Neurons differentiated from neural stem cells mature to form a neuronal network. Neuronal maturation enables neurotransmission that regulates brain function. Therefore, abnormal neuronal differentiation causes dysfunction in neurotransmission, and is involved in the onset of various neuropsychiatric disorders. Most of the drugs currently available for the treatment of neuropsychiatric disorders act on membrane receptors and reuptake transporters of neurotransmitters, and control neurotransmission. These membrane proteins have a high affinity for a specific neurotransmitter, and are highly expressed in synapses. By contrast, xenobiotic transporters have a relatively lower affinity for neurotransmitters, but widely recognize various organic compounds, and are also expressed in brain neural cells. It has remained largely unknown why such xenobiotic transporters are expressed in neural cells that play a key role in neurotransmission. We have therefore attempted to clarify the physiological roles of organic cation transporters (OCTs) in neural stem cells in order to obtain new insight into the treatment of neuropsychiatric disorders. The carnitine/organic cation transporter OCTN1/SLC22A4 is expressed at much higher levels in neural stem cells compared with other OCTs, and promotes their differentiation into neurons through the uptake of the food-derived hydrophilic antioxidant ergothioneine after oral administration. In this review, we introduce current topics on the physiological/pathophysiological roles of OCTs in neural stem cells, and discuss their possible application to the treatment of neuropsychiatric disorders.
In most mammalian species, adult neurogenesis appears to occur only in the olfactory bulb and hippocampal dentate gyrus, where neural stem/progenitor cells exist to create new neurons. The discovery of multi-potential neural stem/progenitor cells (NPCs) in the adult brain has precipitated a novel therapeutic strategy for harnessing these endogenous cells to aid in recovery from neurodegenerative disorders. During neurodegeneration, a plethora of endogenous factors, including cytokines, chemokines, neurotransmitters, blood-derived factors, and reactive oxygen species, are released by the activation of resident microglia, astrocytes, and infiltrating peripheral macrophages. It is interesting that these endogenous factors affect the proliferation, migration, differentiation, and survival of newly generated cells involved in the incorporation of newly generated neurons into the brain's circuitry. The unique profile of these endogenous factors can vary the degree of neuroregeneration after neurodegeneration. We show that adult neurogenesis-activating signals are regulated by endogenous factors produced during neurodegeneration.
Brown adipose tissue is a critical regulator of metabolic health, and contributes to thermogenesis by uncoupling oxidative phosphorylation through the action of mitochondrial uncoupling protein 1 (Ucp1). Recent studies have shown that cold exposure and the stimulation of β3-adrenergic receptors induce the development of brown cell-like “beige” adipocytes in white adipose tissue. Brown and/or beige adipocyte-mediated thermogenesis suppresses high-fat diet-associated obesity. Therefore, the development of brown/beige adipocytes may prevent obesity and metabolic diseases. In the present study, we elucidated whether naturally occurring compounds contribute to regulating the cellular differentiation of brown/beige adipocytes. We screened for the up-regulated expression of Ucp1 during beige adipogenesis using extracts of crude herbal drugs frequently used in Kampo prescriptions (therapeutic drugs in Japanese traditional medicine). This screening revealed that the extract prepared from Citri Unshiu Pericarpium [the peel of Citrus unshiu (Swingle) Marcov.] increased the expression of Ucp1 in beige adipocytes. We also focused on the function of clock genes in regulating brown/beige adipogenesis. Therefore, another aim of the present study was to evaluate naturally occurring compounds that regulate brain and muscle Arnt-like 1 (Bmal1) gene expression. In this review, we focus on naturally occurring compounds that affect regulatory processes in brown/beige adipogenesis, and discuss better preventive strategies for the management of obesity and other metabolic disorders.
The mesenchymal stem cell (MSC) is a type of tissue stem cell. In clinical studies, cultured MSCs have shown important therapeutic effects on diseases via both the reduction of neurological defects and the regulation of immune responses. However, in vivo MSC localization, function, and properties are poorly understood; therefore, the molecular understanding of MSC hierarchy is less advanced compared to hematopoietic stem cell hierarchy. Runt-related transcription factor 2 (Runx2) is an essential transcriptional regulator of osteoblast differentiation from MSCs. Runx2 deficiency in Paired-related homeobox 1 (Prrx1)-derived cells (Runx2Prrx1−/− mice) results in defective intramembranous ossification. Double-positive cells for Prrx1-GFP, and stem cell antigen-1 (Sca1) (Prrx1+Sca1+ cells) in the calvaria, express Runx2 at lower levels, and are more homogeneous and primitive compared with Prrx1+Sca1− cells. Our results suggest that osteoblast differentiation in vivo may begin at the Prrx1+Sca1+ MSC stage, with sequential progression to Prrx1+Sca1− cells, followed by Osterix+Prrx1−Sca1− osteoblast precursors, which eventually form mature α1(I)-collagen+ osteoblasts. This research will enable us to better understand the in vivo molecular biology features of MSCs, leading to their therapeutic applications for tissue repair and regeneration.
This review describes the initial development of good laboratory practice (GLP) and follows the discoveries of quality control problems in labs that conducted tests in U.S. pharmaceutical companies. In addition to introducing the essence of the GLP standards, how the GLP ensures the reconstructability and reproducibility of study results is explained in detail. Issues in nonclinical safety studies in drug development and approaches of the Japanese Pharmaceuticals and Medical Devices Agency to overcome them are also described. It is hoped that this review is helpful not only to those who work on drug development but also to faculties and students who work in academia and are involved in basic research when they attempt to resolve problems related to ensuring the reliability of basic research and research integrity.
Many nonclinical and clinical studies are conducted to submit new drug applications for chemical entities. Nonclinical studies cover pharmacology, pharmacokinetic, and toxicology aspects and provide pharmacologic evidence as well as kinetic and toxicologic profiles of the compounds. The risks and benefits of compounds are evaluated based on these nonclinical studies, especially before initiation of the first human trials. Therefore, using adequate procedures, highly controlled, quality nonclinical data should be obtained. This section shares and discusses items required of good laboratory practice (GLP)-compliant organizations and management systems in GLP facilities in the pharmaceutical industry as well as those required for GLP inspections by the Japanese Pharmaceuticals and Medical Devices Agency. In addition, it explains standard operating procedures for conducting quality, non-GLP, pharmacology, and pharmacokinetic studies.
There is currently a major effort to promote drug discovery in academia as a way to seed new drug development in the pharmaceutical industry. However, there are concerns in industry about the quality of drug candidates generated in academic institutions. These concerns encompass culture and perceptions with respect to intellectual property management, the process of product development, and the reliability of scientific data. Questions about data reliability underscore the particularly serious problem of mistrust in academic research. Therefore, the author became interested in the topic of industry standards for quality assurance (QA) and arranged training workshops at Okayama University on the appropriate methods for recording experimental notes by lecturers involved in QA. The outcomes are presented here.
The Bridging Research Accelerating Network Program of the Japan Agency for Medical Research and Development has increased academic research on nonclinical studies to acquire proof of concept for pharmaceuticals, and recently some universities with special technological knowledge have started collaborative research with pharmaceutical companies. In such joint research, companies often repeat studies conducted by academic institutions to ensure that the study data meet the reliability requirements for new drug applications (NDAs). Conducting repeated studies is costly and time consuming and delays the R&D process prior to filing NDAs. If reliable study data could be generated by academia, it would enhance the speed of drug development and promote the early launch of new drugs. This review explains aspects of research reliability which must be noted by academia, particularly with regard to studies cited in papers submitted to scientific journals or for NDAs. It also explains methods for maintaining records in experimental notebooks and how to correct records. The standards for “attributable, legible, contemporaneous, original, accurate” data, commonly referred to as the ALCOA standards, which ensure the integrity of raw data, are also introduced. In addition, the research reliability of facilities is discussed, such as how measurement equipment should be maintained and how experimental records should be stored. Ensuring the reliability of the study implementation process and the facility/equipment support process makes it possible to reconstitute studies and improve the reproducibility of the results, which is a fundamental principle of science. This review will be useful for pharmacy education in universities.
Cancer chemotherapy has progressed remarkably with conventional and molecular-targeted anticancer drugs as well as immune checkpoint inhibitors. However, adverse drug reaction (ADR) management remains a challenge in cancer chemotherapy. Therefore, improving the quality of medical care through clinical pharmacology research is warranted. Intravenous injection of bendamustine in patients with follicular or mantle cell lymphoma frequently causes venous irritation. Because the underlying mechanisms are not clear, we investigated the factors responsible for bendamustine-induced venous irritation. Based on the results of our analysis, we altered the administration regimen and observed that the incidence of venous irritation, which manifested in a concentration-dependent manner following conventional approaches, significantly decreased when following the modified regimen. Guidelines on the management of chemotherapy-induced nausea and vomiting recommend aprepitant, a selective neurokinin-1 (NK-1) receptor antagonist, 5-hydroxytryptamine 3 (5-HT3) receptor antagonists, and dexamethasone as prophylactic antiemetics. Pretreatment with high-dose chemotherapy before hematopoietic stem cell transplantation has extremely high emetogenic potential. This can be countered by using aprepitant in combination with conventional antiemetics. However, the safety and efficacy of such combinations are unexplored. Upon evaluation, we observed improved antiemetic effects without an increase in ADRs. At this symposium, I highlight the significance of clinical pharmacology research for promoting individualized cancer chemotherapy.
Oral molecular-targeted agents are used clinically for the treatment of various types of cancer. However, even when treatment is started at the dosage indicated in the medical package insert, we have experienced many cases in which treatment had to be stopped early owing to the occurrence of serious side effects or an insufficient therapeutic effect. In recent years, a wide range of studies has been conducted on the therapeutic drug monitoring (TDM) of oral molecular-targeted therapeutic agents to prevent serious side effects and maximize the therapeutic effect. In Japan, the TDM of imatinib has been covered by insurance since 2012, and the TDM of sunitinib has been covered since 2018. In contrast, tyrosine kinase inhibitors may have severe side effects, but their TDM is not covered by medical insurance. We aimed to identify a safe, highly effective chemotherapy regimen based on scientific evidence gathered from Japanese patients. We examined the relationship between the plasma concentration of drugs and clinical findings, such as side effects and treatment effects, at our hospital. In this symposium review, we introduce our results based on the treatment of patients with renal cell carcinoma.
The use of a drug administration plan and therapeutic drug monitoring (TDM) based on pharmacokinetic-pharmacodynamic (PK-PD) analysis is important for the effective use of antimicrobial agents to treat infections. We focused on the use of beta-lactam agents, anti-methicillin-resistant Staphylococcus aureus (MRSA) agents, and an antifungal agent as antimicrobial agents and examined their efficacy in patients under special clinical conditions from the viewpoint of safety and TDM. Our PK-PD analysis of the use of an administration plan to set an optimum serum level for beta-lactam agents or anti-MRSA drugs for the treatment of pneumonia, acute renal failure during continuous hemodialysis filtration, febrile neutropenia, or malignant tumors confirmed the necessity of managing the optimal serum level. PK-PD analysis was also useful for TDM of voriconazole and intubation administration in long-term use from the viewpoint of preventing the onset of side effects. PK-PD analysis appears to be a useful tool in antibiotic therapy and TDM for developing a pharmacokinetic “individual difference” for “individualization therapy” under special clinical conditions. PK-PD analysis utilizes the restrictive information that is obtained by a clinic to the maximum and allows coordination with the mission of hospital pharmacists to provide adequate antibiotic therapy.
Brain function is controlled by the balance between the excitatory and inhibitory systems. If this balance is disrupted and the excitatory system dominates, convulsions or epileptic seizures are induced. Neuronal hyperexcitability in the brain leads to marked changes in the function of the neurons, which adversely affect the stability of the neural network. Many of the currently used antiepileptic drugs are symptomatic treatments that suppress the electrical hyperexcitability of the cerebrum. Although patients with epilepsy should continuously take antiepileptic drugs to control their seizures, approximately 20% of patients are drug resistant. The brain has the ability to control neuronal functions within acceptable limits while it maintains the amount of synaptic inputs that form the basis of information accumulation. Neuronal self-regulation is known as homeostatic scaling by which the intensity of all excitatory synapses is suppressed when neuronal excitability is increased. However, the molecular mechanisms of homeostatic scaling and their pathophysiological significance in vivo remain unclear. Repeated treatment with a subconvulsive dosage of pentylenetetrazol (PTZ), a γ-aminobutyric acid (GABA)A receptor antagonist, is known to induce kindling in mice, which is a common animal model used to study epilepsy. We found that PTZ-induced kindling was potentiated in mice deficient in the transcription factor neuronal PAS domain protein 4 (Npas4), the expression of which is immediately induced in response to neuronal activity. At this symposium, we will discuss the possibility of Npas4 as a novel target molecule for epilepsy treatment.
Benzodiazepine receptor agonists (BZRAs) are used in the treatment of a wide variety of clinical conditions. Although clinical practice guidelines discourage high dosage or long-term use of BZRAs, they are prescribed in clinical settings. This study aimed to investigate whether the pharmacists at multidisciplinary clinical team meetings can help reduce BZRA use and promote appropriate use of these drugs. The psychiatric unit of the Tokyo Women's Medical University Hospital occupies two floors, with 31 beds on Floor A and 34 beds on Floor B. The multidisciplinary clinical team meetings were held once a week in each ward. During the meetings, the pharmacists comprehensively assessed the number of BZRA doses administered and the equivalent diazepam doses, presented their prescription recommendations aimed at dosage reduction, and shared their views with the entire clinical team. This intervention was commenced on Floor A in 2014 and on Floor B in 2015. The average number of BZRAs in each period and equivalent diazepam doses were assessed for 273 psychiatric inpatients hospitalized from April to June in 2013, 2014, and 2015. Changes in the number of BZRA doses administered were assessed per floor per year. The results showed a statistically significant decrease between years with and without interventions. The intervention of pharmacists allowed multidisciplinary clinical team members to gain the same understanding about BZRA use and formulation of drug therapy plans. The results suggest that the intervention of pharmacists at clinical team meetings can strategically lead to decreased BZRA dosages and their proper use.
The pharmacist needs to understand the characteristics of each drug and work on optimizing prescriptions, such as considering dosage and usage schedules to avoid various risks and problems. In this study, multidisciplinary clinical team meetings where pharmacists can effectively share information on the current status of benzodiazepine receptor agonist (BZRA) use and their prescription recommendations with other clinical team members can lead to reduced BZRA dosages. Therefore, this study will be a guide to the intervention of Japanese pharmacists.
The purpose of this study was to investigate the efficacy of two types of medication administration-assisting food. The subjects were 30 caregivers of children from one to eight years old hospitalized in the pediatrics unit of a university hospital, and 30 nurses caring for them. The caregivers gave medications to their children using two types of administration-assisting food, “chocolate” and “jelly”. A questionnaire was prepared to investigate the efficacy of the administration-assisting food, and the caregivers and nurses responded to the questionnaire after the medication was given. The questionnaire data included many positive responses regarding the administration-assisting food, demonstrating its efficacy. The caregivers of children aged ≥4 years responded that the “chocolate” type was more effective than the “jelly” type in administering medications. There also tended to be a positive opinion of the “chocolate” among the nurses of children aged ≥4 years. However, the opinion of the “chocolate” and “jelly” were equivalent among the nurses of children aged <4 years. The reasons for these results were thought to be that the children were at an age when their sense of taste was developing and changing, plus correlations with past experience of the food and differences in the properties of the administration-assisting food. Easiness of swallowing of administration-assisting foods may be important for children whose taste is underdeveloped. However, the taste of administration-assisting foods may be important for children with taste development. Selecting administration-assisting foods based on these factors may be useful for the smooth administration of medication.
Reduction of corticosteroid responsiveness is one of the important clinical problems in chronic obstructive pulmonary disease (COPD). In this study, we determined the effects of neutralization of tumor necrosis factor-α (TNF-α) on corticosteroid insensitivity in mice models of airway inflammation induced by poly(I:C) and tobacco smoke (TS) exposure. Mice (male A/J strain, 5 weeks old) were exposed to TS for 10 d, or TS for 11 d and poly(I:C) for 3 d. Anti-TNF-α antibody was intranasally treated once every other day 2 h before the TS exposure, and dexamethasone 21-phosphate (DEX) was treated 30 min before the TS or poly(I:C) exposure. On the next day of the last stimulation, mice were sacrificed. The combination treatment of DEX and TNF-α neutralization was significantly attenuated the increase of the numbers of inflammatory cells in BALF and the TNF-α mRNA expression levels induced by TS and poly(I:C) exposure, even though TNF-α neutralization alone had little effect. These data indicated that neutralization of TNF-α restores corticosteroid responsiveness. Therefore, our study suggests that targeting TNF-α signaling pathway provides a new therapeutic approach to corticosteroid refractory airway diseases.