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Glibenclamide pretreatment attenuates early hematoma expansion of warfarin-associated intracerebral hemorrhage in rats by alleviating perihematomal blood-brain barrier dysfunction

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Chinese Neurosurgical Journal 2024年第1期10卷 8-19页

作者： Zongwei Zeng Liang Liang Zhou Feng Peiwen Guo Xiaoke Hao Jishu Xian Hua Feng Yujie Chen Zhi Chen Department of Neurosurgery and State Key Laboratory of Trauma Burn and Combined InjurySouthwest HospitalThird Military Medical University(Army Medical University)Chongqing 400038China Department of Neurosurgery The 945Th Hospital of PLAYaanSichuan Province 625099China Department of Rehabilitation Southwest HospitalThird Military Medical University(Army Medical University)Chongqing 400038China Chongqing Key Laboratory of Precision Neuromedicine and Neuroregeneration Southwest HospitalThird Military Medical University(Army Medical University)Chongqing 400038China Chongqing Clinical Research Center for Neurosurgery Southwest HospitalThird Military Medical University(Army Medical University)Chongqing 400038China

Background Hematoma expansion is a determinant of poor outcome of intracerebral hemorrhage but occurs frequently,especially in warfarin-associated intracerebral hemorrhage(W-ICH).In the present study,we employ the warfarin-associated intracerebral hemorrhage(W-ICH)rat model,to explore the efficacy and potential mechanism of glibenclamide pretreatment on hematoma expansion after intracerebral hemorrhage,hoping to provide proof of concept that glibenclamide in stroke primary and secondary prevention is also potentially beneficial for intracerebral hemorrhage patients at early stage.Methods In the present study,we tested whether glibenclamide,a common hypoglycemic drug,could attenuate hematoma expansion in a rat model of W-ICH.Hematoma expansion was evaluated using magnetic resonance imaging;brain injury was evaluated by brain edema and neuronal death;and functional outcome was evaluated by neurological scores.Then blood-brain barrier integrity was assessed using Evans blue extravasation and tight junction-related protein.Results The data indicated that glibenclamide pretreatment significantly attenuated hematoma expansion at 24 h after W-ICH,thus mitigating brain edema and neuronal death and promoting neurological function recovery,which may benefit from alleviating blood-brain barrier disruption by suppressing matrix metallopeptidase-9.Conclusions The results indicate that glibenclamide pretreatment in stroke primary and secondary prevention might be a promising therapy for hematoma expansion at the early stage of W-ICH.

关键词： Intracerebral hemorrhage warfarin Glibenclamide Hematoma expansion Blood-brain barrier Matrix metallopeptidase-9

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Individualized anti-thrombotic therapy for acute myocardial infarction complicated with left ventricular thrombus: A case report

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World Journal of Clinical Cases 2024年第4期12卷 835-841页

作者： Yan Song Hua Li Xia Zhang Lei Wang Hong-Yan Xu Zhi-Chao Lu Xiao-Gang Wang Bo Liu Department of Clinical Pharmacy Zibo Municipal HospitalZibo 255400Shandong ProvinceChina Department of Cardiology Zibo Municipal HospitalZibo 255400Shandong ProvinceChina Department of Pharmacy Zibo Municipal HospitalZibo 255400Shandong ProvinceChina Department of Imaging Zibo Municipal HospitalZibo 255400Shandong ProvinceChina Department of Pulmonary and Critical Care Medicine Department of Clinical MicrobiologyZibo City Key Laboratory of Respiratory Infection and Clinical MicrobiologyZibo City Engineering Technology Research Center of Etiology Molecular DiagnosisZibo Municipal HospitalZibo 255400Shandong ProvinceChina

BACKGROUND Presently,there is no established standard anti-blood clot therapy for patients facing acute myocardial infarction(AMI)complicated by left ventricular thrombus(LVT).While vitamin K antagonists are the preferred choice for oral blood thinning,determining the best course of blood-thinning medication remains challenging.It is unclear if non-vitamin K antagonist oral blood thinners have different effectiveness in treating LVT.This study significantly contributes to the medical community.CASE SUMMARY The blood-thinning treatment of a patient with AMI and LVT was analyzed.Triple blood-thinning therapy included daily enteric-coated aspirin tablets at 0.1 g,daily clopidogrel hydrogen sulfate at 75 mg,and dabigatran etexilate at 110 mg twice daily.After 15 d,the patient’s LVT did not decrease but instead increased.Clinical pharmacists comprehensively analyzed the cases from the perspective of the patient’s disease status and drug interaction.The drug regimen was reformulated for the patient,replacing dabigatran etexilate with warfarin,and was administered for six months.The clinical pharmacist provided the patient with professional and standardized pharmaceutical services.The patient’s condition was discharged after meeting the international normalized ratio value(2-3)criteria.The patient fully complied with the follow-up,and the time in the therapeutic range was 78.57%,with no serious adverse effects during pharmaceutical monitoring.CONCLUSION warfarin proves to be an effective drug for patients with AMI complicated by LVT,and its blood-thinning course lasts for six months.

关键词： Myocardial infarction Left ventricular thrombus Dabigatran etexilate warfarin Clinical pharmacist Case report

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The combination of EGCG with warfarin reduces deep vein thrombosis in rabbits through modulating HIF-1αand VEGF via the PI3K/AKT and ERK1/2 signaling pathways

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Chinese Journal of Natural Medicines 2022年第9期20卷 679-690页

作者： LI Yan GE Jing-Ping MA Ke YIN Yuan-Yuan HE Juan GU Jian-Ping Department of Vascular and Interventional Radiology Nanjing First HospitalNanjing Medical UniversityNanjing 210006China Department of Acupuncture Qinhuai District Hospital of Traditional Chinese MedicineNanjing 210000China

Deep venous thrombosis(DVT)poses a major challenge to public health worldwide.Endothelial cell injury evokes inflammatory and oxidative responses that contribute to thrombus formation.Tea polyphenol(TP)in the form of epigallocatechin-3-gallate(EGCG)has anti-inflammatory and oxidative effect that may ameliorate DVT.However,the precise mechanism remains incompletely understood.The current study was designed to investigate the anti-DVT mechanism of EGCG in combination with warfarin(an oral anticoagulant).Rabbits were randomly divided into five groups.A DVT model of rats was established through ligation of the inferior vena cava(IVC)and left common iliac vein,and the animals were orally administered with EGCG,warfarin,or vehicle for seven days.In vitro studies included pretreatment of human umbilical vein endothelial cells(HUVECs)with different concentrations of EGCG for 2 h before exposure to hydrogen peroxide.Thrombus weight and length were examined.Histopathological changes were observed by hematoxylin-eosin staining.Blood samples were collected for detecting coagulation function,including thrombin and prothrombin times,activated partial thromboplastin time,and fibrinogen levels.Protein expression in thrombosed IVCs and HUVECs was evaluated by Western blot,immunohistochemical analysis,and/or immunofluorescence staining.RT-qPCR was used to determine the levels of AGTR-1 and VEGF mRNA in IVCs and HUVECs.The viability of HUVECs was examined by CCK-8 assay.Flow cytometry was performed to detect cell apoptosis and ROS generation was assessed by 2′,7ʹ-dichlorofluorescein diacetate reagent.In vitro and in vivo studies showed that EGCG combined with warfarin significantly reduced thrombus weight and length,and apoptosis in HUVECs.Our findings indicated that the combination of EGCG and warfarin protects HUVECs from oxidative stress and prevents apoptosis.However,HIF-1αsilencing weakened these effects,which indicated that HIF-1αmay participate in DVT.Furthermore,HIF-1αsilencing significantly up-regulated cell apoptosis and

关键词： Deep vein thrombosis EGCG warfarin HIF-1α VEGF PI3K/AKT ERK1/2

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Application of fresh frozen plasma transfusion in the management of excessive warfarin-associated anticoagulation

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Blood Science 2022年第2期4卷 57-64页

作者： Yuanyuan Luo Chunya Ma Yang Yu Department of Transfusion Medicine First Medical Center of PLA General HospitalBeijingP.R.China

warfarin is a commonly used oral anticoagulant.Patients with artificial valve replacement,atrial fibrillation,pulmonary embolism,deep vein thrombosis,and other diseases require long-term anticoagulant oral treatment with warfarin.As warfarin exhibits prompt action with long maintenance time,it has become a key drug for the treatment of patients at risk of developing thrombosis or thromboembolism.warfarin is a bican coumarin anticoagulant,that exhibits competitive action against vitamin K as its mechanism of action,thereby inhibiting the synthesis of coagulation factors—predominantly the vitamin K-dependent coagulation factors II,VII,IX,and X—in hepatocytes.Long-term warfarin is known to significantly increase the risk of organ bleeding in some patients,while some patients may need to reverse the anticoagulation effect.For instance,patients scheduled for emergency or invasive surgery may require rapid anticoagulation reversal.During such medical circumstances,fresh frozen plasma(FFP)is clinically used for the reversal of excess warfarin-associated anticoagulation,as it contains all the coagulation factors that can alleviate the abnormal blood anticoagulation status in such patients.Accordingly,this article aims to perform an in-depth review of relevant literature on the reversal of warfarin with FFP,and insightful deliberation of the application and efficacy of this clinical intervention.

关键词： Anticoagulation reversal Fresh frozen plasma warfarin

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Effectiveness and safety of apixaban and rivaroxaban vs warfarin in patients with atrial fibrillation and chronic kidney disease

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World Journal of Nephrology 2023年第5期12卷 132-146页

作者： Sylvie Perreault Laurie-Anne Boivin Proulx Aurélie Lenglet Ziad A Massy Marc Dorais Faculty of Pharmacy University of MontrealQuebecMontreal H3C3J7Canada Department of Cardiology Faculty of MedicineUniversity of Ottawa Heart InstituteOntarioOttawa K1Y4W7Canada Department of Pharmacy Amiens-Picardie Hospital University CenterAmiens 80000France Faculty of Pharmacy MP3CV LaboratoryUR7545University of Picardie Jules VerneAmiens 80000France Division of Nephrology University of Paris Ouest-Versailles-Saint-Quentin-en-Yvelines(UVSQ)VillejuifFrance.AP-HP Ambroise-ParéHospitalBoulogne Billancourt/Paris 92104France StatSciences Inc. Notre-Dame-de-l’Île-PerrotQuebecMontreal J7W 3K8Canada

BACKGROUND Randomized controlled trials(RCTs)of direct oral anticoagulants(DOACs)included a low proportion of atrial fibrillation(AF)patients with chronic kidney disease(CKD),and suggested that DOACs are safe and effective in patients with mild-to-moderate CKD.In a metanalysis of RCTs and observational studies,DOACs were associated with better efficacy(vs warfarin)in early CKD and had similar efficacy and safety profiles in patients with stages IV-V CKD.But few studies have provided data on the safety and effectiveness of each DOAC vs warfarin in patients with stage III CKD.The effectiveness and safety of DOACs in those patients are still subject to debate.AIM To assess and compare the effectiveness and safety of apixaban and rivaroxaban vs warfarin in this patient population.METHODS A cohort of patients with an inpatient or outpatient code for AF and stage III CKD who were newly prescribed apixaban and rivaroxaban was created using the administrative databases from the Quebec province of Canada between 2013 and 2017.The primary effectiveness outcome was a composite of ischemic stroke,systemic embolism,and death,whereas the primary safety outcome was a composite of major bleeding within a year of DOAC vs warfarin initiation.Treatment groups were compared in an under-treatment analysis using inverse probability of treatment weighting and Cox proportional hazards.RESULTS A total of 8899 included patients filled out a new oral anticoagulation therapy claim;3335 for warfarin and 5564 for DOACs.Compared with warfarin,15 mg and 20 mg rivaroxaban presented a similar effectiveness and safety composite risk.Apixaban 5.0 mg was associated with a lower effectiveness composite risk[Hazard ratio(HR)0.76;95%confidence interval(CI):0.65-0.88]and a similar safety risk(HR 0.94;95%CI:0.66-1.35).Apixaban 2.5 mg was associated with a similar effectiveness composite(HR 1.00;95%CI:0.79-1.26)and a lower safety risk(HR 0.65;95%CI:0.43-0.99.Although,apixaban 5.0 mg was associated with a better effectiveness(HR 0.76;95%CI:0.65-0.88),but a

关键词： Atrial fibrillation Chronic kidney disease Direct oral anticoagulant Effectiveness Safety warfarin

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Optimal INR level in elderly and non-elderly patients with atrial fibrillation receiving warfarin: a report from the COOL-AF nationwide registry in Thailand

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Journal of Geriatric Cardiology 2020年第10期17卷 612-620页

作者： Rungroj Krittayaphong Rapeephon Kunjara-Na-Ayudhya Pornchai Ngamjanyaporn Smonporn Boonyaratavej Chulalak Komoltri Ahthit Yindeengam Piyamitr Sritara Gregory YHLip Division of Cardiology Department of MedicineFaculty of Medicine Siriraj HospitalMahidol UniversityBangkokThailand Department of Cardiology Vichaiyut Hospital and Medical CenterBangkokThailand Department of Cardiology Chonburi HospitalChonburiThailand Division of Cardiology Department of MedicineFaculty of MedicineChulalongkorn UniversityBangkokThailand Department of Research Promotion Faculty of Medicine Siriraj HospitalMahidol UniversityBangkokThailand Her Majesty Cardiac Center Faculty of Medicine Siriraj HospitalMahidol UniversityBangkokThailand Division of Cardiology Department of MedicineFaculty of Medicine Ramathibodi HospitalMahidol UniversityBangkokThailand Liverpool Centre for Cardiovascular Science University of Liverpool and Liverpool Heart&Chest HospitalLiverpoolUnited Kingdom Aalborg Thrombosis Research Unit Department of Clinical MedicineAalborg UniversityAalborgDenmark

Background Asian population are at increased risk of bleeding during the warfarin treatment,so the recommended optimal international normalized ratio(INR)level may be lower in Asians than in Westerners.The aim of this prospective multicenter study was to determine the optimal INR level in Thai patients with non-valvular atrial fibrillation(NVAF).Methods Patients with NVAF who were on warfarin for stroke prevention were recruited from 27 hospitals in the nationwide COOL-AF registry in Thailand.We collected demographic data,medical history,risk factors for stroke and bleeding,concomitant disease,electrocardiogram and laboratory data including INR and antithrombotic medications.Outcome measurements included ischemic stroke/transient ischemic attack(TIA)and major bleeding.Optimal INR level was assessed by the calculation of incidence density for six INR ranges(<1.5,1.5–1.99,2–2.49,2.5–2.99,3–3.49,and≥3.5).Results A total of 2,232 patients were included.The mean age of patients was 68.5±10.6 years.The mean follow-up duration was 25.7±10.6 months.There were 63 ischemic stroke/TIA and 112 major bleeding events.The lowest prevalence of ischemic stroke/TIA and major bleeding events occurred within the INR range of 2.0–2.99 for patients<70 years and 1.5–2.99 for patients≥70 years.Conclusions The INR range associated with the lowest risk of ischemic stroke/TIA and bleeding in the Thai population was 2.0–2.99 for patients<70 years and 1.5–2.99 for patients≥70 years.The rates of major bleeding and ischemic stroke/TIA were both higher than the rates reported in Western population.

关键词： Bleeding Ischemic stroke Non-valvular atrial fibrillation Optimal international normalized ratio Thailand warfarin

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Pre-treatment with puerarin affects pharmacokinetics of warfarin, but not clopidogrel, in experimental rats

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Chinese Journal of Natural Medicines 2015年第4期13卷 257-263页

作者： LIU An-Chang ZHAO Li-Xia YU Shu-Wen LOU Hong-Xiang Qilu hospital of Shandong University Jinan Central Hospital Affiliated to Shandong University School of Pharmaceutical Sciences Shandong University

The present study was designed to determine the effects of puerarin pre-treatment on the pharmacokinetics of the oral anticoagulant agent warfarin and the antiplatelet agent clopidogrel in rats. In the treatment group, rats was gavaged with warfarin or clopidogrel after repeated treatment with puerarin at intraperitoneal doses of 20, 60, or 200 mg·kg-1 for 7 days, while rats in the control group were administrated only with the same dose warfarin or clopidogrel. Plasma samples were obtained at the prescribed times and analyzed by liquid chromatography tandem mass spectrometry(LC-MS/MS). The results showed that rats treated with puerarin at all the test doses of 20, 60 and 200 mg·kg-1 were found to affect the pharmacokinetics of warfarin, but not clopidogrel, suggesting a potential herb-drug interaction between puerarin and warfarin.

关键词： Puerarin warfarin Clopidogrel Pharmacokinetics Drug interaction

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Local Proinflammatory Effects of Repeated Skin Exposure to warfarin, An Anticoagulant Rodenticide in Rats

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Biomedical and Environmental Sciences 2011年第2期24卷 180-189页

作者： Aleksandra POPOV Ivana MIRKOV Lidija ZOLOTAREVSKI Milena JOVIC Sandra BELIJ Dragan KATARANOVSKI Milena KATARANOVSKI Department of Ecology Institute for Biological Research "Sinisa Stankovic" University of Belgrade Institute for Pathology Military Medical Academy Institute of Zoology Faculty of Biology University of Belgrade Institute of Physiology and Biochemistry Faculty of Biology University of Belgrade

Objective： To evaluate the effects of epicutaneous application of anticoagulant warfarin, by examining the presence of tissue injury and immune/inflammatory activity in exposed skin. Methods： Rats were exposed to warfarin by applying 10 μg of warfarin‐sodium to 10‐12 cm 2 skin （range 0.8‐1 μg per 1 cm 2 ） for 3 consecutive days. Tissue injury was evaluated by lipid peroxidation, histomorphological changes and signs of reparative activity in skin. T cell infiltration and selected aspects of epidermal cell activity were examined as indicators of immune/inflammatory skin response to warfarin application. Results： Repeated warfarin application exerted no effect on skin metabolic viability, but resulted in tissue injury （increased malondialdehyde, MDA, production, evident histo‐morphological changes in epidermis and dermis depicting cell injury and death）. Increased numbers of proliferating cell nuclear antigen （PCNA ＋） cells indicated reparative processes in injured skin. Infiltration of CD3 ＋ cells （T lymphocytes） along with the increased production of tumor necrosis factor‐α （TNF‐α） by epidermal cells from warfarin‐treated skin and their co‐stimulatory effect in an in vitro T‐cell activation assay demonstrated immunomodulatory effects of epicutaneous warfarin. Conclusion： Presented data have documented tissue damage associated with immune/ inflammatory activity in skin exposed to warfarin. Observed effects are relevant to immunotoxic potential of this anticoagulant in settings of external exposure.

关键词： Rats warfarin Epicutaneous exposure Tissue damage Skin inflammation

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VKORC1 genotypes are associated with response to warfarin but free warfarin concentration during initial anticoagulation in healthy Chinese volunteers

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Chinese Medical Journal 2009年第18期122卷 2117-2122页

作者： XIE Shuang LIU Hong TIAN Lei JIANG Juan-juan CHEN Guo-liang LIU Li-wei XU Li LI Yi-shi Key Laboratory of Clinical Trial Research in Cardiovascular Drugs Ministry of Health Fu Wai Hospital Chinese Academy of Medical Sciences Beijing 100037 China Peking Union Medical College Chinese Academy of Medical Sciences Beijing 100037 China

Background The genetic variations in VKORC1 modulate the stable responses to warfarin administration. But the role of VKORC1 polymorphisms during the initial anticoagulation and elimination period in the Hart Chinese population is not clear. Methods Twenty-four healthy Chinese volunteers were grouped according to their VKORC1 genotype. Twelve subjects were in the 3 mg group and 12 in the 6 mg group. VKORC1 genotypes were determined by a polymerase chain reaction （PCR） based restriction fragment length polymorphism （RFLP） assay and sequencing. The international normalized ratio （INR） was measured with an ACL9000 coagulation analyser. Plasma free warfarin concentration was measured with LC/MS/MS. Results In the initial anticoagulation period, the -1639AG and 1173TC carriers compared with the -1639AA and 1173TT carriers had a low INR value. The differences between genotypes with regard to INR values were more obvious in the 3 mg subjects （P 〈0.05）, and were not significantly different among the 6 mg subjects （P〉0.05）. On the contrary, no significant difference of plasma free warfarin concentration between genotypes was observed in each dosage group. It took 96 hours for the INR value and 144 hours for the free warfarin plasma concentration to come back to baselines after the last dose. No significant difference among genotypes and dosing groups was detected in the elimination phase （P〉0.05）. Conclusion VKORC1 polymorphisms are associated with differences in the initial response to warfarin when given at fixed doses, without affecting, as expected, its plasma concentration.

关键词： warfarin VKORC1 genotype international normalized ratio free warfarin plasma concentration

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Whether warfarin Therapy is Associated with Damage on Renal Function in Chinese Patients with Nonvalvular Atrial Fibrillation

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Chinese Medical Journal 2016年第10期129卷 1135-1139页

作者： Yu Kong Xin Du Ri-Bo Tang Ting Zhang Xue-Yuan Guo Jia-Hui Wu Shi-Jun Xia Chang-Sheng Ma Department of Cardiology Beijing Anzhen Hospital Capital Medical University Beijing 100029 China

Background： warfarin is the most common oral anticoagulant to decrease the stroke risk associated with atrial fibrillation （AF）. There are very few prospective studies that have explored whether warfarin has an association with damage on renal function in Chinese patients with nonvalvular AF （NVAF）. The aim of this study was to evaluate the effects of warfarin on renal function and study the factors associated with kidney dysfunction in Chinese adult NVAF patients without dialysis therapy. Methods： From January 2011 to December 2013, a total of 951 NVAF patients from 18 hospitals were enrolled. The estimated glomerular filtration rate （eGFR） was calculated from baseline and fbllow-up serum creatinine levels. Kaplan-Meier survival curves compared the survival of a 〉25% decline in eGFR （hereafter, endpoint）~ while Cox models estimated hazard ratios （HRs） and 95% confidence intervals for this event after adjustment for age, gender, and selected potential risk factors for renal dysfunction. Cox regression analysis of the various clinical potential variables was performed to identify the predictors of a -〉25% decline in eGFR. Results： After a 58-month follow-up, 951 NVAF patients were divided by observation into warfarin （n = 655） and no anticoagulation groups （n = 296） and 120 （12.6%） patients experienced renal endpoint. Kaplan-Meier survival curves showed that the survival period was not different in the two groups （χ2 = 0.178, log-rank P = 0.67）, but patients with systolic blood pressure （SBP）〈140 mmHg have significant difference with patients with SBP ≥140 mmHg （χ2 = 4.903, log-rank P = 0.03）. Multivariate Cox regression analysis revealed baseline eGFR and SBP as independent predictors of the endpoint, with HRs of 1.00, and 1.02, respectively. Conclusion： In patients with NVAF, eGFR and SBP are associated with the deterioration of kidney function while warfarin is not the risk factor of the ≥25% decline in eGFR.

关键词： Anticoagulation Estimated Glomerular Filtration Rate： Nonvalvular Atrial Fibrillation Renal Function warfarin

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