Comparative study of specific activity of rectal suppositories with clopidogrel
DOI:
https://doi.org/10.14739/2409-2932.2021.3.242242Keywords:
atherothrombosis, clopidogrel, rectal suppositories, specific activityAbstract
One of the most effective platelet antiaggregants is clopidogrel, inhibiting platelet activation by selectively binding adenosine diphosphate (ADP) with specific receptors. However, in a number of clinical situations it is necessary to have a pronounced antithrombotic effect in the shortest possible time which gives rise to interest in the transmucose use of the drug, in particular, rectal route. The theoretical preconditions for the development of a rectal administration of clopidogrel are based on the data that the anti-aggregation effect of a substance is carried out by its main metabolite formed after “first hepatic passage”, while clopidogrel itself in this aspect is inactive. On the base of complex physico-chemical, pharmaceutical, biopharmaceutical, rheological and microbiological investigations, the rational composition of clopidogrel rectal dosage form – suppository on a hydrophilic base to prevent atherothrombotic events in patients with myocardial infarction, acute coronary syndrome, ischemic stroke, peripheral arterial occlusion, is proposed by the employees of the Department of Technology of Medications of the Zaporizhzhia State Medical University.
The aim of the work is to investigate the specific activity of rectal suppositories with clopidogrel.
Materials and methods. Experimental suppositories with clopidogrel 0,075 g for rectal administration were used as the objects in pre-line studies. The ability of clopidogrel to reduce the inhibitory effect of ADP on adenylate cyclase activity and decrease the number of binding sites for 2-methylthio-ADP (analogue of ADP) without altering the receptor topography is used as a base of the method of comparative study of its specific activity in the rectal dosage form (suppository) and in comparison with the reference medication Plavix (SANOFI WINTHROP INDUSTRIE, France) in the tablet form. Studies were performed on white non-linear rats of different sexes with different mass 150–210 g, aged 3.5–5.0 months.
Results. Statistically significant differences in the inhibition of induced platelet aggregation were registered after 6 hours of rectal administration of clopidogrel and gastric administration of the reference medication, indicating the effectiveness of the rectal applicative transmucosal route for this active pharmaceutical ingredient (API). On the 5th day of administration, inhibition of induced platelet aggregation significantly increased, and that is supported by literature on the cumulative effect of clopidogrel in daily life. When comparing the digital material of the table, it is obvious that the rectal administration of clopidogrel is more effective in comparison with oral route which is probably due to the rapid delivery of API to the liver and the formation of an active metabolite of clopidogrel inhibiting the induction and spontaneous aggregation of platelets in human’s and animal’s blood. Obtained data provide with sound arguments for development of rectal suppositories with clopidogrel because in clinical care faster achievement of an anti-aggregation effect in patients with acute coronary syndrome is the primary task of clinical pharmacology and pharmacy.
Conclusions. Using the biochemical model of pathology, it was established that the applicative semisolid medication of clopidogrel in the form of rectal suppository exhibited inductive anti-aggregation activity and its administration didn’t reveal any side effects and undesirable events. Rectal suppositories with clopidogrel have been shown to exhibit faster reliable anti-aggregation effect in comparison with intragastric administration.
References
Weber, C., Badimon, L., Mach, F., & van der Vorst, E. (2017). Therapeutic strategies for atherosclerosis and atherothrombosis: Past, present and future. Thrombosis and haemostasis, 117(7), 1258-1264. https://doi.org/10.1160/TH16-10-0814
Grover, S. P., Mackman, N. (2020). Tissue factor in atherosclerosis and atherothrombosis. Atherosclerosis, 307, 80-86. https://doi.org/10.1016/j.atherosclerosis.2020.06.003
Tsigkou, V., Siasos, G., Rovos, K., Tripyla, N., Tousoulis, D. (2018). Peripheral artery disease and antiplatelet treatment. Current opinion in pharmacology, 39, 43-52. https://doi.org/10.1016/j.coph.2018.01.011
Patti, G., Micieli, G., Cimminiello, C., & Bolognese, L. (2020). The Role of Clopidogrel in 2020: A Reappraisal. Cardiovascular therapeutics, 2020, 8703627. https://doi.org/10.1155/2020/8703627
Purohit, T. J., Hanning, S. M., & Wu, Z. (2018). Advances in rectal drug delivery systems. Pharmaceutical development and technology, 23(10), 942-952. https://doi.org/10.1080/10837450.2018.1484766
Hua S. (2019). Physiological and Pharmaceutical Considerations for Rectal Drug Formulations. Frontiers in pharmacology, 10, 1196. https://doi.org/10.3389/fphar.2019.01196
Bijak, M., Szelenberger, R., Saluk, J., & Nowak, P. (2017). Flavonolignans inhibit ADP induced blood platelets activation and aggregation in whole blood. International journal of biological macromolecules, 95, 682-688. https://doi.org/10.1016/j.ijbiomac.2016.12.002
Wang, Z. Y., Chen, M., Zhu, L. L., Yu, L. S., Zeng, S., Xiang, M. X., & Zhou, Q. (2015). Pharmacokinetic drug interactions with clopidogrel: updated review and risk management in combination therapy. Therapeutics and clinical risk management, 11, 449-467. https://doi.org/10.2147/TCRM.S80437
Leader, A., Zelikson-Saporta, R., Pereg, D., Spectre, G., Rozovski, U., Raanani, P., Hermoni, D., & Lishner, M. (2017). The Effect of Combined Aspirin and Clopidogrel Treatment on Cancer Incidence. The American journal of medicine, 130(7), 826-832. https://doi.org/10.1016/j.amjmed.2017.01.022
Jiang, X. L., Samant, S., Lesko, L. J., & Schmidt, S. (2015). Clinical pharmacokinetics and pharmacodynamics of clopidogrel. Clinical pharmacokinetics, 54(2), 147-166. https://doi.org/10.1007/s40262-014-0230-6
Redkina, Ye. А., Gladyshev, V. V., Burlaka, B. S., & Pukhalskaya, I. A. (2018). Vyvchennia vplyvu dopomizhnykh rechovyn na vyvilnennia klopidohreliu z rektalnykh supozytoriiv [The study of excipients’ influence on Clopidogrel releasing from the rectal suppositories]. Current issues in pharmacy and medicine: science and practice, 11(1), 74-78. [in Ukrainian]. https://doi.org/10.14739/2409-2932.2018.1.123717
Redkina, Ye. A., Hladyshev, V. V., & Burlaka, B. S. (2018). Izuchenie strukturno-mekhanicheskikh svoistv suppozitoriev s klopidogrelem [The study of structural-mechanical characteristics of suppositories with clopidogrel]. Current issues in pharmacy and medicine: science and practice, 11(3), 281-285. [in Russian]. https://doi.org/10.14739/2409-2932.2018.3.145218
Redkina, Ye. А., Gladyshev, V. V., Burlaka, B. S., Kechin, I. L. (2018). Vyvchennia vplyvu kontsentratsii poverkhnevo-aktyvnykh rechovyn na vyvilnennia klopidohreliu z rektalnykh supozytoriiv [Study of influence of the surface-active substances concentration on releasing of clopidogrel from the rectal suppository]. Current issues in pharmacy and medicine: science and practice, 11(2), 185-189. [in Ukrainian]. https://doi.org/10.14739/2409-2932.2018.2.133214
Savlenko, E. A. & Tkachenko, E. V. (2017). Znachenie upravleniya riskami dlya kachestva na etape doklinicheskikh issledovanii lekarstvennogo preparata [Importance of risk management for quality at the stage of preclinical studies of a medicinal product]. Upravlinnia yakistiu v farmatsii. Proceedings of the 11th scientific-practical conference (pp. 152). Kharkiv: NfaU. [in Russian].
Murashev, A. N., Popov, V. S., Krasilshchikova, M. S., Zharmukhamedova, T. Yu., Rzhevskiy, D. I., & Khokhlova, O. N. (2015). Natsional'nye osobennosti doklinicheskikh issledovanii i ispol'zovaniya laboratornykh zhivotnykh v Rossii: problemy i perspektivy [National characteristics of preclinical studies and use of laboratory animals in Russia: problems and prospects]. Vedomosti Naucnogo centra ekspertizy sredstv medicinskogo primenenia, (2), 35-39. [in Russian].
Spasov, А. А., Kucheryavenko, A. F., Gаidukоvа, К. А., Sirotenkо, V. C. & Zhukovskaya, O. N. (2020). Izuchenie novogo proizvodnogo benzimidazola, imeyushchego v svoei strukture prostranstvenno zatrudnennyi fenol'nyi zamestitel', na modelyakh arterial'nogo i venoznogo tromboza [Study of a new benzimidazole derivative having in its structure a sterically hindered phenolic substituent on models of arterial and venous thrombosis]. Thromboz, gemostaz i reologiya, (3), 62-66. [in Russian]. https://doi.org/10.25555/THR.2020.3.0930
Gurbel, P. A., O'Connor, C. M., Cummings, C. C., & Serebruany, V. L. (1999). Clopidogrel: the future choice for preventing platelet activation during coronary stenting? Pharmacological research, 40(2), 107-111. https://doi.org/10.1006/phrs.1999.0478
Downloads
Published
How to Cite
Issue
Section
License
Authors who publish with this journal agree to the following terms:
- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access)