Introduction: Given that coronavirus disease 2019 (COVID-19) aggravation is associated with an excessive host immune response, complementary anti-inflammatory treatment is recommended in severe disease. Although dexamethasone is a widely used anti-inflammatory agent in COVID‒19 patients with respiratory failure, its use in patients with mild COVID‒19 not receiving oxygen could have harmful effects. Colchicine, an anti-inflammatory drug, blocks the upstream immune response by inhibiting NALP3 inflammasome activation. This study aimed to assess the efficacy and safety of low-dose colchicine (DRC3633) in mild COVID‒19.

Methods: This study is a prospective, multicenter, placebo-controlled, double-blind randomized, phase 2 clinical trial patients with moderate COVID-19 admitted at nine hospitals in Japan (jRCT2071200078). The primary endpoint is area under the curve (AUC) for the amount of change of serum hypersensitive C-reactive protein (hs-CRP) from baseline to 1, 2, and 4 weeks after initiating investigational drug. Study participants will be randomly assigned to the colchicine or placebo group at a 1:1 ratio. On day 1, patients in the colchicine group will receive 1 mg of colchicine, followed by 0.5 mg of colchicine after 2 h barring gastrointestinal complications. From day 2 to 28, 0.5 mg of colchicine will be administered once daily.

Discussion: An appropriate anti-inflammatory strategy is critical to improve the outcome of severe COVID-19 patients. This study will assess the efficacy of low-dose colchicine not only by the AUC of the amount of change in serum hs-CRP from baseline to several time points, but also by evaluating whether the result of the primary endpoint is consistent with other relevant biomarkers and clinical parameters measured as secondary endpoints.

One cause of hypertension is excessive salt intake. Outside Japan, simplified front-of-package (FOP) labels are widely used as a means of discouraging excessive salt intake. In this survey, we examined FOP labels targeting Japanese hypertension patients. We also proposed and evaluated packaging promoting low-salt foods. A questionnaire survey of adult hypertensive outpatients was conducted between June 11 and December 7, 2018.

The responses of 100 patients were analyzed. Of these, 63％ considered the simplified FOP label useful. Opinions were divided regarding nutrient-specific labels as one type of simplified FOP label, with 42％ of participants selecting labels showing the percentages of guideline daily amount (GDA) with the addition of a text rating indicating values as low, medium, or high, and 46％ selecting a text rating only. Comparison by age group showed that participants <70 years old selected percentages of GDA with a text rating, whereas those ≥70 years old selected a text rating only. A traffic lights type of color rating was considered necessary by 94％ of participants. In a test involving a reversal of thinking, when low-salt foods were treated as regular products and normal-salt foods as salted products, 85％ of participants selected the low-salt foods. These results suggest that package designs using a simplified FOP label may be effective for promoting low-salt foods. Positive results were also obtained for new package designs for low-salt foods. These measures may help Japanese hypertension patients better understand food labels and reduce salt intake, improve their diet, and mitigate their hypertension.

Onasemnogene abeparvovec-xioi (OA) is the first approved gene therapy product for spinal muscular atrophy (SMA) in Japan. Since the product is a vector derived from adeno-associated virus, however, the clinical use categorized as in vivo gene therapy must be under the type I use of the Cartagena Act to preserve environmental biodiversity. On the other hand, very few health care providers have had experiences of dealing with such as a product and the challenges in clinical sites have still been unknown. To understand the current clinical situation of gene therapy for SMA, we had conducted a nation-wide survey for 41 medical institutions that have used or plan to use the product. Among them, 33 institutes responded to the questionnaire and 21 have provided the gene therapy for the patients. Although each facility conducted the gene therapy by using its own protocols for personal protective equipment, inactivation or disposal of the vector, and patient care, 73％ of the facilities took more than a month to introduce the gene therapy into their hospitals and 82％ found it difficult to establish the implementation system complied with the Cartagena Act. The survey indicated the importance of promptly preparing the standardization of procedure dealing with virus-derived medical products including education materials for health care providers for safe and effective gene therapy nation-wide.

Pediatric drug development is challenging due to various difficulties in clinical evaluation and inadequate economic return over development cost. The legislative measures have been taken in several countries, including the European Union (EU) and the United States (US), to advance drug development in pediatrics because of its importance in disease management.

We compared legislation related to promotion of pediatric drug development in the US, the United Kingdom (UK) and Japan. Next, we set the US, a pioneer in addressing off-label use in children, as the standard against which to compare the approval status of pediatric indications in Japan and the UK. According to the drug labels, we identified 72 products approved for pediatric indications in the US between January 2016 and April 2020 which were also approved for adults or children in both Japan and the UK. We calculated the percentage of products with pediatric indications and analyzed the development status of products without pediatric indications.

In the UK, 83％ (60/72) of products had pediatric indications. Of the 12 products without pediatric indications, four were investigated in clinical trials or planned to be developed for pediatric use. In contrast, the percentage of products with pediatric indications in Japan was 44％ (32/72), and of the 40 products without pediatric indications, only two were in development for pediatric use. All of the products reviewed by the Evaluation Committee on Unapproved or Off-labeled Drugs with High Medical Needs of the Japanese Ministry of Health, Labour and Welfare were indicated for pediatric patients. In contrast, only about half (9/19) of the drugs with orphan drug designation had pediatric indications. With reference to the regulatory frameworks in the US and UK, the ＂Designation of Pharmaceuticals for Specific Use＂, established in the 2019 revision of the Pharmaceuticals and Medical Devices Law (PMDL), may offer the better means to promote pediatric drug development in Japan.

Registration of clinical research data in a database and utilization of the data, including industrial use, are currently promoted as a national policy. However, the research participants from whom the data is derived usually provide biological samples and information free of charge. Furthermore, research participants do not obtain any benefits even if the companies gain economic benefits from this data. Therefore, research participants may have a different awareness of the use of data from conventional non-commercial academic use. For promoting the industrial use of research data, research participants who provide samples and information are essential. Therefore, it is crucial to understand the general public's perceptions of who may become research participants in the future.

In March 2021, we conducted an internet survey of the general public in Japan, which included 2,202 respondents with 18.1％ response rate. The results showed the followings： more than 50％ of the respondents were reluctant to provide biological samples for industrial use； a certain percentage（12.4％‒34.0％）of the respondents believed that samples and data were attributed to donors； more than 50％ of the respondents thought companies should divide gained profits to the donors； 50.0％ of the respondents believed the companies should return earnings to the donors by money, and 22.9％‒37.0％ thought they should return profits to society. From these results, we found that researchers must provide clear explanations to the research participants in the informed consent process. In addition, the government also needs to develop legislation, such as clarifying the legal status of samples and data.

One of the most common medical errors is the mix-up of drugs, and a suitable approach for drug packaging is an important preventive measure. However, packaging of investigational drugs, commonly known as “white boxes,” is often of a non-specific design and does not provide adequate measures to prevent drug mix-ups. At Tokyo Medical and Dental University Hospital (hereinafter, referred to as “our hospital”), pharmacists managing investigational drugs and clinical research coordinators have voluntarily taken measures such as underlining and adding necessary items to the labels of investigational drug packages. In this study, we conducted a retrospective survey of measures taken by sponsors and our hospital for investigational drug management by our hospital as of April 2022, and analyzed the problems and future measures. We found that sponsors took countermeasures by emphasizing labeling items on the investigational drug packaging or by using colors in 94.8％ of the cases. Labeling items are emphasized or additional descriptions are entered for 91.4％ of the cases at our hospital. These results suggested that medical institutions consider the current investigational drug packaging as insufficient to prevent mix-ups. Moreover, there is a concern that relying solely on each medical institution to prevent mix-ups in investigational drug packaging may adversely affect the homogeneity of clinical trial protocols. Thus, we believe that sponsors should exchange sufficient information and opinions with medical institutions and cooperate with the regulatory authorities to establish a more effective investigational drug packaging system from the viewpoints of both medical institutions and subjects.

Glucagon-like peptide‒1 (GIP‒1) receptor agonists (GLP‒1 RAs) are incretin derivative hypoglycemic agents that augment endogenous insulin secretion to improve glucose metabolism in patients with diabetes. Recent clinical studies based on the guidelines of the United States Food and Drug Administration suggest that GLP‒1 RAs have cardio-renal protective effects. For example, beneficial effects on major cardio-vascular events have been observed in the LEADER, SUSTAIN‒6, REWIND, HARMONY trials. In addition, renal protective effects have been proven in the ELIXA, LEADER, SUSTAIN‒6, and REWIND trials. Despite this clinical evidence, the precise pharmacological mechanisms of the cardio-renal protective effects of GLP‒1 RAs are unclear.

Therefore, the present narrative review article assessed the assumptive mechanisms of GLP‒1 RAs. The GLP‒1 RAs act on the central and visceral vagal nervous systems to suppress appetite and reduce body weight and thereby help improve insulin resistance and decrease salt burden potentially underlying in patients with diabetes. In the kidney, GLP‒1 RAs inhibit Na reabsorption by inhibiting Na‒H exchanger 3 in the proximal tubule, which induces water and natriuresis. The GLP‒1 RAs also stimulate atrial natriuretic peptide, potentiating natriuresis, leading to a blood pressure lowering. In addition, GLP‒1 RAs improve proteinuria presumably via antioxidant, anti-inflammatory, anti-fibrotic, and anti-atherosclerotic effects. Whether GLP‒1 RAs provide glomerular protection through the Na‒H exchanger 3‒induced optimization of tubulo-glomerular feedback and the macula densa system is still a matter for debate.

In conclusion, this narrative review article provides new insights into the mechanisms of the cardio-renal protective effects of GLP‒1 RAs.