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

Drug-induced liver injury (DILI) remains a major cause of drug withdrawal from the market, and safety concerns in clinical settings. Reactive metabolites, primarily produced by cytochrome P450 enzymes, are known to induce oxidative stress and hepatotoxicity through covalent binding to macromolecules and the generation of reactive oxygen species. Recent evidence suggests that ferroptosis, an iron-dependent form of lipid peroxidation-mediated cell death, is involved in DILI triggered by compounds such as carbon tetrachloride (CCl₄) and acetaminophen (APAP). Arylacetamide deacetylase (AADAC), a hepatic hydrolase previously recognized for its role in drug metabolism, has recently been implicated in tumor suppression and ROS regulation in cancer cells. In this study, our group explored whether AADAC exerts a protective effect against ferroptosis-associated liver injury. Using Aadac knockout (KO) mice, we demonstrated that CCl₄, APAP, and amodiaquine induced more severe liver damage in the absence of Aadac, with elevated ferrous (Fe²⁺) levels, lipid peroxidation, and oxidative stress. We identified that Aadac interacts with ceruloplasmin, a ferroxidase that converts Fe²⁺ to ferric (Fe³⁺), thereby limiting ferroptosis. Notably, this function of Aadac was independent of its enzymatic activity. Furthermore, human AADAC overexpression in Huh-7 cells similarly reduced intracellular Fe²⁺ levels and conferred protection against CCl₄-induced cytotoxicity in a ceruloplasmin-dependent manner. These findings reveal a novel, non-catalytic role for AADAC in iron homeostasis and ferroptosis suppression, suggesting its clinical significance in DILI susceptibility and therapy.

Dysmenorrhea refers to pathological symptoms that occur in association with menstruation during the menstrual period. Treatment options for dysmenorrhea include nonsteroidal anti-inflammatory drugs (NSAIDs) and low-dose estrogen-progestin combination pills. However, some patients do not respond to these treatments, and long-term use can lead to adverse reactions, raising additional problems. To overcome these issues, Kampo (traditional Japanese herbal) medicines are often used, with prescriptions based on Kampo medicine diagnoses. In this study, we investigated the analgesic effects of Kamishoyosan, a Kampo medicine frequently used to treat this disease, using a mouse primary dysmenorrhea (PD) model. Since Kamishoyosan is typically administered over a long term in clinical settings, we also evaluated its effects on PD after single-dose or repeated long-term administration. Oxytocin administration to continuously estradiol-treated mice significantly increased the number of writhing responses (an index of pain), uterine tissue level of prostaglandin F2α (PGF2α), and calcium ion (Ca²⁺) level, while uterine blood flow significantly decreased. In contrast, repeated administration of Kamishoyosan decreased the number of writhing responses. The uterine tissue PGF2α and Ca²⁺ levels reduced after single-dose administration at a high dose and regardless of dosage after repeated administration. Uterine blood flow was improved by single-dose administration regardless of dosage. These results showed that continuous administration of Kamishoyosan exerted analgesic effects on PD symptoms even at non-high doses. Furthermore, Kamishoyosan may reduce PD-related pain by acting on uterine contraction factor (including PG)-producing pathways and uterine blood flow.

Community pharmacists play a vital role in delivering person-oriented services, such as addressing prescription inquiries, providing home care services, and conducting medication follow-ups. Despite their significance, no nationwide surveys have assessed the efficacy of these pharmaceutical activities. Therefore, this study aimed to collect information on these three pharmacist tasks and investigate their effectiveness in preventing serious adverse drug reactions and reducing medical costs. Ten percent of insurance pharmacies in each prefecture were randomly selected to participate in the survey. Data were collected on basic pharmacy information, prescription inquiries, home care services, and medication follow-up, which spanned from 12 June to 18 June 2023. Of the 561 pharmacies pre-registered for the study, valid responses were obtained from 433 pharmacies (77.2%). The reported cases included 3064 prescription inquiries, 765 home care services, and 326 medication follow-ups. Prescription inquiries prevented serious adverse drug reactions in 122 cases, home care services in 209 cases, and medication follow-ups in 13 cases. The cost reductions associated with these activities were ¥28291790, ¥58285600, and ¥2544950, respectively, resulting in a total cost reduction of ¥89122340. The annual cost reduction was ¥33229078321.7, assuming a severity rate of 6.7%. The estimated annual reduction in medical costs specifically attributed to prescription inquiries was ¥8732177830. This study indicates that pharmacists prevent adverse drug reactions and contribute to the safety of drug treatment through prescription inquiries, home care services, and medication follow-up. These tasks reduced annual medical costs by approximately ¥42 billion, highlighting the economic and healthcare benefits of community pharmacy services.

Establishing a robust drug discovery ecosystem is seen as a key priority for enhancing Japan's drug discovery capabilities. Globally, startups play a significant role in advancing drug discovery. The author's research demonstrated that startups have recently expanded their role to late-entry drug discovery, the area where large pharmaceutical companies traditionally had strength, while maintaining their contribution to first-in-target drug discovery. Despite the growing importance of startups, Japan has faced challenges in fostering successful drug discovery startups, falling particularly behind in leveraging modality technologies. The development of promising startups requires the establishment of a robust startup ecosystem, as seen in the U.S. and certain European countries. Japan's ecosystem for supporting drug discovery startups remains fragile due to factors such as low entrepreneurial activity, limited labor mobility, and insufficient investment capital. The author's research has revealed that in Japan's unlisted drug discovery startups, "being a corporate spin-off" and "having a leader in research and development with prior experience in corporate R&D" positively impact the startup's valuation and total funding amounts. In Japan, large pharmaceutical companies still account for the majority of new drug discoveries, with a wealth of promising drug discovery seeds and experienced R&D talent accumulated within these corporations. Facilitating the creation of corporate spin-offs that utilize unexploited seeds within large companies and promoting the transfer of corporate talent to startups could strengthen Japan's drug discovery ecosystem. This paper will also explore potential policy measures to encourage these developments.

Active vitamin D₃ (VDRAs) can cause drug-induced hypercalcemia and acute renal failure. Eldecalcitol (ELD), a VDRA, promotes bone formation more strongly than other VDRAs, such as alfacalcidol (ALF), but whether or not ELD affects serum calcium (Ca) levels and renal function more significantly than other VDRAs is unclear. In Japan, the supply of ALF was temporarily stopped in 2021, and patients at Fukuoka University Hospital who were taking ALF were either switched to ELD or discontinued ALF. We retrospectively investigated how these prescription changes affected serum Ca levels and renal function. Sixty-seven adult patients who were admitted to our hospital for at least 5 d between September 2021 and March 2022 and were taking ALF at the time of admission were divided into 3 groups: 36 patients who continued ALF (ALF-C), 12 who were switched to ELD (ELD-S), and 19 who discontinued VDRAs (DC). The changes in weekly serum Ca levels and renal function during hospitalization were compared between the groups. At the second week of observation, the change in the serum Ca level was 0.01 mg/dL in the ALF-C group, +0.45 mg/dL in the ELD-S group, and -0.37 mg/dL in the DC group, showing a significant difference among these groups. In addition, serum Ca levels were increased in all patients in the ELD-S group at Week 2. The estimated glomerular filtration rate didn't change significantly in any group during hospitalization. These results suggest that serum Ca levels should be measured by Week 2 when ELD is newly started or changed.

Comprehensive exploratory surveys of pharmacist involvement with perioperative patients were conducted to identify the current issues and challenges. In the first survey, patients who underwent surgery under general anesthesia during the weekday day shift at Sapporo Higashi Tokushukai Hospital between April 1 and September 30, 2022, were included. Patient backgrounds, surgery-related information, and initial preoperative pharmacist interviews were investigated. In the second survey, the questionnaire was administered to anesthesiologists and operating room nurses at our hospital between March 1 and March 31, 2023. Of the patients who underwent surgery during the weekday day shift, the initial preoperative pharmacist interview was not conducted for approximately 1 in 10 cases. Patients who were not interviewed were more likely to be hospitalized on weekends, holidays, or at night and were more commonly trauma patients. Both anesthesiologists and operating room nurses indicated that the work of operating room pharmacists "supported their work," "improved the quality of care," and "improved medical safety."

The adult ureter is a delicate structure with an approximate internal diameter of 5 mm located deep within the lower abdomen and surrounded by various tissues. Therefore, due to its positioning, visual identification of the ureter is challenging. Iatrogenic ureteral injuries, which can lead to severe illness, occur during both open and laparoscopic abdominal surgeries, posing a serious clinical concern. Reliable intraoperative identification of the ureters is essential to prevent inadvertent injuries. Ureteral stenting or catheter placement, commonly used procedure for ureteral identification, involve insertion via the urethra and bladder. However, these techniques have limitations, including prolonged surgery time, risk of urinary tract complications, limited diagnostic capability for ureteral injury, and higher medical costs. Optical imaging has the potential to assist in surgeries involving invisible tissues. Recently, novel fluorescent compounds, ASP5354, ZW800-1, and IS-001, has entered phase 3 clinical trials for intravenous use in intraoperative ureteral identification and injury diagnosis. These compounds possess a heptamethine cyanine skeleton that generates near-infrared fluorescence (700-900 nm), exhibit excellent tissue permeability, enable ureteral visualization throughout minimally invasive laparoscopic procedures, and are safe and well tolerated. Notably, no adverse events have been reported in clinical trials to date. This review provides an overview of these promising compounds and their potential effect in improving surgical outcomes.

Under the Food Sanitation Law, standards for the production and specifications of food ingredients for distribution may be established. Food that does not meet these standards is prohibited from being distributed. For pesticide residues in food, maximum residue limits (MRLs) are set for each pesticide and food type. Even pesticides without specific MRLs must comply with a uniform limit of 0.01 ppm. Thus, the positive list system controls pesticide residues in food in Japan. The MRLs for the pesticides were established based on current international agreements and concepts, and are calculated from crop residue trials for registered usage methods where maximum residue concentrations are expected. MRLs are determined if the dietary intake, when draft MRLs are adopted, does not exceed the acceptable daily intake (ADI) and acute reference dose (ARfD) as evaluated by the Food Safety Commission. The residue definition for MRL setting may be selected from the pesticide components themselves but also their metabolites and degradates, determined by considering the feasibility of analytical methods. Exposure to pesticides via food is estimated using monitoring data from quarantine stations and local governments, as well as market basket surveys. Currently, this exposure level is considered tolerable.

In this study, we assessed the information sharing practices between pharmacists and multidisciplinary healthcare professionals such as doctors, care managers, and nurses, and others. We evaluated the effectiveness of "home medical care management guidance reports" and "home-visit drug management guidance reports" prepared by pharmacists. We also identified factors that could enhance collaborative practices. To improve the reports, we introduced a new report form with an overview column and a reply column. We used the SOAP format in the new reports. We found that the response rate for reports from X pharmacy was significantly higher than that of Y pharmacies. A survey revealed that X's reports contained more categories (median of 3 versus 1 in Y's reports). Pharmacy X's reports had a smaller proportion of pharmacotherapy details, and a larger proportion of information regarding patients' living and health conditions, as well as environmental factors. We also found that the character count in X's assessment column was significantly greater (168.5 versus 60), and notably less in the overview sections (12 versus 22) when compared to Y's reports. Suggestions and guidance constituted a significantly larger portion of X's reports (29.8% compared to 10.8% in Y's). Questionnaire feedback from other healthcare professionals to whom the subject pharmacies send reports highlighted the importance of pharmacist-provided information on health and living conditions, based on pharmacological knowledge. Based on these results, to enhance health information sharing, pharmacists should integrate assessments of pharmacotherapy with health and living conditions and effectively communicate this information to other professionals.

It is difficult to appropriately diagnose the severity of fetal heart failure using only ultrasonography. Biomarkers of fetal heart failure in the fetal blood, amniotic fluid, and maternal blood have not been established. Therefore, we investigated natriuretic peptides (NPs) such as Atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and N-terminal proBNP (NT-proBNP) in umbilical cord blood and amniotic fluid in cases of fetuses with congenital heart disease, and investigated whether maternal serum biomarkers could diagnose fetal heart failure. The features of NPs in the umbilical cord blood and amniotic fluid provide a strong basis for their use as biomarkers of fetal heart failure. Maternal serum concentrations of tumor necrosis factor (TNF-α), vascular endothelial growth factor-D (VEGF-D), and heparin-binding epidermal growth factor-like growth factor (HB-EGF) can be used to assess fetal heart failure severity. There are no established transplacental treatments for heart failure in utero, and no animal models or experimental systems of fetal heart failure have been established. We first used an ultra-high-frequency ultrasound imaging system in utero and demonstrated that Hrt2 knockout (KO) embryos had marked left ventricular (LV) dilatation as well as worsening fractional shortening (FS) as gestation progressed, indicating that the embryos can be used as a murine model of fetal heart failure. Subsequently, we evaluated the effect of tadalafil treatment on fetoplacental circulation in Hrt2 KO embryos. LV FS was significantly higher in the tadalafil group than in the control group. Maternal administration of tadalafil improved LV systolic function without altering LV morphological abnormalities in Hrt2 KO embryos. Our findings suggest that tadalafil may effectively treat impaired fetal ventricular systolic function.