Single-walled carbon nanohorn (CNH) is a type of nanocarbon that is a single-graphene nanometer-sized pseudo tubule with a diameter of 2-5 nm and a length of 40-50 nm. About 2000 CNHs assemble to form a spherical aggregate with a diameter of about 100 nm. CNHs have low toxicity and their potential medical applications have therefore attracted much research attention. In this report, we show that the cellular uptake of CNHs can be controlled by chemical functionalization of the CNH surface and that the controllability can be enhanced by downsizing the CNH aggregates.
The Organisation for Economic Co-operation and Development (OECD) estimates that in 2015 the worldwide nanotechnology-related market will reach about US$1 trillion and will create about two million additional jobs. The field began with the general technical industry, including many areas of the pharmaceutical, medical, agricultural, and environmental/energy industries, and recently has expanded to the formulation of nanotechnology. In particular, elements of nanometer-sized research and development (R & D) in the areas of drug delivery systems and nanomedicine are attracting widespread interest. On the other hand, the potential negative effects on human health and the environment of nanomaterials manufactured on the industrial scale have not been investigated in detail. Therefore, although the risks have not been fully clarified, research institutions and international organizations such as the OECD are working in earnest to elucidate them. This paper outlines the status of initiatives in industry and regulatory conditions and trends in individual countries and institutions to determine the safety of nanomaterials from the perspective of international relations.
Recently, it is concerned that nanomaterials induce undesirable biological responses (NanoTox) which is different from conventional materials attributed to their unique physicochemical properties in the world. Therefore, the movements to regulate the development and practical use of nanomaterials are accelerated in North America and Europe in corporation with Organisation for Economic Co-operation and Development (OECD). However, for our enjoying the benefits of nanomateirals, it is most important not to regulate nanomaterials in the blind way but to assure the security of nanomaterials and support the development of nanomaterial industries. These are duty of our country to be advanced country, technology-oriented nation and intellectual property nation. From these viewpoints, we are engaged on not NanoTox study but Nano-Safety Science study. That is, we try to research the relationship between physicochemical properties, biodistribution, intracellular localization, kinetics and biological responses (safety) of nanomaterials for the purpose of the collection and the transmission of safety information of nanomaterials based on scientific evidence lead to a support of nanomaterials' development. In this review, we would like to introduce our Nano-safety science study using mainly amorphous silica nanoparticles.
In the past few years, several kinds of opinions or recommendations on the nanomaterial safety assessment have been published from international or national bodies. Among the reports, the first practical guidance of risk assessment from the regulatory body was published from the European Food Safety Authorities in May 2011, which included the determination of exposure scenario and toxicity testing strategy. In October 2011, European Commission (EC) adopted the definition of “nanomaterial” for regulation. And more recently, Scientific Committee on Consumer Safety of EC released guidance for assessment of nanomaterials in cosmetics in June 2012. A series of activities in EU marks an important step towards realistic safety assessment of nanomaterials. On the other hand, the US FDA announced a draft guidance for industry in June 2011, and then published draft guidance documents for both “Cosmetic Products” and “Food Ingredients and Food Contact Substances” in April 2012. These draft documents do not restrictedly define the physical properties of nanomaterials, but when manufacturing changes alter the dimensions, properties, or effects of an FDA-regulated product, the products are treated as new products. Such international movements indicate that most of nanomaterials with any new properties would be assessed or regulated as new products by most of national authorities in near future, although the approaches are still case by case basis. We will introduce such current international activities and consideration points for regulatory risk assessment.
Universities, research institutions, and venture capitals that possess promising “seed” research or technologies in Japan, are not always familiar with development strategies that lead to commercialization of the products in spite of their excellent science and research. In order to create innovative pharmaceuticals and medical devices originating from Japan, Pharmaceuticals and Medical Devices Agency (PMDA) launched new scientific consultation service, named ‘Pharmaceutical Affairs Consultation on R&D Strategy’ for universities, research institutions, and venture capitals on July 1, 2011. Through these consultations, the guidance and advice on the tests needed in the early development stage and the necessary clinical trials would be provided toward commercialization.
In vivo molecular imaging became a key technology for innovative drug development. Especially, positron emission tomography (PET) has been applied to patho-physiological science, pharmacodynamics/pharmacokinetics (PD/PK) studies, and drug delivery system (DDS) studies, and accelerated the paradigm shift not only from experimental animals to human subjects, but also from PK in blood circulation to PK in target tissues, even in human. Our RIKEN Centre for Molecular Imaging Science has been established to promote such innovative drug developmental studies with PET molecular imaging, as a center of excellence for development of molecular probes. The center is creating novel labeling methods on drug candidate molecules with positron-emitting radionuclides, and is providing the molecular probes suitable for targeting bio-functional molecules and cellular functions, which are useful for evaluation of drug efficacy and pharmacokinetics in human subjects. Animal PET studies with mice, rats, rabbits, marmosets, and macaque monkeys have also been promoted both under anesthetic condition and consciousness, which was a really difficult task but important for comparison with human PET studies. In this sense, mutual collaboration between the research consortia in basic PET field and in clinical PET molecular imaging such as Osaka City University Hospital would be of great value. Here, the concept, outline of our activities, and PK/PD studies with efficient application of molecular imaging is presented. In addition, the results of the first cassette-dose and micro-dose clinical trials approved by Pharmaceuticals and Medical Devices Agency (PMDA) (New Energy and Industrial Technology Development Organization (NEDO) project represented by Prof. Yuichi Sugiyama) are described.
Induced pluripotent stem (iPS) cells are generated from somatic cells by introducing small sets of transcription factors. iPS cells demonstrate pluripotency and the ability to self-renew. In addition, iPS cells can be generated from donor individuals with particular characteristics. Based on these features, iPS cells are expected to be applicable in drug discovery, the study of disease mechanisms and cell therapy. From a technical point of view, “diversity” is the key word. At present, iPS cells can be derived using various techniques, resulting in diversity in the quality of iPS cells generated. Therefore, optimization of the derivation technology is one of the most important issues. Another “diversity” is in the propensities amongst iPS cell lines derived using similar techniques. Thus, strategies for selecting good quality lines remain to be established. Considering such technical hurdles, establishment of an iPS cell bank consisting of high quality and versatile iPS lines is a promising idea because of the merits of cost and quality control. Now, we are exploring relevant parameters for the quality control of banked cells. The challenges facing clinical application of iPS cells are new but not unprecedented. To realize clinical applications of iPS cells, we need to make these challenges clear and overcome them through partnership not only with industry, governments and universities, but also patients and society at large.
At the University of Tokyo Hospital, investigator-driven clinical development of novel drugs and medical devices is mainly supported by the Translational Research Center and Clinical Research Support Center. The former supports non-clinical research and the preparation of test materials and the latter supports clinical trials. The Clinical Research Support Center was established in 2010 by the reorganization of the former Clinical Research Center, which was established in 2001. The center adopted International Conference on Harmonisation-Good Clinical Practice (ICH-GCP) as a standard guideline for clinical trials and prepared standard operation procedures and templates for protocols and informed consent documents in 2001 and, thereafter, provided consultation services to researchers for protocol development. In 2010, the service was extended to project management, data management and monitoring to support the credibility of clinical trials. In 2011, The University of Tokyo Hospital was selected by the government as a base for the early and exploratory clinical development of drugs in the fields of psychological and neurological diseases. For this purpose, a phase 1 unit for early phase clinical pharmacology trials is now being built. The center provides training courses for clinical research coordinators and hold seminars for clinical researchers; however, the biggest challenge remains the education and training of medical students who will lead clinical trials in the future.
In the Ministry of Health, Labour and Welfare's (MHLW) “5-year plan for activating clinical trials”, we have put in place the infrastructure including human resources for supporting not only commercial clinical trials but also those initiated by academic researchers, including clinical research coordinator (CRC) support and consultation for planning clinical trial with biostatistician. We also prepared a data management unit and trained data managers for academic clinical trials. In 2011, the National Cerebral and Cardiovascular Center (NCVC) was selected one of the sites of the MHLW project of structure improvement to execute early phase clinical trials. To clinically develop medical devices invented by the NCVC researchers involved in the project, animal experiments which meet the GLP standards must be finished before the first-in-human clinical trial. We are planning to create the units containing human resources for developing medical devices such as professionals in regulatory affairs, safety tests, and Good Laboratory Practice (GLP) systems. Creation of a smooth pathway from the preclinical to the clinical phases will be key to the efficient development of new medical devices.
Recently many pharmaceutical industries aim at “academic-industrial alliances” to increase opportunities for new drug development. The form of the alliance is mainly a “center-based” one, but recently “open-type” alliance has also become popular. To promote effective collaboration between academia and industries, both parties should obtain clear understanding and support from society through compliance with the social requirement including accountability on the collaborative research and transparency on their relationship. In addition, clinical studies need to comply with the “Ethical Guideline for Clinical Research,” or Good Clinical Practice (GCP). Pharmaceutical industries anticipate seeing the deliverables of academic research, and are working on realization of utilizing them in actual medicinal cases.
In Hokkaido Pharmaceutical University, problem-based learning (PBL) has been introduced as a part of the laboratory and practice curriculum for all school years to promote active learning skills and enhance students' problem-solving ability. The PBL program at our school has been developed using a tutorial study based on scenarios and learning strategies, such as experiments and/or standardized patients (SPs) and role-playing, according to students' developmental stage and learning objectives. The course “Practice VIII/Principles of Clinical Communication” for the fifth-grade students is an example of the new PBL program to improve students' clinical communication skills and ability to design a care plan for patients. We divided 196 students into 49 groups (each group had 4 members). We used the large-class PBL model, in which the students had discussions with several facilitators. The students were presented with a patient-case scenario, in which they were first provided with a brief background of the patient. Afterward, students interviewed SPs to obtain detailed information, based on which a care plan was designed for each patient. Students role-played with SPs as a part of patient support, consulted using the patient care plan, and made Subjective information, Objective information, Assessment, and Plan (SOAP) notes at the end. Some students commented that the PBL program was very helpful in understanding how to design a patient care plan and that they understood the importance of communication in obtaining information for designing a patient care plan.
In Showa University School of pharmacy, 7 competencies for outcome-based education were set up in 2011. We are now creating sequential curriculum in order to achieve these competencies. As a member of team medical treatment, pharmacist must share a patient's information with other members, assess each patient's condition, propose the best medication with evidence, and also check the effect of medication. Therefore, many active practices in a hospital and community and problem-based learning (PBL) tutorials are carried out in curriculum in School of Pharmacy. As a training for the future pharmacists who positively perform primary care with responsibility in community pharmacy, students study the method of clinical assessment (assessment of condition of disease from the patient's complain, and choice of appropriate proposal). Furthermore, the exercise and training of parenteral medication, physical assessment, and first aid, etc. are also taken in the curriculums as new clinical skill. The systematic and gradual interprofessional education curriculum for the team medical education has been carried out aiming at training of active members in medical team in a hospital and community. At this symposium, I will introduce these systematic advanced curriculums for the pharmacist of a new age, and to show the usefulness and learning effect.
Bedside training for fourth-year students, as well as seminars in hospital pharmacy (vital sign seminars) for fifth-year students at the Department of Pharmacy of Kyushu University of Health and Welfare have been implemented using patient training models and various patient simulators. The introduction of simulation-based pharmaceutical education, where no patients are present, promotes visually, aurally, and tactilely simulated learning regarding the evaluation of vital signs and implementation of physical assessment when disease symptoms are present or adverse effects occur. A patient simulator also promotes the creation of training programs for emergency and critical care, with which basic as well as advanced life support can be practiced. In addition, an advanced objective structured clinical examination (OSCE) trial has been implemented to evaluate skills regarding vital signs and physical assessments. Pharmacists are required to examine vital signs and conduct physical assessment from a pharmaceutical point of view. The introduction of these pharmacy clinical skills will improve the efficacy of drugs, work for the prevention or early detection of adverse effects, and promote the appropriate use of drugs. It is considered that simulation-based pharmaceutical education is essential to understand physical assessment, and such education will ideally be applied and developed according to on-site practices.
Introduction of carbon side chain at C3-position of indole ring was accomplished by using Pd-catalyzed allylation and vinylation. The selective vinylation at C3-position of 4-bromoindole was applied to the synthesis of optically active 4-bromotryptophan derivatives, which was used as a starting material for the synthesis of several optically active ergot alkaloids, which were clavicipitic acids, chanoclavine-I, costacalvine, and 1,1-dimethylallyltryptophan (DMAT). The three-step synthesis of optically active clavicipitic acids were accomplished without using a protecting group starting from 4-bromoindole and dl-serine. Some new synthetic reactions using unprotected amino acids were developed. Those were the biomimetic synthesis of tryptophan, the bromination of free aromatic amino acids, and the Pd-catalyzed N-allylation of free amino acids with allylic alcohol in aqueous media. Unique reactivity of π-allyl palladium complex or η3-(benzyl)palladium complex in aqueous media was found through Pd-catalyzed reaction of anthranilic acid, 2-aminobenzamide, and indole with allylic alcohols or benzyl alcohols, respectively.
Tay-Sachs and Sandhoff diseases (GM2 gangliosidoses) are autosomal recessive lysosomal storage diseases caused by gene mutations in HEXA and HEXB, each encoding human lysosomal β-hexosaminidase α-subunits and β-subunits, respectively. In Tay-Sachs disease, excessive accumulation of GM2 ganglioside (GM2), mainly in the central nervous system, is caused by a deficiency of the HexA isozyme (αβ heterodimer), resulting in progressive neurologic disorders. In Sandhoff disease, combined deficiencies of HexA and HexB (ββ homodimer) cause not only the accumulation of GM2 but also of oligosaccharides carrying terminal N-acetylhexosamine residues (GlcNAc-oligosaccharides), resulting in systemic manifestations including hepatosplenomegaly as well as neurologic symptoms. Hence there is little clinically effective treatment for these GM2 gangliosidoses. Recent studies on the molecular pathogenesis in Sandhoff disease patients and disease model mice have shown the involvement of microglial activation and chemokine induction in neuroinflammation and neurodegeneration in this disease. Experimental and therapeutic approaches, including recombinant enzyme replacement, have been performed using Sandhoff disease model mice, suggesting the future application of novel techniques to treat GM2 gangliosidoses (Hex deficiencies), including Sandhoff disease as well as Tay-Sachs disease. In this study, we isolated astrocytes and microglia from the neonatal brain of Sandhoff disease model mice and demonstrated abnormalities of glial cells. Moreover, we demonstrated the therapeutic effect of an intracerebroventricular administration of novel recombinant human HexA carrying a high content of M6P residue in Sandhoff disease model mice.
The drug-drug interactions of tizanidine and cytochrome (CYP) P450 1A2 inhibitors, which potentially alter the hepatic metabolism of tizanidine, were investigated by retrospective survey of medical records with regard to prescription. One thousand five hundred sixty-three patients treated with tizanidine at University of Tsukuba Hospital were investigated. Of those, 713 patients (45.6%) were treated with coadministration of tizanidine and CYP1A2 inhibitors (37 drugs). The patients who received a combination of tizanidine and CYP1A2 inhibitors were characterized as elderly, having multiple diseases, and taking a large number of comedications (over 10 drugs) for a long period as compared with the patients who did not receive CYP1A2 inhibitors. Tizanidine-induced adverse effects were examined in 100 patients treated with coadministration of tizanidine and 8 CYP1A2 inhibitors. Adverse effects (e.g., drowsiness: 10 patients; low blood pressure: 9 patients; low heart rate: 9 patients) were observed in 23 patients (23%) 8±10 days after CYP1A2 inhibitors were coadministered. The patients with tizanidine-induced adverse effects were of older age (64.3±9.8 vs. 57.5±18.1 years, p<0.05) and received a higher daily dose of tizanidine (3.00±0.74 vs. 2.56±0.86 mg/day, p<0.05) than the patients without adverse effects. The present results suggest that coadministration of tizanidine and CYP1A2 inhibitors enhances tizanidine-induced adverse effects, especially in elderly patients treated with a higher dose of tizanidine.
Hospital-acquired pneumonia (HAP) is defined as pneumonia that occurs 48 hours or more after admission, and is an important factor in the high mortality seen in hospital-acquired infections. Recently, pharmacist intervention, such as adjustment of dosing and monitoring for adverse effects, has been reported to improve the effects of infectious disease therapy. The aim of this study was to evaluate the usefulness of early pharmacist intervention during antimicrobial therapy for severe HAP. We retrospectively investigated the reduction rate of C-reactive protein (CRP) levels and duration of antibiotics administration. Patients with severe HAP were classified into 2 groups according to pharmacist intervention from the initial phase of therapy, with 15 in the intervention group and 23 in the control group (no pharmacist intervention). The reduction rate of CRP levels during the 7-day period after initiating antimicrobial therapy was 66.5±17.3% in the intervention group and 35.9±53.9% in the control group, which was significantly different (p<0.05). In addition, the average duration of antibiotics administration in the intervention group was significantly decreased as compared to the control group: the decreased period was 8 days. Our results suggest that pharmacist intervention contributed to reduce inflammation in the early phase and to shorten the duration of antimicrobial therapy.