KINETICS OF ABSORPTION OF A NEW ANTIHYPOXYANT OKAGERM-4 IN NORM AND IN CONDITIONS OF HYPOXIC SYNDROME
DOI:
https://doi.org/10.11603/1811-2471.2019.v0.i2.10381Keywords:
pharmacokinetics, absorption, OKAGERM-4, confined space hypoxiaAbstract
The actual problem of pharmacology is the search for highly effective and safe means of pharmacotherapy for acute hypoxia, which develops in a closed unventilated space and is called confined space hypoxia. Today, in this regard, promising are the coordination compounds of germanium with biologically active ligands in the form of trace elements and organic acids. Previously conducted screening and toxicometric studies revealed a high antihypoxic activity and safety of the first synthesized coordination compound of germanium – manganese (II) tartratogermanat (IV) under the laboratory code OKAGERM-4.
The aim – comparative pharmacokinetic analysis of a potential antihypoxant OKAGERM-4 at the stage of its absorption in normal conditions and on a confined space hypoxia model.
Material and Methods. The experiments were performed on 48 white rats of both sexes weighing 170–200 g, which were divided into two groups. The group 1 was the control, and in animals of the groupn 2, confined space hypoxia was simulated by placing animals for 25 min in isolated sealed volume (10 dm3). To determine the pharmacokinetic profile after 45 min; 3; 6 and 24 h (since intraperitoneal injection) in the serum was determined by the level of OKAGERM-4 by the colorimetric method. Indicators of the absorption process were calculated using the Phoenix WinNonLin 8.1 program.
Results. For OKAGERM-4 at a dose of 96.8 mg/kg, pharmacokinetic curves were constructed. The following pharmacokinetic parameters (M±m) of the OKAGERM-4 absorption were obtained in a two-chamber analysis of concentration dynamics: Cmax (normal) = (7.54±0.29) mg/l; Cmax (hypoxia) = (7.13±0.20) mg/l; tmax (norm) = (1.47±0.04) h; tmax (hypoxia) = (1.52±0.06) h; K01 (norm) = (0.82±0.05) h-1; K01 (hypoxia) = (0.80±0.05) h-1; t1/2α (norm) = (0.85±0.07) h; t1/2α (hypoxia) = (0.87±0.05) h.
Conclusions. It was established experimentally that under conditions of confined space hypoxia, a significant change in the Cmax parameter occurs.
References
Shabanov, P.D., Zarubina, I.V., Novikov, V.Ye., & Tsygan, V.N. (2010). Metabolicheskiye korrektory gipoksii [Metabolic correctors of hypoxia]. Saint-Petersburg: InformNovigator [in Russian].
Pittman, R.N. (2011). Regulation of tissue oxygenation. Colloquium: Series on Integrated Systems Physiology: From Molecule to Function, 3, 3, 1-100. DOI: https://doi.org/10.4199/C00029ED1V01Y201103ISP017
Katschinski, D.M. (2013). Editorial: an introduction and welcome to Hypoxia. Hypoxia, 1, 29-30. DOI: https://doi.org/10.2147/HP.S52866
Wenger, R.H., Kurtcuoglu, V., & Scholz, C.C. (2015). Frequently asked questions in hypoxia research. Hypoxia, 3, 35-43. DOI: https://doi.org/10.2147/HP.S92198
Lukyanova, L.D., Kirova, Yu.I., & Sukoyan, G.V. (2011). Novoye o signalnykh mekhanizmakh adaptatsii k gipoksii i ikh roli v sistemnoy regulyatsii [New about signaling mechanisms of adaptation to hypoxia and their role in systemic regulation]. Patogenez – Pathogenesis, 9, 3, 4-14 [in Russian].
Lukianchuk, V.D., Seyfullina, I.Y., & Shebaldova, K.O. (2013). Porivnialni skryninhovi doslidzhennia v riadu koordynatsiinykh spoluk hermaniiu na modeli hipoksii zamknutoho prostoru [Comparative screening studies in the range of coordination compounds of germanium on the model of closed space hypoxia]. Ukrainskyi zhurnal ekstremalnoi medytsyny im. H.O. Mozhaieva – Ukrainian Journal of Extreme Medicine named after H.O. Mozhaieva, 1, 81-84 [in Ukrainian].
Lukianchuk, V.D., Seifullina, I.Yu., & Zhytina, I.O. (2013). Koordynatsiini spoluky hermaniiu – stratehichnyi vektor poshuku antyhipoksantiv [Coordination compounds of germanium – a strategic vector for the search for antihypoxants]. XII Zizd vseukrainskoho likarskoho tovarystva (VULT) 5–7 veresnia: tez. dop. – XII Congress of All-Ukrainian Medical Society (VULT) 5-7 September 2013: Abstracts of Papers. Kyiv [in Ukrainian].
Lukianchuk, V.D., Zhytina, I.O., & Seifullina, I.Y. (2010). Skryninh i porivnialna otsinka protyishemichnoi efektyvnosti sered koordynatsiinykh spoluk hermaniiu pry hostrii tserebrovaskuliarnii nedostatnosti [Screening and comparative estimation of anti-ischemic efficacy among coordination compounds of germanium in acute cerebrovascular failure]. Farmakolohiia ta likarska toksykolohiia – Pharmacology and Drug Toxicology, 1-2 (14-15), 61-64 [in Ukrainian].
Lukianchuk, V.D., Shutka, A.A., & Seifullina, I.Y. (2010). Porivnialna protyhipoksychna aktyvnist koordynatsiinykh spoluk hermaniiu [Comparative antihypoxic activity of coordination compounds of germanium]. Odeskyi medychnyi zhurnal – Odesa Medical Journal, 2, 11-14 [in Ukrainian].
Luchyshyn, T.R. (2013). Poshuk zasobiv farmakoterapii syndromu endohennoi intoksykatsii sered koordynatsiinykh spoluk hermaniiu [The search for means of pharmacotherapy of endogenous intoxication syndrome among coordination compounds of Germanium]. Extended abstract of Candidate’s thesis. Odesa [in Ukrainian].
Polishchuk, Ye.M. (2015). Eksperymentalne obhruntuvannia dotsilnosti zastosuvannia novoi koordynatsiinoi spoluky Tserebroherm dlia likuvannia travmatychnoho poshkodzhennia holovnoho mozku [Experimental substantiation of expediency of application of the new coordination compound Cerebrogerm for the treatment of traumatic brain damage]. Extended abstract of Candidate’s thesis. Odesa [in Ukrainian].
Litvinenko, D.F., Kozyr, V.A., & Martsynko, O.E. (2016). Poshuk potentsiinykh antyhipoksantiv sered oryhinalnykh heterometalichnykh kompleksiv hermaniiu ta 3d-metaliv na osnovi lymonnoi ta vynnoi kyslot [The search for potential antihypoxants among the original heteronomal complexes of germanium and 3d metals on the basis of citric and tartaric acid]. Farmakolohiia ta likarska toksykolohiia – Pharmacology and Drug Toxicology, 6 (51), 60-65 [in Ukrainian].
Lukyanchuk, V.D., & Litvinenko, D.F. (2017). Toksikometricheskiy analiz novogo antigipoksanta OKAGERM-4 [Toxicometric analysis of the new antihypoxant OKAGERM-4]. Problemy biologii i meditsiny – Problems of Biology and Medicine, 3 (96), 162-165 [in Russian].
Lukianchuk, V.D., Savchenkova, L.V., Nemiatykh, O.D., & Radionov, V.M. (2002). Poshuk ta eksperymentalne vyvchennia potentsiinykh protyhipoksiinykh zasobiv: metodychni rekomendatsii [Search and experimental study of potential antifungal drugs: methodical recommendations]. Kyiv: DFTS MOZ Ukrainy [in Ukrainian].
Yevropeiska konventsiia pro zakhyst khrebetnykh tvaryn vid 1986 r. [European Convention for the Protection of Vertebrates from 1986]. Retrieved from: https://zakon5.rada.gov.ua/laws/show/994_137.4.
Poriadok provedennia naukovymy ustanovamy doslidiv, eksperymentiv na tvarynakh: Nakaz Ministerstva osvity i nauky, molodi ta sportu Ukrainy vid 1 bereznia 2012 r. № 249 [The order of the scientific institutions of experiments, experiments on animals: Order of the Ministry of Education and Science, Youth and Sport of Ukraine, March 1, 2012 No. 249]. Retrieved from: https://zakon.rada.gov.ua/laws/show/z0416-12.
Pro zatverdzhennia Poriadku provedennia doklinichnoho vyvchennia likarskykh zasobiv ta ekspertyzy materialiv doklinichnoho vyvchennia likarskykh zasobiv: Nakaz Ministerstva okhorony zdorovia Ukrainy vid 14 hrudnia 2009 r. № 944 [On Approval of the Procedure for Pre-Clinical Examination of Medicines and Examination of Materials for Preclinical Study of Medicines: Order of the Ministry of Health of Ukraine of December 14, 2009 No. 944]. Retrieved from: https://zakon5.rada.gov.ua/laws/show/z0053-10. DOI: https://doi.org/10.1007/s12045-009-0092-7
Lukyanchuk, V., Kravets, D., & Litvinenko, D. (2017). Study of pharmacometric indexes of dosing regimen of antihypoxant OKAGERM-4. Georgian Medical News, 272, 11, 144-147.
Kresyun, V.Y., Shcherbakov, S.V., & Vidavska, A.H. (2001). Sposib vyznachennia mikrokilkostei hermaniiu v tkanynakh tvaryn: Deklaratsiynyi patent na vynakhid, Ukraina, № 38285. Opubl. 15.05.2001. Byul. № 4. – Method of determining the microhardness of germanium in animal tissues: Declaration Patent for an invention, Ukraine, 2001. No. 38285. Published. May 15, 2001 Bull No. 4 [in Ukrainian].
Phoenix 8.1. Phoenix PK/PD Modeling and Simulation Software Retrieved from: www.certara.com/software.
Rosenbaum, S.E. (2011). Basic Pharmacokinetics and Pharmacodynamics: An Integrated Textbook and Computer Simulations. Hoboken, NJ: John Wiley & Sons, Inc.
Andrushchak, I.Ye. (2014). Modeli ta metody optymizatsii v prohramnomu seredovyshchi pidtrymky farmakokinetychnykh systemnykh doslidzhen: [monohrafiia] [Models and methods of optimization in the software environment supporting pharmacokinetic system research: [monograph]. Lutsk: RVV Luts. NTU [in Ukrainian].
Makarenko, I.Ye., Avdyeyeva, O.I., Vanatiyev, G.V., Rybakova, A.V., Khodko, S.V., Makarova, M.N., & Makarov, V.G. (2013). Vozmozhnyye puti i obyemy vvedeniya lekarstvennykh sredstv laboratornym zhivotnym [Possible paths and volumes of administration of drugs to laboratory animals]. Mezhdunarodnyy vestnik veterinarii – International Journal of Veterinary Medicine, 3, 78-84 [in Russian].
Adams, Kh.A., Flemming, A., Fridrikh, L., Rushulte, Kh. (Eds.) (2009). Atlas po neotlozhnoy pomoshchi [Emergency Atlas]. Moscow: MEDpress-inform, [in Russian].
Blackburn, S.C., & Stanton, M.P. (2014). Anatomy and physiology of the peritoneum. Semin. Pediatr. Surg., 23 (6), 326-330. DOI: https://doi.org/10.1053/j.sempedsurg.2014.06.002
Guyton, A.C., & Hall, J,E. (2016). Textbook of Medical Physiology. 13th Edition. Philadelphia, PA: Elsevier Science.
Shebaldova, K.O. (2014). Eksperymentalne obhruntuvannia rozrobky zasobiv likarskoi profilaktyky hipoksii zamknutoho prostoru v riadu koordynatsiinykh spoluk hermaniiu [Experimental substantiation of development of means of medical prophylaxis of closed space hypoxia in a series of coordination compounds of germanium]. Candidate’s thesis. Kyiv [in Ukrainian].
Seydel, J.K., & Wiese, M. (2002). Drug-Membrane Interactions: Analysis, Modeling. Weinheim: Wiley-VCH Verlag GmbH&Co. KGaA. DOI: https://doi.org/10.1002/3527600639
Sadovnichenko, Yu.A., & Myasoyedov, V.V. (2015). Kletochnyye membrany. Transport veshchestv cherez plazmalemmu: Metod. rek. dlya samost. vneaud. raboty stud. [Cell membranes. Transport of substances through the plasma membrane: Method. recommendations for individual outclass work of students]. Kharkov: KHNMU [in Ukrainian].
Seyfullina, I.I., & Martsinko, Ye.E. (2015). Koordinatsionnyye soyedineniya germaniya (IV) s anionami limonnoy, vinnoy i ksilarovoy kislot [Coordination compounds of germanium (IV) with anions of citric, tartaric and xylaric acids]. Odesa: Odesskiy natsionalnyy universitet imeni I. I. Mechnikova [in Russian].
Zoccal, D.B. (2015). Peripheral chemoreceptors and cardiorespiratory coupling: a link to sympatho-excitation. Experim. Physiol., 2 (100), 2143-2148. DOI: https://doi.org/10.1113/expphysiol.2014.079558
Zilbernagl, S., & Lang, F. (2015). Klinicheskaya patofiziologiya. Atlas. [Clinical pathophysiology. Atlas]. Moscow: Prakticheskaya meditsina [in Russian].
Litvitskiy, P.F. (2016). Gipoksiya [Hypoxia]. Voprosy sovremennoy pediatrii – Questions of Modern Pediatrics, 6, 1, 45-58 [in Russian].
Roach, R.C., Wagner, P.D., Hackett, P.H. (2007). Hypoxia and the Circulation. Springer Science+Business Media, LLC. DOI: https://doi.org/10.1007/978-0-387-75434-5
