In order to improve the adherence to treatment with orally available commercial medicine, we newly developed a method of evaluating the bitterness intensity of various medicines quantitively by a taste sensor. Our evaluation target was amino acid products such as Aminoleban^®EN, basic/acidic drugs, orally available antibiotic drugs, Chinese medicines, and orally disintegrating tablets (ODT). We were also able to find food/drink capable of reducing the bitterness of various medicines such as topiramate pediatric drugs by using various types of sensor probes. The research results and proposals described in our articles are expected to give useful information to improve the adherence to treatment with various orally available medicines.

Next, we focused on the incompatibility of ceftriaxone sodium with calcium-containing products using the ionic product of precipitation. First, appropriate volumes of 2％ (w/v) calcium chloride solution were added to 0.4-2 mg/mL ceftriaxone isotonic sodium chloride solution, to make solutions with a final calcium ion concentration of 1.25 mmol/L. After agitation and storage at 37℃ for 24 h, the number of insoluble microparticles with a diameter of less than 10 μm in a mixed solution determined using a light obscuration particle counter, was increased when the ceftriaxone concentration was > 0.8 mg/mL. Nevertheless, precipitation was not recognized by visual observation. The Saturation Index (defined as the ratio of the ionic product to the solubility product constant) of the prepared mixed solution was 1.1. These results suggest that ceftriaxone should not be co-administered with calcium-containing products even if no precipitation is observed visually.

Third-generation oral cephalosporins are broad-spectrum antimicrobial agents and constitute one of the most used antibiotic classes in Japan. In the “National Action Plan on Antimicrobial Resistance (AMR),” the Japanese government declared implementation of efforts to reduce the use of oral cephalosporins by 50％ by 2020, compared to 2013. Antimicrobial resistance generally occurs due to inappropriate use or low-dosage exposure to antibiotic agents. Therefore, the choice of appropriate antibiotics is essential for implementing antimicrobial stewardship. To evaluate the prophylactic effects of antibiotics in impacted mandibular third molar surgery, we compared the rate of surgical site infection (SSI) in patients who were administered cefcapene-pivoxil (CFPN-PI) orally with that in patients who received amoxicillin (AMPC) orally. We conducted a retrospective study by reviewing the medical charts of patients from Hokkaido University Hospital from April 2016 to March 2017. The patients evaluated were classified into two groups: the AMPC group (n = 164) and the CFPN-PI group (n = 129). The SSI ratio of the CFPN-PI group was significantly higher than that of the AMPC group (CFPN-PI group, 11.6％ (15/129); AMPC group, 2.4％ (4/164); P = 0.002). Multivariate logistic regression analysis demonstrated that “use of CFPN-PI for prophylactic treatment” and “hospitalization after surgery” were independent factors related to the onset of SSI following impacted mandibular third molar surgery. These results demonstrated that AMPC was more effective than CFPN-PI in the prevention of SSI after impacted mandibular third molar surgery, and its regulated dosage can effectively contribute to the optimal use of antimicrobial prophylactic treatment.

Transcatheter arterial chemoembolization (TACE) for the administration of cisplatin (CDDP) has been established as a standard treatment for unresectable advanced hepatocellular carcinoma (HCC) in Japan. However, no antiemetic therapy for nausea and vomiting caused by TACE has been established. The use of dexamethasone as an antiemetic drug is associated with concerns that reactivation of hepatitis B virus (HBV) may occur in patients with HCC caused by persistent HBV infection. This study was conducted in 100 patients (202 courses) with HCC who received TACE using CDDP, and compared the safety and efficacy of granisetron for 3 days and palonosetron for 1 day in antiemetic therapy without dexamethasone. The total control rates of the granisetron group and the palonosetron group in all courses were 55.4％ and 74.5％ (P < 0.01) in the acute phase, 47.8％ and 65.5％ (P < 0.05) in the late phase, and 42.4％ and 58.2％ (P < 0.05) in the overall phase, respectively. The palonosetron group had significantly better antiemetic therapy than the granisetron group. Constipation was significantly more frequent in the granisetron group (54.3％) than in palonosetron group (39.1％) (P < 0.05), but its severity was only grade 2 or less. The results of this study suggest that a single dose of palonosetron is effective as a preventive measure against nausea and vomiting due to TACE using CDDP.

Research into the validity of one-dose packaging of hygroscopic medicines is based on the results of non-packaged medicines or medicines stored in packaging containing only one kind of tablet. Although several medicines are clinically prescribed, the stability of several hygroscopic medicines in one-dose packages is unknown. In this study, hygroscopic medicines Glucobay^® tablets, Phosblock^® tablets, and Magmitt^® tablets were packaged using cellophanepolyethylene laminate, and stored at room temperature and under room humidity conditions for 21 days. The medicines were evaluated for their weight change and hardness, along with a visual inspection. Glucobay^® tablets were significantly heavier due to moisture absorption, their hardness was reduced, and visual inspection revealed differences. In contrast, the packaging of Glucobay^® tablets with Phosblock^® tablets or Magmitt^® tablets inhibited moisture absorption of Glucobay^® tablets, and changes in hardness and visual appearance were suppressed. Packaging of Phosblock^® tablets was more effective than packaging of Magmitt^® tablets, because Phosblock^® tablets are highly absorbent compared with Magmitt^® tablets. In addition, the prevention of moisture absorption of Glucobay^® tablets was correlated with the number of Phosblock^® tablets in one-dose packages. In conclusion, for evaluation of hygroscopic tablets stored in one-dose packages, it is appropriate that analyses are performed using combinations of medicines that are clinically prescribed.

Levetiracetam (LEV) is a renal excretory drug, whose dosage is adjusted according to renal function. There are several case reports on acute kidney injury (AKI) due to LEV. The aim of this study was to determine the risk factors for AKI in patients receiving LEV. All inpatients aged 18 and over who had started to receive LEV between January 1 and December 31, 2017 were enrolled in this study. Obesity, a history of hypertension, hyperuricemia, diabetes, or heart disease, concomitant dehydration, infection, or impaired consciousness, use of antibiotics, nonsteroidal antiinflammatory drugs, or antihypertensive drugs, body mass index, age, and renal and liver functions before LEV administration were examined retrospectively. The study sample consisted of 217 patients, 18 of whom had AKI. All 18 AKI patients had a history of hypertension. A binomial logistic regression analysis showed that a history of diabetes and concomitant infection were significantly associated with the development of AKI. These results suggest that the risk of AKI in patients receiving LEV is increased by having a history of hypertension accompanied with diabetes and infection. Recognition of these factors and further enhancement of renal function monitoring are needed.

Co-administration of methotrexate (MTX) and proton pump inhibitors (PPIs) is reported to increase serum MTX concentrations in patients receiving high-dose MTX therapy. However, the range of MTX high dosage is wide. We attempted to clarify the effects of PPIs co-administration on the elimination of MTX at the fixed dose of 1 g/m² in a retrospective cohort study of 46 patients with hematological malignancies who underwent a total of 91 cycles of chemotherapy. Data on gender, age, concomitant drugs, and laboratory test results were analyzed. The median and first to third quartile of MTX concentrations with and without PPI co-administration at 24, 48, and 72 h postdosing were 17.42 (14.75 - 22.34) vs 19.96 (14.97 - 23.10) (P = 0.627), 0.25 (0.15 - 0.42) vs 0.34 (0.17 - 0.96) (P = 0.159), and 0.06 (0.04 - 0.10) vs 0.07 (0.04 - 0.23) (P = 0.357), respectively. No statistically significant differences were observed in the number of patients with delayed MTX elimination with each PPI. Nausea (all grades) was significantly less frequent in patients receiving PPIs (38％ with vs 68％ without, P < 0.05). Multivariate analysis results indicated that differences in creatinine clearance (24 h after MTX administration and baseline) (OR, 0.92; 95％CI, 0.88 - 0.97), gender (OR, 4.95; 95％CI, 1.55 - 15.81), and age (OR, 1.04; 95％CI, 1.00 - 1.08) were risk factors for delayed MTX elimination. These findings suggest that PPI co-administration does not affect MTX elimination at the dose of 1 g/m², but could relief nausea associated with chemotherapy.

As many generic medications, including orally disintegrating (OD) tablets, are now commercially available, including glimepiride, the third-generation sulfonylurea drug, it is important to provide information regarding their formulation for adequate medical care. In this study, we conducted a tube passing test and a recovery rate measurement in order to investigate the applicability of a simple suspension method recommended for medication support of glimepiride (JP XVII), which includes the brand name glimepiride (Amaryl^®) and 27 generic medications. In addition, a dissolution test for each drug was conducted with comparisons between formulations. The results showed that five companiesʼ generic medications required an additional five minutes suspension time and one companyʼs tablet needed to be cracked with pliers in advance to facilitate the simple suspension method. After the tube passage test, no significant difference was found in any of the generic medications in comparison with the brand name medication in terms of the recovery rate of a drug containing glimepiride. The dissolution behavior showed that generic medications for three companies did not comply with the dissolution requirements. This result shows that the brand name medication and all generic medications are available for use according to the simple suspension method. However, because these medications had different disintegration and suspension times, it is necessary to confirm the disintegration and suspension properties of each medication. This information should be described in the Drug Interview Form or the like.