Osteoarthritis is the most common joint disorder worldwide and one of the leading causes of disability in the elderly. We have reported that the novel sodium hyaluronate derivative chemically linked with diclofenac (DF), diclofenac etalhyaluronate (SI-613), exerted a potent and long-lasting analgesic effect in experimental arthritis models. In this study, we evaluated the properties of residual SI-613 in the knee joint after an intra-articular (IA) administration. After IA administration of fluorescent labeled SI-613 (FA-SI-613) or fluorescent labeled hyaluronic acid (FA-HA) to rabbits, fluorescence intensities in the synovial membrane and cartilage were higher in the FA-SI-613 group until 7 d after administration than in the FA-HA group. After IA administration of radiolabeled SI-613 (¹⁴C-SI-613) to rabbits, the radioactivity remained in the joint cavity and the joint tissues such as synovial membrane and cartilage until 84 d after administration. This residual radioactivity was identified mainly as HA linked with DF, since ¹⁴C-SI-613 was labeled at the benzene ring of DF and since more DF-linked HA oligomer was detected on metabolite analysis than free DF in the synovial membrane and synovial lavage fluid up to 28 d after administration. These results suggested that intra-articularly administered SI-613 remained for a longer time in the joint as HA linked with DF than when HA was administered. Therefore, SI-613 was considered to prolong the pharmacological effects of both HA and DF by remaining in the joint as HA linked with DF.

Additional fees for ward pharmacists' services have been valued for hospitals in Japan. However, the calculation period for services provided to inpatients in the psychiatric ward is limited to 8 weeks. This study aimed to reveal the need for the services of pharmacists in the hospital ward for inpatients hospitalized for >8 weeks in the psychiatric ward. Patients who were hospitalized in the psychiatric ward from September 2016 to February 2017 were analyzed retrospectively. The pharmacists suggested prescriptions for inpatients admitted for >8 weeks, similar to those admitted for <9 weeks, and this supported pharmacotherapy without exacerbating patient outcomes. Moreover, significant decreases in benzodiazepine doses were found between the prior and post prescription suggestions of the pharmacist for inpatients >8 weeks of admission. Healthcare expenditures were also reduced. These results suggest that the prescriptions suggested by pharmacists for inpatients admitted for >8 weeks in the psychiatric ward were useful. In conclusion, our findings show that ward pharmacists' services were necessary not only for the inpatients hospitalized for <9 weeks, but also for those hospitalized for >8 weeks.

Riluzole, a drug used in the management of amyotrophic lateral sclerosis (ALS), is associated with a high incidence of liver failure. It is imperative to determine risk factors and severity of liver injury in patients taking riluzole to devise an appropriate treatment regimen. We, therefore, studied risk factors for liver injury in ALS patients who were prescribed riluzole at Kitasato University East Hospital from 1999 to 2015. Of the 222 patients enrolled in this study, 113 and 109 patients were diagnosed with mild to moderate (grade 1 or 2) and without (grade 0) liver injury, respectively. Prediction of risk factors was determined using binary logistical regression analyses. The results showed that 50.9% (n=113) of ALS patients developed mild to moderate liver injury; 71.7% and 53.1% of patients were concurrently using CYP1A2 inhibitors (p=0.005) and diclofenac (p=0.032), respectively; 55.8% of patients with liver injury had a history of smoking (p=0.011). Multivariate analyses revealed that the concurrent use of CYP1A2 inhibitors [odds ratio (OR) 2.152, 95% confidence interval (CI) 1.225-3.780, p=0.008] and history of smoking (OR 1.938, 95% CI 1.125-3.340, p=0.017) were independent risk factors for liver injury in patients receiving riluzole. In conclusion, treatment of ALS patients with riluzole, smoking habits, and concurrent use of CYP1A2 inhibitors are independent liver injury risk factors. Further studies on liver injury are warranted in ALS patients treated with riluzole to comprehensively understand the underlying mechanisms of riluzole-associated liver toxicity.

Dry powder inhalers (DPI) are frequently used by asthmatic patients, and the usage rate increases every year. The pharmacists at our hospital provided initial inhalation instructions on how the inhaler must be used but did not elaborate on the cleaning of the device. Therefore, the cleaning status of the inhaler is unknown, and there is a possibility of bacterial growth. This study investigated the cleaning status and hygiene of steroid drug inhalers used by elderly asthma patients. We administered a questionnaire to investigate the inhaler cleaning status after inhalation, and conducted a cross-sectional survey on hygiene using ATP measurement and bacterial culture examination. Considering the responses by 53 patients, it became clear that the ATP values of patients who answered “never cleaned” after inhalation were significantly higher than those who answered “cleaned every time”. Moreover, some bacteria were detected in 62% of inhalers; 4 patients' inhalers contained bacteria other than normal oral microbial flora. In conclusion, because the inhalers used by elderly patients are in poor hygienic conditions, we must give cleaning instructions accordingly. We believe that it is necessary to give proper medical instructions along with instructions on the cleaning method with dry cloth.

We previously reported that anticholinergic (AC) drug use increases with age in the elderly Japanese population. In this analysis, we investigated attribution for each AC drug type to total AC burden using different elderly age groups. Prescription records (from 09/23/2015 to 12/31/2016) for outpatients using any AC were extracted from pharmacy claims (primary source) and hospital-based databases. AC burden (number of AC drugs and AC score) and AC type were assessed using the Anticholinergic Cognitive Burden (ACB) scale, Anticholinergic Drug Scale (ADS), Anticholinergic Risk Scale (ARS), and Beers criteria. Age was categorized using three subgroups (65-74, 75-84, and ≥85 years). Overall, 125426, 140634, 35628, and 23149 of the pharmacy outpatients received ≥1 AC drug from the ACB scale, ADS, ARS, or Beers criteria, respectively. The number of AC drugs increased with age for the ACB scale and ADS groups; but decreased for the ARS and Beers criteria. Antihypertensives provided the biggest contribution to AC score using the ACB scale and ADS, and antihistamines for the ARS. Proportional attribution to AC score typically increased with age for antihypertensives (ADS highest proportion: 34.6% for ≥85 years) and cardiac agents, but decreased for antihistamines (ARS lowest proportion: 15.3% for ≥85 years), corticosteroids, and antiepileptics. Similar findings were typically observed for the hospital database. In conclusion, antihypertensives were the principal type of AC drugs using the ACB scale and ADS and their attribution to AC score increased with age. Antihistamines were the principal drug type for the ARS.

Elneopa NF No. 1 and No. 2 infusions are complete parenteral nutrition solutions packaged as four-chambered bags. They have been used for home parenteral nutrition, with insulin injected into the bags for patients whose blood glucose becomes elevated. In this study, the stability of insulin in No. 1 and No. 2 bags was investigated. The quantity of insulin in Elneopa NF No. 2 was significantly lower than that in Elneopa NF No. 1. When insulin was injected into the upper chamber of either product, decreases in insulin levels were not observed. In contrast, the levels of insulin injected into the lower chamber of both products significantly decreased, with a larger difference in Elneopa NF No. 2. As the amino acid content is different between No. 1 and No. 2, amino acids may be considered a potential cause for the degradation of insulin in the bags. In addition, decreases in insulin levels were observed as the solutions passed through infusion sets just after flushing began, with both Elneopa NF No. 1 and No. 2. In conclusion, the concentration of insulin injected into the Elneopa infusion bags decreases, especially in No. 2 bags, and insulin is absorbed by the infusion sets.

Hydrophobically-modified hydroxypropylmethylcellulose (HM-HPMC) is a thickener with a long hydrophobic alkyl side chain. In this study, we investigated the gelation ability and rheological properties of a liposome/HM-HPMC mixed solution. The liposome suspension and the HM-HPMC aqueous solution each had low viscosities, but the viscosity increased rapidly when they were mixed. This is thought to be due to the formation of a 3D network structure caused by the hydrophobic group of HM-HPMC penetrating into the liposomal bilayer membrane, crosslinking the liposomes together. This hypothesis was supported by the fact that gelation did not occur when hydroxypropylmethylcellulose without a hydrophobic group was used. The viscosity of the liposome/HM-HPMC mixed solution decreased rapidly when a shear was applied, but immediately returned to the original gel state when the shear was removed, indicating a reversible reaction. When a strong shear is applied, the hydrophobic group of HM-HPMC detaches from the liposome. When the shear is removed, the liposome is again cross-linked by HM-HPMC. From these results, it was revealed that liposome cross-linked gels can be prepared when HM-HPMC is used.

In Japanese pharmaceutical education, the Model Core Curriculum was revised in 2013 to train pharmacists who can appropriately evaluate literature and use evidence-based medicine (EBM). However, in the investigation of EBM education at pharmaceutical universities in 2015, it was found that literature evaluation was hardly performed in the education of undergraduate students. One of the reason is the lack of EBM lecturers at each universities. Therefore, we adopted team-based learning (TBL) to educate more than 50 undergraduate students on the practical evaluation of literatures and the understanding of EBM concepts. The learning outcomes of this strategy were evaluated using the scores of individual tests before and after the class. As a result, the mean scores on the post-test significantly improved from 4.34 to 6.42 out of 10 total points (p<0.001). We further administered a questionnaire survey regarding the understanding of EBM (the mean score was 4.12). In conclusion, it was suggested that TBL for a large number was effective in EBM education for providing knowledge of literature evaluation and the understanding of fundamental concepts.

Since the first report in 2003, bisphosphonate-related osteonecrosis of the jaw (BRONJ) has been increasing, without effective clinical strategies. Osteoporosis is common in elderly women, and bisphosphonates (BPs) are typical and widely used anti-osteoporotic or anti-bone-resorptive drugs. BRONJ is now a serious concern in dentistry. As BPs are pyrophosphate analogues and bind strongly to bone hydroxyapatite, and the P-C-P structure of BPs is non-hydrolysable, they accumulate in bones upon repeated administration. During bone-resorption, BPs are taken into osteoclasts and exhibit cytotoxicity, producing a long-lasting anti-bone-resorptive effect. BPs are divided into nitrogen-containing BPs (N-BPs) and non-nitrogen-containing BPs (non-N-BPs). N-BPs have far stronger anti-bone-resorptive effects than non-N-BPs, and BRONJ is caused by N-BPs. Our murine experiments have revealed the following. N-BPs, but not non-N-BPs, exhibit direct and potent inflammatory/necrotic effects on soft-tissues. These effects are augmented by lipopolysaccharide (the inflammatory component of bacterial cell-walls) and the accumulation of N-BPs in jawbones is augmented by inflammation. N-BPs are taken into soft-tissue cells via phosphate-transporters, while the non-N-BPs etidronate and clodronate inhibit this transportation. Etidronate, but not clodronate, has the effect of expelling N-BPs that have accumulated in bones. Moreover, etidronate and clodronate each have an analgesic effect, while clodronate has an anti-inflammatory effect via inhibition of phosphate-transporters. These findings suggest that BRONJ may be induced by phosphate-transporter-mediated and infection-promoted mechanisms, and that etidronate and clodronate may be useful for preventing and treating BRONJ. Our clinical trials support etidronate being useful for treating BRONJ, although additional clinical trials of etidronate and clodronate are needed.

Paclitaxel (PTX)-associated acute pain syndrome (P-APS) is characterized by disabling but transient arthralgia and myalgia in up to 80% of patients administered with PTX. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely administered to patients with cancer who have pain or fever, and are mainly used to manage P-APS. In this study, we investigated how P-APS appear in the patients who were administered NSAIDs prior to PTX injection. The incidence or severity and duration of P-APS in patients previously administered NSAIDs were compared to those of patients who were not administered NSAIDs. The relationship between previously administered NSAIDs and rescue administration for the relief of P-APS was also evaluated. It was revealed that the incidence and duration of P-APS were 72% and 4.67±2.30 d, respectively, in the control group and 84% and 6.19±3.30 d, respectively, in the NSAIDs group. There was no significant difference in the incidence and duration and the severity of P-APS between the two groups. Patients who were previously administered NSAIDs tended to obtain less pain relief from NSAIDs administered as rescue medications, and needed other medication. Univariate and multivariate analysis revealed no correlation between previously administered NSAIDs or patient characteristics and the incidence of P-APS. In this study, it was found that clinical condition that needs NSAIDs and previously administered NSAIDs prior to PTX injection do not affect the incidence, severity, and duration of P-APS. These results will help in educating patients about their medications and will contribute to the management of P-APS.

Benzodiazepine receptor agonists (BZDs) should be appropriately used owing to the associated risks of delirium and falls. Since January 2018, the liaison team pharmacist at Iizuka Hospital has been applying digital labels with recommendations for the reduction of use and changes in the medication orders and prescriptions of BZDs on electronic medical records of patients in the surgical ward. This study aimed to verify the effectiveness of reducing the use of BZDs via the implementation of digital labels. Patients in the surgical ward were retrospectively assessed for changes in medication orders and prescription ratios of BZDs before and after the implementation of digital labels. The ratio of the number of digital labels implemented to the number of confirmations of medication orders and prescriptions of BZDs was 15.0% at the start of implementation; however, the ratio gradually and significantly decreased to 3.6%. The medication order ratio of BZDs was 52.2% before the implementation of digital labels; however, this ratio decreased to 2.7% and 5.6% immediately and 4 months after the implementation of digital labels, respectively. The present study showed that medication orders for BZDs were reduced after the implementation of digital labels and that the reduction effect was maintained for a certain period of time. Thus, the liaison team pharmacist-led approach can contribute to the proper use of BZDs.

The dosage of cisplatin is adjusted according to creatinine clearance (Ccr) estimated by the Cockcroft-Gault formula, which is commonly used as a marker for renal function. It is known that different serum creatinine (Scr) levels are reported depending on the analytical methods utilized such as the Scr level by the enzyme method being lower than that by the Jaffe method. Although the enzyme method is used in Japan, most drug dosages, including cisplatin, are adjusted according to the estimated Ccr using the Jaffe method-based Scr level. The purpose of this study was to investigate whether assessment of renal function with or without Scr adjustment affects cisplatin-based chemotherapy in cervical cancer patients. The patients were divided into two groups, normal (Ccr≥60 mL/min with adjusted Scr) and false normal (Ccr<60 mL/min with adjusted Scr, but Ccr≥60 mL/min with non-adjusted Scr). The false normal group had significantly higher rates of cisplatin dose reduction after the second course than the normal group (p<0.05). Leukocytopenia and Grade 2 or higher neutropenia were significantly more common in the false normal group than in the normal group (p<0.05). These results suggest that evaluation of renal function using the adjusted Scr is important for the accurate dosage of cisplatin and that it helps to improve the patient's quality of life. Further investigations may provide useful information for accurate and safe cisplatin-based chemotherapy for cancer patients.

While percent time within therapeutic range (%TTR) of international normalized ratio of prothrombin time (PT-INR) represents the quality of anticoagulation therapy with warfarin, it is often maintained less than 50% in patients with non-valvular atrial fibrillation (NVAF). We aimed to study if implementation of a multi-disciplinary ambulatory anticoagulation service (MAAS) may improve %TTR. Collaborating with cardiologists at Kanto Rosai Hospital, we conducted a MAAS for NVAF patients receiving warfarin from April 2013 to December 2015. Patients who agreed to utilize the service in addition to their appointments with cardiologists visited pharmacists to have counseling about diet, concomitant medications, and lifestyle. According to a protocol, pharmacists made dose adjustment proposals to cardiologists, if necessary. Upon approval by cardiologists, dose modifications were made. We retrospectively reviewed medical records of the patients who participated in the MAAS before and during the service. The study protocol was approved by the institutional review board. We identified 78 eligible patients (44 males and 34 females, aged 51 to 91 years). Their median %TTR increased significantly (p<0.05) from 57% during the pre-MAAS period to 77% during the MAAS period. In addition, the median percent time below therapeutic range (%TBTR) decreased significantly (p<0.05) from 35% during the baseline period to 11% during the MAAS period. The present study indicates that MAAS improves the quality of anticoagulation therapy with warfarin in ambulatory patients with NVAF. Further prospective, randomized studies with a greater number of patients are required to confirm the results of the present study.

A new single nucleotide polymorphisms (SNP) genotyping method has been developed and validated using biological specimens directly as templates for TaqMan PCR without general DNA extraction and purification procedure from dried saliva samples attached on water-soluble papers. This new method can set up at ease and complete PCR analysis including data interpretation in under two hours with additional advantages of application for large-scale clinical research, diagnostics, and epidemiological studies at low cost. Specifically, SNP genotyping of alcohol metabolism-related genes ADH1B (rs1229984) and ALDH2 (rs671) were demonstrated by TaqMan PCR assay using dried saliva samples in the present investigation. In this protocol, by simplifying experimental operations and improving efficiency, omitting and simplifying the time and laborious DNA purification process, it is possible to shorten the experiment time and reduce the risk of human error such as contamination. Furthermore it became possible with great cost reduction. We succeeded in dramatically improving the judgment rate and accuracy of SNP genotyping by the master mix reagent for commercial available real-time TaqMan PCR. Moreover, it becomes possible to stably introduce template DNA into the reaction system, and it will be possible to apply it to copy number variation (CNV) by TaqMan probe method. The SNP analysis process using this optimized water-soluble paper will be applied to gene polymorphism analysis of drug metabolizing enzyme gene CYP, etc., to help efforts to realize personalized medicine.

The application of systematic review (SR) has been increased rapidly in the field of cancer treatment. Complementary and alternative medicine (CAM) for cancer is no exception. The aim of this review is to evaluate and summarize systematic reviews on the CAM use in breast cancer patients. Search sources were Centre for Reviews and Dissemination (CRD), Cochrane Database of Systematic Reviews (CDSR), and PubMed. In addition, we assessed the quality of SR with the Assessing the Methodological Quality of Systematic Reviews (AMSTAR). This review did not consider control groups and outcomes. Thirty-four SRs met a set of criteria. According to interventions, there were twenty SRs which included yoga, acupuncture, and herbal medicines. Meta-analysis of 19 out of 34 reviews showed the followings: (1) acupuncture had a beneficial effect on the frequency of hot flushes, (2) yoga had a beneficial effect on depression and health-related QOL, (3) mindfulness-based stress reduction (MBSR) had a beneficial effect on anxiety and depression, (4) combination of herbal medicine and chemotherapy synergistically improved clinical outcomes, (5) acupuncture did not show significant effect on the severity of hot flushes and cancer-related pain, (6) yoga was unable to be confirmed as having an effect on cancer-related pain and physical well-being. Given the results of AMSTAR, 9 out of 34 reviews were of high quality and 3 reviews were deemed to be of low quality. In conclusion, since most SRs were at moderate or high quality levels, CAM could be helpful for treating specific symptoms related to breast cancer.

Benzodiazepine receptor agonists (BZRAs) are used in the treatment of a wide variety of clinical conditions. Although clinical practice guidelines discourage high dosage or long-term use of BZRAs, they are prescribed in clinical settings. This study aimed to investigate whether the pharmacists at multidisciplinary clinical team meetings can help reduce BZRA use and promote appropriate use of these drugs. The psychiatric unit of the Tokyo Women's Medical University Hospital occupies two floors, with 31 beds on Floor A and 34 beds on Floor B. The multidisciplinary clinical team meetings were held once a week in each ward. During the meetings, the pharmacists comprehensively assessed the number of BZRA doses administered and the equivalent diazepam doses, presented their prescription recommendations aimed at dosage reduction, and shared their views with the entire clinical team. This intervention was commenced on Floor A in 2014 and on Floor B in 2015. The average number of BZRAs in each period and equivalent diazepam doses were assessed for 273 psychiatric inpatients hospitalized from April to June in 2013, 2014, and 2015. Changes in the number of BZRA doses administered were assessed per floor per year. The results showed a statistically significant decrease between years with and without interventions. The intervention of pharmacists allowed multidisciplinary clinical team members to gain the same understanding about BZRA use and formulation of drug therapy plans. The results suggest that the intervention of pharmacists at clinical team meetings can strategically lead to decreased BZRA dosages and their proper use.

The use of medical supply vehicles (mobile pharmacies) as a disaster measure developed after the Great East Japan Earthquake in 2011 when a massive tsunami destroyed the medicine supply system. In the 2016 Kumamoto earthquake, mobile pharmacies were dispatched from Oita, Wakayama, and Hiroshima and contributed to medical treatment in the disaster area. In this study, we conducted an interview to structure the mental conflicts of the pharmacists supporting the disaster victims by means of the mobile pharmacies, a novel medical support tool. We conducted a semi-structured interview of 21 pharmacists. The modified grounded theory approach was used for data collection and analysis. As a result, 36 concepts and 13 categories were generated. The support pharmacists maintained mobile pharmacies as a method for cooperation among multiple occupations, and talked about further collaboration in the operation of mobile pharmacies.

The combination of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin with rituximab (DA-EPOCH-R) is used for non-Hodgkin lymphoma patients. Febrile neutropenia (FN) is a common complication of treatment with myelo-suppressive chemotherapy, so preventing FN is important for maintaining chemotherapy dosage. Recently, pegfilgrastim has been used as the primary prophylaxis of FN in Japan, but there have been few cases reported using pegfilgrastim for the primary prophylaxis in DA-EPOCH-R. In this study, we retrospectively compared the efficacy of pegfilgrastim with that of filgrastim in patients receiving DA-EPOCH-R in Hiroshima University Hospital. Efficacy assessment was based on incidence of FN and serious neutropenia (neutrophil count <500/μL), hospitalization days and chemotherapy dosage level. Ten patients met the inclusion criteria: pegfilgrastim (n=5, 30 cycles) or filgrastim (n=5, 16 cycles). No difference in efficacy existed between pegfilgrastim and filgrastim in the first cycle; however, 2 of 5 patients in filgrastim group reduced dose level in the total cycles of chemotherapy, no patients in pegfilgrastim group reduced. In conclusion, pegfilgrastim seemed better than filgrastim for the primary prophylaxis in DA-EPOCH-R.

The Science Council of Japan issued “The report: Promotion of Social Contributions of Research on Clinical Pharmacy and Pharmaceutical Sciences” on September 29, 2017. This report was prepared based on the analysis of current situation of the four-year doctoral course in the graduate school of pharmacy and the contents of the symposium of 137th annual meeting of the Pharmaceutical Society of Japan (PSJ), “Pharmaceutical Sciences in the Future: The Bridge Linking between Basic and Clinical Research”. The goal of the 4-year doctoral program is to nurture the pharmacist-scientist who has both researcher mind and professionalism as a clinical pharmacist. Research on clinical pharmacy and pharmaceutical sciences is a core research area of the 4-year doctoral course, therefore its promotion is an important issue for the faculty of pharmacy. “Research on clinical pharmacy and pharmaceutical sciences” has to be based on various subjects and needs of the clinical site and be conducted not only at the clinical setting but also in universities, industries, research institutions and so on. Finally, the results have to be fed back to medical care and contribute to society. In this symposium, several representatives from various academic societies and one research institution which have important functions for academic interchanges, will give presentations on issues and initiatives for promoting research on clinical pharmacy and pharmaceutical sciences.

To clarify the volume of water required to paste pediatric powders, we herein established a standard for the powder paste state by measuring yield values when water was added to powders. The powders used in the present study were selected from 8 types including original and generic drugs. Tipepidine hibenzate is prescribed in the pediatric field in combination with ambroxol hydrochloride and l-carbocysteine. The volumes of water needed to achieve the paste state of ambroxol hydrochloride between the original and generic drugs were similar. However, the volumes of water needed for l-carbocysteine markedly differed between the original and generic drugs due to differences in their additives. The spreadability of the mixture when water was added to the powders was evaluated using a spread meter. Among the powders tested in the present study, the yield value to achieve a paste state with the addition of water was approximately 1000 dyne/cm². The optimum volume of water estimated from this yield value using the linear proportional relationship for the amount of powder may be applied to the mixture of each pediatric power for dosage/body weight.