Efficacy and safety of a recombinant soluble human thrombomodulin (ART-123) in preventing oxaliplatin induced peripheral neuropathy (OIPN): Results of a placebo-controlled, randomized, double-blind phase II study

Kato, Takeshi; Kotaka, Masahito; Satake, Hironaga; Makiyama, Akitaka; Tsuji, Yasushi; Shinozaki, Kazuo; Fujiwara, Toshiyoshi; Mizushima, Tsunekazu; Harihara, Yasushi; Nagata, Nobuhiko; Kurihara, Naoto; Kagawa, Yutaka; Kusakawa, Genichi; Sakai, Takumi; Uchida, Yugo; Takamoto, Mikihiro; Asami, Shun; Ando, Masahiko; Saito, Yoji; Hyodo, Ichinosuke

doi:10.1093/annonc/mdy281.144

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“…Accumulating evidence from preclinical studies indicates that exogenously applied TMα reduces HMGB1‐dependent pathological pain including chemotherapy‐induced peripheral neuropathy (CIPN) and that the endogenous TM/thrombin system potentially functions to relieve CIPN (Hayashi et al, 2018; Irie et al, 2017; Nishida et al, 2016; Sekiguchi et al, 2018; Tanaka et al, 2013; Tanaka et al, 2014; Tsubota et al, 2019; Tsujita et al, 2018). A placebo‐controlled, randomized, double‐blind phase II study has shown the promising efficacy of TMα in delaying and reducing CIPN in colon cancer patients undergoing adjuvant chemotherapy with an oxaliplatin‐based regimen (T. Kato et al, 2018). This review thus focuses on the roles of HMGB1 and exogenously applied TMα as well as the endogenous TM/thrombin system in pain regulation.…”

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confidence: 99%

Role of high‐mobility group box 1 and its modulation by thrombomodulin/thrombin axis in neuropathic and inflammatory pain

Tsujita

Tsubota

Sekiguchi

et al. 2020

British J Pharmacology

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High‐mobility group box 1 (HMGB1), a nuclear protein, once released to the extracellular space, facilitates pain signals as well as inflammation. Intraplantar or intraspinal application of HMGB1 elicits hyperalgesia/allodynia in rodents by activating the advanced glycosylation end‐product specific receptor (receptor for advanced glycation end‐products; RAGE) or Toll‐like receptor 4 (TLR4). Endogenous HMGB1 derived from neurons, perineuronal cells or immune cells accumulating in the dorsal root ganglion or sensory nerves participates in somatic and visceral pain consisting of neuropathic and/or inflammatory components. Endothelial thrombomodulin (TM) and recombinant human soluble TM, TMα, markedly increase thrombin‐dependent degradation of HMGB1, and systemic administration of TMα prevents and reverses various HMGB1‐dependent pathological pain. Low MW compounds that directly inactivate HMGB1 or antagonize HMGB1‐targeted receptors would be useful to reduce various forms of intractable pain. Thus, HMGB1 and its receptors are considered to serve as promising targets in developing novel agents to prevent or treat pathological pain. LINKED ARTICLES This article is part of a themed issue on Neurochemistry in Japan. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.4/issuetoc

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