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

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.

Methamphetamine, a psychostimulant drug, acts on dopaminergic neuron terminals projecting from the ventral tegmental area to the nucleus accumbens, which constitutes the reward system in the brain. In addition to dependence triggered by excessive excitation of the reward system, methamphetamine induces various effects, including hallucinations, delusions, and cognitive dysfunction. This means that molecules responsive to methamphetamine are importantly involved in the brain function. This report reviews the functions of Shati/Nat8l and Piccolo, identified as methamphetamine-responsive molecules in the murine nucleus accumbens, in cognitive and psychiatric functions clarified by rodent studies. Shati/Nat8l is related to drug addiction and depression and participates in the synaptic function of the hippocampus to maintain cognitive function. Its upregulation suppresses cognitive disturbance in Alzheimer's disease pathology. In the nucleus accumbens, Piccolo contributes to the behavioral alteration caused by methamphetamine. Piccolo downregulation in the prefrontal cortex induced schizophrenia-like behavioral and neuronal changes in mice. These findings indicate that Shati/Nat8l and Piccolo exert important functions on the brain and are potential targets for brain disorder studies. It is anticipated that understanding of brain function will be achieved through the analysis of methamphetamine-responsive molecules.

In this study we have developed a method of profiling multiple "single-molecules" of enzymes in biological samples, by studying their activities as a form of single-molecule enzyme activity assay. The original method for single-molecule enzyme assay in microfabricated chamber devices was reported many years ago, but we for the first time report the application of this concept to identifying each enzyme in the chamber by simultaneously measuring activities against multiple substrates. Based on this idea, we developed the protein profiling technique to globally detect and "count" different sets of enzymes in biological samples containing various characterized and uncharacterized enzymes. We expect that the methodology will open up the application of single-molecule enzyme assay to discovering and using novel biomarker proteins.

Organic molecules can absorb light energy to form excited states, from which various photophysical and photochemical processes such as heat, emission, and chemical reactions occur during deactivation to ground states. Therefore, it is highly important to control molecular properties in the excited states in many scientific fields including pharmaceutical sciences. Especially, the author has focused on the development of molecular technologies to utilize near-IR light, showing deep tissue penetration favorable for biomedical applications. The author has designed and synthesized 18π-electron tautomeric hydroxybenziphthalocyanines as functional near-IR-light-absorbing compounds with tunable aromaticity. Their near-IR absorption can be controlled by external stimuli such as chemical modifications and solvent effects. Additionally, the benziphthalocyanines were utilized for activatable near-IR photoacoustic imaging probes owing to their nonradiative thermal deactivation processes. The author also succeeded in developing a redox-switchable near-IR dye called benzitetraazaporphyrin. This molecule exhibits strong near-IR absorption in the 20π-electron antiaromatic reduced structure, while the 18π-electron oxidized structure is near-IR silent. The benzitetraazaporphyrin would be useful as near-IR probes working in reductive environments such as cancer cells.

The relationship between the concomitant use of immune checkpoint inhibitors (ICIs) and elevated prothrombin time-to-international standard ratio (PT-INR) in patients receiving warfarin remains unclear. In the present study, 26 patients treated with ICIs during warfarin therapy were examined for increases in PT-INR within 60 d of ICI administration. Of these patients, 13 developed Grade 2 or higher PT-INR elevations, 5 of which required the immediate administration of vitamin K. The increased risk of bleeding and the impact on the continuation of cancer drug therapy are significant burdens for patients. Immune-related adverse events caused by ICIs have been suggested as one of the reasons for increases in PT-INR, and patients taking warfarin and ICIs need to be managed in consideration of the risk of elevated PT-INR by frequently checking the blood coagulation capacity.

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.

Organic chemistry in pharmaceutical education is indispensable for drug discovery and the understanding of biological phenomena and plays an important role in the identity formation of pharmacists. In the Model Core Curriculum for Pharmacy Education (2022 revision), organic chemistry is one of the most fundamental subjects in basic pharmaceutical sciences and plays an important role in the study of other fields. Based on basic pharmacy, the academic goal of pharmacological research is to develop problem-finding skills and foster the problem-solving abilities necessary for research that contributes to the development of pharmacy and medicine. The author devised ways for students to become interested in their research topics and to work on them independently. Specifically, the author adopted a teaching method that respects students' independence in scheduling and selecting synthetic routes. For example, in research to determine the absolute configuration of metabolites of the antibiotic nabumetone, students managed their own schedules and became able to conduct research with a sense of conviction and responsibility. In addition, in research on the synthesis of thiophene derivatives, presenting multiple synthetic routes and allowing students to choose one enabled them to propose the direction of the experiment based on their own opinions. Therefore, it is necessary to devise and support research procedures tailored to individual students.

Hypervalent iodine(III) compounds are known to be exceptionally good oxidizing reagents because they are generally highly reactive, can be used in various molecular designs, and are relatively easy to synthesize and handle. Although they are very useful reagents with a wide range of reactivity, some iodine(III) compounds are difficult to handle due to low solubility and stability issues. In earlier studies, it was found that iodine(III) reagents with an ether group introduced at the ortho-position have improved solubility and stability. Based on these results, new hypervalent iodine compounds were developed by utilizing coordinating properties of functional groups other than the ether group. In this paper, hypervalent iodine compounds with carboxyl or hydroxyl groups introduced into the aromatic ring attached to the iodine atom were successfully synthesized, and their structures were elucidated by X-ray structural analysis. In addition, the reactivity of these compounds is reported based on the successful development of several unique reactions.

Based on the perspectives of the environment, food, and health, this review reflects on previous research examining stem cells for the early detection of chemical hazards and the development of preventive health tools. The risks posed by endocrine-disrupting chemicals in the environment are investigated, including studies on 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), phthalate esters, and bisphenol A. Building on the findings of these studies, this review identifies emerging challenges in the field of endocrine-disrupting chemical research. Moreover, this paper explores innovative testing methods aimed at accurately evaluating the impact of chemicals on human health. The key topics covered include the implementation of developmental neurotoxicity testing methods, the species-specific effects of methylmercury, nanomaterials and the application of human pluripotent cells to assess the effects of low-dose radiation. Additionally, this review highlights transformative approaches in chemical health impact assessment that integrate cell science and artificial intelligence, and addresses challenges related to the application of multi-omics technologies in environmental health and toxicology.