The Core University Program provides a framework for international cooperative research in specifically designated fields and topics, centering around a core university in Japan and its counterpart university in other countries. In this program, individual scientists in the affiliated countries carry out cooperative research projects with sharply focused topics and explicitly delineated goals under leadership of the core universities. The Core University Program which we introduce here has been renewed since 2001 under the support of both the Japan Society for the Promotion of Science (JSPS) and the National Research Council of Thailand (NRCT). Our program aims to conduct cooperative researches particularly focusing on Natural Medicine in the field of Pharmaceutical Sciences. Institute of Natural Medicine at University of Toyama (Japan), Faculty of Pharmaceutical Sciences at Chulalongkorn University (Thailand), and Chulabhorn Research Institute (Thailand) have been taking part in this JSPS-NRCT Core University Program as core universities. The Program is also supported by the 20 institution members in both countries. This program is running the five research subject under a key word of natural medicine which are related to i) age-related diseases, ii) allergy and cancer, iii) hepatitis and infectious diseases, iv) structure, synthesis, and bioactivity of natural medicines, and v) molecular biology of Thai medicinal plant components and database assembling of Thai medicinal plants. The program also encourages university members to strengthen related research activities, to share advanced academic and scientific knowledge on natural medicines.
A project “Cooperative research and educational center for breeding and standardization of medicinal plants and drug development between Japan and China” was launched in 2006 with the support of National Natural Science Foundation of China (NSFC) and Japan Society for the Promotion of Science (JSPS). The project focuses on medicinal plants that are important sources of traditional medicines and modern drugs. Many of these plants exist in Asian countries and have been utilized in health care to maintain quality of life. Recently, the short supply of some important medicinal plants, like Glycyrrhiza sp. and Ephedra sp. has become an issue in Japan and China. We believe that cooperative research by many specialist researchers is a prerequisite for overcoming this problem and for establishing a supply of these resources with their highly added values. Furthermore, with our group's participating researchers utilizing state-of-the-art drug evaluation methods in pharmacological and pharmacutical sciences, the development of new drugs and treatment candidates using the collaborative resources of this project, which include distinguished natural chemists, is anticipated. Another important aim of the project is to foster young scientists. In the project, we are encouraging them to continue their studies to produce new findings regarding traditional medicines and drug development.
The vision to establish this program was to establish and extend cooperative research efforts beyond the intraregional boundaries. The Japan Society for the Promotion of Science (JSPS) has taken an initiative to support an Asian Core Program, which aims to create world-class research hubs within the Asian region and foster the development of the next generation of leading researchers by establishing sustainable collaborative relations among research and educational institutions in Asian countries. Nagoya University strongly supports and is the Core University of this program with Minoru Isobe and Toshio Nishikawa serving as the coordinator. Representing their respective countries/regions, Guo-Qiang Lin and Zhu-Jun Yao (China, Shanghai), Sunggak Kim and Kwan-Soo Kim (Korea), Somsak Ruchirawat (Thailand), and Chun-Chen Liao and Biing-Jiun Uang (China, Taipei) share in the vision to enhance collaborative efforts. As coordinators they have invited many cooperative universities/institutes in their home countries/regions to start the network since 2005. Singapore (Tech-Peng Loh) has joined lately, and Hong Kong is represented by Henry Wong. All cooperating regions also agreed to support this program by acquiring matching funds for the duration of the program, that is, until March 2010. This program is jointly supported by the JSPS (Japan), the NNSFC (China, Beijing), the NSCT (China, Taipei), the KOSEF/CMDS (Korea), the NRCT/CRI (Thailand), and the IUPAC for an East Asian Network Task group project. Pauline Chiu takes the general secretary work. The initiation of the Asian Core Program and the Inauguration Conference (The 0th International Conference on Cutting-Edge Organic Chemistry in Asia; ICCEOCA-0) was held in Nagoya (2006. 3), which was followed by ICCEOCA-1 in Okinawa, Japan (2006. 10), ICCEOCA-2 in Busan, Korea (2007. 9), ICCEOCA-3 in Hangzhou, China (2008. 10). A post symposium of ICCEOCA-1 was held in Hsinchu, Taiwan (2006. 10), and a satellite symposium of ICCEOCA-2 was held in Bangkok, Thailand (2007. 11). Future international conferences will be held in Bangkok (2009. 11) and Taipei (2010).
In 2005, the independent administrative institution the “Japan Society for the Promotion of Sciences (JSPS)” initiated the “Asia and Africa Science Platform Program”, which is a new project aimed to create high potential research hubs in selected fields within the Asian and African region, while fostering the next generation of leading researchers. Another goal is to establish sustainable collaborative relationships among universities and research institutes in Japan and other Asian and African countries. In this project, we consider natural sources existing in partner countries to be the most important factor in the production of medicine. We will search for target compounds and analyze their structures by screening biologically active natural products. Additionally, we will design functional molecules and create process for retrieving a large supply of target compounds based on a bioprospecting strategy. Thailand, Indonesia, and India share the vision of enhancing collaborative efforts. By conducting this researche, we will focus on academic research that is necessary for the development of the pharmaceutical and medical products industry in partner countries. There are four selected research topics as followeds: 1) Development of New Antitumor Agents based on Marine Natural Products; 2) Development of New Anticoagulants and Anti-VEGF; 3) Molecular Epidemiological Investigation of Emerging Infectious Diseases and Development of Novel Diagnosis and Therapeutic Agents; and 4) Medicinal Chemistry on Biologically Active Natural Products from the Traditional Condiments and Medicines. The exchanges might take the form of joint research seminars. The first Medicinal Chemistry Seminar of the AA Scientific Platform Program was co-organized with the 23th Annual Research Conference on Pharmaceutical Sciences, Thailand at Chulalongkorn University, Bangkok, on December 14-15, 2006. The 2nd JSPS seminar was co-organized with the 1st Bioactive Natural Products from Marine Organisms and Endophytic Fungi (BNPME) seminar and held in Phuket, Thailand between October 25-28, 2007. The JSPS 3rd Medicinal Chemistry Seminar of the Asia/Africa Scientific Platform Program was co-organized with The 2nd International Seminar of MPU-AACDD in Tokyo on January 14-15, 2009.
After being distributed in the circulating blood, drugs bind to serum proteins varying degrees. In general, such binding is reversible, and a dynamic equilibrium exists between the bound and unbound molecular species. It is believed that unless there is a specific transport system (e.g. receptor-mediated endocytosis, protein-mediated transport), only unbound drugs are able to penetrate through biomembranes, are distributed to tissues, and undergo metabolism and glomerular filtration. It is also believed that only unbound molecules present in target tissues can exert their pharmacological effects, and that the concentration of unbound molecules in tissues is in proportion to the drug serum concentration. Therefore, drug-serum protein binding is critically involved in the manifestation of the pharmacological effects of a drug as well as its pharmacokinetics. Among serum proteins, human serum albumin (HSA) and α1-acid glycoprotein (AGP) play important roles in protein binding for many drugs, which is of key importance to drug distribution in the body. In addition, they are widely used in clinical settings as blood preparations and drug delivery system carriers. It is thus of great importance from the viewpoint of pharmaceutical science to clarify the structure, function, and pharmaceutical properties of HSA and AGP. Accordingly, since starting my laboratory, the focus of my research has involved molecular pharmaceutical studies on the interactions of drugs and HSA and AGP for the purpose of applying these findings to clinical fields, such as drug treatment, diagnosis and drug discovery. In this review, the molecular properties of HSA and AGP will be briefly outlined. The static and dynamic topology of drug binding sites on these proteins, investigated by various spectroscopic techniques, X-ray crystallography, quantitative structure-activity relationships, molecular modeling, photo affinity labeling, site-directed mutagenesis etc., changes in the serum protein binding of drugs in pathological conditions, such as liver and kidney failure and various inflammation diseases and factors contributing to the changes will then be summarized. Finally, cases in which protein binding displacement can be applied to medical fields will also be introduced.
We studied the relationship between patient-pharmacist communication and asthma treatment, including patient understanding of drug therapy, ability to self-treat with inhaled drugs, and control over asthma. The study was among adult patients who had received inhaled steroidal or other drugs from community pharmacies in Hokkaido, Ibaragi, Tochigi, Kanagawa, and Osaka prefectures for at least one year. During the month of November 2007, pharmacists explained the study to patients and obtain consent before distributing questionnaires to be filled out and mailed back. Survey items covered the nature/extent of the pharmacist's explanation, the patient's degree of understanding, frequency of inhaled steroid use, frequency of asthma attacks, degree of improvement with inhaler use, skill in using inhaled drugs, and self-evaluation of communication with the pharmacist. Analysis was carried out using the 114 valid data sets obtained. The ratio of men to women was 4: 6, and the average age was 61.8 years. Compared with patients citing communication problems with pharmacists, those who had good communication received significantly higher scores in terms of understanding the purpose of inhalers, drug interactions, and side effects, and coping with attacks, as well as in indices of skill in using inhaled drugs. The degree of improvement in asthma attacks was also significantly higher among patients with self-evaluation of good communication with pharmacists. We suggest that communication between patient and pharmacist is associated with understanding of pharmacotherapy, as well as their ability to use inhaled medications and gaining good control over their asthma.
The present study was designed to investigate the possible neuroprotective effect of digoxin induced pharmacological preconditioning (PP) and its probable mechanism. Bilateral carotid artery occlusion (BCAO) of 17 min followed by reperfusion for 24 h was employed to produce ischemia and reperfusion (I/R) induced cerebral injury in male swiss albino mice. Cerebral infarct size was measured using triphenyltetrazolium chloride staining. Memory was assessed using elevated plus maze test. Degree of motor incoordination was evaluated using inclined beam walking test, rota rod test and lateral push test. Digoxin (0.08 mg/kg, i.p.) was administered 24 h before surgery in a separate group of animals to induce PP. BCAO followed by reperfusion, produced significant rise in cerebral infarct size along with impairment of memory and motor coordination. Digoxin treatment produced a significant decrease in cerebral infarct size and reversal of I/R induced impairment of memory and motor incoordination. Digoxin induced neuroprotective effect was abolished significantly by verapamil (15 mg/kg, i.p.), a L-type calcium channel blocker, ruthenium red (3 mg/kg, s.c.), an intracellular ryanodine receptor blocker and 3,4-dichlorobenzamil (Na+/Ca2+ exchanger inhibitor). These findings indicate that digoxin preconditioning exerts a marked neuroprotective effect on the ischemic brain, which is possibly linked to digitalis induced increase in intracellular calcium levels eventually leading to the activation of calcium sensitive signal transduction cascades.
High dose glucocorticoids (GC) are commonly used for the treatment of autoimmune diseases. The frequencies, occurrence day and dose-dependency for side effects may be different among the events such as diabetes mellitus, hyperlipidemia, infectious disease, osteoporosis, and peptic ulcer. We investigated GC-induced side effects in 68 patients treated with GC for autoimmune diseases. Initial dose of GC (prednisolone equivalent) was 0.67±0.35 mg/kg/d. Hypercholesterolemia (66%), hypertension (62%), insomnia (50%), hypertriglyceridemia (44%), excessive appetite (38%), hyperglycemia (18%), digestive symptom (16%), moon-shaped face (13%) and oral candidiasis (12%) were observed in 63 patients treated with GC. Hypercholesterolemia, excessive appetite, digestive symptom, moon-shaped face, and oral candidiasis were associated with the initial dose of prednisolone greater than 0.80 mg/kg/d. Insomnia [median 6 days (range 1-88)], excessive appetite [7 days (2-57)], hypertension [8 days (1-37)], digestive symptom [15 days (1-87)] and hypercholesterolemia [19 days (3-77)] were observed early after 6-19 days starting GC. On the other hand, hypertriglyceridemia [33 days (2-131)], oral candidiasis [35 days (7-52)] and hyperglycemia [60 days (4-134)] were developed after 33-60 days starting GC. Since the frequencies, dose-dependency and occurrence day were different among the side effects of GC, medical staffs including physicians and pharmacists should pay attention such features of the events in the treatment of autoimmune diseases.
We conducted a survey on the immunization requirements of the students in the fourth year of the 4-year-course departments of pharmacy in Japan by using a self-administered questionnaire, which was mailed to the directors of the institutes. Of the 61 departments invited, 54 responded. Program of seroprevalence examination or vaccination was not in place against measles, rubella, mumps and varicella, and hepatitis B in 31.5% (17/54), 53.7% (29/54), 57.4% (31/54), and 68.5% (37/54), respectively. Surveillance of the history of infection and vaccination was carried out in 21 departments, but only 5 departments insisted on documented evidence of immunity. Students who were proven to be susceptible to these diseases were required to receive immunization in most departments that performed seroprevalence examination. Seroprevalence examination was carried out in colleges in 83.3% (25/30), and the expenses were born by department in 70.0% (21/30). On the other hand, vaccination was carried out in colleges in 30.0% (9/30), and the expenses were born by department in 6.7% (2/30). Of the 54 departments, 29, 11, and 3 departments executed these programs in the 3rd year, 4th year, and at the time of admission, respectively. Influenza vaccination during the year of clinical clerkship and tuberculosis skin test was required in 20.4% (11/54) and 37.0% (20/54), respectively; these were carried out in the colleges in 8 and 19 departments and the expenses were born by department in 1 and 18 departments, respectively. Countermeasures against these infectious diseases were found to be insufficient in most departments of pharmacy.
A simple and sensitive fluorophotometric method for the determination of aldehyde was established by utilizing condensation reaction with resorcinol. In the determination of vanillin that is one of aldehydes, the calibration curve exhibited linearity over the vanillin concentration range of 3.0-7600 ng ml-1 at an emission wavelength of 507 nm with an excitation of 410 nm and with the relative standard deviations (n=5) of 2.5%, 2.0% for 7.6 ng ml-1, 760 ng ml-1 of vanillin, respectively. This method was successfully applied in the assay of vanillin in cold medicine.
Hybrid liposomes (HLs) composed of vesicular and micellar surfactants have inhibitory effects on the growth of tumor cells in vitro and in vivo. Successful clinical chemotherapy with drug-free HLs to patient with lymphoma has been reported after approval by the Committe of Bioethics. However, the therapeutic effects of HLs on the metastasis of colon carcinoma cells have not yet been elucidated. In this study, the therapeutic effects of HLs composed of L-α-dimyristoylphosphatidylcholine (DMPC) and polyoxyethylene (23) dodecyl ether [C12(EO)23] on the metastasis of colon carcinoma (Colon26) cells were examined in vivo. Marked high therapeutic effects were obtained in the hepatic metastasis mice model after the treatment with HLs. Furthermore, optical microscopic analysis indicated that HLs could induce the apoptosis of colon carcinoma cells in vivo. No toxicity was observed in the hepatic metastasis mice model after intravenously injecting HLs. Therapeutic effects along with the induction of apoptosis by HLs without any drugs on hepatic metastasis were revealed on the basis of optical microscopic analysis for the first time in vivo.
Chitosan is one of the attractive non-viral carriers for gene delivery including siRNA. However, common chitosan, which has a relatively high molecular weight, is insoluble in water, which might make it difficult to apply clinically. In this study, we investigated the efficacy of low-molecular-weight chitosan (LMWC), which is soluble in water, as a carrier for siRNA delivery. To evaluate the binding affinity and RNA interference (RNAi) of LMWC/siRNA complexes, a multi-well imaging system (IVIS®) was adapted. CT26 cells stably expressing firefly luciferase (CT26/Luc cells) were established to evaluate RNAi. Evaluation of RNAi using lipofectamineTM 2000 was carried out by employing a luminometer with cell lysis and IVIS® without cell lysis. The results were closely correlated, suggesting the advantages of the multi-well imaging system regarding screening, the visualization of results, and nondestructive evaluation. Fluorescence generated by ethidium bromide intercalated in the double strand of siRNA was markedly quenched at a higher ratio of LMWC to siRNA (N/P) and lower pH. Evaluation of the particle size and zeta potential of LMWC/siRNA complexes also indicated the higher binding affinity of LMWC with siRNA. At N/P=300 and pH 6.5, which satisfied the high-level binding affinity of LMWC with siRNA, significantly lower luminescence was detected in CT26/Luc cells treated with LMWC/siRNA compared with those treated with LMWC alone, suggesting the presence of RNAi. These results suggested that LMWC may be an effective carrier for siRNA delivery, and that the multi-well imaging system may be a powerful tool to evaluate the binding affinity and RNAi.
The aim of this study was to document the effect of tramadol as an opioid on individual fibers of rat sciatic nerve. To accomplish this objective, compound action potentials (CAPs) were recorded from isolated nerves treated with tramadol from five different concentration levels. Then recorded CAPs and the control group were analyzed by numerical methods namely Conduction Velocity Distribution (CVD) and Fast Fourier Transform (FFT). The results show that the area under CAP and the time derivative of CAP curves decreases, and the excitability of the nerve trunk falls as well (rheobase and chronaxie increases) with increasing tramadol concentration. CVD deduced by model study was divided into subgroups as SLOW (8-26 m/s), MODERATE (26-44 m/s), MEDIUM (44-60 m/s) and FAST (60-78 m/s). The decrement in percentage relative contribution of these conduction velocity groups starts with a concentration of 0.25 mM tramadol, especially in the subgroup named FAST. The power spectrum shifts from higher frequency region to lower frequency region as the tramadol concentration increases. These findings show that fast conducting fibers are more susceptible to tramadol than medium and moderate groups and tramadol possibly acts on channel activity rather than passive properties (such as space and time constant) of nerve fibers.
Various aqueous and oily diclofenac ophthalmic formulations were subjected to accelerated and long term stability studies. Degradation of diclofenac was found to follow first-order kinetics. Among the aqueous formulations containing preservative, formulation with PMA, PMN, SA, MP/PP and SMS showed diclofenac content above 90% after 6 months of accelerated and 12 months of room temperature storage. Diclofenac 0.1%, w/v aqueous formulation (pH 7.4), with 5-10% overages, containing SMS, MP/PP or PMN look promising taking both stability and corneal permeability in view. However, for use in cataract surgery formulation without preservative appears ideal. Oily ophthalmic formulations except those in olive and mustard oil, had more than 90% drug content after 6 months of accelerated and 12 months of room temperature storage. Diclofenac (0.2%, w/v) ophthalmic solution in sesame oil with 3% overage and containing benzyl alcohol (0.5%, v/v) as preservative, appears ideal, taking both stability and corneal permeability in view.
Partial acid hydrolysis of a new water-absorbing polysaccharide (WAP) from the family Oxalobacteraceae gave six di-, four tri-, two tetra-, two penta-, and one hexasaccharides composed of mannose, glucose, and/or galactose. The structures of oligosaccharides 1-15 were elucidated by extensive 2D NMR spectroscopic analyses. 1H- and 13C-NMR chemical shift assignments of oligosaccharides 1-14 are presented.