Renal dysfunction and drug-drug interactions (DDIs) can affect the clearance of various drugs from the body; however, these effects are difficult to sufficiently evaluate in clinical studies. This article outlines our recent approaches to improve the method of evaluating and providing the drug information on the effects of renal dysfunction and DDIs. These approaches aim to optimize the drug regimens of patients with renal dysfunction and to improve the management of DDIs. The renal excretion ratio (RR) is required to predict alterations in drug clearance in patients with renal dysfunction. However, the estimation of RR requires pharmacokinetic information that is not always provided in the Japanese drug package inserts or interview forms.
A systematic approach to predict changes in drug clearance due to DDIs of the cytochrome p450 (CYP) is described. Uniquely, this method uses a small number of parameters, which are only obtained by in vivo DDI studies, i.e., the contribution ratio of CYPs to oral clearance of substrates (CR), the inhibition ratio of inhibitors (IR) or the increase in clearance by induction (IC). Changes in oral clearance for any combination of drugs can be predicted once these parameters have been calculated for each drug. These predictions were used to construct a pharmacokinetic interaction significance classification system (PISCS) to evaluate the clinical risk of DDIs in daily therapy.

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Hazardous drugs such as anticancer drugs have been detected in the hospital environment and urine of health professionals, and threaten the health of these pharmacy practitioners. These contaminations of the drugs result from the leakage of the drug from the vial at least in part when injections are mixed. In order to decrease the leakage of the drug from the vial, we invented a new rubber stopper for the vials of a hazardous drug, which includes binal bottoms composed of two rubber parts. The result showed that the leakage amount from the vial stoppered with the stopper of binal bottoms was approximately one-seventeenth compared with the amount with a standard single bottom stopper. Since the stopper with binal bottoms includes inner space in itself, a liquid absorber can be stuffed in the space. The leakage amount from the stopper including the liquid absorber was approximately one-fiftieth compared with those from the referenced stopper. Furthermore, the technical improvement which reversed the vial stoppered with the stopper upside down during preparation made the leakage amount undetectable. Since the stopper was composed of separate parts, the outer and inner sides of the stopper can be washed and sterilized before assembly. In addition, the stopper is advantageous for the pharmacy practitioners, since the handling of the vial is almost the same as the one operated conventionally. These results suggest that the stopper is a new candidate item for preventing the exposure and contamination of hazardous drugs.

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The preparation of anticancer drugs necessitates careful work because it can involve the handling of hazardous drugs. In actual clinical settings, liquid leakage can occur if the same rubber stopper is penetrated with injection needles multiple times; special attention should be paid to the fact that the first penetration mark can serve as a site of leakage to increase risk.
Hence, we conducted a confirmatory study to detect air leakage, which can be detected with greater sensitivity than liquid leakage, using a number of methods of penetration with a focus on the viscoelasticity of rubber stoppers.
In the second penetration, when the bevel was oriented perpendicularly to the first penetration (AB method), a leakage rate of 100％ (30/30) was obtained with an 18 G regular-bevel needle penetrating the rubber stopper at a short depth of 0.5 mm from the first penetration mark. When the bevel orientation was changed under otherwise the same conditions (CB method), the leakage rate decreased to 37％ (11/30). When the bevel orientation was completely aligned to the orientation of the first penetration (BB method), the leakage rate further decreased to 0％ (0/30). Another important factor was the depth of penetration; under all conditions examined, lower leakage rates were obtained with a 1.0 mm depth than with 0.5 mm.
As a result, in clinical settings involving two occurrences of penetration, two distinct cases were revealed depending on needle bevel positioning: spills and other forms of leakage prevented by the viscoelasticity of the rubber stopper and those promoted by the same.

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Gefitinib is administered daily for the treatment of non-small-cell lung cancer. Gefitinib treatment is often discontinued, however, because of associated adverse reactions such as skin rashes and hepatic disorder. In the present study, we surveyed the implementation status of non-daily administration of gefitinib to control associated adverse reactions particularly at Nagara Medical Center. Of 56 patients treated with gefitinib from March 2005 to May 2011, 21 received non-daily administration of gefitinib. The non-daily administration method used most frequently was once every 2 days. Of the 21 patients who received non-daily administration of gefitinib, 18 could continue treatment because the associated adverse reactions were controlled. The most common reasons for complementation with non-daily administration were hepatic disorder, anorexia, and dermatitis. Of the 6 patients who received non-daily administration of gefitinib because of hepatic disorder, 5 could continue treatment because hepatic disorder was controlled. The levels of aspartate aminotransferase and alanine aminotransferase were significantly lower during non-daily administration than during daily administration of gefitinib. Control of adverse reactions was essential for the continuation of gefitinib treatment over a long period of time. Therefore, non-daily administration of gefitinib is considered a useful treatment option for the control of adverse reactions induced by gefitinib.

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Traditionally, at Nagara Medical Center, a high dose of dexamethasone, which had an antiemetic effect, was administered to non-small cell lung cancer patients treated with combination therapy of carboplatin and paclitaxel administered every 3 weeks (3w-CP therapy) to prevent anaphylactic shock. In this study, we evaluated the adequacy of aprepitant (APR), an antiemetic drug, to 3w-CP therapy with regard to its efficacy, safety, and cost effectiveness in patients treated with 3w-CP therapy. We divided subjects into 2 groups: a non-administered group (that did not receive APR) and an administered group (that received APR). With regard to efficacy, nausea that had developed in the delayed phase and anorexia that had developed in the delayed and post-delayed phases were significantly suppressed by the coadministration of APR. With regard to safety, the incidence of hot flashes, hiccups and hyperglycemia were increased significantly by the co-administration of APR. With regard to cost effectiveness, the total drug cost related to antiemetic therapy was increased significantly by the co-administration of APR. These results suggest that the use of APR during 3w-CP therapy would be beneficial to prevent the impairment of quality of life as well as the losing of motivation for continuing chemotherapy by inhibiting the incidence of nausea, vomiting, and anorexia especially in the delayed and the post-delayed phases although APR increased total drug cost and deteriorated several chemotherapy-induced side effects.

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Hand hygiene at the time of surgery is performed to reduce the number of resident bacteria. Alcohol-based hand-rubbings containing chlorhexidine gluconate (CHG) are widely used as quick-drying antiseptics. Although alcohol-based hand-rubbings containing 0.2 to 0.5 w/v％ CHG had been used, alcohol-based hand-rubbings containing 1 w/v％ CHG were approved in 2010. In the present study, the bactericidal activity of alcohol-based hand-rubbing containing 1 w/v％ CHG for 27 microbes containing clinical isolates was determined. The alcohol-based hand-rubbing containing 1 w/v％ CHG killed all microbes such as Gram-positive and -negative bacteria and fungi within 15 sec. Furthermore, the alcohol-based hand rubbing containing 1 w/v％ CHG killed the antimicrobial-resistant nosocomial pathogens such as vancomycin-resistant Enterococcus faecalis (VRE), methicillin-resistant Staphylococcus aureus (MRSA), extended spectrum β-lactamase (ESBL)-producing Klebsiella pneumoniae, and multidrug-resistant Pseudomonas aeruginosa (MDRP) within 15 sec. Therefore, our data shows that alcohol-based hand-rubbings containing 1 w/v％ CHG are able to kill resident bacteria and pathogenic microbes including antimicrobial-resistant pathogens in a short time.

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This study aimed to assess the efficacy and safety of dipeptidyl peptidase-4 inhibitor sitagliptin in Japanese patients with type 2 diabetes mellitus. A total of 71 patients aged 33-88 years with a mean baseline hemoglobinA1c (HbA1c) of 8.5％ received sitagliptin 50 mg once daily for 6 months. In this 6-month study, sitagliptin reduced potentially the dose of oral antihyperglycemic drugs, reduced significantly HbA1c levels (difference from baseline －1.2％) with 43.5％ of patients achieving HbA1c levels of < 6.9％. Moreover, sitagliptin had a neutral effect on bodyweight, body mass index and lipid metabolism except for high-density lipoprotein, which decreased significantly, and was generally well tolerated with adverse events being mild in severity.
Multiple linear regression analysis indicated that HbA1c, serum creatinine and triglyceride at baseline, and the dose of pioglitazone before the sitagliptin treatment might be predictors of the reduction of HbA1c levels for 6 months.
After 6 months of sitagliptin therapy, in 70％ of patients who received the combination therapy of glimepiride and metformin and were greater than or equal to 65 years old and/or serum creatinine levels of 1 mg/dL, the daily dose of glimepiride was decreased under 2 mg/day, which could prevent severe hypoglycemia events.
In conclusion, in this study, sitagliptin therapy for 6 months improved glycemic control and was well tolerated with adverse events in Japanese patients with type 2 diabetes.

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This study aimed to assess the risk factors of the hand-foot skin reaction (HFSR) caused by sorafenib in patients with advanced hepatocellular carcinoma, and to elucidate the significant factors on management of HFSR. The study subjects were patients with hepatocellular carcinoma treated by sorafenib from June 2009 to Sep 2010. There were 60 male and seven female patients. The Eastern Cooperative Oncology Group performance status (PS) was 0, 1 and 2 in 54, 21 and 1 patients, respectively. Among 67 patients, all grades of HFSR were observed in 50 patients (74.6％), and the maximum grade of HFSR was 0, 1, 2 and 3 in 17 (25.4％), 12 (17.9％), 35 (52.2％) and 3 patients (4.5％), respectively. In the patients characteristics prior to the administration of sorafenib, the incidence of grade 2 or 3 of HFSR was significantly higher in patients with PS 0 than those with PS 1 or 2. And in the daily life factor, the incidence of grade 2 or 3 of HFSR was significantly higher in patients who have risk of “when grasping an item, working or cooking in which pressure is exerted, the occurrence of stimulation by friction and detergent, etc.” than those without these factors. In the multivariate analysis, PS 0 was an independent significant risk factor of HFSR caused by sorafenib. In conclusion, the strict management of HFSR was warranted in patients with good PS, because the incidence of grade 2 or more of HFSR was significantly higher in patients with good PS.

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