ABSTRACT
Glucocorticoids are used intra-operatively in cochlear implant surgeries to reduce the inflammatory reaction caused by insertion trauma and the foreign body response against the electrode carrier after cochlear implantation. To prevent higher systemic concentrations of glucocorticoids that might cause undesirable systemic side effects, the drug should be applied locally. Since rapid clearance of glucocorticoids occurs in the inner ear fluid spaces, sustained application is supposedly more effective in suppressing foreign body and tissue reactions and in preserving neuronal structures. Embedding of the glucocorticoid dexamethasone into the cochlear implant electrode carrier and its continuous release may solve this problem. The aim of the present study was to examine how dexamethasone concentrations in the electrode carrier influence drug levels in the perilymph at different time points. Silicone rods were implanted through a cochleostomy into the basal turn of the scala tympani of guinea pigs. The silicone rods were loaded homogeneously with 0.1, 1, and 10% concentrations of dexamethasone. After implantation, dexamethasone concentrations in perilymph and cochlear tissue were measured at several time points over a period of up to 7 weeks. The kinetic was concentration-dependent and showed an initial burst release in the 10%- and the 1%-dexamethasone-loaded electrode carrier dummies. The 10%-loaded electrode carrier resulted in a more elevated and longer lasting burst release than the 1%-loaded carrier. Following this initial burst release phase, sustained dexamethasone levels of about 60 and 100 ng/ml were observed in the perilymph for the 1 and 10% loaded rods, respectively, during the remainder of the observation time. The 0.1% loaded carrier dummy achieved very low perilymph drug levels of about 0.5 ng/ml. The cochlear tissue drug concentration shows a similar dynamic to the perilymph drug concentration, but only reaches about 0.005-0.05% of the perilymph drug concentration. Dexamethasone can be released from silicone electrode carrier dummies in a controlled and sustained way over a period of several weeks, leading to constant drug concentrations in the scala tympani perilymph. No accumulation of dexamethasone was observed in the cochlear tissue. In consideration of experimental studies using similar drug depots and investigating physiological effects, an effective dose range between 50 and 100 ng/ml after burst release is suggested for the CI insertion trauma model.
ABSTRACT
Gastroesophageal reflux disease has been implicated in the pathogenesis of adenocarcinoma of the oesophagus. The same applies to laryngopharyngeal reflux (LPR) and squamous cell cancer of the head and neck, but so far, this link has not been proven. The impact of low pH and bile acids has not been studied extensively in cells other than oesophageal cancer cell lines and tissue. The aims of this study were to investigate the pathogenic potential of reflux and its single components on the mucosa of the upper respiratory tract. We measured DNA stability in human miniorgan cultures (MOCs) and primary epithelial cell cultures (EpCs) in response to reflux by the alkaline comet assay. As matrix metalloproteinases (MMPs) are involved in extracellular matrix remodelling processes and may contribute to cancer progression, we studied the expression of MMP1, -9, and -14 in MOCs, EpC, UM-SCC-22B, and FADUDD. DNA strand breaks (DNA-SBs) increased significantly at low pH and after incubation with human or artificial gastric juice. Single incubation with glycochenodeoxycholic acid also showed a significant increase in DNA-SBs. In epithelial cell cultures, human gastric juice increased the number of DNA-SBs at pH 4.5 and 5.5. Artificial gastric juice significantly up regulated the gene expression of MMP9. Western blot analysis confirmed the results of gene expression analysis, but the up regulation of MMP1, -9, and -14 was donor-specific. Reflux has the ability to promote genomic instability and may contribute to micro environmental changes suitable for the initiation of malignancy. Further functional gene analysis may elucidate the role of laryngopharyngeal reflux in the development of head neck squamous cell carcinoma (HNSCC).
