Assessment of Diagnosis Timing of Attention-Deficit/Hyperactivity Disorder in Working-Age Workers with Psychiatric Diseases Using Large Claims Data.

Attention deficit/hyperactivity disorder (ADHD) is a common developmental disorder. This study aims to clarify the timing of diagnosis of ADHD in working-age workers with psychiatric comorbidities using large claims data in Japan. Based on a literature survey, we identified 10 typical comorbidities of ADHD. Among 3064162 participants with social insurance, 215060 working-age workers who were diagnosed with the 10 typical comorbidities of ADHD were included. Cohort 1 consisted of 96994 patients with the index date set as the earliest date of diagnosis of a comorbidity within the 12-month screening and 12-month observation periods. In cohort 2, 107436 patients were included, and the first date of diagnosis of each comorbidity was used as the index month. In cohort 1, 0.19% of the patients were diagnosed with ADHD after being diagnosed with a typical comorbidity. In cohort 2, 4 out of 4 patients with ADHD and obsessive-compulsive disorders were diagnosis ADHD after obsessive-compulsive disorders. Pervasive developmental disorders were the highest comorbidity of ADHD for 62 out of 566 (11.0%) patients. This is the first study to determine the proportion of ADHD with typical comorbidities in working-age workers in Japan. Our findings highlight the need for timely diagnosis of ADHD to improve patients' QOL.

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.

Liver Injury by the Traditional Chinese Medicine Hanshirento, Zenshikunshito, and Ninjin'yoeito in a Patient with Lung Cancer: Probable Causality Assessed by the Updated Roussel Uclaf Causality Assessment Method.

INTRODUCTION: Traditional Chinese medicine (TCM) is a traditional treatment based on herbal medicines and holistic healing. It has resulted in both favorable and unfavorable patient outcomes when used to treat cancer. Cancer patients frequently depend on second opinions and folk remedies. In this case, we report the case of TCM inducing repeated moderate liver injury and delay for chemotherapy. CASE PRESENTATION: A 59-year-old woman was diagnosed with lung cancer and conducted surgery a month ago. She went to a TCM specialty clinic expecting a complete cure for the lung cancer, to improve her physical condition, and to enhance her immunity. She received the TCM formulas hanshirento, zenshikunshito, and ninjin'yoeito. After starting these medicines, she felt severe fatigue but continued them for approximately 2 weeks, After discontinuing the medicine, her fatigue was improved. She was admitted to our hospital for adjuvant chemotherapy. On admission, laboratory tests revealed moderate liver injury (AST: 705 U/L, ALT: 1091 U/L). In view of her medication history, the laboratory tests, and her lifestyle history, we thought that moderate liver injury was caused by TCM, employing the Roussel Uclaf Causality Assessment Method (RUCAM). DISCUSSION: TCM are known to be metabolized by the resident bacteria in the small intestine, but the specific metabolic processes are not well understood. Cancer patients sometimes try TCM from their own research to stay healthy. However, as with our case, TCM rarely induces liver injury, which is not well known to TCM users. Medical staffs need to be vigilant with their drug histories, including TCM, if patients have liver injuries.

Probiotic Prescription Status of Pediatric Patients with Otitis Media Receiving Oral Amoxicillin or Amoxicillin/Clavulanate from April 2016 to March 2017 Using a Japanese Health Insurance Claims Database.

Antibiotic-associated diarrhea (AAD) is a typical side effect of antibiotic treatment, especially in children. Amoxicillin (AMPC) and amoxicillin/clavulanate (AMPC/CVA) are associated with high risk of AAD; however, these antibiotics are important in the pediatric field. Recent research suggests that probiotics prevent pediatric AAD, including that caused by AMPC and AMPC/CVA. Indeed, guidelines for acute otitis media in children recommend the concomitant use of probiotics. However, the prescription status of probiotics for pediatric patients with otitis media receiving oral AMPC and AMPC/CVA remains unknown. We therefore conducted a survey to clarify the current status of these prescriptions and, in particular, to identify specific populations with a low proportion of probiotic prescriptions. Pediatric patients (≤15 years of age) newly prescribed oral AMPC or AMPC/CVA for otitis media between April 2016 and March 2017 were identified from a Japanese health insurance claims database. Eligible patients were divided into the AMPC (1303 patients) and AMPC/CVA (424 patients) groups, in which 659 (50.6%) and 293 (69.1%) patients were prescribed probiotics, respectively. Of the patients receiving probiotic prescriptions in the AMPC and AMPC/CVA groups, 632 (95.9%) and 286 (97.6%) patients received antibiotic-resistant probiotic prescriptions, respectively. When classified by the prescribing clinical department and patient age, the proportions of probiotic prescriptions in Internal Medicine and Pediatrics departments were lower than those in the Otorhinolaryngology department regardless of age. These results indicate the probability of insufficient probiotic prescriptions for pediatric patients with otitis media. Solving this issue may lead to the provision of safer antimicrobial therapy.

Prescription of Colchicine with Other Dangerous Concomitant Medications: A Nation-Wide Survey Using the Japanese Claims Database.

The anti-inflammatory agent colchicine may cause toxic effects such as rhabdomyolysis, pancytopenia, and acute respiratory distress syndrome in cases of overdose and when patients have renal or liver impairment. As colchicine is a substrate for CYP3A4 and P-glycoprotein (P-gp), drug-drug interactions are important factors that cause fatal colchicine-related side effects. Thus, we conducted a nation-wide survey to determine the status of inappropriate colchicine prescriptions in Japan. Patients prescribed the regular use of colchicine from April 2014 to March 2017 were identified using the Japanese large health insurance claims database. As the primary endpoint, we evaluated the concomitant prescription proportions of strong CYP3A4 and/or P-gp inhibitors classified as "contraindications for co-administration" with colchicine in patients with renal or liver impairment. We defined these cases as "inappropriate colchicine prescriptions." Additionally, factors affecting inappropriate colchicine prescriptions were analyzed. Among the 3302 enrolled patients, 43 (1.30%) were inappropriately prescribed colchicine. Of these 43 patients, 11 had baseline renal and/or liver impairment. By multiple regression analysis, the primary diseases "gout" and "Behçet's disease" were extracted as independent factors for inappropriate colchicine prescriptions with odds ratios of 0.40 (95% confidence interval: 0.19-0.84) and 4.93 (95% confidence interval: 2.12-11.5), respectively. We found that approximately 1% of patients had important colchicine interactions. Particularly, Behçet's disease was a risk factor for inappropriate prescriptions, with approximately 25% of patients showing renal and/or liver impairment (classified as "contraindications for co-administration"). These findings may be useful for medical professionals who prescribe colchicine therapy.

Association of the ward pharmacy service with active implementation of therapeutic drug monitoring for vancomycin and teicoplanin-an epidemiological surveillance study using Japanese large health insurance claims database.

BACKGROUND: Ward pharmacists are required for the active implementation of therapeutic drug monitoring (TDM). This epidemiological study verified whether Japanese ward pharmacists contribute to improving the TDM implementation proportions of anti-methicillin-resistant Staphylococcus aureus (MRSA) agents using the large health insurance claims database. METHODS: The patients who received intravenous anti-MRSA agents from April 2012 to March 2017 were enrolled. We defined ward pharmacy service as the "drug management and guidance fee" and/or "inpatient pharmaceutical services premium". In addition, implementation of TDM was identified by "the specific drug treatment management fee". We compared the proportions of TDM implementation for vancomycin (VCM), teicoplanin (TEIC), and arbekacin (ABK) in the ward and non-ward pharmacy service groups. To avoid confounding, the propensity score method was employed. Moreover, the clinical variables affecting TDM implementation in each anti-MRSA agent were analyzed by using a multiple logistic regression model. RESULTS: The following number of patients were included in the study: VCM (n = 2138), TEIC (n = 596), and ABK (n = 142). After propensity score matching, the proportions of TDM implementation for VCM and TEIC were higher in the ward pharmacy service group than in the non-ward pharmacy service group (VCM: 69.2% vs 60.3%, TEIC: 51.4% vs 34.7%), while no significant difference was observed for ABK (21.2% vs 23.1%). As independent clinical variables affecting TDM implementation for VCM and TEIC, several clinical variables, including ward pharmacy services, were extracted. In contrast, no clinical variables were extracted for ABK. CONCLUSIONS: We found that the ward pharmacy service is associated with the active implementation of TDM for anti-MRSA agents, such as VCM and TEIC.

Nonsteroidal anti-inflammatory drugs use in patients with chronic kidney disease are often prescribed from different clinicians than those who diagnosed them.

PURPOSE: When prescribing nonsteroidal anti-inflammatory drugs (NSAIDs) for chronic kidney disease (CKD), patients' pathology and concomitant medications should be considered. In our pharmaceutical experience, NSAIDs are often prescribed by departments that are different from those that diagnosed CKD. That is, NSAIDs may be prescribed for patients without the advice of the clinicians who diagnosed them. In this study, we aimed to elucidate how frequently such cases occur. METHODS: We used the large health insurance claims database constructed by JMDC Inc., Tokyo. We evaluated the proportions of CKD diagnosis and NSAID prescription by different clinical departments and institutions. RESULTS: A total of 224 014 out-patients were included in the analysis; they were divided into CKD (n = 1501) and non-CKD groups (n = 222 513). The internal medicine departments diagnosed CKD most frequently (74.8% of the patients) and surgical departments rarely diagnosed CKD. However, the proportion of prescribed NSAIDs was high in other departments, especially surgical departments. In the CKD group, 50.4% of the patients received CKD diagnosis and NSAID prescription from different clinical departments; 72.8% of the patients received a diagnosis and prescription from different medical institutions. CONCLUSION: Our study revealed that NSAIDs are often prescribed to patients with CKD from different clinicians than those who diagnosed them.

Assessment of statin-induced interstitial pneumonia in patients treated for hyperlipidemia using a health insurance claims database in Japan.

PURPOSE: This study aimed to determine the frequency and risk factors for statin-induced interstitial pneumonia (IP). METHOD: We conducted a retrospective cohort study using a large Japanese health insurance claims database. We determined the statin-induced IP incidence in patients treated with statins for hyperlipidemia (n = 194,814) with 12-month screening and 3-month observation periods. Statin-induced IP was defined as: (1) diagnosis with IP (ICD-10 codes: J70.2-J70.4, J84.1, and J84.9) within 3 months after starting statins; (2) steroid administration starts after starting statins; (3) undergoing laboratory tests for sialylated carbohydrate antigen Krebs von den Lungen-6 or pulmonary surfactant protein-D; and (4) undergoing high-resolution computed tomography (HRCT). Risk factors for IP were defined as presence of lung-related diseases including lung cancer and IP (ICD-10 codes: A15-16, J12-18, 43-46, 60-70, and 80-99) that were known to the risk factors inducing IP during the screening period. RESULTS: Cohort 1 had no IP-inducing risk factors; based on lung-related disease history, we identified 4 cases (male/female: 0/4, 61 ±â€¯2.5 years) and 46,574 controls (male/female: 29,677/16,897, 51.3 ±â€¯9.5 years). In cohort 1, all cases were female and average age was older than that of controls (p < 0.01). Cohort 2 had lung-related disease history that were known to the risk factors inducing IP; we identified 25 cases (male/female: 11/14, 52.8 ±â€¯11.3 years) and 4005 controls (male/female: 2305/1,700, 51.0 ±â€¯10.4 years). IP incidence was higher in cohort 2 than in cohort 1, who had no IP risk factors (0.6% vs. 0.009%, p < 0.01). The adjusted case/control odds ratio in cohort 2 was 3.8 (1.7-8.5) in patients who had taken atorvastatin and 2.5 (1.1 - 5.6) with diabetes mellitus. DISCUSSION: We clarified the incidence (0.009% and 0.6% in patients without and with lung-related disease history that were known to the risk factors inducing IP, respectively) and risk factors for statin-induced IP (elderly females without lung-related disease history; atorvastatin administration in those with lung-related disease history). Physicians and pharmacists should pay close attention to female patients starting atorvastatin, especially those with past histories of lung-related diseases that were known to the risk factors for IP.

Simple Determination of Plasma Ponatinib Concentration Using HPLC.

Ponatinib, a novel tyrosine kinase inhibitor marketed in 2016, is a key drug used for treating chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. This study aimed to develop a simple method for determining plasma ponatinib concentration. The analysis required extraction of a 400-µL sample of plasma and precipitation of proteins using an Oasis HLB cartridge. Ponatinib and bosutinib, which is used as an internal standard, were separated by HPLC using a mobile phase of acetonitrile : 0.037 mol/L KH2PO4 (pH 4.5) (39 : 61, v/v) on a Capcell Pack C18 MG II (25×4.6 mm) monitored at 250 nm, with a flow rate of 1.0 mL/min. This assay method was then used for determining plasma ponatinib concentration in a 42-year-old man treated with ponatinib at 15 mg/d. The calibration curve was found to be linear for the plasma concentration range of 5-250 ng/mL with a regression coefficient (r2) of 0.9999. The coefficients of intra-day and inter-day validation under these concentrations were 2.1-6.0 and 4.5-8.0%, respectively. The assay accuracy was -1.5-9.0%, and the recovery was greater than 86%. The plasma concentration of the patient at 2.5 and 3 h after 15 mg ponatinib administration was 43.6 and 49.3 ng/mL, respectively. This method of HPLC equipped with UV detection for determining plasma ponatinib concentration has several advantages, such as simplicity and applicability to routine therapeutic drug monitoring at hospital laboratories.

Assessment of indomethacin oral spray for the treatment of oropharyngeal mucositis-induced pain during anticancer therapy.

PURPOSE: The efficacy and safety of indomethacin (IM) oral spray (OS) as a pain control therapy for oropharyngeal mucositis due to anticancer chemo- and radiotherapy were assessed in patients with head and neck carcinomas and haematological tumours. METHOD: We observed 35 patients (male/female, 20/15; 53 ± 17 years) with oropharyngeal mucositis who were treated with IM-OS preparation for pain relief at University of Tsukuba Hospital, Japan. Analgesic effects were assessed using the six-grade face scale for pain in 28 patients at the start of IM oral spray treatment. Systemic exposure was assessed by determining urinary excretions of IM in seven patients. RESULTS: Pain relief was achieved in 26 (93%) patients at 25 (5-60) min after applying the IM-OS preparation (15.6 ± 3.4 µg/kg) and analgesic effects were maintained for 120 (10-360) min. The pain was significantly decreased after using the spray (3.6 ± 0.7 vs. 2.4 ± 0.9, p < 0.01). Moreover, urinary IM excretion rates after applying the IM spray preparation were 1.8 ± 0.8% of the IM oral spray dose (130.5 ± 77.7 µg/kg/day), which was markedly lower than that following oral administration of IM (60%). No adverse events were observed following application of the spray. CONCLUSIONS: The present IM spray is an effective and safe preparation for pain relief and can be used as an alternative therapeutic option for oropharyngeal mucositis in cancer patients.