A new district health plan started in April, 2008. Under this new plan, district referral system has been largely changed and become to be formed in following four diseases of cancer, stroke, diabetes and acute myocardial infarction. A special point in the new district health plan is that district pharmacies are defined as “health care facilities”. By this definition, the district pharmacy is expected to play a role as providing center of the drugs and the medical devices corresponding to the four diseases. Moreover, pharmacy of the future has to contribute to play a role of the community health coordination activities such as participation to district referral critical-pathway, home health care and pre-discharge conference in acute care hospital.
Peoples have been much concerned on their healthy life. Recently, many kinds of dietary supplements and food for specified health uses are distributed and consumed in large quantities. Concurrently, medical case insurance in Japan has been accommodating a lot of patients increasingly year by year, when the importance and enlightenment of self-care and primary care of people with nonprescription medications is proposed. The Pharmacists Law defines the responsibility of the pharmacists for the public health and welfare with medication and hygienic affairs. The recent pharmacy education for 6 years in Japan is likely to orient pharmaceutical care practice for contribution to the treatment of patients by appropriate management of medication. The multidisciplinary knowledge on medicines and diseases, and the patient consultation technique are required in the pharmacy practice. The contribution and accountability of the community pharmacists to self-care and primary care with nonprescription medications, as social needs, is expected. In this review, social responsibility on the treatment with nonprescription medications and their information provided by the community pharmacists in future is discussed.
Patient-centered approach is critical in current team-medication, and the importance of the approach is broadly accepted among the medical workers including pharmacists. Nevertheless, based on the experience as a communication trainer for medical workers and a faculty at the pharmacy school, many of pharmacists and/or pharmacy students have certain mental model for the pharmacist-patient relationship similar to the paternalism. Active concern to the decision-making and the health behavior for the patients' own medication is the key for patient-centered approach. Heron's six categories of intervention model show the need for caregivers to support their clients' autonomy with facilitative approach. Coaching, client-centered, behavior-focus support communication method would be useful for the pharmacists to implement the facilitative approach in medical context, especially on the primary care.
Community pharmacy is evolving to provide additional services to patients such as compliance improvement, self-care and OTC consultations and advising on daily activities to supplement medical treatment. Currently in Japan, it has been estimated that 1.5 to 2 million people have chronic hepatitis C. We have attempted to increase the population's knowledge of this important issue with educational brochures about hepatitis C and placing posters encouraging them to ask medical professionals about their health problems. Peg-interferon and ribavirin combination therapy has an efficacy rate of approximately 60%. The side effects might present in different ways and frequency depending on the treatment duration; therefore, pharmacists should monitor patients carefully during the entire treatment period with particular attention to OTC drug use, daily activity, etc. Additionally, for outpatients community pharmacy has responsibility to avoid drug-related adverse events in the patients' daily life, so monitoring for clinical signs of side effects is necessary. We created the “Clinical Pathway for Healthcare Network of Chronic Hepatitis C Treatment via the Medication Notebook Type” (Clinical Pathway) for patients who received Peg-interferon and ribavirin combination therapy. We are beginning to provide the new version of this service to patients as one of the pharmaceutical care components in the community pharmacy. I would like to describe how we cooperate with other community pharmacies using the “Clinical Pathway”, which is to improve patient care in the community pharmacies.
The increase in the number of universities in Japan in spite of a decrease in the number of enrollees is causing a decline in the academic ability of undergraduates. The diversification of selection methods also contributes to the deterioration of the situation. Some students and teachers in high schools still hold the prejudice that only chemistry is important in the entrance examination for schools of pharmacy. To study pharmaceutical sciences, biology is as important as chemistry, and the number of students who have difficulty in obtaining biology course credits is increasing. Logical thinking based on the established knowledge in basic sciences is necessary for a successful clinical clerkship. However, students are inexperienced in logical thinking using the knowledge learned in their classes. This is why practice is needed during the basic pharmaceutical course. We made it compulsory for all second- and third-year students to take practical courses in physics, chemistry, and biology. In addition, a program in which a tutor conducted individual practice for students was carried out. A change in students' sense of purpose in learning was achieved by changing the method and environment of learning.
The six-year pharmacist education course has begun, and now first-year students receive clinical training. Interdisciplinary problem-solving capabilities covering chemistry, biology, molecular biology, pharmacology, pathology, and pharmacokinetics are necessary for new pharmacists. However, the conventional pharmaceutical science education was so separate from other fields that education for interdisciplinary cooperative capability was insufficient. This was especially true of elemental science courses, because they are not directly connected with clinical knowledge, and there is a problem of low student interest in those courses. As a result, students acquired only recall-level knowledge in clinical courses and their problem-solving capabilities in clinical treatment and drug development deteriorated. Therefore we offered a trial lecture aimed to help students recognize the important relationship between elemental science courses and clinical courses and increase their motivation to enroll in these courses. Specifically, the trial lecture covered cancer therapy, in reference to mechanisms of carcinogenesis, epidemiology, physiology of cancer, anticancer drugs with explanations of the mechanism of action of carcinogens, anticancer drugs, and molecular-targeted drugs from the viewpoints of organic chemistry and biochemistry by a specialized teacher. This paper reports on this experimental lecture with evaluations from students.
Pharmacy students in the six-year education system are expected to combine their knowledge obtained from many lectures and to develop problem-solving abilities in therapeutics. These two expectations are considered to be difficult in the conventional education system. Therefore we introduced a new problem-based learning (PBL) method in the class on “pharmacotherapeutics,” which was held in the first semester of the fourth year. In the PBL modules, students studied the etiology, pathology, and appropriate drug therapeutics of a given disease and obtained the knowledge and skills necessary for monitoring patients during treatment. We conducted 12 PBL modules, and students studied one case per module, each lasting a week. To encourage constructive group work and to generate original input formats to provide students with a problem-solving road map, we developed new systems including a class review and portfolio. The new PBL method also included lectures on the overview of each disease and the therapeutic agents (action mechanism, physical properties, pharmacokinetics, and monitoring of the efficacy and adverse reactions). By integrating their knowledge and skills, we hope that the students will be able to acquire problem-solving abilities in therapeutics when they become pharmacists.
Ultrasound (US) has been utilized as a useful tool for diagnosis and therapy. US mediated drug and gene delivery is paid to attention as a non-invasive system. The combination of US and microbubbles generated microjet stream by inducing disruption of bubbles and resulted in enhancing permeability of cell membrane. This phenomenon has been utilized as driving force for drug and gene delivery. Recently, we developed ultrasound sensitive liposome [Bubble liposome (BL)] containing perfluoropropane gas. US combined with BL could effectively transfer gene in vivo compared to conventional cationic liposomes. Using this method, we succeeded to obtain a therapeutic effect in cancer gene therapy with Interleukin-12 corded plasmid DNA. Therefore, it is expected that US combined with BL might be a useful non-viral vector system. From this result, the fusion of liposomal and ultrasound technologies would be important for establishment of advanced cancer therapy.
Gold nanoparticles have unique optical properties such as surface-plasmon and photothermal effects. Such properties have resulted in gold nanoparticles having several clinical applications. Gold nanorods (which are rod-shaped gold nanoparticles) show a surface plasmon band in the near-infrared region. They have therefore been proposed as contrast agents for bioimaging, or as heating devices for photothermal therapy. Polyethylene glycol-modified gold nanorods systemically administrated into mice can be detected with integrating sphere, and the stability of the gold nanorods in blood flow evaluated. After intravenous injection of gold nanorods followed by near-infrared laser irradiation, significant tumor damage triggered by the photothermal effect was observed. To deliver gold nanorods to the target tissue, thermosensitive polymer gel-coated gold nanorods were prepared. After intravenous injection of the gel-modified gold nanorods and irradiation of the tumor, a larger amount of gold was detected in the irradiated tumor than in the non-irradiated tumor. This effect is due to the hydrophobic interaction between the cellular membrane or the extracellular matrix and the gel surfaces induced by the photothermal effect. Furthermore, the photothermal effect enhanced the permeability of the stratum corneum of the skin. As a result of treatment of the skin with ovalbumin and gold nanorods followed by near-infrared light irradiation, a significant amount of protein was detected in the skin. The gold nanorods therefore showed several functions as a photothermal nanodevice for bioimaging, thermal therapy, and a drug delivery system.
The structure of tumor vasculature is crucial for the nanocarrier-mediated chemotherapy. Recently, transforming growth factor-β (TGF-β) inhibitor was reported to increase the tumor accumulation of nanocarriers by changing the structure of tumor vasculature. To indentify the parameters of tumor vasculature function following TGF-β inhibitor (A-83-01) treatment, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was performed using Gd-DTPA and its liposomal formulation (Gd-L) as contrast agents. Observation of tumor MR image before, during, and after injection of contrast agent could calculate the parameters of vascular function, such as volume transfer constant between blood plasma and extracellular space (Ktrans) and fractional plasma volume (vp). A-83-01 treatment significantly increased these parameters within 24 h that was positively related to pericyte coverage and tumor cell proliferation. Furthermore, apparent diffusion coefficient (ADC) determined by diffusion-weighed imaging was decreased by A-83-01 treatment, suggesting the decrease of tumor interstitial fluid pressure. Vascular function of the tumor improved by A-83-01 treatment well assessed on post-Gd-L-enhanced MR images, which predicted delivery of liposomal drug to the tumor. These findings suggest that DCE-MRI and, in particular, Ktrans and vp quantitation, provide important additional information about tumor vasculature by A-83-01 treatment.
The cell-killing effect of boron neutron capture therapy (BNCT) is due to the nuclear reaction of two essentially nontoxic species, boron-10 (10B) and thermal neutrons, whose destructive effect is well observed in boron-loaded tissues. High accumulation and selective delivery of boron into tumor tissue are the most important requirements to achieve efficient neutron capture therapy of cancers. This review focuses on liposomal boron delivery system (BDS) as a recent promising approach that meet these requirements for BNCT. BDS involves two strategies: (1) encapsulation of boron in the aqueous core of liposomes and (2) accumulation of boron in the liposomal bilayer. In this review, recent development of liposomal boron delivery system is summarized.
An immunosuppressive antimetabolite, mycophenolate mofetil (MMF), has been widely used in combination with a calcineurin inhibitor for organ transplantation and autoimmune diseases. A fixed dosing of MMF often causes bone marrow toxicity or cytomegalovirus antigenemia under the optimal dosing of calcineurin inhibitors. Pharmacokinetic characteristics of MMF and its relation to the degree of immune suppression have not been fully clarified in clinical practice. This review summarizes our achievements on pharmacokinetic disposition of mycophenolic acid (MPA) and inosine 5′-monophosphate dehydrogenase (IMPDH) activity in patients with kidney transplantation and with lupus nephritis. Contribution of enterohepatic recirculation to plasma disposition of MPA in lupus nephritis patients was similar to that in tacrolimus-treated kidney transplant recipients. MPA pharmacokinetics in lupus nephritis was characterized by high MPA clearance most likely due to better renal function. In addition, concomitant metal cation decreased MPA concentration in patients receiving tacrolimus but not cyclosporine. This interaction may depend on amount of biliary-excreted MPA glucuronide. Renal clearance of MPA was higher in cyclosporine- than tacrolimus-treated patients. Its ratio to creatinine clearance was much higher than unbound fraction of MPA in each calcineurin inhibitor treatment. These kinetic data revealed the presence of renal tubular secretion in the urinary excretion process. In multivariate analysis, the plasma disposition of MPA and its glucuronides affected IMPDH activity in erythrocytes. The IMPDH activity might be a useful marker reflecting a long-term exposure by MPA. Our findings in this review would contribute to optimal dosing of MMF in immunosuppressive regimen including a calcineurin inhibitor.
The identification of biomarkers is a promising approach for the diagnosis and effective therapy of cancer. In particular, disease proteomics is a potentially useful method for identifying such biomarkers. However, very few biomarker proteins for drug development have been discovered using this approach. The main difficulty is to efficiently select potential biomarkers from the many candidate proteins identified by the proteomics approach. To circumvent this problem, we have developed “antibody proteomics technology” that can screen for biomarker proteins by isolating antibodies against each candidate in a rapid and comprehensive manner. Here, we applied “antibody proteomics technology” to breast cancer-related biomarker discovery and evaluated the utility of this novel technology. Cell extracts derived from breast tumor cells (SKBR3) and normal cells (184A1) were analyzed by two-dimensional differential gel electrophoresis (2D-DIGE) to identify proteins over-expressed in the tumor cells. Candidate proteins were extracted from the gel pieces, immobilized onto a nitrocellulose membrane using a dot blot apparatus and then used as target antigens in scFv-phage enrichment and selection. Following this in vitro phage selection procedure, scFvs binding to 21 different over-expressed proteins in tumor cells were successfully isolated within several weeks. The expression profiles of the identified proteins were then determined by tissue microarray analysis using the scFv-phages. Consequently, we identified three breast tumor-specific proteins. Our data demonstrates the utility of an antibody proteomics system for discovering and validating tumor-related proteins in pharmaceutical proteomics. Currently, we are analyzing the functions of these proteins to use them as diagnostic markers or therapeutic targets.
Synthetic studies of C4-linked imidazole C-nucleosides toward biofunctional molecules are described, in which the following items are covered. 1) Stereoselective synthesis of imidazole C- and pyrazole C-nucleosides via diazafulvene intermediates. 2) Synthesis of tetrahydrofuranylimidazoles using a PhSe group efficiently and its application to the new human histamine H3 receptor (hH3R) agonist, imifuramine, and the first selective human histamine H4 receptor (hH4R) agonist, OUP-16. 3) Synthesis of imidazole ribonucleoside phosphoramidite (Imz-PA) with pivaloyloxymethyl (POM) group for probing the catalytic mechanism of ribozymes. 4) Synthesis of a two-carbon-elongated homologue (Imz-C2-PA) with a combination of POM and 2-cyanoethyl groups. 5) Incorporation of C2-imidazole nucleoside into position 638 of VS ribozyme using Imz-C2-PA and catalytic activities of the thereby generated modified VS ribozyme (G638C2Imz).
Pre-seasonal medication is recommended for cases of cedar pollinosis that are expected to manifest severe symptoms during the season, according to the standard clinical guideline in Japan. This study aims to appraise the value for money of additional costs that accompany the choice of pre-seasonal medication from payer's perspective. Based on the 12 reports of controlled clinical trials with Symptom Score (SS) and Medication Score (MS) comparing pre-seasonal medication with intra-seasonal symptomatic medication, 15 incremental cost-effectiveness ratios (ICERs) and 4 integrated ICERs of each group of targeted agents are estimated. Incremental effects are estimated by reading SS charts, and incremental costs are estimated by reading MS charts and using National Health Insurance Medical Fee Schedule and National Health Insurance Drug Price Standard. Estimated ICERs range from ¥322,195 per quality-adjusted life-year (QALY) to ¥57,088,063 per QALY. Integrated ICERs are: ¥1,128,286 per QALY for 2nd generation histamine H1 receptor antagonists, ¥2,248,018 per QALY for leukotriene receptor antagonists, ¥2,692,911 per QALY for prostaglandin D2 and thromboxane A2 receptor antagonists, ¥1,150,943 per QALY for Th2 cytokine suppressors, and ¥1,291,341 per QALY for all agents. Pre-seasonal medication for cedar pollinosis is cost-effective regardless of the choice of the prophylactic agent among 2nd generation histamine H1 receptor antagonists, leukotriene receptor antagonists, prostaglandin D2 and thromboxane A2 receptor antagonists, or Th2 cytokine suppressors, taking the suggested threshold of ¥5,000,000 per 1 QALY gain in Japan. The use of 2nd generation histamine H1 receptor antagonists and Th2 cytokine suppressors are found more favourable.
Using furosemide (FU) as a model drug, we examined the wet granulation method as a way to improve the taste masking and physical characteristics of orally disintegrating tablets (ODTs). In the wet granulation method, yogurt powder (YO) was used as a corrective and maltitol (MA) was used as a binding agent. The taste masked FU tablets were prepared using the direct compression method. Microcrystalline cellulose (Avicel® PH-302) and mannitol were added as excipients at a mixing ratio of 1/1 by weight. Based on the results of sensory test on taste, the prepared granules markedly improved the taste of FU, and a sufficient masking effect was obtained at the YO/FU ratio of 1 or more. Furthermore, it was found that the masking effect achieved by YO granules made with the wet granulation method was similar to or better than that produced by the granules made with dry granulation method. All types of tablets displayed sufficient hardness (over 3.5×10−2 kN), and rapidly disintegrating tablets were obtained with YO granules produced at a mixing ratio of FU/YO=1/1, which disintegrated within 20 s. Disintegration time lengthened as the mixing ratio of YO to FU increased. In the mixing ratio of FU/YO=1/1, the hardness of tablets with granules made by the wet granulation method exceeded that of tablets with granules made by the dry granulation method, with minimal differences in disintegration time. The hardness and disintegration time of the tablets with granules made by the wet granulation method could be controlled by varying the compression force. In conclusion, YO was found to be a useful additive for masking unpleasant tastes. FU ODTs with improved taste, rapid disintegration and greater hardness could be prepared with YO-containing granules made by the wet granulation method using MA as a binding agent.
After coronary stent implantation, dual-antiplatelet therapy (DAT), such as aspirin and clopidogrel, is essential to prevent stent thrombosis. Proton-pump inhibitors (PPIs) may be used to prevent gastrointestinal (GI) bleeding during DAT, but there is no evidence for the efficacy of PPIs in this setting. Because both clopidogrel and PPIs are metabolized by cytochrome P450 (CYP) 2C19, there is a possibility that, through drug interaction, PPIs diminish the antiplatelet effect of clopidogrel. In this retrospective cohort study, we evaluated the efficacy and safety of rabeprazole in patients receiving DAT of clopidogrel and aspirin after drug-eluting stent implantation. In 199 patients treated with DAT alone (control group) and 103 patients treated with rabeprazole plus DAT (rabeprazole group), we examined the incidences of GI bleeding and major adverse cardiac events (MACE) including stent thrombosis. The incidence of GI bleeding was not significantly different between the groups (hazard ratio 0.47 [95% confidence interval 0.15-1.42], P=0.18; P=0.17 in log-rank test), although no patient with severe bleeding was observed in the rabeprazole group. The use of rabeprazole did not increase the incidence of MACE (hazard ratio 1.28 [95% confidence interval 0.54-3.00], P=0.56; P=0.56 in log-rank test). One patient who developed subacute stent thrombosis under DAT was genetically proven to be a CYP2C19 poor metabolizer. The effect of rabeprazole to prevent GI bleeding is limited in patients receiving DAT. It remains to be confirmed whether these results may depend on CYP2C19 polymorphisms or a class of PPIs.
Long-term neuroplastic changes in dentate gyrus (DG) have been reported after seizure induction and were shown to contribute to epitogenesis of epilepsy. These changes include increased number of newborn granule cells, sprouted mossy fibers, granule cell layer dispersion, etc. The aim of current study is to determine the acute progression of neuroplastic changes involved newly generated granule cells after kainic acid (KA)-induced seizures. Doublecortion (DCX) analysis was used to examine the newly generated granule cells morphology 1-7 days after seizure induction. Quantitative analysis of DCX-labeled cells at different times shows that there are some rapid changes in the dentate gyrus. At day 7 epileptical mice induced an increase of the number of DCX-labeled cells in DG. At days 3 and 7 after epilepsy induction, the percentage of DCX-labeled cells per DG were significantly increased. These results show that seizures are capable to increase the number of new granule cell within a short time for function activation in post-seizure period. Therefore, the rapid changes in the DG might be having a potential for hippocampus neuroplastic function.
Film dosage forms containing metronidazole (MZ) were prepared from natural polysaccharides, such as pullulan (PUL) or sodium alginate (ALG), without heating or controlling the pH. The release profiles of MZ from the films were investigated. In the absence of a drug, the casting method resulted in the polysaccharide forming a circular film, and the presence of MZ affected film formation. The thickness of the film was controllable by adjusting the concentration of ALG, and regular unevenness was observed on the surface of film. The film prepared with PUL or ALG readily swelled in dissolution medium, and released MZ with disintegration. The films prepared from the polysaccharides could be promising candidates as dosage forms containing MZ, and would be expected to show drug dissolution in the surface of skin.