YAKUGAKU ZASSHI, 127(2),225-226, 2007
YAKUGAKU ZASSHI, 127(2),227-230, 2007
Pharmacists are requested to be involved in the management of pharmacotherapy in clinical scenes more extensively than they did ever. It can be said that changes in medical environments such as the collapse of doctors' paternalism, the rising recognition of patients' autonomy in the decision making on their own medical therapy, and the increased accountability of medical care givers to patients have obliged pharmacists to participate in pharmacotherapy as patient's advocates. To meet these social needs the education of students in pharmaceutical universities or colleges should be reconstructed extensively from a traditional research-oriented system to a patient-centered system. In particular the education of applied pharmacotherapy is to be strengthened and enforced. A drastic reform of pharmacist education should be brought in effect.
Key words--pharmacist education; patient's autonomy; care giver; patients' advocate; reform education system
YAKUGAKU ZASSHI, 127(2),231-236, 2007
Serum proteins that are important in the serum protein binding of drugs are human serum albumin (HSA) and α1-acid glycoprotein (AGP). Several binding sites exist on HSA and AGP molecules. HSA, AGP, free fatty acid (FFA), blood urea nitrogen (BUN) and bilirubin, which can all be determined by laboratory test, affect the binding capacities of binding sites on these proteins. The increase and decrease of HSA and AGP influence the binding capacities of all binding sites. As an additional influence on the binding sites on protein molecules, the increment of FFA decrease the binding capacity of site II, while binding capacity of site I is enhanced by FFA. Increase in bilirubin remarkably decreases the binding capacity of site I. BUN data are associated with the amounts of several uremic toxins, 3-carboxy-4-methyl-5-propyl-2-furanpropanate (CMPF), indole-3-acetate (IA), indoxyl sulfate (IS) and hippurate (HA). With CMPF, the binding capacity of site I is decreased, while IA, IS, HA contribute to the binding inhibition of site II of HSA. If we can monitor binding capacities of binding sites of HSA and AGP, laboratory test data can be interpreted from a pharmaceutical perspective regarding protein binding, because changes in laboratory test data that are endogenous substance concentrations have an influence on the binding capacities of those binding sites.
Key words--laboratory test data; human serum albumin; α1-acid glycoprotein; protein binding; binding site; diagnosis
YAKUGAKU ZASSHI, 127(2),237-244, 2007
Effective communication skills facilitate accurate identifications of patient's problems, improvement of the level of patient's satisfaction with the care, and patient's adherence to treatment. Furthermore, a good relationship with patients based on adequate communication lessens patient's anxiety and depression. A patient has his or her own position in a society as a citizen, as a worker and as a family member. A disease threatens such a social background of a patient. We need to recognize that patients suffer not only from diseases, but also from psychosocial distress. Such recognition is the most important basis to improve medical communication that establishes good relationship with patients.
Key words--communication skills; medical interview; listening as more than hearing
YAKUGAKU ZASSHI, 127(2),245-256, 2007
Pharmacist can make an impact on patients' quality of life by providing clinical interventions. These interventions are to be shared with other healthcare professionals and to be utilized to improve quality of care. As an attempt to provide a better care, pharmacists are making patients' record that contains patients' medical history, laboratory values, and conditions. These services are reimbursed by insurance. However, there are some concerns regarding fees for ser
Key words--pharmacist's record; problem-oriented system; pharmaceutical care; clinical skill
YAKUGAKU ZASSHI, 127(2),257-263, 2007
Practicing pharmaceutical care is necessary to promote the appropriate use of medicines. In the practice of pharmaceutical care, monitoring the efficacy and safety of drugs from the pharmacists' point of view is an important role for clinical pharmacists and it is necessary to standardize clinical skills. We would like to introduce the monitoring skills of pharmacotherapy of clinical pharmacists by taking vancomycin injection and injectable anticancer drugs that have different monitoring points as examples.
Key words--therapeutic drug monitoring; pharmaceutical care; clinical skill; vancomycin; anticancer drug; antitumor drug
YAKUGAKU ZASSHI, 127(2),265-266, 2007
YAKUGAKU ZASSHI, 127(2),267-270, 2007
I describe an ideal method of collaboration with a clinical pharmacy education and university education. In the clinical site, there are a lot of clinical problems that the pharmacist should solve. When pharmacy students start clinical training, the pharmaceutical problem might be found. It is necessary to demonstrate it scientifically to improve pharmaceutical problems. Problem-solving ability is necessary for the pharmacist education in the future. But it is difficult to study fundamental research in the hospital. It is necessary to cooperate for us with the university. Fundamental research is needed to guide at the university. A clinical education is guided in the hospital. Cooperation and roles are important.
Key words--pharmacy student; clinical training; education; hospital infection control
YAKUGAKU ZASSHI, 127(2),271-275, 2007
Pharmacists were officially recognized as essential supporters of medical treatment by the Japanese Ministry of Public Welfare in 1992. However, most pharmacists in Japan do not yet play a sufficient role in their duties. Reasons for the above situation include a lack of social understanding regarding their duties and responsibility for the clinical treatment of patients and a lack of awareness on ensuring safe drug therapy by accepting medication errors in prescription, dispensing and administration. No guidelines to minimize these errors have been initiated either. The School of Pharmacy, Department of Pharmacology thus introduced a six-year program to address these problems in April, 2006 in Japan. Accordingly the pharmacist is required to play a bigger role in pharmaceutical treatment in the clinical arena. We must provide the highest level of pharmaceutical care possible to patients, medical, nursing and other hospital personnel and develop pharmaceutical students in the clinical arena. Here, I describe the clinical education trial for pharmaceutical students in Saiseikai Matsusaka Hospital.
Key words--clinical education trial; six-year pharmacy program; pharmaceutical student
YAKUGAKU ZASSHI, 127(2),277-283, 2007
The educational curriculum for pharmaceutical students in Japan will be dramatically changed in April, 2006. There has been active discussion about how to manage the additional two years in the new program to educate students most effectively. In particular, the program of clinical practice in pharmacies, which will be undertaken for 10 weeks, has been received enthusiastically, because it was not considered sufficient in the previous educational program and it will be one of the most important issues in the new curriculum. I am neither a pharmacist nor a professional in pharmaceutical education, but I believe firmly that an effective program of clinical practice in community pharmacies will be indispensable in making the new curriculum successful. I also believe that community pharmacists educated in the new course will change medical systems in this country from the viewpoint of a general thoracic surgeon and chief executive officer of Pharmedico, Co., Ltd. which manages eight pharmacies in Osaka, Japan. In this article, I give my opinions on the advisable vector of clinical practice for pharmaceutical students and the direction of clinical training in the new educational program.
Key words--pharmaceutical practice; educational curriculum; community pharmacist
YAKUGAKU ZASSHI, 127(2),285-290, 2007
From April 2006, pharmaceutical science departments at Japanese universities switched to a six-year system and the relative weight given to clinical education in pharmaceutical science was given a sharp boost. The model core curriculum created in 2002 emphasizes humanist education and education for communication and is characterized by its commitment to educating students as medical professionals from an early stage. The extended duration of the study period will be used for development of problem-discovering ability and the acquisition of planning and practical abilities for problem-solving. To realize these aims, education based on links with the frontline of medical treatment is necessary and a qualitative improvement in guidance personnel is also desirable. In the Kobe district, volunteers working in pharmacies, hospitals, and universities have come together and formed networks to hold study meetings and undertake and present research. The members of these networks are devoting energies to guiding students in practical work training and at the same time are also undertaking initiatives in the area of lifelong learning for pharmacists. Support for lifelong learning is a mission of the university and Kobe Pharmaceutical University has designed a wide range of programs adapted to learners' needs. From among the learners, new networks will be formed with participation also by volunteers from the local community. In this way, efforts are ongoing to build a new educational structure for the six-year pharmaceutical science course.
Key words--model core curriculum; practical work training; lifelong learning; network
YAKUGAKU ZASSHI, 127(2),291-292, 2007
YAKUGAKU ZASSHI, 127(2),293-300, 2007
Antigen delivery to antigen-presenting cells (APCs) is a key issue in developing effective cancer vaccines. Controlling the tissue distribution of antigens, which are administered in a peptide/protein or DNA form, can increase antigen-specific immune responses, including the induction of cytotoxic T lymphocytes. Heat-shock protein 70 (Hsp70), a member of a highly conserved family of molecular chaperones, forms complexes with a variety of tumor-related antigens via its polypeptide binding domain. Because Hsp70 is taken up by APCs through the recognition by Hsp receptors, such as CD91 and LOX-1, its application to antigen delivery systems has been examined both in experimental and clinical settings. A tissue distribution study revealed that Hsp70 is mainly taken up by the liver, especially by hepatocytes, after intravenous injection in mice. A significant amount of Hsp70 was also delivered to regional lymph nodes when it was injected subcutaneously, supporting the hypothesis that Hsp70 is a natural targeting system to APCs. Model antigens were complexed with or conjugated to Hsp70, by which greater antigen-specific immune responses were achieved. Cytoplasmic delivery of Hsp70-antigen further increased the efficacy of the Hsp70-based vaccines. These findings indicate that effective cancer therapy can be achieved by developing Hsp70-based anticancer vaccines when their tissue and intracellular distribution is properly controlled.
Key words--heat-shock protein; DNA vaccine; pharmacokinetics; antigen delivery; intracellular trafficking
YAKUGAKU ZASSHI, 127(2),301-306, 2007
In cancer immunotherapy with dendritic cells (DCs), which are the most potent antigen-presenting cells, it is important that DCs present peptides derived from tumor-associated antigens on major histocompatibility complex (MHC) class I molecules and activate tumor-specific cytotoxic T lymphocytes. However, exogenous antigens are generally presented on MHC class II but not class I molecules. To develop effective immunotherapy for cancer, an antigen delivery carrier that can induce MHC class I presentation of exogenous antigens is necessary. Several strategies to induce DCs to present exogenous antigens on MHC class I molecules have been reported. First, DCs that phagocytosed a particulate form of antigens present peptides derived from the antigens on MHC class I molecules. Second, DCs that incorporated antigens via certain endocytic receptors such as Fc receptors efficiently present peptides on MHC class I molecules. We combined these two strategies and prepared antigen-containing IgG-conjugated liposomes (IgG-liposomes). In this study, we investigated the feasibility of IgG-liposomes as antigen delivery carriers in cancer immunotherapy with DCs. Immunization of mice with DCs that endocytosed ovalbumin (OVA)-containing IgG-liposomes, but not OVA-containing bare liposomes or soluble OVA, completely prevented the growth of OVA-expressing lymphoma cells. These results suggest that IgG-liposomes represent an efficient antigen delivery carrier for DCs in cancer immunotherapy.
Key words--liposome; dendritic cells; tumor immunotherapy; cross presentation; IgG
YAKUGAKU ZASSHI, 127(2),307-317, 2007
The development of a prophylactic/therapeutic HIV-1 vaccine based on recombinant proteins is needed for the control of the worldwide AIDS epidemic. Subunit protein and peptide vaccines are generally very safe, with well-defined components. However, these antigens are often poorly immunogenic, and thus require the use of adjuvants to induce adequate immunity. Particulate adjuvants (e.g. micro/nanoparticles, emulsions, ISCOMS, liposomes, virosomes, and virus-like particles) have been widely investigated as HIV-1 vaccine delivery systems. Antigen uptake by antigen-presenting cells (APC) is enhanced by the association of the antigens with polymeric micro/nanoparticles. The adjuvant effect of micro/nanoparticles appears to largely be a consequence of their uptake into APC. More importantly, particulate antigens have been shown to be more efficient than soluble antigens for the induction of immune responses. Over the past two decades, we have studied the synthesis and clinical applications of core-corona polymeric nanospheres composed of hydrophobic polystyrene and hydrophilic macromonomers. Core-corona type polymeric nanospheres have applications in various technological and biomedical fields, because their chemical structures and particle size can be easily controlled. In this study, we focused on the development of a HIV-1 vaccine using polymeric nanoparticles. We evaluated the immunization strategies for HIV-1-capturing core-corona type polystyrene nanospheres that would efficiently induce HIV-1-specific IgA responses in female mice and the macaque genital tract. Moreover, based on this research, we attempted to develop novel biodegradable nanoparticles composed of poly (γ-glutamic acid) (γ-PGA) for protein-based vaccine delivery. These HIV-1-capturing nanospheres and protein-loaded γ-PGA nanoparticles have shown unique potential as vaccine carriers.
Key words--polymeric nanoparticles; vaccine; drug delivery system; HIV-1
YAKUGAKU ZASSHI, 127(2),319-326, 2007
The mucosal immune system acts as the first line of defense against microbial infection through a dynamic immune network based on innate and acquired mucosal immunity. To prevent infectious diseases, it is pivotal to develop effective mucosal vaccines that can induce both mucosal and systemic immune responses, especially secretory IgA (S-IgA) and plasma IgG, against pathogens. Recent advances in medical and biomolecular engineering technology and progress in cellular and molecular immunology and infectious diseases have made it possible to develop versatile mucosal vaccine systems. In particular, mucosal vaccines have become more attractive due to recent development and adaptation of new types of drug delivery systems not only for the protection of antigens from the harsh conditions of the mucosal environment but also for effective antigen delivery to mucosa-associated lymphoid tissues such as Peyer's patches and nasopharynx-associated lymphoid tissue, the initiation site for the induction of the antigen-specific immune response. In this review, we shed light on the dynamics of the mucosal immune system and recent advances toward the development of prospective mucosal antigen delivery systems for vaccines.
Key words--mucosal vaccine; drug delivery system; Peyer's patch; nasopharynx-associated lymphoid tissue; fusogenic liposome
YAKUGAKU ZASSHI, 127(2),327-339, 2007
An immunosurveillance system for tumor-associated antigens (TAAs) plays an important role in the elimination of cancer cells during the initial stage. Although cancer immunotherapy targeting TAAs has progressed steadily with the development of various vaccine strategies, excellent therapeutic efficacy, as evidenced by marked tumor regression and complete response, has not been reported in a clinical setting to date. To improve the therapeutic effects of cancer immunotherapy, we are attempting to establish an innovative concept, the “cell delivery system,” capable of better controlling the trafficking and biodistribution of immune cells by applying chemokine-chemokine receptor coupling, which regulates leukocytic migration and infiltration of local sites in the living body. This review introduces our approaches that employ an Arg-Gly-Asp (RGD) fiber-mutant adenovirus vector encoding the chemokine or chemokine receptor gene in cancer immunotherapy.
Key words--cell delivery system; chemokine-chemokine receptor coupling; cancer immunotherapy; adenovirus vector; tumor-infiltrating immune cell; dendritic cell
YAKUGAKU ZASSHI, 127(2),341-351, 2007
Nuclear receptors are ligand-inducible transcriptional factors, and regulate various significant biological phenomena such as cell differentiation, proliferation, metabolism, and homeostasis. By the elucidation of the physiological functions of nuclear receptors, they have become one of the most significant molecular targets for drug discovery in the fields of cancer, autoimmune diseases, and metabolic syndrome. In this study, several novel nuclear receptor ligands have been developed, based on the receptor-folding inhibition hypothesis is discussed. In this hypothesis, the antagonists for nuclear receptors are classified into two types, the misfolding inducers and the folding inhibitors, related to the helix 12 (AF-2 region) conformation of the receptor that is significant for the receptor activation. Then, in order to overcome the resistance in the treatment of prostate tumors with androgen antagonists, the novel folding-inhibitor type antagonists such as isoxazole and pyrrolecarboxamide derivatives were designed and synthesized. Some of them exhibited the androgen antagonistic activities in LNCaP cells with mutated androgen receptor in which conventional antagonists such as flutamide and RU56187 were inactive. The folding-inhibitor type vitamin D3 antagonists (DLAM series) are similarly developed. Further, novel non-seco-steroidal vitamin D3 analogs were designed and synthesized by using a 3,3-diphenylpropane derivative, LG190178 as lead compound. The aza analogs exhibited both potent vitamin D agonistic and androgen antagonistic activities. The results indicate the drug design based on the receptor-folding inhibition hypothesis is efficient in medicinal chemistry of nuclear receptors.
Key words--nuclear receptor; androgen antagonist; vitamin D3; receptor-folding inhibition hypothesis
YAKUGAKU ZASSHI, 127(2),353-357, 2007
Antineoplastic drugs have been shown to exert direct effects on the gut and induce the release of serotonin from the enterochromaffin cells of small intestinal mucosa. It is thought that released serotonin stimulates vagal afferent fibers through 5-HT3 receptors located in the vagal afferent terminals in the gastrointestinal tract and initiates sensory signals to the area postrema and the emetic center, thereby initiating nausea and vomiting. A 5-HT3 antagonist competitively inhibits serotonin at its specific binding sites, 5-HT3 receptors, and thereby elicits an antiemetic effect. Therefore 5-HT3 receptor occupancy of serotonin may be an appropriate indicator of the antiemetic activity of 5-HT3 antagonists. We analyzed 5-HT3 receptor occupancy of serotonin by integrating pharmacokinetic and receptor-binding kinetic parameters based on the receptor occupancy theory to compare the strength of the antiemetic effects of three dosage regimens of azasetron hydrochloride. The inhibitory effects on the binding of serotonin to 5-HT3 receptor of regimen 2 (an intravenous bolus injection of 5 mg of azasetron hydrochloride before and 8 h after chemotherapy) and regimen 3 (an intravenous bolus injection of 2.5 mg followed by 7.5 mg continuous intravenous infusion for 24 h) were longer-lasting than those of regimen 1 (an intravenous bolus injection of 10 mg before the start of chemotherapy). Furthermore, a positive relationship was found between the time of inhibitory effects on the binding of serotonin to 5-HT3 receptor and antiemetic effects of azasetron hydrochloride. From these results, dosage regimens 2 and 3 were considered to be more effective in the long term than regimen 1 in prophylaxis of nausea and vomiting induced by cisplatin.
Key words--serotonin; azasetron hydrochloride; 5-HT3 receptor occupancy; antiemetic effect; dosage regimen; cisplatin
YAKUGAKU ZASSHI, 127(2),359-365, 2007
The antinociceptive and anti-inflammatory properties of Corchorus capsularis leaves chloroform extract were investigated in experimental animal models. The antinociceptive activity was measured using the writhing, hot plate and formalin tests, while the anti-inflammatory activity was measured using the carrageenan-induced paw edema test. The extract, obtained after 72 h soaking of the air-dried leaves in chloroform followed by in vacuo evaporation to dryness, was weighed and prepared by serial dilution in DMSO in the doses of 20, 100 and 200 mg/kg. The extract was administered (s.c.) 30 min prior to subjection to the respective assays. The extract was found to exhibit significant (p< 0.05) antinociceptive and anti-inflammatory activities. As a conclusion, the present study confirmed the traditional claims of using C. capsularis to treat various ailments related to inflammation and pain.
Key words--Corchorus capsularis; chloroform extract; antinociceptive activity; anti-inflammatory activity
YAKUGAKU ZASSHI, 127(2),367-374, 2007
A validated and sensitive spectrophotometric method is developed for the quantitation of nicorandil in pharmaceutical formulations. The method is based on the reduction of nitroxy ethyl group of nicorandil to carbonyl derivative and nitrite ion by Zn/NH4Cl. The nitrite ion undergoes diazotization with sulphanilamide in presence of HCl followed by coupling with N-(1-naphthyl) ethylenediamine dihydrochloride (NED) to form a colored product with λmax at 525 nm. Under the optimized experimental condition, Beer's law is obeyed in the concentration range of 0.4-12.0 μg/ml with molar absorptivity of 1.92×104 l mol−1 cm−1. The statistical analysis of calibration data yields the linear regression equation: A=6.304×10−4+9.13×10−2 C with correlation coefficient of 0.9999. The limits of detection and quantification are 0.05 and 0.15 μg/ml, respectively. The results obtained by the proposed method are acceptable with average recoveries of 100.0-100.1%. The results of the proposed method are compared with those of the reference method by point and interval hypothesis tests, which showed excellent agreement and there is no significant difference in accuracy and precision of methods compared.
Key words--nicorandil; spectrophotometry; N-(1-naphthyl)ethylenediamine dihydrochloride; pharmaceutical formulation
YAKUGAKU ZASSHI, 127(2),375-383, 2007
The phosphodiesterase inhibitor milrinone is usually preferred in patients with pulmonary hypertension and myocardial dysfunction after cardiopulmonary bypass. We investigated the effects of low-dose milrinone on pulmonary hypertension in the immediate pre- and postoperative period. Forty-seven patients were randomized to the control and milrinone groups. All patients had mean pulmonary artery pressure greater than 30 mmHg and pulmonary capillary wedge pressure greater than 20 mmHg and were candidates for mitral valve replacement for rheumatic mitral stenosis. Twenty-four patients received a loading dose of milrinone 25 μg/kg−1 during weaning from cardiopulmonary bypass, followed by a maintenance dose of 0.25 μg/kg−1/min−1 to the end of the surgery. Cardiac output and other hemodynamic variables were noted at induction, weaning from bypass, and postoperative 1 h. Pulmonary artery pressure, capillary wedge pressure, and central venous pressure were significantly lower in the milrinone group during weaning after cardiopulmonary bypass, while other variables were roughly similar. However, patients in the control group required higher doses of vasodilators, inotropes, and antiarrhythmic agents. Mean arterial pressure in the milrinone group was significantly lower at 1 h postoperatively than in the control group; however, the patients did not need many more vasopressors. Fluid restriction and diuretic agent use were more significant in the control group. Systemic arterial hypotension and vasopressor requirements with milrinone use at inotropic doses were not observed at the doses used for the study. A total of 21.7% of the patients in the control group required vasopressors in the perioperative period. Both groups demonstrated similar hematologic variables except that the hemoglobin level in the control group was significantly lower during postoperative days 1 and 7. Low-dose milrinone for a short-term during weaning from cardiopulmonary bypass may be used in patients with mitral stenosis and pulmonary hypertension for its effects on pulmonary artery pressures, less inotropic and vasopressor requirements, and fluid balance.
Key words--milrinone; cardiopulmonary bypass; mitral stenosis; pulmonary hypertension
YAKUGAKU ZASSHI, 127(2),385-388, 2007
Hypercholesteremia is one of the risk factors for coronary artery disease. The present study highlights the efficacy of Ayurvedic herbal formulation Triphala (Terminalia chebula, Terminalia belerica, and Emblica officinalis) on total cholesterol, Low density lipoprotein (LDL), Very low density lipoprotein (VLDL), High density lipoprotein (HDL) and free fatty acid in experimentally induced hypercholesteremic rats. Four groups of rats were employed namely control, Triphala treated, hypercholesterolemia rats (4% Cholesterol+1% cholic acid+egg yolk) and Triphala pre-treatment in hypercholesteremic rats. Results showed significant increase in the total cholesterol, LDL, VLDL, and free fatty acid in hypercholesteremic rats were significantly reduced in Triphala treated hypercholesteremic rats. The data demonstrated that Triphala formulation was associated with hypolipidemic effects on the experimentally induced hypercholesteremic rats.
Key words--cholesterol; lipid profile; triphala
YAKUGAKU ZASSHI, 127(2),389-395, 2007
We studied the bioactivities of constituents from two tropical medicinal plants, Cunila spicata and Hyptis fasciculata. These plants found in Brazil belong to the Labiatae family. Four known compounds obtained from these herbs were identified as 3α, 24-dihydoxylurs-12-en-28-oic acid, betulinic acid, aurantiamide acetate, and aurantiamide benzoate by spectroscopic means. 3α, 24-Dihydoxylurs-12-en-28-oic acid has potent inhibitory activity against Streptococcus salivarius, Streptococcus pneumoniae, Streptococcus pyogenes, and Porphyromomas gingivalis. Aurantiamide benzoate exhibited moderate inhibitory activity against xanthine oxidase. It was clarified that herbs Cunila spicata and Hyptis fasciculata are effective against bronchitis and gout.
Key words--Cunila spicata; Hyptis fasciculata; Labiatae; anti-bacteria; anti-xanthine-oxidase; gout