Thromboembolic adverse event study of combined estrogen-progestin preparations using Japanese Adverse Drug Event Report database.

Combined estrogen-progestin preparations (CEPs) are associated with thromboembolic (TE) side effects. The aim of this study was to evaluate the incidence of TE using the Japanese Adverse Drug Event Report (JADER) database. Adverse events recorded from April 2004 to November 2014 in the JADER database were obtained from the Pharmaceuticals and Medical Devices Agency (PMDA) website (www.pmda.go.jp). We calculated the reporting odds ratios (RORs) of suspected CEPs, analyzed the time-to-onset profile, and assessed the hazard type using Weibull shape parameter (WSP). Furthermore, we used the applied association rule mining technique to discover undetected relationships such as the possible risk factors. The total number of reported cases in the JADER contained was 338,224. The RORs (95% confidential interval, CI) of drospirenone combined with ethinyl estradiol (EE, Dro-EE), norethisterone with EE (Ne-EE), levonorgestrel with EE (Lev-EE), desogestrel with EE (Des-EE), and norgestrel with EE (Nor-EE) were 56.2 (44.3-71.4), 29.1 (23.5-35.9), 42.9 (32.3-57.0), 44.7 (32.7-61.1), and 38.6 (26.3-56.7), respectively. The medians (25%-75%) of the time-to-onset of Dro-EE, Ne-EE, Lev-EE, Des-EE, and Nor-EE were 150.0 (75.3-314.0), 128.0 (27.0-279.0), 204.0 (44.0-660.0), 142.0 (41.3-344.0), and 16.5 (8.8-32.0) days, respectively. The 95% CIs of the WSP-ß for Ne-EE, Lev-EE, and Nor-EE were lower and excluded 1. Association rule mining indicated that patients with anemia had a potential risk of developing a TE when using CEPs. Our results suggest that it is important to monitor patients administered CEP for TE. Careful observation is recommended, especially for those using Nor-EE, and this information may be useful for efficient therapeutic planning.

Age-related trends in injection site reaction incidence induced by the tumor necrosis factor-α (TNF-α) inhibitors etanercept and adalimumab: the Food and Drug Administration adverse event reporting system, 2004-2015.

Tumor necrosis factor-α (TNF-α) inhibitors are increasingly being used as treatment for rheumatoid arthritis (RA). However, the administration of these drugs carries the risk of inducing injection site reaction (ISR). ISR gives rise to patient stress, nervousness, and a decrease in quality of life (QoL). In order to alleviate pain and other symptoms, early countermeasures must be taken against this adverse event. In order to improve understanding of the risk factors contributing to the induction of ISR, we evaluated the association between TNF-α inhibitors and ISR by applying a logistic regression model to age-stratified data obtained from the Food and Drug Administration Adverse Event Reporting System (FAERS) database. The FAERS database contains 7,561,254 reports from January 2004 to December 2015. Adjusted reporting odds ratios (RORs) (95% Confidence Intervals) were obtained for interaction terms for age-stratified groups treated with etanercept (ETN) and adalimumab (ADA). The adjusted RORs for ETN* ≥ 70 and ADA* ≥ 70 groups were the lowest among the age-stratified groups undergoing the respective monotherapies. Furthermore, we found that crude RORs for ETN + methotrexate (MTX) combination therapy and ADA + MTX combination therapy were lower than those for the respective monotherapies. This study was the first to evaluate the relationship between aging and ISR using the FAERS database.

Equivalent cross-relaxation rate imaging and diffusion weighted imaging for early prediction of response to bevacizumab-containing treatment in colorectal liver metastases-preliminary study.

PURPOSE: To evaluate and compare the usefulness of equivalent cross-relaxation rate (ECR) imaging (ECRI) and diffusion-weighted imaging (DWI) in the early prediction of the response of bevacizumab-containing treatments of colorectal liver metastases. METHODS AND MATERIAL: Seven patients received bevacizumab-containing treatments for colorectal liver metastases. Serial magnetic resonance imaging was performed to evaluate responses before and 2 weeks after starting chemotherapy. In the ECRI, we adopted the off-resonance technique for preferential saturation of immobile protons to evaluate the ECR values. A single saturation transfer pulse frequency was used at a frequency of 3.5 ppm downfield from the water resonance. In the DWI, the apparent diffusion coefficient (ADC) value commonly used with two b-values was acquired by using diffusion weightings of 0 and 800 s/mm2. The region of interest of the metastatic lesions in the liver was separately measured by ECRI and DWI. Tumor response was assessed by response evaluation criteria in solid tumors criteria 8 weeks after starting chemotherapy. RESULTS: In this study, we had four responders and three nonresponders. There was a significant difference in the pretreatment ECR values between the responders and nonresponders (P=.01); there was no significant difference in the ADC values between the two groups. Analysis of the percentage difference between the pretreatment and post-treatment values, termed as percentage change, showed that there were no significant differences in the percentage change of the ADC values between both groups; however, the percentage change in the ECR value was significantly greater for the responders than for the nonresponders (-41.6%±17.1% vs. -12.9%±6.9%, respectively; P=.04). CONCLUSION: The pretreatment ECR value and percentage change of the ECR value 2 weeks after starting chemotherapy were useful parameters in the early prediction of response to bevacizumab-containing treatment in colorectal liver metastases.

Reduction in the numbers of drugs administered to elderly in-patients with polypharmacy by a multidisciplinary review of medication using electronic medical records.

AIM: Polypharmacy is a major problem for elderly patients in developed countries. We investigated whether a multidisciplinary medication review using electronic medical records could reduce the number of drugs administered to elderly patients receiving polypharmacy. METHODS: The present study included 432 elderly patients (188 women, 244 men; 267 patients aged 65-74 years and 165 patients aged ≥75 years) who were admitted to and discharged from the Department of Neurology and Geriatrics, Gifu University Hospital, between 2004 and 2011; those who died at the hospital were excluded. The names, categories, and numbers of orally administered drugs at admission and discharge were examined retrospectively using electronic medical records. The histories of continuous oral immunotherapy use at the hospital, falls during the 2 years before hospital admission and the presence of fall risk factors were also evaluated. P-values <0.05 were considered statistically significant. RESULTS: On average 1.14 ± 3.07 fewer types of drugs were given to patients at discharge than at admission in patients receiving polypharmacy (P < 0.001). However, the number of drugs given to patients undergoing continuous oral immunotherapy increased by 1.67 ± 3.47 (P < 0.001). The number of drugs was reduced in 33.1% of fallers, and 36.3% of non-fallers. In both fallers and non-fallers, there was a reduction in drug categories associated with falls. CONCLUSIONS: Multidisciplinary medication review using electronic medical records could significantly reduce the numbers of drugs taken by elderly inpatients receiving polypharmacy, including drugs associated with falls, in both fallers and non-fallers Geriatr Gerontol Int 2017; 17: 653-658.

Antacid attenuates the laxative action of magnesia in cancer patients receiving opioid analgesic.

OBJECTIVE: This study was designed to investigate pharmacological interaction between magnesium laxative and antacid in patients receiving opioid analgesic. METHODS: Data obtained from a total of 441 eligible patients receiving opioid analgesic for the first time were retrospectively analysed. The incidence of constipation, defined as stool-free interval of 3 days and more within the first week of opioid intake, was compared between patients who took laxative alone and those who received laxative in combination with antacid. KEY FINDINGS: Laxatives were prescribed in 74% of patients, among them 61% received antacids such as proton pump inhibitor and H2 receptor blocker. Magnesia was the most commonly used laxative (89%). Constipation occurred in 21% and 55% of patients with and without laxatives, respectively. Antacids reversed the laxative action of lower doses (<2000 mg/day) but not higher doses (>2000 mg/day) of magnesia without affecting the effects of other laxatives. Therefore, it is suggested that both acid-dependent and acid-independent mechanisms may operate in the laxative action of magnesia, in which the former may be involved in the action of lower doses of magnesia. CONCLUSION: Care should be taken to avoid the unfavourable pharmacological interaction between low doses of magnesia and antacid.

[Evaluation of the Association of Hand-Foot Syndrome with Anticancer Drugs Using the US Food and Drug Administration Adverse Event Reporting System (FAERS) and Japanese Adverse Drug Event Report (JADER) Databases].

The Japanese Ministry of Health, Labor, and Welfare lists hand-foot syndrome as a serious adverse drug event. Therefore, we evaluated its association with anticancer drug therapy using case reports in the Japanese Adverse Drug Event Report (JADER) and the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). In addition, we calculated the reporting odds ratio (ROR) of anticancer drugs potentially associated with hand-foot syndrome, and applied the Weibull shape parameter to time-to-event data from JADER. We found that JADER contained 338224 reports from April 2004 to November 2014, while FAERS contained 5821354 reports from January 2004 to June 2014. In JADER, the RORs [95% confidence interval (CI)] of hand-foot syndrome for capecitabine, tegafur-gimeracil-oteracil, fluorouracil, sorafenib, and regorafenib were 63.60 (95%CI, 56.19-71.99), 1.30 (95%CI, 0.89-1.89), 0.48 (95%CI, 0.30-0.77), 26.10 (95%CI, 22.86-29.80), and 133.27 (95%CI, 112.85-157.39), respectively. Adverse event symptoms of hand-foot syndrome were observed with most anticancer drugs, which carry warnings of the propensity to cause these effects in their drug information literature. The time-to-event analysis using the Weibull shape parameter revealed differences in the time-dependency of the adverse events of each drug. Therefore, anticancer drugs should be used carefully in clinical practice, and patients may require careful monitoring for symptoms of hand-foot syndrome.

Hyperglycemic adverse events following antipsychotic drug administration in spontaneous adverse event reports.

BACKGROUND: Antipsychotics are potent dopamine antagonists used to treat schizophrenia and bipolar disorder. The aim of this study was to evaluate the relationship between antipsychotic drugs and adverse hyperglycemic events using the FDA Adverse Event Reporting System (FAERS) database. In particular, we focused on adverse hyperglycemic events associated with atypical antipsychotic use, which are major concerns. FINDINGS: We analyzed reports of adverse hyperglycemic events associated with 26 antipsychotic drugs in the FAERS database from January 2004 to March 2013. The Standardized Medical Dictionary for Regulatory Activities Queries (SMQ) preferred terms (PTs) was used to identify adverse hyperglycemic events. The number of adverse hyperglycemic reports for the top eight antipsychotic drugs, quetiapine, olanzapine, risperidone, aripiprazole, haloperidol, clozapine, prochlorperazine, and chlorpromazine was 12,471 (28.9%), 8,423 (37.9%), 5,968 (27.0%), 4,045 (23.7%), 3,445 (31.5%), 2,614 (14.3%), 1,800 (19.8%), and 1,003 (35.7%), respectively. The reporting ratio increased with co-administration of multiple antipsychotic drugs. For example, adverse hyperglycemic events represented 21.6% of reports for quetiapine monotherapy, 39.9% for two-drug polypharmacy, and 66.3% for three-drug polypharmacy. CONCLUSION: Antipsychotic drug polypharmacy may influence signal strength, and may be associated with hyperglycemia. After considering the causality restraints of the current analysis, further robust epidemiological studies are recommended.

Analysis of the time-to-onset of osteonecrosis of jaw with bisphosphonate treatment using the data from a spontaneous reporting system of adverse drug events.

BACKGROUND: Bisphosphonates (BPs) are potent antiresorptive agents used to treat osteoporosis and the complications associated with malignant bone metastasis. The aim of this study was to evaluate the incidence of bisphosphonate-related osteonecrosis of the jaw (BRONJ) using the Japanese Adverse Drug Event Report (JADER) database. In particular, we focused on the time-to-onset profile of BRONJ. FINDINGS: We analyzed reports of BRONJ in the JADER database and calculated the reporting odds ratio (ROR) of BPs potentially associated with BRONJ. We applied the weibull shape parameter to time-to-event data in JADER. The drugs selected for this investigation were seven BPs approved in Japan (alendronate [intraveneous, I.V.], pamidronate, and zoledronate as I.V. BPs; and alendronate (oral), etidronate, minodronate, and risedronate as oral BPs). We analyzed reports of BRONJ events associated with BPs in the JADER database from April 2004 to November 2014. The median value of BRONJ cases caused by alendronate (I.V.), pamidronate, zoledronate, alendronate (oral), etidronate, minodronate, and risedronate were 1342, 812, 486, 863, 1461, 432, and 730 days, respectively. The lower 95 % confidence interval of the Weibull-shape parameter ß for I.V. BPs (pamidronate and zoledronate) exceeded 1. The risk of BRONJ with I.V. BPs increased over time. CONCLUSION: Thus, the incidence of BRONJ with BP treatment should be closely monitored for a 3-year period. Further studies are required to draw conclusions, and we believe that this information about BRONJ induced by BPs will prove beneficial to patients and pharmacists.

Visualization of liver uptake function using the uptake contrast-enhanced ratio in hepatobiliary phase imaging.

PURPOSE: To visualize liver uptake function using the uptake contrast-enhanced ratio in hepatobiliary phase (uptake CERH) magnetic resonance imaging. MATERIALS AND METHODS: Thirty-seven patients with hepatocellular carcinoma (HCC) and 23 with metastatic liver cancer were evaluated. Hepatobiliary phase images were acquired 20min after an intravenous bolus injection of gadoxetic acid disodium. We assumed that the contrast-enhanced ratio in the hepatobiliary phase (CERH) in the spleen was similar to the contrast-enhanced ratio in the extracellular matrix (CEREM). The Uptake CERH value was defined as the percentage signal gain between the precontrast and hepatobiliary phase images (without CEREM). The Uptake CERH value measured the tumor-free liver parenchyma. The association of the uptake CERH value with the biochemical liver function test results, and hepatocellular density in the liver parenchyma was assessed. Correlations were examined using Pearson correlation coefficient and the Mann-Whitney test. RESULTS: The uptake CERH value was correlated with albumin, bilirubin, indocyanine green retention rate at 15min, prothrombin activity(%), platelet count, and cellular density in the liver parenchyma (p<0.01). CONCLUSIONS: Uptake CERH images are useful for visualizing liver uptake function.

Evaluation of parotid gland function using equivalent cross-relaxation rate imaging applied magnetization transfer effect.

Safe imaging modalities are needed for evaluating parotid gland function. The aim of this study was to validate the utility of a magnetic resonance imaging (MRI) tool, equivalent cross-relaxation rate imaging (ECRI), as a measurement of parotid gland function after chemoradiotherapy. Subjects comprised 18 patients with head-neck cancer who underwent ECRI and salivary gland scintigraphy. First, we calculated ECR values (signal intensity on ECRI), maximum uptake rate (MUR) and washout rate (WOR) from salivary gland scintigraphy data at the parotid glands. Second, we investigated correlations between ECR values and each parameter of MUR (uptake function) and WOR (secretory function) obtained by salivary gland scintigraphy at the parotid gland. Next, we investigated each dose-response for ECR, MUR and WOR at the parotid gland. A correlation was detected between ECR values and MUR in both the pre- (r = -0.55, p < 0.01) and post-treatment (r = -0.50, p < 0.05) groups. A significant post-treatment correlation was detected between the percentage change in ECR values at 3-5 months after chemoradiotherapy and median dose to the parotid gland (Pearson correlation, r = -0.62, p < 0.05). However, no correlations were detected between median dose to the parotid gland and either MUR or WOR. ECRI is a new imaging tool for evaluating the uptake function of the parotid gland after chemoradiotherapy.

Preparation of a fast dissolving oral thin film containing dexamethasone: a possible application to antiemesis during cancer chemotherapy.

We prepared fast dissolving oral thin film that contains dexamethasone and base materials, including microcrystalline cellulose, polyethylene glycol, hydroxypropylmethyl cellulose, polysorbate 80 and low-substituted hydroxypropyl cellulose. This preparation showed excellent uniformity and stability, when stored at 40 degrees C and 75% in humidity for up to 24 weeks. The film was disintegrated within 15s after immersion into distilled water. The dissolution test showed that approximately 90% of dexamethasone was dissolved within 5 min. Subsequently, pharmacokinetic properties of dexamethasone were compared in rats with oral administration of 4 mg dexamethasone suspension or topical application of the film preparation containing 4 mg dexamethasone to the oral cavity. Pharmacokinetic parameters were similar between the two groups in which C(max) (h), T(max) (microg/mL), AUC (microg/mL/h) and half-life (h) were 12.7+/-6.6 (mean+/-SD, N=10), 3.4+/-1.4, 93.6+/-37.8 and 1.66+/-0.07, respectively, for oral suspension and 13.3+/-4.0, 3.2+/-1.0, 98.0+/-22.3 and 1.65+/-0.06, respectively, for film preparation. These findings suggest that the fast dissolving oral thin film containing dexamethasone is likely to become one of choices of dexamethasone preparations for antiemesis during cancer chemotherapy.

Development of computer-assisted biohazard safety cabinet for preparation and verification of injectable anticancer agents.

BACKGROUND: Medication errors associated with anticancer agents may cause fatal events. Therefore, exact verification of the prescription order and accurate preparation of the mixture of anticancer injections are required for safe management in cancer chemotherapy. METHODS: A computer-assisted biohazard safety cabinet was newly developed for verification and preparation of anticancer agents. Using a barcode reader, information on prescription orders was transmitted from an electronic medical record to the computer system installed in the safety cabinet. The computer was controlled using a 3-button foot switch, which avoided interruption of the mixing procedure. A monitor on the cabinet wall displayed the required amounts of anticancer injections and any special information for the dissolution or mixing procedure. The names of anticancer agents were verified using a personal digital assistant and the volume of injection taken, which was automatically converted to weight on the basis of the specific gravity of anticancer solution, was recorded on the computer through a digital scale. RESULTS: Accuracy and efficiency in mixing anticancer injections were compared between procedures with and without the present apparatus. Errors in the amounts were much smaller and the time spent in preparation was significantly shorter using the present apparatus. CONCLUSIONS: The present computer-assisted biohazard safety cabinet for preparation of the mixture of anticancer agents is considered to be potentially useful for the safe management in cancer chemotherapy.

Equivalent cross-relaxation rate imaging of axillary lymph nodes in breast cancer.

PURPOSE: To determine whether equivalent cross-relaxation rate (ECR) imaging (ECRI) is a feasible method for optimization of axillary lymph node dissection (ALND) and thereby improve quality-of-life (QOL). MATERIALS AND METHODS: A total of 50 breast cancer patients underwent ECRI, with off-resonance saturation pulse at frequency offset of 5 ppm. ECR threshold values were determined to evaluate metastases to lymph nodes in the ALND group before examining the relationship between ECR value and cellular density. Metastases to lymph nodes of the sentinel lymph node biopsy (SLNB) group were evaluated based on the results of the ALND group. RESULTS: In the ALND group, regions without metastases showed a higher cellular density and ECR value than those with metastases. The relationship of ECR value to cellular density formed two clusters according to the presence or absence of metastasis; cellular density was related to ECR value for both clusters. In the SLNB group, supposing a threshold ECR value of 80%, sensitivity and specificity were 88.2% and 100%, respectively. CONCLUSION: ECRI is a potentially useful method for cellular density imaging of axillary lymph nodes. ECRI provides active information that enables ALND to be avoided, thus improving QOL.

[On the role of clinical information system in near future].

Information and communication technology has been growing up so rapidly. But, we should not forget that what we call "information" implies "digital in format". The digitalized information is essential for transmitting, sharing by many people in real time, processing, fusing, and so on. Creating three-dimensional CGs from a set of large volume image data or doing curved reformation can be performed in a blink of an eye. Now, it is also easy for an operator to get to know the stiffness of the organ through a manipulator by using the power-feedback technology. Organic integration of a variety of medical information provide a new virtual reality world which is valuable space such as a collaboration work place in a operation field. This is one of a model of the information assisted operation system. Therefore, the reader can easily understand that once he get the digitalized information, all that is left is not the technique but the "sensibility". This article is designed for readers to get to know above-mentioned technical aspect and its applicable system. Finally, I believe that technologies regarding the medical information system could contribute to some activities in the surgery in near future.

Equivalent cross-relaxation rate imaging for sentinel lymph node biopsy in breast carcinoma.

Sentinel lymph node biopsy (SLNB) is an important technique for detecting axillary lymph node metastasis in breast carcinoma patients. However, false-negative results are a problem. Equivalent cross-relaxation rate (ECR) imaging (ECRI) is a measurement method that can be used to quantitatively evaluate a change in the structural organization of lymph nodes by magnetic resonance imaging (MRI). We performed axillary ECRI in an attempt to decrease the false-negative results of SLNB. Regions without metastases showed a higher ECR value. On the other hand, regions with metastases showed a lower ECR value. The ECR images were compared with macroscopic histology images in which the presence or absence of axillary lymph node metastasis could be evaluated. ECRI is a potentially useful method for evaluating the efficacy of SLNB.

Equivalent cross-relaxation rate imaging of breast cancer.

PURPOSE: To determine whether equivalent cross-relaxation rate (ECR) imaging is a feasible method for demonstrating breast cancer. MATERIALS AND METHODS: Fifteen breast cancer patients underwent both ECR imaging, with off-resonance saturation pulses at frequency offsets of 7 and 19 ppm (ECR-7 and ECR-19, respectively) from water resonance, and gadolinium (Gd)-enhanced dynamic magnetic resonance imaging (MRI) of the breast. The mean tumor size was 26.5 mm. The tumor outlines defined by their shape and margin on ECR-7 images were compared with the subtraction images produced by the dynamic study, and the distribution of hyperintensity areas and their shapes on ECR-19 images were assessed. All patients had surgery and pathological findings were compared to ECR images. RESULTS: The tumor outline of 13/15 (87%) tumors on ECR-7 images was nearly identical to that on subtraction images; ECR-19 images demonstrated the location and degree of fibrosis. The tumor outline of the other two tumors was less clear on ECR-7 images, and internal hyperintensity on ECR-19 images reflected intratumoral fibrotic foci. ECR-7 and -19 imaging findings allowed identification of four distinct tumor types that reflected the tumor growth patterns and their internal structures associated with fibrosis. CONCLUSION: ECR imaging is a feasible imaging technique for demonstrating breast cancer.

Equivalent cross relaxation rate image for decreasing a false negative case of sentinel lymph node biopsy.

In the breast carcinamas, sentinel lymph node biopsy (SLNB) attracts attention as technique to be settled by axillary lymph node metastasis, but existence of a false negative case is a problem. Equivalent cross relaxation rate image (ECRI) is the measurement method that we can evaluate a change of organization structure quantitatively by magnetic resonance imaging. We executed axillary ECRI as a purpose with decreasing a false negative case of SLNB. ECRI related to a macroscopic image, and it was possible to evaluate yes or no of axillary lymph node metastasis. ECRI is the useful method to evaluate adaptability of SLNB.

Magnetization transfer ratios of musculoskeletal tumors.

The magnetization transfer method is a relatively new technique that creates contrast by the exchange of magnetization protons associated with macromolecules and bulk water protons through cross-relaxation or chemical exchange. We measured the magnetization transfer ratio (MTR) and compared it with the DNA index to determine whether MTR can serve as an indicator of malignancy in musculoskeletal tumors. The DNA index correlated with MTR in such musculoskeletal tumors ( P < 0.05). This suggests that MTR can be used as a parameter to quantitatively indicate malignancy.

Equivalent cross-relaxation rate imaging in the synthetic copolymer gels and invasive ductal carcinomas of the breast.

The values of equivalent cross-relaxation rate (ECR) correlated well with [i] water conditions in various copolymer gels and [ii] nature of malignant cells with regard to nuclear dysplasia and mitotic potential in breast carcinomas. The synthetic copolymer gels composed of any two or three monomers among 2-hydroxyethyl methacrylate (HEMA), glycidyl methacrylate (GMA), N-vinyl-2-pyrrolidinone (N-VP), methyl methacrylate (MMA) and benzyl methacrylate (BMA). The ECR measurement was performed by using an off-resonance saturation pulse under conventional field-echo imaging at frequency within +/- 75 ppm apart from the water resonance frequency. The ECR values were readily to determine and non-time consuming parameter for cross relaxation rate. The ECR values at the frequency offset by 7-ppm (ECR-7) were divided the sample gels two classes, which must correspond to hydrophilic or hydrophobic ones. The sensitivity in the gels was nearly equivalent to the cross-relaxation rate itself. In the breast carcinomas, the ECR-7 correlates with the nature of malignant cells with regard to nuclear dysplasia and mitotic potential. The ECR-7 is better or more accurate than the STR-7 because the SDNRs between carcinoma and glandular tissue increased by approximately 50% on the ECR-7 compared with the STR-7. Thus the ECR values could be a new parameter for malignancy and cell proliferative activity of the breast carcinomas with non-invasive modalities by magnetic resonance imaging.