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

Nanoparticles, including liposomes and lipid nanoparticles, have garnered global attention due to their potential applications in pharmaceuticals, vaccines, and gene therapies. These particles enable targeted delivery of new drug modalities such as highly active small molecules and nucleic acids. However, for widespread use of nanoparticle-based formulations, it is crucial to comprehensively analyze their characteristics to ensure both efficacy and safety, as well as enable consistent production. In this context, this review focuses on our research using atomic force microscopy (AFM) to study liposomes and lipid nanoparticles. Our work significantly contributes to the capability of AFM to measure various types of liposomes in an aqueous medium, providing valuable insights into the mechanical properties of these nanoparticles. We discuss the applications of this AFM technique in assessing the quality of nanoparticle-based pharmaceuticals and developing membrane-active peptides.

Recently, radiotheranostics, which systematically combines diagnosis by nuclear medicine imaging and treatment by internal radiotherapy, constitutes a new modality in cancer treatment, with some clinical reports showing marked effects on cancer. We have been developing multifunctional chelates containing a target recognition unit, a radiation release unit, and a radioactivity pharmacokinetics control unit in the same molecule to develop efficient agents for cancer radiotheranostics based on chemical control of radioactivity pharmacokinetics. Using these compounds, we have achieved improved cancer accumulation and reduced renal accumulation in tumor-bearing mice, and have developed novel hybrid radiotheranostic agents that can be applied to simultaneously perform target-specific molecular imaging using γ-ray emitting radionuclides and internal radiotherapy using α-particle-emitting radionuclides. For example, ¹¹¹In/²²⁵Ac-labeled PSMA-DA1, which targets prostate-specific membrane antigen (PSMA) for radiotheranostics, achieved clear in vivo imaging of PSMA in tumor-bearing mice and showed marked tumor growth inhibition. In addition to PSMA, this platform for radiotheranostics has also shown efficacy against various cancer target molecules, including carbonic anhydrase IX (CA-IX), which is highly expressed in hypoxic regions of cancer, and glucagon-like peptide-1 receptor (GLP-1R), which is highly expressed in insulinomas. This review presents these recent results of our studies on radiotheranostics for cancer.

Nanoplastics (NPs) are plastic fragments that are small enough to be absorbed by organisms through ingestion or inhalation. Recent studies indicate that nanoplastics can be ubiquitous in the environment, and there are growing concerns regarding the impacts of nanoplastics on the health of humans and other organisms. However, quantitative information on nanoplastics in the environment is still very limited, and most previous toxicity studies have used only polystyrene (PS) particles because of a lack of appropriate model particles of other plastics. We developed a nanoprecipitation-based method for the preparation of nanoplastic particles of five major polymers: low-density polyethylene (LDPE), high-density polyethylene (HDPE), polypropylene (PP), polyvinyl chloride (PVC), and polystyrene. A major advantage of our method is that the nanoplastic particles are prepared without using reagents that can remain in the particles as impurities. Analysis of the prepared particles' molecular weight (M_w) distributions, crystallinities, and thermal properties revealed that their compositions and constitutions were within the general ranges for commercial products. The mechanisms underlying the formation of low-density polyethylene particles via our method were investigated by means of a simple population balance model, and particle diameter was found to be linearly correlated with the suspension density of the nanoplastic dispersion up to 0.4 mg·mL^-1. Future studies should focus on improving our method to allow for precise, scale-independent production of nanoplastic particles. Methods for the preparation of labeled particles are also needed so that such particles can be used in nanoplastic risk assessments.

In Japan, the Pharmaceutical and Medical Device Act was amended in December 2019, and now requires pharmacists to follow-up on patients during treatment. Although there have been some studies on the effectiveness of follow-ups by pharmacists, there are no reports on the status of implementation in clinical practice. We conducted a nationwide survey on follow-up care to investigate the actual situation. We randomly selected 10% of community pharmacies in each prefecture and conducted a survey. We built a web-based system for the collection of basic information on the pharmacies and follow-up cases. A total of 561 pharmacies were pre-entered. Of these, 110 pharmacies (19.6%) reported 326 follow-up cases. Information was provided to doctors in 129 cases (39.6%), of which prescription proposals were made in 10 (7.8%) instances. The follow-up implementation rate based on the number of prescriptions dispensed was estimated to be 0.84% (95% confidence interval: 0.76-0.94%). This study revealed the status of follow-ups in clinical practice. Pharmacists can contribute to the optimization of drug treatment by providing follow-up information to doctors and making prescription proposals.

This study aimed to estimate the medical costs associated with febrile neutropenia (FN) prophylaxis with pegfilgrastim and evaluate its impact on survival outcomes in daily practice in Japan. In this single-center retrospective study, we obtained data from 296 Japanese patients with breast cancer receiving fluorouracil, epirubicin, and cyclophosphamide (FEC)-100 chemotherapy; the patients were divided into the pegfilgrastim and non-pegfilgrastim groups. We analyzed the median costs of chemotherapy, drugs for all adverse events (AEs) and FN, and hospitalization due to FN. We also assessed the survival outcomes. The pegfilgrastim group showed a significantly higher median total cost (JPY 872320.0 vs. JPY 466715.0, p<0.001). This difference was associated with the prophylactic use of pegfilgrastim. The median costs of the drugs for all AE treatments were JPY 9030.4 and JPY 24690.6, with the non-pegfilgrastim group showing a significantly higher cost (p<0.001). In 11 patients hospitalized for FN management, no significant difference in hospitalization cost was observed between the pegfilgrastim and non-pegfilgrastim groups (JPY 512390.0 vs. JPY 307555.0, p=0.102). No significant difference in the 3-year overall survival was observed between the pegfilgrastim and non-pegfilgrastim groups (79.9% vs. 88.3%, p=0.672). In this study, although the total medical cost in daily practice increased because of primary prophylaxis with pegfilgrastim, the 3-year overall survival was not impacted by the use of pegfilgrastim. Our study data suggested that the primary prophylaxis pegfilgrastim should be used during FEC-100 chemotherapy based on the patient-related FN risk factors, instead of routine use.

Currently, elderly care facilities that do not offer long-term care are not required to employ pharmacists, and duties such as the dispensing and distribution of medicines are entrusted to external pharmacies. Pharmacists seldom spend sufficient time at the facilities for elderly people requiring special care. Thus, in many cases, the pharmacists have insufficient knowledge of the residents' medication status, leading to their inability in determining whether the residents are receiving a suitable drug therapy. We previously documented various problems in the practices adopted by nursing staff (with negligible intervention by pharmacists) for assisting residents in taking their medications. In the present pilot study, we attempted to eliminate the use of potentially inappropriate medications by stationing a pharmacist at a nursing home for 24 h every week (3 d/week). We proactively collected information from nurses and other nursing staff and observed the residents' actual living conditions and medication use. As a result of this intervention, 56 prescriptions were changed. However, only two of these were changed exclusively based on the prescription information. Most prescriptions were able to change based on the information obtained by the pharmacist present at the facility. Therefore, pharmacists' presence at the facility (at least for a few hours) is necessary, as they can actively intervene and collaborate with other staff to prevent the use of potentially inappropriate medications.

Cardiotoxicity induced by anti-cancer drugs is a significant concern for patients undergoing cancer treatment. Some anti-cancer drugs can damage cardiac muscle cells directly or indirectly, potentially leading to severe heart failure. Various risk factors, including the type and dosage of chemotherapy agents as well as patient background, contribute to the development of cardiotoxicity. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), which enable patient-specific toxicity prediction, hold great promise in this regard. However, the practical implementation of hiPSC-CMs-based prediction of anti-cancer drug-induced cardiotoxicity still faces hurdles. One major challenge involves establishing and optimizing experimental systems for evaluating contractile dysfunction, the ultimate output of heart failure, using hiPSC-CMs. Such efforts are currently underway globally, focusing on tailoring functional evaluation systems to the characteristics of hiPSC-CMs. In this paper, we provide an overview of the contraction mechanisms of cardiac cells and introduce a method of measuring contraction that we have developed, and discuss the current status of contractile function evaluation methods using hiPSC-CMs.

Quantitative NMR (qNMR) is employed to determine the purity of reagents used as standards for HPLC quantification in the Japanese Pharmacopoeia (JP) and has become recognized as a new absolute quantification method in various fields such as pharmaceuticals, foods, and food additives. This report outlines how and why qNMR has been adopted as an official method in the JP and introduces its progression from JP16 to JP18. The results of a survey of companies in the Japan Pharmaceutical Manufacturers' Association regarding how and when to use qNMR from development to manufacturing stages are introduced. The issues involved in the expansion of the use of qNMR in the field of chemical pharmaceuticals in 2017 are discussed and how these were resolved.

My research focused on the effects of various drugs on (1) dopamine formation from p-tyramine catalyzed by polymorphic cytochrome P450 (CYP or P450) 2D6 variants and (2) endogenous steroid hormone hydroxylation catalyzed by CYP3A subfamily members (CYP3A4, CYP3A5, CYP3A7). The activation (cooperativity) of metabolic reactions catalyzed by P450s was especially emphasized. The effects of various psychotropic agents on dopamine formation from p-tyramine, catalyzed by wild-type CYP2D6.1 and CYP2D6 variants, including CYP2D6.2 (Arg296Cys;Ser486Thr), CYP2D6.10 (Pro34Ser;Ser486Thr), and CYP2D6.39 (Ser486Thr) were compared. Michaelis (K_m) and inhibition (K_i) constants of the psychotropic agents in the presence of CYP2D6.10 were higher than those observed in the presence of other CYP2D6 variants. Fluvoxamine, fluoxetine, milnacipran, and haloperidol activated CYP2D6-catalyzed dopamine formation [decreasing the K_m and/or increasing the maximal velocity (k_cat)], and this activation was CYP2D6 variant-dependent. Regarding the CYP3A subfamily, the effects of various compounds including endogenous steroid hormones on the 6β-hydroxylation of steroid hormones, such as testosterone, progesterone, and cortisol, were determined; it was found that testosterone, dehydroepiandrosterone, and/or α-naphthoflavone activated 6β-hydroxylation of cortisol and/or progesterone, but the effects varied in the presence of different CYP3A subfamily members. Further studies are required to confirm the mechanisms and therapeutic relevance of these activation phenomena.