The purpose of this study was to evaluate interactions between antiepileptic drugs in patients with refractory epilepsy. Firstly, to compare the extent of enzyme induction among hepatic enzyme inducers (phenytoin (PHT), phenobarbital (PB), and carbamazepine (CBZ)), we analyzed the effects of these drugs on the pharmacokinetics of clobazam (CLB) and lamotrigine (LTG). Patients using PHT had significantly lower concentration /dose ratios of CLB and LTG than patients using PB or CBZ. However, an additive inducing effect was not observed when PHT was combined with CBZ and/or PB. Secondly, we retrospectively analyzed 2,724 adult patients and 1,826 pediatric patients treated with valproic acid (VPA) to evaluate whether drug interactions affected the incidence of hyperammonemia. We found that the plasma ammonia level increased markedly in a VPA dose-dependent manner. It was significantly elevated in patients who also used hepatic enzyme inducers, and concomitant administration of PHT was associated with the highest risk of hyperammonemia. Thus, PHT strongly induced CYPs and UGTs, and concomitant administration of PHT accelerated VPA metabolism, resulting in an increase of the ammonia level. These findings could be useful for predicting and minimizing drug interactions in patients receiving polypharmacy with antiepileptic drugs.

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Microbiological surveillance in the outpatient service ward and the inpatients' ward of a hospital was conducted to reveal how the specific condition of the hospital - places visited by many outpatients and hospital visitors - affects the distribution of methicillin-resistant Staphylococcus aureus (MRSA). Moreover, given that it has been reported that a type of MRSA produces Panton-Valentine leukocidin (PVL), this study also examined the situation of distribution of this specific type of MRSA.

The colony polymerase chain reaction (PCR) method was applied to the strains collected from different locations of the hospital to identify MRSA and examine whether any PVL genes existed. Furthermore, the identified MRSA strains were classified into hospital-associated MRSA (HA-MRSA) and community-associated MRSA (CA-MRSA) by means of Staphylococcal cassette chromosome mec (SCCmec) typing.

As a result of classification, 70％ of the MRSA identified strains were CA-MRSA. Moreover, CA-MRSA was detected not only from the outpatient service ward but also from the inpatients' ward. These results strongly suggest the possibilities that outpatients bring CA-MRSA into the hospital, and that the behaviors of outpatients in a hospital constitute one of the factors influencing the distribution of MRSA. This study thus proved that strict environment measures are needed more than ever not only in inpatients' wards but also in outpatient service wards. Furthermore 5 strains of PVL were detected. Since only a few reports have been made on PVL, it is necessary to continuously conduct research on it.

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We previously reported that there is a positive correlation between the oral clearance (CL/F) and the apparent volume of distribution (V/F) of the drugs with variable bioavailability (F). The aim of the present study using the computer simulation method was to evaluate the usefulness of the population pharmacokinetic analysis model assuming the covariance of CL/F and V/F(ωcl/f,v/f). The total clearance (CL), volume of distribution (V), and F values in the 1-compertment model were generated for 50 hypothetical subjects, and the peak and/or trough blood concentrations were calculated at steady state following repetitive bolus dosing. The population parameters could be estimated precisely by the covariance model. In addition, the precision of Bayesian analysis using the covariance model was high as compared with that using the non-covariance model. Furthermore, the relative F values estimated from individual CL/F and V/F values (adjusted as mean value = 1) were well correlated with the true F values. These findings suggest that the covariance model assuming ωcl/f,v/f is useful for the population pharmacokinetic analysis of the drugs with variable bioavailability.

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Hypoglycemia with oral hypoglycemic agents (OHAs) is a major clinical problem in patients with type 2 diabetes mellitus. This study evaluated the relationship between OHAs treatment and hypoglycemia using spontaneous adverse event reports database such as the Food and Drug Administration Adverse Event Reporting System (FAERS) and the Japanese Adverse Drug Event Report (JADER) database. We found FAERS to contain 5,821,354 reports from January 2004 to June 2014 and JADER to contain 338,224 reports from April 2004 to November 2014. In FAERS and JADER, the lower limits of 95% confidence intervals of reporting odds ratio (ROR) for hypoglycemia reports were > 1 in most OHAs. The RORs indicate that hypoglycemia is likely associated with glimepiride and glibenclamide in sulfonylurea. The RORs in sulfonylurea and glinide increased with co-administration of alpha-glucosidase inhibitors. We applied the weibull shape parameter to time-to-event data in the JADER database. The shape parameter β of most OHAs were less than 1, which indicates that the hazard was considered to decrease over time. OHAs drug polypharmacy may influence signal strength, and may be associated with hyperglycemia. After considering the causality restraints of the current analysis, further robust epidemiological studies are recommended.

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A “health support pharmacy” is a home pharmacy that provides counseling and support services to help maintain and improve health in the community. In this study, we performed a questionnaire survey on pharmacies in Gifu city to clarify the services provided as “health support pharmacy,” the status and factors of implementation, and the awareness of pharmacy managers about the services. The questionnaire investigated pharmacy attributes, services provided, pharmacy manager's awareness about the services, etc. The results indicate that, regardless of pharmacy attributes, many pharmacies provide“ counseling about the proper use of medicines such as the ways to take and use medicines” and “medication management of the elderly and people requiring care such as the prevention of leaving and forgetting to take medicines” (respectively 72.9% and 71.6%), and pharmacy managers consider that the importance, urgent necessity and feasibility of those services are high. A few pharmacies provide “health support to prevent drug and alcohol abuse and dependence” and “an approach for improvement of the response rate of medical examinations” (respectively 25.3% and 27.1%), which is dependent on pharmacy attributes. Pharmacy managers do not consider that the importance, urgent necessity and feasibility of those services are high. The services provided differ because of different pharmacy attributes and pharmacy manager's awareness, therefore it is important to announce and inform the community about the services so that people can understand and select appropriate services.

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This study investigated whether the review of systems (ROS), an evaluation method that covers all organ systems, improves the quality of pharmaceutical care provided in intensive care units (ICUs). We retrospectively examined patients from the respiratory and emergency intensive care departments admitted to the ICU of our hospital in 2012 (before the introduction of ROS; non-ROS group, n = 93) and in 2014 (after the introduction of ROS; ROS group, n = 65). The number of pharmaceutical interventions and adverse drug events prevented by pharmacists per 1000 patient days were higher in the ROS group (265.7 and 57.8 for the ROS group and 190.8 and 39.9 for the non-ROS group). Pharmacists' proposals were accepted at a significantly higher rate in the ROS group than in the non-ROS group (89.5% vs 72.3%, P < 0.01), and the accepted proposals in the ROS group were implemented for a wider range of organ systems. These results indicate that the ROS was helpful in terms of identifying the patients' clinical manifestations and evaluating the adequacy and safety of medication administered in the ICU, which resulted in improved and precise proposals by pharmacists. Moreover, the ROS approach introduced in this study was considered to be suitable for pharmaceutical activities in the ICU and to contribute to improving the quality of pharmaceutical care.

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This report describes a patient with a gastrointestinal stromal tumor (GIST) of the rectum who developed an erythematous drug eruption and abnormal hepatic function due to imatinib mesilate but was able to continue treatment after desensitization. The patient is a 92-year-old man with a rectal GIST, 94 mm in size. As surgical resection was considered difficult, he was treated medically with imatinib mesilate at a dose of 200 mg/day, half the recommended adult dose. On Day 13 of treatment, a grade 3 drug eruption developed, and abnormal liver function tests were also noted. As the tumor was found to be KIT positive and was thus expected to respond to imatinib, he requested and underwent desensitization to imatinib mesilate. During desensitization therapy, he received imatinib mesilate four times a day at incremental doses, starting at 1 μg, and finished the 10-day course with no adverse drug reactions. A simple suspension method was used to prepare low-dose solutions to reduce the risk of exposure of healthcare professionals to the drug. The trough plasma concentration of imatinib three days after the end of desensitization was 1,560 ng/mL, which is higher than the minimum effective concentration of 1,100 ng/mL. Pharmacists played an important role in preparing dosing solutions, taking the physicochemical properties and biological toxicity of the drug into account in order to achieve the target plasma concentration. Close collaboration with pharmacists is essential to ensure successful desensitization.

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Pegylated liposomal doxorubicin (PLD) is a liposomal formulation of doxorubicin hydrochloride. It was approved for the treatment of ovarian cancer aggravated after chemotherapy. The occurrence of hand-foot syndrome (HFS) associated with the administration of PLD is considered one of the major adverse side effects. The development of Grade2 ≦ HFS (Serious HFS) during the course of PLD therapy calls for dose reduction or discontinuation of subsequent PLD administration. However, the factors that influence the development of HFS are unclear in Japan. Therefore, we focused on the factors influencing the development of HFS in patients receiving PLD therapy for ovarian cancer. The study population consisted of 36 patients. Twenty patients (55.6%) developed HFS while 10 patients (27.8%) developed serious HFS. The patients who did not develop stomatitis during PLD therapy, also never developed serious HFS. In contrast, 37.0% (10/27) of the patients who had developed stomatitis during PLD therapy were reported to have developed serious HFS (P = 0.0390). For the 10 patients with serious HFS, the median time for the occurrence of serious HFS and stomatitis after the initiation of PLD therapy was 3 cycles and 1 cycle, respectively. In conclusion, patients who developed stomatitis during the course of PLD therapy were more likely to develop serious HFS than those who did not. Additionally, stomatitis has been reported to develop prior to serious HFS. Therefore, the occurrence of stomatitis during PLD therapy can aid in the prediction of serious HFS development in future.

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Rapid communication regarding the proper use and safety of dabigatran has indicated the possibility of potentially fatal severe hemorrhagic side effects. We analyzed the safety and risks of hemorrhagic side effects associated with longterm dabigatran administration．We investigated 112 inpatients and outpatients who had received dabigatran between July 2011 and March 2013 for newly acquired non-valvular atrial fibrillation, and obtained information on patient background, dose, use of combined drugs, and side effects. Patients were allocated to groups receiving 220 mg or 300 mg dabigatran, and to groups who developed hemorrhagic or non-hemorrhagic side effects. Patients were significantly older in the 220 mg dabigatran group than in the 300 mg group (P < 0.0001), and Ccr before administration was significantly lower in the former than in the latter (P = 0.0002). The incidence of side effects was 26.8%, gastrointestinal symptoms being the most common at 14.3%. Hemorrhagic side effects occurred in 11.6% of patients, and all involved minor bleeding. The number of patients receiving antiplatelet drugs was also significantly higher in the hemorrhagic side effects group than in the non-hemorrhagic side effects group (P = 0.04). We conclude that the dose of dabigatran should be selected based on age and renal function due to the prevention of severe side effects for long periods. Although all hemorrhagic side effects involved minor bleeding, it is considered advisable to be aware of antiplatelet drugs used in combination.

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Chemotherapy has shifted from hospital care to ambulatory care. To ensure safe and certain ambulatory chemotherapy, a community pharmacist is expected to feed back information about the medicine-taking situation at home to hospital staff.
In this study, we estimated the establishment of a tracing-report system using telephone communication, with the aim of organizing concerted intervention among physicians, hospital pharmacists and community pharmacists.
Among the outpatients who were treated S-1 from June 1, 2014 to April 30, 2015, 25 patients agreed to receive an inquiry call at home. Medication compliance and the number of unused medicines were monitored by a community pharmacist and this information was reported to a physician via a hospital pharmacist by using ‘The Tracing Report.’ The names of diseases were confirmed in 24 patients, and the chemotherapy method was confirmed in 23 patients. Physicians accepted recommendations from pharmacists in 30 out of 47 cases.
In conclusion, the results suggest that an inquiry call from a community pharmacist during ambulatory care, verifying their medicine taking situation, contributed to safe chemotherapy.

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