BackgroundClarithromycin (CAM), a representative macrolide antibiotic, has been used widely at low doses for long-term therapy of chronic inflammatory airway diseases. Anti-inflammatory effects of macrolide antibiotics were first discovered in clinical practice. Although oxidative stress is known as a key pathogenesis factor in chronic airway inflammatory diseases, the mechanism of action of low-dose, long-term CAM therapy remains unclear. We aimed to examine the cytoprotective action of CAM against hydrogen peroxide (H2O2)-induced cell dysfunction, focusing on CAM dose and treatment duration, and using human small airway epithelial cells (SAECs), the main cells involved in chronic airway inflammatory diseases.MethodsSAECs were pretreated with CAM (1, 5 or 10 μM) for 24, 48 or 72 h, and were subsequently exposed to H2O2 for 0.5–4 h. Levels of interleukin (IL)-8, glutathione (GSH) and glutathione disulfide (GSSG), and the activities of nuclear factor (NF)-κB and γ-glutamylcysteine synthetase (γ-GCS) were assayed using specific methods. IL-8 mRNA and NF erythroid 2-related factor 2 (Nrf2) mRNA expression were measured using real-time reverse transcription polymerase chain reaction (RT-PCR). Tukey’s multiple comparison test was used for analysis of statistical significance.ResultsPretreatment with low-dose (1 or 5 μM), long-term (72 h) CAM inhibited H2O2-induced IL-8 levels, NF-κB activity, and IL-8 mRNA expression, and improved the GSH/GSSG ratio via the maintenance of γ-GCS expression levels. Similar to its enhancing effect on the GSH/GSSG ratio, pretreatment with low-dose CAM for 72 h significantly increased Nrf2 mRNA expression (p < 0.01 and p < 0.05). In contrast, these alterations were not observed after pretreatment with high-dose (10 μM) or short-term (24 and 48 h) CAM.ConclusionsCAM is efficacious against cell dysfunction caused by oxidative stress under low-dose, long-term treatment conditions. This effect depended on the suppression of NF-κB activation and improvement of the H2O2-induced oxidant/antioxidant imbalance that is achieved by increasing Nrf2 mRNA expression in SAECs. The present study may provide the first evidence of why low-dose, long-term administration of macrolides is effective for treating chronic inflammatory airway diseases.Electronic supplementary materialThe online version of this article (doi:10.1186/s40360-017-0119-8) contains supplementary material, which is available to authorized users.
BackgroundIt is well known that low-dose, long-term macrolide therapy is effective against chronic inflammatory airway diseases. Oxidative stress is considered to be a key pathogenesis factor in those diseases. However, the mechanism of action of low-dose, long-term macrolide therapy remains unclear. We have reported that clarithromycin (CAM), which is a representative macrolide antibiotic, could inhibit hydrogen peroxide (H2O2)-induced reduction of the glutathione (GSH)/glutathione disulfide (GSSG) ratio in human small airway epithelial cells (SAECs), via the maintenance of GSH levels through an effect on γ-glutamylcysteine synthetase (γ-GCS) expression. In this study, we examined the influence of CAM against H2O2-induced activities of cellular antioxidant enzymes and phosphorylated extracellular signal regulatory kinase (p-ERK) using SAECs, the main cells involved in chronic airway inflammatory diseases.MethodsSAECs were pretreated with CAM (1, 5, and 10 μM) for 72 h, and subsequently exposed to H2O2 (100 μM) for 0.5–2 h. Levels of GSH and GSSG, and activities of glutathione peroxidase (GPx)-1, glutathione reductase (GR), superoxide dismutase (SOD), catalase (CAT), heme oxygenase (HO)-1 and p-ERK were assayed. mRNA expressions of GPx-1 and HO-1 were measured using the real-time reverse transcription polymerase chain reaction (RT-PCR). Tukey’s multiple comparison test was used for analysis of statistical significance.ResultsPretreatment with low-dose (1 and 5 μM) CAM for 72 h inhibited H2O2-induced reductions of GPx-1, GR, SOD, CAT and HO-1 activities, and mRNA expressions of GPx-1 and HO-1, and improved the GSH/GSSG ratio. However, these alterations were not observed after pretreatment with high-dose (10 μM) CAM, which suppressed phosphorylation of cell proliferation-associated ERK to cause a significant (p < 0.01) decrease in cell viability.ConclusionsCAM is efficacious against deterioration of cellular antioxidant enzyme activity caused by oxidative stress under low-dose, long-term treatment conditions. On the other hand, pretreatment with high-dose CAM suppressed phosphorylation of cell proliferation-associated ERK and decreased cell viability. The present study may provide additional evidence as to why low-dose, long-term administration of macrolides is effective for treating chronic inflammatory airway diseases.Electronic supplementary materialThe online version of this article (10.1186/s40780-018-0120-4) contains supplementary material, which is available to authorized users.
Drugs are sometimes covered with oblate or agar jelly. It is said that the medicinal eŠect of drugs covered with oblate is slow, but no studies have reported results conˆrming this. Therefore, we examined the dissolution behavior when the drug was covered with oblate or agar jelly. Three types of commercially available formulations of benzodiazepine were used: medazepam sugarcoated tablets, prazepam uncoated tablets, and clorazepate dipotassium capsules. Dissolution tests were performed using solutions of pH 1.2 and 5.6 to simulate normal gastric juice and gastric anacidity, respectively. Drugs covered with oblate were tested by the paddle method, and those covered with agar jelly were tested using the rotating basket method. Dissolution of clorazepate capsules not covered with oblate increased by approximately 10% when the pH was adjusted from 1.2 to 5.6, while those of medazepam and prazepam tablets decreased by approximately 40! 60%. In contrast, the dissolution decreased signiˆcantly at both pH values for each drug covered with oblate. Dissolution further decreased when the amount of oblate was doubled. No detectable dissolution of medazepam tablets or of clorazepate capsules occurred when the drug was covered with agar jelly. Dissolution of prazepam tablets covered with agar jelly was only about 10% at the end of the test. These results indicate that dissolution is slowed and prolonged when a drug is covered with oblate or agar jelly, permitting sustained release of the drug. But, it is necessary to improve a suitable method for the dissolution.
Background/Aim: Interstitial lung disease (ILD) is a serious adverse event (AE) associated with the use of immune checkpoint inhibitors (ICIs). However, the risk factors for developing ICI-related ILD remain poorly understood. Therefore, this study investigated the effect of concomitant analgesics on developing ICI-related ILD using the Japanese Adverse Drug Event Report (JADER) database. Patients and Methods: All the reported AE data were downloaded from the Pharmaceuticals and Medical Devices Agency website, and the JADER data between January 2014 and March 2021 were analysed. The relationship between ICI-related ILD and concomitant use of analgesics was assessed using reporting odds ratio (ROR) and 95% confidence interval. We investigated whether the effect of developing ILD varied according to the type of analgesics used during ICI treatment. Results: Positive signals for ICI-related ILD development were detected for the concomitant use of the narcotic analgesics codeine, fentanyl and oxycodone, but not with morphine.
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