Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan最新文献

In Japan, the use of organomercury compounds is regulated in textile products (diapers, diaper covers, bibs, underwear, sanitary pads, sanitary panties, gloves, hosiery), adhesive, paint, wax, and shoe polish buffers. This is stated in Act No. 112 of 1973, 'Act on Control of Household Products Containing Harmful Substances'. In this study, we modified the currently used official method. The modified method uses cyclohexane/ethyl acetate (3 : 1) as the extraction solvent instead of carbon tetrachloride. The phenyl mercuric acetate as the organomercury compounds was quantified by a direct thermal decomposition mercury analyzer accurately, precisely, and safely. The calibration curves for determining the level of phenyl mercuric acetate were shown to be linear in the range of 0.12-6.0 ng mercury (Hg). The quantitation limit (Hg: 4.7 ng/g) was adequately low relative to the regulation value (Hg: 1 µg/g). The modified method exhibited a recovery rate of phenyl mercuric acetate in various household products of 38-87% with relative standard deviations of 1.5-19.5% when the standard solution (60 ng Hg) was added to the samples (1.0 g). In addition, we found that the use of suction filtration during the extraction from textile products such as thick socks provided high recovery. Thus, the modified method would be applicable for measuring levels of the organomercury compounds in various controlled household products.

Starting in 1976, I worked as a pharmacy resident in the Department of Pharmaceutical Services at Hiroshima University Hospital, starting in 1976. I simultaneously worked as a pharmaceutical researcher outside the hospital pharmacist hours. I encountered a female patient with eye disease in 1998 during drug counseling hours for an outpatient. She left for a weeklong overseas travel within 3 days. She had one bottle of ophthalmic solution for anti-inflammatory treatment; her ophthalmologist instructed her to schedule her next visit when the bottle was empty as her condition was not severe and wanted to provide a simple guideline for scheduling a follow-up. She then asked me when the ophthalmic solution bottle would be empty. I could not immediately answer her question despite my 22 years of experience as a pharmacist. I realized a gap in the field in this moment, which inspired me to become an ophthalmology research pharmacist who answered important questions such as these. In my experience, apart from me, only a few pharmacists have participated in clinical ophthalmic research over the past 50 years. Upon my retirement, and based on my experience, my message to young researchers is to remain in research in this field to help improve the outcomes and quality of life for those with eye diseases.

As I recently retired from Chiba University, I would like to describe how I began my research career, some of my accomplishments in the research field of modeling and simulation, and future prospects in this area. Here, I discuss the research topics of drug interactions, the oral absorption of drugs, analyses of between-group and individual differences in pharmacokinetics based on the theories of physiologically-based pharmacokinetics and population pharmacokinetics, and my roles in implementation of the drug interaction guideline. Furthermore, I also discuss modeling topics unrelated to pharmacokinetics, i.e., the analyses of the long-term progression of chronic diseases, such as Alzheimer's disease, Parkinson's disease, and chronic obstructive pulmonary disease using individual patient information; the spread of the coronavirus disease 2019 (COVID-19) pandemic; and prognostic factors of chronic heart failure with the view towards personalized medicine. After completing my Master's course at Hokkaido University, I joined a pharmaceutical company and worked as a pharmacokinetics researcher for 21 years, while obtaining my doctoral degree. I spent the next 9 years as a hospital pharmacist focusing on scientific research at the University of Tokyo Hospital, and the last 10 years as a Professor of Clinical Pharmacology and Pharmacometrics at Chiba University. My career is, therefore, characterized by involvement in pharmaceutical sciences from many different perspectives. This description focuses rather on the background of the studies than scientific details.

Studies investigating pharmacy accessibility have demonstrated value for analyzing healthcare resource distribution and regional disparities. However, researchers have not yet conducted a comprehensive investigation of the geographical distribution of pharmacies. This study aimed to examine the geographic accessibility and functionality of pharmacies in Wakayama Prefecture using a geographic information system. This cross-sectional study analyzed pharmacies, hospitals, and clinics in Wakayama Prefecture from November 2024 to March 2025. The investigation was conducted at the secondary medical region level, evaluating the population percentage within pharmacy service areas. The study also collected and analyzed data on pharmacy-to-population ratios, operating hours, numbers of full-time pharmacists, and pharmacy functions. Results indicated that pharmacies were predominantly concentrated in northern and coastal regions. The Wakayama Medical Region showed the highest population percentage (69.4%) within an 800-m service radius, while the Gobo Medical Region showed the lowest (35.6%). Analysis of pharmacy functions revealed disparities exceeding 20% for 24-hour service and home dispensing services. These findings suggest that despite Wakayama Prefecture's pharmacy density exceeding the national average, accessibility challenges persist due to regional disparities within the prefecture. The results emphasize the need to address regional disparities in pharmacy accessibility and promote equitable distribution of medical resources. Future research should include a survey tailored to the needs of local residents to identify areas for improvement.

Cells are involved in various biological events by transporting message substances such as proteins and nucleic acids to target cells. Recently, it was revealed that extracellular vesicles (EVs), which are cell-secreted membrane particles, function as intercellular delivery vehicles. As EVs reflect the characteristics of their parent cells, the development of novel EV-based therapies is expected. Moreover, it has become clear that microorganisms also secrete EVs. Probiotics are live microorganisms that confer a health benefit on the host and known to secret EVs. However, the information about the characteristics of probiotic-derived EVs is not fully understood. Furthermore, there were no technologies to modify the functionality of probiotic-derived EVs, such as formulation and drug loading, which are essential for their practical application. Therefore, we aimed at elucidation of the usefulness of probiotic-derived EVs and development of technologies for their functionalization. First, as an evaluation of the usefulness of probiotic-derived EVs, we evaluated the effects on the innate immune response, which is the initial immune response of the host. Next, we elucidated the pharmacokinetics and immunostimulatory effects of EVs when administered to the mice. Furthermore, we developed a novel functional modification technology of EVs by combining the amino acid metabolism mechanism and the bio-orthogonal reaction, aiming at the application of probiotic-derived EVs to immunotherapy. These findings will be helpful for the development of immunotherapy based on probiotic-derived EVs with superior safety and efficacy.

Fibromyalgia (FM) is a chronic disorder characterized by widespread pain and various accompanying symptoms, with complex mechanisms involving both peripheral and central nervous systems that remain unclear. Herein, we introduce a study employing a reserpine-induced rat model of FM, investigating the spinal dorsal horn in particular. In reserpine-induced FM model rats, we observed pronounced mechanical hypersensitivity of cutaneous and muscular C-fiber nociceptors. Moreover, increased expression of the ASIC3 (one of acid-sensing ion channel) in dorsal root ganglia implicated its role in peripheral sensitization. Within the spinal dorsal horn, enhanced microglial activation was evident; pharmacological inhibition with minocycline significantly attenuated mechanical hyperalgesia, indicating the critical involvement of microglial activity in central pain processing. Furthermore, patch-clamp recordings revealed altered synaptic transmission characterized by enhanced spontaneous excitatory postsynaptic currents (EPSCs) and reduced inhibitory postsynaptic currents (IPSCs), contributing to heightened pain signaling in the FM model. These findings suggest that an imbalance of intensified excitatory and diminished inhibitory neurotransmission in the spinal dorsal horn leads to impaired sensory gating and augmented nociceptive transmission to higher centers, a pivotal mechanism in the pathophysiology of FM.

Although clinical questions regarding treatment and disease mechanisms frequently arise in clinical practice, clear answers may not always be available. Investigating these issues could lead to new therapeutic strategies and further advancements in clinical pharmacies. This review presents three examples in which meta-analysis was used as a link between basic and clinical studies to resolve clinical questions. First, the effect of non-steroidal anti-inflammatory drugs (NSAIDs) on the risk of cisplatin-induced nephrotoxicity (CIN) was examined. A meta-analysis indicated that NSAID use was a risk factor (odds ratio: 1.88; 95% confidence interval: 1.44-2.45). Based on these results, basic studies that used rat kidney cells revealed that 17 NSAIDs have varying effects on CIN. Second, the dose-dependency of magnesium sulfate, a known preventive agent for CIN, was evaluated. Although a basic study suggested dose dependency, clinical evidence is limited. A meta-regression analysis demonstrated a dose-dependent preventive effect of magnesium sulfate within 5-20 mEq, supporting a rational dose setting in clinical practice. Third, we assessed the effect of acid suppressants (ASs) on the efficacy of immune checkpoint inhibitors (ICIs). A meta-analysis showed that AS use was associated with reduced overall survival in patients treated with ICIs. Subgroup analysis revealed that, although proton pump inhibitors (PPIs) negatively affected survival, histamine-2 receptor antagonists (H2RAs) did not, suggesting that H2RAs are potential alternatives to PPIs in ICI-treated patients. These studies suggest that meta-analyses based on reverse translational research are useful in resolving clinical questions and are expected to contribute to further advances in clinical pharmacies.

The cytokine interleukin 6 (IL-6) has redundant biological activities in regulating the proliferation, differentiation, and function of various cell types. IL-6 regulates inflammation, immune responses, and hematopoiesis, as well as homeostasis of the nervous, renal, hormonal, and bone systems. IL-6 is also involved in tumorigenesis, including myeloma cell growth. The janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is one of the key IL-6 signals both in normal and pathological conditions. In particular, STAT3 plays essential roles in mediating IL-6 signals, and its dysregulation can induce cancer and/or autoimmune diseases. In addition to biological and molecular mechanisms of IL-6-mediated signals, we have identified STAT3-interacting proteins, which regulate STAT3-mediated signals at various steps and mediate crosstalk between STAT3 and other intracellular signaling pathways. This review focuses on tyrosine kinase 2 (TYK2) and signal-transducing adapter protein-2 (STAP-2), followed by their potential as therapeutic targets in the development of novel treatments.

Notable advances have recently been achieved in drug therapies for renal cell carcinoma (RCC). Several tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) have been approved for metastatic RCC (mRCC). The current first-line treatment for mRCC involves combination therapies using TKIs and ICIs. However, there is no consensus on which TKI+ICI therapy is best or how to select the appropriate therapy for individual patients with RCC. The kidney expresses various metabolic enzymes, including CYP and uridine diphosphate glucose (UDP)-glucuronosyltransferase (UGT). Although information on CYP and UGT expression in the kidney is limited compared to our understanding of liver expression, the main CYP and UGT subtypes expressed at high levels in the kidney are estimated to be CYP2B6, CYP3A5, CYP4A11, CYP4F2, UGT1A6, UGT1A9, and UGT2B7. In RCC, the expression profiles and levels of these enzymes are somewhat altered compared with normal kidney. The main known subtypes of CYP and UGT in RCC are CYP1B1, CYP3A5, CYP4A11, UGT1A6, UGT1A9, UGT1A10, and UGT2B7. High CYP expression has been reported in several cancers, possibly conferring resistance to anti-cancer drugs including TKIs, due to extensive drug metabolism. Additionally, CYP and UGT expression levels may possibly affect cancer prognosis by metabolizing endogenous substrates, regardless of their role in anti-cancer drug metabolism. In this review, I discuss CYP and UGT expression level profiles in RCC based on previously published papers, including ours, and examine possible relationships between these enzyme expression profiles and treatment outcomes for patients with RCC.

The use of Japanese herbal medicines (Kampo medicines), rooted in centuries of traditional practice, lacks extensive Western scientific validation regarding their safety. Concerns include potential risks such as placental dysplasia, miscarriage, teratogenicity, and fetotoxicity when administered to pregnant women. Therefore, scientific safety evaluations are crucial for the appropriate use of Kampo medicines during pregnancy. Critical physiological processes such as implantation, invasion into the endometrium, placentation, and fetal development are vital for establishing a successful pregnancy. The placenta, forming from implantation until birth, is essential for fetal growth and nutrition. Proper placental function relies on the regulated differentiation and development of specific trophoblast cell lineages. If Kampo medicines impact these cell lineages, there may be increased risks of fetal developmental issues and pregnancy complications. current studies often neglect evaluating placental function or formation, focusing primarily on fetal toxicity and teratogenicity. Thus, assays for placental function and placentation toxicity are needed. This review consolidates existing knowledge on the effects of Kampo medicines, herbs and herbal medicines on pregnancy and placentation, emphasizing the necessity for scientific safety assessments to guide their use during pregnancy. Ensuring accurate information and safety of Kampo medicines, herbs and herbal medicines for pregnant women is essential to safeguard the health of the mother, fetus, and placenta.