Effect of Chronic Administration of 5-(3-chlorophenyl)-4-Hexyl-2,4 -Dihydro-3<i>H</i>-1,2,4-Triazole-3-Thione (TP-315)—A New Anticonvulsant Drug Candidate—On Living Organisms
About 70 million people suffer from epilepsy—a chronic neurodegenerative disease. In most cases, the cause of the disease is unknown, but epilepsy can also develop as the result of a stroke, trauma to the brain, or the use of psychotropic substances. The treatment of epilepsy is mainly based on the...
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MDPI AG
2021-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/7/3358 |
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| author | Anna Makuch-Kocka Marta Andres-Mach Mirosław Zagaja Anna Śmiech Magdalena Pizoń Jolanta Flieger Judyta Cielecka-Piontek Tomasz Plech |
| author_facet | Anna Makuch-Kocka Marta Andres-Mach Mirosław Zagaja Anna Śmiech Magdalena Pizoń Jolanta Flieger Judyta Cielecka-Piontek Tomasz Plech |
| author_sort | Anna Makuch-Kocka |
| collection | DOAJ |
| description | About 70 million people suffer from epilepsy—a chronic neurodegenerative disease. In most cases, the cause of the disease is unknown, but epilepsy can also develop as the result of a stroke, trauma to the brain, or the use of psychotropic substances. The treatment of epilepsy is mainly based on the administration of anticonvulsants, which the patient must most often use throughout their life. Despite significant progress in research on antiepileptic drugs, about 30% of patients still have drug-resistant epilepsy, which is insensitive to pharmacotherapy used so far. In our recent studies, we have shown that 4-alkyl-5-aryl-1,2,4-triazole-3-thiones act on the voltage-gated sodium channels and exhibit anticonvulsant activity in an MES (maximal electroshock-induced seizure) and 6Hz test in mice. Previous studies have shown their beneficial toxic and pharmacological profile, but their effect on a living organism during chronic use is still unknown. In the presented study, on the basis of the previously conducted tests and the PAMPA (parallel artificial membrane permeability assay) BBB (blood–brain barrier) test, we selected one 1,2,4-triazole-3-thione derivative—TP-315—for further studies aimed at assessing the impact of its chronic use on a living organism. After long-term administration of TP-315 to Albino Swiss mice, its effect on the functional parameters of internal organs was assessed by performing biochemical, morphological, and histopathological examinations. It was also determined whether the tested compound inhibits selected isoforms of the CYP450 enzyme system. On the basis of the conducted tests, it was found that TP-315 does not show nephrotoxic nor hepatotoxic effects and does not cause changes in hematological parameters. In vitro tests showed that TP-315 did not inhibit CYP2B6, CYP2D6, CYP3A4, or CYP3A5 enzymes at the concentration found in the serum of mice subjected to long-term exposure to this compound. |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T12:54:47Z |
| publishDate | 2021-03-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-079e79539b4b47faaad4505cb73427e92023-11-21T11:58:06ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-03-01227335810.3390/ijms22073358Effect of Chronic Administration of 5-(3-chlorophenyl)-4-Hexyl-2,4 -Dihydro-3<i>H</i>-1,2,4-Triazole-3-Thione (TP-315)—A New Anticonvulsant Drug Candidate—On Living OrganismsAnna Makuch-Kocka0Marta Andres-Mach1Mirosław Zagaja2Anna Śmiech3Magdalena Pizoń4Jolanta Flieger5Judyta Cielecka-Piontek6Tomasz Plech7Department of Pharmacology, Faculty of Health Sciences, Medical University of Lublin, 20-093 Lublin, PolandIsobolographic Analysis Laboratory, Institute of Rural Health, 20-090 Lublin, PolandIsobolographic Analysis Laboratory, Institute of Rural Health, 20-090 Lublin, PolandSub-Department of Pathomorphology and Forensic Veterinary Medicine, Department and Clinic of Animal Internal Diseases, University of Life Sciences in Lublin, 20-612 Lublin, PolandDepartment of Analytical Chemistry, Faculty of Pharmacy, Medical University of Lublin, 20-093 Lublin, PolandDepartment of Analytical Chemistry, Faculty of Pharmacy, Medical University of Lublin, 20-093 Lublin, PolandDepartment of Pharmacognosy, Faculty of Pharmacy, Poznan University of Medical Sciences, 61-781 Poznań, PolandDepartment of Pharmacology, Faculty of Health Sciences, Medical University of Lublin, 20-093 Lublin, PolandAbout 70 million people suffer from epilepsy—a chronic neurodegenerative disease. In most cases, the cause of the disease is unknown, but epilepsy can also develop as the result of a stroke, trauma to the brain, or the use of psychotropic substances. The treatment of epilepsy is mainly based on the administration of anticonvulsants, which the patient must most often use throughout their life. Despite significant progress in research on antiepileptic drugs, about 30% of patients still have drug-resistant epilepsy, which is insensitive to pharmacotherapy used so far. In our recent studies, we have shown that 4-alkyl-5-aryl-1,2,4-triazole-3-thiones act on the voltage-gated sodium channels and exhibit anticonvulsant activity in an MES (maximal electroshock-induced seizure) and 6Hz test in mice. Previous studies have shown their beneficial toxic and pharmacological profile, but their effect on a living organism during chronic use is still unknown. In the presented study, on the basis of the previously conducted tests and the PAMPA (parallel artificial membrane permeability assay) BBB (blood–brain barrier) test, we selected one 1,2,4-triazole-3-thione derivative—TP-315—for further studies aimed at assessing the impact of its chronic use on a living organism. After long-term administration of TP-315 to Albino Swiss mice, its effect on the functional parameters of internal organs was assessed by performing biochemical, morphological, and histopathological examinations. It was also determined whether the tested compound inhibits selected isoforms of the CYP450 enzyme system. On the basis of the conducted tests, it was found that TP-315 does not show nephrotoxic nor hepatotoxic effects and does not cause changes in hematological parameters. In vitro tests showed that TP-315 did not inhibit CYP2B6, CYP2D6, CYP3A4, or CYP3A5 enzymes at the concentration found in the serum of mice subjected to long-term exposure to this compound.https://www.mdpi.com/1422-0067/22/7/3358epilepsyhepatotoxicitynephrotoxicity1,2,4-triazole-3-thione derivativesCYP450 enzymesantiepileptic drugs |
| spellingShingle | Anna Makuch-Kocka Marta Andres-Mach Mirosław Zagaja Anna Śmiech Magdalena Pizoń Jolanta Flieger Judyta Cielecka-Piontek Tomasz Plech Effect of Chronic Administration of 5-(3-chlorophenyl)-4-Hexyl-2,4 -Dihydro-3<i>H</i>-1,2,4-Triazole-3-Thione (TP-315)—A New Anticonvulsant Drug Candidate—On Living Organisms International Journal of Molecular Sciences epilepsy hepatotoxicity nephrotoxicity 1,2,4-triazole-3-thione derivatives CYP450 enzymes antiepileptic drugs |
| title | Effect of Chronic Administration of 5-(3-chlorophenyl)-4-Hexyl-2,4 -Dihydro-3<i>H</i>-1,2,4-Triazole-3-Thione (TP-315)—A New Anticonvulsant Drug Candidate—On Living Organisms |
| title_full | Effect of Chronic Administration of 5-(3-chlorophenyl)-4-Hexyl-2,4 -Dihydro-3<i>H</i>-1,2,4-Triazole-3-Thione (TP-315)—A New Anticonvulsant Drug Candidate—On Living Organisms |
| title_fullStr | Effect of Chronic Administration of 5-(3-chlorophenyl)-4-Hexyl-2,4 -Dihydro-3<i>H</i>-1,2,4-Triazole-3-Thione (TP-315)—A New Anticonvulsant Drug Candidate—On Living Organisms |
| title_full_unstemmed | Effect of Chronic Administration of 5-(3-chlorophenyl)-4-Hexyl-2,4 -Dihydro-3<i>H</i>-1,2,4-Triazole-3-Thione (TP-315)—A New Anticonvulsant Drug Candidate—On Living Organisms |
| title_short | Effect of Chronic Administration of 5-(3-chlorophenyl)-4-Hexyl-2,4 -Dihydro-3<i>H</i>-1,2,4-Triazole-3-Thione (TP-315)—A New Anticonvulsant Drug Candidate—On Living Organisms |
| title_sort | effect of chronic administration of 5 3 chlorophenyl 4 hexyl 2 4 dihydro 3 i h i 1 2 4 triazole 3 thione tp 315 a new anticonvulsant drug candidate on living organisms |
| topic | epilepsy hepatotoxicity nephrotoxicity 1,2,4-triazole-3-thione derivatives CYP450 enzymes antiepileptic drugs |
| url | https://www.mdpi.com/1422-0067/22/7/3358 |
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