Discovery and Development of S6821 and S7958 as Potent TAS2R8 Antagonists.

In humans, bitter taste is mediated by 25 TAS2Rs. Many compounds, including certain active pharmaceutical ingredients, excipients, and nutraceuticals, impart their bitter taste (or in part) through TAS2R8 activation. However, effective TAS2R8 blockers that can either suppress or reduce the bitterness of these compounds have not been described. We are hereby reporting a series of novel 3-(pyrazol-4-yl) imidazolidine-2,4-diones as potent and selective TAS2R8 antagonists. In human sensory tests, S6821 and S7958, two of the most potent analogues from the series, demonstrated efficacy in blocking TAS2R8-mediated bitterness and were selected for development. Following data evaluation by expert panels of a number of national and multinational regulatory bodies, including the US, the EU, and Japan, S6821 and S7958 were approved as safe under conditions of intended use as bitter taste blockers.

Relationship Between Electrode-to-Modiolus Distance and Current Levels for Adults With Cochlear Implants.

HYPOTHESIS: Electrode-to-modiolus distance is correlated with clinically programmed stimulation levels. BACKGROUND: Conventional wisdom has long supposed a significant relationship between cochlear implant (CI) stimulation levels and electrode-to-modiolus distance; however, to date, no such formal investigation has been completed. Thus, the purpose of this project was to investigate the relationship between stimulation levels and electrode-to-modiolus distance. A strong correlation between the two would suggest that stimulation levels might be used to estimate electrode-to-modiolus geometry. METHODS: Electrode-to-modiolus distance was determined via CT imaging using validated CI position analysis software in 137 implanted ears from the three manufacturers holding FDA approval in the United States. Analysis included 2,365 total electrodes, with 1,472 from precurved arrays. Distances were compared to clinically programmed C/M levels that were converted to charge units. RESULTS: Mean modiolar distance with perimodiolar and lateral wall electrodes was 0.47 and 1.15 mm, respectively. Mean suprathreshold charge values were significantly different between each manufacturer. When combining all data, we found a moderate positive correlation (r = 0.367, p < 0.01) that was driven both by the different charge values across companies, and that the company with the highest mean charge values only offers straight electrode arrays. When grouped by electrode type, however, we found a weak correlation (r = 0.12, p < 0.01) for perimodiolar array electrodes only. When considering a single array type from any one manufacturer, only one was observed where distance mildly predicted charge. CONCLUSION: Our results suggest that electrode distance minimally contributes to the current level required for suprathreshold stimulation.

Localization and interaural time difference (ITD) thresholds for cochlear implant recipients with preserved acoustic hearing in the implanted ear.

The purpose of this study was to investigate horizontal plane localization and interaural time difference (ITD) thresholds for 14 adult cochlear implant recipients with hearing preservation in the implanted ear. Localization to broadband noise was assessed in an anechoic chamber with a 33-loudspeaker array extending from -90 to +90°. Three listening conditions were tested including bilateral hearing aids, bimodal (implant + contralateral hearing aid) and best aided (implant + bilateral hearing aids). ITD thresholds were assessed, under headphones, for low-frequency stimuli including a 250-Hz tone and bandpass noise (100-900 Hz). Localization, in overall rms error, was significantly poorer in the bimodal condition (mean: 60.2°) as compared to both bilateral hearing aids (mean: 46.1°) and the best-aided condition (mean: 43.4°). ITD thresholds were assessed for the same 14 adult implant recipients as well as 5 normal-hearing adults. ITD thresholds were highly variable across the implant recipients ranging from the range of normal to ITDs not present in real-world listening environments (range: 43 to over 1600 µs). ITD thresholds were significantly correlated with localization, the degree of interaural asymmetry in low-frequency hearing, and the degree of hearing preservation related benefit in the speech reception threshold (SRT). These data suggest that implant recipients with hearing preservation in the implanted ear have access to binaural cues and that the sensitivity to ITDs is significantly correlated with localization and degree of preserved hearing in the implanted ear.