In 2003, Meijo University has developed a new program to train students in master's degree in the field of clinical practice. This new curriculum has three big pillars of educational goal: Problem-Based Learning (PBL), communication skill and clinical pharmacy practice training. Before exposing students to clinical training, they must learn first how to solve various patients' problems through PBL and enhance their communication skill. To provide a clinical environment, education and training, the Faculty of Pharmacy cooperated with the School of Medicine of Fujita Health University. Master's students together with other members of the healthcare team observe patient's disease state and most especially monitor pharmacotherapy. At first, students will be trained for a month at the pharmacy division and experience one week-nursing job. Next, they will be trained at the clinical divisions such as General Internal Medicine, Cardiology, Endocrinology, Gastroenterology, Respiratory Medicine, Hematology, Chemotherapy, Gastroenterological Surgery, Psychiatry, and Emergency Unit. Students rotate three-month training on four clinical divisions during one year. The head physicians of the medical department hold concurrent post as professors and share responsibility with the pharmacy faculty in training the students. To have its venue where students, faculty and physicians conduct their discussion on clinical cases, a pharmacy satellite seminar class room was set up at Fujita Health University hospital. Through this, pharmacy students and faculty had more opportunities to exchange knowledge on medicine and pharmacy. Master's students are expected to acquire professionalism, ethical knowledge and pharmaceutical care skills through the clinical pharmacy practice program.
Drugs have to be absorbed through various mucosal membranes including the gastrointestinal (GI) mucosa to express their systemic effects. However, there are a number of factors governing mucosal absorption of drugs and, for drugs with low bioavailability, the reason for the low bioavailability should be analyzed and clarified to improve the bioavailability. This review deals with the results of our biopharmaceutical studies to analyze factors controlling drug absorption and our trials to improve the absorption, especially from the GI tract and oral cavity.
Because it is difficult to achieve local drug activity following administration by the conventional intravenous and oral routes, I sought to develop a new route of administration utilizing drug absorption from the liver surface in order to target that organ. Although direct application to the liver surface should yield local drug distribution, drug absorption from the liver surface has not been reported in the literature. Therefore, we analyzed, as a model, the efficiency of absorption of several organic anions and dextrans of various molecular weights following application to the rat liver surface in vivo using a cylindrical diffusion cell. Each compound appeared gradually in the plasma, followed by excretion into the bile and/or urine, indicating the possibility of drug absorption from the liver surface. The absorption process from the liver surface may not involve a specific transport system because dose and transport inhibitors had no detectable effect. In addition, molecular weight was found to be a determinant of absorption through the liver surface. The efficiency of targeting desired region in the liver was enhanced considerably by application to the liver surface, compared to intravenous administration. Moreover, I have obtained several promising results from the application of this new drug delivery system to anticancer drugs and gene therapy. On the other hand, I have also clarified the characteristics of drug absorption from the surfaces of the kidney, stomach, cecum and small intestine, and plan to apply the physiological findings to other fields.
In the post-genomic era, cytokine or antibody therapy has received attention for advanced drug therapies. Indeed, attempts are being made to develop a wide variety of therapeutic proteins for diseases including cancer, hepatitis and autoimmune conditions. Unfortunately, however, the utilization of bioactive proteins in clinical practice is often limited because of their inherent instability and pleiotropic actions in vivo. Our laboratory aims to overcome two major problems, details of which will be addressed in separate sections to follow. (i) Development of a powerful system to rapidly create functional mutant proteins (muteins) with enhanced receptor affinity and receptor specificity using a phage display technique (biological DDS). (ii) Establishment of a novel polymer-conjugation system to dramatically improve in vivo stability and selectively of bioactive proteins (polymeric DDS). We are currently attempting to combine both approaches to create a protein-drug innovation system to further promote pharmaco-proteomic-based drug development. In this review, we will describe DDS-based technology for creating functional mutants for advanced medical applications, using tumor necrosis factor-alpha (TNF) as an example.
This study was designed to determine the effects of Wu-Zi-Yan-Zong-Fang on amyloid-β25-35-induced cognitive deficits in rats and neurotoxicity in pheochromocytoma cells and the possible mechanism of action. In vivo studies showed that Wu-Zi-Yan-Zong-Fang significantly ameliorated the spatial memory and retention deficits, decreased acetylcholinesterase activity, and increased acetylcholine content caused by intracerebroventricular injection of amyloid-β25-35. In vitro results showed that Wu-Zi-Yan-Zong-Fang increased cell viability and the activity of superoxide dismutase and catalase and decreased the release of lactate dehydrogenase and the level of malondialdehyde. Wu-Zi-Yan-Zong-Fang also significantly reduced the percentage of apoptotic cells and blocked the increase in the intracellular concentration of Ca2+. These data suggest that Wu-Zi-Yan-Zong-Fang has potent protective effects for the treatment of Alzheimer's disease in future.
The control of delayed emesis is very important in order to continue ambulatory chemotherapy. We performed retrospective study that examined the efficacy of preventive treatment (granisetron+dexamethasone+domperidone) for delayed emesis induced by FOLFOX4 chemotherapy for advanced and recurrent colorectal cancer. The subjects were 92 patients who underwent FOLFOX4 chemotherapy at the Cancer Institute Hospital of JFCR (group with preventive treatment: 50, group without preventive treatment: 42), and the observation period was set as the 1st-9th cycle. The complete nausea inhibition rate was 50.0% in the group with and 21.5% in the group without preventive treatment, showing a significantly higher inhibition rate in the former (p=0.0047). The complete vomiting inhibition rates were 86.0% and 66.7%, respectively, again showing a significantly higher inhibition rate in the former (p=0.015). On multivariate analysis (multiple logistic analysis), the development of nausea/vomiting and preventive treatment for delayed emesis were significantly associated, showing that the treatment was an independent preventive factor. All adverse reactions induced by preventive treatment were mild, suggesting no safety-related problem. These findings suggested the usefulness of preventive treatment with granisetron, dexamethasone, and domperidone for FOLFOX4 chemotherapy-induced delayed emesis.
Hachi-mi-jio-gan extract (Harncare®; HE), a galenical produced from the traditional Chinese herbal mixture Ba-Wei-Die-Huang-Wan, has been reported to improve lower urinary tract symptoms (LUTS) in patients. The present study was undertaken to clarify the pharmacological effects of HE on smooth muscle contraction and on pharmacologically relevant (muscarinic, 1,4-DHP and purinergic) receptors in the rat bladder. Additionally, the effects of repeated oral treatment with HE on the hepatic cytochrome P-450 (CYP) and on blood biochemical values in rats were examined. HE (10 mg/ml) inhibited significantly the acetylcholine-induced contraction of isolated rat bladder strips. The pD2 value in the absence and presence of HE (10 mg/ml) was 5.14±0.16 and 3.99±0.17, respectively. HE (0.1 to 10 mg/ml) inhibited the specific binding of [N-methyl-3H]scopolamine methyl chloride ([3H]NMS), (+)-[3H]PN 200-110 and αβ-methylene ATP [2,8-3H]tetrasodium salt ([3H]αβ-MeATP) in the rat bladder in a concentration-dependent manner. The respective IC50 values were 6.85±0.94, 7.08±0.72 and 1.34±0.23 mg/ml. Based on IC50 values, the binding activity of HE for purinergic receptors was shown to be significantly (about 7 times) greater than that for muscarinic and 1,4-DHP receptors. Repeated oral administration of HE (10, 30 and 100 mg/kg/day) for 4 weeks had little or no effect on the level and activity of hepatic CYP or on blood biochemical values in rats. In conclusion, the present study has shown that HE exerts significant binding activity for pharmacologically relevant receptors in the rat bladder and a relaxant effect on the acetylcholine-induced contraction of isolated muscle strips. HE seemed to exhibit little pharmacokinetic interaction with drugs.
In April 2008, a system of special health checks and health guidance was initiated with the aim of identifying people with metabolic syndrome (visceral fat syndrome) and pre-metabolic syndrome. In this study, we investigated the relationship between health check results and abdominal circumference in 632 university faculty members. The standard value for abdominal circumference in women (≥90) is set higher than that for men (≥85). When this standard value is used, only 7.4% of women may be able to receive special health guidance. In the future, a follow-up survey of female subjects focusing on the difference in the standard value and an evaluation of its relationship with lifestyle-related diseases will probably be necessary. In the present study, significant positive correlations were seen between abdominal circumference and GPT and γ-GTP, which are related to hepatic function, and between abdominal circumference and uric acid levels in males. These results indicate the possibility that abdominal circumference is related to alcohol intake. In addition, white blood cell count, red blood cell count, hemoglobin level, and hematocrit level were significantly higher in subjects with large abdominal circumference, and there were differences in hematopoietic function. There have been virtually no studies on the relationship between visceral fat and hepatic and hematopoietic functions, and a follow-up study of the present subjects in the future may shed new light on risk factors for various diseases with abdominal circumference as an indicator.
Voacanga africana (Apocynaceae) is a small tropical African tree. The root bark and seeds of this tree contain a number of alkaloids, including ibogaine (a hallucinogenic/aphrodisiac compound in bark), tabersonine (a major constituteent of seeds) and other voacanga alkaloids, traditionally used in Africa for religious purposes. Recently, some kinds of products containing this plant (root bark and seeds) have been distributed in the drug market in expectation of its hallucinogenic/aphrodisiac effects. There has been no report that has discussed quantitative analyses of these alkaloids in the products and their botanical origins. In this study, to investigate the trend of such a non-controlled psychotropic plant of abuse, a simultaneous analytical method was developed using LC/MS for the voacanga alkaloids including ibogaine and tabersonine in the commercial products of V. africana. Moreover, the botanical origins of these products were investigated by DNA analyses. As a result of the LC/MS analyses, the products were classified into two chemical types; an ibogaine-type and a tabersonine-type. The samples of the ibogaine-type contain ibogaine (0.05-0.6%) and other voacanga alkaloids; voacamine, voacamidine and voacangine, while those of the tabersonine-type mainly contain tabersonine (0.6-1.6%). The sequence analyses of chloroplast DNA, trnL-F region suggested that most of the products were derived from V. africana or closely related plants. They were classified into four genotypes based on nucleotide sequence of the trnL-F IGS region. The proposed methods of chemical and DNA analyses would be useful for investigating the trend in the distribution of the products of V. africana.
To ascertain the prevalence of allergy symptoms and consumer measures for eye, nose, skin, food, and asthma by prefecture. The self-evaluation questionnaire was mailed to 100,000 subjects throughout Japan by the OTC distribution network of Fujiyakuhin Co., Ltd. The prevalence of allergy symptoms for eye, nose, skin, food, and asthma was 17.3, 26.7, 14.5, 4.5, and 5.4%, respectively. These values were comparable with those of previous studies. The ratio of consultation behavior in respondents reporting allergy symptoms was estimated to be 26.4-82.1%. The usage rate of OTC drugs in respondents reporting non-consultation and the rate of combined use of prescription and OTC drugs were 2.9-51.1% and 7.0-44.1%, respectively. The positive likelihood ratio for subjective allergy in persons having an allergy history of “both parent and child” was 13.9, and this ratio for subjective child allergy in persons having an allergy history of “either parents” and “both parents” was 4.39 and 15.7. The relationship between consumer measures and the allergy history of subjects and families was observed in various combinations. In this study, the allergy prevalence of eye and food not reported in a previous study was estimated. Furthermore, it appears that there are points which make one think anew about the allergy information offered to consumers and patients by both OTC manufacturers/distributors and pharmacists.
Applicability of atmospheric pressure photoionization mass spectrometry (APPI-MS) to the analysis of hydrophilic drugs was investigated. Model compounds with moderate to high hydrophilicity was tested, and most compounds showed good signal response with APPI-MS, but some compounds with high molecular polarity like folic acid derivatives, glycoside and some nucleic acid derivatives showed very weak signal responses. By observing relationship between the compounds' physicochemical properties and APPI response, compounds with higher lipophilicity and less polar surface area were considered to be advantageous for APPI-MS. To provide information for applying APPI-MS to the analysis of hydrophilic drugs, approximate lower limit of calculated octanol-water partition coefficient and the higher limit of the number of oxygen and nitrogen atoms were determined to be -0.95 and 6, respectively. These APPI-applicable model compounds could be analyzed by reversed-phase high performance liquid chromatography-APPI-tandem mass spectrometry.
Methotrexate (MTX), i.e., MTX-polygluatmate 1 (MTX-PG1), exerts its antirheumatic effects mainly by ≤6 (MTX-PG2-7) via folypolyglutamyl synthase in cells. The authors developed a new method using fluorescence polarization immunoassay to determine MTX-PG1-7 concentrations in erythrocytes (RBC). MTX-PG2-7 in RBC of rheumatoid arthritis (RA) patients receiving MTX was converted to MTX in the presence of plasma γ-glutamyl hydrolase and mercaptoethanol at 37°C. The MTX in RBC was extracted in a perchloric acid deproteinization step then on a solid-phase extraction column. The concentration of MTX was measured by TDX analyzer. The mean MTX recovery rate was 76.1% (n=8). The intraday and interday coefficients of variation were <11.3% (n=8) and <12.4% (n=3), respectively, at low and high concentrations (30-300 nmol/l). The calibration curve was linear over the range 30-300 nmol/l. The total concentration of MTX-PGs (mean±S.D.) in RBC obtained from 95 Japanese RA patient blood samples was 97.3±8.1 nmol/l for the MTX dose of 0.13±0.05 mg/week/kg. This newly developed method for the quantification of MTX-PGs in RBC is sensitive and accurate and can be applied for routine monitoring of MTX therapy in RA patients.
Lithium carbonate is used to treat depressive episodes in patients with manic depressive disorder. Lithium toxicity is closely related to serum levels of lithium, and can occur with doses of lithium carbonate close to those used in therapy. Herein we report a case in which pharmaceutical intervention led to a patient's early recovery. The patient was hospitalized with a complaint of dyspnea, and clinical findings revealed signs of bradyarrhythmia. We investigated the medications the patient brought with him and the record of his prescribed medications in his drug notebook. From this we found that he had been taking imidapril (an angiotensin-converting enzyme inhibitor) in addition to lithium carbonate, and surmised that lithium toxicity may have occurred from the drug interactions between the lithium carbonate and imidapril in this patient. To prevent the level of toxicity from advancing, we proposed to the physician in charge that the patient's serum lithium levels be measured immediately and that all drugs be discontinued. By receiving care centered on detoxification, the patient avoided measures such as placement of a permanent pacemaker and thereby made a quick recovery from a dangerous state. This is a good example of a case in which pharmaceutical intervention improved the patient's quality of life (QOL) and contributed to conserving limited medical resources. As shown by this case, regular checks of patients' current medications and drug notebooks at the time of hospitalization are an effective means of implementing pharmaceutical interventions that can contribute to medical care.