Two major trends are materializing: the super-aging of society and information technology (IT-ization). Thus, the most important action to benefit patients and society is to establish a medical information network supported by a trustworthy human network. This network should be organized by the people involved in local community healthcare. As such, it is essential for the human network to include not only hospitals and clinics (medical practitioners) but also community pharmacies (pharmacists). This need is apparent, because in the past, drug hazards recurred because fundamental improvement of the means to prevent those hazards was not possible without pharmacists where and when those incidences occurred. The medical information to be IT-ized would include drug notebooks and prescription cards, although electronic medical charts will be the ultimate source of information. The following points will be discussed in this paper: (a) Legal requirements for physical assessments by pharmacists, (b) Physical assessments by hospital pharmacists, (c) Physical assessments by community pharmacists, and (d) Security requirements for the Act for Protection of Personal Information, Articles 20-22.
We tested a community electronic prescription system (K-CHOPS/PPISS) that we developed in Kagawa, Japan, which connects the prescribing physicians, pharmacists at community pharmacies, and patients through a community data center server. Physicians can send prescriptions, diagnoses, and laboratory data to the datacenter. Pharmacists in community pharmacies can access their patients' information through the datacenter and can return corrected prescriptions and reports containing guidance and adverse events to the hospital or clinic where the prescription was issued. Patients can then see their dispensed medications on their PCs, cellular phones, and smart phones. Additionally, patients can input medication-taking records, allergy and adverse drug reactions (ADR), any over-the-counter drug and supplements that they take, and their physical condition through the devices. The system enables pharmacists to appropriately advise and monitor ADR based on patient clinical data and enables physicians to accurately know the medications handed to patients and advisories issued by the pharmacists. Further, physicians and pharmacists can see the patients' condition which they entered on their devices if the patients agree. These would be helpful for avoiding ADR. The information accumulated in the data center can be potentially utilized for evaluation of the effectiveness and ADR of medications and for development of innovative medication. Discussion of the pros and cons for such utilization is needed.
In Japan, information technology (IT) in the medical field has prevailed as a means for handling claims for health insurance reimbursement. In contrast, IT is primarily used for electronic medical records in Western countries. Originally, preparation of health insurance claims was one of the outcomes of computerized medical information in Japan. As its protocols are already well established in Japan, information from the insurance claim system is hard to integrate into the Electronic Medical Chart system. To ensure drug safety, it is necessary to determine the number of users, and to accurately tabulate the incidence of adverse events. For this purpose, three kinds of information are required: prescription information, dispensing information, and drug administration information. Prescription information and dispensing information should be consistent with each other in content. Dispensing information is essential to identify the “substance” when adverse events occur. Drug administration information is the “true drug history”. With these three kinds of information, it should be possible to enter drug safety data as evidence. To accurately capture these three kinds of information, it is necessary to utilize Standard Drug Code and Standard Usage Master, suggesting that it may be necessary to reconstruct the current system.
There is no concept of rare disease (RD) but Nambyo (intractable disease) since 1972. In 1995 the definition of Nambyo included the concept of rareness and the frequency for a Nambyo is less than 50000 in Japanese population. Currently Nambyo are selected for special research support, and special treatment of medical expenses. The budget for research is 10 billion yen. The approximate number of medical recipients is estimated to be 700000. The measures already developed for Nambyo are not comprehensive, therefore currently several additional measures are being envisaged. We are now planning to join the Orphanet. The expectations for Orphanet Japan are to: Enhance international collaboration of RD, providing international up-to-date information of RD in Japanese, inform historical and up-to-date research of Nambyo, and promote information exchange, joint research and network establishment. It is necessary to make a Patient Registry for rare disease, and hopefully have a structure to integrate worldwide registry with same concept. Recently “International Rare Disease Research Consortium (IRDiRC)” was formed. The purpose of this consortium is to make an international coordination of the rare disease research, and to integrate the knowledge of the rare disease research. We will also talk about the Patient Registry by Patient Advocacy group, including Patient Reported Outcome (PRO).
In Japan, large scale heath databases were constructed in a few years, such as National Claim insurance and health checkup database (NDB) and Japanese Sentinel project. But there are some legal issues for making adequate balance between privacy and public benefit by using such databases. NDB is carried based on the act for elderly person's health care but in this act, nothing is mentioned for using this database for general public benefit. Therefore researchers who use this database are forced to pay much concern about anonymization and information security that may disturb the research work itself. Japanese Sentinel project is a national project to detecting drug adverse reaction using large scale distributed clinical databases of large hospitals. Although patients give the future consent for general such purpose for public good, it is still under discussion using insufficiently anonymized data. Generally speaking, researchers of study for public benefit will not infringe patient's privacy, but vague and complex requirements of legislation about personal data protection may disturb the researches. Medical science does not progress without using clinical information, therefore the adequate legislation that is simple and clear for both researchers and patients is strongly required. In Japan, the specific act for balancing privacy and public benefit is now under discussion. The author recommended the researchers including the field of pharmacology should pay attention to, participate in the discussion of, and make suggestion to such act or regulations.
Within an epithelial cellular sheet, the paracellular pathway can be divided into two routes: one between two adjacent cells and one at tricellular contacts, where the vertices of three cells meet. For epithelial barrier function, tight junctions restrict solute permeability through the paracellular pathway between two cells, while tricellular contacts contain specialized structures of tight junctions, named tricellular tight junctions (tTJs). Two types of membrane proteins, tricellulin and angulin family proteins (angulin-1/LSR, angulin-2/ILDR1 and angulin-3/ILDR2) have been identified as molecular components of tTJs. Angulins recruit triellulin to tTJs and these tTJ-associated proteins are required for normal tTJ formation as well as strong epithelial barrier function. Furthermore, mutations in tricellulin and angulin-2/ILDR1 genes cause autosomal recessive familial deafness, DFNB49 and DFNB42, respectively. Further analyses of the angulin-tricellulin system should lead to better understanding of the molecular mechanism and regulation of tTJs.
Skin is the structure that covers our body and protects it from not only the entry of pathogens or allergens but also from the leakage of water, solutes or nutrients. These outside-in and inside-out skin barrier functions are dependent on the epidermis, a stratified epithelial cellular sheet. While mucus covers the epidermis in fish and amphibian tadpoles, terminally differentiated cornified cellular sheets called stratum corneum (SC) constitute the outermost epidermal barrier in amphibian adults, reptiles, birds and mammals. Beneath the mucus or SC, apical paracellular spaces of epidermal cells are sealed with tight junctions (TJs) that limit paracellular leakage of water and electrolytes to maintain fluid homeostasis. We applied time-of-flight secondary-ion-mass-spectrometry (TOF-SIMS) imaging technology to analyze the SC in skin sections, and found that the SC consisting of three layers of distinct functional properties. Under the barriers of the SC and TJ, antigen-presenting dendritic cells called Langerhans cells (LCs) distribute within the epidermis. LCs elongate their dendrites to penetrate through epidermal TJs upon activation and uptake antigens from extra-TJ environment. During antigen uptake, new TJs are formed between keratinocytes and LC dendrites to maintain the integrity of epidermal TJ barriers. To understand the epidermal barrier system and its deficiency observed in human skin diseases, we need to re-evaluate human epidermal barrier as a composite barrier consisting of SC and TJs and to investigate the molecular mechanism and immunological consequences of the extra-TJ antigen uptake activity of LCs.
Most pathogens invade body through the mucosal epithelium, which is a primary target to prevent the infectious diseases. Mucosal vaccine has been considered to be an effective strategy to establish immunosurveillance against pathogens by the induction of antigen-specific immune responses at both mucosal and systemic immune compartments. The development of antigen delivery system and mucosal adjuvants are required for the sufficient induction of protective immunity in the development of mucosal vaccine. In this review, we shed light on the recent advances in the development of antigen delivery system using microbial functions for mucosal vaccines.
Chronic hepatitis C virus (HCV) infection is a global public health issue because ～30% of HCV-carriers develop severe liver diseases including hepatic steatosis, cirrhosis, and hepatocellular carcinoma. Not only viral factors but also host/viral interactions are promising targets for antiviral preventive and therapeutic strategies. Recent studies showed that a tight junction protein claudin 1 is involved in HCV entry into host cells. Consistent with these studies, we isolated the several hepatic Huh7-derived cell clones defective in claudin 1 as HCV-resistant mutants, and cellular permissiveness to HCV was restored by expression of claudin 1 into these cell mutants. These results strongly suggest that claudin 1 is a promising target for antiviral therapy. We thus tried to isolate antibodies against extracellular domain of human claudin 1. Finally we established four mouse anti-claudin 1 monoclonal antibodies by using DNA immunization method and hybridoma screening with the above claudin 1-defective mutant. In the cell culture-infection system using Huh7.5.1 cells and HCV-JFH1 strain, these four antibodies efficiently inhibited infection by HCV in a dose-dependent manner, but do not affect tight junction localization of claudin 1 and cellular barrier function. These monoclonal antibodies targeting claudin 1 might be useful for preventing HCV infection, such as after liver transplantation, and also blocking viral spread in HCV-infected patients.
Epithelium plays pivotal roles in biological barrier separating the inside of body and the outside environment. Ninety percent of malignant tumors are derived from epithelium. Most pathological microorganisms invade into the body from mucosal epithelium. Thus, epithelium is potential targets for drug development. Claudins (CLs), a family of tetra-transmembrane protein consisting of over 20 members, are structural and functional components of tight junction-seals in epithelium. Modulation of CL-seals enhanced mucosal absorption of drugs. CLs are often over-expressed in malignant tumors. CL-4 expression is increased in the epithelial cells covering the mucosal immune tissues. Very recently, CLs are also expected to be targets for traumatic brain injury and regenerative therapy. In this review, we overview the past, the present and the future of CLs-targeted drug development.
Complexity in signaling networks is often derived from co-opting particular sets of molecules for multiple operations. Understanding how cells achieve such sophisticated processing using a finite set of molecules within a confined space - what we call the “signaling paradox”- is critical to cell biology and bioengineering as well as the emerging field of synthetic biology. We have recently developed a series of chemical-molecular tools that allow for inducible, quick-onset and specific perturbation of various signaling molecules. The present technique has been employed to unravel several important, previously unresolved questions regarding the regulatory mechanisms of potassium ion channels, the membrane targeting mechanisms of small GTPases and positive feedback machinery in neutrophil migration. Using this novel technique in conjunction with conventional fluorescence imaging and biochemical analysis, we are currently further dissecting intricate signaling networks in living cells. Ultimately, we will generate completely orthogonal machinery in cells to achieve existing, as well as novel, cellular functions. Our synthetic, multidisciplinary approach will elucidate the signaling paradox in cells created by nature.
Pain and stress alleviation after acupuncture treatment was assessed in this study. Patients responded to a questionnaire designed to determine the amount of stress they were experiencing, and data were obtained for patient salivary amylase, cortisol, secretary IgA (s-IgA), and leptin receptor (OBRb). As a part of this study on acute pain, 6 factors were extracted from the questionnaire. The second factor (pain removal) was well correlated with salivary amylase activity in patients with cervico-omo-brachial syndrome. An evaluation of cumulative acupuncture treatments showed that salivary cortisol increased and s-IgA decreased. In addition, a decreased s-IgA level significantly correlated with chronic pain removal. The questionnaire correlated well with measurements of salivary markers suggesting that they can be taken as indices of therapeutic efficacy in acupuncture treatment.
On dispensing powdered antineoplastic medicines, it is important to prevent cross-contamination and environmental exposure. Recently, we developed a method for blending powdered medicine in a disposable ointment container using a planetary centrifugal mixer. The disposable container prevents cross-contamination. In addition, environmental exposure associated with washing the apparatus does not arise because no blending blade is used. In this study, we aimed to confirm the uniformity of the mixture and weight loss of medicine in the blending procedure. We blended colored lactose powder with Leukerin® or Mablin® powders using the new method and the ordinary pestle and mortar method. Then, the blending state was monitored using image analysis. Blending variables, such as the blending ratio (1:9-9:1), container size (35-125 mL), and charging rate (20-50%) in the container were also investigated under the operational conditions of 500 rpm and 50 s. At a 20% charging rate in a 35 mL container, the blending precision of the mixtures was not influenced by the blending ratio, and was less than 6.08%, indicating homogeneity. With an increase in the charging rate, however, the blending precision decreased. The possible amount of both mixtures rose to about 17 g with a 20% charging rate in a 125 mL container. Furthermore, weight loss of medicines with this method was smaller than that with the pestle and mortar method, suggesting that this method is safer for pharmacists. In conclusion, we have established a precise and safe method for blending powdered medicines in pharmacies.
The adsorption of Bevacizumab, Trastuzumab, Rituximab, Nedaplatin, Vincristine sulfate, Nogitecan hydrochloride, Actinomycin D and Ramosetron hydrochloride to 0.2 μm endotoxin-retentive in-line filters was evaluated with pediatric doses by UV spectrophotometry. The results indicated that some drug adsorption was shown with Nogitecan hydrochloride, Actinomycin D and Ramosetron hydrochloride, and good recovery was shown with the other five drugs. For the three drugs which showed some losses, drug recovery was investigated at multiple test doses. The approximation formula for each drug adsorption was recorded as Y=100−A/X (X: dose (mg), Y: recovery rate (%), A: a constant for individual drug). The results showed there was high correlation between the reciprocal of test drug dose and the recovery rate. Furthermore, in the cases where adsorption to the filter were observed, it was found that it was possible to determine the relationship between dose and the recovery rate from a filterability test with one point pediatric dose. Since the recovery rate obtained from the approximation formula with multiple doses and that calculated from the prediction formula with one point pediatric dose were almost the same, then it was concluded that it is not necessary to conduct the filterability tests with multiple doses. We have shown that using UV spectrophotometry and carrying out a filterability test using one point pediatric dose is relatively easy method and reduces the effort and expense. This method for analysis of drug adsorption is extremely useful when using in-line filters with infusion therapy.
Since osteoporosis is a major public health problem in Japan, it is important to clarify the effect of high-mineral drinking water consumption on osteogenesis. Therefore, in this study, we investigated the relationship between high-mineral drinking water consumption and osteogenesis in ovariectomized rats that received a low-calcium diet and purified water (PW group) or a low-calcium diet and high-mineral drinking water (CR group). High-mineral drinking water affected the rats' body weight. After 3 months, the bone density of the CR group was higher than that of the PW group (p<0.05). Furthermore, the CR group showed a decrease in the amount of calcium in the bones after 3 months. These results suggest that high-mineral drinking water contributes to the maintenance of bone density and not to the amount of calcium in bone. On the other hand, serum alkaline phosphatase levels in the PW group at 3 months were higher than those in the CR group, which indicates that the blood concentration of calcium in the CR group was maintained. Moreover, the amount of magnesium in the bones and the blood concentration of magnesium in the CR group after 3 months were higher than the corresponding values in the PW group. These results suggest that consumption of high-mineral drinking water could be beneficial for osteogenesis (i.e., for maintaining bone quantity).