Oxaliplatin (OXA) is used in chemotherapy for various cancer types and is associated with acute and chronic neurotoxicity. However, a preventive strategy for OXA-induced peripheral neuropathy (OIPN) and its underlying mechanism remain unclear. We examined the effects of renin-angiotensin-aldosterone system inhibitors (RAASIs) on OIPN by performing a retrospective multicenter study and an in vitro assay. We retrospectively evaluated electronic medical records of 976 patients who underwent one or more courses of OXA-containing regimens at Ehime, Okayama, and Tokushima University Hospitals. The primary endpoint was the incidence of OIPN during or after OXA administration. The effects of RAASIs and OXA on the neurite length in PC12 cells were determined. The combined administration of an OXA-containing regimen and RAASI significantly inhibited the cumulative incidence grade-2 or higher OIPN (log-rank test; P=0.0001). RAASIs markedly suppressed the development of both acute and chronic OIPN (multivariate analysis; P=0.017 and P=0.011). In an in vitro assay, 10 µM OXA suppressed the neurite length; treatment with 1 μM aliskiren, spironolactone, 10 μM candesartan, and enalapril significantly restored neurite length to the control level. Moreover, 1 μM SCH772984 (a selective inhibitor of extracellular signal-regulated kinase, ERK1/2) and 500 μM SQ22536 (a cell-permeable adenylate cyclase [AC] inhibitor) markedly abolished neuroprotective effects of candesartan and enalapril. These results indicate that RAASIs possess preventive or therapeutic effects in acute and chronic OIPN, candesartan and enalapril may directly increase in the activity of ERK1/2 and AC in PC12 cells.

Various actions trigger pleasure (reward) or aversion (punishment) as emotional responses. Emotional factors that negatively affect brain neural control processes for long periods of time might cause various mental diseases by inducing neuronal changes. In the present study, newly developed PC12m12 cells which are highly sensitivity to neurotransmitters such as acetylcholine (ACh), were used. Exposing the cells to plasma from rats that had been subjected to intracranial self-stimulation (ICSS) markedly upregulated neurite outgrowth. In addition, voluntary running in a wheel or forced on a rotating rod was used to induce behavioral excitation in rats, and examinations of their plasma confirmed that the ICSS-induced neurite outgrowth was not associated with the ICSS behavior itself. Furthermore, immunoblotting and treatment with U0126, an ERK (extracellular signal-regulated kinase) antagonist, showed that the ICSS-induced neurite outgrowth was related to neuronal ERK activity. Exposing the same cells to plasma from rats that had been subjected to immobilization (IMM) also increased neurite outgrowth. Although the degree of enhancement was not as great as that seen after the ICSS rat plasma treatment, it was less than that observed after treatment with ACh as a positive control. These results indicate that ICSS or IMM lead to varying degrees of morphological changes, such as enhanced neurite outgrowth, in PC12m12 cells, but the neuronal signal transduction pathways underlying these effects differ; i.e.,the former morphological change might involve the activation of the ERK pathway, whereas the latter changes might not. Using PC12m12 cells which exhibit sensitivity to neurotransmitters, it might be possible to clarify the pathogeneses of mental diseases at the neuronal level and search for therapeutic drugs.

OBJECTIVES:Dipeptidyl peptidase-4 inhibitors (DPP-4Is) can be classified into three categories according to their binding subsites. We wished to clarify the efficacy of switching between DPP-4Is according to their binding subsites.MATERIALS AND METHODS:We undertook a retrospective study of the medical records of patients who switched from one DPP-4I to another.RESULTS:Among 62 patients eligible for study inclusion, the mean change in the glycated hemoglobin (HbA1c) level between different categories of DPP-4I was -0.35 (95% CI, -0.12 to -0.58; n = 59). The mean change in the HbA1c level between each class of DPP-4I was calculated. From class 3 to class 2 it was -0.45 (n = 25); from class 3 to class 1 it was -0.36 (n = 17); from class 1 to class 2 it was -0.24 (n = 7); from class 1 to class 3 it was 0.33 (n = 4); from class 2 to class 1 it was -0.30 (n = 5); from class 2 to class 3 it was -1.30 (n = 1).CONCLUSIONS:When switching DPP-4Is because of insufficient efficacy, consideration of their DPP-4 binding site may be beneficial.

Staphylococcus epidermidis infections are a common occurrence in hospitals, particularly in catheter-related bloodstream and surgical site infections and infective endocarditis. Higher daptomycin minimum inhibitory concentration (MIC) values may be associated with daptomycin treatment failure among patients with S. epidermidis infections. We therefore conducted a retrospective cohort study to determine the predictive value of daptomycin susceptibility. A retrospective study was undertaken in 1,337 patients with S. epidermidis infections. Data were collected from 1 January 2013 to 31 December 2016 at Ehime University Hospital, and included the following clinicopathological factors for evaluation: age, sex, resistance to vancomycin or teicoplanin, and history of antimicrobial therapy. Multiple analysis was performed using logistic regression to identify factors that independently and significantly affected the daptomycin resistance. Daptomycin-resistant S. epidermidis was identified in 38 (2.8%) patients. According to the multiple analysis, only higher MIC values (≥16 mg/L) for teicoplanin ( P < 0.0001) were independently associated with an increased risk of developing daptomycin resistance. In conclusion, higher teicoplanin MIC values may predict resistance to daptomycin treatment in S. epidermidis infections.

OBJECTIVE:The appropriate use of analgesic drugs based on their degree of analgesia and adverse effects is important for pain management. Although it has been reported that AM404, a metabolite of acetaminophen, has anticonvulsant effects in several animal seizure models, little is known about the relation between acetaminophen and seizures. We therefore investigated the effects of acetaminophen on seizure susceptibility in several mouse seizure and epilepsy models and compared the effects with those of nonsteroidal anti-inflammatory drugs (NSAIDs).METHODS:Anticonvulsant activity was evaluated in ICR mice using maximum electroshock-induced seizure tests and acute pentylenetetrazol-induced seizure tests. Electrical kindling via corneal stimulation and pentylenetetrazol administration were used to establish animal kindling epilepsy models. Proconvulsive activity was examined using an electroconvulsive shock test with low-stimulus currents.RESULTS:Acetaminophen showed slight, but not statistically significant, anticonvulsant activity in both the maximum electroshock-induced seizure test (300-600mg/kg i.p.) and acute pentylenetetrazol-induced seizure test (100-600mg/kg i.p.). In contrast, acetaminophen exhibited significant anticonvulsant effects in corneal electroshock-kindled and pentylenetetrazol-kindled mice (ED50 values: 251 and 310mg/kg i.p., respectively). When the proconvulsive effects of NSAIDs were examined in the low-current electroconvulsive shock-induced seizure model, the nonselective cyclooxygenase (COX)-1 and COX-2 inhibitors indomethacin, diclofenac, and loxoprofen induced dose-dependent proconvulsant activity. Celecoxib, a COX-2 selective inhibitor, had no proconvulsant activity.CONCLUSION:These findings suggest that acetaminophen has a significant anticonvulsant effect and that its profile is completely different from that of NSAIDs.

A Japanese guideline for the safe handling of anticancer drugs recommends a closed system drug transfer device (CSTD). We gradually introduced the PhaSealTM system from preparation to administration of all anticancer drugs to inpatients on holidays as well as weekdays. We evaluated whether the CSTD handling of 36 pharmacists was appropriate or not and also retrospectively compared outcomes before and after the introduction of CSTD. In nine pharmacists who had more than 4 items of an inappropriate handling of CSTD, the median noncompliance ratio after re-training was significantly improved from 4 to 1 items (P = 0.008). We subsequently administered a questionnaire for 36 pharmacists. The customer satisfaction analysis indicated two issues for improvement: anxiety over appropriate preparation on the double audit system of pharmacists and anxiety over miss priming after liquid sensor. On the other hand, the median introduction ratio per day of CSTD between February and April 2016 and between September and October 2016 was significantly increased on weekdays and holidays (P < 0.001 and P < 0.001, respectively). In addition, the median preparation time per day between February and April 2016 and between September and October 2016 was not significantly increased on weekdays and holidays (P = 0.514 and P = 0.423, respectively). These results suggest that our training for pharmacists contributed to an appropriate handling of CSTD, resulting in the safe handling of all anticancer drugs to inpatients on weekdays as well as holidays and the risk management of pharmacists without increase of the preparation time.

Ulcerative colitis (UC) is a refractory disease that causes chronic inflammation or ulceration in the mucosa of the large intestine with multiple relapses. Although several drugs, including 5-aminosalicylic acid, steroids, immunosuppressants, and infliximab, are used for UC therapy, patients suffer from side effects of these drugs, and a new safer therapeutic agent is desired. Eucommia ulmoides OLIV. leaf extract (ELE) has an anti-inflammatory effect. Therefore, we examined the effect of ELE on UC using a chronic dextran sulfate sodium (DSS)-induced colitis model in mice. Chronic DSS-induced colitis was triggered by alternately repeating 5 days' DSS and 7 days' water administration in mice for 29d. The severity of DSS-induced colitis was evaluated by daily body weight and bloody stool score, and colon length and myeloperoxidase (MPO) activity in colon tissue on day 29. ELE (3 or 9%) was administered in combination by feeding for 29 d, and the effect on colitis was evaluated. The mice given DSS exhibited chronic colitis symptoms with body weight loss, increased bloody stool score and MPO activity, and shortened colon length. Administration of 3 or 9% ELE suppressed the body weight loss, bloody stool score, colon shortening, and MPO activity in a dose-dependent manner. Histological analysis showed that the ELE-treated mice had less damages and leukocyte infiltration in the mucosal layer of the large intestine compared to DSS alone group. These results suggested that ELE has the potential to prevent the development of DSS-induced colitis and a therapeutic effect on UC in a safe manner.

BackgroundPharmaceutical intervention enables safe and effective pharmacotherapy by avoiding of adverse drug reactions (ADRs) and efficacy attenuations. Many prescriptions require optimization, and pharmaceutical interventions are inextricably associated with the prevention of potential drug-related problems (DRPs). Although the analysis and understanding of pharmaceutical interventions can lead to improvement in prescription, the analysis of routine pharmaceutical interventions in Japan in insufficient. Thus, we conducted this study to understand potential DRPs by analyzing routine pharmaceutical interventions made by pharmacists in Japan.MethodsPharmacists register the details of pharmaceutical interventions (excluding personal patient information) in a web-based database. We classified data of pharmaceutical interventions into 13 DRP types, 43 DRP subtypes, and 10 intervention categories (e.g., avoidance of serious ADRs and renal dosing recommendations). These data were analyzed with a focus on renal dysfunction and polypharmacy.ResultsDuring the study period, 2376 pharmaceutical interventions were performed. Overall, 68.2% of pharmaceutical interventions were for patients aged over 65years. The most frequently detected potential DRP was overdosage, followed by omission of prescription, contraindications, and duplication of a drug with similar effect. The main cause of contraindication and overdosage was renal function deterioration, and that of polypharmacy was duplication of a drug with similar effect. Using our original evidence-based approach, we found that 2376 pharmaceutical interventions prevented ADRs for 1678 drugs, with potential cost savings of up to USD 2,657,820.ConclusionsOur results indicate that the analysis of routine pharmaceutical interventions is beneficial for detecting potential DRPs. Our findings also show that, in an aging society, pharmacists have an important role in providing medication safety, with potential cost savings.

PurposeAs the major toxicity induced by pemetrexed plus carboplatin is severe hematologic toxicities, the aim of this study was to determine the risk factors for severe hematologic toxicities in lung cancer patients.MethodsWe retrospectively investigated data from lung cancer patients who had received pemetrexed plus carboplatin, with or without bevacizumab. This observational study was carried out at Ehime University Hospital using electronic medical records dating from July 2009 to March 2015. Severe hematologic toxicities were defined as grade 3 or 4, according to the Common Terminology Criteria for Adverse Events, version 4.0.ResultsForty-two patients were included in the study. The incidence of grade 3 or 4 hematologic toxicities during the first cycle of chemotherapy and during all cycles was 19.0% and 16.1%, respectively. Multivariate time-depend generalized estimating equations logistic regression analysis revealed that regular use of non- steroidal anti-inflammatory drugs (NSAIDs) was significantly associated with an increased risk of severe hematologic toxicities during all cycles (adjusted odds ratio (OR): 8.32, 95% confidence interval (CI): 1.27-54.38; p = 0.03), whereas creatinine clearance of <45 mL/min was not significantly associated with an increased risk of severe hematologic toxicities during all cycles (adjusted OR: 0.91, 95% CI: 0.25-3.34; p = 0.88).ConclusionsThe results suggest that severe hematologic toxicities in patients receiving carboplatin-based pemetrexed may be significantly induced by the inhibition of renal tubular pemetrexed secretion through drug-drug interactions between NSAIDs and pemetrexed rather than through glomerular filtration of pemetrexed, even with moderate to sufficient renal function.

Case description: A 4-year-old boy presented with tuberous sclerosis and symptomatic partial epilepsy of the upper right extremity. Topiramate was prescribed for the treatment of epilepsy, and seizure behavior was well controlled. However, the patient experienced a significantly increased seizure frequency immediately after the administration of clarithromycin and pranlukast treatment during topiramate treatment. Topiramate is metabolized by CYP3A4, which is inhibited by clarithromycin and pranlukast. Thus, pharmacokinetic interactions may have occurred. This is the first report of a possible drug interaction between topiramate, clarithromycin, and pranlukast.

Background: The performance of a population pharmacokinetic model in predicting trough concentrations after the initial vancomycin dose was evaluated in patients with albuminuria compared with patients who did not have albuminuria. Methods: Data were collected from 52 patients infected with methicillin-resistant Staphylococcus aureus (excluding patients undergoing dialysis and acute kidney injury) and treated with vancomycin. The data included urinary albumin concentration. Results: The calculated mean prediction error and mean absolute error for the serum trough concentrations of vancomycin (with 95% confidence intervals) were 4.65 (4.13–5.17) and 6.1 (5.65–6.51), respectively, in microalbuminuria and 0.33 (−0.2 to 0.86) and 4.02 (3.59–4.45), respectively, in those without. There was no significant difference observed in serum creatinine concentration, age, weight, estimation of vancomycin trough concentration in serum, and actual trough concentration of vancomycin in serum between individuals with microalbuminuria and those without albuminuria. Conclusions: Microalbuminuria in patients with diabetes is a marker of the difference between predicted vancomycin trough concentrations and actual vancomycin trough concentrations.

Purpose The therapeutic benefit of a three-drug combination of antiemetics has not been established in moderately emetogenic chemotherapy (MEC). The aim of this study was to compare the antiemetic effectiveness and cost-saving of palonosetron plus dexamethasone (control group) with aprepitant, granisetron, and dexamethasone (study group) in cancer patients who received MEC. Methods We switched the standard antiemetic treatment from the control group to the study group in gastrointestinal cancer patients who received MEC after October 2015. The antiemetics in both groups were modified using salvage antiemetic therapy at the clinicians' discretion, according to the severity of chemotherapy-induced nausea and vomiting. We retrospectively reviewed the electronic medical records from patients, before and after switching groups, from between April 2014 and March 2016. Results We evaluated 443 treatment courses in 83 patients. The proportion of courses that included salvage antiemetic therapy in the control group and the study group was 34.8 % (116/333) and 8.2 % (9/110), respectively, and was statistically significant (p < 0.001). The mean integrated costs of antiemetics per course in the control group and the study group were 193 ± 55 USD and 143 ± 38 USD, respectively. Multivariate logistic regression analysis revealed that the study group was significantly associated with a reduced risk of requiring salvage antiemetic therapy (p = 0.038). Conclusions These results suggest that the antiemetic effectiveness and cost-saving of a three-drug combination of aprepitant, generic granisetron, and dexamethasone was superior to a two-drug combination of palonosetron plus dexamethasone in gastrointestinal cancer patients who received MEC.

Abstract Purpose: Oral mucositis is a frequent and dose-limiting side effect of radiotherapy or chemotherapy in cancer patients. We investigated the effect of basic fibroblast growth factor on radiation-induced oral mucositis in male Syrian hamsters. Method: Oral mucositis was induced in male Syrian hamsters by a single dose of 30-Gy irradiation. Eight days after irradiation, treatment with gel containing trafermin (basic fibroblast growth factor) at 1 or 10 μg up to day-21 was initiated. Re-epithelialization was graded using a six-point scoring system for oral mucositis. Samples of hamster cheek pouches were removed for histopathologic analyses and immunohistochemistry. Results: The oral-mucositis score decreased in a dose-dependent manner upon trafermin treatment. Trafermin (10 μg) improved oral mucositis significantly compared with vehicle. Histopathology revealed that the degree of re-epithelialization was improved by treatment with trafermin (10 μg) compared with treatment with vehicle. Conclusions: Administration of trafermin (10 μg) can prevent mucosal damage to hamster cheek pouches induced by irradiation.

Background Venous pain induced by peripheral intravenous administration of oxaliplatin remains clinically unresolved. Objective The aim of this study was to determine the efficacy of comprehensive intervention care for venous pain in colorectal cancer patients receiving oxaliplatin. Setting A Japanese tertiary hospital. Method We treated all outpatients after April 2012 with comprehensive intervention care including pre-warming of the oxaliplatin solution, use of a hot compress, and pH adjustment by combination with dexamethasone. We retrospectively reviewed the electronic medical records from colorectal cancer patients who had received oxaliplatin via a peripheral vein between December 2009 and June 2014. Main outcome measures The primary endpoint of this study was the incidence of venous pain at the administration site during oxaliplatin infusion, according to injection site reaction grade ≥ 2. Results We evaluated 271 treatment courses in 59 patients. Venous pain occurred in 42 courses (15.5%) among 26 patients. Multivariate logistic regression analysis revealed that female gender and body mass index ≥ 25 kg/m2 were significantly associated with an increased risk of venous pain during all courses (adjusted odds ratio [OR]: 3.18, 95% confidence interval [CI] 1.35–7.92; P < 0.01; and adjusted OR: 3.37, 95% CI 1.26–9.40; P = 0.02, respectively), whereas comprehensive intervention care were significantly associated with reduced risk of venous pain during all courses (adjusted OR: 0.10, 95% CI 0.02–0.44; P < 0.01). Conclusion Comprehensive intervention care is a clinical treatment option for oxaliplatin-induced peripheral venous pain in patients with colorectal cancer, especially females with obesity.

Treatment with antipsychotic drugs has been associated with hyperprolactinemia. The same antipsychotic drugs have also been associated with side effects such as menstruation disorders. The aim of this study was to evaluate the prevalence of hyperprolactinemia and menstruation disorders in women undergoing anti psychotic treatment. We performed a retrospective chart review study of psychiatric patients who underwent laboratory testing for serum prolactin (PRL) level between March 2011 and March 2015 in Ehime University Hospital. Patients presenting with and without menstruation disorders were evaluated to determine if they presented concomitant hyperprolactinemia. Patients with menstrual disorders had a significant increase in serum PRL level with a mean of approximately 90 ng/mL. Those with menstrual disorders presented increased PRL levels by 2-fold that of patients without menstrual disorder. However, there was no significant difference in the equivalent dose of chlorpromazine between these two groups. Additionally, about 70% of patients with menstrual disorders received risperidone treatment. The receiver operating characteristic curve showed that the optimal cutoff point of serum PRL level associated with the development of menstrual disorders was 60 ng/mL. Based on these results, we concluded that patients with menstrual disorders presented increased serum PRL, and that most of them underwent treatment with risperidone.

OBJECTIVE:Because teicoplanin has a long serum half-life, a longer period of time is needed to achieve a steady-state concentration compared with vancomycin. The administration of an initial loading dose has been recommended to reach an effective teicoplanin serum concentration for the treatment of methicillin-resistant Staphylococcus aureus (MRSA). However, little is known regarding factors that affect teicoplanin concentration. This study aimed to retrospectively determine which factors are associated with achieving an optimal teicoplanin trough level. METHODS:We analyzed patients with MRSA infections who were treated with teicoplanin intravenously between January 2010 and July 2014. The effect of loading dose administration was evaluated in patients treated with 1,200 mg or 1,600 mg of teicoplanin, respectively. RESULTS:Approximately 32% (31/97) of patients achieved the trough concentration target (≥ 15 µg/mL) on the 3rd or 4th day. Multivariate analysis showed that loading doses and body surface area (BSA) were associated with trough concentration > 15 µg/mL on the 3rd or 4th day. Moreover, patients treated with the 2-day loading dose (1,600 mg group: 800 mg/day on 2 days) promptly achieved a trough concentration > 15 µg/mL on the 3rd or 4th day compared with those receiving a 1-day loading dose (1,200 mg group: 800 mg/day on only 1 day). The receiver operating characteristic curve showed that the optimal cut-off point of estimated glomerular filtration rate (eGFR) was 56 mL/min with 1-day loading dose to achieve a trough concentration target > 15 µg/mL. CONCLUSION:These results suggested that patients with decreased renal function (eGFR < 56 mL/min) can safely achieve an optimal trough level with the 1-day loading dose. In patients with normal renal function (eGFR ≥ 56 mL/min), administration of a 2-day loading dose may be needed to rapidly achieve a trough concentration ≥ 15 µg/mL. .

Limited sharing of information occurs between hospitals and community pharmacies regarding outpatients receiving oral chemotherapy. We therefore developed the sharing system of patient information between hospital and community pharmacies using the monitoring sheet of tegafur/gimeracil/oteracil potassium (S-1). After October 2013, community pharmacies monitored adverse events in patients receiving S-1 using the monitoring sheet, and subsequently provided this information to our hospital by fax. A medical clerk entered the information into the electronic medical records, thus providing feedback to hospital physicians. In this study, we retrospectively investigated adverse events in outpatients who had received S-1 between September 2012 and October 2014. In total, sixty-seven patients were included in the study. The proportion of patients who experienced adverse events in the control group and the monitoring sheet group was 69.0% and 76.0%, respectively. The proportion of patients who developed lacrimation in the control group and the monitoring sheet group was 11.9% and 36.0%, respectively, which was statistically significant (P = 0.03). On the other hand, the proportion of patients who managed any adverse events in the control group and the monitoring sheet group was 45.2% and 68.0%, respectively. The proportion of patients who managed lacrimation in the control group and the monitoring sheet group was 11.9% and 32.0%, respectively, which was not statistically significant (P = 0.06). These results suggest that this sharing system contributed to the identification of adverse events induced by S-1, resulting in appropriate management for patients who developed these adverse events by hospital physicians and community pharmacists.

Aim: In mammals, rewarding and aversive states are motivational drivers of behavioral expression. However, it is unclear whether such states affect neuronal functions at the level of individual neurons. In the present study, the neuronal effects of rewarding and aversive states were investigated in using PC12 mutant cells (PC12m3 cells) with low sensitivity to nerve growth factor. Main methods: The intracranial self-stimulation (ICSS) and immobilization (IMM) methods were used to create rewarding and aversive states, respectively, in rats. Furthermore, experiments involving voluntary running on a wheel and forced running on a rotating rod were used to evaluate the effects of behavioral excitement on neurons. Then, the effects of plasma samples collected from the animals on neurite extension were examined microscopically, and p38 mitogen-activated protein kinase (MAPK) activity was assessed using Western blotting. Key findings: Plasma samples from the ICSS and IMM rats facilitated neurite outgrowth to different degrees. However, their effects were not influenced by behavioral excitement. Furthermore, the plasma from the ICSS rats also induced upregulated p38 MAPK activity, whereas that from the IMM rats produced the same or slightly lower levels of MAPK activity to the control plasma. Significance: These findings indicate that rewarding and aversive states might cause morphological changes, such as neurite extension. As for the effects of these states on p38 MAPK activity, the former state might directly increase p38 MAPK activity, but the latter state might have no effect or cause a slight reduction in p38 MAPK activity.