Folia Pharmacologica Japonica最新文献

Interleukin (IL)-19, a member of the IL-10 cytokine family, has been recognized for its anti-inflammatory functions in conditions such as inflammatory bowel disease and dermatitis. However, its role in liver diseases remains largely unexplored. In this study, we investigated the pathophysiological significance of IL-19 using a murine model of nonalcoholic fatty liver disease (NAFLD/NASH). Mice lacking IL-19 fed a customized CDAHFD diet exhibited delayed weight recovery, exacerbated inflammatory cell infiltration, enhanced fibrosis, and elevated serum liver injury markers and pro-inflammatory cytokines compared with wild-type mice. IL-19 was primarily produced by Kupffer cells in the liver and acted on hepatocytes to activate STAT3 signaling, suppress lipogenic gene expression, and enhance ATP production and PPARα activity. These actions shifted fatty acid utilization toward energy metabolism, thereby attenuating lipid accumulation and hepatocellular injury. Collectively, our findings suggest that IL-19 functions as a protective regulator suppressing steatosis and fibrogenesis. Future studies integrating steatosis and fibrosis models are warranted to further delineate its mechanisms and to evaluate the potential of IL-19 as a biomarker and therapeutic target in chronic liver diseases.

Steroid hormone receptors (SRs) play pivotal roles in the fundamental biological functions related to reproduction, development, and homeostasis. They are also closely associated with various pathophysiologies, including hormone-dependent cancers, metabolic syndromes, and neuropsychiatric disorders. SRs are ligand-dependent transcription factors belonging to the nuclear receptor superfamily. This superfamily also includes orphan nuclear receptors, such as estrogen-related receptors (ERRs) comprising three subtypes of α, β, and γ. Despite their high homology with estrogen receptors (ERs), ERRs cannot bind any endogenous steroid hormones and can activate gene transcription in a ligand-independent manner. Recently, ERRs have attracted considerable attention for their involvement in stem cell pluripotency, senescence, and other poorly understood biological processes. Although subcellular and subnuclear dynamics are crucial for SR function, how ERRs behave in living cells to activate or repress their target genes remains incompletely understood. We have investigated the behaviors of ERRs using fluorescent protein labeling, focusing on whether ERRs exhibit dynamic changes similar to SRs and whether these changes relate to their functional activity. In this review, we summarize findings from studies of molecular behavior, highlighting the coregulation of estrogen signaling by ERs and ERRs, the subnuclear movement of ERRs related to transcriptional repression, and the promotion of lactate metabolism by a novel lactate-responsive protein, LRPGC1, through interaction with ERRγ. We hope these insights contribute to elucidating fundamental biomedical processes and the pathological mechanisms linked to aberrant nuclear receptor signaling pathways.

Pharmacology role-play is a participatory learning exercise in which students take on the roles of healthcare providers and patients or family members, explaining diseases and pharmacological treatments based on presented case scenarios, and actively learning through mutual communication. Traditionally conducted face-to-face within a single university, this exercise has shifted to online formats during the COVID-19 pandemic, and more recently, attempts have been made to implement inter-university online sessions that utilize remote collaborative learning. In this study, we compared the educational outcomes of online role-play conducted independently at Kochi University and Ehime University in 2020 with those of an inter-university online role-play jointly conducted by both universities in 2021. Participants were third-year medical students at Kochi University and second-year medical students at Ehime University. After completing all assignments, students were asked to complete a post-session questionnaire. Five-point Likert scale responses were analyzed, and free-text comments were further examined using text mining with co-occurrence network analysis. The results indicated that inter-university role-play, compared with single-university sessions, facilitated the recognition of diverse perspectives and promoted deeper reflection through discussion. This experience contributed to enhanced understanding of patients' perspectives, increased motivation for becoming physicians, and improved learning attitudes. These findings suggest that inter-university online role-play is an effective educational approach for enhancing learning outcomes in pharmacology education.

Hereditary angioedema (HAE) is a rare life-threatening disease with recurrent edema. We outline the pharmacological characteristics and study results of a new drug, garadacimab (human anti-activated factor XII [FXIIa] monoclonal antibody), which has novel mechanism of action and suppresses acute HAE attacks. In HAE, excessive bradykinin production, an inflammatory mediator increasing vascular permeability, causes edema, and activation of factor XII initiates bradykinin production. Garadacimab suppresses bradykinin production by inhibiting FXIIa. HAE attacks include fatal laryngeal edema, and overall severity varies substantially among patients. There is an unmet medical need for treatment to reduce its frequency and severity. For prophylactic treatment, a convenient drug with long-administration interval is desired to reduce patients' burden. Based on results of Phase I study in healthy subjects and Phase II study of multiple doses in patients, efficacy and safety of monthly administration of 200 mg garadacimab were compared in 64 patients (ITT: 39 in garadacimab and 25 in placebo) in Phase III study. The primary endpoint, monthly attack frequency was significantly lower in garadacimab than placebo (0.27 vs. 2.01; P < 0.001), with relative reduction rate 87%. Monthly subcutaneous administration of 200 mg garadacimab showed favorable safety profile. The proportion of patients who remained attack-free during the 6-month was 62% in garadacimab and 0% in placebo, and effect after the first dose was maintained throughout the study period. Since this drug is administered subcutaneously once a month with autoinjector, reduction of patients' burden is also expected.

The treatment of recurrent or metastatic cervical cancer has entered a new era, with immune checkpoint inhibitors now being used as first-line standard of care options. Meanwhile, there is a lack of second-line and subsequent treatment options that can adapt to this changing treatment landscape, highlighting the need for the development of new treatments with novel mechanisms of action. Tisotumab vedotin (recombinant) is an antibody-drug conjugate (ADC) consisting of tisotumab, an anti-human tissue factor (TF) monoclonal antibody (IgG1κ), the microtubule inhibitor monomethyl auristatin E (MMAE), and a valine-citrulline linker. When the linker is cleaved by a protease in a tumor cell, MMAE is released to induce cell cycle arrest and apoptosis via disruption of the microtubular network. In non-clinical studies, tisotumab vedotin demonstrated concentration-dependent cytotoxic and anti-tumor activities. Tisotumab vedotin also mediated antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) activities. In a global Phase III study of tisotumab vedotin as second- or third-line therapy in patients with recurrent or metastatic cervical cancer (Study SGNTV-003/innovaTV 301), the drug demonstrated higher efficacy than the investigator's choice of chemotherapy. Although some eye-related adverse events occurred as unique toxicities, the safety profile of tisotumab vedotin was generally manageable. The results of analysis in the Japanese subpopulation of the SGNTV-003 (innovaTV 301) study were consistent with those of the overall population. Based on these results, tisotumab vedotin received regulatory approval in Japan in March 2025 for the indication of "advanced or recurrent cervical cancer that has progressed after cancer chemotherapy".

Difelikefalin (KORSUVA^® IV Injection Syringe for Dialysis) is a novel kappa opioid receptor (KOR) agonist. In September 2023, difelikefalin was approved for the treatment of pruritus in hemodialysis patients. Pruritus is a major symptom that significantly reduces the quality of life of hemodialysis patients, even with improved dialysis techniques, dialysis membranes, and dialysate solutions. The factors that contribute to pruritus include dry skin, accumulation of uremic toxins, overproduction of chemical mediators and altered immune function, and disruption of the opioid balance. In nonclinical studies, difelikefalin showed highly selective for KOR and antipruritic effects in animal models of histamine- and substance P-induced itching. It also showed anti-inflammatory effects by suppressing cytokine release in human monocyte-derived macrophages and TNFα and IL-1β induced by lipopolysaccharide administration in mice. In the phase 3 clinical trial in Japanese hemodialysis patients, difelikefalin showed significant improvement compared to placebo in the primary endpoint of the change from baseline in the weekly mean NRS score at week 4. It also improved sleep disturbance and itch-related quality of life, and the improvement in itch was sustained up to 58 weeks. Furthermore, there was no increase in adverse drug reactions with long-term treatment, and no delayed adverse events were observed. In conclusion, the novel KOR agonist difelikefalin is expected to be a new treatment option for pruritus on dialysis.

Pharmaceuticals used for pregnant women must be safe for the babies while therapeutic to the mothers. To ensure the safety of drugs, developmental neurotoxicity should be evaluated although it is currently not a mandatory requirement in the US and Europe at the regulatory level. Organisation for Economic Co-operation and Development (OECD) has constituted the test guideline (TG426) to assess developmental neurotoxicity. TG426 requires various assessments using animals (assuming rats), including the brain weight, neuropathology, locomotion, sensorimotor function, and learning ability of dams from the mother treated with the chemical during pregnancy. Due to the huge burden of the cost, time, and labor, the number of chemicals evaluated for developmental neurotoxicity by TG426 remains around 200. To boost the pace of the assessment, OCED has constituted a novel guideline (No. 377) adopting in vitro test batteries. OCED has also evaluated the utility of the neurobehavior of zebrafish larvae in the assessment of developmental neurotoxicity. In this review, I focus on valproic acid, a therapeutic drug to treat epilepsy and bipolar disorder and a well-known developmental neurotoxicant, and summarize the studies using zebrafish neurobehavior to assess the developmental neurotoxicity of valproic acid. The utility and validity of zebrafish neurobehavior for developmental neurotoxicity testing are discussed by comparing the findings from rodents and humans.