Publications by authors named "Yuko Honda"

41 Publications

Pulmonary Actinomycosis and Mucormycosis Coinfection in a Patient With Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia Undergoing Chemotherapy.

J Pediatr Hematol Oncol 2021 Apr 26. Epub 2021 Apr 26.

Department of Pediatrics, Kitakyushu City Yahata Hospital Department of Pediatrics, School of Medicine, University of Occupational and Environmental Health, Kitakyushu Department of Pediatrics, Kagoshima University Graduate School of Medical and Dental of Sciences, Kagoshima, Japan.

Mucormycosis is an opportunistic and progressive infection, while actinomycosis usually grows gradually and rarely develops in immunocompromised patients. Here we report a patient with Philadelphia chromosome-positive acute lymphoblastic leukemia who developed a pulmonary actinomycosis and mucormycosis coinfection. Once the diagnosis of actinomycosis was confirmed by bronchoscopy, lobectomy performed before stem cell transplantation revealed mucormycosis. The patient successfully underwent transplantation using a therapeutic antifungal agent for mucormycosis. When an immunocompromised patient develops an infection of unknown etiology, physicians should consider these pathogens as the possible cause. In addition, surgical intervention should be considered as an important treatment option.
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http://dx.doi.org/10.1097/MPH.0000000000002181DOI Listing
April 2021

De novo filament formation by human hair keratins K85 and K35 follows a filament development pattern distinct from cytokeratin filament networks.

FEBS Open Bio 2021 May 3;11(5):1299-1312. Epub 2021 Apr 3.

Faculty of Biotechnology and Life Science, Sojo University, Kumamoto, Japan.

In human hair follicles, the hair-forming cells express 16 hair keratin genes depending on the differentiation stages. K85 and K35 are the first hair keratins expressed in cortical cells at the early stage of the differentiation. Two types of mutations in the gene encoding K85 are associated with ectodermal dysplasia of hair and nail type. Here, we transfected cultured SW-13 cells with human K85 and K35 genes and characterized filament formation. The K85-K35 pair formed short filaments in the cytoplasm, which gradually elongated and became thicker and entangled around the nucleus, indicating that K85-K35 promotes lateral association of short intermediate filaments (IFs) into bundles but cannot form IF networks in the cytoplasm. Of the K85 mutations related to ectodermal dysplasia of hair and nail type, a two-nucleotide (C T ) deletion (delCT) in the protein tail domain of K85 interfered with the K85-K35 filament formation and gave only aggregates, whereas a missense mutation (233A>G) that replaces Arg with His (R78H) in the head domain of K85 did not interfere with the filament formation. Transfection of cultured MCF-7 cells with all the hair keratin gene combinations, K85-K35, K85(R78H)-K35 and K85(delCT)-K35, as well as the individual hair keratin genes, formed well-developed cytoplasmic IF networks, probably by incorporating into the endogenous cytokeratin IF networks. Thus, the unique de novo assembly properties of the K85-K35 pair might play a key role in the early stage of hair formation.
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http://dx.doi.org/10.1002/2211-5463.13126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091587PMC
May 2021

Prolongation of clot lysis time by a direct thrombin inhibitor melagatran mediated by paradoxical enhancement of thrombin generation: comparison with a direct factor Xa inhibitor edoxaban.

Blood Coagul Fibrinolysis 2021 Apr;32(3):209-215

Biological Research Laboratories, R & D Division, Daiichi Sankyo Co., Ltd, Tokyo, Japan.

Previously, we reported that a direct thrombin inhibitor melagatran paradoxically increased thrombin generation in human plasma in the presence of thrombomodulin. The aim of this study is to test the hypothesis that melagatran may exert a deleterious effect on tissue-type plasminogen activator (t-PA)-induced fibrinolysis via enhancement of thrombin generation and subsequent activation of thrombin-activatable fibrinolysis inhibitor (TAFI) and factor XIII (FXIII). Clot formation in human plasma containing t-PA and thrombomodulin was induced by tissue factor. The absorbance at 405 nm was measured to obtain clot lysis time. Effects of melagatran and a factor Xa inhibitor edoxaban on clot lysis time were determined. In the presence of thrombomodulin, melagatran significantly prolonged clot lysis time, but edoxaban shortened it. In the absence of thrombomodulin, melagatran did not inhibit fibrinolysis. Prolongation of clot lysis time by melagatran was reversed by activated protein C (which suppressed thrombin generation increased by melagatran) and a TAFIa inhibitor. Melagatran significantly suppressed plasmin generation, while edoxaban significantly increased it. However, both melagatran and edoxaban suppressed FXIII activation. In the clot formed in the presence of melagatran and edoxaban, the fibrin fibre was thin compared with control, showing no clear difference in the clot structures between melagatran and edoxaban. These results indicated that melagatran, not edoxaban, prolonged clot lysis time through the paradoxical enhancement of thrombin generation, and subsequent TAFI activation and inhibition of plasmin generation. Neither FXIII activation nor change in fibrin clot structure contributed to the inhibition of fibrinolysis by melagatran.
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http://dx.doi.org/10.1097/MBC.0000000000001020DOI Listing
April 2021

Edoxaban, a direct oral factor Xa inhibitor, ameliorates coagulation, microvascular thrombus formation, and acute liver injury in a lipopolysaccharide-induced coagulopathy model in rats.

J Thromb Thrombolysis 2021 Feb 3. Epub 2021 Feb 3.

Pharmacovigilance Department, Daiichi Sankyo Co., Ltd., Tokyo, 103-8426, Japan.

Infection increases the risk of thrombosis through the activation of inflammation and coagulation. Edoxaban, a direct oral factor Xa inhibitor, is used for the prevention and treatment of thrombotic diseases. The aim of this study was to determine the effects of edoxaban on microvascular thrombus formation in a rat model of lipopolysaccharide (LPS)-induced coagulopathy. Rats were intravenously injected with 7.5 mg/kg of LPS (Escherichia coli 055:B5). Immediately after LPS injection, the rats were treated with subcutaneous injection of edoxaban. At 2 and 6 h after the injection of LPS, biomarkers of coagulation and organ damages and inflammatory cytokines were measured. Microvascular thrombus formation in organs was evaluated using I-fibrinogen (human) or by the pathological analysis. Mortality was examined 24 h after LPS injection. After the injection of LPS, D-dimer and thrombin-antithrombin complex increased and platelet numbers decreased, indicating the activation of coagulation. Microvascular thrombi were found in the liver. Markers of liver injury (aspartate aminotransferase and alanine aminotransferase) also increased. Treatment with edoxaban attenuated the changes in the coagulation markers and microvascular thrombus formation in the liver. Edoxaban suppressed the increase in the liver injury markers and reduced the mortality. Edoxaban did not affect the levels of inflammatory cytokines. In conclusions, edoxaban significantly inhibited the activation of coagulation, the formation of microvascular thrombus in the liver and the liver damage, and reduced mortality in rats injected with LPS. These results suggest that the FXa inhibition by edoxaban might be a beneficial therapy for the management of infection-associated thrombosis.
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http://dx.doi.org/10.1007/s11239-021-02381-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856452PMC
February 2021

Improving Acute In-Hospital Stroke Care by Reorganization of an In-Hospital Stroke Code Protocol.

J Stroke Cerebrovasc Dis 2021 Jan 4;30(1):105433. Epub 2020 Nov 4.

Department of Stroke and Cerebrovascular Medicine, Kyorin University, Tokyo, Japan.

Background And Purpose: Delays in recognition and assessment of in-hospital strokes (IHS) can lead to poor outcomes. The aim was to examine whether reorganized IHS code protocol can reduce treatment time.

Methods: IHS code protocol was developed, educational workshops were held for medical personnel. In the protocol, any medical personnel should directly consult a stroke neurologist before any diagnostic studies. Time intervals were compared between the pre- and post-implementation periods and between direct consultation with a stroke neurologist (DC group) and non-DC group in the post-implementation period.

Results: A total of 145 patients were included (pre, 42; post, 103). Time from recognition to stroke neurologist assessment (91 vs. 35 min, p = 0.002) and time from recognition to neuroimaging (123 vs. 74, p = 0.013) were significantly lower in the post-implementation period. Time from stroke neurologist assessment to groin puncture was significantly lower (135 vs. 81, p = 0.037). In the post-implementation period, DC group showed significant time savings from last known well (LKW) to recognition (93 vs. 260, p = 0.001), LKW to stroke neurologist assessment (145 vs. 378, p = 0.001), and recognition to stroke neurologist assessment (16 vs. 76, p < 0.001) compared with non-DC group.

Conclusions: Reorganization of IHS code protocol reduced time from stroke recognition to assessment and treatment time. Reorganized IHS code and direct consultation with a stroke neurologist improved the initial response time.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.105433DOI Listing
January 2021

Recurrent Shoulder Tip Pain After Ventriculoperitoneal Shunt Placement Associated with Infectious Peritonitis with Propionibacterium acnes; A Case Report and Review of the Literature.

J UOEH 2020 ;42(2):209-216

Department of Neurosurgery, School of Medicine, University of Occupational and Environmental Health, Japan.

Ventriculoperitoneal (VP) shunt placement is commonly performed for the treatment of hydrocephalus, and several complications of this procedure are well known. Radiating shoulder tip pain after VP shunt placement has been reported as an unusual complication in a few cases, associated with dislocation of the peritoneal catheter. We described the case of a 9-year-old girl who presented with recurrent radiating shoulder tip pain after VP shunt placement. The pain recurred after peritoneal catheter repositioning because of peritoneal inflammation and adhesion due to peritonitis with Propionibacterium acnes (P. acnes). This bacterium was isolated using 16S ribosomal RNA gene polymerase chain reaction (16S rRNA gene PCR), and anaerobic and prolonged culture tests. After antibacterial treatment, ventriculoarterial (VA) shunt placement was successfully performed. Hemidiaphragm irritation by the peritoneal catheter leads to radiating shoulder tip pain, and peritoneal inflammation and adhesion caused by infectious peritonitis may cause recurrence of this despite catheter repositioning. Clinicians should be aware of shoulder pain as a complication of VP shunt placement, and should consider VA shunt placement as an alternative treatment if this symptom recurs after catheter repositioning. Furthermore, 16S rRNA gene PCR and anaerobic and prolonged culture tests should be considered to detect P. acnes infection.
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http://dx.doi.org/10.7888/juoeh.42.209DOI Listing
August 2020

Combined effect of a direct oral anticoagulant edoxaban and an inhibitor of activated thrombin-activatable fibrinolysis inhibitor on clot lysis.

J Thromb Thrombolysis 2020 Jan;49(1):94-99

End-Organ Disease Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

Fibrinolysis is regulated by the thrombin/thrombin-activatable fibrinolysis inhibitor (TAFI) system. Thus, anticoagulants and inhibitors of TAFI are expected to accelerate fibrinolysis. The combined effects of an anticoagulant and a TAFIa inhibitor on fibrinolysis remain unknown. The aim of this study was to evaluate the combined effect of edoxaban, an oral direct factor Xa (FXa) inhibitor, and a TAFIa inhibitor, potato tuber carboxypeptidase inhibitor (PCI) on tissue-type plasminogen activator (t-PA)-induced clot lysis in human plasma in vitro. Pooled human plasma (containing 180 ng/mL t-PA and 0.1 nM thrombomodulin) was mixed with edoxaban and/or PCI. Clot formation was induced by 2.5 pM tissue factor and 4 µM phospholipids and clot lysis time was examined. Plasma plasmin-α2 antiplasmin complex (PAP) concentration was measured as a marker of plasmin generation. Edoxaban or PCI alone significantly shortened the t-PA-induced clot lysis time and plasma PAP concentration. The combination of these compounds significantly accelerated the clot lysis compared with the inhibitors alone. Addition of PCI (0.3, 1, and 3 μg/mL) to 75 ng/mL edoxaban increased plasma PAP concentration compared with edoxaban alone; however, compared with PCI alone only the combination of 0.3 μg/mL PCI + 75 ng/mL edoxaban showed the significant increase in PAP concentration. Concomitant use of an oral direct FXa inhibitor, edoxaban, and a TAFIa inhibitor, PCI, significantly accelerate fibrinolysis via enhancement of plasmin generation. These results suggest that the combination of edoxaban and a TAFIa inhibitor might be beneficial for the treatment of thromboembolic diseases.
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http://dx.doi.org/10.1007/s11239-019-01929-3DOI Listing
January 2020

[A Pediatric Case of Xanthogranuloma in the Suprasellar Region Detected by a Severe Short Stature after 6 Years Growth Failure].

J UOEH 2019 ;41(2):249-257

Department of Pediatrics, School of Medicine, University of Occupational and Environmental Health, Japan.

Here we report a case of a 12-year-old girl who was referred to our department because of marked short stature of more than -5 SD below the median. Although her growth failure began suddenly at 6 years of age, she never had an examination because she had no other symptoms. Brain MRI examination suggested a tumor in the suprasellar region, and endocrine examination revealed combined pituitery hormone deficiency due to the tumor. Before surgery, the supplementation with hydrocortisone and levothyroxine was initiated. The pathological diagnosis of the surgically removed tumor was xanthogranuloma. The pattern of her growth curve showed a growth failure with sudden onset, which is a typical pattern of short stature secondary to pituitary disfunction including growth hormone deficiency associated with brain tumors. This case suggests that growth failure could be the only symptom in pediatric cases with brain tumors. Improved awareness regarding the association of growth failure with brain tumors is needed for earlier diagnosis and treatment. Furthermore, the growth curves should be carefully evaluated in regular health examinations at school.
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http://dx.doi.org/10.7888/juoeh.41.249DOI Listing
December 2019

A direct oral anticoagulant edoxaban accelerated fibrinolysis via enhancement of plasmin generation in human plasma: dependent on thrombin-activatable fibrinolysis inhibitor.

J Thromb Thrombolysis 2019 Jul;48(1):103-110

End-Organ Disease Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

A direct oral anticoagulant, edoxaban, is as effective as vitamin K antagonists for the treatment of venous thromboembolism (VTE). However, the mechanism underlying the treatment effect on VTE remains to be determined. The aims of this study were to evaluate the effect of edoxaban on tissue plasminogen activator (t-PA)-induced clot lysis in human plasma and to determine the roles of plasmin and thrombin-activatable fibrinolysis inhibitor (TAFI) in the profibrinolytic effect by edoxaban. Pooled human normal plasma or TAFI-deficient plasma (containing 180 ng/mL t-PA and 0.1 nM thrombomodulin) was mixed with edoxaban or an activated TAFI inhibitor, potato tuber carboxypeptidase inhibitor (PCI). Clot was induced by adding tissue factor and phospholipids. Clot lysis time and plasma plasmin-α2 antiplasmin complex (PAP) concentration were determined. Clot structure was imaged with a scanning electron microscope. In normal plasma, edoxaban at clinically relevant concentrations (75, 150, and 300 ng/mL) and PCI significantly shortened clot lysis time. PCI increased PAP concentration and a correlation between PAP concentration and percent of clot lysis was observed. Edoxaban also dose-dependently elevated PAP concentration. In TAFI-deficient plasma, the effects of edoxaban and PCI on clot lysis and PAP concentration were markedly diminished as compared with normal plasma. Fibrin fibers were thinner in clots formed in the presence of edoxaban. In conclusion, edoxaban at clinically relevant concentrations accelerates t-PA-induced fibrinolysis via increasing plasmin generation in human plasma. The effects of edoxaban is mainly dependent on TAFI. The profibrinolytic effect of edoxaban might contribute to the efficacy for the treatment of VTE.
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http://dx.doi.org/10.1007/s11239-019-01851-8DOI Listing
July 2019

Predictable Value of Functional Independence Measure Differs between Anterior and Posterior Circulation Ischemic Strokes.

Eur Neurol 2018 21;80(5-6):313-320. Epub 2019 Mar 21.

Department of Stroke and Cerebrovascular Medicine, Kyorin University, Mitaka, Tokyo, Japan.

Background: The functional independence measure (FIM) is a standard tool to provide a detailed evaluation of ADL of patients with disabilities. This study aimed to show the differences in FIM scores as an outcome predictor between patients with anterior circulation (AC) and posterior circulation (PC) strokes.

Methods: Consecutive patients with acute ischemic stroke hospitalized within 7 days after onset were investigated. Baseline NIHSS scores, 1st-FIM (< 72 h after -admission to stroke unit), 2nd-FIM (< 72 h before discharge), and modified Rankin Scale (mRS) scores were collected. Logistic regression analyses were used to identify predictors of a favorable outcome (mRS 0-2) at 3-month after stroke.

Results: Three hundred eighty-five patients (median age, 78 years; male, 59%; median length of stroke unit stay, 20 days) were included. The median baseline NIHSS, 1st- and 2nd-FIM scores were 4 (interquartile range 2-9), 65 (33-91), and 98 (54-122) respectively. Baseline NIHSS (3 vs. 4, p = 0.01) and mRS score at 3-month (1 vs. 2, p = 0.01) were lower, and 1st-FIM (75 vs. 64, p < 0.01) and 2nd-FIM (113 vs. 95, p = 0.01) were higher in 82 patients with PC than 303 patients with AC strokes. On multivariate logistic regression analysis, 2nd-FIM score was an independent predictor of favorable outcomes in both PC (OR 1.18, 95% CI 1.04-1.48, p < 0.01) and AC (OR 1.12, 95% CI 1.06-1.20, p < 0.01) strokes. The optimal cutoff scores of 2nd-FIM for predicting favorable outcome were 104 for PC (sensitivity 0.82, specificity 0.88) and 93 for AC (0.88-0.90) strokes.

Conclusions: The differences in outcome predictability by FIM score between AC and PC strokes should be considered, although FIM scores at discharge from stroke unit were useful to predict a favorable outcome.
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http://dx.doi.org/10.1159/000499132DOI Listing
June 2019

Chronic mandibular osteomyelitis caused by Granulicatella adiacens in an immunocompetent child.

J Infect Chemother 2019 May 27;25(5):376-378. Epub 2018 Dec 27.

Department of Pediatrics, School of Medicine, University of Occupational and Environmental Health, Japan.

We report a pediatric case aged 10 years with Granulicatella adiacens-associated chronic mandibular osteomyelitis. The causative pathogen was uncertain because polymicrobial species were detected from the bacterial culture in bone marrow fluid. In contrast, G. adiacens was predominantly identified in the clone library analysis of the bacterial 16S rRNA gene sequence. Vancomycin to which G. adiacens was reported to be susceptible was not administrated sufficiently to this patient because of its adverse event, whereas linezolid and ciprofloxacin was alternatively effective for the treatment of chronic mandibular osteomyelitis.
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http://dx.doi.org/10.1016/j.jiac.2018.12.001DOI Listing
May 2019

[A Pediatric Case of Acquired Hemophilia A: The Usefulness of the Activated Partial Thromboplastin Time (APTT) Cross-Mixing Test for Early Diagnosis].

J UOEH 2018;40(4):331-337

Department of Pediatrics, School of Medicine, University of Occupational and Environmental Health, Japan.

Acquired hemophilia A (AHA), a bleeding disorder caused by autoantibodies against FVIII, has the potential for life-threatening bleeding. The annual onset rate is said to be one in 4 million people, but diagnosis examples increase in adults because a disorder concept penetrated. AHA is quite rare in children, with an incidence rate of 0.045 per 1 million, but early detection is crucial because serious bleeding can happen, as in adults. We report a pediatric case who received an early diagnosis of AHA by an activated partial thromboplastin time (APTT) cross-mixing test. The 12-year-old girl had neither a past history nor a family history of bleeding episodes. She presented with intramuscular bleeding and epistaxis without trauma or medication. At diagnosis, her blood test showed prolonged APTT. Other hemostatic tests, such as the platelet count, prothrombin time and fibrinogen concentration, were within the normal range. We administered an APTT cross-mixing test that detected an inhibitor pattern and inhibitory antibodies against factors VIII. As a result, we administered prednisolone and the inhibitor disappeared after 1.5 months. In conclusion, AHA is a bleeding disorder which should be considered even in children due to the potential for life-threatening bleeding. Furthermore, the APTT cross-mixing test is useful for screening coagulation factor deficiencies and inhibitors.
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http://dx.doi.org/10.7888/juoeh.40.331DOI Listing
March 2019

Subcutaneous Heparin Therapy for Patients with Cancer-Associated Stroke.

J Stroke Cerebrovasc Dis 2019 Feb 5;28(2):399-404. Epub 2018 Nov 5.

Stroke Center, Kyorin University, Mitaka, Tokyo, Japan; Department of Stroke and Cerebrovascular Medicine, Kyorin University, Mitaka, Tokyo, Japan.

Background: Anticoagulation therapy, particularly subcutaneous heparin therapy, is recommended for cancer-associated thrombosis. However, not starting or discontinuing anticoagulation was not rare. The aim of the present study was to examine the practical issues related to anticoagulation therapy and effects of subcutaneous heparin therapy for cancer-associated stroke.

Methods: Patients with cancer-associated stroke in our stroke center between October 2014 and August 2017 who were diagnosed as having acute ischemic stroke based on diffusion-weighted imaging were retrospectively enrolled. Baseline clinical characteristics, heparin injection, reasons for no subcutaneous heparin therapy, and clinical outcomes were collected.

Results: A total of 59 patients with cancer-associated stroke (75 ± 10 years old, male 42%) were enrolled. Lung cancer was the most frequently observed cancer (n = 17, 29%), followed by gastric cancer (n = 8, 14%) and pancreatic cancer (n = 8, 14%). Of the 19 patients (32%) who underwent subcutaneous heparin therapy, it was discontinued in 9 (47%), mainly because of patients' medical conditions (deterioration of cancer or hemorrhagic complication). Ten patients with long-term subcutaneous heparin therapy did not have stroke recurrence. In contrast, among nine patients who discontinued subcutaneous heparin therapy, three (33%) had recurrence of ischemic stroke. Of the 40 patients without subcutaneous heparin therapy, the main reasons for no subcutaneous heparin therapy were the patients' medical conditions (n = 22, 55%).

Conclusions: Although subcutaneous heparin therapy was given to only one third of cancer-associated stroke patients, long-term subcutaneous heparin therapy might prevent recurrence of cancer-associated stroke.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2018.10.012DOI Listing
February 2019

Prevention of Stent Thrombosis in Rats by a Direct Oral Factor Xa Inhibitor Edoxaban.

Pharmacology 2019 19;103(1-2):17-22. Epub 2018 Oct 19.

Rare Disease Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

Background/aims: Stent thrombosis is a serious complication after percutaneous coronary intervention and femoropopliteal endovascular intervention. The aim of this study was to determine the antithrombotic effects of a direct factor Xa inhibitor edoxaban alone or in combination with antiplatelet agents in a rat model of stent thrombosis.

Methods: Stainless steel stents (4 stents per rat) were placed in an extracorporeal arteriovenous shunt. The shunt was inserted into the carotid artery and the jugular vein in each rat to circulate blood. Stent thrombosis was induced by exposing the stents to arterial blood for 30 min. Protein content of the thrombus was measured. Edoxaban and antiplatelet agents (aspirin, clopidogrel, and ticagrelor) were orally administered before the thrombus induction.

Results: Edoxaban (0.3-3 mg/kg), clopidogrel (1-10 mg/kg), aspirin (10-100 mg/kg), and ticagrelor (0.3-3 mg/kg) exerted significant and dose-dependent antithrombotic effects in a rat stent thrombosis model. The effect of edoxaban was comparable to that of antiplatelet agents. The combination of submaximal doses of edoxaban and clopidogrel or aspirin significantly potentiated the antithrombotic effects compared with antiplatelet agents alone.

Conclusion: These results suggest that edoxaban alone and in combination with clopidogrel or aspirin are promising antithrombotic therapies for the prevention of stent thrombosis.
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http://dx.doi.org/10.1159/000494059DOI Listing
March 2019

A direct oral factor Xa inhibitor edoxaban ameliorates neointimal hyperplasia following vascular injury and thrombosis in apolipoprotein E-deficient mice.

J Thromb Thrombolysis 2018 Jul;46(1):95-101

Rare Disease and LCM Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

Vascular injury activates the coagulation cascade. Some studies report that coagulation factor Xa and thrombin are implicated in proliferation of vascular smooth muscle cells and neointimal hyperplasia after vascular injury. The aim of this study was to determine the effect of an oral direct factor Xa inhibitor, edoxaban, on neointimal hyperplasia following the carotid artery injury in apolipoprotein E (ApoE)-deficient mice. Vascular injury was induced by the application of 10% ferric chloride to the carotid artery for 3 min in ApoE-deficient mice. After vascular injury, all animals were fed with high-cholesterol chow for 6 weeks. Edoxaban at 15 mg/kg was orally administered to the mice 1 h before (n = 10) or 1 h after (n = 9) ferric chloride injury, and thereafter 10 mg/kg edoxaban was orally administered b.i.d. for 6 weeks. Thrombus formation and neointimal hyperplasia were evaluated. Treatment with 15 mg/kg edoxaban before vascular injury almost completely inhibited thrombus formation, and following chronic administration of edoxaban significantly suppressed neointimal hyperplasia. In the mice treated with edoxaban after vascular injury, there was wide interindividual variability. In some mice (four out of nine) the neointimal hyperplasia was inhibited like in edoxaban-pretreated mice, but there was no statistical difference compared with control. This study demonstrated that inhibition of the coagulation and thrombosis by edoxaban ameliorated neointimal hyperplasia caused by vascular injury and high-cholesterol diets in ApoE-deficient mice. This suggests that factor Xa has a crucial role in the formation of neointima following vascular injury.The abstract should be followed by 3-4 bullet points that highlight major findings. The final bullet point should emphasize future directions for research.
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http://dx.doi.org/10.1007/s11239-018-1673-7DOI Listing
July 2018

Tranexamic Acid Failed to Reverse the Anticoagulant Effect and Bleeding by an Oral Direct Factor Xa Inhibitor Edoxaban.

Pharmacology 2018 3;101(1-2):92-95. Epub 2017 Nov 3.

Department of Medical Science, Tokyo, Japan.

Background/aims: Agents to reverse the anticoagulant effect of edoxaban, an oral direct factor Xa inhibitor, would be desirable in emergency situations. The aim of this study is to determine the effect of tranexamic acid, an antifibrinolytic agent, on the anticoagulant activity and bleeding by edoxaban in rats.

Methods: A supratherapeutic dose of edoxaban (3 mg/kg) was intravenously administered to rats. Three minutes after dosing, tranexamic acid (100 mg/kg) was given intravenously. Bleeding was induced by making an incision with a blade on the planta 8 min after edoxaban injection and bleeding time was measured. Prothrombin time (PT) and clot lysis were examined.

Results: A supratherapeutic dose of edoxaban significantly prolonged PT and bleeding time. Tranexamic acid did not affect PT or bleeding time prolonged by edoxaban, although tranexamic acid significantly inhibited clot lysis in rat plasma.

Conclusion: An antifibrinolytic agent tranexamic acid failed to reverse the anticoagulant effect and bleeding by edoxaban in rats.
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http://dx.doi.org/10.1159/000484172DOI Listing
August 2018

Pulmonary and pleural metastasis of intracranial anaplastic meningioma in a 3-year-old boy: A case report.

Mol Clin Oncol 2017 Oct 14;7(4):633-636. Epub 2017 Aug 14.

Department of Pediatrics, University of Occupational and Environmental Health, Kitakyushu, Fukuoka 807-8555, Japan.

In adults, meningiomas occasionally display aggressive behavior and may occasionally metastasize. By contrast, pediatric meningiomas are rare, and there is limited information regarding their clinical characteristics, treatment and prognosis. We herein report the case of a 3-year-old boy with anaplastic meningioma with a history of local recurrence and late pulmonary metastasis. At diagnosis, a 70-mm mass lesion in was identified in the right frontal lobe, with intratumoral hemorrhage. The tumor was attached to the falx cerebri and was completely resected. The histological diagnosis was anaplastic meningioma, World Health Organization grade III. Two months after the surgery, the meningioma recurred at the same site. Although the patient received radiotherapy after a second operation, the tumor metastasized to the lung and pleura 8 months after the initial operation. The metastasis was resistant to treatment, even after gross total resection, and the effectiveness of further radiotherapy was limited. The patient succumbed to the disease 1 year and 4 months after the initial diagnosis. The findings of the present case and a review of the relevant literature suggest that recurrence and metastasis of meningiomas are difficult to predict. Therefore, such patients should be carefully monitored throughout the follow-up period.
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http://dx.doi.org/10.3892/mco.2017.1375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5639299PMC
October 2017

Successful resolution of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis during the treatment course of acute lymphoblastic leukemia.

Pediatr Neonatol 2017 12 17;58(6):555-557. Epub 2017 May 17.

Department of Pediatrics, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan.

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http://dx.doi.org/10.1016/j.pedneo.2016.11.004DOI Listing
December 2017

Prevention of arterial thrombosis by edoxaban, an oral factor Xa inhibitor in rats: monotherapy and in combination with antiplatelet agents.

Eur J Pharmacol 2016 Sep 7;786:246-252. Epub 2016 Jun 7.

Biological Research Laboratories, R & D Division, Daiichi Sankyo Co., Ltd, Tokyo, Japan. Electronic address:

In addition to platelet aggregation, coagulation activation is considered to be involved in arterial thrombosis. In this study, we determined antithrombotic effects of edoxaban, an oral factor Xa (FXa) inhibitor, as both a monotherapy and in combination with antiplatelet agents in a rat model of arterial thrombosis. We further examined its effects on a procoagulant biomarker and bleeding. Arterial thrombosis was induced by topical application of 15% ferric chloride to rat abdominal aortas. Bleeding time was measured by a tail incision method. Edoxaban, clopidogrel, and aspirin were orally administered 30min, 4h, and 2h before thrombus or bleeding induction. As a biomarker of coagulation activation, plasma thrombin-antithrombin complex (TAT) was measured. Edoxaban dose-dependently prevented arterial thrombosis in a manner comparable to clopidogrel and aspirin. The combination of edoxaban plus clopidogrel or edoxaban plus aspirin significantly potentiated the antithrombotic effects compared with these drugs alone. The combination of edoxaban and clopidogrel was more potent than clopidogrel and aspirin. Plasma TAT concentration was elevated after thrombus induction and suppressed by edoxaban and clopidogrel, but not by aspirin, suggesting P2Y12 receptor-mediated platelet procoagulant activity. Bleeding time was prolonged by the coadministration of edoxaban and clopidogrel, but not by edoxaban and aspirin. In conclusion, the present study demonstrates that the monotherapy with edoxaban and combination therapy with edoxaban plus clopidogrel or edoxaban plus aspirin are promising options for the prevention of arterial thrombosis as effective as the standard antiplatelet agents; however, a combination of edoxaban and clopidogrel increased the risk of bleeding.
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http://dx.doi.org/10.1016/j.ejphar.2016.06.011DOI Listing
September 2016

Edoxaban, a direct factor Xa inhibitor, suppresses tissue-factor induced human platelet aggregation and clot-bound factor Xa in vitro: Comparison with an antithrombin-dependent factor Xa inhibitor, fondaparinux.

Thromb Res 2016 May 26;141:17-21. Epub 2016 Feb 26.

Biological Research Laboratories, R & D Division, Daiichi Sankyo Co., Ltd, Tokyo, Japan. Electronic address:

Introduction: Tissue factor-induced platelet aggregation and factor Xa (FXa) activity bound to clot contribute to the formation and growth of thrombus. The effects of edoxaban, a direct FXa inhibitor, on these responses were determined and compared with that of fondaparinux, an antithrombin-dependent (indirect) FXa inhibitor.

Material And Methods: Human platelet aggregation was induced by human tissue factor (Dade Innovin or RecombiPlasTin) in platelet-rich plasma spiked with edoxaban or fondaparinux. Clot formed from human whole blood was incubated with 0.9μM prothrombin in the absence or presence of FXa inhibitors. As the index of FXa activity, the amount of prothrombin fragment F1+2 was measured with an ELISA. Free FXa activity was measured using human FXa and its chromogenic substrate S-2222.

Results: Edoxaban inhibited tissue factor-induced platelet aggregation in a concentration-dependent manner with the IC50 values of 150 and 110nM for Dade Innovin and RecombiPlasTin-induced platelet aggregation, respectively. At 1μM, edoxaban completely inhibited the aggregation. Fondaparinux inhibited RecombiPlasTin-induced aggregation with the IC50 of 9.3μM, but did not show complete inhibition up to 30μM and had no effect on Dade Innovin-induced aggregation. Edoxaban inhibited both free and clot-bound FXa with the IC50 of 2.3 and 8.2nM, respectively. Fondaparinux inhibited free FXa (IC50 5.4nM), but 40-times higher concentration were required to inhibit clot-bound FXa (IC50 217nM).

Conclusions: Edoxaban, a direct FXa inhibitor, was a more potent inhibitor of tissue factor-induced platelet aggregation and clot-bound FXa than fondaparinux, an indirect FXa inhibitor.
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http://dx.doi.org/10.1016/j.thromres.2016.02.028DOI Listing
May 2016

Volumetric analyses of cerebral white matter hyperintensity lesions on magnetic resonance imaging in a Japanese population undergoing medical check-up.

Geriatr Gerontol Int 2015 Dec;15 Suppl 1:43-7

Department of Neurosurgery, Kyorin University School of Medicine, Tokyo, Japan.

Aim: To clarify growth patterns, spatial distribution and risk factors of cerebral white matter hyperintensity (WMH) lesions on magnetic resonance imaging.

Methods: We analyzed volumes of cerebral WMH lesions in those who underwent brain magnetic resonance imaging as a hospital-based health check-up in 2012 and 2013 by using a computational quantitative image analysis software (Software for NeuroImage Processing in Experimental Research). After excluding subjects not suitable for volumetric analyses because of pathological brain conditions, a total of 1047 healthy participants (mean age 56.6 years) were included for the analyses. First, the relationship of computational volumetry and conventional qualitative visual evaluation by Shinohara grading was evaluated. Volumes of WMH lesions were analyzed according to age and the different cerebral lobes. Finally, clinical risk factors associated with WMH lesions were assessed.

Results: Volumes of WMH lesions were significantly correlated with Shinohara grading (P < 0.001). WMH lesions significantly enlarged with aging (P < 0.001) except for the occipital lobe, especially in participants aged 50 years or older. Age and systolic blood pressure were significantly related to volumes of WMH lesions in all the lobes, whereas diastolic blood pressure was not related only in the occipital lobe.

Conclusion: Based on computational quantitative volumetric analyses, cerebral WMH lesions increased with age, and were associated with blood pressure. However, the occipital lobe was the only exception to these findings.
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http://dx.doi.org/10.1111/ggi.12672DOI Listing
December 2015

Long-Term Morbidity and Mortality in Children with Chronic Graft-versus-Host Disease Classified by National Institutes of Health Consensus Criteria after Allogeneic Hematopoietic Stem Cell Transplantation.

Biol Blood Marrow Transplant 2015 Nov 31;21(11):1973-80. Epub 2015 Jul 31.

Department of Pediatrics, National Kyushu Cancer Center, Fukuoka, Japan.

We report the long-term morbidity and mortality of 105 pediatric patients who developed chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). According to the consensus criteria of the National Institutes of Health, the global severity of cGVHD was mild in 26 patients (25%), moderate in 30 patients (29%), and severe in 49 patients (47%). Patients with severe cGVHD had a significantly lower cumulative incidence of cGVHD remission and higher probability of continuing cGVHD at 8 years from cGVHD diagnosis compared with those with mild or moderate cGVHD. The 10-year cumulative incidence of nonrelapse mortality in severe cGVHD patients was significantly higher and the probability of disease-free survival was significantly lower than those among patients with mild and moderate cGVHD. Of the 59 patients who survived for more than 5 years, 20 (34%) (4 with moderate and 16 with severe cGVHD) had persistent functional impairment caused by cGVHD with a Karnofsky/Lansky performance score of 90% in 3 patients, 80% in 4 patients, and below 70% in 13 patients at the time of relapse, death, or last follow-up. Better therapeutic strategies are needed to lower the incidence of severe cGVHD, considering the longer life expectancy of pediatric HSCT survivors.
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http://dx.doi.org/10.1016/j.bbmt.2015.07.025DOI Listing
November 2015

Thrombin generation induced by tissue factor plus ADP in human platelet rich plasma: A potential new measurement to assess the effect of the concomitant use of an oral factor Xa inhibitor edoxaban and P2Y12 receptor antagonists.

Thromb Res 2015 May 9;135(5):958-62. Epub 2015 Mar 9.

Biological Research Laboratories, R & D Division, Daiichi Sankyo Co., Ltd, Tokyo, Japan. Electronic address:

Introduction: Patients with atrial fibrillation undergoing percutaneous coronary intervention may require combination therapy with anticoagulants and antiplatelet agents. The objectives of this study were to establish an assay which can evaluate the effects of both anticoagulants and P2Y12 receptor antagonists and determine the effects of edoxaban, a direct factor Xa inhibitor, and P2Y12 receptor antagonists (clopidogrel and ticagrelor) alone and when combined.

Material And Methods: Human platelet-rich plasma (PRP) from healthy subjects was stimulated with adenosine diphosphate (ADP) plus tissue factor. Thrombin generation was measured by means of calibrated automated thrombography.

Results: Combination of 10μM ADP and low concentration (0.25 pM) tissue factor induced reproducible thrombin generation in human PRP. Edoxaban (40 and 80ng/mL), active metabolite of clopidogrel (AM-clopidogrel, 10 and 20μg/mL), and ticagrelor (3μg/mL) alone inhibited ADP plus tissue factor-induced thrombin generation. Edoxaban suppressed all 5 parameters (lag time, peak, time to peak, endogenous thrombin potential, and maximum rate), whereas AM-clopidogrel and ticagrelor inhibited 4 and 3 parameters, respectively. Concomitant treatment with edoxaban and AM-clopidogrel or ticagrelor produced an additive inhibition of thrombin generation compared to the single treatments.

Conclusions: The thrombin generation assay induced by ADP plus tissue factor can detect the activities of both edoxaban and P2Y12 receptor antagonists. Combination of edoxaban and a P2Y12 receptor antagonist shows additive inhibition. These results suggest that ADP plus tissue factor-induced thrombin generation may be a useful measurement to assess the combination effects of anticoagulants and P2Y12 receptor antagonists in a single assay.
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http://dx.doi.org/10.1016/j.thromres.2015.03.001DOI Listing
May 2015

Treatment of venous thrombosis with an oral direct factor Xa inhibitor edoxaban by single and multiple administrations in rats.

Eur J Pharmacol 2014 Nov 30;742:15-21. Epub 2014 Aug 30.

Biological Research Laboratories, R & D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.

Edoxaban is an oral and direct activated factor X inhibitor. In this study, the acute treatment effect of edoxaban on venous thrombosis is investigated in rats by single and multiple administrations, and compared to the conventional parenteral anticoagulants, enoxaparin and fondaparinux. Venous thrombus was induced in the inferior vena cava by partial stenosis plus topical application of 10% ferric chloride for 5min. After 1-h thrombus maturation, oral edoxaban and subcutaneous enoxaparin and fondaparinux were given. In the single administration experiment, thrombus weight was measured 1 or 4h after thrombus induction. In the multiple administration experiments, edoxaban was orally administered once daily (QD) and twice daily (BID) for 3 days. In the single administration experiment, oral administration of edoxaban (3.0 and 10mg/kg) 1h after thrombus formation significantly regressed the venous thrombus compared to the thrombus at 1h after thrombus formation. Similarly the significant venous thrombus regression was observed with enoxaparin (10mg/kg) and fondaparinux (0.30-3.0mg/kg). In the multiple administration experiment, both QD and BID administration of edoxaban at daily doses of 5 and 10mg/kg exerted significant treatment effects. QD administration of edoxaban including lower doses (1-10mg/kg) significantly reduced thrombus weight. Edoxaban administered QD and BID was effective in the treatment of venous thrombosis, and the treatment effect of edoxaban was comparable to the conventional parenteral anticoagulants. These data demonstrate the potential of edoxaban as an oral anticoagulant in the acute treatment of venous thromboembolism.
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http://dx.doi.org/10.1016/j.ejphar.2014.08.020DOI Listing
November 2014

Clinical characteristics of 15 children with juvenile myelomonocytic leukaemia who developed blast crisis: MDS Committee of Japanese Society of Paediatric Haematology/Oncology.

Br J Haematol 2014 Jun 4;165(5):682-7. Epub 2014 Mar 4.

Department of Paediatrics, University of Occupational and Environmental Health, Kitakyusyu, Japan.

Juvenile myelomonocytic leukaemia (JMML) is a rare haematopoietic stem cell disease of early childhood, which can progress to blast crisis in some children. A total of 153 children diagnosed with JMML were reported to the Myelodysplastic Syndrome Committee in Japan between 1989 and 2007; 15 of them (9·8%) had 20% or more blasts in the bone marrow (blast crisis) during the disease course. Blast crisis occurred during observation without therapy (n = 3) or with oral 6-mercaptopurine treatment (n = 9) and in relapse after haematopoietic stem cell transplantation (HSCT; n = 3). Six patients had a complex karyotype (5 including monosomy 7) and an additional three patients had isolated monosomy 7 at blast crisis. Seven patients received HSCT after blast crisis and four of them achieved remission. Eleven out of the 15 patients died; the cause of death was disease progression in 10 patients and transplant-related complication in one patient. In summary, patients with blast crisis have poor prognosis and can be cured only by HSCT. The emergence of monosomy 7 and complex karyotype may be characteristic of blast crisis in a substantial subset of children.
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http://dx.doi.org/10.1111/bjh.12796DOI Listing
June 2014

In vitro assembly properties of human type I and II hair keratins.

Cell Struct Funct 2014 15;39(1):31-43. Epub 2014 Jan 15.

Department of Anatomy and Physiology, Faculty of Medicine, Saga University.

Multiple type I and II hair keratins are expressed in hair-forming cells but the role of each protein in hair fiber formation remains obscure. In this study, recombinant proteins of human type I hair keratins (K35, K36 and K38) and type II hair keratins (K81 and K85) were prepared using bacterial expression systems. The heterotypic subunit interactions between the type I and II hair keratins were characterized using two-dimensional gel electrophoresis and surface plasmon resonance (SPR). Gel electrophoresis showed that the heterotypic complex-forming urea concentrations differ depending on the combination of keratins. K35-K85 and K36-K81 formed relatively stable heterotypic complexes. SPR revealed that soluble K35 bound to immobilized K85 with a higher affinity than to immobilized K81. The in vitro intermediate filament (IF) assembly of the hair keratins was explored by negative-staining electron microscopy. While K35-K81, K36-K81 and K35-K36-K81 formed IFs, K35-K85 afforded tight bundles of short IFs and large paracrystalline assemblies, and K36-K85 formed IF tangles. K85 promotes lateral association rather than elongation of short IFs. The in vitro assembly properties of hair keratins depended on the combination of type I and II hair keratins. Our data suggest the functional significance of K35-K85 and K36-K81 with distinct assembly properties in the formation of macrofibrils.
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http://dx.doi.org/10.1247/csf.13021DOI Listing
October 2014

Comparison of antithrombotic and hemorrhagic effects of edoxaban, a novel factor Xa inhibitor, with unfractionated heparin, dalteparin, lepirudin and warfarin in rats.

Thromb Res 2013 Aug 12;132(2):234-9. Epub 2013 Jun 12.

Biological Research Laboratories, R & D Division, Daiichi Sankyo Co., Ltd. Electronic address:

Background: Edoxaban is a novel, potent and orally active direct Factor Xa (FXa) inhibitor under development for prophylaxis and treatment of thromboembolic diseases. Properties of dose response and margin of safety of anticoagulants are the key factors for a positive risk/benefit of novel oral anticoagulants.

Objectives: To compare the dose response of antithrombotic effect and margin of safety between antithrombotic and hemorrhagic effects of edoxaban with conventional anticoagulants, unfractionated heparin (UFH), dalteparin (low molecular weight heparin), lepirudin, and warfarin in rat models of thrombosis and hemorrhage.

Methods: Rats were treated with edoxaban, UFH, dalteparin, and lepirudin by continuous intravenous (iv) infusion, or with oral warfarin for 4 days before inducing thrombosis or bleeding. Thrombosis was induced by inserting a platinum wire into the inferior vena cava for 60 minutes. Tail template bleeding time was measured after making an incision on the tail.

Results: In rats, iv infusion of edoxaban inhibited venous thrombosis in a dose-dependent manner. The other anticoagulants also exerted dose-dependent antithrombotic effects. The slopes of the dose-response curves of edoxaban were significantly shallower than the slopes of UFH, dalteparin, and warfarin. At supratherapeutic doses, edoxaban prolonged bleeding time in a rat tail bleeding model. To determine bleeding risk, the margins between antithrombotic and bleeding-time prolongation were compared. The margins of safety of edoxaban were wider than those of UFH, dalteparin, lepirudin, and warfarin.

Conclusions: These results suggest that edoxaban may be more easily controlled and has the potential for a more positive risk/benefit ratio compared to conventional anticoagulants.
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http://dx.doi.org/10.1016/j.thromres.2013.05.020DOI Listing
August 2013

Impact of antithrombin deficiency on efficacy of edoxaban and antithrombin-dependent anticoagulants, fondaparinux, enoxaparin, and heparin.

Thromb Res 2013 Jun 11;131(6):540-6. Epub 2013 May 11.

Biological Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.

Introduction: Oral factor Xa (FXa) inhibitors are a novel class of anticoagulants that, unlike heparins, are expected to demonstrate antithrombotic effects independent of plasma antithrombin (AT) concentrations. We utilized heterozygous AT-deficient (AT+/-) mice to determine the impact of AT deficiency on anticoagulant and antithrombotic effects of edoxaban, a direct FXa inhibitor, and compared with heparins (fondaparinux, enoxaparin, and unfractionated heparin [UHF]).

Materials And Methods: The effects of edoxaban and heparins on in vitro prothrombin time and activated partial thromboplastin time were measured in plasma obtained from wild type (AT+/+) and AT+/- male mice. To assess the antithrombotic effects of these anticoagulants in vivo, venous thrombosis was induced in the inferior vena cava by FeCl3 treatment. Potency ratios of antithrombotic effects in AT+/- compared with AT+/+ mice were analyzed by a parallel line assay.

Results: In vitro studies demonstrated that the clotting-time prolongation effects of edoxaban were not affected by heterozygous AT deficiency whereas those of AT-dependent anticoagulants were attenuated. In AT+/- mice, the antithrombotic effects of AT-dependent anticoagulants were less potent than those in AT+/+ mice. In contrast, edoxaban was equipotent in preventing thrombus formation in both wild-type and AT-deficient mice. The attenuated antithrombotic effects of fondaparinux, enoxaparin, and UFH in AT-deficient mice were restored by AT supplementation. Edoxaban exerts a comparable antithrombotic effect even in mice with low plasma AT antigen and activity to that in wild-type mice.

Conclusion: Edoxaban may potentially be prioritized over AT-dependent anticoagulants in patients with lower plasma AT concentration.
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http://dx.doi.org/10.1016/j.thromres.2013.04.016DOI Listing
June 2013

The localization of oxytocin receptors in the islets of Langerhans in the rat pancreas.

Regul Pept 2013 May 14;183:42-5. Epub 2013 Mar 14.

Division of Histology and Neuroanatomy, Department of Anatomy and Physiology, Faculty of Medicine, Saga University, Nabeshima 5-1-1, Saga 849-8501, Japan. Electronic address:

In this study, oxytocin receptors (OTRs) in the islets of Langerhans were detected using real-time RT-PCR and immunohistochemical technique. Indeed, OTR mRNA was expressed in the rat pancreas. Double immunohistochemical staining for OTR and either glucagon or insulin demonstrated their co-localization in A-cells or B-cells, respectively. OTR-immunoreactivity in A-cells was stronger than that of B-cells. All A-cells and 94.8% of B-cells were OTR-immunoreactive. We reveal the statistically significant relations of OTR with A-cells and B-cells in the islets of Langerhans. This is the first demonstration of the OTR localization in the islets of Langerhans immunohistochemically. It suggests that oxytocin (OT) is involved in the release of insulin and glucagon.
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http://dx.doi.org/10.1016/j.regpep.2013.03.019DOI Listing
May 2013

The effects of warfarin and edoxaban, an oral direct factor Xa inhibitor, on gammacarboxylated (Gla-osteocalcin) and undercarboxylated osteocalcin (uc-osteocalcin) in rats.

Thromb Res 2013 Jan 19;131(1):59-63. Epub 2012 Sep 19.

Biological Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.

Introduction: Osteocalcin plays a role in bone homeostasis. The vitamin K cycle is essential for the gamma-carboxylation of glutamic acid residues in osteocalcin. Some evidence suggests that long-term warfarin therapy, which inhibits the vitamin K cycle and prevents gamma-carboxylation, is associated with increased bone-fracture risk. The aim of this study was to determine the effects of warfarin and edoxaban, a direct factor Xa inhibitor, on the serum concentration of total, gamma-carboxylated (Gla-osteocalcin) and undercarboxylated osteocalcin (uc-osteocalcin) in rats.

Materials And Methods: Rats received orally administered warfarin or edoxaban, and 24h later serum and plasma were prepared. Osteocalcin level in serum was measured with ELISA. A Gla-osteocalcin was precipitated by the addition of hydroxyapatite, and the resulting supernatant was used for measuring uc-osteocalcin. Prothrombin time (PT) of plasma was also measured.

Results: Warfarin at 1mg/kg (a dose which prolonged PT 2.62-fold) markedly increased the serum level of uc-osteocalcin and slightly increased the total osteocalcin level compared with control in rats. Serum Gla-osteocalcin significantly decreased by warfarin. Edoxaban at 1mg/kg (an antithrombotic dose) and 54mg/kg (a dose which prolonged PT 2.25-fold) had no effects on total, uc-, and Gla-osteocalcin levels.

Conclusions: This study demonstrates that warfarin impaired the carboxylation of osteocalcin in rats. In contrast, edoxaban at or higher doses than needed for an antithrombotic effect sustained the circulating Gla-osteocalcin level. These findings suggest that edoxaban has no effects on the production of Gla-osteocalcin and thus, may have a lower risk of adverse effects on bone health.
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http://dx.doi.org/10.1016/j.thromres.2012.08.304DOI Listing
January 2013