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

I graduated from the Faculty of Pharmacy and then worked in the Faculty of Medicine, and my research has always focused on applying basic research to clinical practice. I first encountered purine metabolism research when I worked at the Teikyo University School of Medicine. I completed my doctoral studies by applying the measurement of 5'-methylthioadenosine (MTA), a source of adenine, to clinical cases. As part of research into hyperuricemia and gout, which are related to purine metabolism, we established a method for measuring the purine content in foods and reported the amounts of purine in many foodstuffs together with previous values. That research project was largely due to the dedication of students working on their graduation research after moving to the Faculty of Pharmacy. The resulting analytical data are included in treatment guidelines for hyperuricemia and gout, and are used as reference values in lifestyle guidance, especially dietary therapy, for actual patients. Furthermore, we performed micro-analysis of urinary stones, which are a common complication in patients with hyperuricemia and gout. In urinary stones, proteins related to inflammation and immunity were commonly detected, as well as proteins that differed depending on the type of stone, indicating different formation processes. I hope that the results of these research projects can be used to benefit society.

In the motor neurons of amyotrophic lateral sclerosis (ALS) patients, excessive (G4C2)n repeats in the intronic region of the C9orf72 gene are transcribed to RNA, forming G-quadruplexes that sequester RNA-binding proteins, leading to gelation within the cytoplasm as one of the many mechanisms leading to pathogenesis. While ALS patients frequently harbor over 700 repeats, this kind of 100% GC-rich region is very difficult to clone, and past studies report the necessity to add additional sequences in the middle to clone more than a few dozen repeats. The goal of this study was the in vitro production of the longest repetitive RNA to date consisting solely of (G4C2)n repeats. T4 DNA ligase was used to connect (G4C2)10 stretches of DNA with 3nt overhangs. Then, using a heat-resistant T7 RNA polymerase, the RNA obtained contained transcripts over 100 repeats. Artificial biomimetic RNA gels generated by scaling up this synthesis method are expected to contribute to elucidating the molecular mechanisms of repetitive sequence-related pathogenesis, as well as screening for drugs that can disrupt the gel structure.

In recent years, chemical modifications of RNA, known as the epitranscriptome, have been shown to influence not only the regulation of gene expression but also diseases such as neurodegenerative disorders and viral infections. Among them, N⁶-methyladenosine (m⁶A), which is highly abundant in transcripts, has been shown to regulate RNA stability, localization, and translation and has also been implicated in development, differentiation, and cancer. However, there are limitations in understanding the role of individual m⁶As in disease and biological phenomena using enzymatic knockdown methods that alter RNA methylation levels throughout the cell; if RNA methylation states can be selectively regulated by RNA sequences, the function of RNA methylation in a variety of biological phenomena can be elucidated. With this background, systems have been developed to selectively and temporally control the methylation state of specific adenosine. Using RNA-binding proteins that can freely alter the sequence of the RNA to which they bind, we created sequence-specific demethylases and methylases and demonstrated that these artificial proteins can regulate the methylation state of adenosine near the target sequence of the RNA-binding protein. In addition, the switching of methylation and demethylation activities by external stimuli is being developed in combination with external stimulus-dependent heterodimeric systems. In this review, developments in molecular tools for the sequence-selective regulation of epitranscriptomes are presented.

Lansoprazole is a proton pump inhibitor (PPI), frequently used for the treatment of gastroesophageal reflux disease. It may also be used in pregnant women; however, the safety of lansoprazole exposure during pregnancy remains unclear. In this study, we assessed the risk of major malformation and the effects on other pregnancy and birth outcomes resulting from lansoprazole exposure during the first trimester based on data from two Japanese facilities that provided counseling on drug use during pregnancy between 1988 and 2017. The study included 106 cases of lansoprazole exposure and 1788 control individuals. The risk of major malformation following exposure to lansoprazole after the first trimester was compared with that of the control group administered non-teratogenic drugs during the first trimester. The incidence of major malformation in singleton liveborn infants was 1.0% (1/96) in the lansoprazole group and 1.9% (31/1670) in the control group. Adjusted multivariable logistic regression analysis revealed no significant difference in the incidence between the control and lansoprazole groups [adjusted OR: 0.51 (95% confidence interval: 0.07-3.79), p=0.507]. Furthermore, no differences were observed between the two groups in the incidence of stillbirth, miscarriage, and birth weight. The results indicate that lansoprazole exposure during the first trimester is not associated with an increased risk of major malformations. Overall, our findings provide valuable insight for selecting gastroesophageal reflux disease medications for use in pregnant women.

The angiotensin system participates in regulation of neuronal activity in the central and peripheral nervous systems, in addition to its role in the control of cardiovascular functions and fluid balance. A fundamental study employing laboratory animals and retrospective analysis of hospitals' medical records have recently suggested that treatment with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II AT₁ receptor blockers (ARBs) reduces the development of diabetic peripheral neuropathy (DPN) accompanying type 2 diabetes. To validate this novel notion, we conducted a retrospective cohort study, using pharmacy claims data obtained from 148 branches of a chain pharmacy. Of 8188 older people with type 2 diabetes, 6093 underwent antihypertensive pharmacotherapy. The proportion of individuals receiving anti-DPN agents or antiplatelet agents was significantly greater in the antihypertensive agent-treated group than the untreated group. After some confounding factors were balanced between the anti-DPN agent-treated and untreated patients by a propensity score matching, multivariate logistic analyses indicated significant negative association of prescription of ACEIs and ARBs (adjusted odds ratios were 0.54 [95% confidence interval, 0.33-0.89] and 0.75 [0.59-0.96], respectively), but not the other antihypertensive agents, with intake of anti-DPN agents. On the other hand, prescription of most antihypertensive agents including ACEIs and ARBs was positively associated with intake of antiplatelet agents, when analyzed in the same manner. These data suggest that the angiotensin system inhibition reduces DPN development in older diabetic patients, while the onset of hypertension, as indicated by prescription of antihypertensive agents, promotes arterial circulatory disturbance, as indicated by prescription of antiplatelet agents.

In recent years, functional foods have attracted increasing attention due to growing health consciousness. When functional food ingredients are poorly water-soluble, they largely fail to be absorbed due to their low solubility in the digestive tract, limiting their ability to exert their functions. To develop poorly water-soluble compounds into viable functional food ingredients, it is important to increase their gastrointestinal absorption so that they can fully exert their functions, and to ensure their safety and efficacy through ADMET research. β-Carotene exerts physiological activities including antioxidant effects, and functions as a source of vitamin A, but it is completely insoluble in water, so it is poorly absorbed from the digestive tract, rendering it difficult to use efficiently as a functional food ingredient. To overcome this problem, we are conducting research on drug delivery system to improve β-carotene solubility and thereby improve its digestive absorption by applying our unique amorphous solid dispersion production technology. To date, we have produced amorphous solid dispersions with dramatically improved water solubility by adding polymers and emulsifiers to β-carotene and kneading these mixtures under heat. The resultant amorphous solid dispersion showed unprecedentedly high gastrointestinal absorption, enhanced inhibition of allergic dermatitis, and enhanced amelioration of cognitive impairment. No major safety issues associated with long-term continuous administration were observed. In this paper, we introduce our efforts to effectively deliver poorly water-soluble compounds such as β-carotene in functional foods.

Pemetrexed is a folate analog inhibitor for the treatment of non-small-cell lung cancer (NSCLC). Prophylactic supplementation with vitamin B₁₂ and folic acid reduces hematotoxicity associated with pemetrexed. Metformin, the antidiabetic agent, has been associated with the potential side effect of vitamin B₁₂ deficiency. This retrospective observational study aimed to evaluate the effect of concomitant metformin use on hematologic adverse events in patients with NSCLC undergoing pemetrexed-based chemotherapy using the Medical Data Vision Database. Patients with stage III or higher NSCLC who received pemetrexed from April 2008 to May 2021 were categorized into metformin-treated (MTF) and non-metformin-treated (non-MTF) groups. The primary outcome was the proportion of granulocyte colony-stimulating factor (G-CSF) administration during cycle (C) 1 to C2 or C2 to C3 of pemetrexed therapy. Propensity score matching (PSM) was used to balance the baseline characteristics between the groups. A total of 1174 patients met the inclusion criteria (54 in MTF and 1120 in non-MTF). After PSM, 52 patients were included in each group. The median metformin dosage in the MTF group was 500 mg/d before and 625 mg/d after PSM. There were no significant differences between the MTF and non-MTF groups in G-CSF administration (15.4 vs. 21.2%, p=0.446). Multivariate logistic regression analysis also showed that metformin use did not significantly affect hematologic toxicity (odds ratio: 1.208, 95% CI: 0.554-2.634). This suggests that the concomitant use of a relatively low dose of metformin is unlikely to significantly increase the risk of hematotoxicity in Japanese patients with NSCLC receiving pemetrexed-based chemotherapy.

Ixazomib (IXA) is a convenient oral anticancer drug; however, due to its fixed dosage, IXA tolerability among elderly Japanese individuals may be reduced. Therefore, this study aimed to clarify the difference in relative dose intensity (RDI) of IXA in IRd therapy in elderly patients. Between October 2018 and September 2023, patients who underwent IRd therapy (IXA, lenalidomide, and dexamethasone combination treatment) at Ogaki Municipal Hospital were enrolled in the study and categorized into two age groups: ≥75 years (group O, n=16) and <75 years (group Y, n=6). We retrospectively analyzed RDI of IXA, in IRd therapy. In addition, we evaluated the reasons for dose reduction or delayed treatment. The median initial IXA dose was 3 mg (range: 2.3-4 mg) and 4 mg (range: 3-4 mg) in group O and Y, respectively (p=0.122). The median RDI in group O (65.8%, range: 51.1-91.7%) was significantly lower than in group Y (93.3%, range: 80.5-100.0%) (p=0.002). Among them, anorexia was more common in group O than in group Y (p=0.049). In group O, dose adjustments were made due to anorexia (n=10), diarrhea (n=5), nausea (n=2), and fatigue (n=2). In group Y, adjustments were made due to diarrhea (n=2) and thrombocytopenia (n=1). Upon IXA (4 mg) administration, the rate of dose adjustments due to gastrointestinal symptoms were 75% and 17% in group O and Y, respectively (p=0.051). Overall, RDI was lower in group O owing to gastrointestinal symptoms. This suggests that the fixed IXA dosage (4 mg) is less tolerable in older individuals.

Under the School Safety and Health Act, which came into force in 2009, school pharmacists are now required to engage in the duties of health counselling and health guidance in addition to school environmental health. However, the proportion of school pharmacists involved in health education is low, and not all of them are qualified to participate. Therefore, this study targets school principals, school nurse-teachers, physical education supervisors, health coordinators, science supervisors, nutrition teachers (dietitians), and school pharmacists from among the teaching staff of all public schools in Funabashi city. Here, a survey was conducted on issues related to school health that are important at the school site, in which school pharmacists should participate. Health issues identified at school sites included dependence on smartphones or other devices, leftover food, food likes and dislikes, lack of sleep, dealing with food allergies and anaphylaxis, and handling menstrual problems or pain. School pharmacists were also asked about matters of school health in which they would like to participate. These issues differed significantly among those participating in the survey, with responses including correct use of drugs, overdose, drug abuse prevention, prevention of energy drink overdose, anti-smoking education, and infectious disease control.