measures the clotting profile of bovine or human plasma incubated with Ca2+ and a test compound. The HTS assay can be a valuable new tool for coagulation diagnostics in hospitals, for research in coagulation disorders, for drug discovery and for venom research. A major effect following envenomation by many venomous snakes is perturbation of blood coagulation caused by haemotoxic compounds present in the venom. These compounds, such as anticoagulants, are potential leads in drug discovery for cardiovascular diseases. The assay was implemented in an integrated analytical approach consisting of reversed-phase liquid chromatography (LC) for separation of crude venom components in combination with parallel post-column coagulation screening and mass spectrometry (MS). The approach was applied for the rapid assessment and identification of profiles of haemotoxic compounds in snake venoms. Procoagulant and anticoagulant activities were correlated with accurate masses from the parallel MS measurements, facilitating the detection of peptides showing strong anticoagulant activity. PMID:29186818

The high-resolution crystal structure of a 24-kDa gyrase B fragment from E. coli complexed with one of the most potent coumarin inhibitors, clorobiocin.

PubMed

Tsai, F T; Singh, O M; Skarzynski, T; Wonacott, A J; Weston, S; Tucker, A; Pauptit, R A; Breeze, A L; Poyser, J P; O'Brien, R; Ladbury, J E; Wigley, D B

1997-05-01

Coumarin antibiotics, such as clorobiocin, novobiocin, and coumermycin A1, inhibit the supercoiling activity of gyrase by binding to the gyrase B (GyrB) subunit. Previous crystallographic studies of a 24-kDa N-terminal domain of GyrB from E. coli complexed with novobiocin and a cyclothialidine analogue have shown that both ligands act by binding at the ATP-binding site. Clorobiocin is a natural antibiotic isolated from several Streptomyces strains and differs from novobiocin in that the methyl group at the 8 position in the coumarin ring of novobiocin is replaced by a chlorine atom, and the carbamoyl at the 3' position of the noviose sugar is substituted by a 5-methyl-2-pyrrolylcarbonyl group. To understand the difference in affinity, in order that this information might be exploited in rational drug design, the crystal structure of the 24-kDa GyrB fragment in complex with clorobiocin was determined to high resolution. This structure was determined independently in two laboratories, which allowed the validation of equivalent interpretations. The clorobiocin complex structure is compared with the crystal structures of gyrase complexes with novobiocin and 5'-adenylyl-beta, gamma-imidodiphosphate, and with information on the bound conformation of novobiocin in the p24-novobiocin complex obtained by heteronuclear isotope-filtered NMR experiments in solution. Moreover, to understand the differences in energetics of binding of clorobiocin and novobiocin to the protein, the results from isothermal titration calorimetry are also presented.

Evaluation of Optical Coherence Tomography for the Measurement of the Effects of Activators and Anticoagulants on the Blood Coagulation In Vitro

PubMed Central

Geng, Jinhai; Liu, Gangjun; Chen, Zhongping

2013-01-01

Optical properties of human blood during coagulation were studied using optical coherence tomography (OCT) and the parameter of clotting time derived from the 1/e light penetration depth (d1/e) versus time was developed in our previous work. In this study, in order to know if a new OCT test can characterize the blood-coagulation process under different treatments in vitro, the effects of two different activators (calcium ions and thrombin) and anticoagulants, i.e., acetylsalicylic acid (ASA, a well-known drug aspirin) and melagatran (a direct thrombin inhibitor), at various concentrations are evaluated. A swept-source OCT system with a 1300 nm center wavelength is used for detecting the blood-coagulation process in vitro under a static condition. A dynamic study of d1/e reveals a typical behavior due to coagulation induced by both calcium ions and thrombin, and the clotting time is concentration-dependent. Dose-dependent ASA and melagatran prolong the clotting times. ASA and melagatran have different effects on blood coagulation. As expected, melagatran is much more effective than ASA in anticoagulation by the OCT measurements. The OCT assay appears to be a simple method for the measurement of blood coagulation to assess the effects of activators and anticoagulants, which can be used for activator and anticoagulant screening. PMID:23392340

Evaluation of optical coherence tomography for the measurement of the effects of activators and anticoagulants on the blood coagulation in vitro.

PubMed

Xu, Xiangqun; Geng, Jinhai; Liu, Gangjun; Chen, Zhongping

2013-08-01

Optical properties of human blood during coagulation were studied using optical coherence tomography (OCT) and the parameter of clotting time derived from the 1/e light penetration depth (d(1/e)) versus time was developed in our previous work. In this study, in order to know if a new OCT test can characterize the blood-coagulation process under different treatments in vitro, the effects of two different activators (calcium ions and thrombin) and anticoagulants, i.e., acetylsalicylic acid (ASA, a well-known drug aspirin) and melagatran (a direct thrombin inhibitor), at various concentrations are evaluated. A swept-source OCT system with a 1300 nm center wavelength is used for detecting the blood-coagulation process in vitro under a static condition. A dynamic study of d1/e reveals a typical behavior due to coagulation induced by both calcium ions and thrombin, and the clotting time is concentration-dependent. Dose-dependent ASA and melagatran prolong the clotting times. ASA and melagatran have different effects on blood coagulation. As expected, melagatran is much more effective than ASA in anticoagulation by the OCT measurements. The OCT assay appears to be a simple method for the measurement of blood coagulation to assess the effects of activators and anticoagulants, which can be used for activator and anticoagulant screening.

A highly sensitive and selective off-on fluorescent chemosensor for hydrazine based on coumarin β-diketone

NASA Astrophysics Data System (ADS)

Wu, Wei-Na; Wu, Hao; Wang, Yuan; Mao, Xian-Jie; Zhao, Xiao-Lei; Xu, Zhou-Qing; Fan, Yun-Chang; Xu, Zhi-Hong

2018-01-01

A coumarin-based sensor C1, namely 3-acetoacetylcoumarin was designed, synthesized and applied for hydrazine detection. Hydrazinolysis of the chemosensor gives a fluorescent coumarin-pyrazole product C1 - N2H4 [3-(3-methyl-1H-pyrazol-5-yl)coumarin], and thus resulting in a prominent fluorescence off-on response toward hydrazine under physiological conditions. The probe is highly selective toward hydrazine over cations, anions and other biologically/environmentally abundant analytes. The detection limit of the probe is 3.2 ppb. The sensing mechanism was supported by 1H NMR, IR, MS and DFT calculation. The application of the fluorescent probe in monitoring intracellular hydrazine in glioma cell line U251 was also demonstrated.

Structure-Activity Relationship Analysis of 3-phenylcoumarin-Based Monoamine Oxidase B Inhibitors

NASA Astrophysics Data System (ADS)

Rauhamäki, Sanna; Postila, Pekka A.; Niinivehmas, Sanna; Kortet, Sami; Schildt, Emmi; Pasanen, Mira; Manivannan, Elangovan; Ahinko, Mira; Koskimies, Pasi; Nyberg, Niina; Huuskonen, Pasi; Multamäki, Elina; Pasanen, Markku; Juvonen, Risto O.; Raunio, Hannu; Huuskonen, Juhani; Pentikäinen, Olli T.

2018-03-01

Monoamine oxidase B (MAO-B) catalyzes deamination of monoamines such as neurotransmitters dopamine and norepinephrine. Accordingly, small-molecule MAO-B inhibitors potentially alleviate the symptoms of dopamine-linked neuropathologies such as depression or Parkinson’s disease. Coumarin with a functionalized 3-phenyl ring system is a promising scaffold for building potent MAO-B inhibitors. Here, a vast set of 3-phenylcoumarin derivatives was designed using virtual combinatorial chemistry or rationally de novo and synthesized using microwave chemistry. The derivatives inhibited the MAO-B at 100 nM - 1 µM. The IC50 value of the most potent derivative 1 was 56 nM. A docking-based structure-activity relationship analysis summarizes the atom-level determinants of the MAO-B inhibition by the derivatives. Finally, the cross-reactivity of the derivatives was tested against monoamine oxidase A and a specific subset of enzymes linked to estradiol metabolism, known to have coumarin-based inhibitors. Overall, the results indicate that the 3-phenylcoumarins, especially derivative 1, present unique pharmacological features worth considering in future drug development.

[Perioperative management of new oral anticoagulants].

PubMed

Samama, Charles-Marc; Pernod, Gilles; Albaladejo, Pierre; Sie, Pierre

2014-06-01

New oral anticoagulants do represent a major step forward as compared to low molecular weight heparins and vitamin K antagonists. Several issues deserve attention regarding their perioperative management. Three (and very soon four or five) active molecules are available on the market, adding to the major intra- and inter-individual variability, to the high number of drug-drug interactions, and to the interferences of renal function and many other parameters. New tests are available including the diluted thrombin time for dabigatran and a specific anti-Xa test for rivaroxaban and apixaban. No antidote is approved yet. Scheduled surgery: the safest suggestion is to mimic the perioperative management of vitamin K antagonist, with a 5-day interruption and low molecular weight heparin bridging whenever necessary. Emergency procedures: several suggestions issued from the Groupe d'Intérêt en Hémostase Péri-opératoire are proposed. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

In vitro Drug Metabolism Investigation of 7-Ethoxycoumarin in Human, Monkey, Dog and Rat Hepatocytes by High Resolution LC-MS/MS.

PubMed

Feng, Wan-Yong; Wen, Jenny; Stauber, Kathe

2018-04-18

Recently, it has been an increasing concern on the bioactivation and adverse reactions associated with consumption of herbal and nature products such as coumarin family. 7-ethoxycoumarin is one of coumarin family compounds, but little information is available regarding its potential reactive metabolites. In this study, we investigated its metabolism in cryopreserved male/female mixed human, male Cynomolgus monkey, male Beagle dog and male Sprague Dawley rat hepatocytes. Following the incubation of 7-ethoxylcoumarin in the hepatocytes for 2 hr, 28 metabolites were detected and identified using high resolution LC-Q-Exactive system in the positive ion and negative ion modes. O-deethylation, glucuronidation, sulfation, oxygenation, oxidative ring-opening, hydrogenation, glutathionation, dehydrogenation, cysteination, glucosidation, methylation, and hydrolysis were observed. At least sixteen metabolites were newly identified. M1 (O-deethylation, mono-oxygenation and glucuronidation), M3 (O-deethylation and glucuronidation), M5 (hydrolysis and mono-oxygenation), M14 (Odeethylation), M16 (hydrolysis), M22 (oxidative ring-opening and oxygenation) and M27 (mono-oxygenation) appeared to be major metabolites in human hepatocytes. M3, M5, M8, M13 (mono-oxygenation), M14, M16, M18 (O-deethylation and sulfation), M22 and M27 appeared to be major metabolites in monkey hepatocytes. M14, M16, M18, M20 (glutathionation and dehydrogenation) and M27 appeared to be major metabolites in dog hepatocytes. M1 (O-deethylation, mono-oxygenation and glucuronidation), M3, M5, M13, M14, M16, M17 (cysteination), M18, M20, and M22 appeared to be major metabolites in rat hepatocytes. Species differences in metabolism of 7-ethoxylcoumarin in hepatocytes were observed across humans, monkeys, dogs and rats. The analysis of metabolites suggests that 7-ethoxylcoumarin may undergo 3,4-epoxidation responsible for formation of glutathione and its derived cysteine conjugates, and carboxylic acid and its glucuronides, glucosides and sulfate, besides well-known 7-hydroxycoumarin, coumarin-7-O-glucuronide, and coumarin-7-O-glucuronide. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Preparation of low molecular weight Sargassum fusiforme polysaccharide and its anticoagulant activity

NASA Astrophysics Data System (ADS)

Sun, Yuhao; Chen, Xiaolin; Liu, Song; Yu, Huahua; Li, Rongfeng; Wang, Xueqin; Qin, Yukun; Li, Pengcheng

2017-10-01

Heparin has been used as an anticoagulant drug for many years, but it has significant side effects. In the search for good substitutes, low molecular weight (MW) polysaccharides from Sargassum fusiforme have been examined and confirmed to possess biological activities. Here, S. fusiforme polysaccharides (SFP) were extracted and subjected to a hydrogen peroxide (H2O2) oxidation method for the preparation of low-MW SFP (LSFP). The effects of temperature, pH, and H2O2 concentration on the degradation process were also examined. Several LSFP of 36, 9, 5.7, and 2.7 kDa were obtained under different conditions, and their anticoagulant activities studied in vitro. The results showed that SFP and LSFP prolonged activated partial thromboplastin (APTT), prothrombin (PT) and thrombin times (TT) significantly, indicating that these low MW polysaccharides possessed anticoagulant activity in the intrinsic, extrinsic, and common coagulation pathways. As these effects were related to the MW of the polysaccharides in APTT and TT but not in PT, the contents of the monosaccharide fucose and sulfate and the polysaccharide MW could have exerted combined effects. The details of this mechanism require further verification.

Discontinuation risk comparison among 'real-world' newly anticoagulated atrial fibrillation patients: Apixaban, warfarin, dabigatran, or rivaroxaban.

PubMed

Lip, Gregory Y H; Pan, Xianying; Kamble, Shital; Kawabata, Hugh; Mardekian, Jack; Masseria, Cristina; Phatak, Hemant

2018-01-01

Discontinuation of oral anticoagulants may expose non-valvular atrial fibrillation (NVAF) patients to an increased risk of stroke. This study describes the real-world discontinuation rates and compared the risk of drug discontinuation among NVAF patients initiating apixaban, warfarin, dabigatran, or rivaroxaban. This retrospective cohort study evaluated newly-anticoagulated NVAF patients in the MarketScan® data population from 01/01/2012 through 12/31/2014. Discontinuation was defined as a lack of subsequent prescription of the index drug within 30 days after the last supply day of the last prescription. A Cox model was used to estimate the hazard ratio (HR) of discontinuation, adjusted for age, sex, and comorbidities. Among 45,361 eligible NVAF patients, 15,461 (34.1%) initiated warfarin; 7,438 (16.4%) apixaban; 4,661 (10.3%) dabigatran; and 17,801 (39.2%) initiated rivaroxaban treatment. Compared to warfarin, patients who initiated dabigatran (adjusted HR [aHR]: 0.84, 95% confidence interval [CI]: 0.80-0.87, P<0.001), rivaroxaban (aHR: 0.70, 95% CI: 0.68-0.73, P<0.001), or apixaban (aHR: 0.57, 95% CI: 0.55-0.60, P<0.001) were 16%, 30%, and 43% less likely to discontinue treatment, respectively. When compared to apixaban, patients who initiated dabigatran (aHR: 1.46, 95% CI: 1.38-1.54, P<0.001) or rivaroxaban (aHR: 1.23, 95% CI: 1.17-1.28, P<0.001) were more likely to discontinue treatment. Among newly-anticoagulated NVAF patients in the real-world setting, initiation on rivaroxaban, dabigatran, or apixaban was associated with a significantly lower risk of discontinuation compared to warfarin. When compared to apixaban, patients who initiated treatment with warfarin, dabigatran, or rivaroxaban were more likely to discontinue treatment.

Possible Rivaroxaban Failure during the Postpartum Period.

PubMed

Rudd, Kelly M; Winans, Amanda R McFee; Panneerselvam, Narmadha

2015-11-01

Rivaroxaban, a factor Xa inhibitor, is a direct-acting oral anticoagulant (DOAC) indicated for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and for reducing the risk of DVT and PE recurrence. To our knowledge, no data are presently available to guide DOAC dosing in the postpartum period when pharmacokinetic and pharmacodynamic changes induced by pregnancy have an impact on drug clearance and increase hypercoagulability for a period of 6-8 weeks after delivery. We describe the case of a 35-year-old postpartum woman who presented to the emergency department with a diagnosis of a new multiple segmental PE 5 days after starting rivaroxaban therapy for a diagnosis of DVT. No precipitating cause, including noncompliance, was identified as a source of thrombosis embolization or extension. The patient was admitted, a heparin infusion was started for the management of PE, and rivaroxaban was discontinued. She was transitioned to enoxaparin 1 mg/kg (90 mg) subcutaneously every 12 hours the next day, bridged to warfarin, and discharged home on the overlapping regimen with close follow-up by the pharmacist-managed outpatient Anticoagulation Management Service. To our knowledge, this is the first case report of potential failure associated with rivaroxaban therapy in the postpartum period, possibly due to pharmacokinetic alterations seen in the postpartum period contributing to decreased drug exposure, yielding reduced anticoagulant efficacy. Clinicians should carefully weigh the risks and benefits of DOAC therapy in postpartum patients or other special populations requiring anticoagulation therapy. This report also highlights the need for further research identifying the impact of pharmacokinetic changes induced by special populations and the need to develop monitoring assays for such clinical situations. © 2015 Pharmacotherapy Publications, Inc.

Evaluation of analgesic, anti-inflammatory, anti-depressant and anti-coagulant properties of Lactuca sativa (CV. Grand Rapids) plant tissues and cell suspension in rats.

PubMed

Ismail, Hammad; Mirza, Bushra

2015-06-27

Lactuca sativa (lettuce) has been traditionally used for relieving pain, inflammation, stomach problems including indigestion and lack of appetite. Moreover, the therapeutic significance of L. sativa includes its anticonvulsant, sedative-hypnotic and antioxidant properties. In the present study, the MC (methanol and chloroform; 1:1) and aqueous extracts of seed and leaf along with cell suspension exudate were prepared. These extracts were explored for their analgesic, anti-inflammatory, antidepressant and anticoagulant effects by hot plate analgesic assay; carrageenan induced hind paw edema test, forced swimming test and capillary method for blood clotting respectively in a rat model. The results were analyzed using one-way Analysis of Variance (ANOVA) followed by Turkey multiple comparison test. Interestingly, the extracts and the cell suspension exudate showed dual inhibition by reducing pain and inflammation. The results indicated that the aqueous extracts of leaf exhibited highest analgesic and anti-inflammatory activities followed by leaf MC, cell suspension exudate, seed aqueous and seed MC extracts. The current findings show that aqueous and MC extracts of seed have the least immobility time in the forced swimming test, which could act as an anti-depressant on the central nervous system. The leaf extracts and cell suspension exudate also expressed moderate anti-depressant activities. In anticoagulant assay, the coagulation time of aspirin (positive control) and MC extract of leaf was comparable, suggesting strong anti-coagulant effect. Additionally, no abnormal behavior or lethality was observed in any animal tested. Taken together, L. sativa can potentially act as a strong herbal drug due to its multiple pharmaceutical effects and is therefore of interest in drug discovery and development of formulations.

Performance of coagulation tests in patients on therapeutic doses of rivaroxaban. A cross-sectional pharmacodynamic study based on peak and trough plasma levels.

PubMed

Francart, Suzanne J; Hawes, Emily M; Deal, Allison M; Adcock, Dorothy M; Gosselin, Robert; Jeanneret, Cheryl; Friedman, Kenneth D; Moll, Stephan

2014-06-01

Knowledge of anticoagulation status during rivaroxaban therapy is desirable in certain clinical situations. It was the study objective to determine coagulation tests most useful for assessing rivaroxaban's anticoagulant effect. Peak and trough blood samples from 29 patients taking rivaroxaban 20 mg daily were collected. Mass spectrometry and various coagulation assays were performed. "On-therapy range" was defined as the rivaroxaban concentrations determined by LC-MS/MS. A "misprediction percentage" was calculated based on how often results of each coagulation assay were in the normal reference range, while the rivaroxaban concentration was in the "on-therapy" range. The on-therapy range was 8.9-660 ng/ml. The misprediction percentages for prothrombin time (PT) and activated partial thromboplastin time (aPTT), using multiple reagents and coagulometers, ranged from 10%-52% and 31%-59%, respectively. PT, aPTT and activated clotting time (ACT) were insensitive to trough rivaroxaban: 59%, 62%, and 80% of samples had a normal result, respectively. Over 95% of PT and ACT values were elevated at peak. Four different rivaroxaban calibrated anti-Xa assays had R² values >0.98, demonstrating strong correlations with rivaroxaban drug levels. In conclusion, PT, aPTT and ACT are often normal in patients on therapeutic doses of rivaroxaban. However, PT and ACT may have clinical utility at higher drug plasma levels. Rivaroxaban calibrated anti-factor Xa assays can accurately identify low and high on-therapy rivaroxaban drug levels and, therefore, have superior utility in all clinical situations where assessment of anticoagulation status may be beneficial.

Is there a role for pharmacokinetic/pharmacodynamic-guided dosing for novel oral anticoagulants?

PubMed

Chan, Noel; Sager, Philip T; Lawrence, Jack; Ortel, Thomas's; Reilly, Paul; Berkowitz, Scott; Kubitza, Dagmar; Eikelboom, John; Florian, Jeffry; Stockbridge, Norman; Rose, Martin; Temple, Robert; Seltzer, Jonathan H

2018-05-01

The novel direct oral anticoagulants (NOACs) represent a major advance in oral anticoagulant therapy and are replacing vitamin K antagonists as the preferred options for many indications. Given in fixed doses without routine laboratory monitoring, they have been shown to be at least as effective in reducing thromboembolic stroke as dose-adjusted warfarin in phase 3 randomized trials and less likely to cause hemorrhagic stroke. Pharmacokinetic and/or pharmacodynamic subanalyses of the major NOAC trials in patients with atrial fibrillation have established relationships between clinical characteristics, and drug levels and/or pharmacodynamic responses with both efficacy and safety. Based on these analyses, pharmaceutical manufacturers and regulatory authorities have provided contraindications and dosing recommendations based on clinical characteristics that are associated with drug levels and/or pharmacodynamic responses, stroke reduction, and bleeding risk to optimize the risk-benefit profile of the NOACs in the real world. The current fixed-dosing strategy of NOACs has triggered discussions about the potential value of laboratory monitoring and dose adjustment in customizing drug exposure to further improve the safety and efficacy of the NOACs in patients with atrial fibrillation. As there is neither high-quality evidence nor consensus about the potential role of laboratory monitoring and dose adjustment for the NOACs, a Cardiac Research Safety Consortium "Think Tank" meeting was held at the American College of Cardiology Heart House in December 2015 to discussions these issues. This manuscript reports on the deliberations and the conclusions reached at that meeting. Copyright © 2017. Published by Elsevier Inc.

Recent advances in the diagnosis and treatment of heparin-induced thrombocytopenia

PubMed Central

Bakchoul, Tamam

2012-01-01

Heparin-induced thrombocytopenia (HIT) is a drug-mediated, prothrombotic disorder caused by immunization against platelet factor 4 (PF4) after complex formation with heparin or other polyanions. After their binding to PF4/heparin complexes on the platelet surface, HIT antibodies are capable of intravascular platelet activation by cross-linking Fcγ receptor IIA leading to a platelet count decrease and/or thrombosis. Diagnosis of HIT is often difficult. This, and the low specificity of the commercially available immunoassays, leads currently to substantial overdiagnosis of HIT. Timing of onset, the moderate nature of thrombocytopenia, and the common concurrence of thrombosis are very important factors, which help to differentiate HIT from other potential causes of thrombocytopenia. A combination of a clinical pretest scoring system and laboratory investigation is usually necessary to diagnose HIT. Although HIT is considered to be a rare complication of heparin treatment, the very high number of hospital inpatients, and increasingly also hospital outpatients receiving heparin, still result in a considerable number of patients developing HIT. If HIT occurs, potentially devastating complications such as life-threatening thrombosis make it one of the most serious adverse drug reactions. If HIT is strongly suspected, all heparin must be stopped and an alternative nonheparin anticoagulant started at a therapeutic dose to prevent thromboembolic complications. However, the nonheparin alternative anticoagulants bear a considerable bleeding risk, especially if given to patients with thrombocytopenia due to other reasons than HIT. While established drugs for HIT are disappearing from the market (lepirudin, danaparoid), bivalirudin, fondaparinux and potentially the new anticoagulants such as dabigatran, rivaroxaban and apixaban provide new treatment options. PMID:23606934

[Scope of the latest RE-LY substudies: clinical implications].

PubMed

Ruiz-Giménez Arrieta, N

2012-03-01

The approval of the use of dabiatran in stroke prevention in patients with nonvalvular atrial fibrilation (NVAF) is based on the results of the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial, one of the largest studies to date in this entity. In this trial, dabigatran showed similar safety and efficacy to warfarin in primary and secondary prevention of stroke in patients with AF. At a dose of 150 mg twice daily, dabigatran was superior to warfarin in the prevention of stroke or systemic embolism and the 110 mg dose twice daily showed similar efficacy and greater safety, given the lower incidence of hemorrhage. These results were consistently found in the various subanalyses, with some slight differences of interest for clinical practice. The ideal candidates for dabiatran are patients with NVAF suitable for cardioversion, who require short periods of anticoagulation, patients in remote geographical areas with difficulty in achieving good anticoagulation control or good control with anti-vitamin K treatment due to IRN fluctuations, and patients with a low risk of hemorrhage and a CHADS score ≥ 3 and/or with prior stroke, whenever there are no contraindications. The choice of dabigatran dose should be evaluated according to the patient's individual characteristics (caution must be exercised when prescribing this drug in the elderly and in renal insufficiency) and embolic and/or hemorrhagic risk. Studies of the long-term safety of this drug, pharmacoeconomic analyses in Spain and post-commercialization pharmacovigilance data are required before the definitive uses of this drug can be established. Copyright © 2012 Elsevier España, S.L. All rights reserved.

The effect of bariatric surgery on direct-acting oral anticoagulant drug levels.

PubMed

Rottenstreich, Amihai; Barkai, Aviv; Arad, Ariela; Raccah, Bruria Hirsh; Kalish, Yosef

2018-03-01

To determine direct-acting oral anticoagulant (DOAC) blood levels in post-bariatric surgery (BS) patients treated with long-term anticoagulation therapy. We identified from medical records patients who underwent BS during 2005-2016 and who were treated with DOACs. We offered testing DOAC blood levels to these patients and to age, sex, body mass index, and serum creatinine-matched individuals treated by DOACs who did not undergo BS. Overall, 36 individuals were enrolled, 18 post-BS patients and 18 control subjects. Of the post-BS patients, 12 underwent laparoscopic sleeve gastrectomy, 4 laparoscopic adjustable gastric banding and 2 laparoscopic Roux-en-Y gastric bypass surgery. Median time lapsed from surgery until study inclusion was 4.9years. Five post-BS patients had peak drug levels below expected levels compared to none of the control subjects (P=0.05). For patients who used apixaban (n=9) and dabigatran (n=2), peak drug levels were within the expected range. In contrast, for the 7 patients who used rivaroxaban, levels were below the expected range in 5, including all four who underwent sleeve gastrectomy and one following adjustable gastric banding. Peak rivaroxaban levels were significantly lower in the post-BS than the control group (P=0.02). This preliminary study suggests that all DOACs, particularly rivaroxaban, be cautiously used following BS, if used at all. Given that vitamin-K antagonists can be easily monitored, they may be a better choice, until more data on DOAC use in this patient population are available. Copyright © 2017 Elsevier Ltd. All rights reserved.

In vitro antifungal activity of coumarin extracted from Loeselia mexicana Brand.

PubMed

Navarro-García, Victor M; Rojas, Gabriela; Avilés, Margarita; Fuentes, Macrina; Zepeda, Gerardo

2011-09-01

The bis-coumarin daphnoretin and its monomeric precursors scopoletin and umbelliferone were isolated for the first time from the aerial part of Loeselia mexicana Brand (a vegetal species used in Mexican traditional medicine) using chromatographic techniques. The structures of these compounds were determined by (1) H and (13) C NMR analyses. These coumarins were evaluated for in vitro antifungal activity. The three compounds tested showed significant antifungal activity. © 2011 Blackwell Verlag GmbH.

Synthesis and characterization of mixed monolayer protected gold nanorods and their Raman activities

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mlambo, Mbuso; Nanotechnology Innovation Centre, Advanced Materials Division, Mintek, Private Bag X3015, Randburg 2125; Mdluli, Phumlani S.

2013-10-15

Graphical abstract: Gold nanorods surface functionalization. - Highlights: • Mixed monolayer protected gold nanorods. • Surface enhanced Raman spectroscopy. • HS-(CH{sub 2}){sub 11}-NHCO-coumarin as a Raman active compound. - Abstract: The cetyltrimethylammonium bromide (CTAB) gold nanorods (AuNRs) were prepared by seed-mediated route followed by the addition of a Raman active compound (HS-(CH{sub 2}){sub 11}-NHCO-coumarin) on the gold nanorods surfaces. Different stoichiometric mixtures of HS-(CH{sub 2}){sub 11}-NHCO-coumarin and HS-PEG-(CH{sub 2}){sub 11}COOH were evaluated for their Raman activities. The lowest stoichiometric ratio HS-(CH{sub 2}){sub 11}-NHCO-coumarin adsorbed on gold nanorods surface was detected and enhanced by Raman spectroscopy. The produced mixed monolayer protectedmore » gold nanorods were characterized by UV-vis spectrometer for optical properties, transmission electron microscope (TEM) for structural properties (shape and aspect ratio) and their zeta potentials (charges) were obtained from ZetaSizer to determine the stability of the produced mixed monolayer protected gold nanorods. The Raman results showed a surface enhanced Raman scattering (SERS) enhancement at the lowest stoichiometric ratio of 1% HS-(CH{sub 2}){sub 11}-NHCO-coumarin compared to high ratio of 50% HS-(CH{sub 2}){sub 11}-NHCO-coumarin on the surface of gold nanorods.« less

Controversies regarding the new oral anticoagulants for stroke prevention in patients with atrial fibrillation.

PubMed

Mohanty, Bibhu D; Looser, Patrick M; Gokanapudy, Lakshmi R; Handa, Rishi; Mohanty, Sudipta; Choi, Sharon S; Goldman, Martin E; Fuster, Valentin; Halperin, Jonathan L

2014-06-01

Increasing use of the new oral anticoagulants (NOACs) - dabigatran, rivaroxaban, and apixaban - has prompted considerable discussion in the medical community even as warfarin remains the mainstay of therapy. This article raises 10 controversial issues regarding the use of NOACs for stroke prevention in patients with atrial fibrillation, and offers a review of the latest available evidence. We provide a brief overview of the mechanism and dosing of these drugs, as well as a summary of the key clinical trials that have brought them into the spotlight. Comparative considerations relative to warfarin such as NOAC safety, efficacy, bleeding risk, reversibility, drug-transitioning and use in patients well controlled on warfarin are addressed. Use in select populations such as the elderly, those with coronary disease, renal impairment, or on multiple anti-platelet drugs is also discussed. Finally, we consider such specific issues as comparative efficacy, off-label use, cost, rebound and management during events. Ultimately, the rise of the NOACs to mainstream use will depend on further data and clinical experience amongst the medical community. © The Author(s) 2014.

Comparative evaluation of flavone from Mucuna pruriens and coumarin from Ionidium suffruticosum for hypolipidemic activity in rats fed with high Fat diet

PubMed Central

2012-01-01

The objective of the study is a comparative evaluation of flavone isolated from Mucuna pruriens and coumarin isolated from Ionidium suffruticosum was assessed for the hypolipidemic activity in rats fed with high fat diet. The acute toxicity study was found that flavone (M.pruriens) and coumarin (I.suffruticosum) are safe up to 100mg/kg, so one tenth of this dose (10mg/kg) was consider as a evaluation dose. High fat diet group of rats showed significant (p<0.001) elevation in plasma total and LDL-cholesterol, triglycerides and phospholipids. Administration of flavone (M. pruriens) and coumarin isolated from (I.suffruticosum) at the dose of 10mg/kg b.wt/day along with high fat diet significantly (p<0.001) prevented the rise in the plasma total and LDL-cholesterol, triglycerides and phospholipids than that of other extracts. However, treatment of coumarin isolated from (I.suffruticosum) had showed more cardio protective effect against hyperlipidemia than that of flavone (M.pruriens). PMID:23031584

Coumarin benzothiazole derivatives as chemosensors for cyanide anions

NASA Astrophysics Data System (ADS)

Wang, Kangnan; Liu, Zhiqiang; Guan, Ruifang; Cao, Duxia; Chen, Hongyu; Shan, Yanyan; Wu, Qianqian; Xu, Yongxiao

2015-06-01

Four coumarin benzothiazole derivatives, N-(benzo[d]thiazol-2-yl)-2-oxo-2H-chromene-3-carboxamide (1), (Z)-N-(3-methylbenzo[d]thiazol-2(3H)-ylidene)-2-oxo-2H-chromene-3-carboxamide (2), 7-(diethylamino)-N-(benzo[d]thiazol-2-yl)-2-oxo-2H-chromene-3-carboxamide (3) and (Z)-7-(diethylamino)-N-(3-methylbenzo[d]thiazol-2(3H)-ylidene)-2-oxo-2H-chromene-3-carboxamide) (4), have been synthesized. Their crystal structures, photophysical properties in acetonitrile and recognition properties for cyanide anions have been investigated. All the compounds are generally planar, especially compound 1 exhibits perfect planarity with dihedral angle between benzothiazolyl group and coumarin group being only 3.63°. Coumarin benzothiazole compounds 1 and 3 can recognize cyanide anions by Michael addition reaction and compound 3 exhibits color change from yellow to colorless and green fluorescence was quenched completely, which can be observed by naked eye. Coumarin benzothiazolyliden compound 4 can recognize cyanide anions with fluorescence turn-on response based on the copper complex ensemble displacement mechanism.

A coumarin with an unusual structure from Cuphea ignea, its cytotoxicity and antioxidant activities.

PubMed

Moustafa, E S; Swilam, N F; Ghanem, O B; Hashim, A N; Nawwar, M A; Lindequist, U; Linscheid, M W

2018-04-02

Phenolic metabolite profiling using two dimensional paper chromatographic analysis (2 DPC) was used for assaying the complex mixture of phenolics of an aqueous ethanol aerial part extract of Cuphea ignea (Lytheraceae). A coumarin with a rare structure, namely, 7-hydroxy 3-methoxy coumarin 5-O-β-glucopyranoside was isolated from the investigated extract. The structure was elucidated by conventional methods and spectral analysis, including one and two dimensional NMR (1D and 2D NMR), as well as by interpretation of the spectra obtained by high resolution electrospray ionization mass technique (HRESIMS). The rare coumarin significantly inhibited reactive oxygen species production with an ED50 value of 6.31±1.64 μg/ml and 5.78±0.66 μg/ml as determined by the the free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH) and the oxygen radical absorption capacity (ORAC) assay respectively. The isolated coumarin presented a cytotoxic activity assessed by using the neutral red assay (NRU) against lung cancer cell line (H23) with IC50 of 40.38±2.75 μg/ml.

Rapid method for the determination of coumarin, vanillin, and ethyl vanillin in vanilla extract by reversed-phase liquid chromatography with ultraviolet detection.

PubMed

Ali, Laila; Perfetti, Gracia; Diachenko, Gregory

2008-01-01

A method is described for determining coumarin, vanillin, and ethyl vanillin in vanilla extract products. A product is diluted one-thousand-fold and then analyzed by reversed-phase liquid chromatography using a C18 column and a mobile phase consisting of 55% acetonitrile-45% aqueous acetic acid (1%) solution at a flow rate of 1.0 mL/min. Peaks are detected with a UV detector set at 275 nm. Vanilla extracts were spiked with 250, 500, and 1000 microg/g each of coumarin, vanillin, and ethyl vanillin. Recoveries averaged 97.4, 97.8, and 99.8% for coumarin, vanillin, and ethyl vanillin, respectively, with coefficient of variation values of 1.8, 1.3, and 1.3%, respectively. No significant difference was observed among the 3 spiking levels. A survey of 23 domestic and imported vanilla extract products was conducted using the method. None of the samples contained coumarin. The surveyed samples contained between 0.4 to 13.1 and 0.4 to 2.2 mg/g vanillin and ethyl vanillin, respectively.

2018 New Drug Update.

PubMed

Hussar, Daniel A; Finn, Laura A

2018-04-01

Five new drugs marketed within the last year, which are used for medical problems often experienced by the elderly, have been selected for consideration in this review. The uses and most important properties of these agents are discussed, and a rating for each new drug is determined using the New Drug Comparison Rating system developed by the author (DAH). Advantages, disadvantages, and other important information regarding each new drug are identified and used as the basis for determining the rating. The drugs include an anticoagulant, an antiparkinson agent, an agent for tardive dyskinesia, an agent for psoriasis, and an agent for constipation. The drugs reviewed are betrixaban, safinamide mesylate, valbenazine tosylate, guselkumab, and plecanatide.

Evaluation of the interaction of coumarins with biomembrane models studied by differential scanning calorimetry and Langmuir-Blodgett techniques.

PubMed

Sarpietro, Maria Grazia; Giuffrida, Maria Chiara; Ottimo, Sara; Micieli, Dorotea; Castelli, Francesco

2011-04-25

Three coumarins, scopoletin (1), esculetin (2), and esculin (3), were investigated by differential scanning calorimetry and Langmuir-Blodgett techniques to gain information about the interaction of these compounds with cellular membranes. Phospholipids assembled as multilamellar vesicles or monolayers (at the air-water interface) were used as biomembrane models. Differential scanning calorimetry was employed to study the interaction of these coumarins with multilamellar vesicles and to evaluate their absorption by multilamellar vesicles. These experiments indicated that 1-3 interact in this manner to different extents. The Langmuir-Blodgett technique was used to study the effect of these coumarins on the organization of phospholipids assembled as a monolayer. The data obtained were in agreement with those obtained in the calorimetric experiments.

β-glucuronidase inhibitory studies on coumarin derivatives.

PubMed

Khan, Khalid Mohammed; Fakhri, Muhammad Imran; Shaikh, Nimra Naveed; Saad, Syed Muhammad; Hussain, Shafqat; Perveen, Shahnaz; Choudhary, Muhammad Iqbal

2014-01-01

Twenty-three (23) derivatives of coumarin (5-27) were synthesized and screened for their in vitro β- glucuronidase (E. coli) inhibitory activities. Only three compounds, 7,8-dihydroxy-4-methyl-2H-chromen-2-one (9) (IC50 = 52.39 ± 1.85 µM), 3-chloro-6-hexyl-7-hydroxy-4-methyl-2H-chromen-2-one (18) (IC50 = 60.50 ± 0.87 µM), and 3,6- dichloro-7-hydroxy-4-methyl-2H-chromen-2-one (15) (IC50 = 380.26 ± 0.92 µM) displayed activities against β- glucuronidase as compared to standard D-saccharic acid 1,4-lactone (IC50 = 45.75 ± 2.16 µM). The results indicated that the activity of the synthetic coumarins depends upon the substituents present on the coumarin skeleton.

Improving cost-effectiveness of and outcomes from drug therapy in patients with atrial fibrillation in managed care: role of the pharmacist.

PubMed

Johnson, Samuel G

2009-08-01

The medical care costs for procedures, medications, and testing associated with atrial fibrillation (AF) in the United States are high and projected to increase markedly in the future as the number of Americans affected grows. The burden on patient quality of life, the health care system, and society are pharmacoeconomic considerations in managing AF. To identify key pharmacoeconomic considerations in managing AF and describe ways in which managed care pharmacists can improve the cost-effectiveness of and outcomes from drug therapy for AF. The high medical care costs of AF are largely the result of the high cost of hospitalization and inpatient procedures. Recurrence of AF dramatically increases costs, especially for hospital care. Managed care pharmacists have many opportunities to provide cost-effective care to and improve outcomes in patients with AF. Policy and process review, population management, and case management are key strategies for improving outcomes in patients with AF. Pharmacist input into policy and process review, including pharmacy benefits design, formulary management, and the use of information technology, can help ensure that the use of drug therapy for AF is cost-effective. Population management strategies, such as development of clinical pathways and patient registries, seek to improve the quality, consistency, and cost-effectiveness of care and the likelihood that desired therapeutic outcomes are achieved through targeted interventions. Case management strategies focus on longitudinal care for individuals in order to improve quality. Pharmacist-managed anticoagulation services and antiarrhythmic drug monitoring are the 2 most widely known case management strategies for patients with AF. Managed care pharmacists can screen patients with AF for the use of anticoagulation, which is needed to prevent embolic stroke but is under-used, even though recommended by evidence-based guidelines. The clinical efficacy and cost-effectiveness of pharmacist-managed anticoagulation services for patients with AF are well documented. Pharmacist-managed antiarrhythmic drug monitoring is a less well-known case management strategy that facilitates early detection and intervention to minimize toxicity. Managed care pharmacists can play an instrumental role in implementing strategies to improve the cost-effectiveness of and outcomes from drug therapy for AF.

Analysis of limette and bergamot distilled essential oils by HPLC.

PubMed

Buiarelli, Francesca; Cartoni, Giampaolo; Coccioli, Franco; Jasionowska, Renata; Mazzarino, Monica

2002-04-01

This work examines the distilled essential oils of limette and bergamot in order to assess the presence of low volatile substances such as coumarins (bergapten) which, being toxic, must be eliminated before using these oils in the food industry. The quantitative determination of coumarins was carried out by spectrofluorimetric detection. The substances present in the chromatograms, obtained by HPLC with UV detection at 254 nm, were then identified. Moreover, a new coumarin that is present in small quantities was identified using HPLC-MS.

Risk of stroke and oral anticoagulant use in atrial fibrillation: a cross-sectional survey

PubMed Central

Holt, Tim A; Hunter, Tina D; Gunnarsson, Candace; Khan, Nada; Cload, Paul; Lip, Gregory YH

2012-01-01

Background Oral anticoagulants substantially reduce the risk of stroke in atrial fibrillation but are underutilised in current practice. Aim To measure the distribution of stroke risk in patients with atrial fibrillation (using the CHADS2 and CHA2DS2-VASc scores) and changes in oral anticoagulant use during 2007–2010. Design and setting Longitudinal series of cross-sectional survey in 583 UK practices linked to the QResearch® database providing 99 351 anonymised electronic records from people with atrial fibrillation. Method The proportion of patients in each CHADS2 and CHA2DS2-VASc risk band in 2010 was calculated; for each of the years 2007–2010, the proportions with risk scores ≥2 that were using anticoagulants or antiplatelet agents were estimated. The proportions identified at high risk were re-estimated using alternative definitions of hypertension based on coded data. Finally, the prevalence of comorbid conditions in treated and untreated high-risk (CHADS2 ≥2) groups was derived. Results The proportion at high risk of stroke in 2010 was 56.9% according to the CHADS2 ≥2 threshold, and 84.5% according to CHA2DS2-VASc ≥2 threshold. The proportions of these groups receiving anticoagulants were 53.0% and 50.7% respectively and increased during 2007–2010. The means of identifying the population of individuals with hypertension significantly influenced the estimated proportion at high risk. Comorbid conditions associated with avoidance of anticoagulants included history of falls, use of nonsteroidal anti-inflammatory drugs, and dementia. Conclusion Oral anticoagulant use in atrial fibrillation has increased in UK practice since 2007, but remains suboptimal. Improved coding of hypertension is required to support systematic identification of individuals at high risk of stroke and could be assisted by practice-based software. PMID:23265231

Magnetic resonance venography to assess thrombus resolution with edoxaban monotherapy versus parenteral anticoagulation/warfarin for symptomatic deep vein thrombosis: A multicenter feasibility study.

PubMed

Piazza, Gregory; Mani, Venkatesh; Goldhaber, Samuel Z; Grosso, Michael A; Mercuri, Michele; Lanz, Hans J; Schussler, Steven; Hsu, Ching; Chinigo, Amy; Ritchie, Bruce; Nadar, Venkatesh; Cannon, Kevin; Pullman, John; Concha, Mauricio; Schul, Marlin; Fayad, Zahi A

2016-08-01

The feasibility of magnetic resonance venography (MRV) for measuring change in thrombus volume with a novel anticoagulation regimen versus standard anticoagulation in patients with symptomatic deep vein thrombosis (DVT) has not been assessed. Our aim was to study the feasibility of MRV to measure change in thrombus volume in patients with acute symptomatic objectively confirmed proximal DVT in an open-label multicenter trial (edoxaban Thrombus Reduction Imaging Study, eTRIS). We randomized patients in a 2:1 allocation ratio to edoxaban 90 mg/day for 10 days followed by 60 mg/day versus parenteral anticoagulation bridging to warfarin for 3 months. The primary efficacy outcome was a surrogate end point of the relative change in MRV-quantified thrombus volume from baseline to Day 14-21. A total of 85 eligible patients from 26 study sites were randomized to edoxaban monotherapy (n=56) versus parenteral anticoagulation as a 'bridge' to warfarin (n=29). The mean relative change in MRV-quantified thrombus volume from baseline to Day 14-21 was similar in patients treated with edoxaban and parenteral anticoagulation as a 'bridge' to warfarin (-50.1% vs -58.9%; 95% confidence interval of treatment difference, -12.7%, 30.2%). However, thrombus extension was observed in eight patients in the edoxaban monotherapy group and in none in the warfarin group. Rates of recurrent venous thromboembolism (3.6% vs 3.6%, p=0.45) and clinically relevant non-major bleeding (5.4% vs 7.1%, p=0.34) were also similar. No major bleeds occurred in either on-treatment group during the study period. In conclusion, MRV can assess change in thrombus volume in patients with acute DVT randomized to two different anticoagulant regimens.ClinicalTrials.gov IDENTIFIER NCT01662908: INVESTIGATIONAL NEW DRUG IND APPLICATION EDOXABAN IND # 63266. © The Author(s) 2016.

Magnetic resonance venography to assess thrombus resolution with edoxaban monotherapy versus parenteral anticoagulation/warfarin for symptomatic deep vein thrombosis: A multicenter feasibility study

PubMed Central

Piazza, Gregory; Mani, Venkatesh; Goldhaber, Samuel Z; Grosso, Michael A; Mercuri, Michele; Lanz, Hans J; Schussler, Steven; Hsu, Ching; Chinigo, Amy; Ritchie, Bruce; Nadar, Venkatesh; Cannon, Kevin; Pullman, John; Concha, Mauricio; Schul, Marlin; Fayad, Zahi A

2016-01-01

The feasibility of magnetic resonance venography (MRV) for measuring change in thrombus volume with a novel anticoagulation regimen versus standard anticoagulation in patients with symptomatic deep vein thrombosis (DVT) has not been assessed. Our aim was to study the feasibility of MRV to measure change in thrombus volume in patients with acute symptomatic objectively confirmed proximal DVT in an open-label multicenter trial (edoxaban Thrombus Reduction Imaging Study, eTRIS). We randomized patients in a 2:1 allocation ratio to edoxaban 90 mg/day for 10 days followed by 60 mg/day versus parenteral anticoagulation bridging to warfarin for 3 months. The primary efficacy outcome was a surrogate end point of the relative change in MRV-quantified thrombus volume from baseline to Day 14–21. A total of 85 eligible patients from 26 study sites were randomized to edoxaban monotherapy (n=56) versus parenteral anticoagulation as a ‘bridge’ to warfarin (n=29). The mean relative change in MRV-quantified thrombus volume from baseline to Day 14–21 was similar in patients treated with edoxaban and parenteral anticoagulation as a ‘bridge’ to warfarin (−50.1% vs −58.9%; 95% confidence interval of treatment difference, −12.7%, 30.2%). However, thrombus extension was observed in eight patients in the edoxaban monotherapy group and in none in the warfarin group. Rates of recurrent venous thromboembolism (3.6% vs 3.6%, p=0.45) and clinically relevant non-major bleeding (5.4% vs 7.1%, p=0.34) were also similar. No major bleeds occurred in either on-treatment group during the study period. In conclusion, MRV can assess change in thrombus volume in patients with acute DVT randomized to two different anticoagulant regimens. ClinicalTrials.gov Identifier: NCT01662908 Investigational New Drug (IND) Application: Edoxaban IND # 63266 PMID:27165711

[Analysis on long-term compliance of anticoagulation treatment and demands of disease management in patients with atrial fibrillation].

PubMed

Zuo, Hui-juan; Su, Jiang-lian; Lin, Yun; Zeng, Zhe-chun; Wang, Jin-wen

2010-08-24

To analyze the long-term compliance of oral anticoagulant therapy and the demands of disease management in patient with atrial fibrillation (AF). Inpatients with AF taking warfarin were collected from Department of Internal Medicine from January 1 to December 31, 2008. Inpatients from departments of surgery, ophthalmology, otorhinolaryngology, dermatology and pediatrics and those on a previous warfarin therapy were excluded. The data of patient profiles, medical history and anticoagulant treatment were collected from electronic medical record. And the status of anticoagulant treatment one year later and demands of disease management were inquired by telephone. A total of 268 AF patients received a telephone survey. Among them, 145 patients (54.1%) continued taking warfarin. Gender, age, type of AF, duration of AF and history of ischemic stroke was not significantly associated with the compliance of anticoagulant treatment. The odds ratio was 1.74 (95%CI: 0.67-4.47), 0.87 (95%CI: 0.30-2.53), 1.59 (95%CI: 0.35-1.09), 1.09 (95%CI: 0.61-1.93) and 0.44 (95%CI: 0.12-1.60) respectively. Among patients on warfarin, INR was monitored monthly in 88 patients (60.7%) and 70 patients (48.3%) had an INR value of 2.0-3.0. Among 123 withdrawal patients, 88 patients (71.5%) terminated treatment within 6 month. The common reasons included patient ignorance about long-term anticoagulant treatment (35.0%) and switching to aspirin because of a poor effect (24.4%). About 80% of patients wished to obtain instructions about INR monitoring and adjustment of drug dosage. Among them, 196/268 patients (73.1%) wished for a regular follow-up. And 176/196 patients (89.8%) opted for a telephone follow-up and 150/176 patients (85.2%) wanted to receive monthly instructions. The compliance of anticoagulation treatment and the target-meeting proportion of INR value are relative low. And the common reasons of withdrawal are patient ignorance about long-term anticoagulant treatment and switching to aspirin because of a poor effect. Disease management will meet most of AF patients' demands.

Real-World Use of Apixaban for Stroke Prevention in Atrial Fibrillation: A Systematic Review and Meta-Analysis.

PubMed

Proietti, Marco; Romanazzi, Imma; Romiti, Giulio Francesco; Farcomeni, Alessio; Lip, Gregory Y H

2018-01-01

The use of oral anticoagulant therapy for stroke prevention in atrial fibrillation has been transformed by the availability of the nonvitamin K antagonist oral anticoagulants. Real-world studies on the use of nonvitamin K antagonist oral anticoagulants would help elucidate their effectiveness and safety in daily clinical practice. Apixaban was the third nonvitamin K antagonist oral anticoagulants introduced to clinical practice, and increasing real-world studies have been published. Our aim was to summarize current evidence about real-world studies on apixaban for stroke prevention in atrial fibrillation. We performed a systematic review and meta-analysis of all observational real-world studies comparing apixaban with other available oral anticoagulant drugs. From the original 9680 results retrieved, 16 studies have been included in the final meta-analysis. Compared with warfarin, apixaban regular dose was more effective in reducing any thromboembolic event (odds ratio: 0.77; 95% confidence interval: 0.64-0.93), but no significant difference was found for stroke risk. Apixaban was as effective as dabigatran and rivaroxaban in reducing thromboembolic events and stroke. The risk of major bleeding was significantly lower for apixaban compared with warfarin, dabigatran, and rivaroxaban (relative risk reduction, 38%, 35%, and 46%, respectively). Similarly, the risk for intracranial hemorrhage was significantly lower for apixaban than warfarin and rivaroxaban (46% and 54%, respectively) but not dabigatran. The risk of gastrointestinal bleeding was lower with apixaban when compared with all oral anticoagulant agents ( P <0.00001 for all comparisons). Use of apixaban in real-life is associated with an overall similar effectiveness in reducing stroke and any thromboembolic events when compared with warfarin. A better safety profile was found with apixaban compared with warfarin, dabigatran, and rivaroxaban. © 2017 American Heart Association, Inc.

Evaluation of the antithrombotic abilities of non-vitamin K antagonist oral anticoagulants using the Total Thrombus-formation Analysis System®.

PubMed

Idemoto, Yoshiaki; Miura, Shin-Ichiro; Norimatsu, Kenji; Suematsu, Yasunori; Hitaka, Yuka; Shiga, Yuhei; Morii, Joji; Imaizumi, Satoshi; Kuwano, Takashi; Iwata, Atsushi; Zhang, Bo; Ogawa, Masahiro; Saku, Keijiro

2017-03-01

The Total Thrombus-formation Analysis System (T-TAS ® ) is a novel automated microchip flow-chamber system for the quantitative evaluation of thrombus formation under blood flow conditions. T-TAS ® uses two types of microchip to evaluate thrombus formation: the AR-chip quantifies white thrombus formation and the PL-chip quantifies platelet thrombus formation. We assessed the antithrombotic abilities of various non-vitamin K antagonist oral anticoagulants (NOACs) using T-TAS ® . One hundred and three consecutive patients who were hospitalized with cardiovascular diseases were enrolled. We divided the patients into 2 groups; a control group that did not receive an anticoagulant (non-AC group) and an anticoagulant group (AC group). The AC group was further divided into warfarin, dabigatran, rivaroxaban and apixaban groups. We performed common coagulation tests and evaluated the area under the flow pressure curve (AR-AUC and PL-AUC) to quantify antithrombotic ability using T-TAS ® at the trough. There were no significant differences in patient characteristics between the non-AC and AC groups. Only 55.1 % of patients in the AC group achieved the target blood pressure (BP) of less than 130/80 mmHg. Compared with the non-AC group, AR-AUC was significantly decreased in the AC, warfarin, dabigatran and apixaban groups. Only the rivaroxaban group did not show a significant decrease in AR-AUC. NOACs showed a significant decrease in PL-AUC compared with the non-AC group. In conclusion, T-TAS ® was a useful tool for evaluating anticoagulation activity. NOACs was significantly effective as an antiplatelet agent. BP control should be a higher priority than the selection of an anticoagulant drug, especially NOACs.

Supercritical CO2 Extraction of Lavandula angustifolia Mill. Flowers: Optimisation of Oxygenated Monoterpenes, Coumarin and Herniarin Content.

PubMed

Jerković, Igor; Molnar, Maja; Vidović, Senka; Vladić, Jelena; Jokić, Stela

2017-11-01

Lavandula angustifolia is good source of oxygenated monoterpenes containing coumarins as well, which are all soluble in supercritical CO 2 (SC-CO 2 ). The study objective is to investigate SC-CO 2 extraction parameters on: the total yield; GC-MS profile of the extracts; relative content of oxygenated monoterpenes; the amount of coumarin and herniarin; and to determine optimal SC-CO 2 extraction conditions by response surface methodology (RSM). SC-CO 2 extraction was performed under different pressure, temperature and CO 2 flow rate determined by Box-Behnken design (BBD). The sample mass and the extraction time were kept constant. The chemical profiles and relative content of oxygenated monoterpenes (as coumarin equivalents, CE) were determined by GC-MS. Coumarin and herniarin concentrations were dosed by HPLC. SC-CO 2 extracts contained linalool (57.4-217.9 mg CE/100 g), camphor (10.6-154.4 mg CE/100 g), borneol (6.2-99.9 mg CE/100 g), 1,8-cineole (5.0-70.4 mg CE/100 g), linalyl acetate (86.1-267.9 mg CE/100 g), coumarin (0.95-18.16 mg/100 g), and herniarin (0.95-13.63 mg/100 g). The interaction between the pressure and CO 2 flow rate as well as between the temperature and CO 2 flow rate showed statistically significant influence on the extraction yield. Applying BBD, the optimum extraction conditions for higher monoterpenes and lower coumarin content were at 10 MPa, 41°C and CO 2 flow rate 2.3 kg/h, and at 30 MPa, 50°C and CO 2 flow rate 3 kg/h for higher monoterpenes and coumarin content. SC-CO 2 extraction is a viable technique for obtaining lavender extracts with desirable flavour components. The second-order model based on BBD predicts the results for SC-CO 2 extraction quite satisfactorily. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Transport mechanism of chitosan-N-acetylcysteine, chitosan oligosaccharides or carboxymethyl chitosan decorated coumarin-6 loaded nanostructured lipid carriers across the rabbit ocular.

PubMed

Li, Jinyu; Tan, Guoxin; Cheng, Bingchao; Liu, Dandan; Pan, Weisan

2017-11-01

To facilitate the hydrophobic drugs modeled by coumarin-6 (Cou-6) acrossing the cornea to the anterior chamber of the rabbit eye, chitosan (CS) derivatives including chitosan-N-acetyl-l-cysteine (CS-NAC), chitosan oligosaccharides (COS) and carboxymethyl chitosan (CMCS) modified nanostructured lipid carriers (NLCs) were designed and characterized. We found that, with similar size distribution and positivecharges, different CS derivatives based on NLCs led to distinctive delivery performance. In vivo precorneal retention study on rabbits revealed that these CS derivatives coating exhibited a stronger resistant effect than Cou-6 eye drops and Cou-6-NLC (P<0.05), moreover, the AUC (0-∞) , C max and MRT (0-∞) of them followed the sequence of CMCS-Cou-6-NLC

Bivalirudin for Pediatric Procedural Anticoagulation: A Narrative Review.

PubMed

Zaleski, Katherine L; DiNardo, James A; Nasr, Viviane G

2018-02-14

Bivalirudin (Angiomax; The Medicines Company, Parsippany, NJ), a direct thrombin inhibitor, has found increasing utilization as a heparin alternative in the pediatric population, most commonly for the treatment of thrombosis secondary to heparin-induced thrombocytopenia. Due to the relative rarity of heparin-induced thrombocytopenia as well as the lack of Food and Drug Administration-approved indications in this age group, much of what is known regarding the pharmacokinetics and pharmacodynamics of bivalirudin in this population has been extrapolated from adult data. This narrative review will present recommendations regarding the use of bivalirudin for procedural anticoagulation in the pediatric population based on the published literature.

Size-Tunable and Functional Core-Shell Structured Silica Nanoparticles for Drug Release

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chi, Fangli; Guo, Ya Nan; Liu, Jun

2010-02-18

Size-tunable silica cross-linked micellar core-shell nanoparticles (SCMCSNs) were successfully synthesized from a Pluronic nonionic surfactant (F127) template system with organic swelling agents such as 1,3,5-trimethylbenzene (TMB) and octanoic acid at room temperature. The size and morphology of SCMCSNs were directly evidenced by TEM imaging and DLS measurements (up to ~90 nm). Pyrene and coumarin 153 (C153) were used as fluorescent probe molecules to investigate the effect and location of swelling agent molecules. Papaverine as a model drug was used to measure the loading capacity and release property of nanoparticles. The swelling agents can enlarge the nanoparticle size and improve themore » drug loading capacity of nanoparticles. Moreover, the carboxylic acid group of fatty acid can adjust the release behavior of the nanoparticles.« less

European cardiac nurses' current practice and knowledge on anticoagulation therapy.

PubMed

Oterhals, Kjersti; Deaton, Christi; De Geest, Sabina; Jaarsma, Tiny; Lenzen, Mattie; Moons, Philip; Mårtensson, Jan; Smith, Karen; Stewart, Simon; Strömberg, Anna; Thompson, David R; Norekvål, Tone M

2014-06-01

Successful management of warfarin, new anti-thrombotic agents and self-monitoring devices requires that health care professionals effectively counsel and educate patients. Previous studies indicate that health care professionals do not always have the knowledge to provide patients with the correct information. The purpose of this study was to investigate European cardiovascular nurses' knowledge on the overall management of anticoagulation therapy and examine if this knowledge was influenced by level of education and years in clinical practice. A questionnaire including 47 items on practice patterns and knowledge on warfarin, new anticoagulants, warfarin-drug and warfarin-food interactions, and self-management of International Normalized Ratio (INR) was distributed to the attendants at a European conference in 2012. The response rate was 32% (n=206), of whom 84% reported having direct patient contact. Warfarin was the most common used oral anticoagulation in daily practice. One third offered their patients both patient self-testing and patient self-management of INR. The mean total score on the knowledge questions was 28±6 (maximum possible score 53). Nurses in direct patient care had a higher mean score (p=0.011). Knowledge on warfarin and medication-interactions were low, but knowledge on warfarin-diet interactions and how to advise patients on warfarin as somewhat better. European cardiac nurses need to improve their knowledge and practice patterns on oral anticoagulation therapy. This area of knowledge is important in order to deliver optimal care to cardiac patients and to minimise adverse effects of the treatment.

Stroke Prevention in Atrial Fibrillation: Focus on Latin America

PubMed Central

Massaro, Ayrton R.; Lippp, Gregory Y. H.

2016-01-01

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, with an estimated prevalence of 1-2% in North America and Europe. The increased prevalence of AF in Latin America is associated with an ageing general population, along with poor control of key risk factors, including hypertension. As a result, stroke prevalence and associated mortality have increased dramatically in the region. Therefore, the need for effective anticoagulation strategies in Latin America is clear. The aim of this review is to provide a contemporary overview of anticoagulants for stroke prevention. The use of vitamin K antagonists (VKAs, eg, warfarin) and aspirin in the prevention of stroke in patients with AF in Latin America remains common, although around one fifth of all AF patients receive no anticoagulation. Warfarin use is complicated by a lack of access to effective monitoring services coupled with an unpredictable pharmacokinetic profile. The overuse of aspirin is associated with significant bleeding risks and reduced efficacy for stroke prevention in this patient group. The non-VKA oral anticoagulants (NOACbs) represent a potential means of overcoming many limitations associated with VKA and aspirin use, including a reduction in the need for monitoring and a reduced risk of hemorrhagic events. The ultimate decision of which anticoagulant drug to utilize in AF patients depends on a multitude of factors. More research is needed to appreciate the impact of these factors in the Latin American population and thereby reduce the burden of AF-associated stroke in this region. PMID:28558081

Practical aspects of treatment with target specific anticoagulants: initiation, payment and current market, transitions, and venous thromboembolism treatment.

PubMed

Mahan, Charles E

2015-04-01

Target specific anticoagulants (TSOACs) have recently been introduced to the US market for multiple indications including venous thromboembolism (VTE) prevention in total hip and knee replacement surgeries, VTE treatment and reduction in the risk of stroke in patients with non-valvular atrial fibrillation (NVAF). Currently, three TSOACs are available including rivaroxaban, apixaban, and dabigatran with edoxaban currently under Food and Drug Administration review for VTE treatment and stroke prevention in NVAF. The introduction of these agents has created a paradigm shift in anticoagulation by considerably simplifying treatment and anticoagulant initiation for patients by giving clinicians the opportunity to use a rapid onset, rapid offset, oral agent. The availability of these rapid onset TSOACs is allowing for outpatient treatment of low risk pulmonary embolism and deep vein thrombosis which can greatly reduce healthcare costs by avoiding inpatient hospitalizations and treatment for the disease. Additionally with this practice, the complications of an inpatient hospitalization may also be avoided such as nosocomial infections. Single-agent approaches with TSOACs represent a paradigm shift in the treatment of VTE versus the complicated overlap of a parenteral agent with warfarin. Transitions between anticoagulants, including TSOACs, are a high-risk period for the patient, and clinicians must carefully consider patient characteristics such as renal function as well as the agents that are being transitioned. TSOAC use appears to be growing slowly with improved payment coverage throughout the US.

Short-Term Anticoagulant Therapy and Thrombus Location Are Independent Risk Factors for Delayed Recanalization of Deep Vein Thrombosis.

PubMed

Zhang, Chuanlin; Fu, Qining; Zhao, Yu; Mu, Shaoyu; Liu, Liping

2016-01-21

Prompt recanalization of the vein containing the thrombus is an important goal during the initial treatment of DVT, and risk factors for delayed recanalization in patients with deep vein thrombosis (DVT) in the lower extremities need to be determined. A total of 174 patients with DVT in lower extremities were recruited from June 2014 to March 2015 at our hospital. Duplex ultrasound scanning was conducted for all patients at 1 and 6 months after baseline evaluation. We divided the patients into recanalization and non-recanalization groups and analyzed risk factors for delayed recanalization. The univariate analysis revealed that an oral anticoagulant time of less than 3 months and venous thrombus location were risk factors for delayed recanalization (P<0.01). However, age, gender, hypertension, diabetes, pulmonary embolism, incidence factors, the use of catheter-directed thrombolytic (CDT) drugs, and inferior vena cava filter (IVCF) implantation had no influence on the incidence of delayed recanalization in patients with DVT (P>0.05). The multivariate analysis showed that patients with an anticoagulant time of less than 3 months had a lower incidence of recanalization than those with an anticoagulant time of more than 3 months (OR=2.358, P<0.05). The risk of delayed recanalization in patients with proximal DVT was 7 times higher than that in patients with distal DVT. Duration of anticoagulant treatment of less than 3 months and venous thrombus location are independent risk factors for delayed recanalization of DVT in the lower extremities.

Effect of chronic kidney disease on warfarin management in a pharmacist-managed anticoagulation clinic.

PubMed

Kleinow, Megan E; Garwood, Candice L; Clemente, Jennifer L; Whittaker, Peter

2011-09-01

There is growing evidence that kidney disease affects hepatically cleared drugs. Accordingly, we hypothesized that chronic kidney disease (CKD) would disrupt anticoagulation of warfarin-treated patients and thereby increase the amount of management required to maintain appropriate anticoagulation. Specifically, we anticipated that more dose manipulations (both dose changes and transient dose adjustments) and shorter times between scheduled clinic visits would be required for anticoagulation patients with CKD. To determine how CKD affected warfarin maintenance dose, anticoagulation stability, the proportion of clinic visits that necessitated a dose manipulation (either a change in the prescribed weekly dose or a transient dose adjustment), and the length of time between scheduled visits in 2 pharmacist-managed anticoagulation clinics. Our retrospective, cohort chart review investigated warfarin response in anticoagulation clinic patients. From the clinic database of patients with an international normalized ratio (INR) target range of 2.0-3.0, we matched 20 of 24 patients with CKD (estimated creatinine clearance less than 60 mL per minute) to 20 comparison group patients (estimated creatinine clearance greater than 60 mL per minute) based on parameters demonstrated to affect warfarin dose: ethnicity, gender, age, body surface area, and simvastatin use. We calculated the average weekly dose used to maintain target INR (assessment period range=116-1,408 days). To evaluate anticoagulation stability and patient management, we quantified several parameters, including the percentage of total time in therapeutic range, the proportion of clinic visits that required a dose change, and the time between scheduled visits. We compared group means using t-tests, and categorical data were compared using Fisher's exact test. Our population was predominantly female (75%) and of African ancestry (95%); average age 60 years. Patients with CKD required a 24% lower dose than the comparison group (mean [SD]=35.9 [10.7] vs. 47.0 [11.2] mg per week, P=0.003) and spent less time in therapeutic range required increased clinic management versus the comparison group, as indicated by a significantly higher proportion of clinic visits at which dose changes occurred (22% vs. 12%, P<0.001) and a decreased time between scheduled visits (mean [SD] of 16.0 [3.2] days vs. 19.7 [3.4] days, respectively, P=0.001). CKD was associated with both decreased warfarin maintenance dose and decreased anticoagulation stability which, in turn, required more frequent and intensive anticoagulation clinic management.

Creatinine Versus Cystatin C: Differing Estimates of Renal Function in Hospitalized Veterans Receiving Anticoagulants.

PubMed

Wang, Christina Hao; Rubinsky, Anna D; Minichiello, Tracy; Shlipak, Michael G; Price, Erika Leemann

2018-05-31

Current practice in anticoagulation dosing relies on kidney function estimated by serum creatinine using the Cockcroft-Gault equation. However, creatinine can be unreliable in patients with low or high muscle mass. Cystatin C provides an alternative estimation of glomerular filtration rate (eGFR) that is independent of muscle. We compared cystatin C-based eGFR (eGFR cys ) with multiple creatinine-based estimates of kidney function in hospitalized patients receiving anticoagulants, to assess for discordant results that could impact medication dosing. Retrospective chart review of hospitalized patients over 1 year who received non-vitamin K antagonist anticoagulation, and who had same-day measurements of cystatin C and creatinine. Seventy-five inpatient veterans (median age 68) at the San Francisco VA Medical Center (SFVAMC). We compared the median difference between eGFR by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) study equation using cystatin C (eGFR cys ) and eGFRs using three creatinine-based equations: CKD-EPI (eGFR EPI ), Modified Diet in Renal Disease (eGFR MDRD ), and Cockcroft-Gault (eGFR CG ). We categorized patients into standard KDIGO kidney stages and into drug-dosing categories based on each creatinine equation and calculated proportions of patients reclassified across these categories based on cystatin C. Cystatin C predicted overall lower eGFR compared to creatinine-based equations, with a median difference of - 7.1 (IQR - 17.2, 2.6) mL/min/1.73 m 2 versus eGFR EPI , - 21.2 (IQR - 43.7, - 8.1) mL/min/1.73 m 2 versus eGFR MDRD , and - 25.9 (IQR - 46.8, - 8.7) mL/min/1.73 m 2 versus eGFR CG . Thirty-one to 52% of patients were reclassified into lower drug-dosing categories using cystatin C compared to creatinine-based estimates. We found substantial discordance in eGFR comparing cystatin C with creatinine in this group of anticoagulated inpatients. Our sample size was limited and included few women. Further investigation is needed to confirm these findings and evaluate implications for bleeding and other clinical outcomes. Not applicable.

A prodrug approach to the use of coumarins as potential therapeutics for superficial mycoses.

PubMed

Mercer, Derry K; Robertson, Jennifer; Wright, Kristine; Miller, Lorna; Smith, Shane; Stewart, Colin S; O Neil, Deborah A

2013-01-01

Superficial mycoses are fungal infections of the outer layers of the skin, hair and nails that affect 20-25% of the world's population, with increasing incidence. Treatment of superficial mycoses, predominantly caused by dermatophytes, is by topical and/or oral regimens. New therapeutic options with improved efficacy and/or safety profiles are desirable. There is renewed interest in natural product-based antimicrobials as alternatives to conventional treatments, including the treatment of superficial mycoses. We investigated the potential of coumarins as dermatophyte-specific antifungal agents and describe for the first time their potential utility as topical antifungals for superficial mycoses using a prodrug approach. Here we demonstrate that an inactive coumarin glycone, esculin, is hydrolysed to the antifungal coumarin aglycone, esculetin by dermatophytes. Esculin is hydrolysed to esculetin β-glucosidases. We demonstrate that β-glucosidases are produced by dermatophytes as well as members of the dermal microbiota, and that this activity is sufficient to hydrolyse esculin to esculetin with concomitant antifungal activity. A β-glucosidase inhibitor (conduritol B epoxide), inhibited antifungal activity by preventing esculin hydrolysis. Esculin demonstrates good aqueous solubility (<6 g/l) and could be readily formulated and delivered topically as an inactive prodrug in a water-based gel or cream. This work demonstrates proof-of-principle for a therapeutic application of glycosylated coumarins as inactive prodrugs that could be converted to an active antifungal in situ. It is anticipated that this approach will be applicable to other coumarin glycones.

A Prodrug Approach to the Use of Coumarins as Potential Therapeutics for Superficial Mycoses

PubMed Central

Mercer, Derry K.; Robertson, Jennifer; Wright, Kristine; Miller, Lorna; Smith, Shane; Stewart, Colin S.; O′Neil, Deborah A.

2013-01-01

Superficial mycoses are fungal infections of the outer layers of the skin, hair and nails that affect 20–25% of the world's population, with increasing incidence. Treatment of superficial mycoses, predominantly caused by dermatophytes, is by topical and/or oral regimens. New therapeutic options with improved efficacy and/or safety profiles are desirable. There is renewed interest in natural product-based antimicrobials as alternatives to conventional treatments, including the treatment of superficial mycoses. We investigated the potential of coumarins as dermatophyte-specific antifungal agents and describe for the first time their potential utility as topical antifungals for superficial mycoses using a prodrug approach. Here we demonstrate that an inactive coumarin glycone, esculin, is hydrolysed to the antifungal coumarin aglycone, esculetin by dermatophytes. Esculin is hydrolysed to esculetin β-glucosidases. We demonstrate that β-glucosidases are produced by dermatophytes as well as members of the dermal microbiota, and that this activity is sufficient to hydrolyse esculin to esculetin with concomitant antifungal activity. A β-glucosidase inhibitor (conduritol B epoxide), inhibited antifungal activity by preventing esculin hydrolysis. Esculin demonstrates good aqueous solubility (<6 g/l) and could be readily formulated and delivered topically as an inactive prodrug in a water-based gel or cream. This work demonstrates proof-of-principle for a therapeutic application of glycosylated coumarins as inactive prodrugs that could be converted to an active antifungal in situ. It is anticipated that this approach will be applicable to other coumarin glycones. PMID:24260474

New oral anticoagulant and antiplatelet agents for neurosurgeons.

PubMed

Kimpton, George; Dabbous, Bassam; Leach, Paul

2015-01-01

Until recently, warfarin, clopidogrel and aspirin have provided the mainstay for prevention of thrombotic disease in cardiac patients. However, new classes of drugs have recently emerged that promise better clinical outcomes and lower risks. Use of such agents has increased, but increased risk and severity of intra-cranial haemorrhage (ICH) still remain. These cases of intra-cranial bleeds present as emergencies to neurosurgical units. It is of paramount importance that neurosurgical practitioners are aware of those new drugs, useful monitoring tests and available emergency reversal options in case the patient needs emergency intervention. In this review we survey newly available agents in the U.K. at the time of publication. We look at the data provided by the manufacturers, related publications and international guidelines for their use and reversal. New anticoagulants offer a lower incidence of ICH compared with warfarin. Advanced and accurate monitoring tests are emerging, as are prospective data on reversal of anticoagulation in bleeding. Some standard coagulation tests may be of use, whilst reversal agents are available and being evaluated. The trial data shows that new antiplatelet agents have similar or increased incidence and severity of intra-cranial ICH compared with clopidogrel. There is currently limited data on monitoring or reversal. We suggest they may be managed similarly to clopidogrel by using platelet reactivity assays, optimising platelet count and using platelet transfusion with adjunctive agents.

Discovery of Novel Nonactive Site Inhibitors of the Prothrombinase Enzyme Complex.

PubMed

Kapoor, Karan; McGill, Nicole; Peterson, Cynthia B; Meyers, Harold V; Blackburn, Michael N; Baudry, Jerome

2016-03-28

The risk of serious bleeding is a major liability of anticoagulant drugs that are active-site competitive inhibitors targeting the Factor Xa (FXa) prothrombin (PT) binding site. The present work identifies several new classes of small molecule anticoagulants that can act as nonactive site inhibitors of the prothrombinase (PTase) complex composed of FXa and Factor Va (FVa). These new classes of anticoagulants were identified, using a novel agnostic computational approach to identify previously unrecognized binding pockets at the FXa-FVa interface. From about three million docking calculations of 281,128 compounds in a conformational ensemble of FXa heavy chains identified by molecular dynamics (MD) simulations, 97 compounds and their structural analogues were selected for experimental validation, through a series of inhibition assays. The compound selection was based on their predicted binding affinities to FXa and their ability to successfully bind to multiple protein conformations while showing selectivity for particular binding sites at the FXa/FVa interface. From these, thirty-one (31) compounds were experimentally identified as nonactive site inhibitors. Concentration-based assays further identified 10 compounds represented by four small-molecule families of inhibitors that achieve dose-independent partial inhibition of PTase activity in a nonactive site-dependent and self-limiting mechanism. Several compounds were identified for their ability to bind to protein conformations only seen during MD, highlighting the importance of accounting for protein flexibility in structure-based drug discovery approaches.

SKLB060 Reversibly Binds to Colchicine Site of Tubulin and Possesses Efficacy in Multidrug-Resistant Cell Lines.

PubMed

Yan, Wei; Yang, Tao; Yang, Jianhong; Wang, Taijin; Yu, Yamei; Wang, Yuxi; Chen, Qiang; Bai, Peng; Li, Dan; Ye, Haoyu; Qiu, Qiang; Zhou, Yongzhao; Hu, Yiguo; Yang, Shengyong; Wei, Yuquan; Li, Weimin; Chen, Lijuan

2018-05-22

Many tubulin inhibitors are in clinical use as anti-cancer drugs. In our previous study, a novel series of 4-substituted coumarins derivatives were identified as novel tubulin inhibitors. Here, we report the anti-cancer activity and underlying mechanism of one of the 4-substituted coumarins derivatives (SKLB060). The anti-cancer activity of SKLB060 was tested on 13 different cancer cell lines and four xenograft cancer models. Immunofluorescence staining, cell cycle analysis, and tubulin polymerization assay were employed to study the inhibition of tubulin. N, N '-Ethylenebis(iodoacetamide) assay was used to measure binding to the colchicine site. Wound-healing migration and tube formation assays were performed on human umbilical vascular endothelial cells to study anti-vascular activity (the ability to inhibit blood vessel growth). Mitotic block reversibility and structural biology assays were used to investigate the SKLB060-tubulin bound model. SKLB060 inhibited tubulin polymerization and subsequently induced G2/M cell cycle arrest and apoptosis in cancer cells. SKLB060 bound to the colchicine site of β-tubulin and showed antivascular activity in vitro. Moreover, SKLB060 induced reversible cell cycle arrest and reversible inhibition of tubulin polymerization. A mitotic block reversibility assay showed that the effects of SKLB060 have greater reversibility than those of colcemid (a reversible tubulin inhibitor), indicating that SKLB060 binds to tubulin in a totally reversible manner. The crystal structures of SKLB060-tubulin complexes confirmed that SKLB060 binds to the colchicine site, and the natural coumarin ring in SKLB060 enables reversible binding. These results reveal that SKLB060 is a powerful and reversible microtubule inhibitor that binds to the colchicine site and is effective in multidrug-resistant cell lines. © 2018 The Author(s). Published by S. Karger AG, Basel.

Purification of coumarin compounds from Cortex fraxinus by adsorption chromatography.

PubMed

Yu, Minglan; Sun, Ailing; Zhang, Yongqing; Liu, Renmin

2014-10-01

In this paper, a chromatographic method for isolation and purification of coumarin compounds from Cortex fraxinus was established by using Superose 12 as the separation media for the first time. The conditions for separation were optimized. Four kinds of coumarin compounds including aesuletin, aesculin, fraxetin and fraxin were obtained. The purity of these compounds were 98.5, 99.1, 97.9 and 97.3%, respectively, which were determined by HPLC area normalization method. The chemical structures of the separated compounds were identified according to (1)H and (13)C nuclear magnetic resonance data. The retention behavior of the separated coumarin compounds on Superose 12 was also discussed. The retention is based on a mixture of hydrogen bonding and hydrophobic interactions between the coumarin compounds and the residues of the cross-linking reagents used in the manufacturing process of Superose 12. The results of this paper indicate that Superose 12 is not only suitable for size-exclusion chromatography of proteins and other biological macromolecules but also for low-molecular-weight natural products. © The Author [2013]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

[Quantitative method for simultaneous assay of four coumarins with one marker in Fraxini Cortex].

PubMed

Feng, Weihong; Wang, Zhimin; Zhang, Qiwei; Liu, Limei; Wang, Jinyu; Yang, Fei

2011-07-01

To establish a new quantitative method for simultaneous determination of multi-coumarins in Fraxini Cortex by using one chemical reference substance, and validate its feasibilities. The new quality evaluation method, quantitative analysis of multi-components by singer-marker (QAMS), was established and validated with Fraxini Cortex. Four main coumarins were selected as analytes to evaluate the quality and their relative correlation factors (RCF) were determined by HPLC-DAD. Within the linear range, the values of RCF at 340 nm of aesculin to asculetin, fraxin and fraxetin were 1.771, 0.799, 1.409, respectively. And the contents of aesculin in samples of Fraxini Cortex were authentically determined by the external standard method, and the contents of the three other coumarins were calculated by their RCF. The contents of these four coumarins in all samples were also determined by the external standard method. Within a certain range, the RCF had a good reproducibility (RSD 2.5%-3.9%). Significant differences were not observed between the quantitative results of two methods. It is feasible and suitable to evaluate the quality of Fraxini Cortex and its Yinpian by QAMS.

Magnetic nanoparticles modified with DTPA-AMC-rare earth for fluorescent and magnetic resonance dual mode imaging.

PubMed

Liu, Zengchen; Li, Bo; Wang, Baodui; Yang, Zhengyin; Wang, Qin; Li, Tianrong; Qin, Dongdong; Li, Yong; Wang, Mingfang; Yan, Mihui

2012-07-28

In the present study, we report new water-soluble cell fluorescence imaging and contrast agents that are based on DTPA-AMC(7-amino-4-methyl coumarin)-Eu(3+) and DTPA-AMC(7-amino-4-methyl coumarin)-Gd(3+) compounds conjugated to Fe(3)O(4) NPs via a PEG-NH(2) linker. The novel Fe(3)O(4) NP-conjugates present two main advantages for cell fluorescence labelling: water solubility and targeting ability. The in vitro experiments demonstrate that water-soluble Fe(3)O(4) NPs-DBI-PEG-NH-DTPA-AMC(7-amino-4-methyl coumarin)-Eu(3+) has excellent cell permeating activity. Moreover, the relaxation rate test of Fe(3)O(4) NPs-DBI-PEG-NH-DTPA-AMC(7-amino-4-methyl coumarin)-Gd(3+) shows a higher T1 relaxation effect than traditional DTPA-Gd(3+) MRI agents. According to in vivo liver MRI experiments, better contrast of the liver was achieved after addition of Fe(3)O(4) NPs-DBI-PEG-NH-DTPA-AMC(7-amino-4-methyl coumarin)-Gd(3+). The results will provide a significant guide for researchers exploring the biomedical applications of superparamagnetic Fe(3)O(4) NPs.

Drug name alert: potential for confusion between pradax and plavix.

PubMed

Koczmara, Christine; Hyland, Sylvia

2011-01-01

In this article, the authors highlight an incident that involved a mix-up between the oral anticoagulant medication Pradax (dabigatran etexilate) and the antiplatelet medication Plavix (clopidogrel). Because critical care nurses may admit or care for patients who are receiving (or have received) one of these medications, it is important that they be aware of the potential for confusion between these two drug names throughout the medication-use process.

The use of novel oral anticoagulants for thromboprophylaxis after elective major orthopedic surgery

PubMed Central

Rachidi, Saleh; Aldin, Ehab Saad; Greenberg, Charles; Sachs, Barton; Streiff, Michael; Zeidan, Amer M

2014-01-01

Venous thromboembolism is a common cause of morbidity and mortality among patients undergoing elective orthopedic surgery. Due to the high incidence of venous thromboembolism in this setting, perioperative anticoagulation is the recommended approach for thromboprophylaxis. Low molecular weight heparin (LMWH), fondaparinux and warfarin are the agents commonly used for thromboprophylaxis. The well-recognized limitations of warfarin and the inconvenience and discomfort associated with the subcutaneous administration of low molecular weight heparin and fondaparinux inspired intense investigation to develop novel oral anticoagulants (NOACs) with more predictable pharmacokinetics, fewer drug interactions and no need for regular laboratory monitoring. Three NOACs have been demonstrated to be effective for thromboprophylaxis after total hip arthroplasty (THA) and total knee arthroplasty (TKA) in large randomized controlled trials. Here we review the pharmacology of rivaroxaban, dabigatran, and apixaban, summarize the major clinical trials of these agents in thromboprophylaxis after THA and TKA, and discuss the clinical factors to be considered by providers when selecting a NOAC for their patients. PMID:24219550

Use of apixaban after development of suspected rivaroxaban-induced hepatic steatosis; a case report.

PubMed

Anastasia, Emily J; Rosenstein, Robert S; Bergsman, Jeffrey A; Parra, David

2015-09-01

Postmarketing reports have emerged associating rivaroxaban with drug-induced liver injury (DILI); however, management strategies of patients with suspected rivaroxaban-induced liver injury requiring continued anticoagulation have not been published. The present report describes a 67-year-old male with atrial fibrillation receiving rivaroxaban who developed a 16-fold elevation in alanine transaminase, a nearly two-fold elevation in total bilirubin, and ultrasound confirmed hepatic steatosis. The patient was switched from rivaroxaban to apixaban with subsequent rapid resolution of laboratory abnormalities. Rapid improvement in liver function tests despite use of an alternative factor Xa inhibitor suggests that rivaroxaban's mechanism of hepatotoxicity may be unrelated to its pharmacologic action. When using rivaroxaban, clinicians should be aware of the small but potentially serious risk of DILI. Because most anticoagulants have been associated with DILI, selection of an alternative anticoagulant may be challenging; however, the use of apixaban in this case suggests it may be a reasonable alternative.

Medical Treatment for Postthrombotic Syndrome

PubMed Central

Palacios, Federico Silva; Rathbun, Suman Wasan

2017-01-01

Deep vein thrombosis (DVT) is a prevalent disease. About 20 to 30% of patients with DVT will develop postthrombotic syndrome (PTS) within months after the initial diagnosis of DVT. There is no gold standard for diagnosis of PTS, but clinical signs include pitting edema, hyperpigmentation, phlebectatic crown, venous eczema, and varicose veins. Several scoring systems have been developed for diagnostic evaluation. Conservative treatment includes compression therapy, medications, lifestyle modification, and exercise. Compression therapy, the mainstay and most proven noninvasive therapy for patients with PTS, can be prescribed as compression stockings, bandaging, adjustable compression wrap devices, and intermittent pneumatic compression. Medications may be used to both prevent and treat PTS and include anticoagulation, anti-inflammatories, vasoactive drugs, antibiotics, and diuretics. Exercise, weight loss, smoking cessation, and leg elevation are also recommended. Areas of further research include the duration, compliance, and strength of compression stockings in the prevention of PTS after DVT; the use of intermittent compression devices; the optimal medical anticoagulant regimen after endovascular therapy; and the role of newer anticoagulants as anti-inflammatory agents. PMID:28265131

Tyrosinase inhibitor activity of coumarin-resveratrol hybrids.

PubMed

Fais, Antonella; Corda, Marcella; Era, Benedetta; Fadda, M Benedetta; Matos, Maria Joao; Quezada, Elias; Santana, Lourdes; Picciau, Carmen; Podda, Gianni; Delogu, Giovanna

2009-07-13

In the present work we report on the contribution of the coumarin moiety to tyrosinase inhibition. Coumarin-resveratrol hybrids 1-8 have been resynthesized to investigate the structure-activity relationships and the IC(50) values of these compounds were measured. The results showed that these compounds exhibited tyrosinase inhibitory activity. Compound 3-(3',4',5'-trihydroxyphenyl)-6,8-dihydroxycoumarin (8)is the most potentcompound (0.27 mM), more so than umbelliferone (0.42 mM), used as reference compound. The kinetic studies revealed that compound 8 caused non-competitive tyrosinase inhibition.

Coagulation Testing in Acute Ischemic Stroke Patients Taking Non-Vitamin K Antagonist Oral Anticoagulants.

PubMed

Purrucker, Jan C; Haas, Kirsten; Rizos, Timolaos; Khan, Shujah; Poli, Sven; Kraft, Peter; Kleinschnitz, Christoph; Dziewas, Rainer; Binder, Andreas; Palm, Frederick; Jander, Sebastian; Soda, Hassan; Heuschmann, Peter U; Veltkamp, Roland

2017-01-01

In patients who present with acute ischemic stroke while on treatment with non-vitamin K antagonist oral anticoagulants (NOACs), coagulation testing is necessary to confirm the eligibility for thrombolytic therapy. We evaluated the current use of coagulation testing in routine clinical practice in patients who were on NOAC treatment at the time of acute ischemic stroke. Prospective multicenter observational RASUNOA registry (Registry of Acute Stroke Under New Oral Anticoagulants; February 2012-2015). Results of locally performed nonspecific (international normalized ratio, activated partial thromboplastin time, and thrombin time) and specific (antifactor Xa tests, hemoclot assay) coagulation tests were documented. The implications of test results for thrombolysis decision-making were explored. In the 290 patients enrolled, nonspecific coagulation tests were performed in ≥95% and specific coagulation tests in 26.9% of patients. Normal values of activated partial thromboplastin time and international normalized ratio did not reliably rule out peak drug levels at the time of the diagnostic tests (false-negative rates 11%-44% [95% confidence interval 1%-69%]). Twelve percent of patients apparently failed to take the prescribed NOAC prior to the acute event. Only 5.7% (9/159) of patients in the 4.5-hour time window received thrombolysis, and NOAC treatment was documented as main reason for not administering thrombolysis in 52.7% (79/150) of patients. NOAC treatment currently poses a significant barrier to thrombolysis in ischemic stroke. Because nonspecific coagulation test results within normal range have a high false-negative rate for detection of relevant drug concentrations, rapid drug-specific tests for thrombolysis decision-making should be established. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01850797. © 2016 American Heart Association, Inc.

Water-soluble constituents of the root barks of Fraxinus rhynchophylla (Chinese drug Qinpi).

PubMed

Xiao, Kai; Song, Qing-Hong; Zhang, Shu-Wei; Xuan, Li-Jiang

2008-01-01

Chemical studies on the roots of Fraxinus rhynchophylla led to the isolation of fraxisecoside (1), a novel coumarin-secoiridoid hybrid glycoside, namely, fraxetin-8-O-[11'-methyl-oleosidyl-(7'-->6'')]-beta-D-glucopyranoside and 14 known compounds. Their structures were elucidated based on chemical evidence and spectroscopic analysis, including extensive 2D NMR methods. Compound 2 was first isolated as a pure compound. Compound 1 exhibited moderate PTP1B inhibition activity. Compounds 1 and 2 showed inhibition activity against B- and T-cell proliferation, without cytotoxicity.

The essential role of coumarin secretion for Fe acquisition from alkaline soil

PubMed Central

Clemens, Stephan; Weber, Michael

2016-01-01

ABSTRACT Plant productivity is limited by the scarcity of the essential micronutrient iron particularly in alkaline soils. The root secretion of phenolics has long been recognized as a component of the acidification-reduction strategy to acquire iron (strategy I). However, very little molecular insight into this process was available until recently several research groups independently discovered the important role of coumarins for the growth of Arabidopsis thaliana under Fe-limited conditions. Genome-wide analyses of iron deficiency responses, mutant screening and metabolomics experiments all converged on the finding that the synthesis and root exudation of scopoletin, esculetin and other coumarins is essential for iron uptake from substrates with low iron availability. Here we describe the evidence supporting this conclusion and discuss important questions that now have to be addressed in order to better understand the mechanistic basis of coumarin-dependent iron uptake and its significance within the plant kingdom. PMID:26618918

Influence of solvent and substituent on excited state characteristics of laser grade coumarin dyes.

PubMed

Sharma, Vijay K; Saharo, P D; Sharma, Neera; Rastogi, Ramesh C; Ghoshal, S K; Mohan, D

2003-04-01

Absorption and fluorescence emission of 4 and 7 substituted coumarins viz. C 440, C 490, C 485 and C 311 have been studied in various polar and non-polar organic solvents. These coumarin dyes are substituted with alkyl, amine and fluorine groups at 4- and 7-positions. They give different absorption and emission spectra in different solvents. The study leads to a possible assignment of energy level scheme for such coumarins including the effect on ground state and excited state dipole moments due to substitutions. Excited state dipole moments of these dyes are calculated by solvetochromic data experimentally and theoretically these are calculated by PM 3 method. The dipole moments in excited state, for all molecules investigated here, are higher than the corresponding values in the ground state. The increase in dipole moment has been explained in terms of the nature of excited state and resonance structure.

Use of Guidelines for Reducing Stroke Risk in Patients With Nonvalvular Atrial Fibrillation: A Review From a Latin American Perspective

PubMed Central

Silva, Gisele Sampaio; Ameriso, Sebastián F.

2017-01-01

Atrial fibrillation (AF) is a prominent risk factor for stroke and a leading cause of death and disability throughout Latin America. Contemporary evidence-based guidelines for the management of AF and stroke incorporate the use of practical and relatively simple scoring methods to estimate both stroke and bleeding risk, in order to assist in matching patients with appropriate interventions. This review examines consistencies and differences among guidelines for reducing stroke risk in patients with AF, assessing the role of user-friendly scoring methods to determine appropriate patients for anticoagulation and other treatment options. Current options include warfarin and direct oral anticoagulants such as dabigatran, rivaroxaban, apixaban, and edoxaban. These agents have been found to be superior or noninferior to standard vitamin K antagonist anticoagulation in large randomized trials. Potential benefits of these agents mainly include lower ischemic stroke rates, reduced intracranial bleeding, no need for regular monitoring, and fewer drug–drug and drug–food interactions. Expert opinions regarding clinical situations for which data are presently lacking, such as emergency bleeding and stroke in anticoagulated patients, are also provided. Enhanced attention and adherence to evidence-based guidelines are essential components for a strategy to reduce stroke morbidity and mortality across Latin America. PMID:28992764

Computational investigation of potential dosing schedules for a switch of medication from warfarin to rivaroxaban—an oral, direct Factor Xa inhibitor

PubMed Central

Burghaus, Rolf; Coboeken, Katrin; Gaub, Thomas; Niederalt, Christoph; Sensse, Anke; Siegmund, Hans-Ulrich; Weiss, Wolfgang; Mueck, Wolfgang; Tanigawa, Takahiko; Lippert, Jörg

2014-01-01

The long-lasting anticoagulant effect of vitamin K antagonists can be problematic in cases of adverse drug reactions or when patients are switched to another anticoagulant therapy. The objective of this study was to examine in silico the anticoagulant effect of rivaroxaban, an oral, direct Factor Xa inhibitor, combined with the residual effect of discontinued warfarin. Our simulations were based on the recommended anticoagulant dosing regimen for stroke prevention in patients with atrial fibrillation. The effects of the combination of discontinued warfarin plus rivaroxaban were simulated using an extended version of a previously validated blood coagulation computer model. A strong synergistic effect of the two distinct mechanisms of action was observed in the first 2–3 days after warfarin discontinuation; thereafter, the effect was close to additive. Nomograms for the introduction of rivaroxaban therapy after warfarin discontinuation were derived for Caucasian and Japanese patients using safety and efficacy criteria described previously, together with the coagulation model. The findings of our study provide a mechanistic pharmacologic rationale for dosing schedules during the therapy switch from warfarin to rivaroxaban and support the switching strategies as outlined in the Summary of Product Characteristics and Prescribing Information for rivaroxaban. PMID:25426077

Computational investigation of potential dosing schedules for a switch of medication from warfarin to rivaroxaban-an oral, direct Factor Xa inhibitor.

PubMed

Burghaus, Rolf; Coboeken, Katrin; Gaub, Thomas; Niederalt, Christoph; Sensse, Anke; Siegmund, Hans-Ulrich; Weiss, Wolfgang; Mueck, Wolfgang; Tanigawa, Takahiko; Lippert, Jörg

2014-01-01

The long-lasting anticoagulant effect of vitamin K antagonists can be problematic in cases of adverse drug reactions or when patients are switched to another anticoagulant therapy. The objective of this study was to examine in silico the anticoagulant effect of rivaroxaban, an oral, direct Factor Xa inhibitor, combined with the residual effect of discontinued warfarin. Our simulations were based on the recommended anticoagulant dosing regimen for stroke prevention in patients with atrial fibrillation. The effects of the combination of discontinued warfarin plus rivaroxaban were simulated using an extended version of a previously validated blood coagulation computer model. A strong synergistic effect of the two distinct mechanisms of action was observed in the first 2-3 days after warfarin discontinuation; thereafter, the effect was close to additive. Nomograms for the introduction of rivaroxaban therapy after warfarin discontinuation were derived for Caucasian and Japanese patients using safety and efficacy criteria described previously, together with the coagulation model. The findings of our study provide a mechanistic pharmacologic rationale for dosing schedules during the therapy switch from warfarin to rivaroxaban and support the switching strategies as outlined in the Summary of Product Characteristics and Prescribing Information for rivaroxaban.

The effectiveness of computerized drug-lab alerts: a systematic review and meta-analysis.

PubMed

Bayoumi, Imaan; Al Balas, Mosab; Handler, Steven M; Dolovich, Lisa; Hutchison, Brian; Holbrook, Anne

2014-06-01

Inadequate lab monitoring of drugs is a potential cause of ADEs (adverse drug events) which is remediable. To determine the effectiveness of computerized drug-lab alerts to improve medication-related outcomes. Citations from the Computerized Clinical Decision Support System Systematic Review (CCDSSR) and MMIT (Medications Management through Health Information Technology) databases, which had searched MEDLINE, EMBASE, CINAHL, Cochrane Database of Systematic Reviews, International Pharmaceutical Abstracts from 1974 to March 27, 2013. Randomized controlled trials (RCTs) of clinician-targeted computerized drug lab alerts conducted in any healthcare setting. Two reviewers performed full text review to determine study eligibility. A single reviewer abstracted data and evaluated validity of included studies using Cochrane handbook domains. Thirty-six studies met the inclusion criteria (25 single drug studies with 22,504 participants, 14 targeting anticoagulation; 11 multi-drug studies with 56,769 participants). ADEs were reported as an outcome in only four trials, all targeting anticoagulants. Computerized drug-lab alerts did not reduce ADEs (OR 0.89, 95% CI 0.79-1.00, p=0.05), length of hospital stay (SMD 0.00, 95%CI -0.93 to 0.93, p=0.055, 1 study), likelihood of hypoglycemia (OR 1.29, 95% CI 0.31-5.37) or likelihood of bleeding, but were associated with increased likelihood of prescribing changes (OR 1.73, 95% CI 1.21-2.47) or lab monitoring (OR 1.47, 95% confidence interval 1.12-1.94) in accordance with the alert. There is no evidence that computerized drug-lab alerts are associated with important clinical benefits, but there is evidence of improvement in selected clinical surrogate outcomes (time in therapeutic range for vitamin K antagonists), and changes in process outcomes (lab monitoring and prescribing decisions). Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Cost analysis of a managed care decentralized outpatient pharmacy anticoagulation service.

PubMed

Anderson, Robert J

2004-01-01

To determine the per-patient-per-month (PPPM) cost of a decentralized outpatient pharmacy anticoagulation service (OPAS) in patients with chronic atrial fibrillation (AF) who were maintained on warfarin sodium therapy in a managed care setting, to compare the annual costs versus the risk for stroke, and to assess the quality of the anticoagulant management. Data were collected retrospectively from clinical, research, and administrative claims databases. Patient demographic data were stratified to include age and risk factors for stroke. Inclusion criteria for the study were adult patients (>18 years) who were maintained on chronic warfarin therapy with a diagnosis of AF (diagnosis code 427.31) and continuously enrolled during calendar year 2000. The cost analysis included the personnel cost of clinical pharmacy specialists, direct and indirect cost of laboratory tests for international normalized ratios (INR), and anticoagulant (warfarin plus bridge therapy with a low molecular weight heparin) drug cost and dispensing fee. The percentage of INR values within or near target was used to evaluate the effectiveness of the service. A total of 97 patients on chronic warfarin therapy for AF were identified for cost analysis. The demographics for these patients included the following: 71% were male, with 32% of the patients over the age of 75 years, and 60% had 1 or more identifiable risk factors for stroke. Utilizing established criteria, 80.4% of the sample was considered to be at high risk for ischemic stroke. A majority of the patients (94.8%) had nonvalvular disease, with an INR goal in the range of 2 to 3 in 91.8% of the cases. The PPPM cost for the OPAS monitoring service was $51.25, distributed as $13.78 (27%) in personnel costs for monitoring pharmacists, $18.38 (36%) for lab tests, and $19.09 (37%) for anticoagulant drug costs. These costs did not significantly differ among patient groups with various risks for ischemic stroke. For nonvalvular AF patients, the percentage of INR values within each individual patient.s specific INR goal range was 60.4%; the percentage within or near goal was 74.6%. The average PPPM cost for pharmacist and laboratory monitoring as well as anticoagulant medication for CY 2000 was estimated to be $51.25. The annual costs were comparable among AF patients with different risks for ischemic stroke. The percentage of INR values within the individual patient.s stated target goal was 60.4%. Effective monitoring to maintain patients within their target INR goal is relatively inexpensive compared with the cost of complications such as ischemic stroke or intracranial bleeding.

Determination of coumarins in the roots of Angelica dahurica by supercritical fluid chromatography.

PubMed

Pfeifer, Isabella; Murauer, Adele; Ganzera, Markus

2016-09-10

The fact that supercritical fluid chromatography (SFC) offers many desirable features is known for a long time. Yet, the number of applications on natural products is still limited, because robust and user-friendly instrumentation became available just a few years ago. As coumarins hardly have been studied by this technique we developed the first SFC assay for their determination in crude plant material. After method optimization eight standard compounds, including simple coumarins, linear and angular furanocoumarins, could be baseline separated in 6min using an Acquity UPC(2) CSH Fluoro-Phenyl 1.7μm column with supercritical CO2, methanol and diethylamine as mobile phase. Method validation confirmed that the assay is linear (R(2)≥0.9995), precise (intra-day variation≤5.8%; inter-day variation≤4.4%) and accurate (recovery rates from 96.5 to 104.2%). Detection limits determined at 300nm were below 2ng on-column, and the method showed to be well suited for the analysis of coumarins in Angelica dahurica roots. It was observed that qualitative as well as quantitative composition vary significantly. In all samples Imperatorin (0.09-0.28%) was the major coumarin, followed either by Isoimperatorin or Oxypeucedanin; the total coumarin content ranged from 0.16 to 0.77%. The results were in good agreement to published data, so that because of its speed and green nature SFC is definitely an interesting alternative for the analysis of this important class of natural products. Copyright © 2016 Elsevier B.V. All rights reserved.

In silico genotoxicity of coumarins: application of the Phenol-Explorer food database to functional food science.

PubMed

Guardado Yordi, E; Matos, M J; Pérez Martínez, A; Tornes, A C; Santana, L; Molina, E; Uriarte, E

2017-08-01

Coumarins are a group of phytochemicals that may be beneficial or harmful to health depending on their type and dosage and the matrix that contains them. Some of these compounds have been proven to display pro-oxidant and clastogenic activities. Therefore, in the current work, we have studied the coumarins that are present in food sources extracted from the Phenol-Explorer database in order to predict their clastogenic activity and identify the structure-activity relationships and genotoxic structural alerts using alternative methods in the field of computational toxicology. It was necessary to compile information on the type and amount of coumarins in different food sources through the analysis of databases of food composition available online. A virtual screening using a clastogenic model and different software, such as MODESLAB, ChemDraw and STATISTIC, was performed. As a result, a table of food composition was prepared and qualitative information from this data was extracted. The virtual screening showed that the esterified substituents inactivate molecules, while the methoxyl and hydroxyl substituents contribute to their activity and constitute, together with the basic structures of the studied subclasses, clastogenic structural alerts. Chemical subclasses of simple coumarins and furocoumarins were classified as active (xanthotoxin, isopimpinellin, esculin, scopoletin, scopolin and bergapten). In silico genotoxicity was mainly predicted for coumarins found in beer, sherry, dried parsley, fresh parsley and raw celery stalks. The results obtained can be interesting for the future design of functional foods and dietary supplements. These studies constitute a reference for the genotoxic chemoinformatic analysis of bioactive compounds present in databases of food composition.

Synthesis, Structure-Activity Relationships (SAR) and in Silico Studies of Coumarin Derivatives with Antifungal Activity

PubMed Central

de Araújo, Rodrigo S. A.; Guerra, Felipe Q. S.; de O. Lima, Edeltrudes; de Simone, Carlos A.; Tavares, Josean F.; Scotti, Luciana; Scotti, Marcus T.; de Aquino, Thiago M.; de Moura, Ricardo O.; Mendonça, Francisco J. B.; Barbosa-Filho, José M.

2013-01-01

The increased incidence of opportunistic fungal infections, associated with greater resistance to the antifungal drugs currently in use has highlighted the need for new solutions. In this study twenty four coumarin derivatives were screened in vitro for antifungal activity against strains of Aspergillus. Some of the compounds exhibited significant antifungal activity with MICs values ranging between 16 and 32 μg/mL. The structure-activity relationships (SAR) study demonstrated that O-substitutions are essential for antifungal activity. It also showed that the presence of a short aliphatic chain and/or electron withdrawing groups (NO2 and/or acetate) favor activity. These findings were confirmed using density functional theory (DFT), when calculating the LUMO density. In Principal Component Analysis (PCA), two significant principal components (PCs) explained more than 60% of the total variance. The best Partial Least Squares Regression (PLS) model showed an r2 of 0.86 and q2cv of 0.64 corroborating the SAR observations as well as demonstrating a greater probe N1 interaction for active compounds. Descriptors generated by TIP correlogram demonstrated the importance of the molecular shape for antifungal activity. PMID:23306152

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hirode, Mitsuhiro; Ono, Atsushi; Miyagishima, Toshikazu

We have constructed a large-scale transcriptome database of rat liver treated with various drugs. In an effort to identify a biomarker for diagnosis of hepatic phospholipidosis, we extracted 78 probe sets of rat hepatic genes from data of 5 drugs, amiodarone, amitriptyline, clomipramine, imipramine, and ketoconazole, which actually induced this phenotype. Principal component analysis (PCA) using these probes clearly separated dose- and time-dependent clusters of treated groups from their controls. Moreover, 6 drugs (chloramphenicol, chlorpromazine, gentamicin, perhexiline, promethazine, and tamoxifen), which were reported to cause phospholipidosis but judged as negative by histopathological examination, were designated as positive by PCA usingmore » these probe sets. Eight drugs (carbon tetrachloride, coumarin, tetracycline, metformin, hydroxyzine, diltiazem, 2-bromoethylamine, and ethionamide), which showed phospholipidosis-like vacuolar formation in the histopathology, could be distinguished from the typical drugs causing phospholipidosis. Moreover, the possible induction of phospholipidosis was predictable by the expression of these genes 24 h after single administration in some of the drugs. We conclude that these identified 78 probe sets could be useful for diagnosis of phospholipidosis, and that toxicogenomics would be a promising approach for prediction of this type of toxicity.« less

Photovaporisation prostatique au laser chez les patients à haut risque hémorragique

PubMed Central

Bouabdallah, Zakaria; Kharbouchi, Amine; Colau, Alexandre; Cariou, Gerard

2013-01-01

Introduction Les patients sous traitement anticoagulant sont à risque élevé de saignement lors de la résection transurétrale de la prostate ou de l'adénomectomie par taille vésicale et ils se voient souvent récuser pour la chirurgie de l'hyperplasie bénigne de la prostate symptomatique. En Utilisant la photovaporisation de la prostate, les patients à haut risque peuvent subir en toute sécurité la chirurgie. Nous avons évalué l'innocuité et l'efficacité de la photovaporisation de la prostate (PVP) chez les patients sous anticoagulants en cours avec les dérivés de la coumarine, l'aspirine ou le clopidogrel, se plaignant de symptômes d'hypertrophie bénigne de la prostate. Méthodes Entre janvier 2009 et mai 2010, 47 hommes sous anticoagulation systémique ont subi une photovaporisation de la prostate. Les données ont été recueillies sur les caractéristiques démographiques, les comorbidités, les complications, la natrémie, l'hémoglobine, le débit urinaire maximal, le résidu post-mictionnel, l'IPSS et les complications. Résultats L'âge moyen était de 78 ans, le volume prostatique moyen était de 44g et le PSA était de 3.4ng/ml. Parmi les 10 patients (21.2%) étaient sous AVK, 27 (57.4%) étaient sous aspirine, 2 (4.2%) étaient sous clopidogrel, un sous fondaparinux et 6 (12.7%) étaient sous 2 anticoagulants ou plus. Le score ASA moyen était de 3. La durée moyenne de fonctionnement de l'appareil était de 38 minutes, l'énergie moyenne utilisée était de 200kJ. La durée moyenne d'hospitalisation était de 2 jours. Les complications survenant dans les 30 jours comprenaient une infection urinaire chez 5 patients (10.6%), une dysurie chez 4 patients et une hémorragie retardée chez 4 autres (8.5%). Un seul de ces patients a nécessité une transfusion sanguine et aucun patient n'a nécessité une réintervention. En 3 mois de suivi un seul patient a nécessité une incision du col vésical pour sclérose du col. Aucune incontinence ou sténose urétrale n'a été rapportée. Des améliorations significatives ont été notées dans l'IPSS, le débit urinaire maximal et le résidu post-mictionnel. Conclusion La PVP est caractérisé par d'excellentes propriétés hémostatiques et taux très faible de complications peropératoires même chez les patients sous 2 ou plusieurs agents anticoagulants. Sur la base de nos résultats péri-opératoires, nous recommandons la PVP comme traitement chirurgical de première intention chez les patients à haut risque de hémorragique souffrant de symptômes d'hypertrophie bénigne de la prostate. PMID:24570773

Effect of gamma-oryzanol on cytochrome P450 activities in human liver microsomes.

PubMed

Umehara, Ken; Shimokawa, Yoshihiko; Miyamoto, Gohachiro

2004-07-01

The effects of gamma-oryzanol, a drug mainly used for the treatment of hyperlipidaemia, on several cytochrome P450 (CYP) specific reactions in human liver microsomes were investigated to predict drug interactions with gamma-oryzanol in vivo from in vitro data. The following eight CYP catalytic reactions were used in this study: CYP1A1/2-mediated 7-ethoxyresorufin O-deethylation, CYP2A6-mediated coumarin 7-hydroxylation, CYP2B6-mediated 7-benzyloxyresorufin O-debenzylation, CYP2C8/9-mediated tolbutamide methylhydroxylation, CYP2C19-mediated S-mephenytoin 4'-hydroxylation, CYP2D6-mediated bufuralol 1'-hydroxylation, CYP2E1-mediated chlorzoxazone 6-hydroxylation, and CYP3A4-mediated testosterone 6beta-hydroxylation. gamma-Oryzanol had little inhibitory effects on CYP activities, indicating that this compound would not be expected to cause clinically significant interactions with other CYP-metabolized drugs at expected therapeutic concentrations.

Safety of percutaneous nephrolithotomy in patients on chronic anticoagulant or antiplatelet therapy.

PubMed

Fernández-Baltar, C; Pérez-Fentes, D; Sánchez-García, J F; García-Freire, C

2018-01-22

In developed countries, the incidence of cardiovascular disease is increasing, therefore, anticoagulant and antiplatelet drugs are a widespread treatment nowadays. Percutaneous nephrolithotomy (PNL) is the first-line treatment for large or complex stones (> 2 cm) and remains an alternative for the smaller ones. The objective of this study is to analyze whether PNL surgery is a safe procedure in patients under a treatment discontinuation protocol for anticoagulant or antiplatelet therapies. We retrospectively studied 301 patients who underwent PNL in our hospital between 2008 and 2016 and identified 46 patients on chronic antiplatelet or anticoagulation treatment. With respect to PNL outcomes, the stone-free rate was similar (78 vs 74%, p = 0.762) in both groups, without any significant differences in the overall postoperative complications (17 vs 26%, p = 0.203). The incidence of hemorrhagic complications was similar between groups (12 vs 9%, p = 0.492), as demonstrated by the mean drop in hemoglobin (Hb), which was comparable in both cohorts (2.2 ± 1.3 vs 2.0 ± 1.4 p = 0.270) and the blood transfusion rate (14% in group A and 8% in group B, p = 0.205). No thromboembolic events were found within the year after the PNL procedure. PNL is a safe and effective intervention in patients under a treatment discontinuation protocol for anticoagulant or antiplatelet therapies. Although our study demonstrates the feasibility of this protocol, new scientific evidence aims to stratify the thromboembolic and bleeding risk of each patient to individualize the perioperative management thereafter.

Short-Term Anticoagulant Therapy and Thrombus Location Are Independent Risk Factors for Delayed Recanalization of Deep Vein Thrombosis

PubMed Central

Zhang, Chuanlin; Fu, Qining; Zhao, Yu; Mu, Shaoyu; Liu, Liping

2016-01-01

Background Prompt recanalization of the vein containing the thrombus is an important goal during the initial treatment of DVT, and risk factors for delayed recanalization in patients with deep vein thrombosis (DVT) in the lower extremities need to be determined. Material/Methods A total of 174 patients with DVT in lower extremities were recruited from June 2014 to March 2015 at our hospital. Duplex ultrasound scanning was conducted for all patients at 1 and 6 months after baseline evaluation. We divided the patients into recanalization and non-recanalization groups and analyzed risk factors for delayed recanalization. Results The univariate analysis revealed that an oral anticoagulant time of less than 3 months and venous thrombus location were risk factors for delayed recanalization (P<0.01). However, age, gender, hypertension, diabetes, pulmonary embolism, incidence factors, the use of catheter-directed thrombolytic (CDT) drugs, and inferior vena cava filter (IVCF) implantation had no influence on the incidence of delayed recanalization in patients with DVT (P>0.05). The multivariate analysis showed that patients with an anticoagulant time of less than 3 months had a lower incidence of recanalization than those with an anticoagulant time of more than 3 months (OR=2.358, P<0.05). The risk of delayed recanalization in patients with proximal DVT was 7 times higher than that in patients with distal DVT. Conclusions Duration of anticoagulant treatment of less than 3 months and venous thrombus location are independent risk factors for delayed recanalization of DVT in the lower extremities. PMID:26790571

Coumarin incorporated triazoles: a new class of anticonvulsants.

PubMed

Bhat, Mashooq A; Al-Omar, Mohammed A

2011-01-01

A series of coumarin incorporated 1,2,4- triazole compounds (1-14) were evaluated for their possible anticonvulsant and neurotoxic properties, log P values, pharmacophoric mapping and three dimensional structure analysis. Compound (6) with para-fluoro substitution showed significant anticonvulsant activity.

[Coumarins of Anemone raddeana Regel and their biological activity].

PubMed

Ren, Feng-Zhi; Chen, Shu-Hong; Zheng, Zhi-Hui; Zhang, Xue-Xia; Li, Li-Hong; Dong, Ai-Hua

2012-02-01

To study the coumarins of Anemone raddeana Regel, the compounds were separated by silica gel column chromatography and HPLC. Their structures were identified by their physicochemical property and spectral analysis. Two new compounds were isolated and identified as 4, 7-dimethoxyl-5-methyl-6-hydroxy coumarin (1) and 4, 7-dimethoxyl-5-formyl-6-hydroxycoumarin (2). The bioassays indicated that compounds 1 and 2 could significantly inhibit the proliferation of cancer cell, and showed the agonist effect on the transactivity of retinoic acid receptor-alpha (RARalpha). In addition, the two compounds had inhibitory effect against human leukocyte elastase (HLE).

Simultaneous quantification of polymethoxylated flavones and coumarins in Fructus aurantii and Fructus aurantii immaturus using HPLC-ESI-MS/MS.

PubMed

Chen, Hai-Fang; Zhang, Wu-Gang; Yuan, Jin-Bin; Li, Yan-Gang; Yang, Shi-Lin; Yang, Wu-Liang

2012-02-05

The major lipid-soluble constituents in Fructus aurantii (zhiqiao) and Fructus aurantii immaturus (zhishi) are polymethoxylated flavones (PMFs) and coumarins. In the present study, a high-performance liquid chromatography with electrospray ionization tandem mass spectrometry method was developed to quantify PMFs (nobiletin, tangeretin, 5-hydroxy-6,7,8,4'-tetramethoxyflavone, and natsudaidai) and coumarins (marmin, meranzin hydrate, and auraptene) simultaneously. PMFs and coumarins were detected by electrospray ionization tandem mass spectrometry in positive ion mode and quantified with multiple reaction monitor. Samples were separated on a Diamonsil C₁₈ (150 mm × 4.6 mm, 5 μm) column using acetonitrile and formic acid-water solution as a mobile phase in gradient mode with a flow rate at 0.5 mL/min. All calibration curves showed good linearity (r² > 0.9977) within the test ranges. Variations of the intraday and interday precisions were less than 4.07%. The recoveries of the components were within the range of 95.79%-105.04% and the relative standard deviations were less than 3.82%. The method developed was validated with acceptable accuracy, precision, and extraction recoveries and can be applied for the identification and quantification of four PMFs and three coumarins in citrus herbs. Copyright © 2011 Elsevier B.V. All rights reserved.

Distribution Assessments of Coumarins from Angelicae Pubescentis Radix in Rat Cerebrospinal Fluid and Brain by Liquid Chromatography Tandem Mass Spectrometry Analysis.

PubMed

Yang, Yan-Fang; Zhang, Lei; Yang, Xiu-Wei

2018-01-20

Angelicae Pubescentis Radix (APR) is a widely-used traditional Chinese medicine. Pharmacological studies have begun to probe its biological activities on neurological disorders recently. To assess the brain penetration and distribution of APR, a validated ultra-performance liquid chromatography tandem mass spectrometry method was applied to the simultaneous determinations of the main coumarins from APR in the rat cerebrospinal fluid (CSF) and brain after oral administration of APR extract, including psoralen, xanthotoxin, bergapten, isoimperatorin, columbianetin, columbianetin acetate, columbianadin, oxypeucedanin hydrate, angelol B, osthole, meranzin hydrate and nodakenetin. Most of the tested coumarins entered the rat CSF and brain quickly, and double-peak phenomena in concentration-time curves were similar to those of their plasma pharmacokinetics. Columbianetin had the highest concentration in the CSF and brain, while psoralen and columbianetin acetate had the largest percent of CSF/plasma and brain/plasma, indicating that these three coumarins may be worthy of further research on the possible nervous effects. Correlations between the in vivo brain distributions and plasma pharmacokinetics of these coumarins were well verified. These results provided valuable information for the overall in vivo brain distribution characteristics of APR and also for its further studies on the active substances for the central nervous system.

Trypanocidal constituents in plants: 7. Mammea-type coumarins.

PubMed

Reyes-Chilpa, Ricardo; Estrada-Muñiz, Elizabeth; Vega-Avila, Elisa; Abe, Fumiko; Kinjo, Junei; Hernández-Ortega, Simón

2008-08-01

Calophyllum brasiliense and Mammea americana (Clusiaceae) are two trees from the tropical rain forests of the American continent. A previous screening showed high trypanocidal activity in the extracts of these species. Several mammea-type coumarins, triterpenoids and biflavonoids were isolated from the leaves of C. brasiliense. Mammea A/AA was obtained from the fruit peels of M. americana. These compounds were tested in vitro against epimastigotes and trypomastigotes of Trypanosoma cruzi, the etiologic agent of Chagas disease. The most potent compounds were mammea A/BA, A/BB, A/AA, A/BD and B/BA, with MC100 values in the range of 15 to 90 microg/ml. Coumarins with a cyclized gamma,gamma-dimethylallyl substituent on C-6, such as mammea B/BA, cyclo F + B/BB cyclo F, and isomammeigin, showed MC100 values > 200 microg/ml. Several active coumarins were also tested against normal human lymphocytes in vitro, which showed that mammea A/AA and A/BA were not toxic. Other compounds from C. brasiliense, such as the triterpenoids, friedelin, canophyllol, the biflavonoid amentoflavone, and protocatechuic and shikimic acids, were inactive against the epimastigotes. The isopropylidenedioxy derivative of shikimic acid was inactive, and its structure was confirmed by X-ray diffraction. Our results suggest that mammea-type coumarins could be a valuable source of trypanocidal compounds.

Irritant and cytotoxic coumarins from Angelica glauca Edgew roots.

PubMed

Saeed, M Asif; Sabir, A W

2008-01-01

Irritant and cytotoxic potentiality of six coumarins, isolated for the first time from the roots of Angelica glauca identified as 5,6,7-trimethoxycoumarin, 6-methoxy-7,8-methylenedioxycoumarin, bergapten, decursinol angelate, decursin, and nodakenetin, were investigated. The irritant potential was explored by open mouse ear assay, evaluating their ID(50) after acute and by IU (Irritant units) after chronic effects, while the cytotoxic capability was explored by their LC(50), using brine shrimp (Artemia salina) larvae (nauplii). All the coumarins exhibited well-defined irritancy on mouse's ears, compared with the positive controlled euphorbium reaction and cytotoxic response against brine shrimp larvae, compared with the positive control colchicine. Decursinol angelate and decursin were the most potent and persistent irritant compounds with least ID(50), whose reactions lasted for 48 h. 6-Methoxy-7,8-methylenedioxycoumarin and bergaten revealed an intermediate irritant reactions, while 5,6,7-trimethoxycoumarin and nodakenetin displayed the least irritant and least persistent reactions on mouse ears. Both decursin and decursinol angelate also appeared to be the stronger cytotoxic agents than other coumarins. 5,6,7-trimethoxycoumarin displayed an intermediate cytotoxic behaviour, while other three coumarins, i.e., 6-methoxy-7,8-methylenedioxycoumarin, bergapten, and nodakenetin, exhibited the least cytotoxic capacity against brine shrimp larvae.

Critique of medicinal conspicuousness of Parsley(Petroselinum crispum): a culinary herb of Mediterranean region.

PubMed

Mahmood, Sidra; Hussain, Shahzad; Malik, Farnaz

2014-01-01

WHO estimates, around 80% of the especially developing world is indigent on complementary and alternative medicines which are prodigiously derived from herbal material. Parsley (Petroselinum crispum) is an important culinary herb originated from the Mediterranean region. It possesses small and dark seeds with volatile oil content. Petroselinum crispum is now planted throughout the world due to its usage in food industry, perfume manufacturing, soaps, and creams. Its main constituents subsume coumarins, furanocoumarins (bergapten, imperatori), ascorbic acid, carotenoids, flavonoids, apiole, various terpenoic compounds, phenyl propanoids, phathalides, and tocopherol. Due to these constituents, it has been annunciated to possess a number of possible medicinal emblematics including, antimicrobial, antianemic, menorrhagic, anticoagulant, antihyperlipidemic, antihepatotoxic, antihypertensive, diuretic effects, hypoglycaemic, hypouricemic, anti oxidative and estrogenic activities. In Morocco, Parsley is mostly used as an elixir to treat arterial hypertension, diabetes, cardiac and renal diseases. Antioxidant and antibacterial activities of parsley, made it propitious in food systems. Its ELI17 gene has been corroborated as a particularly fast-responding gene. There is a requisite for extensive research to avail the maximal benefits of this significant medicinal plant. The aim of this review paper is to divulge the chemical constituents of parsley that are explicitly related to substantial medicinal facets.

A Green, Enantioselective Synthesis of Warfarin for the Undergraduate Organic Laboratory

ERIC Educational Resources Information Center

Wong, Terence C.; Sultana, Camille M.; Vosburg, David A.

2010-01-01

The enantioselective synthesis of drugs is of fundamental importance in the pharmaceutical industry. In this experiment, students synthesize either enantiomer of warfarin, a widely used anticoagulant, in a single step from inexpensive starting materials. Stereoselectivity is induced by a commercial organocatalyst, ("R","R")- or…

Chiral drug analysis using mass spectrometric detection relevant to research and practice in clinical and forensic toxicology.

PubMed

Schwaninger, Andrea E; Meyer, Markus R; Maurer, Hans H

2012-12-21

This paper reviews analytical approaches published in 2002-2012 for chiral drug analysis and their relevance in research and practice in the field of clinical and forensic toxicology. Separation systems such as gas chromatography, high performance liquid chromatography, capillary electromigration, and supercritical fluid chromatography, all coupled to mass spectrometry, are discussed. Typical applications are reviewed for relevant chiral analytes such as amphetamines and amphetamine-derived designer drugs, methadone, tramadol, psychotropic and other CNS acting drugs, anticoagulants, cardiovascular drugs, and some other drugs. Usefulness of chiral drug analysis in the interpretation of analytical results in clinical and forensic toxicology is discussed as well. Copyright © 2012 Elsevier B.V. All rights reserved.

40 CFR 721.2155 - Alkoxyamino-alkyl-coumarin (generic).

Code of Federal Regulations, 2010 CFR

2010-07-01

...). 721.2155 Section 721.2155 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) TOXIC SUBSTANCES CONTROL ACT SIGNIFICANT NEW USES OF CHEMICAL SUBSTANCES Significant New Uses for Specific Chemical Substances § 721.2155 Alkoxyamino-alkyl-coumarin (generic). (a) Chemical substance and significant new uses...

Antiviral effect of compounds derived from the seeds of Mammea americana and Tabernaemontana cymosa on Dengue and Chikungunya virus infections.

PubMed

Gómez-Calderón, Cecilia; Mesa-Castro, Carol; Robledo, Sara; Gómez, Sergio; Bolivar-Avila, Santiago; Diaz-Castillo, Fredyc; Martínez-Gutierrez, Marlen

2017-01-18

The transmission of Dengue virus (DENV) and Chikungunya virus (CHIKV) has increased worldwide, due in part to the lack of a specific antiviral treatment. For this reason, the search for compounds with antiviral potential, either as licensed drugs or in natural products, is a research priority. The objective of this study was to identify some of the compounds that are present in Mammea americana (M. americana) and Tabernaemontana cymosa (T. cymosa) plants and, subsequently, to evaluate their cytotoxicity in VERO cells and their potential antiviral effects on DENV and CHIKV infections in those same cells. Dry ethanolic extracts of M. americana and T. cymosa seeds were subjected to open column chromatographic fractionation, leading to the identification of four compounds: two coumarins, derived from M. americana; and lupeol acetate and voacangine derived from T. cymosa.. The cytotoxicity of each compound was subsequently assessed by the MTT method (at concentrations from 400 to 6.25 μg/mL). Pre- and post-treatment antiviral assays were performed at non-toxic concentrations; the resulting DENV inhibition was evaluated by Real-Time PCR, and the CHIKV inhibition was tested by the plating method. The results were analyzed by means of statistical analysis. The compounds showed low toxicity at concentrations ≤ 200 μg/mL. The compounds coumarin A and coumarin B, which are derived from the M. americana plant, significantly inhibited infection with both viruses during the implementation of the two experimental strategies employed here (post-treatment with inhibition percentages greater than 50%, p < 0.01; and pre-treatment with percentages of inhibition greater than 40%, p < 0.01). However, the lupeol acetate and voacangine compounds, which were derived from the T. cymosa plant, only significantly inhibited the DENV infection during the post-treatment strategy (at inhibition percentages greater than 70%, p < 0.01). In vitro, the coumarins are capable of inhibiting infection by DENV and CHIKV (with inhibition percentages above 50% in different experimental strategies), which could indicate that these two compounds are potential antivirals for treating Dengue and Chikungunya fever. Additionally, lupeol acetate and voacangine efficiently inhibit infection with DENV, also turning them into promising antivirals for Dengue fever.

Consensus recommendations for preventing and managing bleeding complications associated with novel oral anticoagulants in singapore.

PubMed

Ng, Heng Joo; Chee, Yen Lin; Ponnudurai, Kuperan; Lim, Lay Cheng; Tan, Daryl; Tay, Jam Chin; Handa, Pankaj Kumar; Akbar Ali, Mufeedha; Lee, Lai Heng

2013-11-01

Novel oral anticoagulants (NOACs) have at least equivalent efficacy compared to standard anticoagulants with similar bleeding risk. Optimal management strategies for bleeding complications associated with NOACs are currently unestablished. A working group comprising haematologists and vascular medicine specialists representing the major institutions in Singapore was convened to produce this consensus recommendation. A Medline and EMBASE search was conducted for articles related to the 3 available NOACs (dabigatran, rivaroxaban, apixaban), bleeding and its management. Additional information was obtained from the product monographs and bibliographic search of articles identified. The NOACs still has substantial interactions with a number of drugs for which concomitant administration should best be avoided. As they are renally excreted, albeit to different degrees, NOACs should not be prescribed to patients with creatinine clearance of <30 mLs/min. Meticulous consideration of risk versus benefits should be exercised before starting a patient on a NOAC. In patients presenting with bleeding, risk stratification of the severity of bleeding as well as identification of the source of bleeding should be performed. In life-threatening bleeds, recombinant activated factor VIIa and prothrombin complex may be considered although their effectiveness is currently unsupported by firm clinical evidence. The NOACs have varying effect on the prothrombin time and activated partial thromboplastin time which has to be interpreted with caution. Routine monitoring of drug level is not usually required. NOACs are an important advancement in antithrombotic management and careful patient selection and monitoring will permit optimisation of their potential and limit bleeding events.

New Anticoagulant Agents: Incidence of Adverse Drug Reactions and New Signals Thereof.

PubMed

Treceño-Lobato, Carlos; Jiménez-Serranía, María-Isabel; Martínez-García, Raquel; Corzo-Delibes, Francisco; Martín Arias, Luis H

2018-06-04

The aim of this study was to evaluate the adverse drug reaction (ADR) incidence rate and new signals thereof for classic compared with new anticoagulants in real-life ambulatory settings. The authors performed an observational cross-sectional study in two cohorts of surveyed patients treated with vitamin K antagonists (VKAs; acenocoumarol or warfarin) or nonvitamin K antagonist oral anticoagulants (NOACs; apixaban, edoxaban, rivaroxaban, dabigatran etexilate). Descriptive, clinical, and ADRs data were reported and analyzed through a bivariate analysis (odds ratio [OR]) to compare the ADRs incidence rate and an adaptation of Bayesian methodology (false discovery rate [FDR] < 0.05) to detect new signals. A total of 334 patients were surveyed-average international normalized ratio (INR) of 2.6-and 45.4% taking new anticoagulants. Note that 835 ADRs were reported; 2.5 per patient (2.8 in the VKA cohort, 2.1 in the NOAC cohort). The authors obtained higher risk of epistaxis (OR, 2.18; 95% confidence interval [CI], 1.01-4.74) and hematoma (OR, 2.43; 95% CI, 1.39-4.25) with VKAs and lower risk of global bleeding symptoms with NOACs (OR, 0.45; 95% CI, 0.28-0.71). After standardizing the data, a significant risk of diarrhea with VKAs was observed (OR, 3.37; 95% CI, 1.09-10.41). They also detected an intense positive signal regarding the use of VKAs and osteoporosis (FDR < 0.001), specifically acenocoumarol (FDR < 0.002). NOACs presented lower risk of bleeding, especially dabigatran (FDR < 0.031), and of dermatological pathologies with apixaban being the safest (FDR = 0.050). The lower risk of global bleeding and a potential protective effect against osteoporosis in patients treated with NOACs postulate them as safer than VKAs. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Assessing prescribing of NSAIDs, antiplatelets, and anticoagulants in Canadian family medicine using chart review.

PubMed

Hamilton, Kevin; Davis, Christine; Falk, Jamie; Singer, Alex; Bugden, Shawn

2016-10-01

Background Drug-related problems have been identified as a major contributor to emergency room visits, hospitalizations, and death. The most commonly implicated medications are nonsteroidal anti-inflammatory drugs (NSAIDs), antiplatelets, and anticoagulants. Considering a significant proportion of these harms are preventable, indicators to identify risky prescribing before they lead to harm have been developed. Objective To examine the prevalence and patterns of potentially inappropriate prescriptions (PIPs) in a primary care population who are using high-risk medications. Setting This study was performed within two multi-disciplinary family medicine teaching clinics in Winnipeg, Canada. Method A cross-sectional electronic/paper chart audit was conducted within two multi-disciplinary family medicine teaching clinics to evaluate the prevalence of 13 evidence-based high-risk prescriptions. Patients were included if they were prescribed an oral NSAID, antiplatelet, or an anticoagulant within the 12 month period between June 2012 and June 2013. Main outcome measure The proportion of PIPs associated with an increased bleeding risk for NSAIDs, antiplatelets, and anticoagulants. Results Of the 567 patients included in the review, 198 (35 %) patients had received at least 1 PIP in the past year. The most common PIP was the use of an oral NSAID with one or more GI risk factors without adequate gastro-protection. Only 34 (6 %) of these patients received a full medication review performed by a pharmacist. Although not statistically significant, patients who received a medication review had fewer inappropriate prescriptions (27 % with review, 35 % without). Conclusion Over one-third of the patients who were using high-risk medications were using them potentially inappropriately. Although pharmacists have been shown to reduce the amount of inappropriate prescribing, very few patients using these medications were referred to the pharmacist for a full medication review. These data suggest that there is opportunity for the identification and assessment of these patients when prescribing or dispensing these high-risk medications.

A RCT study of Rivaroxaban, low-molecular-weight heparin, and sequential medication regimens for the prevention of venous thrombosis after internal fixation of hip fracture.

PubMed

Tang, Yilun; Wang, Kunzheng; Shi, Zhibin; Yang, Pei; Dang, Xiaoqian

2017-08-01

The guidelines for the prevention of venous thromboembolism in orthopedic surgeries have reached a consensus on the postoperative conventional anticoagulation. However, the choice of anticoagulant drugs is yet controversial. The use of the drug rivaroxaban is expensive. Since the compliance of patients with low-molecular-weight heparin is considerably low, a cost-effective, efficacious and convenient anticoagulant program is essential. The present study investigated the efficacy, safety, patient compliance, and cost-effectiveness of low-molecular-weight heparin with sequential Rivaroxaban anticoagulant therapy in patients with a hip fracture, following internal fixation. A total of 287 patients with hip fractures were randomized into three groups: Rivaroxaban alone, Enoxaparin alone, and Enoxaparin followed by Rivaroxaban. The primary endpoint was the incidence of postoperative VTE, whereas the secondary endpoints were the compliance and treatment costs. Adverse reactions included bleeding and wound complications. The incidences of VTE were 5.21%, 14.74%, and 10.42% in the Rivaroxaban, low-molecular-weight heparin, and sequential therapy groups, respectively. The VTE-related mortality rates were 0%, 1.05%, and 1.04%. The average hospital stay was 12±8,15±7, and 11±5d, whereas the compliance rates of the three groups were 82.3%, 71.6%, and 88.5%, respectively. The incidences of adverse incisions were 14.6%, 4.2%, and 6.3% for the three groups examined. The effects and the incidence of postoperative bleeding in the treatment of low-molecular-weight heparin followed by Rivaroxaban did not differ significantly from that of Rivaroxaban alone. However, the postoperative drainage, the cost of treatment and the incidence of VTE reduced significantly, whereas the incidences of adverse incisions and the patient compliance were increased. ChiCTR-INR-17010495. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Biotransformation of aesculin by human gut bacteria and identification of its metabolites in rat urine.

PubMed

Ding, Wei-Jun; Deng, Yun; Feng, Hao; Liu, Wei-Wei; Hu, Rong; Li, Xiang; Gu, Zhe-Ming; Dong, Xiao-Ping

2009-03-28

To observe the biotransformation process of a Chinese compound, aesculin, by human gut bacteria, and to identify its metabolites in rat urine. Representative human gut bacteria were collected from 20 healthy volunteers, and then utilized in vitro to biotransform aesculin under anaerobic conditions. At 0, 2, 4, 8, 12, 16, 24, 48 and 72 h post-incubation, 10 mL of culture medium was collected. Metabolites of aesculin were extracted 3 x from rat urine with methanol and analyzed by HPLC. For in vivo metabolite analysis, aesculetin (100 mg/kg) was administered to rats via stomach gavage, rat urine was collected from 6 to 48 h post-administration, and metabolite analysis was performed by LC/ESI-MS and MS/MS in the positive and negative modes. Human gut bacteria could completely convert aesculin into aesculetin in vitro. The biotransformation process occurred from 8 to 24 h post-incubation, with its highest activity was seen from 8 to 12 h. The in vitro process was much slower than the in vivo process. In contrast to the in vitro model, six aesculetin metabolites were identified in rat urine, including 6-hydroxy-7-gluco-coumarin (M1), 6-hydroxy-7-sulf-coumarin (M2), 6, 7-di-gluco-coumarin (M3), 6-glc-7-gluco-coumarin (M4), 6-O-methyl-7-gluco-coumarin (M5) and 6-O-methyl-7-sulf-coumarin (M6). Of which, M2 and M6 were novel metabolites. Aesculin can be transferred into aesculetin by human gut bacteria and is further modified by the host in vivo. The diverse metabolites of aesculin may explain its pleiotropic pharmaceutical effects.

Novel coumarin modified GLP-1 derivatives with enhanced plasma stability and prolonged in vivo glucose-lowering ability.

PubMed

Han, Jing; Sun, Lidan; Huang, Xun; Li, Zheng; Zhang, Chenyu; Qian, Hai; Huang, Wenlong

2014-12-01

The short biological half-life limits the therapeutic use of glucagon-like peptide-1 (GLP-1) and chemical modification to improve the interaction of peptides with serum albumin represents an effective strategy to develop long-acting peptide analogues. Coumarin, a natural product, is known to bind tightly to plasma proteins and possesses many biological activities. Therefore, we designed and synthesized a series of coumarin-modified GLP-1 derivatives, hypothesizing that conjugation with coumarin would retain the therapeutic effects and prolong the biological half-life of the conjugates. Four cysteine-modified GLP-1 analogues (1-4) were prepared using Gly8 -GLP-1(7-36)-NH2 peptide as a starting point. These analogues were conjugated with two coumarin maleimides to yield eight compounds (conjugates 6-13) for testing. Activation of human GLP-1 receptors, stability to enzymic inactivation in plasma and binding to human albumin were assessed in vitro. In vivo, effects on oral glucose tolerance tests (OGTT) in rats and on blood glucose levels in db/db mice were studied. Most conjugates showed well preserved receptor activation efficacy, enhanced albumin-binding properties and improved in vitro plasma stability and conjugate 7 was selected to undergo further assessment. In rats, conjugate 7 had a longer circulating t1/2 than exendin-4 or liraglutide. A prolonged antidiabetic effect of conjugate 7 was observed after OGTT in rats and a prolonged hypoglycaemic effect in db/db mice. Cysteine-specific coumarin conjugation with GLP-1 offers a useful approach to the development of long-acting incretin-based antidiabetic agents. Conjugate 7 is a promising long-lasting GLP-1 derivative deserving further investigation. © 2014 The British Pharmacological Society.

Novel coumarin modified GLP-1 derivatives with enhanced plasma stability and prolonged in vivo glucose-lowering ability

PubMed Central

Han, Jing; Sun, Lidan; Huang, Xun; Li, Zheng; Zhang, Chenyu; Qian, Hai; Huang, Wenlong

2014-01-01

Background and Purpose The short biological half-life limits the therapeutic use of glucagon-like peptide-1 (GLP-1) and chemical modification to improve the interaction of peptides with serum albumin represents an effective strategy to develop long-acting peptide analogues. Coumarin, a natural product, is known to bind tightly to plasma proteins and possesses many biological activities. Therefore, we designed and synthesized a series of coumarin-modified GLP-1 derivatives, hypothesizing that conjugation with coumarin would retain the therapeutic effects and prolong the biological half-life of the conjugates. Experimental Approach Four cysteine-modified GLP-1 analogues (1–4) were prepared using Gly8-GLP-1(7–36)-NH2 peptide as a starting point. These analogues were conjugated with two coumarin maleimides to yield eight compounds (conjugates 6–13) for testing. Activation of human GLP-1 receptors, stability to enzymic inactivation in plasma and binding to human albumin were assessed in vitro. In vivo, effects on oral glucose tolerance tests (OGTT) in rats and on blood glucose levels in db/db mice were studied. Key Results Most conjugates showed well preserved receptor activation efficacy, enhanced albumin-binding properties and improved in vitro plasma stability and conjugate 7 was selected to undergo further assessment. In rats, conjugate 7 had a longer circulating t1/2 than exendin-4 or liraglutide. A prolonged antidiabetic effect of conjugate 7 was observed after OGTT in rats and a prolonged hypoglycaemic effect in db/db mice. Conclusions and Implications Cysteine-specific coumarin conjugation with GLP-1 offers a useful approach to the development of long-acting incretin-based antidiabetic agents. Conjugate 7 is a promising long-lasting GLP-1 derivative deserving further investigation. PMID:25039358

Understanding the Molecular Determinant of Reversible Human Monoamine Oxidase B Inhibitors Containing 2H-Chromen-2-One Core: Structure-Based and Ligand-Based Derived Three-Dimensional Quantitative Structure-Activity Relationships Predictive Models.

PubMed

Mladenović, Milan; Patsilinakos, Alexandros; Pirolli, Adele; Sabatino, Manuela; Ragno, Rino

2017-04-24

Monoamine oxidase B (MAO B) catalyzes the oxidative deamination of aryalkylamines neurotransmitters with concomitant reduction of oxygen to hydrogen peroxide. Consequently, the enzyme's malfunction can induce oxidative damage to mitochondrial DNA and mediates development of Parkinson's disease. Thus, MAO B emerges as a promising target for developing pharmaceuticals potentially useful to treat this vicious neurodegenerative condition. Aiming to contribute to the development of drugs with the reversible mechanism of MAO B inhibition only, herein, an extended in silico-in vitro procedure for the selection of novel MAO B inhibitors is demonstrated, including the following: (1) definition of optimized and validated structure-based three-dimensional (3-D) quantitative structure-activity relationships (QSAR) models derived from available cocrystallized inhibitor-MAO B complexes; (2) elaboration of SAR features for either irreversible or reversible MAO B inhibitors to characterize and improve coumarin-based inhibitor activity (Protein Data Bank ID: 2V61 ) as the most potent reversible lead compound; (3) definition of structure-based (SB) and ligand-based (LB) alignment rule assessments by which virtually any untested potential MAO B inhibitor might be evaluated; (4) predictive ability validation of the best 3-D QSAR model through SB/LB modeling of four coumarin-based external test sets (267 compounds); (5) design and SB/LB alignment of novel coumarin-based scaffolds experimentally validated through synthesis and biological evaluation in vitro. Due to the wide range of molecular diversity within the 3-D QSAR training set and derived features, the selected N probe-derived 3-D QSAR model proves to be a valuable tool for virtual screening (VS) of novel MAO B inhibitors and a platform for design, synthesis and evaluation of novel active structures. Accordingly, six highly active and selective MAO B inhibitors (picomolar to low nanomolar range of activity) were disclosed as a result of rational SB/LB 3D QSAR design; therefore, D123 (IC 50 = 0.83 nM, K i = 0.25 nM) and D124 (IC 50 = 0.97 nM, K i = 0.29 nM) are potential lead candidates as anti-Parkinson's drugs.

Predicting Major Bleeding in Ischemic Stroke Patients With Atrial Fibrillation.

PubMed

Hilkens, Nina A; Algra, Ale; Greving, Jacoba P

2017-11-01

Performance of risk scores for major bleeding in patients with atrial fibrillation and a previous transient ischemic attack or ischemic stroke is not well established. We aimed to validate risk scores for major bleeding in patients with atrial fibrillation treated with oral anticoagulants after cerebral ischemia and explore the net benefit of oral anticoagulants among bleeding risk categories. We analyzed 3623 patients with a history of transient ischemic attack or stroke included in the RE-LY trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). We assessed performance of HEMORR 2 HAGES (hepatic or renal disease, ethanol abuse, malignancy, older age, reduced platelet count or function, hypertension [uncontrolled], anemia, genetic factors, excessive fall risk, and stroke), Shireman, HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly), ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation), and ORBIT scores (older age, reduced haemoglobin/haematocrit/history of anaemia, bleeding history, insufficient kidney function, and treatment with antiplatelet) with C statistics and calibration plots. Net benefit of oral anticoagulants was explored by comparing risk reduction in ischemic stroke with risk increase in major bleedings on warfarin. During 6922 person-years of follow-up, 266 patients experienced a major bleed (3.8 per 100 person-years). C statistics ranged from 0.62 (Shireman) to 0.67 (ATRIA). Calibration was poor for ATRIA and moderate for other models. The reduction in recurrent ischemic strokes on warfarin was larger than the increase in major bleeding risk, irrespective of bleeding risk category. Performance of prediction models for major bleeding in patients with cerebral ischemia and atrial fibrillation is modest but comparable with performance in patients with only atrial fibrillation. Bleeding risk scores cannot guide treatment decisions for oral anticoagulants but may still be useful to identify modifiable risk factors for bleeding. Clinical usefulness may be best for ORBIT, which is based on a limited number of easily obtainable variables and showed reasonable performance. © 2017 American Heart Association, Inc.

A cost-analysis model for anticoagulant treatment in the hospital setting.

PubMed

Mody, Samir H; Huynh, Lynn; Zhuo, Daisy Y; Tran, Kevin N; Lefebvre, Patrick; Bookhart, Brahim

2014-07-01

Rivaroxaban is the first oral factor Xa inhibitor approved in the US to reduce the risk of stroke and blood clots among people with non-valvular atrial fibrillation, treat deep vein thrombosis (DVT), treat pulmonary embolism (PE), reduce the risk of recurrence of DVT and PE, and prevent DVT and PE after knee or hip replacement surgery. The objective of this study was to evaluate the costs from a hospital perspective of treating patients with rivaroxaban vs other anticoagulant agents across these five populations. An economic model was developed using treatment regimens from the ROCKET-AF, EINSTEIN-DVT and PE, and RECORD1-3 randomized clinical trials. The distribution of hospital admissions used in the model across the different populations was derived from the 2010 Healthcare Cost and Utilization Project database. The model compared total costs of anticoagulant treatment, monitoring, inpatient stay, and administration for patients receiving rivaroxaban vs other anticoagulant agents. The length of inpatient stay (LOS) was determined from the literature. Across all populations, rivaroxaban was associated with an overall mean cost savings of $1520 per patient. The largest cost savings associated with rivaroxaban was observed in patients with DVT or PE ($6205 and $2742 per patient, respectively). The main driver of the cost savings resulted from the reduction in LOS associated with rivaroxaban, contributing to ∼90% of the total savings. Furthermore, the overall mean anticoagulant treatment cost was lower for rivaroxaban vs the reference groups. The distribution of patients across indications used in the model may not be generalizable to all hospitals, where practice patterns may vary, and average LOS cost may not reflect the actual reimbursements that hospitals received. From a hospital perspective, the use of rivaroxaban may be associated with cost savings when compared to other anticoagulant treatments due to lower drug cost and shorter LOS associated with rivaroxaban.

Discovery of novel aminobenzisoxazole derivatives as orally available factor IXa inhibitors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sakurada, Isao; Endo, Toshiya; Hikita, Katsuyoshi

2017-06-01

Using structure based drug design, novel aminobenzisoxazoles as coagulation factor IXa inhibitors were designed and synthesized. Highly selective inhibition of FIXa over FXa was demonstrated. Anticoagulation profile of selected compounds was evaluated by aPTT and PT tests. In vitro ADMET and pharmacokinetic (PK) profiles were also evaluated.

Photophysics of a coumarin based Schiff base in solvents of varying polarities

NASA Astrophysics Data System (ADS)

Ghosh, Saptarshi; Roy, Nayan; Singh, T. Sanjoy; Chattopadhyay, Nitin

2018-01-01

The present work reports detailed photophysics of a coumarin based Schiff base, namely, (E)-7-(((8-hydroxyquinolin-2-yl)methylene)amino)-4-methyl-2H-chromen-2-one (HMC) in different solvents of varying polarity exploiting steady state absorption, fluorescence and time resolved fluorescence spectroscopy. The dominant photophysical features of HMC are discussed in terms of emission from an intramolecular charge transfer (ICT) excited state. Molecular orbital (MO) diagrams as obtained from DFT based computational analysis confirms the occurrence of charge transfer from 8‧-hydroxy quinoline moiety of the molecule to the coumarin part. The notable difference in the photophysical response of HMC from its analogous coumarin (C480) lies in a lower magnitude of fluorescence quantum yield of the former, particularly in the solvents of low polarity, which is rationalized by considering the higher rate of non-radiative decay of HMC in apolar solvents. Phosphorescence emission as well as phosphorescence lifetime of HMC has also been reported in 77 K frozen matrix.

Comparisons of the spectroscopic and microbiological activities among coumarin-3-carboxylate, o-phenanthroline and zinc(II) complexes

NASA Astrophysics Data System (ADS)

Islas, María S.; Martínez Medina, Juan J.; Piro, Oscar E.; Echeverría, Gustavo A.; Ferrer, Evelina G.; Williams, Patricia A. M.

2018-06-01

Coumarins (2H-chromen-2-one) are oxygen-containing heterocyclic compounds that belong to the benzopyranones family. In this work we have synthesized different coordination complexes with coumarin-3-carboxylic acid (HCCA), o-phenanthroline (phen) and zinc(II). In the reported [Zn(CCA)2(H2O)2] complex, coumarin-3-carboxylate (CCA) is acting as a bidentate ligand while in the two prepared complexes, [Zn(phen)3]CCA(NO3) (obtained as a single crystal) and [Zn(CCA)2phen].4H2O, CCA is acting as a counterion of the complex cation [Zn(phen)3]+2 or coordinated to the metal center along with phen, respectively. These compounds were characterized on the basis of elemental analysis and thermogravimetry. NMR, FTIR and Raman spectroscopies of the compounds and the CCA potassium salt (KCCA) allow to determine several similarities and differences among them. Finally, their behavior against alkaline phosphatase enzyme and their antimicrobial activities were also measured.

Fluorescent Polymer Incorporating Triazolyl Coumarin Units for Cu2+ Detection via Planarization of Ict-Based Fluorophore

PubMed Central

Ngororabanga, Jean Marie Vianney; Du Plessis, Jacolien; Mama, Neliswa

2017-01-01

A novel fluorescent polymer with pendant triazolyl coumarin units was synthesized through radical polymerization. The polymer showed reasonable sensitivity and selectivity towards Cu2+ in acetonitrile in comparison to other tested metal ions with a significant quenching effect on fluorescence and blue shifting in the range of 20 nm. The blue shift was assigned to the conformation changes of the diethylamino group from the coumarin moiety which led to planarization of the triazolyl coumarin units. The possible binding modes for Cu2+ towards the polymer were determined through the comparison of the emission responses of the polymer, starting vinyl monomer and reference compound, and the triazole ring was identified as one of the possible binding sites for Cu2+. The detection limits of the polymer and vinyl monomer towards Cu2+ were determined from fluorescence titration experiments and a higher sensitivity (35 times) was observed for the polymer compared with its starting monomer. PMID:28867764

Fluorescent Polymer Incorporating Triazolyl Coumarin Units for Cu2+ Detection via Planarization of Ict-Based Fluorophore.

PubMed

Ngororabanga, Jean Marie Vianney; Du Plessis, Jacolien; Mama, Neliswa

2017-08-30

A novel fluorescent polymer with pendant triazolyl coumarin units was synthesized through radical polymerization. The polymer showed reasonable sensitivity and selectivity towards Cu 2+ in acetonitrile in comparison to other tested metal ions with a significant quenching effect on fluorescence and blue shifting in the range of 20 nm. The blue shift was assigned to the conformation changes of the diethylamino group from the coumarin moiety which led to planarization of the triazolyl coumarin units. The possible binding modes for Cu 2+ towards the polymer were determined through the comparison of the emission responses of the polymer, starting vinyl monomer and reference compound, and the triazole ring was identified as one of the possible binding sites for Cu 2+ . The detection limits of the polymer and vinyl monomer towards Cu 2+ were determined from fluorescence titration experiments and a higher sensitivity (35 times) was observed for the polymer compared with its starting monomer.

Bovine and porcine heparins: different drugs with similar effects on human haemodialysis

PubMed Central

2013-01-01

Background Heparins from porcine and bovine intestinal mucosa differ in their structure and also in their effects on coagulation, thrombosis and bleeding. However, they are used as undistinguishable drugs. Methods We compared bovine and porcine intestinal heparin administered to patients undergoing a particular protocol of haemodialysis. We compared plasma concentrations of these two drugs and also evaluated how they affect patients and the dialyzer used. Results Compared with porcine heparin, bovine heparin achieved only 76% of the maximum plasma concentration as IU mL-1. This observation is consistent with the activities observed in the respective pharmaceutical preparations. When the plasma concentrations were expressed on weight basis, bovine heparin achieved a maximum concentration 1.5 fold higher than porcine heparin. The reduced anticoagulant activity and higher concentration, on weight basis, achieved in the plasma of patients under dialysis using bovine instead of porcine heparin did not affect significantly the patients or the dialyzer used. The heparin dose is still in a range, which confers security and safety to the patients. Discussion Despite no apparent difference between bovine and porcine intestinal heparins in the haemodialysis practice, these two types of heparins should be used as distinct drugs due to their differences in structure and biological effects. Conclusions The reduced anticoagulant activity achieved in the plasma of patients under dialysis using bovine instead of porcine heparin did not affect significantly the patients or the dialyzer. PMID:23763719

Antiproliferative effect of isopentenylated coumarins on several cancer cell lines.

PubMed

Kawaii, S; Tomono, Y; Ogawa, K; Sugiura, M; Yano, M; Yoshizawa, Y; Ito, C; Furukawa, H

2001-01-01

33 coumarins, mainly the simple isopentenylated coumarins and derived pyrano- and furanocoumarins, were examined for their antiproliferative activity towards several cancer and normal human cell lines. The pyrano- and furanocoumarins showed strong activity against the cancer cell lines, whereas they had weak antiproliferative activity against the normal human cell lines. The decreasing rank order of potency was osthenone (10), clausarin (25), clausenidin (26), dentatin (24), nordentatin (23), imperatorin (29), seselin (27), xanthyletin (21), suberosin (17), phebalosin (8) and osthol (12). The structure-activity relationship established from the results revealed that the 1,1-dimethylallyl and isopentenyl groups have an important role for antiproliferative activity.

Dietary vitamin K variability affects International Normalized Ratio (INR) coagulation indices.

PubMed

Couris, Rebecca; Tataronis, Gary; McCloskey, William; Oertel, Lynn; Dallal, Gerard; Dwyer, Johanna; Blumberg, Jeffrey B

2006-03-01

Changes in daily vitamin K intake may contribute to marked variations in the International Normalized Ratio (INR) coagulation index in patients receiving oral warfarin anticoagulant therapy, with potentially serious adverse outcomes. Thus, patients receiving warfarin therapy are routinely counseled regarding this drug-nutrient interaction and are instructed to maintain consistent vitamin K intakes, though little quantitative information about this relationship is available. To determine the quantitative impact of variability in dietary vitamin K(1) (phylloquinone) intake, assessed by a validated patient self-monitoring instrument, on weekly INR in patients receiving warfarin anticoagulant therapy. A prospective dietary assessment study was conducted at the Massachusetts General Hospital in Boston. Sixty outpatients (37 males and 23 females) were selected with a mean age 60.3 +/- 16.8 years, who began oral warfarin anticoagulant therapy within 14 days prior to their first clinic visit to an outpatient anticoagulation therapy unit. Exclusion criteria included more than 2 drinks of alcohol per day, inability to speak English, and concurrent disease states affecting warfarin therapy such as liver disease and terminal illness. Over the five-week study period, participants recorded daily intakes in specified amounts of all food items appearing on a validated dietary self-assessment tool. Concomitant use of prescription and/or non-prescription medications was also obtained. Concurrent daily warfarin dose and adherence to the drug regimen, concomitant use of prescription and/or non-prescription medications known to interact with warfarin, and weekly INR were obtained. Week-to-week changes in vitamin K intake, warfarin dose, and INR were determined and cross-correlated. Forty-three patients (28 males and 15 females) completed the study and 17 dropped out. Pearson's correlation coefficient revealed the variability in INR and changes in vitamin K intake were inversely correlated (r = -0.600, p < 0.01). Multiple regression analysis (r = 0.848) indicated that a weekly change of 714 mug dietary vitamin K significantly altered weekly INR by 1 unit (p < 0.01) and a weekly change of 14.5 mg warfarin significantly altered weekly INR by 1 unit (p < 0.01) after adjustment for age, sex, weight, height, and concomitant use of medications known to interact with warfarin. Patients taking warfarin and consuming markedly changing amounts of vitamin K may have a variable weekly INR with potentially unstable anticoagulant outcomes.

The optimal duration of anticoagulant therapy after unprovoked venous thromboembolism - still a challenging issue.

PubMed

Elmi, Giovanna; Di Pasquale, Giuseppe; Pesavento, Raffaele

2017-03-01

As about 50 % of patients with unprovoked venous thromboembolism (VTE) will develop new episodes after discontinuing therapy, indefinite treatment is suggested in patients with low or moderate bleeding risk. Baseline and post-baseline factors can help clinicians to identify patients at high risk of recurrence, who require extended treatment. Residual vein obstruction and D-dimer assay have been shown to be suitable methods for assessing the risk of VTE recurrences after a first unprovoked VTE. In treatment for VTE the use of direct oral anticoagulants (DOAC) is growing instead of the standard adjusted dose of vitamin K antagonists. The DOAC safety profile has recently been strengthened with systematic reviews and meta-analyses. Idarucizumab is only approved for the reversal of dabigatran etexilate; intravenous antidotes for factor Xa inhibitors are under development. Their advent is of great interest. In the extended treatment of VTE sulodexide has been demonstrated to significantly decrease the risk of recurrences with an excellent safety profile. Aspirin is substantially less effective than oral anticoagulants in preventing recurrences but could play a role among patients who decided to stop anticoagulants. In conclusion, for the secondary prevention of VTE several options are available, without a recognised best choice regarding the treatment duration and the choice of drugs. An individual strategy taking into account risk of recurrence, bleeding risk, therapeutic options, and patient preferences is appropriate.

Relations of Anticoagulant Therapy with Cognitive Impairment among Patients with Atrial Fibrillation: A Meta-Analysis and Systematic Review.

PubMed

Cheng, Wenke; Liu, Weijun; Li, Bin; Li, Dongfang

2018-03-02

Currently, it is considered that atrial fibrillation (AF) is a risk factor for cognitive impairment and dementia, which is independent of stroke. However, the relationship between anticoagulant drugs and cognitive function in patients with atrial fibrillation is unknown. This study aimed to complete a meta-analysis, and investigate the association between Anticoagulant therapy and cognitive impairment in patients undergoing AF. Two investigators systematically searched the Cochrane Library, PubMed, Embase databases and Web of Science for all studies showing associations. Hazard ratios (HRs) were extracted and pooled. 8 studies included 471057 participants; TTR < 25% vs TTR> 75%; (HR 3.02, 95% CI 1.12-8.91; P=0.03); TTR 25-50% vs TTR> 75% (HR 2.44, 95% CI 0.95-6.22; P=0.06); TTR 50-75% vs TTR> 75% (HR 1.75, 95% CI 0.90-3.99; P=0.1); OAC vs No OAC (HR 0.71, 95% CI.69-0.74; P<0.00001) NOAC vs warfarin (HR0.51, 95% CI0.37-0.71; P<0.00001). Oral anticoagulants (OAC) significantly reduce the occurrence of cognitive impairment in patients with atrial fibrillation. Compared with warfarin, NOAC has an efficiently protective effect on cognition. In the range of INR2-3, with the increase of TTR, the incidence of cognitive impairment is lower.

Bio-pesticidal and anti-microbial coumarins from Angelica dahurica (Fisch. Ex Hoffm)

USDA-ARS?s Scientific Manuscript database

Angelica dahurica is an important traditional Chinese herb which is widely used in curing acne, ulcers, carbuncles, rheumatism, headaches and toothaches. A systematic antifungal bioassay-guided fractionation of the ethyl acetate extract from A. dahurica led to the isolation of six coumarins, namely...

Dabigatran – a case history demonstrating the need for comprehensive approaches to optimize the use of new drugs

PubMed Central

Malmström, Rickard E.; Godman, Brian B.; Diogene, Eduard; Baumgärtel, Christoph; Bennie, Marion; Bishop, Iain; Brzezinska, Anna; Bucsics, Anna; Campbell, Stephen; Ferrario, Alessandra; Finlayson, Alexander E.; Fürst, Jurij; Garuoliene, Kristina; Gomes, Miguel; Gutiérrez-Ibarluzea, Iñaki; Haycox, Alan; Hviding, Krystyna; Herholz, Harald; Hoffmann, Mikael; Jan, Saira; Jones, Jan; Joppi, Roberta; Kalaba, Marija; Kvalheim, Christina; Laius, Ott; Langner, Irene; Lonsdale, Julie; Lööv, Sven-Äke; Malinowska, Kamila; McCullagh, Laura; Paterson, Ken; Markovic-Pekovic, Vanda; Martin, Andrew; Piessnegger, Jutta; Selke, Gisbert; Sermet, Catherine; Simoens, Steven; Tulunay, Cankat; Tomek, Dominik; Vončina, Luka; Vlahovic-Palcevski, Vera; Wale, Janet; Wilcock, Michael; Wladysiuk, Magdalena; van Woerkom, Menno; Zara, Corrine; Gustafsson, Lars L.

2013-01-01

Background: There are potential conflicts between authorities and companies to fund new premium priced drugs especially where there are safety and/or budget concerns. Dabigatran, a new oral anticoagulant for the prevention of stroke in patients with non-valvular atrial fibrillation (AF), exemplifies this issue. Whilst new effective treatments are needed, there are issues in the elderly with dabigatran due to variable drug concentrations, no known antidote and dependence on renal elimination. Published studies have shown dabigatran to be cost-effective but there are budget concerns given the prevalence of AF. There are also issues with potentially re-designing anticoagulant services. This has resulted in activities across countries to better manage its use. Objective: To (i) review authority activities in over 30 countries and regions, (ii) use the findings to develop new models to better manage the entry of new drugs, and (iii) review the implications for all major stakeholder groups. Methodology: Descriptive review and appraisal of activities regarding dabigatran and the development of guidance for groups through an iterative process. Results: There has been a plethora of activities among authorities to manage the prescribing of dabigatran including extensive pre-launch activities, risk sharing arrangements, prescribing restrictions, and monitoring of prescribing post-launch. Reimbursement has been denied in some countries due to concerns with its budget impact and/or excessive bleeding. Development of a new model and future guidance is proposed to better manage the entry of new drugs, centering on three pillars of pre-, peri-, and post-launch activities. Conclusion: Models for introducing new drugs are essential to optimize their prescribing especially where there are concerns. Without such models, new drugs may be withdrawn prematurely and/or struggle for funding. PMID:23717279

Study on antithrombotic and antiplatelet activities of low molecular weight fucoidan from Laminaria japonica

NASA Astrophysics Data System (ADS)

Chen, Anjin; Zhang, Fang; Shi, Jie; Zhao, Xue

2012-06-01

The antithrombotic and antiplatelet effects of two fucoidan fractions with low molecular weight and different sulfate content from Laminaria japonica were compared in order to examine the influence of chemical character on their antithrombotic activity and the possible mechanism. Both LMW fucoidan fractions exhibited favorable antithrombotic activity in an Fecl3-induced arterial thrombosis. The antithrombotic activity of LMW fucoidan was related with decrease of TXB2 and whole blood viscosity and hematocrit. LMW fucoidan showed a correlation between anticoagulant, antiaggregant and antithrombotic effects in vivo. For LMW fucoidan, antithrombotic activity required high dose of 5-10 nmol kg-1, concomitantly with increase in anticoagulant activity and inhibition of platelet aggregation. Administration of LMW fucoidan significantly promoted the 6-keto-PGF1α content and decreased the TXB2 content, indicating its inhibition of tissue factor pathway and regulation of metabolism of arachidonic acid. By comparison, highly sulfated fucoidan LF2 with Mw 3900 seemed to be a more suitable choice for antithrombotic drug for its antithrombotic activity accompanied with specific inhibitory activity on platelet aggregation, low anticoagulant activity and low hemorrhagic risk in vivo.

Metabolome analysis of Arabidopsis thaliana roots identifies a key metabolic pathway for iron acquisition.

PubMed

Schmidt, Holger; Günther, Carmen; Weber, Michael; Spörlein, Cornelia; Loscher, Sebastian; Böttcher, Christoph; Schobert, Rainer; Clemens, Stephan

2014-01-01

Fe deficiency compromises both human health and plant productivity. Thus, it is important to understand plant Fe acquisition strategies for the development of crop plants which are more Fe-efficient under Fe-limited conditions, such as alkaline soils, and have higher Fe density in their edible tissues. Root secretion of phenolic compounds has long been hypothesized to be a component of the reduction strategy of Fe acquisition in non-graminaceous plants. We therefore subjected roots of Arabidopsis thaliana plants grown under Fe-replete and Fe-deplete conditions to comprehensive metabolome analysis by gas chromatography-mass spectrometry and ultra-pressure liquid chromatography electrospray ionization quadrupole time-of-flight mass spectrometry. Scopoletin and other coumarins were found among the metabolites showing the strongest response to two different Fe-limited conditions, the cultivation in Fe-free medium and in medium with an alkaline pH. A coumarin biosynthesis mutant defective in ortho-hydroxylation of cinnamic acids was unable to grow on alkaline soil in the absence of Fe fertilization. Co-cultivation with wild-type plants partially rescued the Fe deficiency phenotype indicating a contribution of extracellular coumarins to Fe solubilization. Indeed, coumarins were detected in root exudates of wild-type plants. Direct infusion mass spectrometry as well as UV/vis spectroscopy indicated that coumarins are acting both as reductants of Fe(III) and as ligands of Fe(II).

Simultaneous determination of five coumarins in Angelicae dahuricae Radix by HPLC/UV and LC-ESI-MS/MS.

PubMed

Park, Ah Yeon; Park, So-Young; Lee, Jaehyun; Jung, Mihye; Kim, Jinwoong; Kang, Sam Sik; Youm, Jeong-Rok; Han, Sang Beom

2009-10-01

Rapid, simple and reliable HPLC/UV and LC-ESI-MS/MS methods for the simultaneous determination of five active coumarins of Angelicae dahuricae Radix, byakangelicol (1), oxypeucedanin (2), imperatorin (3), phellopterin (4) and isoimperatorin (5) were developed and validated. The separation condition for HPLC/UV was optimized using a Develosil RPAQUEOUS C(30) column using 70% acetonitrile in water as the mobile phase. This HPLC/UV method was successful for providing the baseline separation of the five coumarins with no interfering peaks detected in the 70% ethanol extract of Angelicae dahuricae Radix. The specific determination of the five coumarins was also accomplished by a triple quadrupole tandem mass spectrometer equipped with an electrospray ionization source (LC-ESI-MS/MS). Multiple reaction monitoring (MRM) in the positive mode was used to enhance the selectivity of detection. The LC-ESI-MS/MS methods were successfully applied for the determination of the five major coumarins in Angelicae dahuricae Radix. These HPLC/UV and LC-ESI-MS/MS methods were validated in terms of recovery, linearity, accuracy and precision (intra- and inter-day validation). Taken together, the shorter analysis time involved makes these HPLC/UV and LC-ESI-MS/MS methods valuable for the commercial quality control of Angelicae dahuricae Radix extracts and its pharmaceutical preparations. Copyright (c) 2009 John Wiley & Sons, Ltd.

Pharmacogenetic Variation in Over 100 Genes in Patients Receiving Acenocumarol

PubMed Central

Gonzalez-Covarrubias, Vanessa; Urena-Carrion, Javier; Villegas-Torres, Beatriz; Cossío-Aranda, J. Eduardo; Trevethan-Cravioto, Sergio; Izaguirre-Avila, Raul; Fiscal-López, O. Javier; Soberon, Xavier

2017-01-01

Coumarins are widely prescribed worldwide, and in Mexico acenocumarol is the preferred form. It is well known that despite its efficacy, coumarins show a high variability for dose requirements. We investigated the pharmacogenetic variation of 110 genes in patients receiving acenocumarol using a targeted NGS approach. We report relevant population differentiation for variants on CYP2C8, CYP2C19, CYP4F11, CYP4F2, PROS, and GGCX, VKORC1, CYP2C18, NQO1. A higher proportion of novel-to-known variants for 10 genes was identified on 41 core pharmacogenomics genes related to the PK (29), PD (3), of coumarins, and coagulation proteins (9) including, CYP1A1, CYP3A4, CYP3A5, and F8, and a low proportion of novel-to-known variants on CYP2E1, VKORC1, and SULT1A1/2. Using a Bayesian approach, we identified variants influencing acenocumarol dosing on, VKORC1 (2), SULT1A1 (1), and CYP2D8P (1) explaining 40–55% of dose variability. A collection of pharmacogenetic variation on 110 genes related to the PK/PD of coumarins is also presented. Our results offer an initial insight into the use of a targeted NGS approach in the pharmacogenomics of coumarins in Mexican Mestizos. PMID:29218011

Caspase-1 Specific Light-Up Probe with Aggregation-Induced Emission Characteristics for Inhibitor Screening of Coumarin-Originated Natural Products.

PubMed

Lin, Hao; Yang, Haitao; Huang, Shuai; Wang, Fujia; Wang, Dong-Mei; Liu, Bin; Tang, Yi-Da; Zhang, Chong-Jing

2018-04-18

Caspase-1 is a key player in pyroptosis and inflammation. Caspase-1 inhibition is found to be beneficial to various diseases. Coumarin-originated natural products have an anti-inflammation function, but their direct inhibition effect to caspase-1 remains unexplored. To evaluate their interactions, the widely used commercial coumarin-based probe (Ac-YVAD-AMC) is not suitable, as the background signal from coumarin-originated natural products could interfere with the screening results. Therefore, fluorescent probes using a large Stokes shift could help solve this problem. In this work, we chose the fluorophore of tetraphenylethylene-thiophene (TPETH) with aggregation-induced emission characteristics and a large Stokes shift of about 200 nm to develop a molecular probe. Bioconjugation between TPETH and hydrophilic peptides (DDYVADC) through a thiol-ene reaction generated a light-up probe, C1-P3. The probe has little background signal in aqueous media and exerts a fluorescent turn-on effect in the presence of caspase-1. Moreover, when evaluating the inhibition potency of coumarin-originated natural products, the new probe could generate a true and objective result but not for the commercial probe (Ac-YVAD-AMC), which is evidenced by HPLC analysis. The quick light-up response and accurate screening results make C1-P3 very useful in fundamental study and inhibitior screening toward caspase-1.

Heparin: Past, Present, and Future.

PubMed

Oduah, Eziafa I; Linhardt, Robert J; Sharfstein, Susan T

2016-07-04

Heparin, the most widely used anticoagulant drug in the world today, remains an animal-derived product with the attendant risks of adulteration and contamination. A contamination crisis in 2007-2008 increased the impetus to provide non-animal-derived sources of heparin, produced under cGMP conditions. In addition, recent studies suggest that heparin may have significant antineoplastic activity, separate and distinct from its anticoagulant activity, while other studies indicate a role for heparin in treating inflammation, infertility, and infectious disease. A variety of strategies have been proposed to produce a bioengineered heparin. In this review, we discuss several of these strategies including microbial production, mammalian cell production, and chemoenzymatic modification. We also propose strategies for creating "designer" heparins and heparan-sulfates with various biochemical and physiological properties.

Acquired antiprothrombin antibodies: an unusual cause of bleeding.

PubMed

Carvalho, Cristiana; Viveiro, Carolina; Maia, Paulo; Rezende, Teresa

2013-01-07

Acquired inhibitors of coagulation causing bleeding manifestations are rare in children. They emerge, normally in the context of autoimmune diseases or drug ingestion, but transient and self-limiting cases can occur after viral infection. We describe, an otherwise healthy, 7-year-old girl who had gingival bleeding after a tooth extraction. The prothrombin time (PT) and the activated partial thromboplastin time (APTT) were both prolonged with evidence of an immediate acting inhibitor (lupic anticoagulant). Further coagulation studies demonstrated prothrombin (FII) deficiency and prothrombin directed (FII) antibodies. The serological tests to detect an underlying autoimmune disease were all negative. The coagulation studies normalised alongside the disappearance of the antibody. This article presents lupus anticoagulant hypoprothrombinaemia syndrome (LAHS) as a rare case of acquired bleeding diathesis in childhood.

Synthesis of novel coumarin nucleus-based DPA drug-like molecular entity: In vitro DNA/Cu(II) binding, DNA cleavage and pro-oxidant mechanism for anticancer action

PubMed Central

Khan, Saman; Malla, Ali Mohammed; Zafar, Atif

2017-01-01

Despite substantial research on cancer therapeutics, systemic toxicity and drug-resistance limits the clinical application of many drugs like cisplatin. Therefore, new chemotherapeutic strategies against different malignancies are needed. Targeted cancer therapy is a new paradigm for cancer therapeutics which targets pathways or chemical entities specific to cancer cells than normal ones. Unlike normal cells, cancer cells contain elevated copper which plays an integral role in angiogenesis. Copper is an important metal ion associated with chromatin DNA, particularly with guanine. Thus, targeting copper via copper-specific chelators in cancer cells can serve as an effective anticancer strategy. New pharmacophore di(2-picolyl)amine (DPA)-3(bromoacetyl) coumarin (ligand-L) was synthesized and characterized by IR, ESI-MS, 1H- and 13C-NMR. Binding ability of ligand-L to DNA/Cu(II) was evaluated using a plethora of biophysical techniques which revealed ligand-L-DNA and ligand-L-Cu(II) interaction. Competitive displacement assay and docking confirmed non-intercalative binding mode of ligand-L with ctDNA. Cyclic voltammetry confirmed ligand-L causes quasi reversible Cu(II)/Cu(I) conversion. Further, acute toxicity studies revealed no toxic effects of ligand-L on mice. To evaluate the chemotherapeutic potential and anticancer mechanism of ligand-L, DNA damage via pBR322 cleavage assay and reactive oxygen species (ROS) generation were studied. Results demonstrate that ligand-L causes DNA cleavage involving ROS generation in the presence of Cu(II). In conclusion, ligand-L causes redox cycling of Cu(II) to generate ROS which leads to oxidative DNA damage and pro-oxidant cancer cell death. These findings will establish ligand-L as a lead molecule to synthesize new molecules with better copper chelating and pro-oxidant properties against different malignancies. PMID:28763458

Comparison of estimated glomerular filtration rate equations for dosing new oral anticoagulants in patients with atrial fibrillation.

PubMed

Manzano-Fernández, Sergio; Andreu-Cayuelas, José M; Marín, Francisco; Orenes-Piñero, Esteban; Gallego, Pilar; Valdés, Mariano; Vicente, Vicente; Lip, Gregory Y H; Roldán, Vanessa

2015-06-01

New oral anticoagulants require dosing adjustment according to renal function. We aimed to determine discordance in hypothetical recommended dosing of these drugs using different estimated glomerular filtration rate equations in patients with atrial fibrillation. Cross-sectional analysis of 910 patients with atrial fibrillation and an indication for oral anticoagulation. The glomerular filtration rate was estimated using the Cockcroft-Gault, Modification of Diet in Renal Disease and Chronic Kidney Disease Epidemiology Collaboration equations. For dabigatran, rivaroxaban, and apixaban we identified dose discordance when there was disagreement in the recommended dose based on different equations. Among the overall population, relative to Cockcroft-Gault, discordance in dabigatran dosage was 11.4% for Modification of Diet in Renal Disease and 10% for Chronic Kidney Disease Epidemiology Collaboration, discordance in rivaroxaban dosage was 10% for Modification of Diet in Renal Disease and 8.5% for the Chronic Kidney Disease Epidemiology Collaboration. The lowest discordance was observed for apixaban: 1.4% for Modification of Diet in Renal Disease and 1.5% for the Chronic Kidney Disease Epidemiology Collaboration. In patients with Cockcroft-Gault<60mL/min or elderly patients, discordances in dabigatran and rivaroxaban dosages were higher, ranging from 13.2% to 30.4%. Discordance in apixaban dosage remained<5% in these patients. Discordance in new oral anticoagulation dosages using different equations is frequent, especially among elderly patients with renal impairment. This discordance was higher in dabigatran and rivaroxaban dosages than in apixaban dosages. Further studies are needed to clarify the clinical importance of these discordances and the optimal anticoagulant dosages depending on the use of different equations to estimate renal function. Copyright © 2014 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

[Perioperative coagulation management in microsurgery: report of the consensus workshops in the course of the 31st and 32nd Annual Meeting of the German-language Working Group for microsurgery of the peripheral nerves and vessels (DAM) November 2009 in Erlangen and November 2010 in Basel].

PubMed

Schmitz, M; Riss, R; Kneser, U; Jokuszies, A; Harder, Y; Beier, J P; Schäfer, D J; Vogt, P M; Fansa, H; Andree, C; Pierer, G; Horch, R E

2011-12-01

Microsurgery is a very relevant component of reconstructive surgery. In this context anticoagulation plays an increasing role. At the moment there are no unanimously accepted prospective studies or generally accepted regimes available that could serve as evidence-based guidelines for the prevention of thrombosis in microsurgery. With regard to this problem the aim of a series of workshops during the annual meetings of the German-speaking group for microsurgery in 2009 and 2010 was to establish a first possible consensus. This article reflects the main aspects of the ongoing development of a generally acceptable guideline for anticoagulation in microsurgery as interim report of these consensus workshops. Basically there are 3 main agents in thromboprophylaxis available: antiplatelet drugs, dextran and heparin. In the course of the workshops no general use of aspirin or dextran for anticoagulation in microsurgery was recommended. The use of heparin as anticoagulation agent is advisable for different indications. Low molecular heparins (LMH) have certain advantages in comparison to unfractionated heparins (UFH) and are therefore preferred by most participants. Indications for UFH are still complex microsurgical revisions, renal failure and some specific constellations in patients undergoing reconstruction of the lower extremity, where the continuous administration of heparin is recommended. At the moment of clamp release a single-shot of UFH is still given by many microsurgeons, despite a lack of scientific evidence. Future prospective clinical trials and the establishment of a generally accepted evidence-based guideline regarding anticoagulation treatment in microsurgery are deemed necessary. © Georg Thieme Verlag KG Stuttgart · New York.

Differential morphological, cytological and biochemical responses of two rice cultivars to coumarin

USDA-ARS?s Scientific Manuscript database

Plants are often exposed to allelochemicals in the environment produced by neighboring plants. Coumarin is a common allelochemical produced by many higher plants. Two cultivars (susceptible BS-2000 and less susceptible BR-41) of rice (Oryza sativa L.) were selected to compare their differential root...

Convenient Microscale Synthesis of a Coumarin Laser Dye Analog

ERIC Educational Resources Information Center

Aktoudianakis, Evangelos; Dicks, Andrew P.

2006-01-01

Coumarin (2H-1-benzopyran-2-one) and its derivatives constitute a fascinating class of organic substances that are utilized industrially in areas such as cosmetics, food preservatives, insecticides and fluorescent laser dyes. The product can be synthesized, purified, and characterized within two hours with benefits of microscale reactivity being…

Drug–drug interactions between antithrombotic medications and the risk of gastrointestinal bleeding

PubMed Central

Delaney, Joseph A.; Opatrny, Lucie; Brophy, James M.; Suissa, Samy

2007-01-01

Background Anticoagulants and antiplatelet drugs (e.g., warfarin, clopidogrel and acetylsalicylic acid) are key therapeutic agents in the treatment of cardiovascular diseases. However, drug–drug interactions may lead to a greatly increased risk of gastrointestinal bleeding when these drugs are combined. We assessed whether antithrombotic drug combinations increased the risk of such bleeding in a general practice population. Methods We conducted a population-based, retrospective case–control study using records in the United Kingdom General Practice Research Database from 2000 through 2005. Cases were identified as patients over 18 years of age with a first-ever diagnosis of gastrointestinal bleeding. They were matched with controls by physician practice, patient age and index date (date of diagnosis of bleeding). All eligible patients had to have at least 3 years of follow-up data in the database. Drug exposure was considered to be any prescription issued in the 90 days before the index date. Results There were 4028 cases with a diagnosis of gastrointestinal bleeding and 40 171 matched controls. The prescribing of acetylsalicylic acid with either clopidogrel (adjusted rate ratio [RR] 3.90, 95% confidence interval [CI] 2.78–5.47) or warfarin (adjusted RR 6.48, 95% CI 4.25–9.87) was associated with a greater risk of gastrointestinal bleeding than that observed with each drug alone. The same was true when a nonsteroidal anti-inflammatory drug was combined with either clopidogrel (adjusted RR 2.93, 95% CI 1.74–4.93) or warfarin (RR 4.60, 95% CI 2.77–7.64). Interpretation Drug combinations involving antiplatelets and anticoagulants are associated with a high risk of gastrointestinal bleeding beyond that associated with each drug used alone. Physicians should be aware of these risks to better assess their patients' therapeutic risk–benefit profiles. PMID:17698822

Structure-Guided Design of a High-Affinity Platelet Integrin αIIbβ3 Receptor Antagonist That Disrupts Mg2+ Binding to the MIDAS | Center for Cancer Research

Cancer.gov

A Better Fit. An improved anticoagulant drug called RUC-2 (ball and stick structure) fits snugly into its binding pocket on integrin (blue), a protein found on the surface of platelets. RUC-2 binds both subunits of integrin, inhibiting the excessive blood coagulation that can lead to strokes and heart attacks. Unlike similar drugs that alter integrin's structure when they bind

Perspective on the Use of Sulfated Polysaccharides from Marine Organisms as a Source of New Antithrombotic Drugs

PubMed Central

Mourão, Paulo A. S.

2015-01-01

Thromboembolic diseases are increasing worldwide and always require anticoagulant therapy. We still need safer and more secure antithrombotic drugs than those presently available. Sulfated polysaccharides from marine organisms may constitute a new source for the development of such drugs. Investigation of these compounds usually attempts to reproduce the therapeutic effects of heparin. However, we may need to follow different routes, focusing particularly in the following aspects: (1) defining precisely the specific structures required for interaction of these sulfated polysaccharides with proteins of the coagulation system; (2) looking for alternative mechanisms of action, distinct from those of heparin; (3) identifying side effects (mostly pro-coagulant action and hypotension rather than bleeding) and preparing derivatives that retain the desired antithrombotic action but are devoid of side effects; (4) considering that sulfated polysaccharides with low anticoagulant action on in vitro assays may display potent effects on animal models of experimental thrombosis; and finally (5) investigating the antithrombotic effect of these sulfated polysaccharides after oral administration or preparing derivatives that may achieve this effect. If these aspects are successfully addressed, sulfated polysaccharides from marine organisms may conquer the frontier of antithrombotic therapy and open new avenues for treatment or prevention of thromboembolic diseases. PMID:25955754

Biotechnological engineering of heparin/heparan sulphate: a novel area of multi-target drug discovery.

PubMed

Rusnati, Marco; Oreste, Pasqua; Zoppetti, Giorgio; Presta, Marco

2005-01-01

Heparin is a sulphated glycosaminoglycan currently used as an anticoagulant and antithrombotic drug. It consists largely of 2-O-sulphated IdoA not l&r arrow N, 6-O-disulphated GlcN disaccharide units. Other disaccharides containing unsulphated IdoA or GlcA and N-sulphated or N-acetylated GlcN are also present as minor components. This heterogeneity is more pronounced in heparan sulphate (HS), where the low-sulphated disaccharides are the most abundant. Heparin/HS bind to a variety of biologically active polypeptides, including enzymes, growth factors and cytokines, and viral proteins. This capacity can be exploited to design multi-target heparin/HS-derived drugs for pharmacological interventions in a variety of pathologic conditions besides coagulation and thrombosis, including neoplasia and viral infection. The capsular K5 polysaccharide from Escherichia coli has the same structure as the heparin precursor N-acetyl heparosan. The possibility of producing K5 polysaccharide derivatives by chemical and enzymatic modifications, thus generating heparin/HS-like compounds, has been demonstrated. These K5 polysaccharide derivatives are endowed with different biological properties, including anticoagulant/antithrombotic, antineoplastic, and anti-AIDS activities. Here, the literature data are discussed and the possible therapeutic implications for this novel class of multi-target "biotechnological heparin/HS" molecules are outlined.

Warfarin Toxicity and Individual Variability—Clinical Case

PubMed Central

Piatkov, Irina; Rochester, Colin; Jones, Trudi; Boyages, Steven

2010-01-01

Warfarin is a widely used anticoagulant in the treatment and prevention of thrombosis, in the treatment for chronic atrial fibrillation, mechanical valves, pulmonary embolism, and dilated cardiomyopathy. It is tasteless and colorless, was used as a poison, and is still marketed as a pesticide against rats and mice. Several long-acting warfarin derivatives—superwarfarin anticoagulants—such as brodifacoum, diphenadione, chlorophacinone, bromadiolone, are used as pesticides and can produce profound and prolonged anticoagulation. Several factors increase the risk of warfarin toxicity. However, polymorphisms in cytochrome P450 genes and drug interactions account for most of the risk for toxicity complications. Each person is unique in their degree of susceptibility to toxic agents. The toxicity interpretation and the health risk of most toxic substances are a subject of uncertainty. Genetically determined low metabolic capacity in an individual can dramatically alter the toxin and metabolite levels from those normally expected, which is crucial for drugs with a narrow therapeutic index, like warfarin. Personalized approaches in interpretation have the potential to remove some of the scientific uncertainties in toxicity cases. PMID:22069565

Drug-Induced Hematologic Syndromes

PubMed Central

Mintzer, David M.; Billet, Shira N.; Chmielewski, Lauren

2009-01-01

Objective. Drugs can induce almost the entire spectrum of hematologic disorders, affecting white cells, red cells, platelets, and the coagulation system. This paper aims to emphasize the broad range of drug-induced hematological syndromes and to highlight some of the newer drugs and syndromes. Methods. Medline literature on drug-induced hematologic syndromes was reviewed. Most reports and reviews focus on individual drugs or cytopenias. Results. Drug-induced syndromes include hemolytic anemias, methemoglobinemia, red cell aplasia, sideroblastic anemia, megaloblastic anemia, polycythemia, aplastic anemia, leukocytosis, neutropenia, eosinophilia, immune thrombocytopenia, microangiopathic syndromes, hypercoagulability, hypoprothrombinemia, circulating anticoagulants, myelodysplasia, and acute leukemia. Some of the classic drugs known to cause hematologic abnormalities have been replaced by newer drugs, including biologics, accompanied by their own syndromes and unintended side effects. Conclusions. Drugs can induce toxicities spanning many hematologic syndromes, mediated by a variety of mechanisms. Physicians need to be alert to the potential for iatrogenic drug-induced hematologic complications. PMID:19960059

Diversity-Oriented Synthesis of Coumarin-Linked Benzimidazoles via a One-Pot, Three-Step, Intramolecular Knoevenagel Cyclization.

PubMed

Yao, Po-Hsin Eric; Kumar, Sunil; Liu, Yu-Li; Fang, Chiu-Ping; Liu, Chia-Chen; Sun, Chung-Ming

2017-04-10

Diversity-oriented synthesis of coumarin-linked benzimidazoles from N-(2-aminophenyl)-2-cyanoacetamide was achieved via a one-pot, three-step sequential reaction in excellent yields. In situ intramolecular cyclization of the cyanoacetamide afforded benzimidazoles which subsequently underwent a Knoevenagel condensation of the 2-cyanomethylbenzimidazoles with salicylaldehydes promoted by triethylamine to reach the target compounds. An important intermediate, 2-(2-imino-2H-chromen-3-yl)-1H-benzimidazole was characterized by X-ray analysis and further hydrolyzed to 2-(coumarin-3-yl)benzimidazole in acidic condition. Among the synthesized compounds, some were found to be promising inhibitors of porcine kidney d-amino acid oxidase (pkDAO).

Mobile Health Technology for Atrial Fibrillation Management Integrating Decision Support, Education, and Patient Involvement: mAF App Trial.

PubMed

Guo, Yutao; Chen, Yundai; Lane, Deirdre A; Liu, Lihong; Wang, Yutang; Lip, Gregory Y H

2017-12-01

Mobile Health technology for the management of patients with atrial fibrillation is unknown. The simple mobile AF (mAF) App was designed to incorporate clinical decision-support tools (CHA 2 DS 2 -VASc [Congestive heart failure, Hypertension, Age ≥75 years, Diabetes Mellitus, Prior Stroke or TIA, Vascular disease, Age 65-74 years, Sex category], HAS-BLED [Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly, Drugs/alcohol concomitantly], SAMe-TT 2 R 2 [Sex, Age <60 years, Medical history, Treatment, Tobacco use, Race] scores), educational materials, and patient involvement strategies with self-care protocols and structured follow-up. Patients with atrial fibrillation were randomized into 2 groups (mAF App vs usual care) in a cluster randomized design pilot study. Patients' knowledge, quality of life, drug adherence, and anticoagulation satisfaction were evaluated at baseline, 1 month, and 3 months. Usability, feasibility, and acceptability of the mAF App were assessed at 1 month. A total of 113 patients were randomized to mAF App intervention (mean age, 67.4 years; 57.5% were male; mean follow-up, 69 days), and 96 patients were randomized to usual care (mean age, 70.9 years; 55.2% were male; mean follow-up, 95 days). More than 90% of patients reported that the mAF App was easy, user-friendly, helpful, and associated with significant improvements in knowledge compared with the usual care arm (P values for trend <.05). Drug adherence and anticoagulant satisfaction were significantly better with the mAF App versus usual care (all P < .05). Quality of life scores were significantly increased in the mAF App arm versus usual care, with anxiety and depression reduced (all P < .05). The pilot mAFA Trial is the first prospective randomized trial of Mobile Health technology in patients with atrial fibrillation, demonstrating that the mAF App, integrating clinical decision support, education, and patient-involvement strategies, significantly improved knowledge, drug adherence, quality of life, and anticoagulation satisfaction. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Direct Oral Anticoagulants in Emergency Trauma Admissions.

PubMed

Maegele, Marc; Grottke, Oliver; Schöchl, Herbert; Sakowitz, Oliver A; Spannagl, Michael; Koscielny, Jürgen

2016-09-05

Direct (non-vitamin-K-dependent) oral anticoagulants (DOAC) are given as an alternative to vitamin K antagonists (VKA) to prevent stroke and embolic disease in patients with atrial fibrillation that is not due to pathology of the heart valves. Fatal hemorrhage is rarer when DOACs are given (nonvalvular atrial fibrillation: odds ratio [OR] 0.68; 95% confidence interval [95% CI: 0.48; 0.96], and venous thromboembolism: OR 0.54; [0.22; 1.32]). 48% of emergency trauma patients need an emergency operation or early surgery. Clotting disturbances elevate the mortality of such patients to 43%, compared to 17% in patients without a clotting disturbance. This underscores the impor tance of the proper, targeted treatment of trauma patients who are aking DOAC. This review is based on articles retrieved by a selective search in PubMed and on a summary of expert opinion and the recommendations of the relevant medical specialty societies. Peak DOAC levels are reached 2-4 hours after the drug is taken. In patients with normal renal and hepatic function, no drug accumulation, and no drug interactions, the plasma level of DOAC 24 hours after administration is generally too low to cause any clinically relevant risk of bleeding. The risk of drug accumulation is higher in patients with renal dysfunction (creatinine clearance [CrCl] of 30 mL/min or less). Dabigatran levels can be estimated from the thrombin time, ecarin clotting time, and diluted thrombin time, while levels of factor Xa inhibitors can be estimated by means of calibrated chromogenic anti-factor Xa activity tests. Routine clotting studies do not reliably reflect the anticoagulant activity of DOAC. Surgery should be postponed, if possible, until at least 24-48 hours after the last dose of DOAC. For patients with mild, non-life threatening hemorrhage, it suffices to discontinue DOAC; for patients with severe hemorrhage, there are special treatment algorithms that should be followed. DOACs in the setting of hemorrhage are a clinical challenge in the traumatological emergency room because of the inadequate validity of the relevant laboratory tests. An emergency antidote is now available only for dabigatran.

Investigation of the biotransformation of osthole by liquid chromatography/tandem mass spectrometry.

PubMed

Li, Jie; Chan, Wan

2013-02-23

Osthole is an active ingredient and one of the major coumarin compounds that were identified in the genus Cnidium moonnieri (L.) Cussion, the fruit of which was used as traditional Chinese medicine to treat male impotence, ringworm infection and blood stasis conventionally. Recent studies revealed that osthole has diverse pharmacological effects, such as improving male sexual dysfunction, anti-diabetes, and anti-hypertentions. The inhibition of thrombosis and platelet aggregation and protection of central nerve were also observed. On the other hand, the metabolism of osthole has not yet been investigated thoroughly. Herein the biotransformation of osthole in rat was investigated after oral administration of osthole by using efficient and sensitive ultra-performance liquid chromatography-tandem quadrupole-time of flight mass spectrometry (UPLC-QTOF/MS). Eighteen osthole metabolites and the parent drug were detected and identified in rat urine. Fourteen metabolites of osthole were identified and characterized for the first time. Structures of metabolites of osthole were elucidated by comparing fragment pattern under MS/MS scan and change of molecular weight with those of osthole. The main phase I metabolic pathways were summed as 7-demethylation, 8-dehydrogenation, hydroxylation on coumarin and 3,4-epoxide. Sulfate conjugates were detected as phase II metabolites of osthole. Copyright © 2012 Elsevier B.V. All rights reserved.

Simultaneous determination of five minor coumarins and flavonoids in Glycyrrhiza uralensis by solid-phase extraction and high-performance liquid chromatography/electrospray ionization tandem mass spectrometry.

PubMed

Qiao, Xue; Liu, Chun-Fang; Ji, Shuai; Lin, Xiong-Hao; Guo, De-An; Ye, Min

2014-02-01

Minor phenolic compounds in licorice (Glycyrrhiza uralensis) have recently been proved for diverse bioactivities and favorable bioavailability, indicating that they may play an important role in the therapeutic effects or herb-drug interactions of licorice. However, so far, their abundance in licorice remains unknown. In this study, a reliable solid-phase extraction coupled with a high-performance liquid chromatography and diode array detection method was established to determine the minor phenolic compounds in licorice. The analytes were enriched by a three-step solid-phase extraction method, and then separated on a YMC ODS-A column by gradient elution. Five coumarins and flavonoids were identified by electrospray ionization tandem mass spectrometry, and then quantified using high-performance liquid chromatography and diode array detection. The amounts of glycycoumarin, dehydroglyasperin C, glycyrol, licoflavonol, and glycyrin in G. uralensis were 0.81 ± 0.28, 1.25 ± 0.59, 0.20 ± 0.08, 0.12 ± 0.04, and 0.17 ± 0.08 mg/g, respectively. Abundances of these compounds in other Glycyrrhiza species (G. glabra, G. inflata, and G. yunnanesis) were remarkably lower than G. uralensis. Georg Thieme Verlag KG Stuttgart · New York.

Decursin attenuates kainic acid-induced seizures in mice.

PubMed

Lee, Jong-Keun; Jeong, Ji Woon; Jang, Taeik; Lee, Go-Woon; Han, Hogyu; Kang, Jae-Seon; Kim, Ik-Hwan

2014-11-12

Epilepsy is a neurological disorder with recurrent unprovoked seizures as the main symptom. Of the coumarin derivatives in Angelica gigas, decursin, a major coumarin component, was reported to exhibit significant protective activity against glutamate-induced neurotoxicity when added to primary cultures of rat cortical cells. This study served to investigate the effects of decursin on a kainic acid (KA)-induced status epilepticus model. Thirty minutes after intraperitoneal injections of decursin (20 mg/kg) in male 7-week-old C57BL/6 mice, the animals were treated with KA (30 mg/kg, intraperitoneally) and then examined for behavioral seizure score, electroencephalogram, seizure-related expressed protein levels, neuronal cell loss, neurodegeneration, and astrogliosis. KA injections significantly enhanced neurodegenerative conditions but treatment with decursin 30 min before KA injection reduced the detrimental effects of KA in mice. The decursin-treated KA-injected group showed significantly decreased behavioral seizure activity and remarkably attenuated intense and high-frequency seizure discharges in the parietal cortex for 2 h compared with the group treated only with KA. Furthermore, in-vivo results indicated that decursin strongly inhibits selective neuronal death, astrogliosis, and oxidative stress induced by KA administration. Therefore decursin is able to attenuate KA-induced seizures and could have potential as an antiepileptic drug.

Dermal absorption behavior of fluorescent molecules in nanoparticles on human and porcine skin models.

PubMed

Debotton, Nir; Badihi, Amit; Robinpour, Mano; Enk, Claes D; Benita, Simon

2017-05-30

The percutaneous passage of poorly skin absorbed molecules can be improved using nanocarriers, particularly biodegradable polymeric nanospheres (NSs) or nanocapsules (NCs). However, penetration of the encapsulated molecules may be affected by other factors than the nanocarrier properties. To gain insight information on the skin absorption of two fluorescent cargos, DiIC 18 (5) and coumarin-6 were incorporated in NSs or NCs and topically applied on various human and porcine skin samples. 3D imaging techniques suggest that NSs and NCs enhanced deep dermal penetration of both probes similarly, when applied on excised human skin irrespective of the nature of the cargo. However, when ex vivo pig skin was utilized, the cutaneous absorption of DiIC 18 (5) was more pronounced by means of PLGA NCs than NSs. In contrast, PLGA NSs noticeably improved the porcine skin penetration of coumarin-6, as compared to the NCs. Furthermore, the porcine skin results were reproducible when triplicated whereas from various human skin samples, as expected, the results were not sufficiently reproducible and large deviations were observed. The overall findings from this comprehensive comparison emphasize the potential of PLGA NCs or NSs to promote cutaneous bioavailability of encapsulated drugs, exhibiting different physicochemical properties but depending on the nature of the skin. Copyright © 2017 Elsevier B.V. All rights reserved.

Coumarins in horse chestnut flowers: isolation and quantification by UPLC method.

PubMed

Dudek-Makuch, Marlena; Matławska, Irena

2013-01-01

The coumarins: scopoletin, esculetin and fraxetin were isolated from the flowers of horse chestnut (Aesculus hippocastanum L., Hippocastanaceae) and identified by spectrophotometric methods (UV, 1H, 13C NMR, ESI-MS). Their content, determined using the Ultra Performance Liquid Chromatography (UPLC), was 0.41, 0.13 and 0.05%, respectively.

Preparation and characterization of mesoporous ZnO-ZrO2 doped by Cr, Nd and Dy as a catalyst for conversion of coumarin using ultrasensitive fluorometric method

NASA Astrophysics Data System (ADS)

Ibrahim, M. M.

2017-04-01

Doping of mesoporous ZnO-ZrO2 nanoparticles with transition metal and lanthanides (Cr, Nd, Dy) were used as a catalyst to develop an ultrasensitive fluorometric method for the conversion of non fluorescent coumarin to highly fluorescent 7-hydroxycoumarin using H2O2 or light. It was found that doped- ZnO-ZrO2 mixed oxide can catalyze the decomposition of H2O2 to produce •OH radicals, which in turn convert coumarin to 7-hydroxycoumarin. At contrast, the doping has deleterious effect on conversion of coumarin by light due to high band gap and high concentrations of doping increase the recombination rate of electron and holes. Doped mixed oxides prepared by impregnation method and characterized by studying their structural, surface and optical properties. Chromium doped ZnO-ZrO2 had the highest rate of formation of hydroxyl radical due to decomposition of H2O2 and therefore 7-hydroxycoumarin due to surface area, small crystal size and high redox potential.

Solvent as electron donor: Donor/acceptor electronic coupling is a dynamical variable

DOE Office of Scientific and Technical Information (OSTI.GOV)

Castner, E.W. Jr.; Kennedy, D.; Cave, R.J.

2000-04-06

The authors combine analysis of measurements by femtosecond optical spectroscopy, computer simulations, and the generalized Mulliken-Hush (GMH) theory in the study of electron-transfer reactions and electron donor-acceptor interactions. The study focus is on ultrafast photoinduced electron-transfer reactions from aromatic amine solvent donors to excited-state acceptors. The experimental results from femtosecond dynamical measurements fall into three categories: six coumarin acceptors reductively quenched by N,N-dimethylaniline (DMA), eight electron-donating amine solvents reductively quenching coumarin 152 (7-(dimethylamino)-4-(trifluoromethyl)-coumarin), and reductive quenching dynamics of two coumarins by DMA as a function of dilution in the nonreactive solvents toluene and chlorobenzene. Applying a combination of molecular dynamicsmore » trajectories, semiempirical quantum mechanical calculations (of the relevant adiabatic electronic states), and GMH theory to the C152/DMA photoreaction, the authors calculate the electron donor/acceptor interaction parameter H{sub DA} at various time frames, H{sub DA} is strongly modulated by both inner-sphere and outer-sphere nuclear dynamics, leading us to conclude that H{sub DA} must be considered as a dynamical variable.« less

Lanthanide and transition metal complexes of bioactive coumarins: molecular modeling and spectroscopic studies.

PubMed

Georgieva, I; Mihaylov, Tz; Trendafilova, N

2014-06-01

The present paper summarizes theoretical and spectroscopic investigations on a series of active coumarins and their lanthanide and transition metal complexes with application in medicine and pharmacy. Molecular modeling as well as IR, Raman, NMR and electronic spectral simulations at different levels of theory were performed to obtain important molecular descriptors: total energy, formation energy, binding energy, stability, conformations, structural parameters, electron density distribution, molecular electrostatic potential, Fukui functions, atomic charges, and reactive indexes. The computations are performed both in gas phase and in solution with consideration of the solvent effect on the molecular structural and energetic parameters. The investigations have shown that the advanced computational methods are reliable for prediction of the metal-coumarin binding mode, electron density distribution, thermodynamic properties as well as the strength and nature of the metal-coumarin interaction (not experimentally accessible) and correctly interpret the experimental spectroscopic data. Known results from biological tests for cytotoxic, antimicrobial, anti-fungal, spasmolytic and anti-HIV activities on the studied metal complexes are reported and discussed. Copyright © 2014 Elsevier Inc. All rights reserved.

A 1-year drug utilization evaluation of protamine in hospitalized patients to identify possible future roles of heparin and low molecular weight heparin reversal agents.

PubMed

Mahan, Charles E

2014-04-01

Despite widespread use of unfractionated heparin (UFH) and low molecular weight heparin (LMWH), protamine sulfate remains the only reversal agent for UFH that is approved by the Food and Drug Administration within the US. Availability of new reversal agents for approved anticoagulants and those in development may improve patient safety and care. Delparantag (PMX-60056) is a novel small molecule that shows ability to neutralize the anticoagulation effects of UFH and LMWH in animals and humans. This study examined the 1-year utilization of protamine within an acute care hospital in order to determine the need for a novel reversing agent like delparantag. All patients having documented protamine administration within a 1-year period were included. Pharmacy automated dispensing machines and computerized medication management systems were queried for all doses of protamine withdrawn, billed for, or dispensed. Scanned medical records were reviewed and protamine and anticoagulant information was abstracted. Primary procedural group categorizations for protamine patients were coronary artery bypass graft, cardiac valve surgeries, abdominal aortic aneurysm and other open abdominal surgeries, fistula placement, non-cardiac vascular, cardiac catheter and electrophysiology lab, and "other." Average doses of protamine administered were 439, 423, 126, 26, 46, 36, and 35 mg in these groups, respectively. Four major bleeds and one serious adverse event occurred over the year period. Protamine is used in a wide array of procedures. Evaluating protamine's current use may be beneficial in identifying roles for future UFH and LMWH reversal agent use.

Apixaban: Effective and Safe in Preventing Thromboembolic Events in Patients with Atrial Fibrillation and Renal Failure.

PubMed

Cortese, Francesca; Scicchitano, Pietro; Gesualdo, Michele; Ricci, Gabriella; Carbonara, Santa; Franchini, Carlo; Pia Schiavone, Brigida Immacolata; Corbo, Filomena; Ciccone, Marco Matteo

2017-11-17

Thromboembolic events, principally stroke, represent one of the leading causes of morbidity and mortality among subjects with atrial fibrillation. Chronic kidney disease determines a further increase of thromboembolic events, bleeding and mortality and complicates the pharmacological management of patients with atrial fibrillation, mainly due to the side effects of antiarrhythmic and anticoagulant drugs with renal excretion. Apixaban is a new oral anticoagulant characterized by good bioavailability and renal elimination accounting for only 25%, showing a safety profile and effectiveness in patients with renal impairment. In this manuscript, we reviewed literature data on the use of apixaban in the management of non-valvular atrial fibrillation in patients with renal failure, in order to clarify an often-debated topic in clinical practice. A PubMed search was performed on the terms atrial fibrillation, apixaban and renal failure with the aim of identifying relevant manuscripts, large randomized clinical trials, meta-analyses, and current guidelines. Literature data show that apixaban could represent an interesting alternative to warfarin and other selective antagonists of coagulation factors in patients with impaired renal function. About the risk of major bleeding, apixaban appears to be safer than warfarin in the presence of any degree of renal failure. Apixaban show to be an effective anticoagulant in patients with atrial fibrillation, even superior to warfarin in reducing the risk of stroke and systemic embolism regardless of the presence of renal insufficiency. Moreover, Food and Drug Administration allows the use of apixaban in patients with end stage renal disease on hemodialysis. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

The Influence of Socioeconomic Status on Selection of Anticoagulation for Atrial Fibrillation.

PubMed

Sholzberg, Michelle; Gomes, Tara; Juurlink, David N; Yao, Zhan; Mamdani, Muhammad M; Laupacis, Andreas

2016-01-01

Without third-party insurance, access to marketed drugs is limited to those who can afford to pay. We examined this phenomenon in the context of anticoagulation for patients with nonvalvular atrial fibrillation (NVAF). To determine whether, among older Ontarians receiving anticoagulation for NVAF, patients of higher socioeconomic status (SES) were more likely to switch from warfarin to dabigatran prior to its addition to the provincial formulary. Population-based retrospective cohort study of Ontarians aged 66 years and older, between 2008 and 2012. Socioeconomic status, as approximated by median neighborhood income. We identified two groups of older adults with nonvalvular atrial fibrillation: those who appeared to switch from warfarin to dabigatran after its market approval but prior to its inclusion on the provincial formulary ("switchers"), and those with ongoing warfarin use during the same interval ("non-switchers"). We studied 34,797 patients, including 3183 "switchers" and 31,614 "non-switchers". We found that higher SES was associated with switching to dabigatran prior to its coverage on the provincial formulary (p<0.0001). In multivariable analysis, subjects in the highest quintile were 50% more likely to switch to dabigatran than those in the lowest income quintile (11.3% vs. 7.3%; adjusted odds ratio 1.50; 95% CI 1.32 to 1.68). Following dabigatran's addition to the formulary, the income gradient disappeared. We documented socioeconomic inequality in access to dabigatran among patients receiving warfarin for NVAF. This disparity was eliminated following the drug's addition to the provincial formulary, highlighting the importance of timely reimbursement decisions.

Photoreversible Covalent Hydrogels for Soft-Matter Additive Manufacturing.

PubMed

Kabb, Christopher P; O'Bryan, Christopher S; Deng, Christopher C; Angelini, Thomas E; Sumerlin, Brent S

2018-05-16

Reversible covalent chemistry provides access to robust materials with the ability to be degraded and reformed upon exposure to an appropriate stimulus. Photoresponsive units are attractive for this purpose, as the spatial and temporal application of light is easily controlled. Coumarin derivatives undergo a [2 + 2] cycloaddition upon exposure to long-wave UV irradiation (365 nm), and this process can be reversed using short-wave UV light (254 nm). Therefore, polymers cross-linked by coumarin groups are excellent candidates as reversible covalent gels. In this work, copolymerization of coumarin-containing monomers with the hydrophilic comonomer N, N-dimethylacrylamide yielded water-soluble, linear polymers that could be cured with long-wave UV light into free-standing hydrogels, even in the absence of a photoinitiator. Importantly, the gels were reverted back to soluble copolymers upon short-wave UV irradiation. This process could be cycled, allowing for recycling and remolding of the hydrogel into additional shapes. Further, this hydrogel can be imprinted with patterns through a mask-based, post-gelation photoetching method. Traditional limitations of this technique, such as the requirement for uniform etching in one direction, have been overcome by combining these materials with a soft-matter additive manufacturing methodology. In a representative application of this approach, we printed solid structures in which the interior coumarin-cross-linked gel is surrounded by a nondegradable gel. Upon exposure to short-wave UV irradiation, the coumarin-cross-linked gel was reverted to soluble prepolymers that were washed away to yield hollow hydrogel objects.

Inhibitory effects and structural insights for a novel series of coumarin-based compounds that selectively target human CA IX and CA XII carbonic anhydrases.

PubMed

De Luca, Laura; Mancuso, Francesca; Ferro, Stefania; Buemi, Maria Rosa; Angeli, Andrea; Del Prete, Sonia; Capasso, Clemente; Supuran, Claudiu T; Gitto, Rosaria

2018-01-01

Coumarin derivatives are a peculiar class of inhibitors of the family of metalloenzymes carbonic anhydrases (CA, EC 4.2.1.1). Several coumarins display higher affinity and selectivity toward most relevant and druggable CA isoforms. By decorating the natural compound umbelliferone (1) we have identified a new series of coumarin-based compounds demonstrating high CA inhibitory effects with nanomolar affinity for hCA IX and hCA XII isoforms that were considered a target amenable to develop antitumor agents. The most active tested compounds proved to be potent inhibitors with K i values equal to that of the well-known inhibitor acetazolamide (AAZ), that lacks selectivity over ubiquitous hCA I and hCA II. As suggested by docking studies the coumarins, that are lacking of the canonical metal binding groups, do not interact with Zinc ion within the catalytic site as found for classical sulfonamide type inhibitors of CAs. Thus, the studied inhibitors might possess a non-classical inhibitory mode of action preventing the carbon dioxide to entry into catalytic cavity and its conversion into bicarbonate ion. Specifically, the most active inhibitor of hCA XII compound 18i (K i value of 5.5 nM) and its supposed hydrolytic products could establish a web of H-bond interactions within the enzymatic cavity. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Pathological and biochemical evaluation of coumarin and chlorophyllin against aflatoxicosis in rat.

PubMed

Abdel-Latif, Mohamed S; Elmeleigy, Khaled M; Aly, Tahany A A; Khattab, Marwa S; Mohamed, Sara M

2017-06-14

Aflatoxin contamination of animal diet has adverse effects on animal health and productivity. This study was performed to investigate the effect of using coumarin and/or chlorophyllin in rat diet against aflatoxicosis. Fifty-four rats were assigned into 7 groups (6 rats each). G1 was a negative control. G2 received water with coumarin 0.5%. G3 received water with chlorophyllin 0.5%. G4 received water with coumarin 0.5% and chlorophyllin 0.5%. G5-8 fed aflatoxin B 1 1000ppb in diet. Group 6-8 were administered similar treatments as G2-4. The experiment ended after 8 weeks. Random glucose, total lipid, total cholesterol, total triglycerides, total protein, serum ALT, AST, creatinine, and urea were measured. Histopathology of liver, kidney and pancreas and immunohistochemical staining of placental glutathione-S-transferase (GST-P) in liver were performed. The glucose serum level, cholesterol, AST, and ALT were elevated in G5 compared to G6-8. The liver and kidney lesions in G5 included vacuolation and necrosis which subsided in G6-8. The necrosis and inflammatory cells infiltration in the pancreas of G5 were absent in G6-8. GST-P positive hepatocytes were abundant in G5, few in G6 and absent in G7 and G8. In conclusion, the chlorophyllin and coumarin possessed protective and anti-carcinogenic effect against aflatoxicosis in rats. Copyright © 2017 Elsevier GmbH. All rights reserved.

Ex Vivo and in Vivo Evaluation of the Effect of Coating a Coumarin-6-Labeled Nanostructured Lipid Carrier with Chitosan-N-acetylcysteine on Rabbit Ocular Distribution.

PubMed

Liu, Dandan; Li, Jinyu; Cheng, Bingchao; Wu, Qingyin; Pan, Hao

2017-08-07

This study is focused on further understanding the characteristics of chitosan-N-acetylcysteine surface-modified nanostructured lipid carriers (CS-NAC-NLCs) in their interaction with ocular mucosa. Coumarin-6 (C6)-labeled NLCs, including uncoated NLCs, chitosan hydrochloride (CH)-, and CS-NAC-coated NLCs, were developed using a melt-emulsification technique and subsequently decorated with different types or portions of chitosan derivatives. Mucoadhesion was evaluated ex vivo using a flow-through process with fluorescence detection. The results demonstrated that the presence of CS-NAC on the C6-NLC surface provided the most obvious enhancement in adhesion due to the formation of both noncovalent (ionic) and covalent (disulfide bridges) interactions with mucus chains. Meanwhile, the concentration of CS-NAC in the formulation positively influenced the viscosity of the nanoparticles and hence prolonged their retention in the ocular tissue. Transcorneal penetration studies revealed that CS-NAC-NLC particles were able to penetrate through the entire corneal epithelium primarily via a transcellular route. The transport depth and velocity strongly relied on the modification material and the particle size. Ex vivo fluorescence imaging and in vivo ocular distribution investigations showed that C6 was broadly distributed in rabbit eye tissues and absorbed by aqueous humor after CS-NAC-NLC instillation. In relation to C6 eye drops, CS-NAC-NLCs achieved considerably higher C max (4.01-fold), MRT 0-∞ (1.87-fold), and AUC 0-∞ (16.29-fold) in the aqueous humor. Moreover, the increase in drug absorption was greater in the cornea than in the conjunctiva. Thereby, it is possible to draw a conclusion that CS-NAC-NLCs presented great potential for drug application to the front portion of the eye.

[Cases of suspected poisoning in small animal practice - a retrospective and prospective survey].

PubMed

Allkämper, Svenja; Kösters, Sarah; Campe, Amely; Kietzmann, Manfred; Kreienbrock, Lothar

2018-06-01

Systematic survey of data from cases of suspected poisoning in small animal practices. In 11 exemplary selected small animal practices, patient files from cases of suspected poisoning over 2006/2007, data entry forms of poisonings 2009-2010 and the contact group, which are all patients with at least one visit in 2007, were analysed. In 2007, approximately 1 in 200 dog and 1 in 500 cat patients were presented with poisoning. More than 70 % of cases concerned dogs. Some breeds of hunting dogs were more frequently affected than expected from their percentage in the practice population. Suspicion of poisoning was retrospective mainly founded in neutered dogs. In addition to numerous unspecific symptoms, bleeding was frequently observed. With central nervous system symptoms or a critical general condition a founded suspicion was observed more frequently. In cases of unfounded suspicion, inflammation of the gastrointestinal tract was mostly present. Other frequently seen diseases were infections, tumours and autoimmune diseases. The main toxins in the retrospective evaluation were coumarin derivatives (37 %), drugs (10 %) and chocolate (7 %). The prospective survey yielded a higher percentage of poisoning with drugs and plants. The diagnosis was mainly based on case history and clinical signs. Therapy was predominantly symptomatic. Poisoning with coumarin derivatives is the most frequent intoxication in dogs, but also cats. The risk from permethrin for cats remains current. In daily practice, therapy is mostly symptomatic without any specific toxicological evidence. Consequently, the causative toxin is frequently unknown. Therefore, additional methods for elimination (stomach/rectal lavage, medical coal, lipid therapy) should be included as therapeutical options. For a successful systematic prospective survey in daily practice a good collaboration between practice and investigator is necessary. Schattauer GmbH.

IMM-H004, A New Coumarin Derivative, Improved Focal Cerebral Ischemia via Blood-Brain Barrier Protection in Rats.

PubMed

Niu, Fei; Song, Xiu-Yun; Hu, Jin-Feng; Zuo, Wei; Kong, Ling-Lei; Wang, Xiao-Feng; Han, Ning; Chen, Nai-Hong

2017-10-01

IMM-H004 (7-hydroxy-5-methoxy-4-methyl-3-[4-methylpiperazin-1-yl]-2H-chromen-2-one) is a novel coumarin derivative that showed better effect in improving global cerebral ischemia in rats. However, the effects and mechanisms in focal cerebral ischemia were not clear. Blood-brain barrier (BBB) protection is a vital strategy for the treatment of cerebral ischemia. This study is to investigate whether IMM-H004 improves brain ischemia injury via BBB protection. Focal brain ischemia model was induced by middle cerebral artery occlusion for 1 hour and reperfusion (MCAO/R) for 24 hours in rats. IMM-H004 (1.5, 3, 6 mg/kg) and edaravone (positive drug, 6 mg/kg) were administered after 5 minutes of occlusion. Neurological score and TTC staining were used to evaluate the effect of IMM-H004. Evans Blue (EB) staining and electron microscopy were used to assess BBB permeability. Western blot, reverse transcription-polymerase chain reaction, and immunohistochemistry were used to detect the expression of BBB structure-related proteins. Compared with the model group, IMM-H004 in the focal brain ischemia model improved neurological function and reduced cerebral infarction size and edema content. IMM-H004 sharply reduced the EB content and alleviated BBB structure. In addition, IMM-H004 increased the level of zonula occludens (ZO-1) and occluding, decreased the level of aquaporin 4 and matrix metalloproteinase 9, either in cortex or in hippocampus. And all of these changed were related to BBB protection. IMM-H004 improved cerebral ischemia injury via BBB protection. For a potential therapy drug of cerebral ischemia, IMM-H004 merits further study. Copyright © 2017. Published by Elsevier Inc.

Oviposition Deterrent Activities of Pachyrhizus erosus Seed Extract and Other Natural Products on Plutella xylostella (Lepidoptera: Plutellidae)

PubMed Central

Basukriadi, Adi; Wilkins, Richard M.

2014-01-01

Abstract An extract of a rotenone-containing plant yam bean, Pachyrhizus erosus (L.) Urban, seeds was tested against the diamondback moth, Plutella xylostella (L.) in a greenhouse to determine its potential as an oviposition deterrent and compared with coumarin and rutin, known as diamondback moth oviposition deterrent compounds, rotenone, and an extract of Peruvian cube root, at a concentration of 0.5% (w/v). Oviposition deterrent index (ODI) was used to determine effects of extracts or compounds in inhibiting oviposition of diamondback moth. Coumarin showed a stronger deterrent effect than the yam bean seed extract with a higher ODI value. On the contrary, rotenone, rutin, and the cube root extract, containing 6.7% (w/w) of rotenone, showed no significant deterrent effects having low or negative ODI values, suggesting that the deterrent effect of the yam bean seed extract is not due to rotenone content of the yam bean seeds. The extract of yam bean seed and coumarin partially deterred the moth from laying eggs on treated leaves in a concentration-dependent manner. The effective concentration for 50% deterrency of coumarin and the yam bean seed extract were 0.11 and 0.83% (w/v), respectively. However, the yam bean seed extract showed a residual deterrent effect on the moth even at 3 d after the treatment and is probably because of its low volatile nature. A long-term deterrency of the yam bean seed extract is an advantage over coumarins. Both the yam bean seed extract and coumarin deterred diamondback moth from laying eggs in total darkness, indicating their nonvisual deterrent effect. This made the extract an effective deterrence to diamondback moth in light and in darkness. To conclude, this study revealed the potential of the crude extract of the yam bean seed to prevent diamondback moth from ovipositing on its plant host. PMID:25525107

Oviposition deterrent activities of Pachyrhizus erosus seed extract and other natural products on Plutella xylostella (Lepidoptera: Plutellidae).

PubMed

Basukriadi, Adi; Wilkins, Richard M

2014-01-01

An extract of a rotenone-containing plant yam bean, Pachyrhizus erosus (L.) Urban, seeds was tested against the diamondback moth, Plutella xylostella (L.) in a greenhouse to determine its potential as an oviposition deterrent and compared with coumarin and rutin, known as diamondback moth oviposition deterrent compounds, rotenone, and an extract of Peruvian cube root, at a concentration of 0.5% (w/v). Oviposition deterrent index (ODI) was used to determine effects of extracts or compounds in inhibiting oviposition of diamondback moth. Coumarin showed a stronger deterrent effect than the yam bean seed extract with a higher ODI value. On the contrary, rotenone, rutin, and the cube root extract, containing 6.7% (w/w) of rotenone, showed no significant deterrent effects having low or negative ODI values, suggesting that the deterrent effect of the yam bean seed extract is not due to rotenone content of the yam bean seeds. The extract of yam bean seed and coumarin partially deterred the moth from laying eggs on treated leaves in a concentration-dependent manner. The effective concentration for 50% deterrency of coumarin and the yam bean seed extract were 0.11 and 0.83% (w/v), respectively. However, the yam bean seed extract showed a residual deterrent effect on the moth even at 3 d after the treatment and is probably because of its low volatile nature. A long-term deterrency of the yam bean seed extract is an advantage over coumarins. Both the yam bean seed extract and coumarin deterred diamondback moth from laying eggs in total darkness, indicating their nonvisual deterrent effect. This made the extract an effective deterrence to diamondback moth in light and in darkness. To conclude, this study revealed the potential of the crude extract of the yam bean seed to prevent diamondback moth from ovipositing on its plant host. © The Author 2014. Published by Oxford University Press on behalf of the Entomological Society of America.

Cloning, Functional Characterization and Site-Directed Mutagenesis of 4-Coumarate: Coenzyme A Ligase (4CL) Involved in Coumarin Biosynthesis in Peucedanum praeruptorum Dunn

PubMed Central

Liu, Tingting; Yao, Ruolan; Zhao, Yucheng; Xu, Sheng; Huang, Chuanlong; Luo, Jun; Kong, Lingyi

2017-01-01

Coumarins are the main bioactive compounds in Peucedanum praeruptorum Dunn, a common Chinese herbal medicine. Nevertheless, the genes involved in the biosynthesis of core structure of coumarin in P. praeruptorum have not been identified yet. 4-Coumarate: CoA ligase (4CL) catalyzes the formation of hydroxycinnamates CoA esters, and plays an essential role at the divergence point from general phenylpropanoid metabolism to major branch pathway of coumarin. Here, three novel putative 4CL genes (Pp4CL1, Pp4CL7, and Pp4CL10) were isolated from P. praeruptorum. Biochemical characterization of the recombinant proteins revealed that Pp4CL1 utilized p-coumaric and ferulic acids as its two main substrates for coumarin biosynthesis in P. praeruptorum. Furthermore, Pp4CL1 also exhibited activity toward caffeic, cinnamic, isoferulic, and o-coumaric acids and represented a bona fide 4CL. Pp4CL7 and Pp4CL10 had no catalytic activity toward hydroxycinnamic acid compounds. But they had close phylogenetic relationship to true 4CLs and were defined as 4CL-like genes. Among all putative 4CLs, Pp4CL1 was the most highly expressed gene in roots, and its expression level was significantly up-regulated in mature roots compared with seedlings. Subcellular localization studies showed that Pp4CL1 and Pp4CL10 proteins were localized in the cytosol. In addition, site-directed mutagenesis of Pp4CL1 demonstrated that amino acids of Tyr-239, Ala-243, Met-306, Ala-309, Gly-334, Lys-441, Gln-446, and Lys-526 were essential for substrate binding or catalytic activities. The characterization and site-directed mutagenesis studies of Pp4CL1 lays a solid foundation for elucidating the biosynthetic mechanisms of coumarins in P. praeruptorum and provides further insights in understanding the structure–function relationships of this important family of proteins. PMID:28144249

Non-Vitamin K Oral Anticoagulants (NOACs) A Review of Clinical Management and Laboratory Issues.

PubMed

Blann, Andrew

2016-01-01

The non-vitamin K oral anticoagulants (NOACs) are set to replace vitamin K antagonists (principally warfarin), unfractionated heparin and low molecular weight heparin as the leading antithrombotic prophylaxis in several medical and surgical settings. As a group, NOACs have a better safety profile and at least an equivalent (and sometimes superior) efficacy profile than their comparator. The objective of this review is to provide the practitioner with a comprehensive, balanced and contemporary view of these drugs and their applications. More specifically, it focuses on the evidence base for their licences, use in clinical practice (such as in renal dysfunction, orthopaedic surgery, atrial fibrillation, and venous thromboembolism, and the effects of co-medications), responses to actual or perceived haemorrhage, and the role of the laboratory.

Atrial fibrillation and stroke: the evolving role of rhythm control.

PubMed

Patel, Taral K; Passman, Rod S

2013-06-01

Atrial fibrillation (AF) remains a major risk factor for stroke. Unfortunately, clinical trials have failed to demonstrate that a strategy of rhythm control--therapy to maintain normal sinus rhythm (NSR)--reduces stroke risk. The apparent lack of benefit of rhythm control likely reflects the difficulty in maintaining NSR using currently available therapies. However, there are signals from several trials that the presence of NSR is indeed beneficial and associated with better outcomes related to stroke and mortality. Most electrophysiologists feel that as rhythm control strategies continue to improve, the crucial link between rhythm control and stroke reduction will finally be demonstrated. Therefore, AF specialists tend to be aggressive in their attempts to maintain NSR, especially in patients who have symptomatic AF. A step-wise approach from antiarrhythmic drugs to catheter ablation to cardiac surgery is generally used. In select patients, catheter ablation or cardiac surgery may supersede antiarrhythmic drugs. The choice depends on the type of AF, concurrent heart disease, drug toxicity profiles, procedural risks, and patient preferences. Regardless of strategy, given the limited effectiveness of currently available rhythm control therapies, oral anticoagulation is still recommended for stroke prophylaxis in AF patients with other stroke risk factors. Major challenges in atrial fibrillation management include selecting patients most likely to benefit from rhythm control, choosing specific antiarrhythmic drugs or procedures to achieve rhythm control, long-term monitoring to gauge the efficacy of rhythm control, and determining which (if any) patients may safely discontinue anticoagulation if long-term NSR is achieved.

Novel factor Xa inhibitors: a patent review.

PubMed

de Candia, Modesto; Lopopolo, Gianfranco; Altomare, Cosimo

2009-11-01

New oral anticoagulants with favorable safety profiles and fixed doses are required for the management of thromboembolism and stroke prevention in patients with atrial fibrillation. Among them, fXa inhibitors (the so-called xabans) are attractive options that can overcome limitations (e.g., bleeding) of the current oral antithrombotic therapy. The rational design of small-molecule direct fXa inhibitors, whose importance is testified by the growing number of publications and patents recently registered, has been fully supported by the X-ray crystallography of enzyme-ligand complexes. Pubmed, SciFinder Scholar, ISI web of knowledge(SM), http://ep.espacenet.com/ and Google websites were used as the main sources for literature retrieving, and > 100 patents filed between 2006 and April 2009, reviewed and discussed herein, highlight the variety among the P1 and P4 moieties on suitable scaffolds. The replacement of the benzamidine P1 moiety, which characterizes the first generation, with less basic bioisosteric or nonpolar neutral P1 groups led to the disclosure of numerous fXa inhibitors with high potency, selectivity and oral bioavailability. Novel selective fXa inhibitors with stable pharmacokinetics, better therapeutic windows and ease-of-use than the existing anticoagulants are currently under advanced stage clinical trials. Available data from Phase II and Phase III studies reflect the drive towards fXa inhibitors as potentially more effective and safer antithrombotic drugs. Their development is expected to address two major needs for anticoagulation, namely safety and ease-of-use, and to significantly affect the anticoagulant market.

Aligning health care policy with evidence-based medicine: the case for funding direct oral anticoagulants in atrial fibrillation.

PubMed

Stone, James A; Earl, Karen M; O'Neill, Blair J; Sharma, Mukul; Huynh, Thao; Leblanc, Kori; Ward, Richard; Teal, Philip A; Cox, Jafna L

2014-10-01

Misalignment between evidence-informed clinical care guideline recommendations and reimbursement policy has created care gaps that lead to suboptimal outcomes for patients denied access to guideline-based therapies. The purpose of this article is to make the case for addressing this growing access barrier to optimal care. Stroke prevention in atrial fibrillation (AF) is discussed as an example. Stroke is an extremely costly disease, imposing a significant human, societal, and economic burden. Stroke in the setting of AF carries an 80% probability of death or disability. Although two-thirds of these strokes are preventable with appropriate anticoagulation, this has historically been underprescribed and poorly managed. National and international guidelines endorse the direct oral anticoagulants as first-line therapy for this indication. However, no Canadian province has provided these agents with an unrestricted listing. These decisions appear to be founded on silo-based cost assessment-the drug costs rather than the total system costs-and thus overlook several important cost-drivers in stroke. The discordance between best scientific evidence and public policy requires health care providers to use a potentially suboptimal therapy in contravention of guideline recommendations. It represents a significant obstacle for knowledge translation efforts that aim to increase the appropriate anticoagulation of Canadians with AF. As health care professionals, we have a responsibility to our patients to engage with policy-makers in addressing and resolving this barrier to optimal patient care. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Fitting the right non-vitamin K antagonist oral anticoagulant to the right patient with non-valvular atrial fibrillation: an evidence-based choice.

PubMed

Li, Yan-Guang; Pastori, Daniele; Lip, Gregory Y H

2018-06-01

Atrial fibrillation (AF) is the most prevalent arrhythmia and is associated with an increased risk of ischemic stroke (IS) and systemic embolism (SE). Stroke prevention is a key element for the overall management of AF patients. The non-vitamin K antagonist oral anticoagulants (NOACs), such as dabigatran, rivaroxaban, apixaban and edoxaban, are at least as effective as warfarin in reducing IS/SE with a lower rate of major bleeding. Various analyses from the large Phase III randomized trials demonstrated different efficacy and safety of NOACs in specific subgroups of patients. The randomized trials are supplemented by effectiveness and safety data from real-world observational cohorts following the availability of these drugs for use in everyday clinical practice. Given the clinical heterogeneity of AF patients, the available data from trials and real-world studies allow us to fit the right NOAC to the particular patient's characteristics, with the aim of optimizing outcomes for the individual patient. This review article aims to provide a summary of the evidence on the performance of NOACs in AF patients with specific clinical characteristics. Evidence-based suggestions are presented to provide a simple and viable strategy for clinicians for the choice of a particular NOAC. KEY MESSAGE Given the different performance of the new-oral anticoagulants in patients with the different clinical situation, evidence-based choice of fitting the right new-oral anticoagulants to the patients is provided in this review article.

NOACs replace VKA as preferred oral anticoagulant among new patients: a drug utilization study in 560 pharmacies in The Netherlands.

PubMed

van den Heuvel, J M; Hövels, A M; Büller, H R; Mantel-Teeuwisse, A K; de Boer, A; Maitland-van der Zee, A H

2018-01-01

In 2012, around 400.000 patients in the Netherlands were treated with Vitamin K Antagonists (VKA) for thromboembolic diseases. Since 2011, non-VKA oral anticoagulants (NOACs) are available. NOACs do not require frequent INR monitoring which benefits patients, but also imposes a risk of reduced therapy adherence. The objective of this study is to describe uptake and patient adherence of NOACs in The Netherlands until October 2016. Prescription data for 247.927 patients across 560 pharmacies were used to describe patient profiles, uptake of NOACs among new naive patients and switch between VKA and NOACs, and calculate therapy adherence as the Proportion of Days Covered (PDC). During the studied period the share of NOACs in oral anticoagulants has grown to 57% of prescriptions to new patients. More than 70% of new NOAC users were new naive patients and around 26% switched from VKA. The overall share of NOACs among starters is largest in the group of patients of 50-80 years. Calculated compliance rate for NOAC patients shows that 88% of all users are adherent with a PDC higher than 80%. NOAC have overtaken VKA as the major treatment prescribed to new oral anticoagulant patients, and the number of starters on VKA is decreasing. Patients are generally adherent to NOACs during the implementation phase, the period that the medication is used. Fear for inadherence by itself does not need to be a reason for not prescribing NOACs instead of VKA.

The N-terminal-truncated recombinant fibrin(ogen)olytic serine protease improves its functional property, demonstrates in vivo anticoagulant and plasma defibrinogenation activity as well as pre-clinical safety in rodent model.

PubMed

Bora, Bandana; Gogoi, Debananda; Tripathy, Debabrata; Kurkalang, Sillarine; Ramani, Sheetal; Chatterjee, Anupam; Mukherjee, Ashis K

2018-05-01

An N-terminal truncated fibrino(geno)lytic serine protease gene encoding a ~42kDa protein from Bacillus cereus strain AB01 was produced by error prone PCR, cloned into pET19b vector, and expressed in E5 coli BL21 DE3 cells. The deletion of 24 amino acid residues from N-terminal of wild-type Bacifrinase improves the catalytic activity of [Bacifrinase (ΔN24)]. The anticoagulant potency of [Bacifrinase (ΔN24)] was comparable to Nattokinase and Warfarin and results showed that its anticoagulant action is contributed by progressive defibrinogenation and antiplatelet activities. Nonetheless, at the tested concentration of 2.0μM [Bacifrinase (ΔN24)] did not show in vitro cytotoxicity or chromosomal aberrations on human embryonic kidney cells-293 (HEK-293) and human peripheral blood lymphocytes (HPBL) cells. [Bacifrinase (ΔN24)], at a dose of 2mg/kg, did not show toxicity, adverse pharmacological effects, tissue necrosis or hemorrhagic effect after 72h of its administration in Swiss albino mice. However, at the tested doses of 0.125 to 0.5mg/kg, it demonstrated significant in anticoagulant effect as well as defibrinogenation after 6h of administration in mice. We propose that [Bacifrinase (ΔN24)] may serve as prototype for the development of potent drug to prevent hyperfibrinogenemia related disorders. Copyright © 2018 Elsevier B.V. All rights reserved.

Co-sensitization of ruthenium(II) dye-sensitized solar cells by coumarin based dyes

NASA Astrophysics Data System (ADS)

Athanas, Anish Babu; Thangaraj, Shankar; Kalaiyar, Swarnalatha

2018-05-01

Co-sensitization technique has been appraised for attaining enhanced performance in dye-sensitized solar cells (DSSCs). DSSCs are fabricated with a heteroleptic Ru(II) sensitizer (RDAB1) containing 4,4‧-diamino-2,2‧-bipyridine (dabpy) ligand, co-sensitized with electron donor-acceptor type coumarin containing thiophene (CT) and indole (CI) moieties. The individual overall power conversion efficiency of the sensitizer is 5.44%. Enhanced power conversion efficiencies of 6.34% and 7.09% were observed when RDAB1 was co-sensitized with Coumarin containing CI and CT respectively. The enhanced PCE can be attributed to the presence of co-sensitizers which effectively overcome the light absorption by I-/I3-, dye aggregation and charge recombination.

The design, synthesis, and evaluation of coumarin ring derivatives of the novobiocin scaffold that exhibit antiproliferative activity.

PubMed

Donnelly, Alison C; Mays, Jared R; Burlison, Joseph A; Nelson, John T; Vielhauer, George; Holzbeierlein, Jeffrey; Blagg, Brian S J

2008-11-21

Novobiocin, a known DNA gyrase inhibitor, binds to a nucleotide-binding site located on the Hsp90 C-terminus and induces degradation of Hsp90-dependent client proteins at approximately 700 microM in breast cancer cells (SKBr3). Although many analogues of novobiocin have been synthesized, it was only recently demonstrated that monomeric species exhibit antiproliferative activity against various cancer cell lines. To further refine the essential elements of the coumarin core, a series of modified coumarin derivatives was synthesized and evaluated to elucidate structure-activity relationships for novobiocin as an anticancer agent. Results obtained from these studies have produced novobiocin analogues that manifest low micromolar activity against several cancer cell lines.

Coumarin-BODIPY hybrids by heteroatom linkage: versatile, tunable and photostable dye lasers for UV irradiation.

PubMed

Esnal, I; Duran-Sampedro, G; Agarrabeitia, A R; Bañuelos, J; García-Moreno, I; Macías, M A; Peña-Cabrera, E; López-Arbeloa, I; de la Moya, S; Ortiz, M J

2015-03-28

Linking amino and hydroxycoumarins to BODIPYs through the amino or hydroxyl group lets the easy construction of unprecedented photostable coumarin-BODIPY hybrids with broadened and enhanced absorption in the UV spectral region, and outstanding wavelength-tunable laser action within the green-to-red spectral region (∼520-680 nm). These laser dyes allow the generation of a valuable tunable UV (∼260-350 nm) laser source by frequency doubling, which is essential to study accurately the photochemistry of biological molecules under solar irradiation. The tunability is achieved by selecting the substitution pattern of the hybrid. Key factors are the linking heteroatom (nitrogen vs. oxygen), the number of coumarin units joined to the BODIPY framework and the involved linking positions.

Anti-inflammatory and antimicrobial coumarins from the stems of Eurya chinensis.

PubMed

Song, Jia-Ling; Yuan, Yao; Tan, Hai-Bo; Huang, Ri-Ming; Liu, Hong-Xin; Xu, Zhi-Fang; Qiu, Sheng-Xiang

2017-03-01

Two new coumarins, named (±)-euryacoumarin A (1) and 6-demethylobtusinin (2), and one new natural coumarin, named euryacoumarin B (3), along with two known compounds, scopoletin (4) and obtusinol (5), were isolated from the stems of Eurya chinensis. Their structures were elucidated by means of extensive spectroscopic methods and comparison with data reported in the literatures. Compound 1 exhibited significant inhibition of LPS-induced nitric oxide (NO) production in RAW264.7 cells with IC 50 value of 35.64 ± 1.73 μM, and showed marginal antibacterial activities against Bacillus subtilis and B. cereus with MIC values of 50.59 ± 2.12 and 35.42 ± 0.96 μM, respectively.

Optical gain characteristics of C 460 and C 450.

PubMed

Sharma, Vijay K; Sahare, P D; Pandey, A; Mohan, D

2003-03-15

Dye concentration dependent gain spectra for Coumarin 460 (C 460) and Coumarin 450 (C 450) in ethanol have been studied using Amplified Spontaneous Emission (ASE) technique under Nitrogen laser (337.1 nm) excitation in the concentration range 10(-2)-10(-5) m/l. The dependence of lasing wavelength and peak gain on concentration have been understood in terms of variation of fluorescence lifetime, which is due to photo-physical processes such as radiation trapping and concentration-quenching. Pump intensity dependence of efficiency is also explained in terms of fluorescence lifetime. A comparison of the stability of the two dyes has also been made on the basis of the functional groups at different positions of the basic coumarin. Copyright 2002 Elsevier Science B.V.

Atropisomerisation in sterically hindered α,β-disubstituted cyclopentenones derived from an intermolecular cobalt(0)-mediated Pauson-Khand reaction.

PubMed

Moulton, Benjamin E; Lynam, Jason M; Duhme-Klair, Anne-Kathrin; Zheng, Wenxu; Lin, Zhenyang; Fairlamb, Ian J S

2010-12-07

4-(2-Phenylethynyl)-2H-chromen-2-one reacts with norbornene and Co(2)(CO)(8) in an intermolecular Pauson-Khand reaction by focused microwave dielectric heating. Two regioisomeric products are formed; the electron-deficient coumarin moiety preferentially occupies the β-position of the cyclopentenone ring system, whereas the phenyl occupies the α-position. The sterically hindered α,β-(2,3)-disubstituted cyclopentenone regioisomeric products exhibit pronounced atropisomerisation, and the magnitude of the energetic barrier to interconversion between these atropisomers is dependent on the relative position of the coumarin moieties. Interconversion is slow when the coumarin is found in the α-position, whereas interconversion is relatively fast when found in the β-position.

[Study of the interaction mechanism between brodifacoum and DNA by spectroscopy].

PubMed

Duan, Yun-qing; Min, Shun-geng

2009-04-01

The interaction between brodifacoum (3-[3-(4'-bromophenyl-4) 1,2,3,4-tetralin-10]-4-hydroxyl-coumarin) (BDF), an anticoagulant rodenticide, and calf thymus DNA (ct-DNA) was studied by UV spectrum and fluorescence spectrum. The results were summarized as follows: There was a hypochromic effect of low concentration ct-DNA on the UV spectra. The fluorescence quenching studies showed a regular decrease in the fluorescence intensity after addition of ct-DNA by the static quenching mode with a quenching constant (Ksv) of 1.21 x 10(4) L x mol(-1) at 27 degrees C. The BDF possibly bonded to ct-DNA mainly via Van der Waals forces by the corresponding thermodynamics parameter. KI quenching experiment found that there was not obvious protection of ct-DNA to BDF. The fluorescence intensity of BDF/ct-DNA system changed with the variation in ionic strength Quenching of ct-DNA on the fluorescence of BDF/beta-CD inclusion complex was reduced in contrast with the free BDF, which showed that beta-CD could provide BDF with protection. So the comprehensive interaction mode of BDF with ct-DNA may be the groove binding by the above results. It was indicated that there had been static-electro interaction between BDF and ct-DNA at the same time. The conjunct action of Van der Waals forces and electrostatic attraction favorably provide BDF bonding interaction in the groove of ct-DNA.

Nanoparticles and the blood coagulation system. Part II: safety concerns

PubMed Central

Ilinskaya, Anna N; Dobrovolskaia, Marina A

2014-01-01

Nanoparticle interactions with the blood coagulation system can be beneficial or adverse depending on the intended use of a nanomaterial. Nanoparticles can be engineered to be procoagulant or to carry coagulation-initiating factors to treat certain disorders. Likewise, they can be designed to be anticoagulant or to carry anticoagulant drugs to intervene in other pathological conditions in which coagulation is a concern. An overview of the coagulation system was given and a discussion of a desirable interface between this system and engineered nanomaterials was assessed in part I, which was published in the May 2013 issue of Nanomedicine. Unwanted pro- and anti-coagulant properties of nanoparticles represent significant concerns in the field of nanomedicine, and often hamper the development and transition into the clinic of many promising engineered nanocarriers. This part will focus on the undesirable effects of engineered nanomaterials on the blood coagulation system. We will discuss the relationship between the physicochemical properties of nanoparticles (e.g., size, charge and hydrophobicity) that determine their negative effects on the blood coagulation system in order to understand how manipulation of these properties can help to overcome unwanted side effects. PMID:23730696

Understanding and Managing Atrial Fibrillation in Patients with Kidney Disease.

PubMed

Khouri, Yazan; Stephens, Tiona; Ayuba, Gloria; AlAmeri, Hazim; Juratli, Nour; McCullough, Peter A

2015-01-01

Chronic kidney disease (CKD) is on the rise due to the increased rate of related comorbidities such as diabetes and hypertension. Patients with CKD are at higher risk of cardiovascular events and atrial fibrillation is more common in this patient population. It is estimated that the prevalence of chronic atrial fibrillation in patients with CKD is two to three times higher than general population. Furthermore, patients with CKD are less likely to stay in sinus rhythm. Atrial fibrillation presents a major burden in this population due to difficult treatment decisions in the setting of a lack of evidence from randomized clinical trials. Patients with CKD have higher risk of stroke with more than half having a CHADS2 score ≥ 2. Anticoagulation have been shown to significantly decrease embolic stroke risk, however bleeding complications such as hemorrhagic stroke is twofold higher with warfarin. Although newer novel anticoagulation drugs have shown promise with lower intracranial hemorrhage risk in comparison to warfarin, lack clinical trial data in CKD and the unavailability of an antidote remains an issue. In this review, we discuss the treatment options available including anticoagulation and the evidence behind them in patients with chronic kidney disease suffering from atrial fibrillation.

MECHANISM OF THE HEMORRHAGIC PHENOMENON PRODUCED IN MALE RATS BY FEEDING OF IRRADIATED BEEF. Progress Report No. 5, March 15, 1960 to September 15, 1960

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mellette, S.J.

Studies of the difference between male and female animals in susceptibility to hypoprothrombinemia and hemorrhage were continued with animals fed irradiated beef diets and extended to include other diets and also the administration of anticoagulant drugs. Sex differences similar to those of animals fed beef diets are demonstrated in rats receiving a commercial stock diet. A considerable difference was found between two commercial diets in terms of the maintenance of normal coagulation factors. Male animals in several age ranges were found to be more sensitive to the effect of large single doses of the anticoagulant warfarin sodium (coumadin) than aremore » females. Pre-treatment with estradiol benzoate improved the prothrombin levels and the survival of male rats receiving the anticoagulant. A greater mortality after coumadin occurred in females pre-treated with androgens. A/sub c/G levels decreased during continued administration of testosterone to females fed stock as well as beef diets. Strain differences in prothrombin were also noted, and estrogenic activity was demonstrated for both menadione and K/sub i/. (P.C.H.)« less

Recommendations for the use of new oral anticoagulants (NOACs) after TIA or stroke caused by atrial fibrillation (AF), after a consensus conference among Italian neurologists (the Venice group).

PubMed

Toso, Vito

2014-05-01

Vascular neurologists of Veneto and Friuli Venezia Giulia, north-east regions of Italy, have sought an agreement on the two following questions: (A) what prophylactic treatment should we recommend to patients with a stroke ascribed to atrial fibrillation (AF), who were not previously on antithrombotic treatment, to prevent further strokes? (B) What should we do in the event of an ischemic or hemorrhagic stroke associated with AF in patients who were already on antithrombotic treatment? There was a unanimous consensus for preferring the new oral anticoagulants (NOACs) in patients not taking any antithrombotics and in cases treated with antithrombotic drugs (coumadin and/or antiplatelets), due to a lower incidence of intracranial bleeding complications and a noninferiority for recurrent stroke or TIA. Even after intracranial bleeding complications, when it is useful or necessary to continue anticoagulant treatment, the group of experts preferred the NOACs, suggesting, however, to be very cautious in cases with widespread leukoaraiosis or microbleeds, practice frequent monitoring of creatinine clearance (CrCl) and avoid using NOACs when CrCl is <30 mL/min.

Ibrutinib-associated bleeding: pathogenesis, management and risk reduction strategies.

PubMed

Shatzel, J J; Olson, S R; Tao, D L; McCarty, O J T; Danilov, A V; DeLoughery, T G

2017-05-01

Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase (Btk) that has proven to be an effective therapeutic agent for multiple B-cell-mediated lymphoproliferative disorders. Ibrutinib, however, carries an increased bleeding risk compared with standard chemotherapy. Bleeding events range from minor mucocutaneous bleeding to life-threatening hemorrhage, due in large part to the effects of ibrutinib on several distinct platelet signaling pathways. There is currently a minimal amount of data to guide clinicians regarding the use of ibrutinib in patients at high risk of bleeding or on anticoagulant or antiplatelet therapy. In addition, the potential cardiovascular protective effects of ibrutinib monotherapy in patients at risk of vascular disease are unknown. Patients should be cautioned against using non-steroidal anti-inflammatory drugs, fish oils, vitamin E and aspirin-containing products, and consider replacing ibrutinib with a different agent if dual antiplatelet therapy is indicated. Patients should not take vitamin K antagonists concurrently with ibrutinib; direct oral anticoagulants should be used if extended anticoagulation is strongly indicated. In this review, we describe the pathophysiology of ibrutinib-mediated bleeding and suggest risk reduction strategies for common clinical scenarios associated with ibrutinib. © 2017 International Society on Thrombosis and Haemostasis.

Outcomes of temporary interruption of rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: results from the rivaroxaban once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation (ROCKET AF).

PubMed

Sherwood, Matthew W; Douketis, James D; Patel, Manesh R; Piccini, Jonathan P; Hellkamp, Anne S; Lokhnygina, Yuliya; Spyropoulos, Alex C; Hankey, Graeme J; Singer, Daniel E; Nessel, Christopher C; Mahaffey, Kenneth W; Fox, Keith A A; Califf, Robert M; Becker, Richard C

2014-05-06

During long-term anticoagulation in atrial fibrillation, temporary interruptions (TIs) of therapy are common, but the relationship between patient outcomes and TIs has not been well studied. We sought to determine reasons for TI, the characteristics of patients undergoing TI, and the relationship between anticoagulant and outcomes among patients with TI. In the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF), a randomized, double-blind, double-dummy study of rivaroxaban and warfarin in nonvalvular atrial fibrillation, baseline characteristics, management, and outcomes, including stroke, non-central nervous system systemic embolism, death, myocardial infarction, and bleeding, were reported in participants who experienced TI (3-30 days) for any reason. The at-risk period for outcomes associated with TI was from TI start to 30 days after resumption of study drug. In 14 236 participants who received at least 1 dose of study drug, 4692 (33%) experienced TI. Participants with TI were similar to the overall ROCKET AF population in regard to baseline clinical characteristics. Only 6% (n=483) of TI incidences involved bridging therapy. Stroke/systemic embolism rates during the at-risk period were similar in rivaroxaban-treated and warfarin-treated participants (0.30% versus 0.41% per 30 days; hazard ratio [confidence interval]=0.74 [0.36-1.50]; P=0.40). Risk of major bleeding during the at-risk period was also similar in rivaroxaban-treated and warfarin-treated participants (0.99% versus 0.79% per 30 days; hazard ratio [confidence interval]=1.26 [0.80-2.00]; P=0.32). TI of oral anticoagulation is common and is associated with substantial stroke risks and bleeding risks that were similar among patients treated with rivaroxaban or warfarin. Further investigation is needed to determine the optimal management strategy in patients with atrial fibrillation requiring TI of anticoagulation. http://www.clinicaltrials.gov. Unique identifier: NCT00403767.

Outcomes of Temporary Interruption of Rivaroxaban Compared With Warfarin in Patients With Nonvalvular Atrial Fibrillation

PubMed Central

Sherwood, Matthew W.; Douketis, James D.; Patel, Manesh R.; Piccini, Jonathan P.; Hellkamp, Anne S.; Lokhnygina, Yuliya; Spyropoulos, Alex C.; Hankey, Graeme J.; Singer, Daniel E.; Nessel, Christopher C.; Mahaffey, Kenneth W.; Fox, Keith A. A.; Califf, Robert M.; Becker, Richard C.

2014-01-01

Background During long-term anticoagulation in atrial fibrillation, temporary interruptions (TIs) of therapy are common, but the relationship between patient outcomes and TIs has not been well studied. We sought to determine reasons for TI, the characteristics of patients undergoing TI, and the relationship between anticoagulant and outcomes among patients with TI. Methods and Results In the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF), a randomized, double-blind, double-dummy study of rivaroxaban and warfarin in nonvalvular atrial fibrillation, baseline characteristics, management, and outcomes, including stroke, non–central nervous system systemic embolism, death, myocardial infarction, and bleeding, were reported in participants who experienced TI (3–30 days) for any reason. The at-risk period for outcomes associated with TI was from TI start to 30 days after resumption of study drug. In 14 236 participants who received at least 1 dose of study drug, 4692 (33%) experienced TI. Participants with TI were similar to the overall ROCKET AF population in regard to baseline clinical characteristics. Only 6% (n=483) of TI incidences involved bridging therapy. Stroke/systemic embolism rates during the at-risk period were similar in rivaroxaban-treated and warfarin-treated participants (0.30% versus 0.41% per 30 days; hazard ratio [confidence interval]=0.74 [0.36–1.50]; P=0.40). Risk of major bleeding during the at-risk period was also similar in rivaroxaban-treated and warfarin-treated participants (0.99% versus 0.79% per 30 days; hazard ratio [confidence interval]=1.26 [0.80–2.00]; P=0.32). Conclusions TI of oral anticoagulation is common and is associated with substantial stroke risks and bleeding risks that were similar among patients treated with rivaroxaban or warfarin. Further investigation is needed to determine the optimal management strategy in patients with atrial fibrillation requiring TI of anticoagulation. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00403767. PMID:24552831

High-throughput screening of PLGA thin films utilizing hydrophobic fluorescent dyes for hydrophobic drug compounds.

PubMed

Steele, Terry W J; Huang, Charlotte L; Kumar, Saranya; Widjaja, Effendi; Chiang Boey, Freddy Yin; Loo, Joachim S C; Venkatraman, Subbu S

2011-10-01

Hydrophobic, antirestenotic drugs such as paclitaxel (PCTX) and rapamycin are often incorporated into thin film coatings for local delivery using implantable medical devices and polymers such as drug-eluting stents and balloons. Selecting the optimum coating formulation through screening the release profile of these drugs in thin films is time consuming and labor intensive. We describe here a high-throughput assay utilizing three model hydrophobic fluorescent compounds: fluorescein diacetate (FDAc), coumarin-6, and rhodamine 6G that were incorporated into poly(d,l-lactide-co-glycolide) (PLGA) and PLGA-polyethylene glycol films. Raman microscopy determined the hydrophobic fluorescent dye distribution within the PLGA thin films in comparison with that of PCTX. Their subsequent release was screened in a high-throughput assay and directly compared with HPLC quantification of PCTX release. It was observed that PCTX controlled-release kinetics could be mimicked by a hydrophobic dye that had similar octanol-water partition coefficient values and homogeneous dissolution in a PLGA matrix as the drug. In particular, FDAc was found to be the optimal hydrophobic dye at modeling the burst release as well as the total amount of PCTX released over a period of 30 days. Copyright © 2011 Wiley-Liss, Inc.

Monitoring of anticoagulant therapy in heart disease: considerations for the current assays.

PubMed

Boroumand, Mohammadali; Goodarzynejad, Hamidreza

2010-01-01

Clinicians should be aware of new developments to familiarize themselves with pharmacokinetic and pharmacodynamic characteristics of new anticoagulant agents to appropriately and safely use them. For the moment, cardiologists and other clinicians also require to master currently available drugs, realizing the mechanism of action, side effects, and laboratory monitoring to measure their anticoagulant effects. Warfarin and heparin have narrow therapeutic window with high inter- and intra-patient variability, thereby the use of either drug needs careful laboratory monitoring and dose adjustment to ensure proper antithrombotic protection while minimizing the bleeding risk. The prothrombin time (PT) and the activated partial thromboplastin time (aPTT) are laboratory tests commonly used to monitor warfarin and heparin, respectively. These two tests depend highly on the combination of reagent and instrument utilized. Results for a single specimen tested in different laboratories are variable; this is mostly attributable to the specific reagents and to a much lesser degree to the instrument used. The PT stands alone as the single coagulation test that has undergone the most extensive attempt at assay standardization. The international normalized ratio (INR) was introduced to "normalize" all PT reagents to a World Health Organization (WHO) reference thromboplastin preparation standard, such that a PT measured anywhere in the world would result in an INR value similar to that which would have been achieved had the WHO reference thromboplastin been utilized. However, INRs are reproducible between laboratories for only those patients who are stably anticoagulated with vitamin K antagonists (VKAs) (i.e., at least 6 weeks of VKA therapy), and are not reliable or reproducible between laboratories for patients for whom VKA therapy has recently been started or any other clinical conditions associated with a prolonged PT such as liver disease, disseminated intravascular coagulation, and congenital factor deficiencies. In contrast to marked progress in the standardization of PT reagents for INR reporting, no standardization system has been globally adopted for standardization of PTT reagents. Recently College of American Pathologists recommend that individual laboratories establish their own therapeutic range by using aPTT values calibrated against accepted therapeutic unfractionated heparin (UFH) levels calibrated against accepted therapeutic UFH levels performing anti-Xa test (which is the most accurate assay for monitoring UFH therapy).Herein, we review recent data on the monitoring of conventional anticoagulant agents. Marked interlaboratory variability still exists for PT, INR, and PTT tests. Further research should be focused on improving the standardization and calibration of these assays.

Management of NSAID-associated peptic ulcer disease.

PubMed

Melcarne, Luigi; García-Iglesias, Pilar; Calvet, Xavier

2016-06-01

Non-steroidal anti-inflammatory drug (NSAID) use increases the risk of gastrointestinal complications such as ulcers or bleeding. The presence of factors like advanced age, history of peptic ulcer, Helicobacter pylori infection and the use of anticoagulants or antiplatelet agents increase this risk further. COX-2 inhibitors and antisecretory drugs, particularly proton pump inhibitors, help to minimize the risk of gastrointestinal complications in high-risk patients. This review presents a practical approach to the prevention and treatment of NSAID-associated peptic ulcer disease and examines the new advances in the rational use of NSAIDs.

Flavonoids, Phenolic Acids and Coumarins from the Roots of Althaea officinalis.

PubMed

Gudej, J

1991-06-01

From the roots of ALTHAEA OFFICINALIS two flavonoid glycosides were separated. Phenolic acids and coumarins were investigated chromatographically. The structures of the compounds were established on the basis of acid hydrolysis and spectroscopic methods (UV, (1)H-NMR, (13)C-NMR) as hypolaetin 8-glucoside and the new flavonoid sulphate - isoscutellarein 4'-methyl ether 8-glucoside-2''-SO (3)K.

Insights into structure–activity relationship of GABAA receptor modulating coumarins and furanocoumarins

PubMed Central

Singhuber, Judith; Baburin, Igor; Ecker, Gerhard F.; Kopp, Brigitte; Hering, Steffen

2011-01-01

The coumarins imperatorin and osthole are known to exert anticonvulsant activity. We have therefore analyzed the modulation of GABA-induced chloride currents (IGABA) by a selection of 18 coumarin derivatives on recombinant α1β2γ2S GABAA receptors expressed in Xenopus laevis oocytes by means of the two-microelectrode voltage clamp technique. Osthole (EC50=14±1 μM) and oxypeucedanin (EC50=25±8 μM) displayed the highest efficiency with IGABA potentiation of 116±4% and 547±56%, respectively. IGABA enhancement by osthole and oxypeucedanin was not inhibited by flumazenil (1 μM) indicating an interaction with a binding site distinct from the benzodiazepine binding site. In general, prenyl residues are essential for the positive modulatory activity, while longer side chains or bulkier residues (e.g. geranyl residues) diminish IGABA modulation. Generation of a binary classification tree revealed the importance of polarisability, which is sufficient to distinguish actives from inactives. A 4-point pharmacophore model based on oxypeucedanin – comprising three hydrophobic and one aromatic feature – identified 6 out of 7 actives as hits. In summary, (oxy-)prenylated coumarin derivatives from natural origin represent new GABAA receptor modulators. PMID:21749864

Fluorescence labeling of carbonylated lipids and proteins in cells using coumarin-hydrazide

PubMed Central

Vemula, Venukumar; Ni, Zhixu; Fedorova, Maria

2015-01-01

Carbonylation is a generic term which refers to reactive carbonyl groups present in biomolecules due to oxidative reactions induced by reactive oxygen species. Carbonylated proteins, lipids and nucleic acids have been intensively studied and often associated with onset or progression of oxidative stress related disorders. In order to reveal underlying carbonylation pathways and biological relevance, it is crucial to study their intracellular formation and spatial distribution. Carbonylated species are usually identified and quantified in cell lysates and body fluids after derivatization using specific chemical probes. However, spatial cellular and tissue distribution have been less often investigated. Here, we report coumarin-hydrazide, a fluorescent chemical probe for time- and cost-efficient labeling of cellular carbonyls followed by fluorescence microscopy to evaluate their intracellular formation both in time and space. The specificity of coumarin-hydrazide was confirmed in time- and dose-dependent experiments using human primary fibroblasts stressed with paraquat and compared with conventional DNPH-based immunocytochemistry. Both techniques stained carbonylated species accumulated in cytoplasm with strong perinuclear clustering. Using a complimentary array of analytical methods specificity of coumarin-hydrazide probe towards both protein- and lipid-bound carbonyls has been shown. Additionally, co-distribution of carbonylated species and oxidized phospholipids was demonstrated. PMID:25974625

Preferred Molecular Orientation of Coumarin 343 on TiO 2 Surfaces: Application to Dye-Sensitized Solar Cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

McCree-Grey, Jonathan; Cole, Jacqueline M.; Evans, Peter J.

2015-07-21

The dye…TiO2 interfacial structure in working electrodes of dye-sensitized solar cells (DSCs) is known to influence its photovoltaic device performance. Despite this, direct and quantitative reports of such structure remain sparse. This case study presents the application of X-ray reflectometry to determine the preferred structural orientation and molecular packing of the organic dye, coumarin 343, adsorbed onto amorphous TiO2. Results show that the dye molecules are, on average, tilted by 61.1° relative to the TiO2 surface, and are separated from each other by 8.2 Å. These findings emulate the molecular packing arrangement of a monolayer of coumarin 343 within itsmore » crystal structure. This suggests that the dye adsorbs onto TiO2 in one of its lowest energy configurations, i.e. dye…TiO2 self assembly is driven more by thermodynamic rather than kinetic means. Complementary DSC device tests illustrate that this interfacial structure compromises photovoltaic performance, unless a suitably sized co-adsorbant is interdispersed between the coumarin 343 chromophores on the TiO2 surface.« less

Pharmacogenetics in cardiovascular diseases: State of the art and implementation-recommendations of the French National Network of Pharmacogenetics (RNPGx).

PubMed

Lamoureux, Fabien; Duflot, Thomas

2017-04-01

The use of genomic markers to predict drug response and effectiveness has the potential to improve healthcare by increasing drug efficacy and minimizing adverse effects. Polymorphisms associated with inter-individual variability in drug metabolism, transport, or pharmacodynamics of major cardiovascular drugs have been identified. These include single nucleotide polymorphisms (SNP) affecting clinical outcomes in patients receiving antiplatelet agents, oral anticoagulants and statins. Based on clinical evidence supporting genetic testing in the management of cardiovascular diseases using these drug classes, this short review presents clinical guidance regarding current pharmacogenetics implementation in routine medical practice. Copyright © 2017 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.

Lupus anticoagulants and antiphospholipid antibodies

MedlinePlus

Blood clots - lupus anticoagulants; DVT - anticoagulants ... Most often, lupus anticoagulants and aPL are found in people with diseases such as systemic lupus erythematosus (SLE). Lupus anticoagulants and ...

Mobilization of Iron by Plant-Borne Coumarins.

PubMed

Tsai, Huei Hsuan; Schmidt, Wolfgang

2017-06-01

Iron is one of the most abundant elements in soils, but its low phytoavailability at high pH restricts plant communities on alkaline soils to taxa that have evolved efficient strategies to increase iron solubility. Recent evidence provides support for a previously underestimated role of root-secreted coumarins in mobilizing iron through reduction and chelation as part of an orchestrated strategy evolved to improve the acquisition of iron from recalcitrant pools. Understanding the mechanisms that tune the production of iron-mobilizing coumarins and their intricate interplay with other biosynthesis pathways could yield clues for deciphering the molecular basis of 'iron efficiency' - the ability of plants to thrive on soils with limited iron availability - and may open avenues for generating iron-fortified crops. Copyright © 2017 Elsevier Ltd. All rights reserved.

Tetrapeptide-coumarin conjugate 3D networks based on hydrogen-bonded charge transfer complexes: gel formation and dye release.

PubMed

Guo, Zongxia; Gong, Ruiying; Jiang, Yi; Wan, Xiaobo

2015-08-14

Oligopeptide-based derivatives are important synthons for bio-based functional materials. In this article, a Gly-(L-Val)-Gly-(L-Val)-coumarin (GVGV-Cou) conjugate was synthesized, which forms 3D networks in ethanol. The gel nanostructures were characterized by UV-vis spectroscopy, FT-IR spectroscopy, X-ray diffraction (XRD), SEM and TEM. It is suggested that the formation of charge transfer (CT) complexes between the coumarin moieties is the main driving force for the gel formation. The capability of the gel to encapsulate and release dyes was explored. Both Congo Red (CR) and Methylene Blue (MB) can be trapped in the CT gel matrix and released over time. The present gel might be used as a functional soft material for guest encapsulation and release.

Single-molecule detection by two-photon excitation of fluorescence

NASA Astrophysics Data System (ADS)

Zander, Christoph; Brand, Leif; Eggeling, C.; Drexhage, Karl-Heinz; Seidel, Claus A. M.

1997-05-01

Using a mode-locked titanium: sapphire laser at 700 nm for two-photon excitation we studied fluorescence bursts from individual coumarin 120 molecules in water and triacetin. Fluorescence lifetimes and multichannel scaler traces have been measured simultaneously. Due to the fact that scattered excitation light as well as Raman scattered photons can be suppressed by a short-pass filter a very low background level was achieved. To identify the fluorophore by its characteristic fluorescence lifetime the time-resolved fluorescence signals were analyzed by a maximum likelihood estimator. The obtained average fluorescence lifetimes (tau) av equals 4.8 +/- 1.2 ns for coumarin 120 in water and (tau) av equals 3.3 +/- 0.6 for coumarin 120 in triacetin are in good agreement with results obtained from separate measurements at higher concentrations.

Novel fluorescent pH sensor based on coumarin with piperazine and imidazole substituents.

PubMed

Saleh, Na'il; Al-Soud, Yaseen A; Nau, Werner M

2008-12-01

A new coumarin derivative containing piperazine and imidazole moieties is reported as a fluorophore for hydrogen ions sensing. The fluorescence enhancement of the studied sensor with an increase in hydrogen ions concentration is based on the hindering of photoinduced electron transfer from the piperazinyl amine and the imidazolyl amine to the coumarin fluorophore by protonation. The presented sensor has a novel design of fluorophore-spacer-receptor(1)-receptor(2) format, which is proposed to sense two ranges of pH (from 2.5 to 5.5) and (from 10 to 12) instead of sensing one pH range. A model compound, in which the piperazinyl ring is absent, was synthesized as well to confirm the novel pH sensing of the proposed sensor.

The Design, Synthesis and Evaluation of Coumarin Ring Derivatives of the Novobiocin Scaffold that Exhibit Anti-proliferative Activity

PubMed Central

Donnelly, Alison C.; Mays, Jared R.; Burlison, Joseph A.; Nelson, John T.; Vielhauer, George; Holzbeierlein, Jeffrey; Blagg, Brian S. J.

2009-01-01

Novobiocin, a known DNA gyrase inhibitor, binds to a nucleotide-binding site located on the C-terminus of Hsp90 and induces degradation of Hsp90-dependent client proteins at ~700 μM in breast cancer cells (SkBr3). Although many analogues of novobiocin have been synthesized, it was only recently demonstrated that monomeric species can exhibit anti-proliferative activity against various cancer cell lines. To further refine the essential elements of the coumarin core, a series of modified coumarin derivatives was synthesized and evaluated for elucidation of structure–activity relationships for novobiocin as an anti-cancer agent. Results obtained from these studies have produced novobiocin analogues that manifest low micromolar activity against several cancer cell lines. PMID:18939877

Safety and Efficacy of Novel Oral Anticoagulants vs Low Molecular Weight Heparin for Thromboprophylaxis in Large-Volume Liposuction and Body Contouring Procedures.

PubMed

Morales, Rolando; Ruff, Eric; Patronella, Christopher; Mentz, Henry; Newall, Germán; Hustak, Kristi L; Fortes, Paul; Bush, Amelia

2016-04-01

Preventing venous thromboembolism (VTE) remains an important topic in the plastic surgery community. However, there is little consensus regarding appropriate VTE prophylaxis for patients undergoing common body contouring procedures. This study compared the use of two novel oral anticoagulants (Rivaroxaban and Apixiban) vs low molecular weight heparin (LMWH) for postoperative chemical prophylaxis in body contouring plastic surgery procedures. A single center retrospective chart review of 1572 patients who underwent body contouring plastic surgery procedures from January 2012 to February 2015 was performed. Major complications associated with chemical prophylaxis were reviewed including hematomas requiring surgical evacuation, acute blood loss anemia requiring transfusions, and thrombotic or hemorrhagic events. Drug-related adverse events occurred in 1.27% (n = 20) of patients. The complications encountered by the 454 patients on LMWH consisted of 0.88% (n = 4) with hematomas requiring surgical evacuation, 0.44% (n = 2) with decreased hemoglobin requiring transfusions, and 0.22% (n = 1) with a deep vein thrombosis (DVT). The complications encountered by 703 patients on with Rivaroxaban consisted of 1.3% (n = 9) with hematomas requiring surgical evacuation, 0.43% (n = 3) with decreased hemoglobin requiring transfusions, and 0.1% (n = 1) with a DVT and pulmonary embolism. The complications encountered by 415 patients on with Apixaban consisted of 0.48% (n = 2) with a DVT. Novel oral anticoagulants (Rivaroxaban and Apixiban) are comparable to LMWH for chemical prophylaxis after body contouring procedures with similar rates of drug-related complications. Further investigation is warranted with more clinical cases in order to recommend the use of this medication for routine postoperative chemical prophylaxis after body contouring procedures. 3 Therapeutic. © 2016 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: journals.permissions@oup.com.

Co-morbidities and bleeding in elderly patients with haemophilia-A survey of the German, Austrian and Swiss Society of Thrombosis and Haemostasis Research (GTH).

PubMed

Miesbach, W; Reitter-Pfoertner, S-E; Klamroth, R; Langer, F; Wolf, H-H; Tiede, A; Siegmund, B; Scholz, U; Müller, P R; Eichler, H; Pabinger, I

2017-09-01

Nowadays patients with haemophilia survive longer due to improvements in haemophilia care. It has been hypothesized that the bleeding type and frequency may vary with age and are influenced by co-morbidities and co-medication in elderly patients. To investigate a large group of patients older than 60 years of age with haemophilia concerning haemophilia treatment, bleeding pattern changes, co-morbidities, co-medication, bleeding sites and patient mortality. A retrospective multi-centre data collection study was initiated on behalf of the German, Austrian and Swiss Society of Thrombosis and Haemostasis Research (GTH). Parameters of interest were investigated over the 5 years prior to study entry. A total of 185 haemophilia patients (mean age, 69.0±7.0 years, 29% with severe haemophilia) were included in the study. Regular prophylaxis was performed in 30% of the patients with severe haemophilia. In total, the annual bleeding rate was 2.49 and in patients with severe haemophilia 5.61, mostly caused by joint bleeds. Hypertension was the most common co-morbidity, but it occurred significantly less frequently than in an age-matched general population older than 70 years; 12% of the patients suffered from ischaemic heart disease, and 13% of the patients received anticoagulant or antiplatelet therapy. Within the observation period, 17% of the patients with severe haemophilia developed a higher frequency of bleeding symptoms, which was significantly associated with the use of antiplatelet or anticoagulant drugs. The most common co-morbidity of the patient population was hypertension, a considerable part had ischemic heart disease and antiplatelet or anticoagulant drugs. © 2017 John Wiley & Sons Ltd.

Liver injury with novel oral anticoagulants: assessing post-marketing reports in the US Food and Drug Administration adverse event reporting system.

PubMed

Raschi, Emanuel; Poluzzi, Elisabetta; Koci, Ariola; Salvo, Francesco; Pariente, Antoine; Biselli, Maurizio; Moretti, Ugo; Moore, Nicholas; De Ponti, Fabrizio

2015-08-01

We assessed the hepatic safety of novel oral anticoagulants (NOACs) analyzing the publicly available US-FDA adverse event reporting system (FAERS). We extracted reports of drug-induced liver injury (DILI) associated with NOACs, including acute liver failure (ALF) events. Based on US marketing authorizations, we performed disproportionality analyses, calculating reporting odds ratios (RORs) with 95% confidence interval (CI), also to test for event- and drug-related competition bias, and case-by-case evaluation for concomitant medications. DILI reports represented 3.7% (n = 146) and 1.7% (n = 222) of all reports for rivaroxaban and dabigatran, respectively. No statistically significant association was found for dabigatran, in primary and secondary analyses. Disproportionality signals emerged for rivaroxaban in primary analysis (ALF: n = 25, ROR = 2.08, 95% CI 1.34, 3.08). In a large proportion of DILI reports concomitant hepatotoxic and/or interacting drugs were recorded: 42% and 37% (rivaroxaban and dabigatran, respectively), especially statins, paracetamol and amiodarone. Among ALF reports, fatal outcome occurred in 49% of cases (44% and 51%, rivaroxaban and dabigatran, respectively), whereas rapid onset of the event (<1 week) was detected in 46% of patients (47% and 44%, respectively). The disproportionality signal for rivaroxaban calls for further comparative population-based studies to characterize and quantify the actual DILI risk of NOACs, taking into account drug- and patient-related risk factors. As DILI is unpredictable, our findings strengthen the role of (a) timely pharmacovigilance to detect post-marketing signals of DILI through FAERS and other data sources, (b) clinicians to assess early, on a case-by-case basis, the potential responsibility of NOACs when they diagnose a liver injury. © 2015 The British Pharmacological Society.

East Asian perspective on the interaction between proton pump inhibitors and clopidogrel.

PubMed

Zou, Duowu; Goh, Khean-Lee

2017-06-01

Both proton pump inhibitors (PPIs) and clopidogrel are widely prescribed in the Asia-Pacific population. PPIs are the mainstay therapeutic agents for prophylaxis against aspirin gastropathy and for acid-related disorders including gastroesophageal reflux disease. They are also co-prescribed with oral anticoagulant agents and with dual-antiplatelet therapy for the treatment and prevention of gastrointestinal bleeding. Clopidogrel belongs to the drug class of thienopyridines and is currently the most widely prescribed oral anticoagulant agent either alone or in combination with aspirin. Platelet inhibition by clopidogrel is prone to significant inter-individual variability and is believed to be affected by several factors such as genetics and drug-drug interactions. Since it was first reported in 2009, the potential for drug-drug interactions between PPIs and clopidogrel has remained headline news, and its significance in clinical practice is the subject of an ongoing debate. For East Asian patients in particular, the clinical relevance of the interaction between PPIs and clopidogrel remains unclear because of conflicting data, as well as underrepresentation of East Asian subjects in landmark trials. Increased CYP2C19 genetic polymorphisms in individuals from Asia-Pacific countries only fuel the confusion. Recent studies in East Asian cohorts suggests that the potential of PPIs to attenuate the efficacy of clopidogrel could be minimized by the use of newer PPIs with weaker affinity for the CYP2C19 isoenzyme, namely, pantoprazole, dexlansoprazole, and rabeprazole. This review aims to help clinicians choose the most appropriate PPI for co-prescription with clopidogrel in patients from Asia-Pacific countries. © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

Characterization of nanoparticle uptake by endothelial cells.

PubMed

Davda, Jasmine; Labhasetwar, Vinod

2002-02-21

Endothelium is an important target for drug or gene therapy because of its important role in the biological system. In this paper, we have characterized nanoparticle uptake by endothelial cells in cell culture. Nanoparticles were formulated using poly DL-lactide-co-glycolide polymer containing bovine serum albumin as a model protein and 6-coumarin as a fluorescent marker. It was observed that the cellular uptake of nanoparticles depends on the time of incubation and the concentration of nanoparticles in the medium. The uptake of nanoparticles was rapid with confocal microscopy demonstrating their localization mostly in the cytoplasm. The mitogenic study demonstrated biocompatability of nanoparticles with the cells. The study thus demonstrates that nanoparticles could be used for localizing therapeutic agents or gene into endothelial cells. Nanoparticles localized in the endothelium could provide prolonged drug effects because of their sustained release characterics, and also could protect the encapsulated agent from enzymatic degradation.

Preanesthetic Assessment of Herbal and Dietary Supplement Use

DTIC Science & Technology

2000-10-01

anticoagulant therapy. Ginkgo has been reported to diminish the effectiveness of anticonvulsants such as carbamazepine, phenytoin , and phenobarbital by lowering...been implicated in drug interactions (DeSmet & D Arcy, 1996). Vitamin B6 can nullify the effects of L-dopa in patients with Parkinson disease...Intraoperative Parkinsonism has been associated with a neuroleptic malignant- like syndrome potentially creating unnecessary and inappropriate delay in

Identification of anthranilamide derivatives as potential factor Xa inhibitors: drug design, synthesis and biological evaluation.

PubMed

Xing, Junhao; Yang, Lingyun; Li, Hui; Li, Qing; Zhao, Leilei; Wang, Xinning; Zhang, Yuan; Zhou, Muxing; Zhou, Jinpei; Zhang, Huibin

2015-05-05

The coagulation enzyme factor Xa (fXa) plays a crucial role in the blood coagulation cascade. In this study, three-dimensional fragment based drug design (FBDD) combined with structure-based pharmacophore (SBP) model and structural consensus docking were employed to identify novel fXa inhibitors. After a multi-stage virtual screening (VS) workflow, two hit compounds 3780 and 319 having persistent high performance were identified. Then, these two hit compounds and several analogs were synthesized and screened for in-vitro inhibition of fXa. The experimental data showed that most of the designed compounds displayed significant in vitro potency against fXa. Among them, compound 9b displayed the greatest in vitro potency against fXa with the IC50 value of 23 nM and excellent selectivity versus thrombin (IC50 = 40 μM). Moreover, the prolongation of the prothrombin time (PT) was measured for compound 9b to evaluate its in vitro anticoagulant activity. As a result, compound 9b exhibited pronounced anticoagulant activity with the 2 × PT value of 8.7 μM. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Real-time monitoring of human blood clotting using a lateral excited film bulk acoustic resonator

NASA Astrophysics Data System (ADS)

Chen, Da; Wang, Jingjng; Wang, Peng; Guo, Qiuquan; Zhang, Zhen; Ma, Jilong

2017-04-01

Frequent assay of hemostatic status is an essential issue for the millions of patients using anticoagulant drugs. In this paper, we presented a micro-fabricated film bulk acoustic sensor for the real-time monitoring of blood clotting and the measurement of hemostatic parameters. The device was made of an Au/ZnO/Si3N4 film stack and excited by a lateral electric field. It operated under a shear mode resonance with the frequency of 1.42 GHz and had a quality factor of 342 in human blood. During the clotting process of blood, the resonant frequency decreased along with the change of blood viscosity and showed an apparent step-ladder curve, revealing the sequential clotting stages. An important hemostatic parameter, prothrombin time, was quantitatively determined from the frequency response for different dilutions of the blood samples. The effect of a typical anticoagulant drug (heparin) on the prothrombin time was exemplarily shown. The proposed sensor displayed a good consistency and clinical comparability with the standard coagulometric methods. Thanks to the availability of direct digital signals, excellent potentials of miniaturization and integration, the proposed sensor has promising application for point-of-care coagulation technologies.

Oral surgery in patients under antithrombotic therapy: perioperative bleeding as a significant risk factor for postoperative hemorrhage.

PubMed

Rocha, Amanda L; Souza, Alessandra F; Martins, Maria A P; Fraga, Marina G; Travassos, Denise V; Oliveira, Ana C B; Ribeiro, Daniel D; Silva, Tarcília A

2018-01-01

: To investigate perioperative and postoperative bleeding, complications in patients under therapy with anticoagulant or antiplatelet drugs submitted to oral surgery. To evaluate the risk of bleeding and safety for dental surgery, a retrospective chart review was performed. Medical and dental records of patients taking oral antithrombotic drugs undergoing dental surgery between 2010 and 2015 were reviewed. Results were statistically analyzed using Fisher's exact test, t test or the χ test. One hundred and seventy-nine patients underwent 293 surgical procedures. A total of eight cases of perioperative and 12 episodes of postoperative bleeding were documented. The complications were generally managed with local measures and did not require hospitalization. We found significant association of postoperative hemorrhage with increased perioperative bleeding (P = 0.043) and combination of anticoagulant and antiplatelet therapy (P < 0.001). The chance of postoperative hemorrhage for procedures with increased perioperative bleeding is 8.8 times bigger than procedures without perioperative bleeding. Dental surgery in patients under antithrombotic therapy might be carried out without altering the regimen because of low risk of perioperative and postoperative bleeding. However, patients with increased perioperative bleeding should be closely followed up because of postoperative complications risk.

Effects of daily ingestion of cranberry juice on the pharmacokinetics of warfarin, tizanidine, and midazolam--probes of CYP2C9, CYP1A2, and CYP3A4.

PubMed

Lilja, J J; Backman, J T; Neuvonen, P J

2007-06-01

Case reports suggest that cranberry juice can increase the anticoagulant effect of warfarin. We investigated the effects of cranberry juice on R-S-warfarin, tizanidine, and midazolam; probes of CYP2C9, CYP1A2, and CYP3A4. Ten healthy volunteers took 200 ml cranberry juice or water t.i.d. for 10 days. On day 5, they ingested 10 mg racemic R-S-warfarin, 1 mg tizanidine, and 0.5 mg midazolam, with juice or water, followed by monitoring of drug concentrations and thromboplastin time. Cranberry juice did not increase the peak plasma concentration or area under concentration-time curve (AUC) of the probe drugs or their metabolites, but slightly decreased (7%; P=0.051) the AUC of S-warfarin. Cranberry juice did not change the anticoagulant effect of warfarin. Daily ingestion of cranberry juice does not inhibit the activities of CYP2C9, CYP1A2, or CYP3A4. A pharmacokinetic mechanism for the cranberry juice-warfarin interaction seems unlikely.

Assessment of Degree of Anticoagulation Control in Patients With Atrial Fibrillation in Primary Health Care in Galicia, Spain: ANFAGAL Study.

PubMed

Cinza-Sanjurjo, Sergio; Rey-Aldana, Daniel; Gestal-Pereira, Enrique; Calvo-Gómez, Carlos

2015-09-01

To determine the degree of control of patients on anticoagulants in follow-up in primary care in Galicia and investigate whether time in therapeutic range as estimated using the number of acceptable controls is comparable with the estimation using the Rosendaal method. Transversal study that included patients older than 65 years, diagnosed with nonvalvular atrial fibrillation, on anticoagulants for at least 1 year. Control was considered good when the time in therapeutic range was greater than 65%, estimated by the Rosendaal method, or 60% estimated by the number of acceptable controls. We enrolled 511 patients (53.0% women; mean [standard deviation] age, 77.8 [0.6] years). Overall, 41.5% of the patients were in therapeutic range at fewer than 60% of the controls and 42.7% spent less than 65% of follow-up in therapeutic range, as estimated with the Rosendaal method. In the group of patients with poor control, we observed more drugs (6.8 [0.4] vs 5.7 [0.3]; P<.0001), greater presence of kidney disease (24.3% vs 17.0%; P=.05), and higher HAS-BLED scores (3.8 [0.1] vs 2.5 [0.1]; P<.0001). The cutoff of 60% for number of acceptable controls had a sensitivity and specificity of 79.4% and 86.7%, respectively, with an area under the curve of 0.92 (95%CI, 0.87-0.97). More than 40% of patients on anticoagulants do not reach the minimum time in therapeutic range to benefit from anticoagulation. The factors associated with worse control were kidney disease and high risk of cerebral hemorrhage. The 2 methods of estimation are comparable. Copyright © 2014 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

Biotransformations with plant tissue cultures.

PubMed

Carew, D P; Bainbridge, T

1976-01-01

Suspension cultures of Catharanthus roseus, Apocynum cannabinum and Conium maculatum were examined for their capacity to transform aniline, anisole, acetanilide, benzoic acid and coumarin. None of the cultures transformed acetanilide but each produced acetanilide when fed aniline. All three cultures converted benzoic acid to its para-hydroxy derivative. Coumarin was selectively hydroxylated at the 7-position by Catharanthus and Conium and anisole was O-demethylated only by older Catharanthus tissue.

Simultaneous determination of aegeline and six coumarins from different parts of the plant Aegle marmelos using UHPLC-PDA-MS and chiral separation of aegeline using HPLC-ToF-MS

USDA-ARS?s Scientific Manuscript database

A fast UHPLC-PDA method was developed for the simultaneous analysis of one alkaloid, aegeline, and six coumarins namely: umbelliferone; scopoletin; marmesinin; 8-hydroxypsoralen angelicin and marmelosin from leaf, fruit, root and bark of Aegle marmelos (L.) Corrêa (Rutaceae). The method was validate...

Practical management of bleeding in patients receiving non-vitamin K antagonist oral anticoagulants.

PubMed

Weitz, Jeffrey I; Pollack, Charles V

2015-11-25

Non-vitamin K antagonist oral anticoagulants (NOACs) are increasingly used in the prevention and treatment of venous thromboembolism and in the prevention of stroke in patients with non-valvular atrial fibrillation. In phase III clinical trials and meta-analyses, the NOACs were at least as effective as vitamin K antagonists (VKAs) and were associated with a similar or lower incidence of major bleeding, including consistent and significant decreases in intracranial bleeding, although with an increase in gastrointestinal bleeding for some agents compared with VKAs. Subsequent real-world evidence supports these outcomes. Despite this, physicians have concerns about serious bleeding or emergencies because there are no specific reversal agents for the NOACs. However, in clinical trials, patients receiving NOACs generally had similar or better outcomes after these events than those taking VKAs. As with any bleeding, anticoagulant-related bleeding should first be stratified according to severity and location; risk can be minimised by ongoing assessment. Management protocols for NOAC-related bleeding are similar to those for VKAs but should take into account the pharmacological profile of the specific drug. Because of their short half-lives, NOAC-related mild bleeding can often be controlled by temporarily withholding treatment. More severe bleeding requires standard escalating haemodynamic support measures, and non-specific reversal agents can be considered in life-threatening situations, based on limited clinical data. Specific and rapid reversal agents are not currently available for any oral anticoagulant and restoration of coagulation may not necessarily lead to better outcomes. Nevertheless, specific NOAC reversal agents are in development and show promise in healthy volunteers.

Pacemaker diagnostics in atrial fibrillation: limited usefulness for therapy initiation in a pacemaker practice.

PubMed

Yedlapati, Neeraja; Fisher, John D

2014-09-01

We aimed to determine the practical value of pacemaker diagnostics for atrial fibrillation (AF) in an unselected general pacemaker practice, specifically workflow and initiation of anticoagulation or antiarrhythmic drug (AAD) therapy. We prospectively followed consecutive pacemaker interrogations over a period of 1 year to identify patients with AF (burden from 1% to 99%). We contacted referring physicians with AF details, and then determined whether the information resulted in therapeutic changes. Of the 1,100 pacemakers interrogated, 728 were dual chamber (DDDs) with AF diagnostic capability. AF was recorded in 73 (10%) but seven had limited information, leaving 66 patients; of these, 42 (63%) patients were already anticoagulated and in five (7%) patients, anticoagulation had been stopped because of complications. Initial diagnosis of AF was made by the pacemaker in 17 patients (26% of 66; 2% of 728); four (6% of 66) patients were newly initiated on anticoagulation. Of the 66 patients, 17 patients were already on AADs; 49 (74%) had satisfactory rate control or had other issues; only two (3% of 66; 0.3% of 728) received new AADs. Of 728 patients with DDD pacemakers, only 17 were newly discovered to have AF, and six (0.8%) had changes in medications based on the pacemaker data. Adding pacemaker-derived data to existing clinical information had little therapeutic impact, due to a combination of cumbersome workflow, and because AF was usually known to practitioners. Developments in automated monitoring systems may provide more accessible and therapeutically useful information. ©2014 Wiley Periodicals, Inc.

Treatment and Prevention of Heparin-Induced Thrombocytopenia

PubMed Central

Dans, Antonio L.; Moores, Lisa K.; Bona, Robert; Davidson, Bruce L.; Schulman, Sam; Crowther, Mark

2012-01-01

Background: Heparin-induced thrombocytopenia (HIT) is an antibody-mediated adverse drug reaction that can lead to devastating thromboembolic complications, including pulmonary embolism, ischemic limb necrosis necessitating limb amputation, acute myocardial infarction, and stroke. Methods: The methods of this guideline follow the Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement. Results: Among the key recommendations for this article are the following: For patients receiving heparin in whom clinicians consider the risk of HIT to be > 1%, we suggest that platelet count monitoring be performed every 2 or 3 days from day 4 to day 14 (or until heparin is stopped, whichever occurs first) (Grade 2C). For patients receiving heparin in whom clinicians consider the risk of HIT to be < 1%, we suggest that platelet counts not be monitored (Grade 2C). In patients with HIT with thrombosis (HITT) or isolated HIT who have normal renal function, we suggest the use of argatroban or lepirudin or danaparoid over other nonheparin anticoagulants (Grade 2C). In patients with HITT and renal insufficiency, we suggest the use of argatroban over other nonheparin anticoagulants (Grade 2C). In patients with acute HIT or subacute HIT who require urgent cardiac surgery, we suggest the use of bivalirudin over other nonheparin anticoagulants or heparin plus antiplatelet agents (Grade 2C). Conclusions: Further studies evaluating the role of fondaparinux and the new oral anticoagulants in the treatment of HIT are needed. PMID:22315270

Dabigatran after Short Heparin Anticoagulation for Acute Intermediate-Risk Pulmonary Embolism: Rationale and Design of the Single-Arm PEITHO-2 Study.

PubMed

Klok, Frederikus A; Ageno, Walter; Barco, Stefano; Binder, Harald; Brenner, Benjamin; Duerschmied, Daniel; Empen, Klaus; Faggiano, Pompilio; Ficker, Joachim H; Galiè, Nazzareno; Ghuysen, Alexandre; Held, Matthias; Heydenreich, Nadine; Huisman, Menno V; Jiménez, David; Kozak, Matija; Lang, Irene M; Lankeit, Mareike; Münzel, Thomas; Petris, Antoniu; Pruszczyk, Piotr; Quitzau, Kurt; Schellong, Sebastian; Schmidt, Kai-Helge; Stefanovic, Branislav S; Verschuren, Franck; Wolf-Puetz, Anamaria; Meyer, Guy; Konstantinides, Stavros V

2017-12-01

Patients with intermediate-risk pulmonary embolism (PE) may, depending on the method and cut-off values used for definition, account for up to 60% of all patients with PE and have an 8% or higher risk of short-term adverse outcome. Although four non-vitamin K-dependent direct oral anticoagulants (NOACs) have been approved for the treatment of venous thromboembolism, their safety and efficacy as well as the optimal anticoagulation regimen using these drugs have not been systematically investigated in intermediate-risk PE. Moreover, it remains unknown how many patients with intermediate-high-risk and intermediate-low-risk PE were included in most of the phase III NOAC trials. The ongoing Pulmonary Embolism International Thrombolysis 2 (PEITHO-2) study is a prospective, multicentre, multinational, single-arm trial investigating whether treatment of acute intermediate-risk PE with parenteral heparin anticoagulation over the first 72 hours, followed by the direct oral thrombin inhibitor dabigatran over 6 months, is effective and safe. The primary efficacy outcome is recurrent symptomatic venous thromboembolism or death related to PE within the first 6 months. The primary safety outcome is major bleeding as defined by the International Society on Thrombosis and Haemostasis. Secondary outcomes include all-cause mortality, the overall duration of hospital stay (index event and repeated hospitalizations) and the temporal pattern of recovery of right ventricular function over the 6-month follow-up period. By applying and evaluating a contemporary risk-tailored treatment strategy for acute PE, PEITHO-2 will implement the recommendations of current guidelines and contribute to their further evolution.

Delphi-RAND consensus of the Spanish Society of Internal Medicine on the controversies in anticoagulant therapy and prophylaxis in medical diseases. INTROMBIN Project (Uncertainty in thromboprophylaxis in internal medicine).

PubMed

Ruiz-Ruiz, F; Medrano, F J; Navarro-Puerto, M A; Rodríguez-Torres, P; Romero-Alonso, A; Santos-Lozano, J M; Alonso-Ortiz Del Rio, C; Varela-Aguilar, J M; Calderón, E J; Marín-León, I

2018-05-21

The aim of this study was to determine the opinion of internists on the management of anticoagulation and thromboembolism prophylaxis in complex clinical scenarios in which the risk-benefit ratio of surgery is narrow and to develop a consensus document on the use of drugs anticoagulant therapy in this patient group. To this end, we identified by consensus the clinical areas of greatest uncertainty, a survey was created with 20 scenarios laid out in 40 clinical questions, and we reviewed the specific literature. The survey was distributed among the internists of the Spanish Society of Internal Medicine (SEMI) and was completed by 290 of its members. The consensus process was implemented by changing the Delphi-RAND appropriateness method in an anonymous, double-round process that enabled an expert panel to identify the areas of agreement and uncertainty. In our case, we also added the survey results to the panel, a methodological innovation that helps provide additional information on the standard clinical practice. The result of the process is a set of 19 recommendations formulated by SEMI experts, which helps establish guidelines for action on anticoagulant therapy in complex scenarios (high risk or active haemorrhage, short life expectancy, coexistence of antiplatelet therapy or comorbidities such as kidney disease and liver disease), which are not uncommon in standard clinical practice. Copyright © 2018 Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI). All rights reserved.

Current status of prediction of drug disposition and toxicity in humans using chimeric mice with humanized liver.

PubMed

Kitamura, Shigeyuki; Sugihara, Kazumi

2014-01-01

1. Human-chimeric mice with humanized liver have been constructed by transplantation of human hepatocytes into several types of mice having genetic modifications that injure endogenous liver cells. Here, we focus on liver urokinase-type plasminogen activator-transgenic severe combined immunodeficiency (uPA/SCID) mice, which are the most widely used human-chimeric mice. Studies so far indicate that drug metabolism, drug transport, pharmacological effects and toxicological action in these mice are broadly similar to those in humans. 2. Expression of various drug-metabolizing enzymes is known to be different between humans and rodents. However, the expression pattern of cytochrome P450, aldehyde oxidase and phase II enzymes in the liver of human-chimeric mice resembles that in humans, not that in the host mice. 3. Metabolism of various drugs, including S-warfarin, zaleplon, ibuprofen, naproxen, coumarin, troglitazone and midazolam, in human-chimeric mice is mediated by human drug-metabolizing enzymes, not by host mouse enzymes, and thus resembles that in humans. 4. Pharmacological and toxicological effects of various drugs in human-chimeric mice are also similar to those in humans. 5. The current consensus is that chimeric mice with humanized liver are useful to predict drug metabolism catalyzed by cytochrome P450, aldehyde oxidase and phase II enzymes in humans in vivo and in vitro. Some remaining issues are discussed in this review.

[Personalized drug therapy-directed clinical pharmacology research based on genetic polymorphisms and pharmacokinetics analysis].

PubMed

Hayashi, Hideki

2013-01-01

In this decade, the field of pharmacogenomics (PGx), which is related to pharmacokinetics (PK) or pharmacodynamics (PD), has attracted much attention because it may provide a possible explanation for individual differences in the clinical efficacy of drugs. For the development of personalized drug therapy, it is important to accumulate evidence from PK/PD/PGx analysis in clinical trials. Warfarin (WF) is one of the most widely prescribed anticoagulants for the prevention and treatment of venous and arterial thromboembolism. However, large interindividual and interethnic differences have been observed in the WF dose required to elicit the anticoagulant effect. We investigated the factors influencing the WF maintenance dose in Japanese patients. Our study confirmed a large interindividual variability in the WF maintenance dose that was due to a VKORC1 1639 G>A polymorphism and differences in body weight, age, and serum albumin. In addition, we found that the CYP4F2 genotype affects the plasma concentration of menaquinone-4, and that this finding was correlated with the WF sensitivity index in Japanese pediatric patients. Methotrexate (MTX) is an antifolate that is widely used to treat rheumatoid arthritis (RA) and cancer. The response to low-dose MTX demonstrated wide interpatient variability; however, the contributing factors remain unclear. We found that the frequency of the RFC1 80A allele was higher in RA patients treated with MTX alone compared with patients who received biological disease-modifying antirheumatic drugs (bDMARDs). This finding may support the combined use of bDMARDs and MTX. Further large-scale prospective clinical trials are required to confirm these findings.

Effect of sodium citrate based anticoagulants on the growth activity of malaria parasites.

PubMed

Liu, Zhong-xiang; Wang, Xian-feng; Li, Shu-mei; Li, Xun; Xue, Cai-fang; Miao, Jun

2004-12-01

To study the effect of anticoagulants based on sodium citrate on the growth activity of malaria parasites. The parasites were treated with 3 anticoagulants (ACD, CD and SC), respectively, and the parasitemia was determined to measure the effect of the anticoagulants on the growth of the parasites. Unsynchronized Plasmodium falciparum was treated with the anticoagulants at different concentrations for 3 h at 37 degrees C. Treated erythrocytes were mixed with normal parasites or treated parasites with normal erythrocytes, which was followed by parasitemia determination of the two cultures to determine the cell target of the anticoagulants. Stage-synchronized parasites (ring, trophozoite and schizont) were treated as above to investigate the stage target. P. berghei was also treated with anticoagulants and inoculated in mice to detect the effect of anticoagulants on the animal malaria parasite by counting the parasitemia. All 3 anticoagulants inhibited falciparum parasite growth and ACD had the strongest potency. The treatments of the erythrocyte and the parasite with anticoagulants respectively showed that the anticoagulants targeted the parasites rather than normal erythrocytes. Stage-synchronized parasite treatment suggested anticoagulants primarily inhibited schizonts. The effect of anticoagulants on P. berghei was similar to that on P. falciparum. ACD showed the most significant inhibitive effect on the growth of malaria parasites and SC was the best anticoagulant based on sodium citrate for malarial experiments.

Novel 2H-chromen-2-one derivatives of resveratrol: Design, synthesis, modeling and use as human monoamine oxidase inhibitors.

PubMed

Ruan, Ban-Feng; Cheng, Hui-Jie; Ren, Jing; Li, Hong-Lin; Guo, Lu-Lu; Zhang, Xing-Xing; Liao, Chenzhong

2015-10-20

Using a fragment-based drug design strategy, two biomedical interesting fragments, resveratrol and coumarin were linked to design a series of novel human monoamine oxidase (hMAO) inhibitors with a scaffold of 3-((E)-3-(2-((E)-styryl)phenyl)acryloyl)-2H-chromen-2-one, which demonstrated a very interesting selectivity profile against hMAO-A and hMAO-B: some compounds with this scaffold are selective hMAO-A inhibitors, whereas some are selective hMAO-B inhibitors. The small changes in the substituents of the coumarin moiety led to this interesting selectivity profile. The most potent selective hMAO-B inhibitor D7 has a selectivity ratio of 20.93, with an IC₅₀ value of 2.78 μM, similar or better than selegiline (IC₅₀ = 2.89 μM), a selective hMAO-B inhibitor currently in the market for the treatment of Parkinson's disease. Our modeling study indicates that Tyr 326 of hMAO-B (or corresponded Ile 335 of hMAO-A) may be the determinant for the specificity of these compounds. The selectivity profile of compounds reported herein suggests that we can further develop both selective hMAO-A and hMAO-B inhibitors based on this novel scaffold. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Methyl galbanate, a novel inhibitor of nitric oxide production in mouse macrophage RAW264.7 cells.

PubMed

Kohno, Susumu; Murata, Tomiyasu; Sugiura, Ayumi; Ito, Chihiro; Iranshahi, Mehrdad; Hikita, Kiyomi; Kaneda, Norio

2011-04-01

It is well known that inflammation is associated with various neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease. An inflammatory mediator, nitric oxide (NO), is produced by inducible NO synthase (iNOS) in microglia and seems to be one of the possible causes of neurodegeneration. Several natural and synthetic compounds which exert anti-inflammatory effects by inhibiting NO production have been reported to date. The aim of this work was to investigate whether any of the 6 terpenoid coumarins (methyl galbanate, galbanic acid, farnesiferol A, badrakemone, umbelliprenin, and aurapten) isolated from Ferula szowitsiana DC. have inhibitory activity against NO production in RAW264.7 mouse macrophage cells stimulated with lipopolysaccharide (LPS) and interferon-γ (IFN-γ). Of the 6 terpenoid coumarins tested, methyl galbanate significantly decreased NO production in LPS/IFN-γ-stimulated RAW264.7 cells. In the presence of methyl galbanate, LPS/IFN-γ-induced iNOS mRNA expression was significantly decreased to 52% of the level found with LPS/IFN-γ stimulation alone. Methyl galbanate slightly attenuated COX-2 mRNA expression. Using the RAW264.7-tsAM5NE co-culture system, we showed that methyl galbanate protected neuronally differentiated tsAM5NE cells from NO-induced cell death by inhibiting the production of NO. Our finding suggests that methyl galbanate may be useful for developing a new drug against neurodegenerative diseases.

Metabolic mechanisms of drug-nutrient interactions.

PubMed

Hathcock, J N

1985-01-01

Metabolic mechanisms of nutrition and drug interactions include 1) the effects of diet on drug metabolism and action and 2) the effects of drugs on nutritional processes. The type, amount, and timing of foods consumed influence drug dissolution, absorption, distribution, metabolism, and excretion. High-fat meals enhance the absorption of griseofulvin and some other drugs. Milk and other sources of calcium inhibit absorption of tetracycline. High-fat meals increase plasma concentrations of free fatty acids and thereby displace many drugs from binding sites on plasma albumin. High-protein diets increase the activity of the mixed-function oxidase system and enhance the metabolism of numerous drugs. High-electrolyte intakes increase excretion of lithium and also diminish the action of diuretic agents. Bile acid sequestrants and some laxatives decrease lipid digestion and absorption, as well as absorption of the fat-soluble vitamins. Numerous drugs, including tetracycline and cholestyramine, bind iron and decrease its absorption. Coumarins inhibit the function of vitamin K. Phenobarbital and other anticonvulsants are inducers of cytochrome P-450 and the mixed-function oxidase system. Long-term treatment with these inducers can cause excessive metabolism and deficiency of vitamin D. Prooxidant drugs such as chloroquine, drugs detoxified by conjugation with glutathione, and alcohol can deplete reduced glutathione with consequent effects on amino acid transport and the redox status of cells. Acid-forming foods acidify the urine and increase the loss of alkaline drugs such as the amphetamines. Base-forming drugs increase the loss of acidic drugs such as barbiturates. The range of metabolic interactions of drugs and nutrients includes the full scope of physiological processes to which drugs and nutrients are subject.

Osthole activates glucose uptake but blocks full activation in L929 fibroblast cells, and inhibits uptake in HCLE cells

PubMed Central

Alabi, Ola D.; Gunnink, Stephen M.; Kuiper, Benjamin D.; Kerk, Samuel A.; Braun, Emily; Louters, Larry L.

2016-01-01

Aims Osthole, a coumarin derivative, has been used in Chinese medicine and studies have suggested a potential use in treatment of diabetes and cancers. Therefore, we investigated the effects of osthole and other coumarins on GLUT1 activity in two cell lines that exclusively express GLUT1. Main Methods We measured the magnitude and time frame of the effects of osthole and related coumarins on glucose uptake in two cells lines; L929 fibroblast cells which have low GLUT1 expression levels and low basal glucose uptake and HCLE cells which have high GLUT1 concentrations and high basal uptake. We also explored the effects of these coumarins in combination with other GLUT1 activators. Key findings Osthole activates glucose uptake in L929 cells with a modest maximum 1.7-fold activation achieved by 50 µM with both activation and recovery occurring within minutes. However, osthole blocks full acute activation of glucose uptake by other, more robust activators. This behavior mimics the effects of other thiol reactive compounds and suggests that osthole is interacting with cysteine residues, possibly within GLUT1 itself. Coumarin, 7-hydroxycoumarin, and 7-methoxycoumarin, do not affect glucose uptake, which is consistent with the notion that the isoprenoid structure in osthole may be important to gain membrane access to GLUT1. In contrast to its effects in L929 cells, osthole inhibits basal glucose uptake in the more active HCLE cells. Significance The differential effects of osthole in L929 and HCLE cells indicated that regulation of GLUT1 varies, likely depending on its membrane concentration. PMID:24657891

Osthole activates glucose uptake but blocks full activation in L929 fibroblast cells, and inhibits uptake in HCLE cells.

PubMed

Alabi, Ola D; Gunnink, Stephen M; Kuiper, Benjamin D; Kerk, Samuel A; Braun, Emily; Louters, Larry L

2014-05-02

Osthole, a coumarin derivative, has been used in Chinese medicine and studies have suggested a potential use in treatment of diabetes and cancers. Therefore, we investigated the effects of osthole and other coumarins on GLUT1 activity in two cell lines that exclusively express GLUT1. We measured the magnitude and time frame of the effects of osthole and related coumarins on glucose uptake in two cells lines; L929 fibroblast cells which have low GLUT1 expression levels and low basal glucose uptake and HCLE cells which have high GLUT1 concentrations and high basal uptake. We also explored the effects of these coumarins in combination with other GLUT1 activators. Osthole activates glucose uptake in L929 cells with a modest maximum 1.7-fold activation achieved by 50 μM with both activation and recovery occurring within minutes. However, osthole blocks full acute activation of glucose uptake by other, more robust activators. This behavior mimics the effects of other thiol reactive compounds and suggests that osthole is interacting with cysteine residues, possibly within GLUT1 itself. Coumarin, 7-hydroxycoumarin, and 7-methoxycoumarin, do not affect glucose uptake, which is consistent with the notion that the isoprenoid structure in osthole may be important to gain membrane access to GLUT1. In contrast to its effects in L929 cells, osthole inhibits basal glucose uptake in the more active HCLE cells. The differential effects of osthole in L929 and HCLE cells indicated that regulation of GLUT1 varies, likely depending on its membrane concentration. Copyright © 2014 Elsevier Inc. All rights reserved.

Parametric investigations on the saturation intensity of Coumarin 102 for stimulated emission depletion application.

PubMed

Qin, H-Y; Zhao, W-X; Zhao, W; Zhang, C; Feng, X-Q; Liu, S-P; Wang, K-G

2018-04-23

Stimulated emission depletion (STED) microscopy performed using continuous-wave (CW) lasers has been investigated and developed by Willig et al. (Nature Methods, 2007, 4(11):915) for nearly a decade. Kuang et al. (Review of Scientific Instruments, 2010, 81:053709) developed the CW STED microscopy technique with 405 nm excitation and 532 nm depletion beams. In their research, Coumarin 102 dye was adopted and was found to be depletable. In this study, a parametric investigation of the depletion of Coumarin 102 dye is carried out experimentally. The influence of the excitation and depletion beam intensities and dye concentrations on the depletion efficiency are studied in detail. The results indicate the following: (1) The highest depletion occurs for the 100 μM Coumarin 102 solution, with a 1.4 μW excitation beam and a 115.3 mW depletion beam. (2) The minimum saturation intensity (Is) of STED, that is 13 MW cm -2 , is observed when the Coumarin 102 solution concentration is 10 μM. (3) Is values calculated directly from the depletion power derived with the cross-sectional area due to the full-width-at-half-maximum (FWHM) of the depletion beam show poor accuracy, where Is may be overestimated. Thus, a correction factor for the cross-sectional area is proposed. We also find that Is is not exactly constant for a fixed excitation beam power and dye concentration. This trend indicates that the conventional suppression function η(x)=e- ln (2)ISTED(x)/Is derived from picosecond STED may cause errors in evaluating the depletion process in CW STED microscopy. © 2018 The Authors Journal of Microscopy © 2018 Royal Microscopical Society.

Novel microtubule-targeted agent 6-chloro-4-(methoxyphenyl) coumarin induces G2-M arrest and apoptosis in HeLa cells

PubMed Central

Ma, Yi-ming; Zhou, Yu-bo; Xie, Chuan-ming; Chen, Dong-mei; Li, Jia

2012-01-01

Aim: To identify a novel coumarin analogue with the highest anticancer activity and to further investigate its anticancer mechanisms. Methods: The viability of cancer cells was investigated using the MTT assay. The cell cycle progression was evaluated using both flow cytometric and Western blotting analysis. Microtubule depolymerization was observed with immunocytochemistry in vivo and a tubulin depolymerization assay in vitro. Apoptosis was demonstrated using Annexin V/Propidium Iodide (PI) double-staining and sub-G1 analysis. Results: Among 36 analogues of coumarin, 6-chloro-4-(methoxyphenyl) coumarin showed the best anticancer activity (IC50 value about 200 nmol/L) in HCT116 cells. The compound had a broad spectrum of anticancer activity against 9 cancer cell lines derived from colon cancer, breast cancer, liver cancer, cervical cancer, leukemia, epidermoid cancer with IC50 value of 75 nmol/L–1.57 μmol/L but with low cytotocitity against WI-38 human lung fibroblasts (IC50 value of 12.128 μmol/L). The compound (0.04–10 μmol/L) induced G2-M phase arrest in HeLa cells in a dose-dependent manner, which was reversible after the compound was removed. The compound (10–300 μmol/L) induced the depolymerization of purified porcine tubulin in vitro. Finally, the compound (0.04–2.5 μmol/L) induced apoptosis of HeLa cells in dose- and time-dependent manners. Conclusion: 6-Chloro-4-(methoxyphenyl) coumarin is a novel microtubule-targeting agent that induces G2–M arrest and apoptosis in HeLa cells. PMID:22266726

Kinetics and Molecular Docking Studies of 6-Formyl Umbelliferone Isolated from Angelica decursiva as an Inhibitor of Cholinesterase and BACE1.

PubMed

Ali, Md Yousof; Seong, Su Hui; Reddy, Machireddy Rajeshkumar; Seo, Sung Yong; Choi, Jae Sue; Jung, Hyun Ah

2017-09-24

Coumarins, which have low toxicity, are present in some natural foods, and are used in various herbal remedies, have attracted interest in recent years because of their potential medicinal properties. In this study, we report the isolation of two natural coumarins, namely umbelliferone ( 1 ) and 6-formyl umbelliferone ( 2 ), from Angelica decursiva , and the synthesis of 8-formyl umbelliferone ( 3 ) from 1 . We investigated the anti-Alzheimer disease (anti-AD) potential of these coumarins by assessing their ability to inhibit acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1). Among these coumarins, 2 exhibited poor inhibitory activity against AChE and BChE, and modest activity against BACE1. Structure-activity relationship analysis showed that 2 has an aldehyde group at the C-6 position, and exhibited strong anti-AD activity, whereas the presence or absence of an aldehyde group at the C-8 position reduced the anti-AD activity of 3 and 1 , respectively. In addition, 2 exhibited concentration-dependent inhibition of peroxynitrite-mediated protein tyrosine nitration. A kinetic study revealed that 2 and 3 non-competitively inhibited BACE1. To confirm enzyme inhibition, we predicted the 3D structures of AChE and BACE1, and used AutoDock 4.2 to simulate binding of coumarins to these enzymes. The blind docking studies demonstrated that these molecules could interact with both the catalytic active sites and peripheral anionic sites of AChE and BACE1. Together, our results indicate that 2 has an interesting inhibitory activity in vitro, and can be used in further studies to develop therapeutic modalities for the treatment of AD.

Anticoagulation and high dose liver radiation. A preliminary report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lightdale, C.J.; Wasser, J.; Coleman, M.

Two groups of patients were observed for evidence of acute radiation hepatitis during high dose radiation to the liver. The first group of 18 patients with metastatic liver disease received an average of 4,050 rad to the whole liver. Half received anticoagulation with warfarin. One patient on anticoagulation developed evidence of acute radiation hepatitis while 2 patients did so without anticoagulation. Eleven patients with Hodgkin's disease received 4,000 rad to the left lobe of the liver during extended field radiation. Four of these 11 patients were anticoagulated to therapeutic range. Only one of the fully anticoagulated patients showed changes onmore » liver scan consistent with radiation hepatitis whereas three did so without anticoagulation. No serious sequelae from anticoagulation occurred in either group. These preliminary data suggest that anticoagulation may be safely administered with high dose hepatic radiation and that further trials with anticoagulation are warranted.« less

A coumarin-pyrazolone based fluorescent probe for selective colorimetric and fluorimetric fluoride detection: Synthesis, spectroscopic properties and DFT calculations

NASA Astrophysics Data System (ADS)

Babür, Banu; Seferoğlu, Nurgül; Seferoğlu, Zeynel

2018-06-01

A novel coumarin based fluorescence anion chemosensor (P-1) bearing pyrazolone as a receptoric part was synthesized and characterized by using FT-IR, 1H/13C NMR and HRMS for the purpose of recognition of anions in DMSO. P-1 has four tautomeric structures and the most stable tautomeric form of P-1 was determined experimentally and theoretically. The chemosensor P-1 consists two receptoric parts as free amide Nsbnd H and enamine Nsbnd H which is stabilized intramolecular H-bonding with coumarin carbonyl oxygen. P-1 interacts selectively with fluoride anion via amide Nsbnd H. The selectivity and sensitivity of probe to various anions were determined with spectrophotometric and 1H NMR titration techniques as experimentally and all results were also explained by theoretical calculations.

Synthesis and biological evaluation of novel tacrine derivatives and tacrine-coumarin hybrids as cholinesterase inhibitors.

PubMed

Hamulakova, Slavka; Janovec, Ladislav; Hrabinova, Martina; Spilovska, Katarina; Korabecny, Jan; Kristian, Pavol; Kuca, Kamil; Imrich, Jan

2014-08-28

A series of novel tacrine derivatives and tacrine-coumarin heterodimers were designed, synthesized, and biologically evaluated for their potential inhibitory effect on both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Of these compounds, tacrine-coumarin heterodimer 7c and tacrine derivative 6b were found to be the most potent inhibitors of human AChE (hAChE), demonstrating IC50 values of 0.0154 and 0.0263 μM. Ligands 6b, 6c, and 7c exhibited the highest levels of inhibitory activity against human BuChE (hBuChE), demonstrating IC50 values that range from 0.228 to 0.328 μM. Docking studies were performed in order to predict the binding modes of compounds 6b and 7c with hAChE/hBuChE.

Determination of coumarin, vanillin, and ethyl vanillin in vanilla extract products: liquid chromatography mass spectrometry method development and validation studies.

PubMed

de Jager, Lowri S; Perfetti, Gracia A; Diachenko, Gregory W

2007-03-23

A LC-MS method was developed for the determination of coumarin, vanillin, and ethyl vanillin in vanilla products. Samples were analyzed using LC-electrospray ionization (ESI)-MS in the positive ionization mode. Limits of detection for the method ranged from 0.051 to 0.073 microg mL(-1). Using the optimized method, 24 vanilla products were analyzed. All samples tested negative for coumarin. Concentrations ranged from 0.38 to 8.59 mg mL(-1) (x =3.73) for vanillin and 0.33 to 2.27 mg mL(-1) (x =1.03) for ethyl vanillin. The measured concentrations are compared to values calculated using UV monitoring and to results reported in a similar survey in 1988. Analytical results, method precision, and accuracy data are presented.

Oral anticoagulants for primary prevention, treatment and secondary prevention of venous thromboembolic disease, and for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis and cost-effectiveness analysis.

PubMed

Sterne, Jonathan Ac; Bodalia, Pritesh N; Bryden, Peter A; Davies, Philippa A; López-López, Jose A; Okoli, George N; Thom, Howard Hz; Caldwell, Deborah M; Dias, Sofia; Eaton, Diane; Higgins, Julian Pt; Hollingworth, Will; Salisbury, Chris; Savović, Jelena; Sofat, Reecha; Stephens-Boal, Annya; Welton, Nicky J; Hingorani, Aroon D

2017-03-01

Warfarin is effective for stroke prevention in atrial fibrillation (AF), but anticoagulation is underused in clinical care. The risk of venous thromboembolic disease during hospitalisation can be reduced by low-molecular-weight heparin (LMWH): warfarin is the most frequently prescribed anticoagulant for treatment and secondary prevention of venous thromboembolism (VTE). Warfarin-related bleeding is a major reason for hospitalisation for adverse drug effects. Warfarin is cheap but therapeutic monitoring increases treatment costs. Novel oral anticoagulants (NOACs) have more rapid onset and offset of action than warfarin, and more predictable dosing requirements. To determine the best oral anticoagulant/s for prevention of stroke in AF and for primary prevention, treatment and secondary prevention of VTE. Four systematic reviews, network meta-analyses (NMAs) and cost-effectiveness analyses (CEAs) of randomised controlled trials. Hospital (VTE primary prevention and acute treatment) and primary care/anticoagulation clinics (AF and VTE secondary prevention). Patients eligible for anticoagulation with warfarin (stroke prevention in AF, acute treatment or secondary prevention of VTE) or LMWH (primary prevention of VTE). NOACs, warfarin and LMWH, together with other interventions (antiplatelet therapy, placebo) evaluated in the evidence network. Efficacy  Stroke, symptomatic VTE, symptomatic deep-vein thrombosis and symptomatic pulmonary embolism. Safety  Major bleeding, clinically relevant bleeding and intracranial haemorrhage. We also considered myocardial infarction and all-cause mortality and evaluated cost-effectiveness. MEDLINE and PREMEDLINE In-Process & Other Non-Indexed Citations, EMBASE and The Cochrane Library, reference lists of published NMAs and trial registries. We searched MEDLINE and PREMEDLINE In-Process & Other Non-Indexed Citations, EMBASE and The Cochrane Library. The stroke prevention in AF review search was run on the 12 March 2014 and updated on 15 September 2014, and covered the period 2010 to September 2014. The search for the three reviews in VTE was run on the 19 March 2014, updated on 15 September 2014, and covered the period 2008 to September 2014. Two reviewers screened search results, extracted and checked data, and assessed risk of bias. For each outcome we conducted standard meta-analysis and NMA. We evaluated cost-effectiveness using discrete-time Markov models. Apixaban (Eliquis ® , Bristol-Myers Squibb, USA; Pfizer, USA) [5 mg bd (twice daily)] was ranked as among the best interventions for stroke prevention in AF, and had the highest expected net benefit. Edoxaban (Lixiana ® , Daiichi Sankyo, Japan) [60 mg od (once daily)] was ranked second for major bleeding and all-cause mortality. Neither the clinical effectiveness analysis nor the CEA provided strong evidence that NOACs should replace postoperative LMWH in primary prevention of VTE. For acute treatment and secondary prevention of VTE, we found little evidence that NOACs offer an efficacy advantage over warfarin, but the risk of bleeding complications was lower for some NOACs than for warfarin. For a willingness-to-pay threshold of > £5000, apixaban (5 mg bd) had the highest expected net benefit for acute treatment of VTE. Aspirin or no pharmacotherapy were likely to be the most cost-effective interventions for secondary prevention of VTE: our results suggest that it is not cost-effective to prescribe NOACs or warfarin for this indication. NOACs have advantages over warfarin in patients with AF, but we found no strong evidence that they should replace warfarin or LMWH in primary prevention, treatment or secondary prevention of VTE. These relate mainly to shortfalls in the primary data: in particular, there were no head-to-head comparisons between different NOAC drugs. Calculating the expected value of sample information to clarify whether or not it would be justifiable to fund one or more head-to-head trials. This study is registered as PROSPERO CRD42013005324, CRD42013005331 and CRD42013005330. The National Institute for Health Research Health Technology Assessment programme.

Palladium-catalyzed substitution of (coumarinyl)methyl acetates with C-, N-, and S-nucleophiles

PubMed Central

Chattopadhyay, Kalicharan; Fenster, Erik; Grenning, Alexander J

2012-01-01

Summary The palladium-catalyzed nucleophilic substitution of (coumarinyl)methyl acetates is described. The reaction proceeds though a palladium π-benzyl-like complex and allows for many different types of C-, N-, and S-nucleophiles to be regioselectively added to the biologically active coumarin motif. This new method was utilized to prepare a 128-membered library of aminated coumarins for biological screening. PMID:23019448

Bibliography of Soviet Laser Developments. Number 71, May - June 1984.

DTIC Science & Technology

1985-08-01

d * Coumarin *o..*....... .. o... -- e. Phthalimide ...... o..... o. .. ... --- f . Cyanine .. ... .o o . .. .. .. see. --- go Xanthene...Barinova, E.Yu. (MGU). Determining the concentration of nitrogen in gallium phosphide from its photoluminescence spectrum. VMUFA, no. 3, 1984, 59-62. 23...characteristics for lasing in solutions of rhodamine 6G in a small-base resonator. OPSPA, v.56, no.5, 1984, 884-888. 5 a’ F, c. Polymethine d. Coumarin e

Bibliography of Soviet Laser Developments, Number 83, May - June 1986.

DTIC Science & Technology

1987-09-01

Polymethine ..................... 8 d. Coumarin .. .o-... . .. . e. Phthalimide ................. --- f. Cyanine ....................... . - - g. Xanthene...KVEKA, no. 6, 1986, 1155-1160. 25. Kostanyan, R.B.; Sanamyan, T.V. 0. Stucy on lifetimes of erbium levels in lutecium aluminum garnet. DANAA, no. 3, 1985...60, no. 5, 1986, 937-942. d. Coumarin e. Phthalimide f. Cyanine g. Xanthene h. POPOP 2. Inorganic Liquids C. GAS LASERS 1. Theory 60. Basov, N.G

Coumarin Derivative Directly Coordinated to Lanthanides Acts as an Excellent Antenna for UV-Vis and Near-IR Emission.

PubMed

Guzmán-Méndez, Óscar; González, Federico; Bernès, Sylvain; Flores-Álamo, Marcos; Ordóñez-Hernández, Javier; García-Ortega, Héctor; Guerrero, Joselin; Qian, Wenjie; Aliaga-Alcalde, Nuria; Gasque, Laura

2018-02-05

A chelating coumarin-derived ligand sensitizes all emitting lanthanide ions in the solid state and gives high absolute quantum yields for ethanol solutions of complexes of Sm, Eu, Tb, and Dy, above 20% for the last two. Crystal structures of these four complexes are [Ln(Cum) 3 (H 2 O)(X)]·X where X = MeOH or EtOH.

Anti-Inflammatory Effect of Angelica gigas via Heme Oxygenase (HO)-1 Expression.

PubMed

Cho, Joon Hyeong; Kwon, Jung Eun; Cho, Youngmi; Kim, Inhye; Kang, Se Chan

2015-06-15

Angelica gigas (AG) is effective against various medical conditions such as bacterial infection, inflammation, and cancer. It contains a number of coumarin compounds and the group of interest is the pyranocoumarin, which comprises decursin and decursinol angelate. This group has an effect on controlling inflammation, which is caused by excessive nitric oxide (NO) production. Heme oxygenases (HOs), particularly HO-1, play a role in regulating the production of NO. Thus, this study aimed to investigate the anti-inflammatory effects of AG by measuring HO-1 expression. Treatments with CH2Cl2 layer and Angelica gigas extract (AGE) showed the highest NO inhibition effects. Decursin, decursinol angelate, and nodakenin were isolated from the CH2Cl2 layer of AGE. Decursin also demonstrated the highest anti-oxidative effect among the coumarins. Although decursin had the best NO inhibition and anti-oxidative effects, the effects of AGE treatment far surpassed that of decursin. This is owing to the combination effect of the coumarins present within AGE, which is a solvent extract of AG. The expression of HO-1 is an effective indicator of the anti-inflammatory effects of AG. Based on the results of the coumarin compounds, HO-1 expression was found to be dose dependent and specific to decursin.

Anti-Inflammatory Effect of Angelica gigas via Heme Oxygenase (HO)-1 Expression

PubMed Central

Cho, Joon Hyeong; Kwon, Jung Eun; Cho, Youngmi; Kim, Inhye; Kang, Se Chan

2015-01-01

Angelica gigas (AG) is effective against various medical conditions such as bacterial infection, inflammation, and cancer. It contains a number of coumarin compounds and the group of interest is the pyranocoumarin, which comprises decursin and decursinol angelate. This group has an effect on controlling inflammation, which is caused by excessive nitric oxide (NO) production. Heme oxygenases (HOs), particularly HO-1, play a role in regulating the production of NO. Thus, this study aimed to investigate the anti-inflammatory effects of AG by measuring HO-1 expression. Treatments with CH2Cl2 layer and Angelica gigas extract (AGE) showed the highest NO inhibition effects. Decursin, decursinol angelate, and nodakenin were isolated from the CH2Cl2 layer of AGE. Decursin also demonstrated the highest anti-oxidative effect among the coumarins. Although decursin had the best NO inhibition and anti-oxidative effects, the effects of AGE treatment far surpassed that of decursin. This is owing to the combination effect of the coumarins present within AGE, which is a solvent extract of AG. The expression of HO-1 is an effective indicator of the anti-inflammatory effects of AG. Based on the results of the coumarin compounds, HO-1 expression was found to be dose dependent and specific to decursin. PMID:26083119

Design and application of a fluorogenic assay for monitoring inflammatory caspase activity.

PubMed

Ranganathan, Raj; Lenti, Gena; Tassone, Nicholas M; Scannell, Brian J; Southern, Cathrine A; Karver, Caitlin E

2018-02-15

Various fluorogenic assays exist for monitoring the activity of inflammatory caspases. However, there are no continuous assays that provide C-terminal substrate sequence specificity for inflammatory caspases. As a first step towards this, we have developed a continuous in vitro assay that relies on monitoring emission from tryptophan after cleavage of a quenching coumarin chromophore. The coumarin can be attached as an amino acid side chain or capping the C-terminus of the peptide. When the coumarin is a side chain, it allows for C-terminal and N-terminal sequence specificities to be explored. Using this assay, we obtained Michaelis-Menten kinetic data for four proof-of-principle peptides: WEHD-AMC (K M  = 15 ± 2 μM), WEHD-MCA (K M  = 93 ± 19 μM), WEHDG-MCA (K M  = 21 ± 6 μM) and WEHDA-MCA (K M  = 151 ± 37 μM), where AMC is 7-amino-4-methylcoumarin and MCA is β-(7-methoxy-coumarin-4-yl)-Ala. The results indicate the viability of this new assay approach in the design of effective fluorogenic substrates for inflammatory caspases. Copyright © 2017 Elsevier Inc. All rights reserved.

Antimicrobial Effects of 7,8-Dihydroxy-6-Methoxycoumarin and 7-Hydroxy-6-Methoxycoumarin Analogues against Foodborne Pathogens and the Antimicrobial Mechanisms Associated with Membrane Permeability.

PubMed

Yang, Ji-Yeon; Park, Jun-Hwan; Lee, Myung-Ji; Lee, Ji-Hoon; Lee, Hoi-Seon

2017-10-03

The antimicrobial effects of 7,8-dihydroxy-6-methoxycoumarin and 7-hydroxy-6-methoxycoumarin isolated from Fraxinus rhynchophylla bark and of their structural analogues were determined in an attempt to develop natural antimicrobial agents against the foodborne pathogens Escherichia coli, Bacillus cereus, Staphylococcus intermedius, and Listeria monocytogenes. To elucidate the relationship between structure and antimicrobial activity for the coumarin analogues, isolated constituents and their structural analogues were evaluated against foodborne pathogens. Based on the culture plate inhibition zones and MICs, 6,7-dimethoxycoumarin, 7,8-dihydroxy-6-methoxycoumarin, 7-hydroxy-6-methoxycoumarin, and 7-methoxycoumarin, containing a methoxy functional group on the coumarin skeleton, had the notable antimicrobial activity against foodborne pathogens. However, 7-hydroxycoumarin and 6,7-dihydroxycoumarin, which contained a hydroxyl functional group on the coumarin skeleton, had no antimicrobial activity against these pathogens. An increase in cell membrane permeability was confirmed by electron microscopy observations, and release of extracellular ATP and cell constituents followed treatment with the ethyl acetate fraction of F. rhynchophylla extract. These findings indicate that F. rhynchophylla extract and coumarin analogues have potential for use as antimicrobial agents against foodborne pathogens and that the antimicrobial mechanisms are associated with the loss of cell membrane integrity.

In Situ Loading of Drugs into Mesoporous Silica SBA-15.

PubMed

Wan, Mi Mi; Li, Yan Yan; Yang, Tian; Zhang, Tao; Sun, Xiao Dan; Zhu, Jian Hua

2016-04-25

In a new strategy for loading drugs into mesoporous silica, a hydrophilic (heparin) or hydrophobic drug (ibuprofen) is encapsulated directly in a one-pot synthesis by evaporation-induced self-assembly. In situ drug loading significantly cuts down the preparation time and dramatically increases the loaded amount and released fraction of the drug, and appropriate drug additives favor a mesoporous structure of the vessels. Drug loading was verified by FTIR spectroscopy and release tests, which revealed much longer release with a larger amount of heparin or ibuprofen compared to postloaded SBA-15. Besides, the in vitro anticoagulation properties of the released heparin and the biocompatibility of the vessels were carefully assessed, including activated partial thromboplastin time, thrombin time, hemolysis, platelet adhesion experiments, and the morphologies of red blood cells. A concept of new drug-release agents with soft core and hard shell is proposed and offers guidance for the design of novel drug-delivery systems. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

[Incidence and clinical characteristics of perioperative pulmonary thromboembolism in Japan in 2008--results from the annual study of Japanese Society of Anesthesiologists, Committee on Patient Safety and Risk Management, Perioperative Pulmonary Thromboembolism Working Group].

PubMed

Kuroiwa, Masayuki; Furuya, Hitoshi; Seo, Norimasa; Kitaguchi, Kastuyasu; Nakamura, Mashio; Sakuma, Masahito; Chuma, Riichiro

2010-05-01

The Japanese Society of Anesthesiologists (JSA) has maintained records of the annual incidence and characteristics of perioperative pulmonary thromboembolism (perioperative PTE) since 2002. The aim of this paper was to provide recent results of the JSA annual study conducted in 2008, and to determine the current factors that tend to prevent perioperative venous thromboembolism (VTE) in Japan. A comprehensive questionnaire designed by the JSA PTE working group was mailed to all institutions certified as teaching hospitals by JSA. The data tics of patients with perioperative PTE, such as types of diseases and surgeries, age, sex, methods used for the prevention of VTE (in some cases), and prognosis of perioperative PTE. The rate of effective responses was 56.1% (634/1116), and 1,177,626 surgeries were registered during the study period. There were 324 patients who were reported to have had PTE, and the incidence was 2.75 per 10,000 surgeries. The incidence of perioperative PTE in 2008 did not change significantly from that in 2005-07. The surgeries that most commonly resulted in perioperative PTE were limb and/or hip joint surgery (5.71 per 10,000 surgeries), craniotomy (4.64 per 10,000), and thoracotomy with laparotomy (3.46 per 10,000 surgeries). The mortality rate of perioperative PTE in 2008 was found to have significantly decreased from that in 2005-07 (15.6% vs. 22.4%; P = 0.01). Further, the rate of patients who received anticoagulant drugs in 2008 was significantly higher than that in 2005-07 (17.6% vs. 10.8%; P = 0.0018). Individual guidelines for the prevention of perioperative VTE were adopted in 55.4% of the training institutions. The increase in the percentage of patients who received anticoagulant drugs around the time of the operation, and the decreased mortality of patients with perioperative PTE suggested that the prophylaxis for perioperative VTE with anticoagulant drugs reduces perioperative mortality.

Monitoring of argatroban and lepirudin anticoagulation in critically ill patients by conventional laboratory parameters and rotational thromboelastometry - a prospectively controlled randomized double-blind clinical trial.

PubMed

Beiderlinden, Martin; Werner, Patrick; Bahlmann, Astrid; Kemper, Johann; Brezina, Tobias; Schäfer, Maximilian; Görlinger, Klaus; Seidel, Holger; Kienbaum, Peter; Treschan, Tanja A

2018-02-09

Argatroban or lepirudin anticoagulation therapy in patients with heparin induced thrombocytopenia (HIT) or HIT suspect is typically monitored using the activated partial thromboplastin time (aPTT). Although aPTT correlates well with plasma levels of argatroban and lepirudin in healthy volunteers, it might not be the method of choice in critically ill patients. However, in-vivo data is lacking for this patient population. Therefore, we studied in vivo whether ROTEM or global clotting times would provide an alternative for monitoring the anticoagulant intensity effects in critically ill patients. This study was part of the double-blind randomized trial "Argatroban versus Lepirudin in critically ill patients (ALicia)", which compared critically ill patients treated with argatroban or lepirudin. Following institutional review board approval and written informed consent, for this sub-study blood of 35 critically ill patients was analysed. Before as well as 12, 24, 48 and 72 h after initiation of argatroban or lepirudin infusion, blood was analysed for aPTT, aPTT ratios, thrombin time (TT), INTEM CT,INTEM CT ratios, EXTEM CT, EXTEM CT ratios and maximum clot firmness (MCF) and correlated with the corresponding plasma concentrations of the direct thrombin inhibitor. To reach a target aPTT of 1.5 to 2 times baseline, median [IQR] plasma concentrations of 0.35 [0.01-1.2] μg/ml argatroban and 0.17 [0.1-0.32] μg/ml lepirudin were required. For both drugs, there was no significant correlation between aPTT and aPTT ratios and plasma concentrations. INTEM CT, INTEM CT ratios, EXTEM CT, EXTEM CT ratios, TT and TT ratios correlated significantly with plasma concentrations of both drugs. Additionally, agreement between argatroban plasma levels and EXTEM CT and EXTEM CT ratios were superior to agreement between argatroban plasma levels and aPTT in the Bland Altman analysis. MCF remained unchanged during therapy with both drugs. In critically ill patients, TT and ROTEM parameters may provide better correlation to argatroban and lepirudin plasma concentrations than aPTT. ClinicalTrials.gov , NCT00798525 , registered on 25 Nov 2008.

Effectiveness and safety of a 10mg warfarin initiation nomogram in Asian population.

PubMed

Chandriah, Haarathi; Kumolosasi, Endang; Islahudin, Farida; Makmor-Bakry, Mohd

2015-05-01

Anticoagulant responses to warfarin vary among patients, based on genetic factors, diet, concomitant medications, and disease state. We evaluated the effectiveness and safety of a 10mg warfarin initiation nomogram in an Asian population. Retrospective cross-sectional audit studies were conducted from March 2009 to March 2010. The use of a 10mg-loading dose to initiate warfarin treatment resulted in 33(84.6%) patients attaining a therapeutic INR within four days (mean time, 2.6 days). There was no significant correlation between age, gender, race, and serum albumin for the time to reach a therapeutic INR. A significant correlation was noted for patient's baseline INR and time to reach a therapeutic INR (P<0.05). No significant differences were observed in time to reach a therapeutic INR in patients treated with specific class of concomitant drugs or patients with specific disease states. The overall incidence of over-anticoagulation was 35.9%; however, no bleeding episodes were encountered. In conclusion, the use of a 10mg warfarin nomogram was effective in rapidly achieving a therapeutic INR. However, the nomogram's safety is debatable owing to the high over-anticoagulation rate warfarin-administered patients. Caution is recommended in the initiation of warfarin treatment using the 10mg nomogram.