Risk Assessment for Heart Failure in Patients with Type 2 Diabetes Mellitus Treated with Dipeptidyl Peptidase 4 Inhibitor Using a Large Claims Dataset.

Heart failure is a prevalent comorbidity in patients with diabetes mellitus (DM). However, it is unclear whether the risk factors for heart failure in DM patients treated with dipeptidyl peptidase-4 (DPP-4) inhibitors are the same as those for the general population. In this study, we evaluated the factors of new-onset heart failure in working-age patients with diabetes who started DPP-4 inhibitor therapy. This study included 7938 working-age patients. The primary endpoint of the study was the proportion of patients developing heart failure within 12 months of starting DPP-4 inhibitor therapy, which was found to be 1.89% (n = 150). In these patients, risk factors of new-onset heart failure were aging, history of atrial fibrillation, and hypertension but not sex, smoking, high body mass index, weight gain of over 10 kg from 20 years of age, levels of low-density lipoprotein or glycated hemoglobin A1c (HbA1c), history of angina pectoris, myocardial infarction, and chronic kidney disease. We confirmed that cardiovascular comorbidities are risk factors for new-onset heart failure in patients with DM, while general risk factors are not. In conclusion, physicians and pharmacists need to carefully monitor working-age patients with cardiovascular history who start DPP-4 inhibitor therapy even if they do not exhibit general risk factors for heart failure.

Failure of liposomal amphotericin B therapy in patients with severe pancreatitis complicated by Candida lusitaniae infection.

Candida lusitaniae is an uncommon pathogen that accounts for approximately 1% of patients with candidiasis. In this report, we present the case of a 24-year-old woman with severe pancreatitis who was emergently admitted to Northern Yokohama Hospital. We started treating the pancreatitis and infections according to her culture results. However, her symptoms, accompanied by a necrotic pancreas, did not improve. Finally, C. lusitaniae was detected in the blood and catheter samples. We started antifungal treatment according to the culture results, but the patient died. Generally, the mortality rate for acute pancreatitis ranges from 3% for patients with interstitial edematous pancreatitis to 17% for those who develop pancreatic necrosis. Although we chose appropriate antibiotics and antifungal agents based on the culture results, the treatments failed. Early detection, sufficient doses of antimicrobials and frequent monitoring using sample culture are crucial because infection control may be inadequate, especially in tissues with low blood flow, such as necrotic tissues.

Identification of the Components of Proton Pump Inhibitors and Potassium-Competitive Acid Blocker That Lead to Cardiovascular Events in Working-Age Individuals: A 12-Month Retrospective Cohort Study Using a Large Claims Database.

This study aimed to identify the components of proton pump inhibitors (PPIs) or potassium-competitive acid blocker (PCAB) that lead to cardiovascular events in individuals of working age. We analyzed large claims data of individuals who were administered PPIs or PCAB. We enrolled working-age individuals administered PPI or PCAB without cardiovascular history with a 12-month screening and 12-month observation period and determined the proportion of cardiovascular events and the predictive factors of cardiovascular events in this population. Among the eligible individuals, 0.5% (456/91098) had cardiovascular events during the 12-month observation period. Predictive factors for cardiovascular events were age for +1 year (p < 0.0001), male sex (p < 0.0001), hypertension (p = 0.0056), and diabetes mellitus (p < 0.0001). The cardiovascular disease risk was higher in working-age individuals administered lansoprazole than in those administered other drugs (vs. rabeprazole; p = 0.0002, vs. omeprazole; p = 0.0046, vs. vonoprazan; p < 0.0001, and vs. esomeprazole; p < 0.0001). We identified the risk for cardiovascular events in individuals being treated with lansoprazole. Lansoprazole is known for its higher CYP2C19 inhibition activity compared with other PPIs or PCAB. A possible mechanism by which lansoprazole may lead to cardiovascular events is inhibiting the generation of epoxyeicosatrienoic acids from arachidonic acids, an intrinsic cardioprotective activator via CYP2C19 inhibition. Thus, we recommend avoiding administering lansoprazole to working-age individuals require PPIs or PCAB.

Simple determination of urine cefazolin concentration in pediatric patients with urinary tract infections using high-performance liquid chromatography.

Recently, global health concerns regarding increasing multidrug resistance have arisen. This study aimed to develop a simple, inexpensive and rapid high-performance liquid chromatography-ultraviolet (HPLC-UV) method for determining urinary concentrations of a first-generation cephem antibiotic in pediatric patients with urinary tract infections (UTIs). HPLC-UV was used to analyze urinary cefazolin concentrations at a detection wavelength of 254 nm. The assay used contained 10-fold diluted urine with an internal standard (cephapirin). The standard calibration curve for cefazolin was linear in the concentration range of 31.25-500 µg/ml (r2  > 0.999). The retention times of cefazolin and the internal standard were 4.2 and 4.9 min, respectively. The within- and between-day coefficients of variation were in the concentration ranges 1.2-15.2 and 5.5-19.2%, respectively. The urinary cefazolin concentration of a pediatric patient with a UTI was 1,476.6 µg/ml, which was over 700-fold higher than the minimum inhibitory concentration of cefazolin (≤2 µg/ml). The developed method is applicable to the confirmation of appropriate use for UTI treatment as therapeutic drug monitoring of cefazolin. Therefore, the findings of this study may contribute to the appropriate use of antibiotics to prevent antimicrobial resistance in pediatric patients with UTIs.

Safety of vancomycin in patients with moderate and severe renal dysfunction.

AIM: The new guidelines in Japan do not recommend a vancomycin (VCM) loading dose for patients with an estimated glomerular filtration rate (eGFR) 30 < and ≤ 80 mL×min-1×1.73m-2 (moderate renal dysfunction) or administration to those with the eGFR < 30 mL×min-1×1.73m-2 (severe renal dysfunction). We investigated the safety and efficiency of VCM in patients with moderate and severe renal dysfunction based on the new guidelines. MATERIALS AND METHODS: The study involved patients admitted to our hospital between April 2014 and March 2018 with an eGFR < 80 mL×min-1×1.73m-2 and treated with VCM. VCM trough concentration and pre- and post-administration renal function were investigated retrospectively. The primary endpoints were the proportion of patients who achieved an effective trough concentration of 10 - 20 µg/mL and rate of acute kidney injury (AKI). RESULTS: We included 64 patients (32 moderate, 32 severe). The mean VCM trough concentration achieved for the first time was 9.3 and 11.6 µg/mL in the moderate and severe renal dysfunction groups, respectively (p = 0.91). The effective trough concentration endpoint was achieved by 50% and 43% of the patients in the severe and moderate renal dysfunction groups, respectively, and no significant difference was found in the AKI rate. The serum creatinine change was significantly different between the groups - the moderate group showed a slight deterioration and the severe renal dysfunction group an improvement. CONCLUSION: It may be necessary to increase the dose for these patients with severe renal dysfunction while implementing a VCM loading dose and monitoring trough concentrations and adverse effects.

Comparison of trough concentration and area under the curve of vancomycin associated with the incidence of nephrotoxicity and predictors of a high trough level.

PURPOSE: A high vancomycin trough concentration during therapy is associated with increased nephrotoxicity, and the recent guidelines for therapeutic monitoring of vancomycin recommend target of the ratio of area under the curve (AUC) to minimum inhibitory concentration. We aimed to determine vancomycin trough concentration and AUC that induce nephrotoxicity and evaluate predictive factors associated with a high serum vancomycin trough level according to the initial dosing strategy. METHODS: We conducted a retrospective cohort study in patients administered intravenous vancomycin from June 2013 to February 2017. Totally, 346 patients were included. RESULTS: 38 experienced nephrotoxicity during therapy. The both trough level and AUC were significant risk factors for the occurrence of vancomycin induced-nephrotoxicity (p < 0.001, p = 0.001). The exposure-response analysis revealed that the trough level of 15 µg/mL was associated with 12.0% nephrotoxicity incidence and AUC of 600 was associated with 12.9% nephrotoxicity incidence. During the treatment, 90 patients had an initial trough concentration of ≥15 µg/mL, and 124 patients had AUC of ≥600 µg h/mL. The multiple logistic regression analysis revealed body weight (p = 0.001), serum creatinine level (p = 0.028), daily vancomycin dose (p = 0.001), and ICU (p = 0.015) were independent predictive factors for a high trough concentration. And same factors were selected for the high AUC. CONCLUSION: The risk factors for vancomycin induced nephrotoxicity were comparable in both trough concentration and AUC. The incidence of nephrotoxicity can be reduced by controlling vancomycin trough concentration similarly AUC and promoting antimicrobial stewardship.

Developing a Japanese version of the 'scale of attitudes toward pharmacist-physician collaboration'.

There are many reports that pharmacotherapy has been optimized to ensure collaboration between physicians and pharmacists. Various scales assess the relationship between physicians and pharmacists as well as medical students and pharmacy students. The Scale of Attitudes Toward Physician-Pharmacist Collaboration (SATP2C) can be applied not only to the physician-pharmacist relationship but also to the medical-pharmacy student relationship. As there is no Japanese version of the SATP2C, we developed one and examined its psychometric properties. SATP2C scores were measured before and after interprofessional education (IPE) to verify responsiveness. The scale showed confirmed reliability: Cronbach's alphas were 0.79 for Responsibility and Accountability, 0.68 for Shared Authority, and 0.67 for Interdisciplinary Education. Pre and post-IPE, each mean subscale score increased: Responsibility and Accountability, 0.7 ± 0.4; Shared Authority, 0.2 ± 0.3; and Interdisciplinary Education, 0.3 ± 0.2. Although the total score increased (1.2 ± 0.7), this was non-significant. The Japanese version of the SATP2C can be considered, at least initially, to have reached an acceptable level of reliability and validity. The new measure is currently the only scale in Japan that can evaluate attitudes toward physician-pharmacist collaboration regarding IPE. Further studies are needed to confirm responsiveness pre- and post-IPE.

Survey of the Time-Onset Profiles of Nedaplatin-Induced Adverse Events in Head and Neck Cancer Therapy.

OBJECTIVE: Cisplatin(CDDP)is a key drug for head and neck cancer therapy, but frequently induces severe adverse events including renal dysfunction. Nedaplatin(CDGP)was developed and is used in Japan; it has certain benefits over CDDP. Unlike CDDP, CDGP treatment does not require hydration. However, CDGP is not used globally and thus safety information is lacking. Therefore, we surveyed safety profiles for CDGP-based chemotherapy. METHODS: A survey was conducted at Showa University Hospital. Thirty-eight patients treated for head and neck cancer combined with radiotherapy(RTx)and tegafur- gimeracil-oteracil(S-1)between April 2012 and March 2015 were included. Laboratory-based adverse events(WBC, Hb, platelet[Plt], SCr, Alb)and oral mucositis were assessed according to CTCAE v5.0. Time-onset profiles for adverse events were evaluated after starting chemoradiotherapy. RESULTS: In 38 patients, Plt nadir was observed following 40(30-70)Gy and sustained for 14(7-35)days. WBC patterns followed similar profiles, but for Hb, nadir was observed following 60(40- 70)Gy and was less frequently sustained throughout the RTx. Alb and SCr levels were not correlated with therapy. Oral mucositis was observed following 50(10-70)Gy. CONCLUSION: In conclusion, at approximately 40 Gy, we observed decreases in WBC and Plt, with an increase in oral mucositis. Based on these results, medical staffs must closely monitor patients, especially at doses within range of 40 Gy.

Risk Associated with Severe Hematological Toxicity in Patients with Urothelial Cancer Receiving Combination Chemotherapy of Gemcitabine and Cisplatin.

INTRODUCTION: Combination chemotherapy of gemcitabine and cisplatin (GC) is the standard treatment for patients with urothelial cancer (UC). However, hematological toxicity is a major side effect of GC therapy in patients with UC. In particular, discontinuation of the GC therapy is associated to adverse events such as hematological toxicity. Some studies have reported general risk factors of hematological toxicity such as age. However, little is known about risk factors for GC therapy-associated hematological toxicity in patients with UC. OBJECTIVE: We aimed to identify risk factors for hematological toxicity in patients with UC receiving GC therapy. METHODS: We performed a retrospective evaluation of the data of 128 patients with UC who received GC therapy. The study end point was defined as the occurrence of grade 4 neutropenia and grade ≥3 thrombocytopenia. Logistic regression analysis was used to determine risk factors that were significantly associated with neutropenia and thrombocytopenia. RESULTS: In total, 62 (48.4%) patients experienced grade 4 neutropenia, and 27 (21.1%) patients experienced grade ≥3 thrombocytopenia. In the multivariate analysis, performance status (PS) ≥1 (odds ratio [OR] 3.764, 95% confidence interval [CI] 1.410-10.047, p = 0.008) and neutrophil count (OR 0.648, 95% CI 0.468-0.898, p = 0.009) were significantly associated with grade 4 neutropenia. Platelet count (PLT) (OR 0.896, 95% CI 0.832-0.966, p = 0.004) and potassium (K) level (OR 6.966, 95% CI 1.313-36.989, p = 0.023) were also significantly associated with grade ≥3 thrombocytopenia. CONCLUSIONS: PS ≥ 1, neutrophil count, PLT, and K level were important risk factors for GC therapy-induced hematological toxicity in patients with UC. To continue GC therapy, further management systems by hematological toxicity risk factors for patients with UC will be required.

Prophylactic Quinolone Prescription Patterns Related to Febrile Neutropenia in Cancer Chemotherapy Outpatients.

OBJECTIVE: The aim of this study is to assess prophylactic prescriptions for febrile neutropenia(FN)caused by chemotherapy. INVESTIGATION: We retrospectively surveyed prophylactic antibiotic prescriptions administered to 930 cancer treatment naive outpatients at Showa University Hospital. Factors associated with prophylactic antibiotic prescriptions were assessed based on patient characteristics, intensity of chemotherapy regimens, laboratory data and diagnoses using logistic regression analysis. RESULTS: The number of patients given prophylactic antibiotic prescriptions was significantly higher in high-risk regimens(n= 349)compared to low-risk regimens(n=288), with an odds ratio of 8.93(6.07-13.14). In logistic regression analysis, significant factors affecting the prophylactic prescription of antibiotics were high-risk regimens(OR: 2.05, p=0.009), age(+ 1 year, OR: 0.98, p=0.002), female sex(OR: 7.10, p<0.001), WBC count(+1.0×10 / 3mL, OR: 1.19, p=0.013)and operation history before and after chemotherapy(OR: 23.19, p<0.001). CONCLUSIONS: Physicians(including pharmacists)should therefore pay attention to the prophylactic prescriptions especially in high-risk female cancer patients with operation history. This prescription pattern provides basic information needed for the proper use of antibiotics in cancer patients.

A Standard Intervention Practice to Promote Appropriate Lamotrigine Therapy by Pharmacists.

The dosage and frequency of lamotrigine administration for each patient must be prescribed carefully according to the disease, age, concomitant medications, and administration period. According to Pharmaceuticals and Medical Devices Agency (PMDA) reports, either the number of patients with adverse events caused by the inappropriate use of lamotrigine or the ratio of the patients who have benefited from the Relief System for Adverse Drug Reactions did not change even after the revision of the package insert in 2015. The procedure for auditing lamotrigine prescriptions was standardized to improve patient safety in our hospitals. The efficacy of standardization was evaluated by investigating the patients' records and prescriptions. A total of 77 patients treated with lamotrigine were examined to evaluate the appropriateness of the dosage and frequency of administration as well as the number of prescription enquiries made by pharmacists retrospectively. In addition, the presence of adverse events such as skin rash was examined using medical records. The number of inappropriate cases found and the prescription questions asked by pharmacists during the 24-month period before and after standardization were compared. The rate of inappropriate prescriptions after standardization was significantly lower than that before (12.1 vs. 29%; p<0.05). The rate of prescription questions raised after standardization was significantly higher than that before (37.0 vs. 1.7%; p<0.05). Moreover, there was no adverse event after standardization. Our standardization practice was effective to easily identify inappropriate prescriptions and provide physicians with the appropriate dosage or frequency of administration for the patients.

The Association between Fever and Prognosis in Lung Cancer Patients with Bone Metastases Receiving Zoledronic Acid.

Zoledronic acid is an established agent used in the management of metastatic bone disease. The administration of zoledronic acid improves overall survival (OS) of lung cancer patients with bone metastases receiving chemotherapy. However, it is currently unknown whether zoledronic acid-induced fever is associated with OS. The purpose of this study was to examine the association between zoledronic acid-induced fever and prognosis in lung cancer patients with bone metastases. We retrospectively analyzed 98 lung cancer patients with bone metastases who had received zoledronic acid. The end point outcome measure was OS. Multivariate analyses were used to estimate the hazard ratio (HR) for OS due to fever after adjusting for covariates. In multivariate analysis, white blood cell (WBC) count, lactate dehydrogenase (LDH) level, fever, chemotherapy, and hypercalcemia were independent prognostic factors, with HRs of 2.834 for WBC count (<10 × 103/µL vs. ≥10 × 103/µL, p < 0.001), 3.044 for LDH level (<250 vs. ≥250 IU/L, p < 0.001), 0.603 for fever (<37.0 vs. ≥37.0°C, p = 0.039), 0.481 for chemotherapy (chemotherapy not administered vs. administered, p = 0.006), and 2.453 for hypercalcemia (<11.0 vs. ≥11.0 mg/dL, p = 0.001). Zoledronic acid-induced fever was the most important prognostic factor in this cohort of lung cancer patients with bone metastases.

Incidence of Ophthalmic Disorders in Patients Treated with the Antineoplastic Agent S-1.

S-1 is an oral antineoplastic agent containing tegafur, gimeracil, and oteracil potassium. Recently, ophthalmic disorders, particularly epiphora, have been reported. We retrospectively investigated the incidence of ophthalmic disorders in patients treated with a regimen containing S-1 at our institution. Ophthalmic disorders were noted in 28 of 261 patients(10.7%). These included epiphora(17 cases), eye discharge(10 cases), conjunctivitis(6cases ), blurred vision(3 cases), and eye discomfort(2 cases), as well as eye pain, pruritus, dry eye, hordeolum, and visual loss(1 case each). The median time from starting treatment to appearance of the condition was 3.0(interquartile range 1.5-4.5)months and the median cumulative S-1 dose was 4.2(interquartile range 2.2-9.5)g. More men than women developed ophthalmic disorders on S-1. The median total dose and duration of treatment were higher in those developed ophthalmic disorders than in those who did not (12.4 g vs 6.3g and 8.6 months vs 4.4 months). Epiphora was the most common of a number of ophthalmic disorders seen in our patients treated with S-1. Patients and physicians should be fully informed of the potential association between S-1 and ophthalmic disorders, and patients receiving this treatment need to be carefully monitored.