Medical facilities and advances in therapeutics have improved world over in recent times. Concomitant with this, the human population has been growing steadily. However, emerging infectious diseases such as severe acute respiratory syndrome (SARS) and AIDS, as well as re-emerging infectious diseases such as Japanese encephalitis and dengue fever, have been spreading in recent times. Three major infectious diseases, namely AIDS, malaria, and tuberculosis, are killing around 8 million people in the world annually. Although drugs effective against these infectious diseases are available at present, drastic therapeutics have not been developed yet. In addition, vaccines against these diseases often cannot prevent infections, because pathogenic viruses or bacteria evade the immune system of the host. Many diseases and emerging infections of pathogenic bacteria cannot be controlled by conventional pharmaceutics. These pathogens secrete regulatory factors. When the produced regulatory factor attains a certain level, an active factor is then produced by the pathogen to destroy the host. Considering these phenomena, we thought investigating characteristic regulatory or active factors will pave the way for developing novel vaccines or diagnostic drugs. Therefore, candidiasis was selected as a model, and application of the secretory protease of Candida albicans was examined for the development of novel drugs. Screening of novel candidates of antigens of C. albicans and vaccine development are also underway. In this paper, our strategy of platform technology against various infectious diseases are introduced.
The SE36 antigen, derived from serine repeat antigen 5 (SERA5) of Plasmodium falciparum, is a promising blood stage malaria vaccine candidate. Previous clinical trials indicated the protective efficacy of BK-SE36 malaria vaccine that is constituted of SE36 recombinant protein and aluminum hydroxide gel. In this study, we assessed the safety, immunogenicity and protective efficacy of SE36/AHG formulated with TLR9 ligand adjuvants K3 CpG oligodeoxyribonucleotides (CpG ODNs) (K3 ODN), D3 ODN or synthetic hemozoin, in two non-human primate models. SE36/AHG with or without each adjuvant was administrated to cynomolgus monkeys. A combination of TLR9 ligand adjuvant with SE36/AHG induced higher humoral and cellular immune response compared with SE36/AHG alone. The most effective TLR9 ligand, K3 ODN, was chosen for further vaccine trials in squirrel monkeys, in combination with SE36/AHG. All monkeys immunized SE36/AHG with K3 ODN effectively suppressed parasitemia and symptoms of malaria following challenge infection. Furthermore, no serious adverse events were observed. Our results show that the novel vaccine formulation of K3 ODN with SE36/AHG is safety, potent immunogenicity and efficacy in nonhuman primates. We are conducting the first in human clinical trials with this formulation.
Hepatocyte growth factor (HGF) was first identified and cloned as a mitogenic protein for hepatocytes, and subsequent studies revealed that HGF has multiple biological effects on a wide variety of cells, including mitogenic, motogenic, morphogenic, anti-apoptotic, and angiogenic activities. It plays roles in organizing tissues during development and regeneration. HGF may be applied for the treatment of acute onset diseases such as fulminant hepatitis, myocardial infarction, acute renal failure, cerebral infarction, and chronic diseases like liver cirrhosis, chronic renal failure, pulmonary fibrosis, cardiomyopathy, and arteriosclerosis obliterans. HGF also has immunomodulatory activities and we previously demonstrated that its administration inhibited acute graft-versus-host disease (GVHD) after treatment with hematopoietic stem cell transplantation. We also demonstrated that HGF inhibited lupus nephritis induced by chronic GVHD and dermal sclerosis in systemic sclerosis using model mice. More than 7 hundred thousand patients suffer from rheumatoid arthritis (RA) in Japan. Although the prognosis of these patients has improved by the treatment of biological agents such as TNF-α and IL-6 blockers, there remain many for whom these agents have not proved beneficial. Recently, using RA model mice, we demonstrated that the HGF antagonist, NK4, can block disease progression of RA through its anti-angiogenic and immunomodulatory actions. In this review article, we discuss the possible roles of HGF signaling for the treatment of immunological reactions in transplantation and autoimmune diseases.
Hepatitis C virus, which affects approximately 170 million people worldwide, is a major causative agent of hepatocellular carcinoma. Anti-HCV treatment is available with the combination of pegylated interferon and ribavirin, and newly approved protease inhibitors. However, because of the diverse anti-HCV efficacy among HCV genotypes and significant side effects, alternative anti-HCV agents are in great demand. Using cell-based systems supporting a part of or the whole HCV life cycle, we identified cyclosporin A, tamoxifen, and benzamide derivatives that inhibited the replication of HCV RNA or the production of infectious HCV particles. In this article, we summarize the mechanistic analyses of the HCV life cycle using these small molecules. Thus, chemical genetics is a powerful approach for revealing molecular mechanisms of the viral life cycle as well as for developing new antiviral agents.
Deuterium (D) labeled compounds are utilized in various scientific fields such as mechanistic elucidation of reactions, preparation of new functional materials, tracers for microanalysis, deuterium labeled heavy drugs and so on. Although the H-D exchange reaction is a straightforward method to produce deuterated organic compounds, many precedent methods require expensive deuterium gas and/or harsh reaction conditions. A part of our leading research agendas is intended to the development of novel and functional heterogeneous platinum-group catalysts and the reclamation of unknown functionalities of existing heterogeneous platinum-group catalysts. During the course of the study, benzylic positions of substrates were site-selectively deuterated under mild and palladium-on-carbon (Pd/C)-catalyzed hydrogenation conditions in heavy water (D2O). Heat conditions promoted the H-D exchange reactivity and facilitated the H-D exchange reaction at not only the benzylic sites but also inactive C-H bonds and heterocyclic nuclei. It is noteworthy that platinum-on-carbon (Pt/C) indicated a quite high affinity toward aromatic nuclei, and the H-D exchange reaction was strongly enhanced by the use of Pt/C as a catalyst under milder conditions. The mixed use of Pd/C and Pt/C was found to be more efficient in the H-D exchange reaction compared to the independent use of Pd/C or Pt/C. Furthermore, simple alkanes could also be efficiently deuterated under rhodium-on-carbon (Rh/C)-catalyzed conditions. The use of ruthenium-on-carbon (Ru/C) enabled the regiospecific and efficient deuterium incorporation at α-positions of alcohols and results were applied as a regio- and stereoselective multi-deuteration method of sugar derivatives.
The diabetes patients have been associated with an increased risk of mortality by breast cancer, and there are differences in the regimen choice and effects of breast cancer treatment between the breast cancer patients with diabetes and their nondiabetic counterparts. However, the pathophysiological relationships of diabetes and breast cancer have not yet been elucidated in detail, therefore its evaluation is strongly required to achieve novel treatment strategies for breast cancer with hyperglycemia. Extracellular circumstances of cancer cells can influence the growth and behavior, resulting in invasion, metastasis and tumor development. We demonstrated that breast cancer cells, MCF-7, cultured in hyperglycemic level significantly promotes the motile activity in comparison to normal physiological glucose level. Moreover, Zn2+ uptake activity into cellular cytosol and the mRNA expression of zinc transporters, ZIP6 and ZIP10, in the high glucose-exposed cells were shown to be especially higher than in the physiological glucose level. The depletion of intracellular Zn2+ by zinc chelation and ZIP6 or ZIP10 knockdown blocked the high migration activity, indicating that Zn2+ transported via ZIP6 and ZIP10 plays an essential role in the promotion of cell motility stimulated in high glucose level. These findings provide a proposing target of the novel strategies for the diagnosis and therapy of breast cancer with hyperglycemia.
An oligonucleotide that can form a triplex with double-stranded DNA is called a triplex-forming oligonucleotide (TFO). TFOs have gained considerable attention because of their potential as gene targeting tools. However, triplex DNA formation involves inherent problems for practical use. The most important problem is that natural nucleotides in TFO do not have sufficient affinity and base pair-selectivity to pyrimidine-purine base pair, like a CG or TA base pair, within dsDNA. This suggests that dsDNA region including a CG or TA base pair cannot be targeted. Therefore, artificial nucleotides, especially with non-natural nucleobases, capable of direct recognition of a CG or TA base pair via hydrogen bond formation have been developed; however, nucleotides with better selectivity and stronger affinity are necessary for implementing this dsDNA-targeting technology using TFOs. Under such a background, we considered that facile and efficient synthesis of various nucleobase derivatives in TFOs would be useful for finding an ideal nucleobase for recognition of a CG or TA base pair because detailed and rational exploration of nucleobase structures is facilitated. Recently, to develop a nucleobase recognizing a CG base pair, we have used post-elongation modification, i.e., modification after oligonucleotide synthesis, for the facile synthesis of nucleobase derivatives. This review mainly summarizes our recent findings on the development of artificial nucleobases and nucleotides for recognition of a CG base pair in triplexes formed between dsDNA and TFOs.
Various factors, including renal function and the combination of nonsteroidal anti-inflammatory drugs, influence the pharmacokinetics of pemetrexed. In this study, we aimed to determine the risk factors for severe adverse events associated with pemetrexed administration. We retrospectively examined the medical records of 82 patients who received pemetrexed. Multiple logistic regression analysis indicated that a creatinine clearance (CCr) of less than 45 mL/min and administration of pemetrexed as early-line treatment were significant risk factors. We then retrospectively compared the adverse events associated with pemetrexed between patients with normal renal function (CCr≥45 mL/min) and those with impaired renal function (CCr<45 mL/min). With regard to hematological toxicity, the frequency of occurrence of grade 3 neutropenia was significantly higher among patients with a CCr of <45 mL/min. With regard to non-hematological toxicity, the frequency of occurrence of grade 2 or higher nausea was significantly higher among patients with a CCr of <45 mL/min. However, the efficacy of pemetrexed did not differ significantly between the 2 groups. Our findings suggest that, for patients with a decline in renal function (CCr <45 mL/min), attention must be paid to the possibility of serious adverse events such as neutropenia and nausea when considering the administration of pemetrexed.
Pharmacists, being compensated through the new dispensing fee, are required to educate patients on their adhesion to the use of prescribed drugs, and to inventory the levels of leftover drugs in outpatients. Recently, Fukuoka City Pharmaceutical Association started a campaign for regulating leftover drugs (Setsuyaku Bag Campaign). Thirty-one pharmacies joined the campaign. Pharmacists distributed convenience bags, called ‘SETSUYAKU-BAG.’ The patients put their leftover drugs in the bags and brought them to community pharmacies. The pharmacists inventoried the returned drugs and reported their results to the doctors. The doctors adjusted the prescriptions accordingly. We counted and analyzed old and new inventories. The number of leftover drugs was 252, for a total value was ¥839655. Cost of leftover drug prescriptions could be reduced by ¥702695, and the value of drugs thrown away was ¥94801. In total, we could reduce the amount of leftover drugs by 83.7%. The cost of leftover drug for one dose package (ODP) is higher than that for non-ODP. However, there were no significant differences in results per age, sex, number and kinds of drugs, prescription days and premium contribution rate. These results suggest that prescription regulation by inventory of leftover drugs in community pharmacies could significantly reduce overall medical expenses. Further studies are necessary in order to account for patients’ health, and to establish more efficient patient education to raise outpatients’ adherence to the new programs.
Since April 2011, a dosage adjustment program has been implemented at Gifu Municipal Hospital. In this program, upon receiving a prescription for renally eliminated drugs, pharmacists verify patients' serum creatinine concentrations by using a computerized medical record system to evaluate the patient's kidney function and suggest the appropriate dosage to doctors, if necessary. In our study, we used questionnaires that were administered to pharmacists and doctors at the hospital to investigate their respective working times and the cost of the program, in order to comprehensively analyze the clinical resource costs of the hospital and evaluate the economic burden of the program for levofloxacin. In addition, we studied the pharmacists' and doctors' attitudes toward the program and the circumstances of prescriptions for patients with renal dysfunction. The questionnaire comprised items such as time required for the program; attitude toward the program, including satisfaction; and attitude toward the circumstances of prescriptions for patients with renal dysfunction. The pharmacists' and doctors' working times and cost of the program were obtained from the questionnaire responses. For cost estimation, we used data from this study as well as those of our previous study that suggested that the levofloxacin program was economically beneficial. Furthermore, their attitudes toward the program and circumstances of prescriptions for patients with renal dysfunction were clarified. Regarding the pharmacists' tasks and interventions, we need to not only investigate attitudes toward them but also perform a cost analysis by the method of the economic evaluation of the medical techniques used in our study.
In recent years there have been over 30000 suicides annually in Japan. This is one of the most serious problems for Japanese society. Because mental disorder is closely associated with suicide, factors related to the increase in mental disorders and suicides should be clarified. In this study, various data regarding social factors were evaluated to assess the correlation of the number of patients with mental disorders and suicides among the 47 prefectures of Japan. Various data regarding social factors, such as income, savings, or rate of divorce, were obtained from the database of the Ministry of Health, Labour and Welfare of Japan. Among the factors, the annual income and the amount of savings were significantly correlated with the number of patients with mental disorder. On the other hand, while the annual income did not have a significant correlation with suicides, the amount of savings had a significant correlation with suicides. In conclusion, the annual income and amount of savings may both be one of the important factors involved in mental disorders, and the savings may also be a factor affecting suicides. These analyses are valuable in helping to clarify the causes of mental disease, and can hopefully contribute to the health and welfare of Japanese.
The usefulness as one of the tools for self-medication of oral rehydration therapy (ORT), recommended as a safe and effective therapy for mild to moderate dehydration, was surveyed by questionnaire for pharmacists in community pharmacies. ORT products were sold in 112 pharmacies (61%), and the common product was OS-1®. Approximately 50% of sellers answered that they had no particular difficulty in explaining ORT. Percentage to answer “hard to describe” is significantly higher in pharmacists who believe there is a need to consider underlying health conditions of customers or patients when implementing ORT. Around 77% of pharmacists considered ORT to be useful in patients as a method of self-medication. A significant number of pharmacists selling ORT products depends on the consultation from customers or patients and provide advice to them confirming that ORT was useful. From these results, it was suggested that further information concerning ORT, such as its use in patients with chronic disorders or signs for completion, and the initiative of pharmacists to participate are necessary for spread the efficacy of ORT for self-medication in patients.
In 2009, the Japan Anti-Doping Agency (JADA) established Sports Pharmacist—a system for certified pharmacists. There are many over-the-counter drugs that contain prohibited substances in Japan, and they are easily available. In Japan, most doping violations are committed when athletes unintentionally take prohibited substances. Therefore, the Sports Pharmacist has a vital role in promoting the prevention of doping. In the present study, surveys involving a total of 350 athletes, (including 260 representatives of Ehime Prefecture in the National Athletic Meets and 90 college students who participated in the intercollegiate athletics Shikoku area meets), on awareness regarding doping and medical drugs were conducted. Using correspondence and logistic regression analyses, the results were examined to develop a model for the prediction of athletes' actions to cope with sickness based on changes in their awareness of anti-doping, and the relationship between them was also analyzed. The survey results suggested that attitudes towards doping were strongly influenced by gender, rather than the athletic ability and whether or not a doping test is scheduled. Their behavior and criteria for the selection of drugs to address sickness were strongly correlated with awareness of anti-doping. Therefore, athletes with an increased awareness of anti-doping are expected to consult a pharmacist prior to using medicine. The Sports Pharmacist should further promote environmental development, such as activities to improve awareness of doping among young athletes and the establishment of medical drug consultation services for athletes (female athletes in particular).