Dose and time-dependent acute and subchronic oral toxicity study of propoxazepam in mice and rats

  • Authors

    • Nikolay Yakovlevich Golovenko Bogatskiy Physical-Chemical Institute of National Academy of Sciences of Ukraine
    • Valentina Nikolayevna Kovalenko
    • Vitalii Borisovich Larionov
    • Аnatoliy Semenovich Reder
    2020-01-23
    https://doi.org/10.14419/ijpt.v8i1.29531
  • Propoxazepam, Acute, subchronic Oral Toxicity, Body and Organ Weights, Food and Water Consumption.
  • Propoxazepam, 7-bromo-5 - (o-chlorophenyl)-3-propoxy - 1,2-dihydro - 3H-1,4-benzodiazepin-2-one, in the models of nociceptive and neuropathic pain showed significant analgesic activity. In order to explore clinical potential of propoxazepam for long term human consumption, toxicology testing in laboratory animals using well-accepted international guidelines is required. Acute toxicity tests were conducted by the oral administration of 2500; 3500; 4000; 4500 and 5000 mg/kg body weight to male and female mice and rats for a period of 3, 7 and 14 day. In subacute study, male rats were administered with various doses of propoxazepam (0.9, 4.5, and 9.0 mg/kg) to evaluate its toxicity for a period of 90 days. The effect of propoxazepam on body weight gain and organ weights, food and water consumptions were analyzed. From the present study, it can be concluded that the acute (3, 7 and 14 days) and subchronic (90 days) oral administrations of propoxazepam did not produce any clinical signs of toxicity or mortality of the male and female mice and rats. These results revealed that the LD50 of propoxazepam is greater than 5000 mg/kg and it therefore, belongs to the category V of relatively non-toxic substances according to the GHS. In the acute toxicity study, neither mortality no significant change in the body weight and the relative organ weights were recorded in all treated mice and rats. Present data set revealed that there wasn`t a strong correlation between body weight with food and water consumptions. The result indicates that the oral administration of propoxazepam did not produce any significant toxic effect in mice and rats and the substance can be safely used for therapeutic use in pharmaceutical formulations.

     

     

  • References

    1. [1] Andronati, S., Semenishyna, E., Pavlovsky, V., Simonov, Y., Makan, S., Boyko, I., Burenkova, N., Gdaniec, M., Cardinael, P., Bouillon, J.P., Mazepa, A. (2010) Synthesis, structure and affinity of novel 3-alkoxy-1,2-dihydro-3H-1,4-benzodiazepin-2-ones for CNS central and peripheral benzodiazepine receptors. Eur J Med Chem 45(4): 1346-1351. https://doi.org/10.1016/j.ejmech.2009.12.027.

      [2] Bannai, M., Ichikawa, M., Nishihara, M, Takahashi, M. (1998) Effect of injection of antisense oligodeoxynucleotides of GAD isozymes into rat ventromedial hypothalamus on food intake and locomotor activity. Brain Res. 784: 305-315. https://doi.org/10.1016/S0006-8993(97)01349-8.

      [3] Bindhu M., Barry Y., Rani S. S., Rick P., Daniel M., Nigel R., Julie K. J., Ken S. Evaluation of OrganWeights for Rodent and Non-Rodent Toxicity Studies: A Review of Regulatory Guidelines and a Survey of Current Practices. Toxicologic Pathology, 35:742–750, 2007. https://doi.org/10.1080/01926230701595292.

      [4] Bruce, H. M., Kennedy G. C. (1951) The central nervous control of food and water intake. J. Camp. Physiol. Psychol. 54: 580-584, I 96 I.

      [5] Cizek LJ, Nocenti M. R. (1965) Relationship between water and food ingestion in the rat. Am J Physiol. 208:615-620. https://doi.org/10.1152/ajplegacy.1965.208.4.615.

      [6] Golovenko N. Ya., Larionov V. B., Reder A. S., Valivodz I. P. (2017) An effector analysis of the interaction of propoxazepam with antagonists of GABA and glycine receptors. Neurochemical Journal 11, No. 4: 302–330. https://doi.org/10.1134/S1819712417040043.

      [7] Golovenko N.Ya., Larionov V.B., Valivodz` I.P. (2017) Absorption and distribution of 14C-Propoxazepam after its intragastral administration. Fiziolohichnyi zhurnal 63, No. 3: 40-48. https://doi.org/10.15407/fz63.03.040.

      [8] Golovenko N.Ya., Larionov V.B., Andronati S.A., Valivodz` I.P., Yurpalova T.A. (2018) Ð harmacodynamic analysis of propoxazepam interaction with GABA-benzodiazepine-receptor-ionophore complex. Neurophysiology 50. 1: 2-11. https://doi.org/10.1007/s11062-018-9711-9.

      [9] Golovenko N. Ya., Voloshchuk N. I., Andronati S. A., Taran I. V., Reder A. S., Pashynska O. S., Larionov V. B. (2018) Antinociception induced by a novel benzodiazepine receptor agonist and bradykinin receptor antagonist in rodent acute and chronic pain models. EJBPS 5, Issue 12: 79-88.

      [10] Kemp J. A., Marshall G. R., Wong E. H., Woodruff G. N., “The affinities, potencies and efficacies of some benzodiazepine-receptor agonists, antagonists and inverse-agonists at rat hippocampal GABAA- receptorsâ€, Br. J. Pharmacol., 91, No. 13, 601-608. (1987). https://doi.org/10.1111/j.1476-5381.1987.tb11253.x.

      [11] Koella W.P. (1985) Animal Experimental Methods in the Study of Antiepileptic Drugs. In: Antiepileptic drugs. Berlin, Heidelberg: Springer-Verlag: 283-340. https://doi.org/10.1007/978-3-642-69518-6_12.

      [12] Larionov V.B., Reder A.S. Ð ropoxazepam, a novel analgesic with multifunctional mechanism of action: review of preclinical data. International scientific and practical conference "Prospects for the development of medicine in EU countries and Ukraine", Wloclavek, Republic of Poland, December 21-22, 2018. P.111-115.

      [13] Naruse T. (1994) Effects of repeated intravenous administration of diazepam on food intake in rats. Fundam Clin Pharmacol 8: 379-384. https://doi.org/10.1111/j.1472-8206.1994.tb00816.x.

      [14] OECD Guideline for Testing of Chemicals (TG 407). Repeated Dose 28-Day Oral Toxicity Study in Rodents. OECD/OEDC. (2008)

      [15] OECD Guidelines for the Testing of Chemicals.408. Repeated Dose 90-day Oral Toxicity Study in Rodents. 2017.

      [16] OECD. Harmonized integrated hazard classification system for human health and environmental effects of chemical substances. 28th Joint Meeting of the Chemicals Committee and the Working Party on Chemicals, Part 2. Paris, France, 1998.

      [17] Randall, L. O., Schallek, W., Heise, G. A., Keith, E. F. and Bagdon, R. E. (1960). The psychosedative properties of methaminodiazepoxide. Journal of Pharmacology and Experimental Zherapeutics, 129: 163-171.

      [18] Robert S. Gable. (2004) Acute toxic effects of club drugs. Journal of Psychoactive Drugs 36(1): 303-313 https://doi.org/10.1080/02791072.2004.10400031.

      [19] Saganuwan S. A. (2017) Toxicity studies of drugs and chemicals in animals: An overview. Bulgarian Journal of Veterinary Medicine 20, No 4: 291–318. https://doi.org/10.15547/bjvm.983.

      [20] Stratford, T.R., Kelley, A.E. (1997) GABA in the nucleus accumbens shell partecipates in the central regulation of feeding behavior. J. Neurosci. 17: 4434 – 4440. https://doi.org/10.1523/JNEUROSCI.17-11-04434.1997.

      [21] Voloshchuk N.І., Тaran І.V., Reder Ð.S., Golovenko M.Ya. (2018) Experimental study of ulcerogenic action of propoxazepam. Reports of Vinnytsia National Medical University 22(1): 6-9. https://doi.org/10.31393/reports-vnmedical-2018-22(1)-01.

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    Yakovlevich Golovenko, N., Nikolayevna Kovalenko, V., Borisovich Larionov, V., & Semenovich Reder, Аnatoliy. (2020). Dose and time-dependent acute and subchronic oral toxicity study of propoxazepam in mice and rats. International Journal of Pharmacology and Toxicology, 8(1), 1-7. https://doi.org/10.14419/ijpt.v8i1.29531