Prevalence of therapeutic drug monitoring and adherence to imatinib in chronic myeloid leukemia in Japan.

OBJECTIVE: The effectiveness of imatinib, a tyrosine kinase inhibitor recommended for the treatment of chronic myeloid leukemia, is associated with high adherence and trough plasma imatinib concentrations of ~ 1,000 ng/mL. However, adherence and therapeutic drug monitoring (TDM) for imatinib have hardly been reported. This study evaluated the prevalence of TDM and adherence to imatinib for chronic myeloid leukemia in Japan. MATERIALS AND METHODS: Monthly insurance claims data for ~ 5.6 million individuals aged 20 - 74 years between June 1, 2005 and December 31, 2017 were studied. Patients with at least one prescription for imatinib were included to calculate adherence and the annual mean prevalence of TDM for imatinib. RESULTS: A total of 498 patients with 9,620 prescriptions of imatinib were included. After 2013, the number of imatinib prescriptions and the number of patients treated with imatinib were over 1,000 and 200, respectively. The mean annual prevalence of TDM for imatinib was 12.2% (95% confidence interval (CI), 8.1 - 16.1%). Antihyperuricemic drugs and steroids increased the likelihood of TDM. The medication possession ratio for assessment of adherence was 93.5% (95% CI: 91.8 - 95.5%). The annual mean prevalence of TDM for imatinib was low, although adherence was high. CONCLUSION: To encourage the measurement of plasma concentrations of imatinib in clinical settings, adding a package insert, a summary of product characteristics, and a patient information leaflet regarding the implementation of TDM is justified and warrants further attention.

Apoptotic Effects of a Thioether Analog of Vitamin K3 in a Human Leukemia Cell Line.

Research suggests that thioether analogs of vitamin K3 (VK3) can act to preserve the phosphorylation of epidermal growth factor receptors by blocking enzymes (phosphatases) responsible for their dephosphorylation. Additionally, these derivatives can induce apoptosis via mitogen-activated protein kinase and caspase-3 activation, inducing reactive oxygen species (ROS) production, and apoptosis. However, vitamin K1 exhibits only weak inhibition of phosphatase activity, while the ability of VK3 to cause oxidative DNA damage has raised concerns about carcinogenicity. Hence, in the current study, we designed, synthesized, and screened a number of VK3 analogs for their ability to enhance phosphorylation activity, without inducing off-target effects, such as DNA damage. 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) assay revealed that each analog produced a different level of cytotoxicity in the Jurkat human leukemia cell line; however, none elicited a cytotoxic effect that differed significantly from that of the control. Of the VK3 analogs, CPD5 exhibited the lowest EC50, and flow cytometry results showed that apoptosis was induced at final concentrations of ≥10 µM; hence, only 0.1, 1, and 10 µM were evaluated in subsequent assays. Furthermore, CPD5 did not cause vitamin K-attributed ROS generation and was found to be associated with a significant increase in caspase 3 expression, indicating that, of the synthesized thioether VK3 analogs, CPD5 was a more potent inducer of apoptosis than VK3. Hence, further elucidation of the apoptosis-inducing effect of CPD5 may reveal its efficacy in other neoplastic cells and its potential as a medication.

Comparison between high and low potency statins in the incidence of open-angle glaucoma: A retrospective cohort study in Japanese working-age population.

Some findings on the association between glaucoma and statins in the Asian population have been reported. We conducted a retrospective cohort study using health insurance claims data maintained by the JMDC Inc., which comprises data on about three million individuals representing 2.4% of the Japanese population. The association between the potency of statins and open-angle glaucoma in Japanese working-age population was examined using a commercially available health insurance claims and enrollment database. We identified 117,036 patients with a prescription of statins between January 1, 2005 and March 31, 2014; 59,535 patients were selected as new statin users. Of these, 49,671 (83%) patients without glaucoma who were prescribed statins for the first time were part of the primary analysis. New users of statin were defined as those with a prescription of statin at the beginning of the study, but without a prescription six months earlier. The cohort comprised 29,435 (59%) and 20,236 (41%) patients with a prescription of high-potency statin (atorvastatin and rosuvastatin) and low-potency statin (pravastatin, fluvastatin, pitavastatin, and simvastatin), respectively. Using Cox proportional hazards regression analysis, hazard ratios (HRs) were estimated for glaucoma adjusted for baseline characteristics. Although some baseline characteristics were not similar between the high-potency and low-potency statin groups, the standardized difference for all covariates was less than 0.1. No associations were found between high-potency statin use and glaucoma (adjusted HR = 1.08; 95% confidence interval, 0.93-1.24) in the primary analyses, using the risk for glaucoma in the low-potency statin group as reference. The risk of glaucoma with individual statin use was not significantly different from that with pravastatin. No significant association was found between high-potency statins and the increased risk of glaucoma in Japanese working-age population. Further studies are needed to examine the association between statins and glaucoma in the elderly population.

Frequency of Clinical Monitoring of Serum Concentrations of Digoxin, Potassium, and Creatinine, and Recording of Electrocardiograms in Digoxin-Treated Patients: A Japanese Claims Database Analysis.

Guidelines for cardiovascular drug therapy recommend monitoring serum digoxin concentration (SDC) in patients receiving digoxin treatment, especially those with renal dysfunction and hypokalemia. However, only a few studies have reported the prevalence of SDC monitoring and laboratory testing in clinical practice. Therefore, the aim of this study was to describe the frequency of SDC monitoring and laboratory testing in digoxin users and to assess the association between SDC monitoring and patient characteristics. We used the Japanese insurance claims data covering approximately 1.7 million patients aged 20-74 years between January 1, 2005 and March 31, 2014. All patients who had at least one prescription for digoxin were included. The frequency of SDC and laboratory tests was calculated and the association between patient characteristics and SDC monitoring was assessed using logistic regression analysis. A total of 98867 prescriptions of digoxin were issued to 3458 patients between 2005 and 2014. The annual mean frequencies of monitoring SDC, serum potassium level and serum creatinine level and of recording electrocardiograms was 16.8, 34.8, 38.7, and 24.1%, respectively. Atrial fibrillation, chronic heart failure, renal diseases, and use of oral anticoagulants were associated with SDC monitoring. We found the frequency of SDC monitoring to be relatively low in Japanese clinical practice.

Vitamin K3 derivative induces apoptotic cell death in neuroblastoma via downregulation of MYCN expression.

Neuroblastoma is a pediatric malignant tumor arising from the sympathetic nervous system. The patients with high-risk neuroblastomas frequently exhibit amplification and high expression of the MYCN gene, resulting in worse clinical outcomes. Vitamin K3 (VK3) is a synthetic VK-like compound that has been known to have antitumor activity against various types of cancers. In the present study, we have asked whether VK3 and its derivative, VK3-OH, could have the antitumor activity against neuroblastoma-derived cells. Based on our results, VK3-OH strongly inhibited cell proliferation and induced apoptotic cell death compared to VK3. Treatment of MYCN-driven neuroblastoma cells with VK3-OH potentiated tumor suppressor p53 accompanied by downregulation of anti-apoptotic Bcl-2 and Mcl-1. Interestingly, VK3-OH also suppressed the MYCN at mRNA and protein levels. Furthermore, we found downregulation of LIN28B following VK3-OH treatment in MYCN-amplified and overexpressed neuroblastoma cells. Collectively, our current findings strongly suggest that VK3-OH provides a potential therapeutic strategy for patients with MYCN-driven neuroblastomas.

Effect of cell differentiation for neuroblastoma by vitamin k analogs.

BACKGROUND: Lack of receptor tyrosine kinase (TrkA), a high-affinity nerve growth factor (NGF) receptor, is closely associated with the malignant progression of neuroblastoma (NB) and its prognosis. Vitamin K3 (VK3) analogs inhibit the activity of protein tyrosine phosphatases (PTPases), which causes hydrolysis of the phosphate groups bound to the tyrosine residues on tyrosine kinase, resulting in sustained tyrosine phosphorylation. METHODS: In order to reverse this abnormal NGF/TrkA signal transduction in NB cells, we synthesized new VK3 analogs and examined their activity against NB cells. RESULTS: VK3 analogs increased or maintained the expression level of c-fos mRNA in the NB cells, which express the downstream genes of NGF/TrkA signal transduction. Moreover, the expression level of GAP-43 mRNA, which is a marker of neurite outgrowth and neuronal differentiation, was increased and morphological differentiation was also observed. VK3 analogs (especially COOH analog) continued to express c-fos and GAP-43 mRNAs and induced differentiation of NB cells after stimulation of NGF by strong inhibition of PTPase without affecting TrkA autophosphorylation. CONCLUSIONS: Vitamin K3 analogs may have potential as clinical therapeutic agents for NB.