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1. ZLN005 improves the survival of polymicrobial sepsis by increasing the bacterial killing via inducing lysosomal acidification and biogenesis in phagocytes

Author

Yosuke Suzuki, Daisuke Kami, Toshihiko Taya, Arata Sano, Takehiro Ogata, Satoaki Matoba, and Satoshi Gojo

Subjects
lysosome acidity, lysosomal biogenesis, bacterial degradation, mitochondrial biogenesis, sepsis, Immunologic diseases. Allergy, RC581-607
Abstract

Polymicrobial sepsis still has a high mortality rate despite the development of antimicrobial agents, elaborate strategies to protect major organs, and the investment of numerous medical resources. Mitochondrial dysfunction, which acts as the center of energy metabolism, is clearly the basis of pathogenesis. Drugs that act on PGC1α, the master regulator of mitochondrial biosynthesis, have shown useful effects in the treatment of sepsis; therefore, we investigated the efficacy of ZLN005, a PGC1α agonist, and found significant improvement in overall survival in an animal model. The mode of action of this effect was examined, and it was shown that the respiratory capacity of mitochondria was enhanced immediately after administration and that the function of TFEB, a transcriptional regulator that promotes lysosome biosynthesis and mutually enhances PGC1α, was enhanced, as was the physical contact between mitochondria and lysosomes. ZLN005 strongly supported immune defense in early sepsis by increasing lysosome volume and acidity and enhancing cargo degradation, resulting in a significant reduction in bacterial load. ZLN005 rapidly acted on two organelles, mitochondria and lysosomes, against sepsis and interactively linked the two to improve the pathogenesis. This is the first demonstration that acidification of lysosomes by a small molecule is a mechanism of action in the therapeutic strategy for sepsis, which will have a significant impact on future drug discovery.

Published
2023
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2. Amelioration of Endotoxemia by a Synthetic Analog of Omega-3 Epoxyeicosanoids

Author

Akira Shikuma, Daisuke Kami, Ryotaro Maeda, Yosuke Suzuki, Arata Sano, Toshihiko Taya, Takehiro Ogata, Anne Konkel, Satoaki Matoba, Wolf-Hagen Schunck, and Satoshi Gojo

Subjects
Omega-3, Unsaturated fatty acids, Mitochondria, Macrophage, Inflammation, Immunologic diseases. Allergy, RC581-607
Abstract

Sepsis, a systemic inflammatory response to pathogenic factors, is a difficult to treat life-threatening condition associated with cytokine and eicosanoid storms and multi-organ damage. Omega-3 polyunsaturated fatty acids, such as eicosapentaenoic (EPA) and docosahexaenoic acid, are the precursors of potent anti-inflammatory lipid mediators, including 17,18-epoxyeicosatetraenoic acid (17,18-EEQ), the main metabolite of EPA generated by cytochrome P450 epoxygenases. Searching for novel therapeutic or preventative agents in sepsis, we tested a metabolically robust synthetic analog of 17,18-EEQ (EEQ-A) for its ability to reduce mortality, organ damage, and pro-inflammatory cytokine transcript level in a mouse model of lipopolysaccharide (LPS)-induced endotoxemia, which is closely related to sepsis. Overall survival significantly improved following preventative EEQ-A administration along with decreased transcript level of pro-inflammatory cytokines. On the other hand, the therapeutic protocol was effective in improving survival at 48 hours but insignificant at 72 hours. Histopathological analyses showed significant reductions in hemorrhagic and necrotic damage and infiltration in the liver. In vitro studies with THP-1 and U937 cells showed EEQ-A mediated repression of LPS-induced M1 polarization and enhancement of IL-4-induced M2 polarization of macrophages. Moreover, EEQ-A attenuated the LPS-induced decline of mitochondrial function in THP-1 cells, as indicated by increased basal respiration and ATP production as well as reduction of the metabolic shift to glycolysis. Taken together, these data demonstrate that EEQ-A has potent anti-inflammatory and immunomodulatory properties that may support therapeutic strategies for ameliorating the endotoxemia.

Published
2022
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3. Periprocedural management and clinical outcomes of invasive procedures after venous thromboembolism: from the COMMAND VTE registry

Author

Kazuki Matsushita, Kiyonori Togi, Tomohisa Tada, Yugo Yamashita, Seiichi Hiramori, Kazushige Kadota, Takeshi Morimoto, Yoshiaki Tsuyuki, Hidewo Amano, Mamoru Toyofuku, Yuta Tsujisaka, Syunsuke Saga, Hiroshi Mabuchi, Command Vte Registry Investigators, Yuji Nishimoto, Tomoki Sasa, Arata Sano, Masaharu Akao, Kosuke Doi, Minako Kinoshita, Kensuke Takabayashi, Fumiya Yoneda, Ryosuke Murai, Takeshi Kimura, Jiro Sakamoto, Maki Oi, Toshiaki Izumi, Kohei Osakada, Takao Kato, Kitae Kim, Yuta Seko, Toru Takase, Reo Hata, Yohei Kobayashi, Koh Ono, Po-Min Chen, and Koichiro Murata

Subjects
medicine.medical_specialty, Hematology, business.industry, Heparin, Surgery, Internal medicine, Medicine, In patient, Cardiology and Cardiovascular Medicine, business, Venous thromboembolism, Invasive Procedure, Major bleeding, medicine.drug
Abstract

Anticoagulation therapy is prescribed for the prevention of recurrence in patients with venous thromboembolism, which could be temporarily interrupted during invasive procedures. The COMMAND VTE Registry is a multicenter registry enrolling 3027 consecutive patients with acute symptomatic VTE in Japan between January 2010 and August 2014. We identified patients who underwent invasive procedures during the entire follow-up period and evaluated periprocedural managements and clinical outcomes at 30 days after invasive procedures. During a median follow-up period of 1213 (IQR: 847–1764) days, 518 patients underwent invasive procedures with the cumulative incidences of 5.8% at 3 months, 11.1% at 1 year, and 24.0% at 5 years. Among 382 patients in high bleeding-risk category of invasive procedures, anticoagulation therapy had been discontinued already in 62 patients (16%) and interrupted temporarily in 288 patients (75%) during the invasive procedures with bridging anticoagulation therapy with heparin in 214 patients (56%). Among 80 patients in low bleeding-risk category, anticoagulation therapy had been already discontinued in 15 patients (19%) and interrupted temporarily in 31 patients (39%) during invasive procedure with bridging anticoagulation therapy with heparin in 17 patients (21%). At 30 days after the invasive procedures, 14 patients (2.7%) experienced recurrent VTE, while 28 patients (5.4%) had major bleeding. This study elucidated the real-world features of peri-procedural management and prognosis in patients with VTE who underwent invasive procedures during follow-up in the large multicenter VTE registry. The 30-day incidence rates of recurrent VTE and major bleeding events were 2.7% and 5.4%.

Published
2021
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4. Risk factors of thrombotic recurrence and major bleeding in patients with intermediate-risk for recurrence of venous thromboembolism

Author

Yugo Yamashita, Kensuke Takabayashi, Kazushige Kadota, Takeshi Morimoto, Masaharu Akao, Yoshiaki Tsuyuki, Koh Ono, Mamoru Toyofuku, Seiichi Hiramori, Hidewo Amano, Takao Kato, Yuji Nishimoto, Moriaki Inoko, Koichiro Murata, Po-Min Chen, Maki Oi, Kohei Osakada, Kazuki Matsushita, Kiyonori Togi, Tomohisa Tada, Yohei Kobayashi, Reo Hata, Tomoki Sasa, Arata Sano, Toru Takase, Command Vte Registry Investigators, Kitae Kim, Minako Kinoshita, Jiro Sakamoto, Hiroshi Mabuchi, and Takeshi Kimura

Subjects
medicine.medical_specialty, Hematology, Proportional hazards model, business.industry, equipment and supplies, Thrombophilia, medicine.disease, Discontinuation, Internal medicine, medicine, Population study, cardiovascular diseases, Risk factor, Cardiology and Cardiovascular Medicine, business, Venous thromboembolism, Major bleeding
Abstract

Prolonged anticoagulation therapy is recommended for patients with intermediate-risk for recurrence of venous thromboembolism (VTE). The current study aimed to identify risk factors of VTE recurrence and major bleeding in intermediate-risk patients. The COMMAND VTE Registry is a multicenter registry enrolled consecutive 3027 patients with acute symptomatic VTE among 29 centers in Japan. The current study population consisted of 1703 patients with intermediate-risk for recurrence. The primary outcome measure was recurrent VTE during the entire follow-up period, and the secondary outcome measures were recurrent VTE and major bleeding during anticoagulation therapy. In the multivariable Cox regression model for recurrent VTE incorporating the status of anticoagulation therapy as a time-updated covariate, off-anticoagulation therapy was strongly associated with an increased risk for recurrent VTE (HR 9.42, 95% CI 5.97–14.86). During anticoagulation therapy, the independent risk factor for recurrent VTE was thrombophilia (HR 3.58, 95% CI 1.56–7.50), while the independent risk factors for major bleeding were age ≥ 75 years (HR 2.04, 95% CI 1.36–3.07), men (HR 1.52, 95% CI 1.02–2.27), history of major bleeding (HR 3.48, 95% CI 1.82–6.14) and thrombocytopenia (HR 3.73, 95% CI 2.04–6.37). Among VTE patients with intermediate-risk for recurrence, discontinuation of anticoagulation therapy was a very strong independent risk factor of recurrence during the entire follow-up period. The independent risk factors of recurrent VTE and those of major bleeding during anticoagulation therapy were different: thrombophilia for recurrent VTE, and advanced age, men, history of major bleeding, and thrombocytopenia for major bleeding. Unique identifier: UMIN000021132. COMMAND VTE Registry: http://www.umin.ac.jp/ctr/index.htm .

Published
2021
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5. Periprocedural management and clinical outcomes of invasive procedures after venous thromboembolism: from the COMMAND VTE registry

Author

Reo, Hata, Yugo, Yamashita, Takeshi, Morimoto, Kazushige, Kadota, Hidewo, Amano, Ryosuke, Murai, Kohei, Osakada, Arata, Sano, Toru, Takase, Seiichi, Hiramori, Kitae, Kim, Maki, Oi, Masaharu, Akao, Kosuke, Doi, Yohei, Kobayashi, Mamoru, Toyofuku, Toshiaki, Izumi, Tomohisa, Tada, Po-Min, Chen, Koichiro, Murata, Yoshiaki, Tsuyuki, Syunsuke, Saga, Yuji, Nishimoto, Tomoki, Sasa, Jiro, Sakamoto, Minako, Kinoshita, Kiyonori, Togi, Hiroshi, Mabuchi, Kensuke, Takabayashi, Yuta, Tsujisaka, Yuta, Seko, Kazuki, Matsushita, Fumiya, Yoneda, Takao, Kato, Koh, Ono, and Takeshi, Kimura

Subjects
Recurrence, Risk Factors, Anticoagulants, Humans, Hemorrhage, Registries, Venous Thromboembolism
Abstract

Anticoagulation therapy is prescribed for the prevention of recurrence in patients with venous thromboembolism, which could be temporarily interrupted during invasive procedures. The COMMAND VTE Registry is a multicenter registry enrolling 3027 consecutive patients with acute symptomatic VTE in Japan between January 2010 and August 2014. We identified patients who underwent invasive procedures during the entire follow-up period and evaluated periprocedural managements and clinical outcomes at 30 days after invasive procedures. During a median follow-up period of 1213 (IQR: 847-1764) days, 518 patients underwent invasive procedures with the cumulative incidences of 5.8% at 3 months, 11.1% at 1 year, and 24.0% at 5 years. Among 382 patients in high bleeding-risk category of invasive procedures, anticoagulation therapy had been discontinued already in 62 patients (16%) and interrupted temporarily in 288 patients (75%) during the invasive procedures with bridging anticoagulation therapy with heparin in 214 patients (56%). Among 80 patients in low bleeding-risk category, anticoagulation therapy had been already discontinued in 15 patients (19%) and interrupted temporarily in 31 patients (39%) during invasive procedure with bridging anticoagulation therapy with heparin in 17 patients (21%). At 30 days after the invasive procedures, 14 patients (2.7%) experienced recurrent VTE, while 28 patients (5.4%) had major bleeding. This study elucidated the real-world features of peri-procedural management and prognosis in patients with VTE who underwent invasive procedures during follow-up in the large multicenter VTE registry. The 30-day incidence rates of recurrent VTE and major bleeding events were 2.7% and 5.4%.

Published
2021

6. EFFECTIVENESS OF PACLITAXEL-COATED BALLOON ANGIOPLASTY FOR DRUG-ELUTING STENT RESTENOSIS IN THE LEFT MAIN CORONARY ARTERY

Author

Akimune Kuwayama, Arata Sano, Koshi Miyake, Masatomo Ozaki, Makoto Takamatsu, Noriyuki Ohashi, Tsuyoshi Goto, Reo Hata, Hiroshi Tasaka, Hiroyuki Tanaka, Kazushige Kadota, Ryosuke Murai, Yuichi Kawase, Takeshi Maruo, Kohei Osakada, Yasushi Fuku, Masanobu Ohya, Shunsuke Kubo, Takenobu Shimada, Mituru Yoshino, Katsuya Miura, Seiji Habara, Harumi Katoh, and Hidewo Amano

Subjects
medicine.medical_specialty, business.industry, medicine.medical_treatment, equipment and supplies, Balloon, medicine.disease, medicine.anatomical_structure, Restenosis, Drug-eluting stent, Internal medicine, Angioplasty, medicine, Cardiology, Stent implantation, Paclitaxel coated balloon, Cardiology and Cardiovascular Medicine, business, Artery
Abstract

In-stent restenosis after drug-eluting stent implantation (DES-ISR) in the left main coronary artery remains challenging to manage. Our aim was to assess the effectiveness of paclitaxel-coated balloon angioplasty for DES-ISR in the left main coronary artery. We identified 91 DES-ISR lesions in the

Published
2019
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7. TCT-750 First Generation Versus Second Generation Drug-eluting Stents for Restenosis with Stent Fracture after Drug-eluting Stents Implantation

Author

Kazuki Matsushita, Arata Sano, Shunsuke Kubo, Hiroyuki Tanaka, Akimune Kuwayama, Takenobu Shimada, Kazushige Kadota, Yasushi Fuku, Masanobu Ohya, Seiji Habara, and Hidewo Amano

Subjects
Drug, medicine.medical_specialty, business.industry, media_common.quotation_subject, medicine.medical_treatment, Stent, Percutaneous coronary intervention, equipment and supplies, medicine.disease, First generation, Surgery, surgical procedures, operative, Restenosis, Conventional PCI, medicine, cardiovascular diseases, Cardiology and Cardiovascular Medicine, business, Complication, media_common
Abstract

Stent fracture (SF) is related to restenosis after drug-eluting stent (DES) implantation. SF being a rare complication, the results of percutaneous coronary intervention (PCI) for restenosis with SF after DES implantation has not been well studied. A total of 19578 lesions (11504 patients) were

Published
2017
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