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YAKUGAKU ZASSHI, 129(7),783-784, 2009
YAKUGAKU ZASSHI, 129(7),785-792, 2009
The 6-year pharmacology education aims at teaching graduating pharmacists necessary knowledge, techniques and appropriate attitude as medical professionals. To attain these goals, a core curriculum model for pharmacology education has been presented. Based on this model, each university is to draw up an individualized new curriculum. As a result, along with subjects not so familiar to the 4 year education such as Clinical Communication Theory and Medicinal Therapy, long-term practical training is to be implemented. It is essential that pharmacists as medical professionals need to have high ethical standards. As for the core curriculum model, contents concerning ethics have been shown in “A. Learning about Humanism”. In our country, “Pharmacist Ethics Regulation” has been established and serves as a model for standards of conduct for pharmacists. Education of these ethical standards needed by pharmacists is considered necessary and important and should be routinely performed within the 6 years of pharmacology education. Therefore ethics education in our schools is given from the 1st year to the first half of the 5th year. Moreover, it is considered important to learn ethical standards not only through lectures but also through on-site experience such as long-term practical training. All kinds of advice concerning the contents necessary for adequate ethics education and for promoting a suitable image of the faculties in charge are welcome.
Key words--ethics; Pharmacist Ethics Regulation; pharmacology education
YAKUGAKU ZASSHI, 129(7),793-806, 2009
Pharmacological education in Japan has focused less on the cultivation of medical care providers than on fostering personnel who could develop and manufacture medical products. Pharmacists who passed the national board were able to take part in providing medical treatment even if they lacked the knowledge or capabilities required in a clinical setting. Given both this educational background and the systematic problem that there was no division of labor in the pharmacological field, and given that they operated in a work environment where there was almost no opportunity for direct contact with patients, pharmacists for many years lacked self-awareness as persons who handle medical products that can affect human lives, and failed to take full account of their role as administrators of these products. However, there has been a significant change in the role of pharmacists and in the environment in which they operate since the pharmacist discipline was first established. Whereas in the past the job of pharmacists was simply to deal with the materials of medical products, the job has changed to involve dealing directly with patients. Currently, most pharmacists are engaged in work that provides direct support to people. Ethical behavior is demanded in clinical situations that involve people's interaction with one another. The need is urgent, therefore, for us to apply an understanding of ethical theory and conduct systematic case method-based ethical education to cultivate an ethical outlook among pharmacological students and pharmacists.
Key words--moral dilemma; pharmaceutical ethics; ethics education; ethical outlook
YAKUGAKU ZASSHI, 129(7),807-813, 2009
Section A of “The core curriculum model for pharmacy education” (2002)- “Learning about Humanism”- outlines the educational contents for ethics in pharmaceutical departments. People who read this section are likely to conclude that the cultivation of human sensitivity is of prime importance in ethics education in pharmacy. However, if a pharmacist found herself or himself on the horns of a moral dilemma during clinical practice, she/he may discover that human sensitivity alone may not provide the answer. When searching for ethically appropriate conduct in concrete cases, both moral insight and good judgment are necessary. The main contents of ethics education in a pharmaceutical department should be instruction in the ethics of medicine and pharmacy and practical exercises in handling moral dilemmas that pharmacists might encounter in actual situations. “Humanism” implies not only humanitarianism but also anthropocentrism. Plants, animals, and ecological systems are considered to be objects of ethical concern in some contemporary ethics, such as L. Siep's “Concrete Ethics (Konkrete Ethik, 2004)”. The pharmacist's job specifications require her or him to treat laboratory animals ethically and to have environmental consciousness. Humanism-based ethics are too narrow for pharmacy ethics. Pharmacy students should learn a more comprehensive ethics that covers social ethics, bioethics, and environmental ethics. Such ethics and moral training should be given, especially, both before and after long-term practical training in hospitals and pharmacies.
Key words--ethics education; core curriculum model; pharmacy education; humanism; moral dilemma
YAKUGAKU ZASSHI, 129(7),815-820, 2009
We introduce a method for measuring drug-metabolizing enzymes and transporters using real-time one-step RT-PCR with TaqMan probes. This method has the advantages of high sensitivity, simplicity, and linearity of quantification over a wide range of mRNA concentrations, making it particularly suitable for evaluating large numbers of samples, as required in expression profile determinations. We also introduce the use of primary cultures of cryopreserved human and cynomolgus monkey hepatocytes as an enzyme induction model. Furthermore, we introduce the combination of real-time one-step RT-PCR and hepatocytes for evaluating the potency of various drugs in inducing drug-metabolizing enzymes and transporters. We discuss the usefulness of evaluating the gene induction of drug-metabolizing enzymes and transporters following exposure to drugs in human and cynomolgus monkey hepatocytes. The combination of real-time one-step RT-PCR and primary cultures of cryopreserved hepatocytes is useful for preclinical drug evaluation and for screening to evaluate the induction potency of new drug candidates.
Key words--mRNA induction; primary culture; cryopreserved cynomolgus monkey hepatocyte; cryopreserved human hepatocyte; drug-metabolizing enzyme
YAKUGAKU ZASSHI, 129(7),821-827, 2009
β-Lactam antibiotics are used for the treatment of various infections such as intra-abdominal infections and bacterial meningitis. β-Lactams act at the infection site and their antibacterial effects relate to the exposure time during which the drug concentrations remain above the minimum inhibitory concentration for bacteria (T>MIC). The penetration into and exposure of β-lactams at the target sites, such as the abdominal cavity and the cerebrospinal space, are therefore considered to be good indicators of their efficacies. However, earlier clinical research has focused primary on the drug concentrations in plasma. We therefore examined the pharmacokinetics-pharmacodynamics of β-lactams at the target sites, and analyzed them using a population pharmacokinetic modeling and statistical technique called Monte Carlo simulation. This review summarizes our recent findings on carbapenem and cephem antibiotics in peritoneal and cerebrospinal fluids, and our new approaches to personalize and optimize β-lactam dosing regimens based on their site-specific pharmacokinetic-pharmacodynamic profiles.
Key words--β-lactam; population pharmacokinetics; Monte Carlo simulation
YAKUGAKU ZASSHI, 129(7),829-842, 2009
We established dose estimation formulae for renal-excretion drugs using the glomerular filtration rate (GFR), tubular secretion clearance (Sc), and unbound fraction of drug in plasma (fp) as a renal function index of physiological development in neonates and infants not more than 2 years of age. A dose ratio of (DC/DA)=clearance ratio of (CLC/CLA)≅(fpC·GFRC)/(fpA·GFRA) for neonates and infants/adults was applied to drugs with fp·GFR>Sc, while DC/DA=CLC/CLA≅(β·BSAC+fpC·GFRC)/(β·BSAA+fpA·GFRA) was applied to drugs with Sc>fp·GFR using the coefficient of each drug (β) and body surface area (BSA). Validity of the estimation formulae was investigated in drugs with fp·GFR>Sc such as vancomycin (VCM), arbekacin (ABK), fosfomycin (FOM) and norfloxacin (NFLX), and in drugs with Sc>fp·GFR such as digoxin (DGX) and amoxicillin (AMPC).
Key words--dose estimation; glomerular filtration rate; tubular secretion clearance; unbound fraction of drug in plasma; neonate; infant
YAKUGAKU ZASSHI, 129(7),843-849, 2009
To identify the major factors predicting the response to Methotrexate (MTX) therapy in rheumatoid arthritis (RA) patients, we evaluated the relationship between the response to MTX and factors such as the concentration of MTX-polyglutamates (MTX-PGs) in erythrocytes (RBCs), genotypes of thymidylate synthase (TYMS) 5'-UTR (2R/3R) and 3'-UTR (−6/+6), 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, and other patient-related factors. Thirty-six Japanese RA patients were enrolled in this cohort study. The concentrations of MTX-PGs in RBCs were measured, and polymorphisms were determined using PCR-RFLP method. As an indicator of the accumulated capacity of MTX-PGs in the RBCs of each patient, the MTX dose/MTX-PGs (AC-MPG, l/week) was calculated. The response to MTX therapy was assessed using the MTX dose for a ≥50% decrease in CRP level (MTX dose for 50%CRP, mg/week), and the relationships between MTX dose for 50%CRP and various other factors were evaluated using multiple linear regression analysis. The MTX dose was 6.9±0.3 mg/week and the MTX-PGs concentration in RBCs was 97.3±8.1 nmol/l (n=36, blood samples=95, mean±S.D.). The range of MTX dose for 50%CRP was 2.0-13.0 mg/week. Most individual AC-MPG levels showed no change during the evaluation period (coefficient of variation=5.9%). Based on the results of multiple linear regression analysis, AC-MPG, TYMS 3'-UTR (−6/+6), and ESR at the start of MTX therapy were associated with the MTX dose for 50%CRP. AC-MPG, TYMS 3'-UTR (−6/+6), and ESR might be the major predictive factors for the response to MTX therapy in Japanese RA patients.
Key words--rheumatoid arthritis; methotrexate; methotrexate-polyglutamates; polymorphism; clinical trial
YAKUGAKU ZASSHI, 129(7),851-854, 2009
An approach for the preparation of tetrandrine sustained release calcium alginate gel beads was described. In vitro the release of tetrandrine from sustained release dosage forms went on a time of 12 hours which fitted non-Fickian diffusion with matrix erosion significantly. In vivo the plasma concentration of tetrandrine extended preparation given in dogs reached Cmax 2.67±0.69 μg/ml approximately at 5.67±0.58 h after oral administration. The AUC0→24 and AUC0→∞ were 24.64±6.77 mg·h/l and 29.75±5.30 mg·h/l, respectively. The elimination half-time was 9.6±2.40 h. While a favorable correlativity existed between in vitro and in vivo with a correlative coefficient of 0.9798 through linear regression. An investigation on the quantitative relationship between in vitro release and in vivo absorption is a highly necessary work guided for manufacture, optimization and in vivo evaluation of sustained release dosage by means of in vitro release or dissolution tests.
Key words--tetrandrine; calcium alginate; sustained release; in vitro; in vivo
YAKUGAKU ZASSHI, 129(7),855-859, 2009
Antithrombotic therapy has become an important goal for the treatment of ischemic disorders such as cerebral ischemia. Our recent studies found that Z-ligustilide (LIG), a characterized 3-n-alkylphthalide constituent of Radix Angelica sinensis essential oil, exerted significant neuroprotection against cerebral ischemic damage in several animal models. The present study evaluated the antithrombotic activity of LIG and its effect on platelet aggregation and coagulation time. LIG (10 or 40 mg/kg) was intragastrically administered to rats once daily for 3 days. Our results showed that LIG significantly and dose-dependently reduced arterial thrombus weight in an arteriovenous shunt thrombosis in rats and platelet aggregation induced by adenosine diphosphate in rats ex vivo. Meanwhile, LIG at 10 or 40 mg/kg had no significant effect on coagulation time, including activated partial thromboplastin time and prothrombin time, in rats ex vivo. The present study demonstrated for the first time that LIG may exert efficient antithrombotic activity through inhibition of platelet aggregation, without effecting coagulation time of peripheral blood. These data, together with the previously reported neuroprotective effects of LIG on cerebral ischemia, suggest that the antithrombotic activity of LIG may contribute to its potential for the treatment of ischemic diseases, including ischemic stroke.
Key words--Radix Angelica sinensis; Z-ligustilide; thrombosis; platelet aggregation; coagulation time
YAKUGAKU ZASSHI, 129(7),861-869, 2009
Tricyclic antidepressants are particularly useful in the treatment of endogenous depression. Since the 1950s, tricyclic antidepressants (TCAs) have also been used for the treatment of gastric ulcer disease. Many TCAs have been evaluated for their antiulcer effects, but there are presently no data in the literature specifically concerning the antidepressant opipramol. This study aimed to investigate the antiulcer effects of opipramol and to determine its potential relationship with oxidant and antioxidant systems. The antiulcer activities of 25, 50 and 100 mg/kg opipramol have been investigated on indomethacin-induced ulcers in rats. Compared with a control group (indomethacin alone), opipramol decreased indomethacin-induced ulcers significantly at all doses used (52%, 71% and 76% respectively). Opipramol also significantly increased the glutathione (GSH), superoxide dismutase (SOD) and nitric oxide (NO) levels in the stomach tissue, all of which were decreased in the control group given only indomethacin. All doses of opipramol also significantly decreased myeloperoxidase (MPO), malondialdehyde (MDA) and catalase (CAT) levels in stomach tissue compared to the control. In conclusion, the activation of enzymatic and non-enzymatic antioxidant mechanisms, as well as the inhibition of some toxic oxidant mechanisms, appear to play a role in the antiulcer effect of opipramol. This new indication for opipramol prompts a rethinking about the possible clinical application of opipramol, particularly for peptic ulcer patients also presenting depression.
Key words--opipramol; ulcer; antioxidant; indomethacin; rat
YAKUGAKU ZASSHI, 129(7),871-879, 2009
Torasemide is a long-acting loop diuretic that combines the effects of both furosemide and spironolactone. It has been reported that torasemide but not furosemide might attenuate myocardial remodeling accompanied by left ventricular (LV) dysfunction. However, nothing is known about the effect of torasemide, long-acting loop diuretic and spironolactone, an aldosterone receptor antagonist in a rat model of chronic heart failure (CHF). Therefore, we compared the therapeutic effects of torasemide, furosemide and spironolactone on the progression of LV remodeling in a rat model of CHF after experimental autoimmune myocarditis (EAM). EAM was elicited in Lewis rats by immunization with porcine cardiac myosin. Twenty-eight days after immunization, rats were treated for 28 days with torasemide, furosemide and spironolactone. Diuretic actions, heart weight/body weight, heart rate, mean blood pressure, myocardial function by echocardiography, cardiac fibrosis, myocyte diameter and cardiac aldosterone synthetase (CYP11B2) were evaluated. Increased cardiac CYP11B2, severe LV remodeling and resultant cardiac dysfunction was found in CHF rats, whereas decreased cardiac CYP11B2, less remodeling and improvement of cardiac function were found in torasemide- and spironolactone-treated CHF rats. Our results indicate that torasemide and spironolactone treatment significantly improved cardiac function and LV remodeling compared with furosemide treatment.
Key words--torasemide; furosemide; spironolactone; fibrosis; cardiac remodeling; heart failure
YAKUGAKU ZASSHI, 129(7),881-886, 2009
Rapid and accurate determination of total ash and acid-insoluble ash of Chinese herbal medicine would be valuable for the quality illustration because current approaches are laborious and time-consuming. This study investigated the feasibility of near infrared spectroscopy in predicting simultaneously the total ash and acid-insoluble ash contents of Prunellae Spica (one of the most widely used Chinese herbal medicine). Samples were collected from ten different geographic regions and scanned under the near-infrared spectroscopy region (4000-12000 cm−1). Models between the spectral data and the results of reference analysis were developed, and subsequently validated. Calibration models based on partial least squares were accurate for the prediction of total ash (R2=0.914; standard errors of prediction=0.373), and acid-insoluble ash (R2=0.905; standard errors of prediction=0.452).
Key words--near infrared spectroscopy; total ash and acid-insoluble ash; Prunellae Spica; Chinese herbal medicine
YAKUGAKU ZASSHI, 129(7),887-896, 2009
This research intends to clarify the future prospects of hospital pharmacists and also the factors which influence on their practices of blood drawing or injection by conducting research on their consciousness. We studied it using mail-in survey targeting on randomly selected 476 hospital pharmacists. Study items were the attribution of responders, the prospects of their status in 10 years later, and the system and practices which influence on their future prospects (for example, injection, blood drawing during TDM, and etc.). The collection rate of the questionnaire/inquiry sheet was 37.0%. Regarding their future prospects in 10 years, 65.1% of responders answered they felt pessimistic. Among those system and practices which could influence on the prospects, they answered “Pharmacy specialist system” as the most optimistic and “Diagnosis related group /Prospective payment system (Japanese version; DPC)” as the most pessimistic. Regarding the above mentioned future prospects for injection and blood drawing during TDM by pharmacists, we implemented an exploratory data analysis by applying responders' attribution to a logistic model. The result of it showed that the pharmacists who work longer years, are in charge of drug information, and work in a hospital having more corresponding number of sickbeds per pharmacist had more positive consciousness to the above-mentioned practices. We hope this study results will be utilized as objective information in the discussion on the expansion of pharmacists' job categories.
Key words--hospital pharmacist; blood drawing; injection; explorative data analysis; questionnaire