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Neurotoxicity assessment of amoxicillin in juvenile rats
S272
Abstracts / Toxicology Letters 238S (2015) S56–S383
diastase/Periodic Acid Schiff and/or Masson trichrome. Results: In humans, the inferior surface of the tongue is lined by a stratified, squamous, non keratinized epithelium which is closely resembled by that of non-human primates. The oral mucosae of minipigs, dogs and rabbits present similar histological features and are comparable. All the rodent species studied have thinner, keratinized mucosae. The thickness of the oral epithelium and lamina propria, as well as the grade of rete ridges/papillae, are more or less proportional to the size of the species. Glycogen is seen in the superficial layers of human, non-human primate and minipig mucosae. Conclusion: Non rodent (monkey, minipig, dog and rabbit) and human mucosae have comparable histological features. Rodent oral mucosae are thinner and keratinized. Impact statement: Based upon this qualitative histological evaluation, the mouth mucosae of nonhuman primates and minipigs were found to be closest to human mouth mucosae. http://dx.doi.org/10.1016/j.toxlet.2015.08.782
P12-071 Transfer of tetravalent dengue vaccine during gestation and lactation in mice G. Ravel 1 , A. Rogue 2 , F. Spézia 2 , N. Mantel 1 , S. Gould 1 , R. Forster 2,∗ 1 2
Sanofi-pasteur, Marcy L’Etoile, France CiToxLAB, Evreux, France
To support the licensure of a recombinant, live, attenuated tetravalent dengue vaccine, a developmental and reproductive toxicity (DART) program was initiated to investigate the potential risk for women of childbearing potential (WOCBP) and their offspring following vaccination. In designing a DART program for a live attenuated vaccine, the selection of the appropriate species is key. The species must be relevant and develop a detectable viremia and humoral response post-vaccination with transfer to the offspring. Based on available preliminary data with the dengue vaccine in non-pregnant animals, the mouse was selected as an appropriate species for the DART studies. A sensitive method was developed to investigate transfer of the RNA vaccine virus to embryos and fetuses through the placenta and to the offspring through the milk in the mouse. The Quantitative Reverse Transcriptase-Polymerase Chain Reaction (RT-qPCR) techniques specific to the vaccine virus sequence were established in maternal serum, milk, embryos and pup serum matrices and fully validated according to current regulatory guidelines. In vivo studies were then conducted to investigate the exposure and transfer of the vaccine in mice. Mouse dams were given one dose of the dengue vaccine during either gestation or lactation. The dams were administered the test vaccine by the intravenous route to maximize the exposure to the virus. Maternal serum, whole embryos, lactating milk and serum of pups were sampled and RNA was extracted using customized extraction procedures. RNA copy numbers were calculated by interpolation from a calibration curve. RNA was detected by qRT-PCR at low level in serum of pregnant females and in embryo samples. Vaccine RNA was not detected in the milk of dams or the serum of pups. These results illustrate the feasibility of techniques for evaluation of placental and milk transfer of the dengue vaccine to offspring and were further extended to the rabbit for the purpose of the development of another live attenuated vaccine. http://dx.doi.org/10.1016/j.toxlet.2015.08.783
P12-072 Neurotoxicity assessment of amoxicillin in juvenile rats O. Atli 1,∗ , U. Demir-Ozkay 2 , S. Ilgin 1 , H. Aydin 2 , E.N. Akbulut 1 , E. Sener 3 1
Anadolu University Faculty of Pharmacy, Department of Pharmaceutical Toxicology, Eskis¸ehir, Turkey 2 Anadolu University Faculty of Pharmacy, Department of Pharmacology, Eskisehir, Turkey 3 Anadolu University Faculty of Pharmacy, Department of Analytical Chemistry, Eskisehir, Turkey Amoxicillin is one of the most commonly prescribed antibiotics for children and childhood is the period to have the highest risk for toxicity cases including drug induced adverse reactions. Some neurological adverse effects (anxiety, hyperactivity, insomnia, confusion, convulsions, behavioral changes, and dizziness) have been reported related to amoxicillin treatment. The present study was designed to determine the effects of repeated-amoxicillin administration on neurologic functions at clinically relevant doses in juvenile rats. For this purpose, behavioral tests (modified forced swimming test, plus-maze tests, activity cage tests, Rota-rod tests, pentylenetetrazole-induced seizure test) were performed and levels of brain gamma amino butyric acid, glutamate, dopamine, serotonin, adrenalin and noradrenalin, which are endogenous mediators regulating mood and behaviors, were also determined for the purpose of identifying possible underlying mechanisms related to neurotoxicity. Moreover, brain glutathione, superoxide dismutase, catalase and malondialdehyde levels were measured in order to evaluate the possible contribution of oxidative stress to the amoxicillin-induced neurotoxicity. According to our results, it has been shown in this study that the amoxicillin treatment in repeated pharmacological doses in juvenile rats triggered depression and shortened the time of the appearance of first seizure. Matching to our results at this point, the serotonin levels in the groups which received 25 and 50 mg/kg amoxicillin were decreased significantly when compared with the control group, which is thought to be related to depression. Also, as an important finding, the glutamate levels in brain homogenates increased significantly in amoxicillin-treated groups. Otherwise, lower superoxide dismutase and catalase activities in brain tissues amoxicillinadministered rats compared to control rats. In conclusion, repeated pharmacological doses of amoxicillin were found to induce neurological toxicity in juvenile rats. Also, altered brain neurotransmitter levels and increased oxidative stress observed in our study were thought to be the possible underlying mechanisms of amoxicillininduced neurotoxicity. http://dx.doi.org/10.1016/j.toxlet.2015.08.784
P12-073 Evaluation of quetiapine-induced hepatotoxicity in rats S. Ilgin 1,∗ , O. Atli 1 , D. Burukoglu 2 , M. Baysal 1 , O. Hinis 1 1 Anadolu University Faculty of Pharmacy, Department of Pharmaceutical Toxicology, Eskis¸ehir, Turkey 2 Eskisehir Osmangazi University Faculty of Medicine, Department of Histology–Embryology, Eskisehir, Turkey
Quetiapine is an atypical antipsychotic agent used to control positive and negative symptoms in patients with schizophrenia.
Abstracts / Toxicology Letters 238S (2015) S56–S383
diastase/Periodic Acid Schiff and/or Masson trichrome. Results: In humans, the inferior surface of the tongue is lined by a stratified, squamous, non keratinized epithelium which is closely resembled by that of non-human primates. The oral mucosae of minipigs, dogs and rabbits present similar histological features and are comparable. All the rodent species studied have thinner, keratinized mucosae. The thickness of the oral epithelium and lamina propria, as well as the grade of rete ridges/papillae, are more or less proportional to the size of the species. Glycogen is seen in the superficial layers of human, non-human primate and minipig mucosae. Conclusion: Non rodent (monkey, minipig, dog and rabbit) and human mucosae have comparable histological features. Rodent oral mucosae are thinner and keratinized. Impact statement: Based upon this qualitative histological evaluation, the mouth mucosae of nonhuman primates and minipigs were found to be closest to human mouth mucosae. http://dx.doi.org/10.1016/j.toxlet.2015.08.782
P12-071 Transfer of tetravalent dengue vaccine during gestation and lactation in mice G. Ravel 1 , A. Rogue 2 , F. Spézia 2 , N. Mantel 1 , S. Gould 1 , R. Forster 2,∗ 1 2
Sanofi-pasteur, Marcy L’Etoile, France CiToxLAB, Evreux, France
To support the licensure of a recombinant, live, attenuated tetravalent dengue vaccine, a developmental and reproductive toxicity (DART) program was initiated to investigate the potential risk for women of childbearing potential (WOCBP) and their offspring following vaccination. In designing a DART program for a live attenuated vaccine, the selection of the appropriate species is key. The species must be relevant and develop a detectable viremia and humoral response post-vaccination with transfer to the offspring. Based on available preliminary data with the dengue vaccine in non-pregnant animals, the mouse was selected as an appropriate species for the DART studies. A sensitive method was developed to investigate transfer of the RNA vaccine virus to embryos and fetuses through the placenta and to the offspring through the milk in the mouse. The Quantitative Reverse Transcriptase-Polymerase Chain Reaction (RT-qPCR) techniques specific to the vaccine virus sequence were established in maternal serum, milk, embryos and pup serum matrices and fully validated according to current regulatory guidelines. In vivo studies were then conducted to investigate the exposure and transfer of the vaccine in mice. Mouse dams were given one dose of the dengue vaccine during either gestation or lactation. The dams were administered the test vaccine by the intravenous route to maximize the exposure to the virus. Maternal serum, whole embryos, lactating milk and serum of pups were sampled and RNA was extracted using customized extraction procedures. RNA copy numbers were calculated by interpolation from a calibration curve. RNA was detected by qRT-PCR at low level in serum of pregnant females and in embryo samples. Vaccine RNA was not detected in the milk of dams or the serum of pups. These results illustrate the feasibility of techniques for evaluation of placental and milk transfer of the dengue vaccine to offspring and were further extended to the rabbit for the purpose of the development of another live attenuated vaccine. http://dx.doi.org/10.1016/j.toxlet.2015.08.783
P12-072 Neurotoxicity assessment of amoxicillin in juvenile rats O. Atli 1,∗ , U. Demir-Ozkay 2 , S. Ilgin 1 , H. Aydin 2 , E.N. Akbulut 1 , E. Sener 3 1
Anadolu University Faculty of Pharmacy, Department of Pharmaceutical Toxicology, Eskis¸ehir, Turkey 2 Anadolu University Faculty of Pharmacy, Department of Pharmacology, Eskisehir, Turkey 3 Anadolu University Faculty of Pharmacy, Department of Analytical Chemistry, Eskisehir, Turkey Amoxicillin is one of the most commonly prescribed antibiotics for children and childhood is the period to have the highest risk for toxicity cases including drug induced adverse reactions. Some neurological adverse effects (anxiety, hyperactivity, insomnia, confusion, convulsions, behavioral changes, and dizziness) have been reported related to amoxicillin treatment. The present study was designed to determine the effects of repeated-amoxicillin administration on neurologic functions at clinically relevant doses in juvenile rats. For this purpose, behavioral tests (modified forced swimming test, plus-maze tests, activity cage tests, Rota-rod tests, pentylenetetrazole-induced seizure test) were performed and levels of brain gamma amino butyric acid, glutamate, dopamine, serotonin, adrenalin and noradrenalin, which are endogenous mediators regulating mood and behaviors, were also determined for the purpose of identifying possible underlying mechanisms related to neurotoxicity. Moreover, brain glutathione, superoxide dismutase, catalase and malondialdehyde levels were measured in order to evaluate the possible contribution of oxidative stress to the amoxicillin-induced neurotoxicity. According to our results, it has been shown in this study that the amoxicillin treatment in repeated pharmacological doses in juvenile rats triggered depression and shortened the time of the appearance of first seizure. Matching to our results at this point, the serotonin levels in the groups which received 25 and 50 mg/kg amoxicillin were decreased significantly when compared with the control group, which is thought to be related to depression. Also, as an important finding, the glutamate levels in brain homogenates increased significantly in amoxicillin-treated groups. Otherwise, lower superoxide dismutase and catalase activities in brain tissues amoxicillinadministered rats compared to control rats. In conclusion, repeated pharmacological doses of amoxicillin were found to induce neurological toxicity in juvenile rats. Also, altered brain neurotransmitter levels and increased oxidative stress observed in our study were thought to be the possible underlying mechanisms of amoxicillininduced neurotoxicity. http://dx.doi.org/10.1016/j.toxlet.2015.08.784
P12-073 Evaluation of quetiapine-induced hepatotoxicity in rats S. Ilgin 1,∗ , O. Atli 1 , D. Burukoglu 2 , M. Baysal 1 , O. Hinis 1 1 Anadolu University Faculty of Pharmacy, Department of Pharmaceutical Toxicology, Eskis¸ehir, Turkey 2 Eskisehir Osmangazi University Faculty of Medicine, Department of Histology–Embryology, Eskisehir, Turkey
Quetiapine is an atypical antipsychotic agent used to control positive and negative symptoms in patients with schizophrenia.