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Allosteric interactions between terfenadine and chlorobutanol on hERG channels
Abstracts / Toxicology Letters 189S (2009) S57–S273
P02 Formulation and evaluation of green tea mouthwash: A new, safe and nontoxic product for children and pregnant women Abdolhossein Moghbel 1,∗ , Ahmad Farajzadeh 2 , Nasrin Aghel 3 , Homaun Agheli 4 , Nafiseh Raisi 1 1
Ahwaz Jundishapur University of Medical Sciences, Pharmaceutics, Ahwaz, Islamic Republic of Iran, 2 Ahwaz Jundishapur University of Medical Sciences, Microbiology, Ahwaz, Islamic Republic of Iran, 3 Ahwaz Jundishapur University of Medical Sciences, Pharmacognosy, Ahwaz, Islamic Republic of Iran, 4 Ahwaz Jundishapur University of Medical Sciences, Medicinal Chemistry, Ahwaz, Islamic Republic of Iran Objective: Green tea (Camellia Sinensis, Teacea) contains antioxidants and antimicrobial agents. The plant affects health of teeth and mouth probably because of the plant tannin. The aim of this study was to prepare a nontoxic, safe and stable formulation of green tea water extract and compare the antibacterial effects of the mouthwash with a same chemical brand on the mouth aerobic bacterial load. Methods: A total of 25 volunteer girl students aged 20–25 years were evaluated by three different concentrations of green tea containing 0.2%, 0.5% and 1% plant tannin at different times, respectively. In second trial, two formulations both containing 1% tannin extract, 20 mg sodium saccharin, q.s. to 100 ml de ionized water with and without 10% ethyl alcohol was compared to a chemical chlorhexidine (0.2%) routine mouthwash as a positive control. Results: Extract containing 1% tannin was more effective than the other concentrations (p < 0.05). Herbal formulation with 10% ethyl alcohol showed more antibacterial effect (p < 0.05). There was no significant difference between herbal (sample) and chemical (control) mouthwashes (p > 0.05). Chemical assay by Folin-Denis method result in 6.23 ± 0.19 mg tannin in 100 mg extract powder. This result was an approval sign of tannin stability in the final formulation. No evidence indicating toxic effects such as irritation, burn, vesicle or mucous disturbance was reported. Conclusion: In spite of similar antibacterial effects of green tea mouth wash with the chemical chlorhexidine it seems that use of a herbal mouthwash is more safe and economical. doi:10.1016/j.toxlet.2009.06.371
P03 Allosteric interactions between terfenadine and chlorobutanol on hERG channels Bernd Zünkler, Anne Friemel ∗ Federal Institute for Drugs and Medical Devices, Pharmacology & Toxicology, Bonn, Germany Several non-cardiovascular drugs have the potential to induce Torsades de Pointes (TdP) cardiac arrhythmias via blockade of the rapid component of the cardiac delayed rectifier K+ current (IKr ) which is encoded by hERG (human ether-à-go-go-related gene). The aim of the present study was to characterise possible allosteric interactions on hERG channels between terfenadine binding to a site located inside the central cavity and chlorobutanol with an unknown binding site on the hERG channel. The whole-cell configuration of the patch-clamp technique was performed on hERG channels stably expressed in HEK (human embryonic kidney) 293 cells. Terfenadine and chlorobutanol synergistically inhibit hERG
S257
currents, and each substance concentration-dependently enhances the inhibitory effect of the other substance. Experiments studying the voltage- and time-dependent inhibitory effects of terfenadine and chlorobutanol on hERG channels demonstrated that the mechanisms of action and, accordingly, the binding sites of both substances on hERG channels are different. Whereas terfenadine seems to bind primarily to the inactivated state of the hERG channel, chlorobutanol seems to inhibit hERG channels primarily in its open state. The observations that the intracellular application of chlorobutanol had no effects on hERG currents and that the effects of chlorobutanol on hERG channels were rapidly reversible on washout might point towards a localization of the binding site for chlorobutanol on the extracellular side of the hERG channel. It is suggested that synergistic effects on hERG channels occur between chlorobutanol and hERG channel blockers binding inside the central cavity of the channel. doi:10.1016/j.toxlet.2009.06.372
P04 The assessment of the ototoxic potential of ethyl benzene Adolf Vyskocil 1,∗ , Tony Leroux 2 , Ginette Truchon 3 , Franc¸ois Lemay 3 , Martine Gendron 2 , France Gagnon 1 , Naima El Majidi 1 , Claude Viau 1 1 Université de Montréal, Département de santé environnementale et santé au travail, Montréal, Canada, 2 Université de Montréal, École d’orthophonie et audiologie, Montréal, Canada, 3 Institut de recherche Robert-Sauvé en santé et en sécurité du travail, Montréal, Canada
Organic solvents can produce ototoxic effects in both man and experimental animals. The objective of this study was to review the literature on the effects of low-level exposure to ethyl benzene on the auditory system and consider its relevance for the occupational settings. Both human and animal investigations were evaluated only for realistic exposure concentrations based on the permissible exposure limits. In Quebec, the time-weighed average exposure value for 8 h (TWAEV) is 100 ppm (434 mg/m3 ) and the shortterm exposure value for 15 min (STEV) is 125 ppm (543 mg/m3 ). In humans, the upper limit for considering ototoxicity data relevant to the occupational exposure situation was set at STEV. Animal data were evaluated only for exposure concentrations up to 100 times the TWAEV. In workers, there is no evidence of either ethyl benzene-induced hearing losses or ototoxic interaction after combined exposure to ethyl benzene and noise. In rats, ethyl benzene affects the auditory function mainly in the cochlear mid-frequency range and ototoxic interaction was observed after combined exposure to noise and ethyl benzene. Further studies with sufficient data on the ethyl benzene exposure of workers are necessary to make a definitive conclusion. Given the current evidence from animal studies, we recommend considering ethyl benzene as a possibly ototoxic agent. doi:10.1016/j.toxlet.2009.06.373
P02 Formulation and evaluation of green tea mouthwash: A new, safe and nontoxic product for children and pregnant women Abdolhossein Moghbel 1,∗ , Ahmad Farajzadeh 2 , Nasrin Aghel 3 , Homaun Agheli 4 , Nafiseh Raisi 1 1
Ahwaz Jundishapur University of Medical Sciences, Pharmaceutics, Ahwaz, Islamic Republic of Iran, 2 Ahwaz Jundishapur University of Medical Sciences, Microbiology, Ahwaz, Islamic Republic of Iran, 3 Ahwaz Jundishapur University of Medical Sciences, Pharmacognosy, Ahwaz, Islamic Republic of Iran, 4 Ahwaz Jundishapur University of Medical Sciences, Medicinal Chemistry, Ahwaz, Islamic Republic of Iran Objective: Green tea (Camellia Sinensis, Teacea) contains antioxidants and antimicrobial agents. The plant affects health of teeth and mouth probably because of the plant tannin. The aim of this study was to prepare a nontoxic, safe and stable formulation of green tea water extract and compare the antibacterial effects of the mouthwash with a same chemical brand on the mouth aerobic bacterial load. Methods: A total of 25 volunteer girl students aged 20–25 years were evaluated by three different concentrations of green tea containing 0.2%, 0.5% and 1% plant tannin at different times, respectively. In second trial, two formulations both containing 1% tannin extract, 20 mg sodium saccharin, q.s. to 100 ml de ionized water with and without 10% ethyl alcohol was compared to a chemical chlorhexidine (0.2%) routine mouthwash as a positive control. Results: Extract containing 1% tannin was more effective than the other concentrations (p < 0.05). Herbal formulation with 10% ethyl alcohol showed more antibacterial effect (p < 0.05). There was no significant difference between herbal (sample) and chemical (control) mouthwashes (p > 0.05). Chemical assay by Folin-Denis method result in 6.23 ± 0.19 mg tannin in 100 mg extract powder. This result was an approval sign of tannin stability in the final formulation. No evidence indicating toxic effects such as irritation, burn, vesicle or mucous disturbance was reported. Conclusion: In spite of similar antibacterial effects of green tea mouth wash with the chemical chlorhexidine it seems that use of a herbal mouthwash is more safe and economical. doi:10.1016/j.toxlet.2009.06.371
P03 Allosteric interactions between terfenadine and chlorobutanol on hERG channels Bernd Zünkler, Anne Friemel ∗ Federal Institute for Drugs and Medical Devices, Pharmacology & Toxicology, Bonn, Germany Several non-cardiovascular drugs have the potential to induce Torsades de Pointes (TdP) cardiac arrhythmias via blockade of the rapid component of the cardiac delayed rectifier K+ current (IKr ) which is encoded by hERG (human ether-à-go-go-related gene). The aim of the present study was to characterise possible allosteric interactions on hERG channels between terfenadine binding to a site located inside the central cavity and chlorobutanol with an unknown binding site on the hERG channel. The whole-cell configuration of the patch-clamp technique was performed on hERG channels stably expressed in HEK (human embryonic kidney) 293 cells. Terfenadine and chlorobutanol synergistically inhibit hERG
S257
currents, and each substance concentration-dependently enhances the inhibitory effect of the other substance. Experiments studying the voltage- and time-dependent inhibitory effects of terfenadine and chlorobutanol on hERG channels demonstrated that the mechanisms of action and, accordingly, the binding sites of both substances on hERG channels are different. Whereas terfenadine seems to bind primarily to the inactivated state of the hERG channel, chlorobutanol seems to inhibit hERG channels primarily in its open state. The observations that the intracellular application of chlorobutanol had no effects on hERG currents and that the effects of chlorobutanol on hERG channels were rapidly reversible on washout might point towards a localization of the binding site for chlorobutanol on the extracellular side of the hERG channel. It is suggested that synergistic effects on hERG channels occur between chlorobutanol and hERG channel blockers binding inside the central cavity of the channel. doi:10.1016/j.toxlet.2009.06.372
P04 The assessment of the ototoxic potential of ethyl benzene Adolf Vyskocil 1,∗ , Tony Leroux 2 , Ginette Truchon 3 , Franc¸ois Lemay 3 , Martine Gendron 2 , France Gagnon 1 , Naima El Majidi 1 , Claude Viau 1 1 Université de Montréal, Département de santé environnementale et santé au travail, Montréal, Canada, 2 Université de Montréal, École d’orthophonie et audiologie, Montréal, Canada, 3 Institut de recherche Robert-Sauvé en santé et en sécurité du travail, Montréal, Canada
Organic solvents can produce ototoxic effects in both man and experimental animals. The objective of this study was to review the literature on the effects of low-level exposure to ethyl benzene on the auditory system and consider its relevance for the occupational settings. Both human and animal investigations were evaluated only for realistic exposure concentrations based on the permissible exposure limits. In Quebec, the time-weighed average exposure value for 8 h (TWAEV) is 100 ppm (434 mg/m3 ) and the shortterm exposure value for 15 min (STEV) is 125 ppm (543 mg/m3 ). In humans, the upper limit for considering ototoxicity data relevant to the occupational exposure situation was set at STEV. Animal data were evaluated only for exposure concentrations up to 100 times the TWAEV. In workers, there is no evidence of either ethyl benzene-induced hearing losses or ototoxic interaction after combined exposure to ethyl benzene and noise. In rats, ethyl benzene affects the auditory function mainly in the cochlear mid-frequency range and ototoxic interaction was observed after combined exposure to noise and ethyl benzene. Further studies with sufficient data on the ethyl benzene exposure of workers are necessary to make a definitive conclusion. Given the current evidence from animal studies, we recommend considering ethyl benzene as a possibly ototoxic agent. doi:10.1016/j.toxlet.2009.06.373