With the spread of new coronavirus infections (COVID-19), universities/colleges have transformed their educational format from conventional group education to distance learning. In order to share information on the new educational format among the members of the society, the Physiological Society of Japan and the Japanese Pharmacological Society (JPS) jointly conducted the “Emergency Joint Survey on Responses of Universities to COVID-19 and Its Impact on Physiology and Pharmacology Education”. The JPS surveyed pharmacology departments/divisions at schools of pharmacy, medicine, dentistry, and veterinary medicine in 202 universities (response rate 89%) from August to September 2020. 85% of the universities changed the lecture method, and 70% changed the practical training. 30%, 30%, and 40% of the lectures were live, on-demand, and mixed (combination of live and on-demand) lectures, respectively. 25% of the practical training was live or a combination of live and on-demand lectures, and 45% was on-demand delivery. There are many problems to do online methods such as stable network environment, lack of the reality for students and difficulty of the check of their understanding. On the other hand, there are unexpected benefits in online methods such as anytime learning, an increase in questions from students and repeatable learning. More than 60% considered employing the newly introduced educational styles even after the pandemic. Students’ mental health problems and disruption of daily rhythms, quality assurance of online education, and copyright issues were also concerned. Pharmacology education faces a significant turning point in introducing and improving distance learning with or post the COVID-19 pandemic.

The pandemic of COVID-19 has drastically changed the education program in universities. An on-demand lecture is one of the common approaches, which are employed to prevent the infection form spreading in the classroom. On-demand lectures generally have a good reception of the students for the reason that they could repeatedly play back the video when needed and attend the class in a relaxed attitude as they like. On the other hand, we often have some concerns about their understanding of the lecture because we could not get enough feedback during the preparation of the video lectures. In addition, majority of us, beginners of on-demand lectures, have to overcome the difficulties in utilizing various tools to support them. Here, I would like to introduce some tips of on-demand lectures. One, who delivers a chalk talk, should obtain a good pen tablet and a suitable video recording software. Because video lectures with a large data size interrupt the comfortable views of the students, the video files should be compressed using a special software. Approachable Q&A systems should greatly enhance the learning efficiency and open the door to the flip teaching. Blended learning, in which face-to-face learning is combined with video lectures to enhance the understanding, has recently attracted more attention in the field of education. The pandemic of COVID-19 might bring a good opportunity to brush up and improve our classes.

Laboratory work is an essential part of natural science education because it provides students with a valuable opportunity to experience practical scientific research firsthand. In laboratory work in pharmacology, students generally learn about biological mechanisms and drug action mechanisms by analyzing drug actions using laboratory animals. Actual experience with hands and eyes is an important factor in the laboratory work. Under the COVID-19 epidemic, however, we were forced to conduct the laboratory work online. For the laboratory work using isolated organs, we used simulation software, in which students can examine effects of a range of drugs on the smooth muscle within the guinea pig ileum. For the behavioral observation practice, we showed the video of the experiments conducted by the instructors beforehand to the students, and asked them to observe and analyze the behavior. In this review, we will share our challenges to online laboratory work.

The role-play for pharmacological education has been developed by Yanagita et al. since 2010 and incorporated into the curriculum of more than 20 medical or pharmaceutical universities in Japan. This case and communication based active learning course provides the practice to acqire fundamental competences for drug therapy, through role playing of medical professionals and patients in simulated clinical settings. The online pharmacological role-play for the first time was performed at Tohoku Medical and Pharmaceutical University Faculty of Medicine during the state of emergency in Japan. We found that the online role-play was as useful as face-to-face role-plays to train appropriate drug prescriptions and communication skills in medical students. In this review, we described the course design, preparation, and operation of online role-play for pharmacological education. We also explained the differences, advantages, and disadvantages between online and face-to-face setting. Finally, we gave examples on-going challenges to the effective use of the online role-play as a core curricular model of pharmacological and pharmacotherapeutic education.

Intracellular Ca²⁺ plays pivotal roles in cardiac contraction by mediating excitation-contraction (EC) coupling and progression of hypertrophy in the heart. Ample evidence suggests that mechanism of EC coupling in immature hearts are different from those in the adults because of the structural immaturity of the sarcoplasmic reticulum (SR) intracellular Ca²⁺ store and the different expression of Ca²⁺-regulatory proteins. However, the detailed molecular mechanism is not completely understood. In the present study, we identified neuronal Ca²⁺ sensor-1 (NCS-1), an EF-hand Ca²⁺ binding protein that is important for neuronal functions, also functions as a novel regulator of EC coupling in young hearts. We found that NCS-1 is highly expressed in immature hearts, and its deletion decreased their contractile functions as well as intracellular Ca²⁺ signals. NCS-1 enhances Ca²⁺ signals mainly by promoting the Inositol 1,4,5-Trisphosphate receptor (IP₃R) function, followed by Ca²⁺/Calmodulin-dependent Protein Kinase II (CaMKII) signaling, which results in a large increase in the SR Ca²⁺ content that enhances SR-dependent EC coupling. In addition, NCS-1 expression increases in the early stages of hypertrophy and promotes progression of hypertrophy at least in part through IP₃R-dependent elevation of nuclear Ca²⁺ signaling. Our results reveal a previously unrecognized mechanism of EC coupling in young heart and the progression of cardiac hypertrophy. Furthermore, we found that NCS-1 contributes to stress tolerance in cardiomyocytes via activation of mitochondrial detoxification pathways. We propose that the proteins involved in NCS-1-mediated Ca²⁺ signaling can be novel therapeutic targets for cardiac diseases, especially in immature hearts.

Heart failure is an important cause of death of children. Especially, overt one within the preweaning period is fulminant and severe. However, there are no drugs with evidence for it. We recently found that angiotensin II (AngII) activates L-type Ca²⁺ channels through AT₁ receptors (AT₁R) and β-arrestin 2 in murine cardiac myocytes only in the preweaning period, indicating that AT₁R/β-arrestin 2 pathway mediates positive inotropic effects before weaning. Indeed, β-arrestin-bias AT₁R agonist (BBA), TRV027 caused significant long-lasting positive inotropic effects in preweaning mice without increasing serum aldosterone concentrations or inducing tachycardia, arrhythmias, increased cardiac oxygen consumption, and reactive oxygen species generation. TRV027 increased the peak amplitude of twitch Ca²⁺ transients not only in preweaning mouse cardiac myocytes but in human iPS cell-derived cardiac myocytes exhibiting the fetal to neonatal phenotype. Moreover, TRV027 also increased contraction of the compromised heart of the model knock-in mice mimicking human congenital dilated cardiomyopathy. Although ~80% of these mice died before weaning, TRV027 significantly increased their survival rate. TRV027 did not cause any obvious adverse effects on their preweaning wildtype littermates. Thus, we reason in this review that BBA can be important therapeutics for preweaning heart failure.

The zebrafish mutant strains to mimic human diseases have been developed to study human diseases and to discover novel therapeutic drugs. The characteristics of zebrafish, small size, large clutch size, ex utero development, body transparency, and genetic tractability are very useful to research approaches like therapeutic drug screening. Here we introduce and discuss zebrafish models of human diseases and methods of drugs screening using them. Specifically, we show examples of therapeutic drug screens using zebrafish models of a muscular dystrophy to identify new candidates to improve phenotypes in skeletal muscle. The drug screening also reveals new drug actions and unexpected directions for future therapeutic ways. Phenotypic drug screen using zebrafish is an important for rapidly developing and validating therapeutics for human diseases.

The ductus arteriosus (DA) maintains the fetal circulation by connecting the aorta and pulmonary arteries. Patent ductus arteriosus (PDA) occurs in >70% extremely-low-birth-weight infants. Patients with PDA exhibit circulatory failure, which is caused by left-to-right shunt. The DA immediately contracts after birth in response to the elevation of blood oxygen tension and to the decline in circulating prostaglandin E₂ (PGE₂). Cyclooxygenase inhibitors targeting smooth muscle cell (SMC) contraction represent only pharmacological treatment for PDA. However, it is important for DA anatomical closure that intimal thickening (IT) is appropriately formed between SMC layer and endothelial cells (EC). IT begins to form before the second-trimester and becomes prominent toward the end of third-trimester as an increase in placenta-derived PGE₂. Immature DAs frequently fail to be close due to poorly formed IT. IT consists of extracellular matrices (ECM) and migrated DA-SMCs from the tunica media. A glycoprotein fibulin-1 is expressed in developing cardiovascular system and binds to multiple ECMs. We found that PGE₂ increased fibulin-1 via EP4 in DA-SMCs, and Fbln1-deficient mice exhibited PDA with poor IT formation. Although EP4 is a Gs-coupled GPCR, fibulin-1 was secreted from DA-SMCs through the phospholipase C-protein kinase C-non-canonical NFκB signaling pathway. Fibulin-1 bound to DA-EC-derived versican which is a binding partner of hyaluronan, which promoted directional DA-SMC migration toward ECs and contributed to IT formation in the DA. Fibulin-1 upregulation by the activation of specific downstream pathway of EP4 may serve a new pharmacological strategy for PDA.

In vivo cardiovascular experiments as part of safety pharmacology studies have been developed for small molecule drug candidates to maximize detection power for potential undesirable pharmacodynamic effects of a drug candidate on physiological functions, and have been established with appropriate expertise. Conscious freely-moving telemeterized non-rodents are generally used for the in vivo cardiovascular experiments. The technology and evaluation best practices for the experiments have been optimized by multiple researchers and as a result, the experiments considerably contribute to the estimation of cardiovascular risks for humans. In addition, as described in ICH E14&S7B Q&A draft, non-clinical studies are gaining importance in the integrated risk assessment for QT prolongation in humans, and high quality data obtained in non-clinical studies are being required. This manuscript introduces actual technology and evaluation for in vivo cardiovascular safety pharmacology studies based on Japan activity for Improvement of Cardiovascular Evaluation by Telemetry system (J-ICET), which is one of the working groups hosted by Japanese Safety Pharmacology Society.

Anamorelin hydrochloride (hereinafter referred to as anamorelin) is an orally active, small-molecule drug with a similar pharmacological action to ghrelin, an endogenous ligand of growth hormone secretagogue receptor type 1a (GHS-R_1a). It was first approved in Japan for the treatment of cancer cachexia, characterized by weight loss and anorexia. Anamorelin stimulated the secretion of growth hormone (GH) from cultured rat pituitary cells and increased plasma GH levels by oral administration to rats, pigs and humans. When anamorelin was orally administered once daily for 6 days to rats, larger body weight gain associated with increased food consumption compared to the control group was observed from after the first dose. Anamorelin is a selective agonist for GHS-R_1a and enhanced GHS-R_1a-mediated pituitary GH secretion and increased food consumption, resulting in body weight gain. In the two Japanese phase II studies in patients with cancer cachexia associated with non-small cell lung cancer (NSCLC), improvement of lean body mass (LBM) and body weight losses and anorexia were demonstrated. The tumor types of target patients in the Japanese phase III study were colorectal, gastric, and pancreatic cancer. As a result, maintenance and increase of LBM and body weight as well as improvement of anorexia were observed, and the efficacy against cancer cachexia associated with colorectal, gastric, and pancreatic cancer was confirmed. There were no observed events considered to be significant safety risks. In conclusion, anamorelin is expected to provide a new therapeutic option for cancer cachexia for which no effective treatment has been available.

Hereditary angioedema (HAE) is a rare disease that causes serious health problem and affects on quality of life for patient due to recurrent episodes of angioedema in various body such as the skin, larynx, digestive tract, and limbs. Many HAE patients have deficiency or dysfunction of C1 inhibitor, impaired regulation of plasma kallikrein activity and overproduction of bradykinin, resulting in leading to episodes of increased capillary hyper permeability and angioedema. Therapy of HAE consists of on-demand treatment for acute attack and prophylactic treatment by suppressing the onset of acute attack in the short and long term. However, no drug has been approved for long-term prophylaxis in Japan. Berotralstat hydrochloride (ORLADEYO Capsules 150 mg) is an oral, selective plasma kallikrein inhibitor approved for the suppression of the onset of acute attacks in HAE in Japan in January 2021. Preclinical studies demonstrated that Berotralstat is a potent and highly specific inhibitor of human plasma kallikrein activity. Berotralstat suppressed bradykinin production in the HUVEC system. Clinical studies demonstrated that oral administration of Berotralstat to HAE type I or type II patients at a dose of 150 mg once daily showed a reduction of HAE attack rate and clinically significant change in angioedema quality of life score. The most common side effect was gastrointestinal symptoms. In conclusion, preclinical and clinical data indicated that Berotralstat is an effective treatment for long-term prophylactic treatment by suppressing the onset of acute attack in HAE patient and is considered to be a useful treatment option for patients.

Pemigatinib (Pemazyre^® Tablets 4.5 mg) is a novel fibroblast growth factor receptor (FGFR) inhibitor, created by Incyte Corporation. The product was approved in March 2021 and was launched in June 2021 for the treatment of patients with locally advanced or metastatic biliary tract cancer (BTC) with a fibroblast growth factor receptor 2 (FGFR2) fusion or rearrangement that has progressed after at least one prior line of systemic therapy. Pemigatinib was shown to selectively inhibit kinase activity of FGFR1～3 (IC₅₀; 0.39～1.2 nM). In cultured cells, pemigatinib inhibited the phosphorylation of FGFR1 and its downstream signals, ERK1/2 and STAT5 in a concentration-dependent manner. Pemigatinib also potently inhibited the growth of various types of cell lines with FGFR 1～3 gene alteration. Pemigatinib was shown to induce concentration-dependent tumor regression in a tumor xenograft model mice in which tumor tissue sections from patients with cholangiocarcinoma (CCA) harboring FGFR2 gene fusions were transplanted. Pemigatinib was well tolerated in Japanese and overseas Phase1 studies (INCB 54828-101 and 202). In the global phase2 study (INCB 54828-202) conducted in CCA patients with FGFR2 gene fusions or rearrangements, significant improvement in the overall response rate was observed. Although several adverse reactions were observed which was based on the mechanism of action of pemigatinib, the safety profile and management of the adverse reactions were favorable. Pemigatinib is expected to contribute to second-line drug treatment after failure of standard therapies in biliary tract cancer.