Folia Pharmacologica Japonica最新文献

Fetal thyroid hormones (THs), essential for brain development, largely depend on maternal supply. Clinical studies have shown that TH alterations in pregnant mothers can lead to permanent neurodevelopmental effects in their children, suggesting that chemicals causing maternal TH disruption may require regulation. However, the quantitative relationship between chemical-induced maternal TH reductions and fetal brain TH disruption, as well as fetal brain developmental abnormalities, is not fully understood. Thus, there is a need for methods that can precisely, rapidly, and quantitatively evaluate TH-disrupting effects of test chemicals that may cause brain abnormalities. Currently, multiple molecular initiating events (MIEs) in the adverse outcome pathways (AOPs) of TH disruption are known, and tests using New Approach Methodologies are being developed to investigate the effects of chemicals on these MIEs. Additionally, the Comparative Thyroid Assay (CTA) is expected to be utilized to comparatively evaluate the decrease in blood TH concentrations, commonly observed as a result of actions on multiple MIEs, in maternal rats along with their offspring. Recently, due to the increasing need for more precise and efficient evaluations and the reduction of animal testing, we have worked on improving the CTA. We proposed a modified CTA that adds new test items: brain TH concentrations and heterotopia (a histological marker of brain TH deficiency), while reducing the number of animals used by 50%. Feasibility studies confirmed that it can detect approximately 20-30% TH disruption in the offspring brain. This review outlines the current efforts to develop new evaluation methods for perinatal TH disruption effects.

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.

Elucidating the neural mechanisms governing changes in individual animal behavior is a key goal in neuroscience. Such research has important implications for behavioral pharmacology and could lead to the development of treatments for psychiatric and neurological disorders. Given that the brain likely represents vast amounts of information through the combined activity of multiple neurons, studying these mechanisms requires the simultaneous recording of many neurons. Recent years have seen significant advancements in techniques for multi-cellular activity recording. Calcium imaging utilizing fluorescent sensors has emerged as a powerful method, enabling the concurrent acquisition of spatial arrangements and temporal activity changes in neuronal populations. This article focuses on deep brain imaging using GRIN lenses, particularly deep brain calcium imaging in freely behaving animals with miniaturized head-mounted microscopes. We compare the strengths and limitations of this approach to other calcium imaging methods, electrophysiological techniques, and fiber photometry. Finally, we discuss future developments in this field, including two-photon microscopy for imaging beyond cell bodies, membrane potential imaging using voltage sensors, and single-cell resolution manipulation of neural activity by integrating spatial light modulators and electrically tunable lenses.

The prevalence of allergic rhinitis (AR) reached 49.2% in 2019. In particular, the prevalence of Japanese cedar (JC) pollinosis is 38.8%, and the onset age of pollinosis is becoming younger. AR is known to be a risk factor for the development of allergic asthma, a potentially life-threatening condition. Allergen immunotherapy (AIT) is a well-documented, safe, effective treatment option for respiratory allergic disease. It has been demonstrated that AIT can provide relief from clinical symptoms and that AIT has the potential to provide long-term post-treatment effect. Unlike pharmacotherapy, AIT addresses the basic immunological mechanisms that are responsible for the development and persistence of allergic conditions. Currently, two main routes of AIT administration, subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT), are commonly available. In Japan, house dust mite (HDM) SLIT tablets have been available since 2015, and JC SLIT tablet had been approved by 2018 without any age limitation. The randomized double-blind, placebo-controlled trials that included pediatric patients have been conducted in Japan. In phase II/III trail with JC SLIT tablets, treatment effect-size (improvement of clinical symptoms compared to placebo) was 46.3% after three years treatment. In addition, AR was improved in 40% (1 year) and 30% (2 years) after discontinuation of SLIT. Several future initiatives including the AIT against cedar pollen allergies were announced by Japanese government. This review covered the findings to date, including immunotherapy not only for JC pollinosis- but also for HDM-induced perennial AR.