Identification of prophylactic drugs for oxaliplatin-induced peripheral neuropathy using big data

Background: Drug repositioning is a cost-effective method to identify novel disease indications for approved drugs; it requires a shorter developmental period than conventional drug discovery methods. We aimed to identify prophylactic drugs for oxaliplatin-induced peripheral neuropathy by drug repositioning using data from large-scale medical information and life science information databases. Methods: Herein, we analyzed the reported data between 2007 and 2017 retrieved from the FDA’s database of spontaneous adverse event reports (FAERS) and the LINCS database provided by the National Institute of Health. The efficacy of the drug candidates for oxaliplatin-induced peripheral neuropathy obtained from the database analysis was examined using a rat model of peripheral neuropathy. Additionally, we compared the incidence of peripheral neuropathy in patients who received oxaliplatin at the Tokushima University Hospital, Japan. The effects of statins on the animal model were examined in six-week-old male Sprague–Dawley rats and seven or eight-week-old male BALB/C mice. Retrospective medical chart review included clinical data from Tokushima University Hospital from April 2009 to March 2018. Results: Simvastatin, indicated for dyslipidemia, significantly reduced the severity of peripheral neuropathy and oxaliplatin-induced hyperalgesia. In the nerve tissue of model rats, the mRNA expression of Gstm1 increased with statin administration. A retrospective medical chart review using clinical data revealed that the incidence of peripheral neuropathy decreased with statin use. Conclusion and relevance: Thus, drug repositioning using data from large-scale basic and clinical databases enables the discovery of new indications for approved drugs with a high probability of success

Drug Repositioning for Cardiac Arrest

The survival rate of cardiac arrest patients is less than 10%; therefore, development of a therapeutic strategy that improves their prognosis is necessary. Herein, we searched data collected from medical facilities throughout Japan for drugs that improve the survival rate of cardiac arrest patients. Candidate drugs, which could improve the prognosis of cardiac arrest patients, were extracted using “TargetMine,” a drug discovery tool. We investigated whether the candidate drugs were among the drugs administered within 1 month after cardiac arrest in data of cardiac arrest cases obtained from the Japan Medical Data Center. Logistic regression analysis was performed, with the explanatory variables being the presence or absence of the administration of those candidate drugs that were administered to ≥10 patients and the objective variable being the “survival discharge.” Adjusted odds ratios for survival discharge were calculated using propensity scores for drugs that significantly improved the proportion of survival discharge; the influence of covariates, such as patient background, medical history, and treatment factors, was excluded by the inverse probability-of-treatment weighted method. Using the search strategy, we extracted 165 drugs with vasodilator activity as candidate drugs. Drugs not approved in Japan, oral medicines, and external medicines were excluded. Then, we investigated whether the candidate drugs were administered to the 2,227 cardiac arrest patients included in this study. The results of the logistic regression analysis showed that three (isosorbide dinitrate, nitroglycerin, and nicardipine) of seven drugs that were administered to ≥10 patients showed significant association with improvement in the proportion of survival discharge. Further analyses using propensity scores revealed that the adjusted odds ratios for survival discharge for patients administered isosorbide dinitrate, nitroglycerin, and nicardipine were 3.35, 5.44, and 4.58, respectively. Thus, it can be suggested that isosorbide dinitrate, nitroglycerin, and nicardipine could be novel therapeutic agents for improving the prognosis of cardiac arrest patients

Effect of propolis on insulin resistance in fructose-drinking rats

Propolis, a honeybee product, contains a variety of biologically active substances. The present study was designed to investigate the effects of propolis on insulin resistance induced by fructose-drinking rats (FDR; type 2 diabetic animal model). Male Wistar rats (6 weeks old) received 15% fructose solution in drinking water for 8 weeks. FDR showed significant increases in plasma levels of insulin, Homeostasis Model Assessment ratio (HOMA-R, an index of insulin resistance), body weight, and systolic blood pressure but not blood glucose levels, when compared with control rats. Brazilian propolis extract (100 and 300mg/kg, p. o.) treatment for 8 weeks significantly decreased the plasma level of insulin, HOMA-R, and body weight, increased plasma triglyceride levels without affecting blood glucose and total cholesterol levels, and tended to decrease systolic blood pressure. In isolated and perfused mesenteric vascular beds of FDR, propolis treatment resulted in a significant reduction of sympathetic nerve-mediated vasoconstrictor response to periarterial nerve stimulation (PNS; 8Hz) and tended to increase the calcitonin gene-related peptide (CGRP) nerve-mediated vasodilator response to PNS, compared with those in untreated FDR. However, propolis treatment did not significantly affect norepinephrine-induced vasoconstriction and CGRP-induced vasodilation. These results suggest that propolis could be an effective functional food to prevent the development of insulin resistance

Royal jelly ameliorates insulin resistance in fructose-drinking rats

Royal jelly (RJ) is known to contain excellent nutrition and a variety of biological activities. The present study was designed to investigate the effects of RJ on insulin resistance (hyperinsulinemia) in fructose-drinking rats (FDR; insulin resistance animal model). Male Wistar rats (6 weeks old) received 15% fructose solution in drinking water for 8 weeks. FDR showed significant increases in plasma levels of insulin and triglyceride, Homeostasis Model Assessment ratio (HOMA-R, an index of insulin resistance), and systolic blood pressure, but not blood glucose levels, when compared with control rats. RJ (100, 300mg/kg, p.o.) treatment for 8 weeks significantly decreased the plasma levels of insulin and triglyceride, HOMA-R, without affecting blood glucose or total cholesterol levels and tended to lower systolic blood pressure. In isolated and perfused mesenteric vascular beds of FDR, RJ treatment resulted in a significant reduction in sympathetic nerve-mediated vasoconstrictor response to periarterial nerve stimulation (PNS) and tended to increase the calcitonin gene-related peptide (CGRP) nervemediated vasodilator response to PNS, compared with those in untreated FDR. However, RJ treatment did not significantly affect norepinephrine-induced vasoconstriction or CGRP-induced vasodilation. These results suggest that RJ could be an effective functional food to prevent insulin resistance associated with the development of hypertension

Dna Authentication of Plantago Herb Based on Nucleotide Sequences of 18S-28S Rrna Internal Transcribed Spacer Region

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