Effect of mammalian-target-of-rapamycin inhibitors on the cancer risk in patients receiving calcineurin inhibitors: Data mining of a spontaneous reporting database.

OBJECTIVE: Calcineurin inhibitors (CNIs), including cyclosporine and tacrolimus, are associated with an increased cancer risk. However, whether mammalian target of rapamycin inhibitors (mTORis), including sirolimus and everolimus, decrease the cancer risk in patients receiving CNIs remains uncertain. We aimed to determine whether mTORis are associated with a decreased cancer risk in patients receiving CNIs using data mining of a spontaneous adverse reaction database. MATERIALS AND METHODS: Disproportionality analysis was conducted using the U.S. Food and Drug Administration Adverse Event Reporting System database (2004 - 2019) with reporting odds ratio and information component being used to indicate a signal. RESULTS: Data subset analyses indicated that sirolimus and everolimus were not associated with a decreased cancer risk in patients receiving cyclosporine or tacrolimus but were associated with an increased risk of nonmelanoma skin cancer (NMSC) and Kaposi's sarcoma. CONCLUSION: mTORis are not associated with a decreased cancer risk but are associated with a further increase in the risk of NMSC and Kaposi's sarcoma in patients receiving CNIs. Further studies are necessary to clarify the mechanism underlying the association between mTORis and NMSC or Kaposi's sarcoma.

Polypharmacy Is Associated With Amiodarone-Induced Hypothyroidism.

Background: Amiodarone is rich in iodine, so in clinical practice amiodarone-induced hypothyroidism (AIH) is a major side effect. This drug is used in patients with arrhythmias, especially atrial fibrillation, the most common sustained arrhythmia. Polypharmacy, which can result in complex drug-drug interactions, occurs in more than 70% of the patients with atrial fibrillation. Therefore, polypharmacy may be involved in the expression of AIH. In this study, we investigated the association between polypharmacy and AIH. Methods: We conducted a retrospective study using data from January 2006 to May 2020 collected from a large, organized database of prescriptions constructed by the Japan Medical Information Research Institute, Inc. (Tokyo, Japan). To investigate the association between number of prescribed drugs with amiodarone and AIH, we divided patients into two groups: polypharmacy (≥ 5 prescribed drugs) and non-polypharmacy (< 5 prescribed drugs). We then performed a sequence symmetry analysis on the two groups: incident thyroxine after incident amiodarone and incident thyroxine before incident amiodarone. Finally, we conducted a case-control study on two further groups: those prescribed thyroxine after incident amiodarone (AIH group; n=555) and those not prescribed thyroxine after incident amiodarone (non-AIH group; n=6,192). Results: Sequence symmetry analysis revealed a significant association between amiodarone and thyroxine in both the polypharmacy and non-polypharmacy groups. The ranges for the adjusted sequence ratio in the two groups were 12.0-16.7 and 7.3-9.0, respectively. The case-control study showed that ≥5 prescribed drugs at the first prescription of amiodarone were found to significantly increase the odds of AIH (odds ratio: 1.48, 95% confidence interval: 1.18-1.84). Conclusion: Polypharmacy was suggested as an independent risk factor for AIH. Careful assessment of the appropriateness of prescription is warranted.

Relationship between polypharmacy and adverse events.

A retrospective data analysis was performed to investigate the association between polypharmacy and adverse events using three different spontaneous adverse event reporting system databases. Multivariate logistic regression analyses were performed to investigate the association between the number of drugs and adverse events, including hepatic disorders, renal disorders, hypersensitivity, and extrapyramidal syndrome. The results showed that the risk of hepatic and renal disorders increased with the number of drugs. Thus, decreasing the number of drugs may reduce the risk of hepatic and renal disorders. Furthermore, attention should be given to specific drugs that may cause hypersensitivity and extrapyramidal syndrome.

Polypharmacy in three different spontaneous adverse drug event databases.

OBJECTIVE: Polypharmacy has become a major problem in medical care worldwide, including in Japan. The purpose of this study was to investigate the current situation of polypharmacy using different spontaneous adverse drug event report databases. MATERIALS AND METHODS: A retrospective data analysis was performed using reports from 2007 to 2015 from three different spontaneous adverse drug event report databases: the Japanese Adverse Drug Event Report (JADER) constructed by the Pharmaceuticals and Medical Devices Agency in Japan, the US Food and Drug Administration (FDA) Adverse Drug Event Reporting System (FAERS) constructed by the FDA in the United States, and the Canada Vigilance Adverse Reaction Online Database (CVARD) constructed by the government of Canada. Polypharmacy trends during the study period were investigated. RESULTS: The mean numbers of drugs per report in the JADER, FAERS, and CVARD databases during the study period were 6.62, 3.76, and 3.44, respectively. The mean number of drugs per report increased with age in all three databases, with a peak at ages 70 - 79 years in all three databases (7.0 drugs for JADER, 4.7 drugs for FAERS, and 4.2 drugs for CVARD). CONCLUSION: Adverse event reports were more likely to develop in the patients treated through polypharmacy. Polypharmacy in Japan should be improved to prevent adverse events. Additionally, the patients aged ≥ 80 years tended to develop adverse events even if the number of prescribed drugs was relatively small. Therefore, polypharmacy should be noted in these patients to prevent adverse events.

Relationship between serum calcium and creatinine in hematopoietic stem cell transplantation patients treated with foscarnet
.

OBJECTIVE: The relationship between serum creatinine and calcium (Ca) was investigated in hematopoietic stem cell transplantation (HSCT) patients treated with foscarnet. MATERIALS AND METHODS: A retrospective study was performed to investigate the development of foscarnet-induced renal dysfunction in patients who received HSCT from April 2010 to November 2018 at the Kindai University Nara Hospital. A total of 80 patients were identified from the medical records, and 42 patients who met the inclusion criteria were enrolled in this study. Renal dysfunction was classified according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. RESULTS: A significant inverse relationship was observed between serum creatinine and Ca levels (r = -0.372; p < 0.0001; y = -0.537x + 9.268). A separate analysis divided into renal dysfunction and non-renal dysfunction groups showed that there was a significant relationship between serum creatinine and Ca levels in the renal dysfunction group (r = -0.531; p < 0.0001; y = -0.617x + 9.239) but not in the non-renal dysfunction group (r = -0.011; p = 0.561; y = -0.023x + 8.934). The optimal cutoff for the minimum Ca level was calculated to be 8.1 mg/mL. CONCLUSION: A significant inverse relationship was observed between serum creatinine and Ca levels in HSCT patients with foscarnet-induced renal dysfunction. Foscarnet-induced renal dysfunction should be noted if Ca levels fall below 8.1 mg/dL. Monitoring Ca levels may be useful for detecting renal dysfunction at early stages in patients treated with foscarnet.

Polypharmacy in elderly patients in Japan: Analysis of Japanese real-world databases.

WHAT IS KNOWN AND OBJECTIVE: Polypharmacy is associated with an increased risk of adverse drug reactions (ADRs) and drug interactions, decreased adherence to medication and increased medical cost. Recently, polypharmacy has become a major problem in medical care in Japan as a result of the increase in the ageing population. The purpose of this study was to investigate the current situation of polypharmacy and the association between polypharmacy and adverse events. METHODS: A retrospective data analysis was performed using two different real-world data from 2007 to 2015 in Japan. The Japanese Adverse Drug Event Report (JADER), a public spontaneous adverse drug reaction database constructed by the Pharmaceuticals and Medical Devices Agency (PMDA), and a large prescription database constructed by a database vendor (Japan Medical Information Research Institute, Inc Japan [JMIRI]) were analysed. Trends of polypharmacy during the study period were investigated. RESULTS AND DISCUSSION: The mean number of drugs per report in the JADER database and per prescription in the JMIRI databases during the study period ranged from 4.8 to 5.6 and 3.5 to 3.7, respectively. The mean number of drugs increased with age in both the JADER and JMIRI databases, and the peak of the mean number of drugs was at 80-89 years (5.74 drugs) in the JADER database and at 90-99 years (4.97 drugs) in the JMIRI database. WHAT IS NEW AND CONCLUSIONS: The number of drugs increased until age 90 years or more, even though adverse events are more likely to occur after the age of 80 in Japan. Therefore, polypharmacy in the elderly should be focused on the patients aged ≥80 years rather than patients aged ≥65 years from the viewpoint of the prevention of adverse events.

Association between malignancy and methotrexate and biological disease-modifying antirheumatic drugs in patients with rheumatoid arthritis
.

OBJECTIVE: This study was aimed at investigating the risk of malignancies in rheumatoid arthritis patients treated with methotrexate (MTX), and whether the addition of biological disease-modifying antirheumatic drugs (bDMARDs) further increases the risk of malignancies in patients receiving MTX therapy, by using data from a spontaneous adverse reaction database. MATERIALS: Patient data from the U.S. Food and Drug Administration's Adverse Event Reporting System (FAERS) from the first quarter of 2004 to the end of 2015 were analyzed. METHODS: A data subset analysis was performed to investigate whether the use of bDMARDs further increased the risk of malignancies in patients receiving MTX therapy. RESULTS: MTX showed significant associations with all malignancies except liver cancer. bDMARDs showed significant associations with stomach cancer, colorectal cancer, prostate cancer, ovarian cancer, malignant melanoma, and lung cancer. In addition, bDMARD use increased the risk of breast, ovarian, and lung cancers in rheumatoid arthritis patients receiving MTX therapy. CONCLUSION: MTX use was significantly associated with various malignancies. Moreover, concomitant use of bDMARDs further increased the risk of breast, ovarian, and lung cancers in MTX-treated patients with rheumatoid arthritis.

Integrative analysis of clinical and bioinformatics databases to identify anticancer properties of digoxin.

Cardiac glycosides, such as digoxin, inhibit Na+/K+-ATPases and cause secondary activation of Na+/Ca2+ exchangers. Preclinical investigations have suggested that digoxin may have anticancer properties. In order to clarify the functional mechanisms of digoxin in cancer, we performed an integrative analysis of clinical and bioinformatics databases. The US Food and Drug Administration Adverse Event Reporting System and the Japan Medical Data Center claims database were used as clinical databases to evaluate reporting odds ratios and adjusted sequence ratios, respectively. The BaseSpace Correlation Engine and Connectivity Map bioinformatics databases were used to investigate molecular pathways related to digoxin anticancer mechanisms. Clinical database analyses suggested an inverse association between digoxin and four cancers: gastric, colon, prostate and haematological malignancy. The bioinformatics database analysis suggested digoxin may exert an anticancer effect via peroxisome proliferator-activated receptor α and apoptotic caspase cascade pathways. Our integrative analysis revealed the possibility of digoxin as a drug repositioning candidate for cancers.

Relationship between the blood concentrations of tacrolimus and voriconazole in hematopoietic stem cell transplant recipients
.

OBJECTIVE: We aimed to clarify the drug interaction between tacrolimus and voriconazole and investigate the relationship between blood concentrations of tacrolimus and voriconazole in hematopoietic stem cell transplantation (HSCT) patients. MATERIALS AND METHODS: A retrospective study was conducted to investigate the relationship between blood concentration of tacrolimus and that of voriconazole at the Kindai University Nara Hospital. Patients who received HSCT and tacrolimus and were prescribed voriconazole for the prevention or treatment of aspergillosis from April 2010 to July 2018 were identified from the medical records. A total of 13 patients (administration route of tacrolimus: intravenously in 6 patients, orally in 7 patients) were enrolled in the present study. RESULTS: No significant correlation was observed between the blood concentration/dose (C/D) ratio of tacrolimus and the blood concentration of voriconazole (r = 0.38; p = 0.402; y = 102.8x + 928.1). However, a significant correlation was observed between the C/D ratio of tacrolimus and the blood concentration of voriconazole in the intravenous-administration group (r = 0.94; p = 0.0048; y = 421.9x + 810.5). Meanwhile, no significant correlation was observed in the oral-administration group (r = 0.43; p = 0.34; y = 7.9x + 719). CONCLUSION: The C/D ratio of tacrolimus was significantly correlated with the blood concentration of voriconazole when tacrolimus was intravenously administered. There was a difference in the mechanism of drug interaction between tacrolimus and voriconazole depending on the administration routes.

Risk of malignant lymphoma in patients with rheumatoid arthritis treated with biological disease-modifying antirheumatic drugs and methotrexate
.

OBJECTIVE: This study investigated whether using biological disease-modifying antirheumatic drugs (bDMARDs) further increases the risk of malignant lymphoma in patients with rheumatoid arthritis undergoing methotrexate therapy using spontaneous adverse reaction databases in different countries. MATERIALS AND METHODS: Patient data were acquired from the US Food and Drug Administration's Adverse Event Reporting System (FAERS), the Japanese Adverse Drug Event Report (JADER), and the Canada Vigilance Adverse Reaction Online Database (CVARD) from the first quarter of 2004 to the end of 2015. Data subset analysis was performed to investigate whether the use of bDMARDs further increased the risk of malignant lymphoma in patients receiving methotrexate therapy. RESULTS: The FAERS subset data indicated a significant association between Hodgkin lymphoma and methotrexate with infliximab (reporting odds ratio (ROR): 8.28. 95% CI: 5.70 - 12.02; information component (IC): 2.04, 95% CI: 1.59 - 2.49). In addition, signal scores suggested that methotrexate with infliximab (ROR: 3.26. 95% CI: 2.68 - 3.98; IC: 1.31, 95% CI: 1.04 - 1.58) was significantly associated with non-Hodgkin lymphoma (NHL). The CVARD subset data also indicated a significant association between NHL and methotrexate with infliximab (ROR: 22.82. 95% CI: 5.02 - 103.78; IC: 1.77, 95% CI: 0.13 - 3.41). However, the JADER subset data revealed no significant associations. CONCLUSION: The present study shows that using infliximab further increases the risk of malignant lymphoma in patients receiving methotrexate therapy.
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Angiotensin receptor blockers and the risk of cancer: data mining of a spontaneous reporting database and a claims database
.

OBJECTIVE: The aim of this study was to examine the associations between angiotensin receptor blockers (ARBs) and the risk of 10 major cancers by employing different pharmacoepidemiological assessments. MATERIALS AND METHODS: Data from the first quarter of 2004 through 2012 were downloaded from the US Food and Drug Administration Adverse Event Reporting System (FAERS). The reporting odds ratio (ROR) and information component (IC) were used to detect the signals. Furthermore, symmetry analysis was applied to the claims database to identify the risk of cancer after using ARBs from January 2005 to July 2013. RESULTS: Significant inverse associations were found for all cancer types assessed as a whole (ROR: 0.78, 95% confidence interval (CI): 0.75 - 0.80; IC: -0.36, 95% CI: -0.40 to -0.31) in the analyses of FAERS database. Likewise, significant inverse association was found for all cancer types assessed as a whole (adjusted sequence ratio: 0.89, 95% CI: 0.82 - 0.96) in claims database. In addition, a significantly decreased risk for breast cancer and increased risks for pancreatic and prostate cancer were found in patients treated with ARBs in the analyses of individual cancers. CONCLUSIONS: Significant inverse association was found between ARB use and all cancer types assessed as a whole. However, in the analyses of individual cancers, the risks of ARB-induced cancer may differ according to cancer site. It may be reasonable to assume that the risks of ARB-induced cancer may differ according to cancer site.
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Inverse Association between Sodium Channel-Blocking Antiepileptic Drug Use and Cancer: Data Mining of Spontaneous Reporting and Claims Databases.

PURPOSE: Voltage-gated sodium channels (VGSCs) are drug targets for the treatment of epilepsy. Recently, a decreased risk of cancer associated with sodium channel-blocking antiepileptic drugs (AEDs) has become a research focus of interest. The purpose of this study was to test the hypothesis that the use of sodium channel-blocking AEDs are inversely associated with cancer, using different methodologies, algorithms, and databases. METHODS: A total of 65,146,507 drug-reaction pairs from the first quarter of 2004 through the end of 2013 were downloaded from the US Food and Drug Administration Adverse Event Reporting System. The reporting odds ratio (ROR) and information component (IC) were used to detect an inverse association between AEDs and cancer. Upper limits of the 95% confidence interval (CI) of < 1 and < 0 for the ROR and IC, respectively, signified inverse associations. Furthermore, using a claims database, which contains 3 million insured persons, an event sequence symmetry analysis (ESSA) was performed to identify an inverse association between AEDs and cancer over the period of January 2005 to May 2014. The upper limit of the 95% CI of adjusted sequence ratio (ASR) < 1 signified an inverse association. RESULTS: In the FAERS database analyses, significant inverse associations were found between sodium channel-blocking AEDs and individual cancers. In the claims database analyses, sodium channel-blocking AED use was inversely associated with diagnoses of colorectal cancer, lung cancer, gastric cancer, and hematological malignancies, with ASRs of 0.72 (95% CI: 0.60 - 0.86), 0.65 (0.51 - 0.81), 0.80 (0.65 - 0.98), and 0.50 (0.37 - 0.66), respectively. Positive associations between sodium channel-blocking AEDs and cancer were not found in the study. CONCLUSION: Multi-methodological approaches using different methodologies, algorithms, and databases suggest that sodium channel-blocking AED use is inversely associated with colorectal cancer, lung cancer, gastric cancer, and hematological malignancies.

Association between statin use and cancer: data mining of a spontaneous reporting database and a claims database.

PURPOSE: In recent years, the potential risk of cancer associated with statin use has been a focus of much interest. However, it remains uncertain whether statin therapy is associated with cancer risk. To examine the association between statin use and the risk of cancer, we conducted data mining using the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) and a large organized database of claims constructed by a database vendor (The Japan Medical Data Center Co., Ltd, Tokyo, Japan [JMDC]). METHODS: Relevant reports in the FAERS, which included data from the first quarter of 2004 through the end of 2012, were identified and analyzed. The reporting odds ratio (ROR) was used to detect spontaneous report signals and was calculated using the case/non-case method. Additionally, signals were detected via the information component (IC) using the IC025 metric. Furthermore, event sequence symmetry analysis (ESSA) was applied to identify the risk of cancer following treatment with statins over the period January 2005 to July 2013. RESULTS: In the FAERS database analyses, significant signals for colorectal cancer and pancreatic cancer were found for statins as a class. In the ESSA, significant associations between statin use and colorectal cancer and pancreatic cancer were found, with adjusted sequence ratios (95% confidence intervals) of 1.20 (1.08-1.34) and 1.31 (1.13-1.53), respectively, at an interval of 48 months. CONCLUSIONS: Multi-methodological approaches using different algorithms and databases suggest that statin use is associated with an increased risk for colorectal cancer and pancreatic cancer.

Evaluation of brilliance and visibility of fluorescence and chemiluminescence solution for training of preparing injections.

Personnel who prepare and administer chemotherapeutic agents have been reported to develop untoward effects. The use of appropriate techniques for preparing these agents is encouraged, and educational training systems that involve the use of a fluorescent or chemiluminescence reagent as placebos have been established to minimize potential exposure to these agents. However, the optimum conditions for the use and visibility of these placebos remain obscure. In this study, our results indicated that the fluorescence intensity of fluorescent reagent decreased when it was used at a concentration greater than 0.01%. Because drops created due to splashes and leaks are extremely small and easily evaporate, it is possible that the fluorescence resulting from such drops readily disappears despite using an anti-evaporation reagent. We also developed a method to evaluate the visibility of the small drop; using this method, we determined the distance at which the drop present on the pin could be seen by the observer. The distance at which the drop was clearly recognized as a pinpoint by using the fluorescence method was almost comparable to that for the chemiluminescence method. In the chemiluminescence method, the drop on the pin was faintly visible as a slightly bright area because of low background when observed at a certain distance that was much greater than that at which the drop was clearly visible; however, such an area was not observed in the fluorescence method. The results of our study will help in the selection of a training method depending on the situation.

Limited sampling strategy for mycophenolic acid in Japanese heart transplant recipients: comparison of cyclosporin and tacrolimus treatment.

BACKGROUND: The purpose of the study was to characterize the pharmacokinetics of mycophenolic acid (MPA) in Japanese heart transplant recipients and to find the time point that has the best correlation with the MPA area under the plasma concentration curve (AUC). METHODS AND RESULTS: Twenty-two Japanese recipients treated with mycophenolate mofetil were evaluated in the study. Approximately 9 months after transplantation, the area under the MPA serum concentration-time curve from 0 to 12 h (AUC(0-12 h)) was evaluated. The MPA AUC(0-12 h) h values in the cyclosporine (CsA) and tacrolimus (FK) groups ranged from 13.11 to 50.98 mug . h/ml and from 39.19 to 93.18 mug . h/ml, respectively. Fourteen models were developed and analyzed for their ability to estimate the MPA AUC(0-12 h) based on a limited number of samples in the CsA group. Sixteen models were developed in the FK group. The best model for predicting the full MPA AUC(0-12 h) in the CsA group was a 3-time-point model that included C(0 h), C(1 h) and C(2 h) (r(2), 0.96; mean prediction error, 0.15+/-7.85%); a 2-time-point model that included C(0 h), and C(2 h) (r(2), 0.94; mean prediction error, 0.495+/-10.35%) was also reliable. In the FK group, a 3-time-point model that included C(1 h), C(2 h) and C(4h) (r(2), 0.73; mean prediction error, 2.73+/-17.09%) was the best model for predicting the full MPA AUC(0-12 h), but it was not reliable in clinical practice. CONCLUSION: A 3-(C(0 h), C(1 h) and C(2 h)) and a 2-time-point model (C(0 h) and C(2 h)) are useful for predicting the full MPA AUC(0-12 h) in Japanese heart transplant recipients treated with CsA but not with FK.