Immediately after the Great East Japan Earthquake of March 2011, Okayama University dispatched a medical assistance team based on the request of Iwate Prefecture. The first team was followed by 12 medical teams. I was one of the members of the fourth and fifth medical teams sent to Rikuzen-takata and Ofunato for a week beginning March 16th to support medical relief operations as a pharmacist during the sub-acute phase of the disaster. As a member of the team at the temporary clinic in Rikuzen-takata, pharmacists such as myself required physical assessment skills to perform related tasks, along with expertise in drug dispensing and consultation. In my next medical team, which headed the pneumonia unit at Oofunato Hospital, I played a critical role in the effective use of medicine reserved/provided for disasters, including antibiotics. Throughout the relief operations, strong clinical reasoning and decision making, as well as good teamwork, proved vital, especially in emergency situations. For future community medical systems, emergency/disaster medicine should be included in pharmacy education. The School of Pharmacy at Okayama University will establish emergency medicine program in the next school year, in cooperation with the Medical, Dental and Health Care Departments.
On April 10, 2011, the author was sent to Yugakukan, a general shelter in Ishinomaki, as member of the first Primary Care for All Team (PCAT) mission, which was composed of medical and welfare service-specialists. Although various volunteers, government officials, and local organizations were gathered there, the situation was under control, and individuals cooperated under common goals. In order for all the organizations to cooperate and unify their purpose, PCAT identified all the key individuals and established the importance of conducting advanced meetings. The target of PCAT was to provide continued support until the shelter regained its capabilities as a local medical, welfare, and healthcare facility. We helped convert Yugakukan into a welfare shelter from a general one, with consideration for the needs of the entire disaster-stricken area. Likewise, we planned for the reduction of incidence by the local staff. As a team of pharmacists, we cooperated with the local key pharmacist, Mr. Yoshirou Tanno, to plan how the local pharmacy could be made more useful for revival. I concentrated on the production of a system for three weeks. During this period, I probed into the importance of the connection among people. Sharing information, building cooperation, and organization collaboration facilitated the smooth operations and development of the shelter. The experience of serving at Yugakukan can be used as indicator of pharmacists' role in the comprehensive care system, including supporting the elderly, whose population is currently rising.
From April 9 to 16, 2011, I joined the first medical team at Ishinomaki as one of the supporting volunteers of Japan Primary Care Association for the 2011 East Japan Earthquake. I participated in launching the intensive care temporary clinic at Yugakukan. Yugakukan was one of the shelters set up right after the earthquake and tsunami on March 11, 2011. Later, it became the care unit for inpatients moved from Ishinomaki City General Hospital, which was crushed by the tsunami. Patients ranged in age and needs: from infant to elderly, and those needing internal and/or surgical medication or artificial dialysis. Under such conditions, we, as the first medical team members dispatched to the shelter, were concerned with the assessment of refugees and establishment of the management system of the shelter. Through the activities, I realized the utmost importance of “networking”. In this paper, the role of pharmacists in disaster medicine, preparation for disaster medicine, and the role and function of pharmacists in community medicine under normal conditions will be demonstrated in relation to this keyword.
The Division of Emergency Pharmacy was established at the School of Pharmaceutical Sciences in Okayama University in 2011. Pharmacists employed by the University Hospital have been assigned to serve as clinical faculty; some of them had been sent as members of medical support teams to the 2011 Great East Japan Earthquake. After the intra-school debrief session by the dispatched faculty in April 2011, both instructors and students recognized the importance of the role of pharmacists in emergency medicine. Although Japan suffers from natural disasters often, pharmacists have not always had the chance to be involved in emergency medicine. As such, in line with the mission of the School, “emergency pharmacy” must be established not only as a subject in pharmacy education but also as an academic category in itself. The Science Council of Japan proposed the social role of a professional pharmacists and its contribution to the quality of medicine. Thus, the establishment of “emergency pharmacy” will realize higher quality of medical services as well as the broader function of pharmacists. The disaster offered the chance to encourage further discussion of what and how pharmacy education should be in the future.
On August 31, 2011, five months after the Great East Japan Earthquake, Miyagi prefecture reported 9357 dead and 2288 missing citizens, whereas Ishinomaki reported 4753 dead and 1302 missing citizens. A total of 12 pharmacists in Miyagi prefecture had lost their lives. Many medical institutions at the time were rendered out of service due to damage. Ishinomaki Red Cross had to serve as headquarters of disaster medicine management for the area. The government of Miyagi and Miyagi Pharmacist Association signed a contract regarding the provision of medical and/or other related tasks. Nevertheless, the contract was not fully applied given the impact of the tsunami, which caused chaos in telecommunication, traffic, and even the functions of the government. Given the nature of the disaster, medical teams equipped only with emergency equipment could not offer appropriate response to the needs of patients with chronicle diseases. “Personal medicine logbook” and pharmacists were keys to relief works during the disaster. Pharmacists played a critical role not only for self-medication by distributing over the counter (OTC) drugs, but also in hygiene management of the shelter. Apart from the establishment of an adoptive management system for large-scale natural disasters, a coordinated system for disaster medical assistance team (DMAT), Japanese Red Cross (JRC), Self-Defense Force (SDF), and other relief work organizations was imperative.
Recently, animal experiments become very difficult to be done in the research and development of cosmetics and cosmeceuticals due to animal welfare and 3Rs (replacement, reduction, refinement) concept. However, usefulness and safety of these preparations must be strictly guaranteed before human use. We thus proposed three sets of extrapolation methods to estimate in vivo profiles from in vitro and in silico approaches, to evaluate permeation profiles through real human skin from those through animal skin and cultured human skin model, and to estimate responses such as usefulness and safety of cosmetics and cosmeceuticals from their skin permeation and concentration profiles. Although we need more data and discussion, the present extrapolation methods must be very useful for estimation of cosmetics and cosmeceuticals without using animal experiments.
In Japan, two patients who had been primary sensitized to hydrolyzed wheat protein (HWP) present in facial soap and subsequently experienced wheat-dependent exercise-induced anaphylaxis (WDEIA) after the ingestion of normal wheat products were reported in 2009 as first cases. Since that report, more than 1900 patients with such an allergy have been reported (through June 20, 2013) from various institutes all around Japan. Importantly, the majority of the patients used the same facial soap (Cha no Shizuku®) containing acid-hydrolyzed wheat protein (acid-HWP). The commercial acid-HWP contained in the facial soap (Glupearl 19S®, average molecular weight of 30-50 kDa) was produced from gluten after partial hydrolysis with hydrogen chloride at 95℃ for 40 minutes. In this presentation, I would like to summarize the mechanism of the induction of immediate hypersensitivity by HWP which has been reported by us and other European groups.
Cosmetics are consumer products intended to contribute to increasing quality of life and designed for long-term daily use. Due to such features of cosmetics, they are required to ensure quality and safety at a high level, as well as to perform well, in response to consumers' demands. Recently, the technology associated with nanomaterials has progressed rapidly and has been applied to various products, including cosmetics. For example, nano-sized titanium dioxide has been formulated in sunscreen products in pursuit of improving its performance. As some researchers and media have expressed concerns about the safety of nanomaterials, a vague feeling of anxiety has been raised in society. In response to this concern, the Japan Cosmetic Industry Association (JCIA) has begun original research related to the safety assurance of nanomaterials formulated in cosmetics, to allow consumers to use cosmetics without such concerns. This paper describes the activities of the JCIA regarding safety research on nanomaterials, including a survey of the actual usage of nanomaterials in cosmetics, analysis of the existence of nanomaterials on the skin, and assessment of skin carcinogenicity of nano-sized titanium dioxide. It also describes the international status of safety assurance and regulation regarding nanomaterials in cosmetics.
Effects of sucrose fatty acid esters (sugar esters) on the intestinal absorption of poorly absorbable drugs were examined by an in situ closed loop method in rats. 5(6)-Carboxyfluorescein (CF) and fluorescein isothiocyanate-dextrans (FDs) with various molecular weights were used as model drugs of poorly absorbable drugs. The absorption of CF from the rat small intestine was significantly enhanced in the presence of various sugar esters and a maximal absorption enhancing effect was observed in the presence of 0.5%(w/v) S-1670. The absorption enhancing effect of S-1670 in the small intestine decreased as the molecular weights of drugs increased. Moreover, we evaluated the intestinal membrane damage with or without various sugar esters. These sugar esters (0.5%(w/v)) did not increase the activities of lactate dehydrogenase (LDH), suggesting that these sugar esters did not cause serious membrane damage to the intestinal epithelium. Furthermore, these sugar esters increased membrane fluidity of lipid layers of the intestinal brush border membranes and decreased the transepithelial electrical resistance (TEER) of Caco-2 cells. Therefore, these findings suggested that these sugar esters might improve the intestinal absorption of poorly absorbable drugs via a transcellular and a paracellular pathways.
Arginine-rich peptides, including oligoarginines (Rn, n=7-12) are cell penetrating peptides (CPPs) and are useful for the intracellular delivery of membrane-impermeable substances. Endocytosed arginine-rich peptides can become trapped in endosomes, and the avoidance of endosomal retention is necessary for achieving effective cytosolic translocation. Our group has succeeded in enhancing the cellular uptake of oligoarginines by introducing short hydrophobic penetration accelerating sequences (Pas). The effectiveness of a Pas segment in improving the oligoarginine-mediated intracellular delivery of a biofunctional peptide was demonstrated through the efficient inhibition of glioma cell growth by a p53 C-terminal-derived retro-inverso peptide. The CPPs were expected to increase the penetration efficiency of low-permeability drugs through the intestinal epithelial cell layer into blood. Drugs conjugated to oligoarginines via a chemically stable linker tend to be retained in the negatively charged intracellular compartment due to the strongly cationic peptides. Our group has proposed the use of a self-cleavable linker strategy that effectively releases the drugs from the oligoarginine peptide. Chemical-triggered self-cleavage produces the parent drug via intramolecular imide formation under physiological conditions. The designed model drug-oligoarginine conjugates were converted with the half-life (t1/2) values of 9-100 min. Conjugates possessing a short t1/2 of 9-10 min improved the transport rate of the parent model drug in a Caco-2 monolayer permeation assay. The Pas attachment to the oligoarginine was also found to be effective in this permeation assay. The Pas attachment may provide a new platform for facilitating arginine-rich CPP-mediated cargo transport.
Transdermal delivery of peptide and protein drugs may be limited by the stratum corneum, which is a protective barrier against the entry of microorganisms and water. Many approaches have been utilized to promote peptide and protein drugs delivery across the stratum corneum, including chemical enhancer modification and physical disruption of barrier function. However, it has been difficult to achieve therapeutic levels of peptide and protein drugs via this route without any skin irritation. Recently, attention has been paid to the possibility of using microneedle arrays in delivering peptide and protein drugs into the skin. As a novel and minimally invasive approach, microneedle arrays are capable of creating superficial pathways across the skin for peptide and protein drugs to achieve enhanced transdermal drug delivery. This method combines the efficacy of conventional injection needles with the convenience of transdermal patches, while minimizing the disadvantages of these administration methods. Therefore, microneedle arrays are a very useful alternative method for delivering peptide and protein drugs from the skin into the systemic circulation without any serious damage to skin. In this review, recent challenges in the developments of microneedle arrays for the delivery of peptide and protein drugs are summarized. Then, future developments of microneedle arrays for the delivery of peptide and protein drugs are also discussed in order to improve their therapeutic efficacy and safety.
Idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) are thought to involve lung injury induced by reactive oxygen species (ROS), in particular superoxide anion. The enzyme, superoxide dismutase (SOD) catalyses the dismutation of superoxide anion to hydrogen peroxide. Lecithinized SOD (PC-SOD) has overcome a number of previous clinical limitations of SOD, including low tissue affinity and low stability in plasma. Recent animal studies suggest that PC-SOD is effective for the treatment of IPF and COPD. We are now performing the clinical study of PC-SOD for IPF patients.
Naturally occurring polyhydroxylated amines such as (+)-1-deoxynojirimycin, polyoxamic acid, anisomycin, (−)swainsonine, and alexine stereoisomers, which have interesting biological activities including glucosidase- and mannosidase-inhibitory activity, immunoregulatory activity, and antibacterial effects, were synthesized stereoselectively starting from (S)-pyroglutamic acid derivatives. α,β-Unsaturated lactams ((S)-5-hydroxymethyl-2-oxo-3-pyrroline derivatives), α,β-unsaturated δ-lactone ((S)-4-amino-2-penten-5-olide derivative), and E-olefin ((S,E)-methyl-4-amino-5-hydroxypent-2-enoate derivative) from (S)-pyroglutamic acid derivatives were dihydroxylated using OsO4 in the presence of N-methyl morpholine N-oxide (NMO) to afford various chiral building blocks with different configurations. The stereoselectivity of cis-dihydroxylation for α,β-unsaturated lactams and α,β-unsaturated δ-lactone was very high, while the stereoselectivity was low for E-olefin. Therefore, the double asymmetric induction of E-olefin using K2OsO4 with chiral ligands was successively applied to yield high stereoselectivity. (2R,3S)-2-Hydroxymethyl-3-hydroxypyrrolidine and Gaissman-Weiss lactone, important intermediates for the preparation of pyrrolizidine alkaloids, were synthesized from a (3R,4R,5R)-3,4-dihydroxy-5-hydroxymethyl-2-pyrrolidinone derivative derived from α,β-unsatulated lactam. (+)-1-Deoxynojirimycin was synthesized from a (2S,3R,4R)-methyl 4-amino-2,3,5-trihydroxypentanoate derivative of E-olefin. (−)-Swainsonine and its stereoisomers were synthesized from (2R,3S,4R)- or (2R,3R,4R)-2-hydroxymethyl-3,4-dihydroxypyrrolidine derivatives of α,β-unsaturated δ-lactone or α,β-unsaturated lactam. The key reaction was diastereoselective allylation of the aldehyde derived from the corresponding 2-hydroxymethylpyrrolidine derivatives with various allylation reagents. The high diastereoselectivity could be explained by cyclic chelate formation between metals and the α-aminocarbonyl group or β-alkoxycarbonyl group, in which the nucleophile approaches from the less hindered face. Four alexine stereoisomers were synthesized from (2R,3R,4S,5R)- and (2R,3R,4S,5S)-2,3-dihydroxymethyl-3,4-dihydroxyl pyrrolidine derivatives of α,β-unsaturated lactam.
Fluorescence imaging is one of the most powerful techniques for visualization of the temporal and spatial biological events in living cells, and is employed in many fields of research. Fluorescent probes, which allow visualization of cations such as Ca2+, Zn2+etc., small biomolecules such as nitric oxide (NO) or enzyme activities in living cells by means of fluorescence microscopy, have become indispensable tools for clarifying functions in biological systems. This review deals with the general principles for the design of bioimaging fluorescent probes by modulating the fluorescence properties of fluorophores, employing mechanisms such as acceptor-excited photoinduced electron transfer (a-PeT), donor-excited photoinduced electron transfer (d-PeT), Förster resonance energy transfer (FRET), intramolecular charge transfer (ICT) and spirocyclization. Especially, the a-PeT and d-PeT mechanisms, which have been established by our group, are widely applicable for the design of bioimaging probes based on many fluorophores and the spirocyclization process is also expected to be useful as a fluorescence off/on switching mechanism. Fluorescence modulation mechanisms are essential for the rational design of novel fluorescence probes for target molecules. Based on these mechanisms, we have developed more than fifty bioimaging probes, of which fourteen are commercially available. The review also describes some applications of the probes developed by our group to in vitro and in vivo systems.
Sources of drug information such as package inserts (PIs) and interview forms (IFs) and existing drug information databases provide primarily document-based and numerical information. For this reason, it is not easy to obtain a complete picture of the information concerning many drugs with similar effects or to understand differences among drugs. The visualization of drug information may help provide a large amount of information in a short period, relieve the burden on medical workers, facilitate a comprehensive understanding and comparison of drugs, and contribute to improvements in patients' QOL. At our department, we are developing an approach to convert information on side effects obtained from PIs of many drugs with similar effects into visual maps reflecting the data structure through competitive learning using the self-organizing map (SOM) technique of Kohonen, which is a powerful method for pattern recognition, to facilitate the grasping of all available information and differences among drugs, to anticipate the appearance of side effects; we are also evaluating the possibility of its clinical application. In this paper, this approach is described by taking the examples of antibiotics, antihypertensive drugs, and diabetes drugs.
A method for the simple and reliable determination of triazolam and midazolam in human plasma using gas chromatography with microelectron capture detection has been developed. Samples (0.5 mL of plasma) were prepared using a simple solvent extraction with 3% isoamyl alcohol/benzene in the presence of NaOH. Two microlitres of the extract were injected onto the capillary column ((5%-phenyl)-methylpolysiloxane). The method was found to be valid in terms of selectivity, linearity, precision, accuracy, and recovery over the concentration range of 0.2 to 20 ng/mL for triazolam, and from 0.5 to 200 ng/mL for midazolam, respectively. Intra- and inter-day precisions determined at three concentrations were from 4.1 to 9.3% for triazolam and from 2.9 to 13.0% for midazolam. The accuracies were within 17.7% for triazolam and within 13.0% for midazolam. This proposed method was successfully applied to a pharmacokinetic study of triazolam or midazolam in healthy volunteers.
Fukuoka University Hospital began to employ a resident pharmacist system in 2006. In the present study, to evaluate our resident program, we conducted a questionnaire survey of graduates who completed program as well as staff of the Pharmaceutical Department of this hospital. In addition, based on the results of this survey, we examined the current state and future of postgraduate training programs that can be offered to those who have completed a 6-year pharmacy course. The proportion of residents and staff who responded to the survey was 76.5% (13/17) and 100% (42/42), respectively. Of these two groups, the program was rated as beneficial by 92% and 72%, respectively. Regarding the contents of the training program, both residents and staff highly evaluated guidance on drug management on wards and the preparation of drugs (including anti-cancer agents) because these were useful for actual work. The necessity and usefulness of a resident program under the 6-year course system were also suggested. According to those graduating from a 6-year pharmacy course, a training program should include training instructions for students in a long-term internship during the 1st year, and specialty pharmacist education during the 2nd year. The results of our study suggest that it is advisable to begin to provide graduates on a 6-year course who participate in a resident program with specialized education focused on ward duties from the latter half of the 1st year based on their undergraduate education.