Folia Pharmacologica Japonica最新文献

Allergen-specific immunotherapy (AIT) has been a longstanding treatment for allergic diseases. Historically, subcutaneous immunotherapy was the main approach, but with the development of sublingual preparations, which are associated with fewer systemic side effects, sublingual immunotherapy is gaining global popularity. In Japan, the approval of standardized sublingual immunotherapy preparations in 2014 has significantly accelerated its adoption. The mechanism of allergic inflammation is divided into sensitization and elicitation phases. The sensitization phase involves the production of antigen-specific IgE antibodies against a particular antigen. These IgE antibodies bind to FcεRI on mast cells and basophils, preparing the body for an allergic response. The elicitation phase occurs when the body, already primed with these antibodies, is re-exposed to the same antigen, triggering inflammation and symptoms. This phase includes mechanisms where IgE-mediated mast cell activation leads to degranulation and where local Th2 cell activation induces inflammation. While the mechanisms of AIT are not fully understood, they are categorized into desensitization and immune tolerance. Desensitization is induced by reducing the responsiveness of mast cells and basophils to the antigen. Immune tolerance involves the production of antigen-specific IgG4 antibodies that compete with IgE for antigen binding, and the induction of regulatory T cells and other anti-inflammatory immune cells producing cytokines such as IL-10. AIT still faces challenges, such as the lack of predictive biomarkers for efficacy. Recent studies indicate that HLA genotypes influence AIT responsiveness. Advances in genetic and single-cell analysis are expected to address these challenges, paving the way for improved treatment outcomes.

Glaucoma is an age-related neurodegenerative disease and the leading cause of blindness, but currently no fundamental treatment has been present. The main treatment is to reduce intraocular pressure, which is expected to delay the progression of the disease. However, there are many glaucoma patients for whom progression cannot be controlled by lowering intraocular pressure alone, and the development of a fundamental treatment is required. Meanwhile, the clinical application of gene therapy is increasing worldwide. Various gene therapy vectors are still being developed, and technological change is much faster in this field. Gene therapy has already been clinically applied to several neurodegenerative diseases, but gene therapy for glaucoma has not yet been established. Our group is investigating the development of a new treatment for glaucoma by gene therapy using neurotrophic factor signaling. And we aim not only to suppress disease progression by neuroprotection, but also to recover the visual function by axonal regeneration.

Itch is an unpleasant sense to evoke desire to scratch skin. Itch not only disturbs daily lives, but also exacerbates inflammation in case of atopic dermatitis (AD). It had been thought that both itch and pain are transduced by the same neurons; however, it is now known that neutrons transducing either itch or pain are distinct. Moreover, TRP channels, a family of calcium channels, play an important role for transducing itch as well as pain, temperature, and pressure. Development of neuroscience and molecular biology has dramatically advanced our understanding of how itch is transduced in recent years. On the other hand, development of immunology has revealed that there exist several immune types in our host defense mechanism and that type 2 immune reaction is dominant in the pathogenesis of allergic diseases including AD. Although it had been already known that type 2 cytokines contribute to the pathogenesis of AD by binding to their receptors on both immune cells and tissue resident cells, it has been recently found that several type 2 cytokines directly transduce the itch signals by binding to peripheral nerves. Due to this discovery, we can understand more deeply the itch mechanism of AD and can develop molecularly targeted drugs for AD targeting type 2 cytokines, which has dramatically changed the treatment of AD. In this review article, we describe the progress of our recent understanding of the itch mechanism and the strategy of treatment against it.

The ocular tissue is one of the most densely populated tissues in the body with extremely small blood vessels, and vascular lesions have been reported to be a factor in vision loss and visual field defects in many ocular diseases. Currently, vascular endothelial growth factor (VEGF)-targeted agents are the first line of treatment for intraocular vascular lesions, however, there are some cases in which they are not fully effective. Therefore, we explored pathogenic molecules other than VEGF, aiming to develop new molecular-targeted therapy. Using an experimental pathological model mimicking intraocular vascular lesions, we found that B-cell CLL/lymphoma 6 member B protein (BCL6B), which has been identified as a Bric-a-brac, Tramtrack, and Broad Complex protein, may play an important role in intraocular angiogenesis and vascular hyperpermeability. In this article, we introduce the usefulness of suppressing BCL6B expression and discuss the possibility of drug discovery by targeting Notch signaling in chorioretinal vascular lesions.

Pregnancy can affect the absorption, distribution, metabolism, and excretion of several drugs due to pregnancy-induced physiological changes. Risperidone, a second-generation antipsychotic, is prescribed to pregnant women when the benefits outweigh the risks to the fetus. Serum concentrations of risperidone and its active metabolite paliperidone in a pregnant woman as well as her newborn were measured, and physiologically-based pharmacokinetic (PBPK) models of both drugs were developed. The effects of pregnancy on pharmacokinetic parameters of both drugs were quantitively assessed by the developed PBPK model. As a result, serum concentrations of risperidone and paliperidone decrease in the pregnant status and abruptly recover to the non-pregnant level after delivery mainly due to cytochrome P450 (CYP) 2D6 activity changes, and therefore, close and careful monitoring of clinical symptoms should be considered during pregnancy and after delivery. In the 10 different models for estimating the renal function of children, the Flanders metadata equation showed the lowest absolute bias and the greatest precision in predicting paliperidone serum concentration in the neonate. PBPK model-informed approach could help with the precision dosing in special populations, such as pregnant women and neonates.