Serotonergic neurons play a critical role in processing reward and aversive information. Rewarding stimuli activate serotonergic neurons in the dorsal raphe nucleus (DRN), whereas optogenetic activation of DRN serotonergic neurons induces reward-like effects. However, the pharmacological enhancement of serotonin neurotransmission does not induce rewarding or aversive effects. These findings suggest the presence of another serotonergic neuron that plays a role opposite to that of the DRN in processing reward and aversion information. Previous reports suggested that the median raphe nucleus (MRN) processes negative emotional stimuli. To elucidate the function of MRN serotonergic neurons in these processes, we recorded the changes in serotonergic activity in mice in response to rewarding and aversive stimuli. We also used optogenetic manipulation to determine whether these changes could induce rewarding and aversive behaviors. The activity of MRN serotonergic neurons decreased in response to rewarding stimuli and increased after aversive stimuli. Optogenetic inhibition of MRN serotonergic neurons induced reward-related behavior, while optogenetic stimulation induced aversion-related behavior. Furthermore, we found that the projection pathway from MRN serotonergic neurons to the interpeduncular nucleus is crucial for these processes. These results indicate that MRN serotonergic neurons play a pivotal role in processing reward and aversive information, functioning oppositely to DRN neurons.

Tumor-specific active drug release from macromolecular antitumor drugs after tumor delivery is critical to achieve efficient cellular uptake of the active drug, thereby ensuring therapeutic efficacy. Upon reaching the tumor tissue, protease-facilitated depegylation of pegylated zinc protoporphyrin with ester bonds between PEG and ZnPP (esPEG-ZnPP) occurs, leading to a faster cellular uptake and superior antitumor efficacy compared to PEG-ZnPP with ether bonds (etPEG-ZnPP). This finding provides a viable strategy for achieving efficient tumor-specific drug release by utilizing an ester linkage between PEG and antitumor drugs. Another strategy involves using styrene-maleic acid copolymer (SMA), an amphiphilic polymer. Drug-encapsulating SMA aggregates disintegrate upon interaction with cell membrane components, releasing the encapsulated active drug. The author has demonstrated an improvement in the tumor accumulation of SMA-based macromolecular drugs by conjugating pirarubicin (THP), an anthracycline antitumor drug, with SMA. Furthermore, by conjugating various molecular weights of N-(2-hydroxypropyl)methacrylamide (HPMA) to THP via a hydrazone bond (P-THP, DP-THP, and SP-THP), the author has established a positive correlation between HPMA molecular weight and therapeutic efficacy as well as toxicity. Notably, P-THPs release THP under acidic conditions within tumor tissue; however, this release occurs solely outside tumor cells due to HPMA-mediated inhibition of cellular uptake. The author is currently developing macromolecular anticancer drugs using albumin for the tumor-targeted release of anticancer agents both intra- and extracellularly. The strategic development of tumor-targeting macromolecular antitumor drugs based on a comprehensive understanding of polymer characteristics and the tumor-specific environment is imperative for effective cancer therapy.

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.

Pesticides, veterinary drugs, and feed additives (hereinafter referred to as “pesticides”) can remain in foods when used in agricultural and livestock products. Since consuming a variety of foods every day can result in ingesting trace amounts of these pesticides, which may be harmful to health, risk management for residual pesticides in foods is necessary to prevent adverse effects. Based on the Food Sanitation Act, the Ministry of Health, Labour and Welfare (MHLW) has established maximum residue limits (MRLs) for each pesticide and each food type. Currently, approximately 770 pesticides have MRLs set. Since May 2006, Japan has implemented a positive list system, prohibiting the distribution of food containing residual pesticides exceeding the MRLs or uniform limit of 0.01 ppm for pesticides without established MRLs. Appropriate analytical methods are required to determine whether pesticides exceed the MRLs or uniform limit. Currently, MHLW has notified ten simultaneous analytical methods and approximately 350 individual analytical methods. However, many pesticides still lack developed analytical methods. These methods should be simple, quick, and accurate, but developing them is challenging. The National Institute of Health Sciences, in cooperation with local health institutes, registered conformity assessment bodies, and universities, is working on developing these analytical methods. This lecture introduces an overview and the challenges of analytical methods for detecting residual pesticides.

As of August 2023, 99 organizations were registered as conformity assessment bodies by the Ministry of Health, Labour, and Welfare in accordance with Article 33 of the Food Sanitation Act. These registered organizations are authorized to conduct inspections of imported food as well as domestic expropriation inspections. In recent years, we have actively participated in a project to develop new test methods, aiming to enhance our contribution as a registered testing organization and to maintain food hygiene by widely applying these developed methods. There is a need to develop new test methods for pesticides and veterinary medicines used in Japan, as well as for several drugs used internationally. Previously, gas chromatography and high-performance liquid chromatography were the standard methods, and only parent compounds were analyzed. Recently, the demand for test methods applicable not only to agricultural products but also to livestock and marine foods has increased, necessitating the analysis of metabolites in addition to parent compounds. Although developing analytical methods to detect certain metabolites has been challenging, advancements in the variety of separation and pretreatment columns, along with the widespread use of LC-MS/MS and GC-MS/MS techniques, have enabled the development of test methods for many compounds. In this study, we introduce a method to solve the challenges and problems associated with test method development.

Veterinary drugs are used worldwide to prevent and treat diseases and promote growth in animals, fisheries, and beekeeping. Despite their effectiveness, the illegal and improper use of these drugs can result in livestock and fishery products, potentially impacting human health by causing allergic reactions, cytotoxicity, and antimicrobial resistance. To mitigate these adverse effects, the Japanese government established a positive list system in 2006. Maximum residue levels (MRLs) have been defined for approximately 300 veterinary drugs. The regulation of certain antimicrobial drugs without defined MRLs uses in zero tolerance. Residual veterinary drugs in meat, fish, eggs, milk, and honey are inspected to ensure compliance with legal limits. Initially, samples are screened using bioassay and LC-MS/MS. If residues are detected, they are confirmed and quantified using more precise methods. We have detailed the detection of residual norfloxacin in honey. Additionally, we are currently developing new analytical methods. This study introduces an analytical method for the residue screening of sulfonamides and quinolones. After residue detection by bioassay, the same test solutions were analyzed by LC-MS/MS for accurate identification and quantification. This method has also proven to be more environmentally friendly compared to other quantitative methods. We present the ingenuity used to realize the combined method, performance evaluation results, examples of applications to actual samples, and future prospects.

Mycotoxins, toxic secondary metabolites produced by fungi, are present in food and feed worldwide. Acute and chronic dietary exposures can induce adverse health effects in humans and animals. Among the various mycotoxins, aflatoxins pose significant health concerns to the general public. In the early 1960s, a total of more than 100000 turkey poults died from an unknown turkey “X” disease in England. The disease was associated with Brazilian groundnut meal contaminated by Aspergillus flavus, from which aflatoxins were first isolated from the fungal culture broth. Subsequent studies revealed that aflatoxin B₁ (AFB₁) is the most potent carcinogen among all aflatoxins, affecting both humans and various animal species. The International Agency for Research on Cancer has classified AFB₁ as a Group 1 human carcinogen. Aflatoxins are present in a wide variety of food items, including cereals, nuts, fruits, and spices. A survey conducted in Japan between 2004 and 2006 revealed that peanut products, cacao products, peppers, and Job’s tears were contaminated with aflatoxins. To reduce exposure, Japan has set a regulatory limit of 10 µg/kg for total aflatoxins [sum of AFB₁, aflatoxin B₂ (AFB₂), aflatoxin G₁ (AFG₁), and aflatoxin G₂ (AFG₂)] for all food items. The National Institute of Health Sciences has developed official analytical methods for determining aflatoxins in foods which are used for quarantine inspection of imported foods. In this symposium, the regulations and analytical methods for aflatoxins are introduced.

Many anticancer drugs, including anthracycline drugs, pose a risk of cardiovascular damage as an adverse reaction. This can detrimentally impact the prognosis and quality of life of patients, potentially leading to the interruption of cancer chemotherapy and compromising cancer treatment. Recently, onco-cardiology (or cardio-oncology) has developed as a new interdisciplinary field that focuses on the prevention and treatment of cardiovascular toxicity of anticancer drugs. In this review, we explore the mechanism underlying the cardiotoxicity of anthracyclines and examine pharmacological agents that safeguard the heart from anthracycline-induced damage. Anthracycline-induced cardiotoxicity primarily involves oxidative stress, characterized by radical production in mitochondria and subsequent apoptosis in cardiomyocytes. While various antioxidant agents, such as resveratrol, vitamin E, and melatonin have demonstrated efficacy in reducing anthracycline-induced cardiotoxicity in animal models, their clinical effectiveness remains inconclusive. Alternatively, dexrazoxane, an intracellular iron chelator, along with standard heart failure medications, such as β-blockers, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers, reduce anthracycline cardiotoxicity and prevent subsequent heart failure in both animal and human studies. Additionally, statins [hydroxymethylglutaryl (HMG)-CoA reductase inhibitors] and ranolazine have emerged as potential candidates for attenuating anthracycline-induced cardiotoxicity in clinical settings. Notably, recent in vitro findings suggest that everolimus, an autophagy/mitophagy-inducing antitumor drug, may protect cardiomyocytes from anthracycline-induced toxicity without reducing the antitumor effects of anthracycline. Although promising, further clinical research is warranted to validate the potential of everolimus as a safer and more effective anthracycline chemotherapeutic strategy.

Semaphorins and their receptors plexins are axon guidance molecules that navigate axons to their final destinations during neural development. Semaphorins and plexins exert distinct roles in regulating biological functions such as the immune system and bone homeostasis. They also participate in the development and progression of various diseases such as osteoporosis and allergic diseases. This review describes the varied phenotypes revealed by the analysis of semaphorin or plexin knockout mice and discusses the association with pathogenesis and therapy of atherosclerosis, agenesis of the corpus callosum, and neuropsychiatric diseases. The deletion of semaphorin 4D in atherosclerosis-prone Apolipoprotein E-deficient mice mitigated atherosclerotic lesions, indicating its crucial involvement in the progression of atherosclerosis. Semaphorin 4D is also implicated in apoptosis induced by the estrogen-dependent generation of soluble semaphorin 4D and the active form of plexin-B1 in the postnatal vaginal opening in mice. Plexin-A1 knockout BALB/cA mice exhibited the agenesis of corpus callosum. This study indicates the crucial role of plexin-A1 in the midline crossing of callosal pioneer axons projecting from the cerebral cortex during the early phase of callosal formation. Adult plexin-A1-deficient mice exhibit reduced prepulse inhibition deficit, an endophenotype of schizophrenia, in addition to excessive self-grooming. Parvalbumin-expressing interneurons in the medial prefrontal cortex are significantly decreased in plexin-A1 knockout mice. In the parvalbumin neurons, oxidative stress is significantly increased in plexin-A1 knockout mice. Accordingly, plexin-A1 deficiency may augment oxidative stress in parvalbumin neurons, thereby impairing the parvalbumin neuron network and leading to behavioral abnormalities relevant to neuropsychiatric diseases.

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.”

Introduction: This study examines current OTC pharmaceuticals in Japan categorized as potential substances for abuse and discusses future initiatives for drug abuse prevention. Methods: The Pharmaceuticals and Medical Devices Agency package inserts search function was used to identify OTC pharmaceuticals containing substances prone to abuse. Subsequently, the corresponding OTC pharmaceuticals containing the designated ingredients were investigated, analyzing their therapeutic and risk categories. Results: In total, 1427 (13.9%) OTC pharmaceuticals contained the designated ingredients, with those containing methylephedrine and dihydrocodeine accounting for the majority (1245/1427, 87.2%). Among the therapeutic categories, oral cold medicines were predominant at 564, followed by antitussives and expectorants at 213, and oral rhinitis medicines at 100. Regarding risk categories, designated schedule II pharmaceuticals predominated in 9 out of 11 therapeutic category classifications. Conclusion: Designated schedule II pharmaceuticals, such as oral cold medicines, antitussives and expectorants, and oral rhinitis medicines, pose a high risk of drug abuse. Addressing this challenge necessitates collaboration between pharmacists and registered sales clerks to implement preventive measures aligned with current trends in drug abuse.