In the past, drug discovery using low-molecular-weight compounds was dominated by structural design based on combinations of non-metallic elements such as carbon, nitrogen, oxygen, and halogens. Recent drug discovery efforts have shown extraordinary progress, an example of which is the adoption of non-universal elements. The approval of boron neutron capture therapy (BNCT) using a neutron accelerator in Japan ahead of other countries is still fresh in our memory. Other small-molecule drugs containing boron atoms have also been developed, and boron is becoming widely recognized as a constituent element for drug discovery. It is known that borane (BH₃) is unstable because of its electron-deficient bonds; nevertheless, its stability has been improved by the formation of clusters through multimerization. Carborane (C₂B₁₀H₁₂), one of the borane clusters, has an icosahedral structure with two carbon atoms and ten boron atoms and exhibits properties that vastly differ from conventional boron compounds. In this symposium review, we will introduce the basic chemistry of carboranes and their application to drug discovery. Boron is an essential element in plant cell wall formation and has extremely low toxicity to humans. I hope that this symposium review will be an opportunity for us to free ourselves from existing prejudices and constraints in drug discovery, and that new modalities that skillfully utilize the characteristics of boron and boron clusters will be developed one after another.

Hexa-coordinated sulfur fluoride compounds have a regular octahedral structure and exhibit distinctive chemical properties. This review describes the application of two hexa-coordinated sulfur fluoride groups as substructures of bioactive compounds. One of them, the pentafluorosulfanyl (SF₅) group, also called a “super-trifluoromethyl group” has attracted considerable attention in recent years because of its strong electron-withdrawing character, high hydrophobicity, and bulky structure. Based on these properties, the SF₅ group has been incorporated in both polar and hydrophobic regions of bioactive compounds, including anti-malarial agents and nuclear receptor ligands. In at least some cases, conversion of conventional functional groups to the SF₅ group has resulted in improved bioactivity and characteristic ligand activity. The second group, the tetrafluorosulfanyl (SF₄) group, is available as a unique linker structure that connects two substructures linearly via a single atom. However, its low chemical stability and the limited scope of current synthetic methods has restricted its utilization. In recent years, research has been directed towards improving its stability and developing new synthetic methods. We designed and synthesized a novel retinoic acid receptor (RAR) ligand containing an SF₄ group as a linker structure and found that it exhibited distinct ligand activity towards RAR. The unique chemical and structural properties of the SF₅ and SF₄ groups are expected to expand the chemical space of bioactive compounds, providing new scope for innovation in medicinal chemistry.

Boronic acids are able to reversibly interact with the diol groups, a commonly found motif in biomolecules including sugars, ribose and catechols. For their carbohydrate-binding properties, they can be regarded as a synthetic mimic of lectins and often termed as “borono-lectins.” Importantly, the borono-lectins platform can be chemically tailored to manifest a broad profile of binding strength and specificity. Besides the structural versatility, some derivatives can undergo a sharp inversion in the state of hydration in synchronization with the molecular recognitions. This feature, when combined with amphiphilic polymeric backbones, translates into many creative principles for fine-tuning or switching the hydration and more complex molecular assemblies in a way interactive with biology. Here we provide a brief overview of our recent efforts on the related applications with special focuses on smart insulin delivery systems and sialic acid detections relevant to cancer diagnosis and treatment among others.

This paper introduces the research of nanomachines utilizing boron chemistry. Boron neutron capture therapy (BNCT) has beeing attracting increasing attention as a minimally invasive cancer treatment, and p-boronophenylalanine (BPA) has been approved as a potent BNCT drug. However, intratumoral retention of BPA remains to be improved. Recently, we have developed a BPA delivery system [poly vinyl alcohol (PVA)–BPA] utilizing PVA. PVA–BPA altered the uptake pathway of BPA by cancer cells and significantly improved the intracellular retention in cancer cells. in the in vivo experiments, PVA–BPA showed improved tumor accumulation and a remarkable tumor growth inhibition upon thermal neutron irradiation. On the other hand, a useful delivery system of bioactive proteins has been strongly demanded. In this study, we have developed the ternary complex micelles for the protein delivery utilizing tannic acid (TA) and block copolymer containing a boronic acid group. The ternary micelles improved the blood retention and tumor accumulation of the loaded proteins, and realized a tumor tissue-selective enzymatic reaction in the enzyme delivery.

We held lectures and practices for the regional community residents with the aim of promoting appropriate use of medications. To evaluate the usefulness of our activity, we conducted medicine-related questionnaire surveys (pre- and post-questionnaires) before and after the lectures and practices, and satisfaction with the activity questionnaire surveys (post-questionnaires) after them. We also evaluated the effect of age difference on the results by dividing the participants into elderly (age ≥65) and non-elderly (age <65), before the analysis. In the both (elderly and non-elderly) groups, the ratio of positive answers in several items of post-questionnaire regarding appropriate use of medications was higher than that of pre-questionnaire. These results suggest that the basic medicine-related knowledge improved by attending the lectures and practices, and indicate that the knowledge of the regional community residents is higher than we imagined. Furthermore, there was no difference in the ratio of positive answers between the both groups, suggesting that our activity is applicable to a wide range of age groups. Our activity benefitted the participants, and not only provided education to the regional community residents regarding appropriate drug use, but also lead to the development of regional community activity, by the coming together of the regional community residents of various age.

Medical expenses are increasing year by year in Japan. However, the quantity of disposed medical opioids is not well known. In this study, we assessed disposed medical opioids in community pharmacies of Fukuoka city and in all of medical organizations of Kumamoto cities for 3 and 2 years, respectively. We collected official opioid disposal reports in Kumamoto city and Fukuoka City Pharmaceutical Association (FCPA) disposal information sheet in Fukuoka city. The total amount of disposed opioids was worth 7.1 million Yen from 2017 to 2019 in Fukuoka city, and 8.9 million Yen in for 2 years (2018 and 2019) in Kumamoto city. In Fukuoka city, the most disposed opioid was 20 mg Oxycontin^®, worth approximately 940000 Yen. In Kumamoto city we assessed data in different organizations. The most disposed opioid was 5 mg Oxinorm^® at a cost of 600000 Yen at the medical institutions over the 2-year study period. The most disposed opioid was 40 mg Oxycontin^®, at a cost of 640000 Yen in community pharmacies. Two hundred micrograms E-fen^® buccal tablet was the most disposed of opioid, was amounting to 960000 Yen in wholesalers. On the whole in Kumamoto city, non-dispensing was the most common reason of disposal. These results indicate that the amount of disposed opioids is huge. Small package simulation studies suggest that smaller package units of MS-Contin^®, Anpec^® suppository, and Abstral^® sublingual tablet may be able to reduce the amount of disposed opioids.

The proteolytic enzyme inhibitor nafamostat mesylate is widely used for the treatment of acute pancreatitis and disseminated intravascular coagulation. This drug may be a risk factor for phlebitis, but this risk has not been studied. Therefore, we aimed to investigate the frequency of phlebitis and its risk factors in patients treated with nafamostat mesylate in intensive care units (ICU) or high care units (HCU). During the study period, 83 patients met the inclusion criteria, and 22 of them (27%) experienced phlebitis. A multivariate logistic regression analysis was performed for severe acute pancreatitis, administration duration, and administration concentration of nafamostat mesylate in ICU or HCU. As a result, the administration of nafamostat mesylate for ≥3 d in the ICU or HCU was an independent predictor of phlebitis caused by nafamostat mesylate [odds ratio (OR), 10.3; 95% confidence interval (CI), 1.28–82.5; p=0.03]. This study suggests that the number of days of nafamostat mesylate administration is associated with phlebitis in patients treated with the drug, and it may be necessary to pay attention to its administration for ≥3 d in ICU or HCU.

In Japan, four different types of hypotonic infusion fluids, namely, types 1–4, are available and used depending on the patient’s condition. Although branded and generic products for each type of hypotonic infusion fluid are available, their physicochemical properties are unknown. For types 1 and 3 fluids, differences in the physicochemical properties of branded and generic products lead to different adverse events when administered. In the present study, we measured titration acidity, pH, and osmolality of branded and generic type 2 hypotonic infusion fluids, which have recently been recognized as useful for maintenance infusion among pediatric patients. We herein assessed their physicochemical information required while selecting a product in clinical practice. Experiments were performed using one branded and two generic products of type 2 hypotonic infusion fluids. Titration acidity was measured via neutralization titration, osmolality was measured via freezing point depression, and pH was measured via potentiometry using a glass electrode. Significant differences in titration acidity, which is a risk factor for metabolic acidosis, and pH, which is a risk factor for pH-dependent changes upon mixing, were observed between the branded and generic products. Our study indicates that titration acidity and pH should be evaluated appropriately to avoid adverse events in clinical practice while selecting a product of type 2 hypotonic infusion fluids. Our findings highlight the importance of evaluating the differences between branded and generic products, specifically when selecting it for pediatric patients with incompletely developed renal function and patients with impaired renal function.

Drug-induced thrombocytopenia is associated with bleeding tendency and suggests the need for the immediate suspected drug withdrawal. Patients with drug-induced thrombocytopenia usually experience an acute drop in platelet (PLT) levels a week or two after starting a new medication. Thrombocytopenia has both immune and non-immune mechanisms. Minocycline (MINO)-induced thrombocytopenia is rare; thus, there are few studies of this condition. In the present study, intravenous administration of MINO led to thrombocytopenia. The female patient was 80 years old. She was receiving radiation therapy for tongue cancer and medication for pain control. She had fever and aspiration pneumonia and was being treated with an antibacterial drug. Empiric therapy consisting of intravenous administration of tazobactam/piperacillin was performed; however, inflammation and fever did not improve. The bacterial drug was changed to vancomycin and cefmetazole. Sputum culture was positive for Enterobacter cloacae thus, we changed her treatment to MINO. Seven days after starting MINO, PLT levels were low; however, they recovered when treatment was stopped. Our findings suggest that MINO may rarely cause severe thrombocytopenia; thus, it is necessary to observe the patient’s blood collection.