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Additional file 1.

Additional file 1. English translations of the Japanese language questionnaires used for each type of participant. There are three types of questionnaires for registered dietitians, pharmacists with registered dietitians/dietitians and pharmacists without registered dietitians/dietitians. The results in our manuscript are based on the answers to some of these questions.

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Kenji Kabeya,1 Hiroki Satoh,2,3 Satoko Hori,4 Yasumasa Miura,5 Yasufumi Sawada2 1Faculty of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan; 2Laboratory of Drug Lifetime Management, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan; 3Interfaculty Initiative in Information Studies, The University of Tokyo, Tokyo 113-0033, Japan; 4Laboratory of Drug Informatics, Keio University Faculty of Pharmacy, Tokyo, 105-8512, Japan; 5Toho Holdings Co., Ltd, Tokyo 155-8655, JapanCorrespondence: Yasufumi Sawada Tel +81 3-5841-1096Fax +81 3-5841-1097Email sawada@mol.f.u-tokyo.ac.jpBackground: Press-through-package (PTP) sheets are common forms of packaging for medicines in Japan. However, patients and/or pharmacists have reported difficulty in extracting tablets or capsules from some PTP sheets.Objective: We used postmarketing surveillance data to identify the characteristics of PTP sheets that patients and pharmacists feel are “hard to use”.Methods: Marketing specialists of Toho Pharmaceutical Co., Ltd. canvassed patients and medical workers during November 2014–April 2016. Among 1,129 anonymous reports of products being “hard to use”, we identified 39 products with 5 or more reports (Problem group). We compared the sizes of the drugs and PTP pockets, the size ratio, the material used for the front of PTPs, the shape of the pockets, the thickness of the pocket wall, and the force needed to release the drug from the PTP (press-out force: POF) in this Problem group with those in a Control group of 97 problem-free products.Results: Logistic regression analyses revealed that a bigger pocket, a smaller drug size and a smaller drug-pocket size ratio increase the risk of being “hard to use”. Regarding the material, aluminum, PCTFE and PE increase the risk, while PP and PVC decrease the risk. Other factors had no significant influence.Conclusion: Pockets in PTP sheets should be designed so as to minimize the gap between the drug and the pocket, and PP or PVC should be used as the front material instead of aluminum, PCTFE or PE. Our results suggest that marketing specialists can play effective roles in postmarketing surveillance.Keywords: marketing specialist, postmarketing surveillance, PTP, package

Kenji Kabeya,1 Hiroki Satoh,2,3 Satoko Hori,4 Yasumasa Miura,5 Yasufumi Sawada2 1Faculty of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan; 2Laboratory of Drug Lifetime Management, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan; 3Interfaculty Initiative in Information Studies, The University of Tokyo, Tokyo 113-0033, Japan; 4Laboratory of Drug Informatics, Keio University Faculty of Pharmacy, Tokyo 105-8512, Japan; 5Toho Holdings Co., Ltd, Tokyo 155-8655, JapanCorrespondence: Yasufumi SawadaLaboratory of Drug Lifetime Management, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo 113-0033, JapanTel +81 3 5841 1096Fax +81 3 5841 1097Email sawada@mol.f.u-tokyo.ac.jpBackground: Medical tablets and capsules are superior with regard to portability and are the most common dosage form in Japan. However, their large size often results in difficulties during ingestion, sometimes leading to reduced medication adherence.Objective: The authors used postmarketing surveillance data to determine the threshold size of medical tablets and capsules that patients feel are too large to ingest.Patients and Methods: The marketing specialists of Toho Pharmaceutical Co., Ltd. collected opinions of patients and medical workers (November 2014–April 2016). Regarding 709 reports from patients stating that the tablet or capsule for too large for ingestion, a dataset was prepared from package inserts of the reported drugs. Two analyses were conducted: histogram analysis of size distribution and geometric analysis using linear approximation. Six indices of tablet/capsule size were considered: length; length + width; length + width + depth; length × width; length × width × depth; and weight.Results: Histogram analysis revealed that length + width + depth is an excellent index of tablet/capsule size, and negative reports on tablet/capsule size drastically increase when this index is ≥ 21 mm. Geometric analysis using linear approximation also revealed similar results.Conclusion: The threshold size of tablets/capsules that patients feel are too large to ingest is length + width + depth = 21 mm. Therefore, when designing or altering tablets/capsules, if length + width + depth is ≥ 21 mm, the drug should be scored, split into smaller doses, or redesigned as an orally disintegrating formulation.Keywords: marketing specialist, size, shape, tablet, capsule, postmarketing surveillance

The quality of the human-machine interface (HMI) in computerized physician order entry (CPOE) systems is a key factor affecting the error rate in the process of entering medication orders. The operation and functions of the HMI in CPOE systems vary among hospitals, since there is still no standardized HMI. Such differences in the HMI may lead to mistakes ; for example in drug selection and specification of the dosage regimen. The aims of this study were to investigate the usage of CPOE systems in hospitals and analyze the problems with their HMIs, by means of a questionnaire sent to doctors who use them. Replies were received from a total of 227 doctors in 17 hospitals. Nine hospitals used systems only requiring the input of up to two characters to display a list of drugs and 38.5% of their users said that they usually input no more than two characters. For greater reliability, however, CPOE systems should require users to input at least 3 characters to select a branded drug.The questionnaire found that no doctors felt negative towards computer-based dosage checking systems so they should be incorporated into CPOE systems. Among users who were familiar with two or more systems, 80.6% felt that there were significant differences in their operation.In conclusion, we feel that the optimization and standardization of the HMIs of CPOE systems are essential for reducing medication errors arising in their use.

When suppositories were prescribed for pediatric patients, they are inserted into the rectum of the patient by the mother in most cases. Therefore, counselling on the proper use of suppositories is essential. In an attempt to facilitate counselling for drug use, we surveyed via questionnaire how the mothers (ranging 26-39 years) of pediatric inpatients (2.5 months-15 years) of the University of Tokyo Hospital use suppositories. The collection ratio of the questionnaire was 100%(42 of 42). The suppositories exhibiting a systemic action such as antipyretic were used in 80% of patients. The directions for use of suppositories were not well appreciated in 15% of mothers. Twenty percent of mothers experienced trouble when inserting the suppositories into their children, and 54% of the trouble was “discharge after insertion of the suppository” . Most of this discharge occurred within 30 minutes after insertion. When the discharge occurred with a stool, 64% of the mothers coped with the trouble as “suspended the use of the suppository” and 36% as “inserted a new one”, and so on. Our results indicate that the study dealing with the problem of the loss of suppositories from the rectum is essential for the proper therapy of patients.

We investigated the effects of grapefruit juice (GFJ) and orange juice (OJ) on drug transport by MDR1 P-glycoprotein (P-gp) and multidrug resistance protein 2 (MRP2), which are efflux transporters expressed in human small intestine. We examined the transcellular transport and uptake of [(3)H]vinblastine (VBL) and [(14)C]saquinavir in a human colon carcinoma cell line (Caco-2) and in porcine kidney epithelial cell lines transfected with human MDR1 cDNA and human MRP2 cDNA, LLC-GA5-COL150, and LLC-MRP2, respectively. In Caco-2 cells, the basal-to-apical transports of [(3)H]VBL and [(14)C]saquinavir were greater than those in the opposite direction. The ratio of basal-to-apical transport to apical-to-basal transport of [(3)H]VBL and [(14)C]saquinavir by Caco-2 cells was reduced in the presence of MK571 (MRPs inhibitor), verapamil (P-gp inhibitor), cyclosporin A (inhibitor of both), 50% ethyl acetate extracts of GFJ and OJ, or their components (6',7'-dihydroxybergamottin, bergamottin, tangeretin, hepatomethoxyflavone, and nobiletin). Studies of transport and uptake of [(3)H]VBL and [(14)C]saquinavir with MDR1 and MRP2 transfectants showed that VBL and saquinavir are transported by both P-gp and MRP2. GFJ and OJ components inhibited the transport by MRP2 as well as P-gp. However, their inhibitory potencies for P-gp or MRP2 were substrate-dependent. The present study has revealed that GFJ and OJ interact with not only P-gp but also MRP2, both of which are expressed at apical membranes and limit the apical-to-basal transport of VBL and saquinavir in Caco-2 cells.

1 Nateglinide, a novel oral hypoglycemic agent, rapidly reaches the maximum serum concentration after oral administration, suggesting that it is rapidly absorbed in the gastrointestinal tract. The aim of this work is to clarify the intestinal absorption mechanism of nateglinide by means of in vitro studies. 2 We examined the transcellular transport and the apical uptake of [(14)C]nateglinide in a human colon carcinoma cell line (Caco-2). We also examined whether nateglinide is transported via monocarboxylate transport-1 (MCT1) by means of an uptake study using MCT1-expressing Xenopus laevis oocytes. 3 In Caco-2 cells, the transcellular transport of [(14)C]nateglinide from the apical to basolateral side was greater than that in the opposite direction. The uptake of [(14)C]nateglinide from the apical side was concentration-dependent, H(+)-dependent, and Na(+)-independent. Kinetic analysis revealed that the Kt and Jmax values of the initial uptake rate of [(14)C]nateglinide were 448 micro M and 43.2 nmol mg protein(-1) 5 min(-1), respectively. Various monocarboxylates, including salicylic acid and valproic acid, and glibenclamide significantly inhibited the uptake of [(14)C]nateglinide. 4 The uptake study using MCT1-expressing oocytes showed that nateglinide inhibits the MCT1-mediated uptake of [(14)C]L-lactic acid, though nateglinide itself is not transported by MCT1. 5 Taken together, these results suggest that the uptake of nateglinide from the apical membranes of Caco-2 cells is, at least in part, mediated by a proton-dependent transport system(s) distinct from MCT1.