N. A. Bizunok^*

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Pharmacology Department, Belarusian State Medical University, Minsk, Republic of Belarus.
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Abstract: This article represents the main positions of the theory of pleiotropic action of biologically active compounds (BACs) and medicines, which has been designed by the author based on her own experimental researches. The term “pleiotropy” means the ability of the BACs and medicines to implement more than one mechanism of action resulting in the specific biological (pharmacological) effect. The interaction of these mechanisms forms a distinct pattern of biological response (pleiotropic pattern), which reflects the change in his character with the increased dose (concentration)-dependent efficacy of BACs and medicines. The article consists of description of different pleiotropic patterns established in experiments on the model of reactive oxygen species (ROS) generation by macrophages dependent on activity of specialized enzyme called Nox2-NAD(P)H oxidase (Nox2, EC 1.6.3.1). Moreover, it consists of explanation of pharmacodynamic nature of pleiotropic patterns by means of application Chou-Talalay median effect equalization and combination index (CI) theory. The novel theory explains unsolved until now universal aspects of activity BACs and medicines, such as slope angles of “dose-effect” dependences in the conditions relevant in vivo, and it is of fundamental interest. However, it has applications in experimental pharmacology, as it allows defining the choice of the individual compounds and combinations, modulating the trust effect selectively and efficiently. This knowledge opens up new approaches to medicines discovery and evaluation, their rational dosing and combining.

Keywords: Reactive Oxygen Species (ROS);Nox2-NAD(P)H Oxidase (Nox2); Slope Angles of Dose-Effect Dependences; Pleiotropy; Pleiotropic Patterns; Polytropism; Pharmacological Affect Nature;Medicines Combinations; Novel Theory of Biologically; Active Compounds (BACs) and Medicines Action

Cite this paper: Bizunok, N. (2013) Theory of pleiotropic action of biologically active compounds and medicines—Basic principles and practical application. Open Journal of Clinical Diagnostics, 3, 94-104. doi: 10.4236/ojcd.2013.33017.

References

[1]   Tallarida, R.J. (2000) Drug synergism and dose-effect data analysis. Chapman and Hall/CRC, Roca Raton. doi:10.1201/9781420036107

[2]   Chou, T.-Ch. (2006) Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacological reviews, 58, 621-681. doi:10.1124/pr.58.3.10

[3]   Sergeev, P.V., Szymanowski, N.L. and Petrov, V.I. (1999) Receptors of physiologically active substances. 2nd Edition, “Seven Winds” Publishing House, Volgograd.

[4]   Stephenson, R.P. (1956) A modification of receptor theory. British Journal of Pharmacology, 11, 379-393.

[5]   Paton, W.D. (1961) A theory of drug action based on rate of drug-receptor combination. Proceedings of the Royal Society B: Biological Sciences, 154, 21-69. doi:10.1098/rspb.1961.0020

[6]   Karlin, A. (1967) On the application of “a plausible model” of allosteric proteins to the receptor for acetylcholine. Journal of Theoretical Biology, 16, 306-320. doi:10.1016/0022-5193(67)90011-2

[7]   Colquhoun, D. (1973) The relation between classical and cooperative models for drug action. In: Rang, H.P., Ed., Drug Receptors, Macmillan Press, London, 149-182.

[8]   Colquhoun, D. (1998) Binding, gating, affinity and efficacy. The interpretation of structure-activity relationships for agonists and of the effects of mutating receptors. British Journal of Pharmacology, 125, 923-948. doi:10.1038/sj.bjp.0702164

[9]   De Lean, A., Stadel, J.M. and Lefkowitz, R.J. (1980) A ternary complex model explains the agonist-specific binding properties of the adenylate cyclase-coupled beta-adrenergic receptor. The Journal of Biological Chemistry, 255, 7108-7117.

[10]   Brugen, A. (1981) Conformational changes and drug action. FedProc, 40, 2723-2728.

[11]   Gero, A. (1983) Desensitization, two-state receptors and pharmacological parameters. Journal of Theoretical Biology, 103, 137-161. doi:10.1016/0022-5193(83)90204-7

[12]   Urban, J.D, Clarke, W.P., Von Zastrow, M., Nichols, D.E., Kobilka, B., Weinstein, H., et al. (2007) Functional selectivity and classical concepts of quantitative pharmacology. The Journal of Pharmacology and Experimental Therapeutics, 320, 1-13. doi:10.1124/jpet.106.104463

[13]   Black, J.W., Leff, P., Shankley, N.P. and Wood, J. (2010) An operational model of pharmacological agonism: The effect of E/[A] curve shape on agonist dissociation constant estimation. British Journal of Pharmacology, 160, S54-S64. doi:10.1111/j.1476-5381.2010.00855.x

[14]   Kenakin, T. (2004) Principles: Receptor theory in pharmacology. Trends in Pharmacological Sciences, 25, 186-192. doi:10.1016/j.tips.2004.02.012

[15]   Strange, P.G. (2008) Agonist binding, agonist affinity and agonist efficacy at G protein-coupled receptors. British Journal of Pharmacology, 153, 1353-1363. doi:10.1038/sj.bjp.0707672

[16]   Lambeth, J.D. (2007) Nox enzymes, ROS, and chronic disease: An example of antagonistic pleiotropy. Free Radical Biology & Medicine, 43, 332-347. doi:10.1016/j.freeradbiomed.2007.03.027

[17]   Ito, M.K., Talbert, R.L. and Tsimikas, S. (2006) Statin-associated pleiotropy: Possible beneficial effects beyond cholesterol reduction. Pharmacotherapy, 26, 85S-97S. doi:10.1592/phco.26.7part2.85S

[18]   Schroder, W., Tzschentke, T.M., Terlinden, R., De Vry, J., Jahnel, U., Christoph, T. and Tallarida, R.J. (2011) Synergistic interaction between the two mechanisms of action of tapentadol in analgesia. The Journal of Pharmacology and Experimental Therapeutics, 337, 312-320. doi:10.1124/jpet.110.175042

[19]   Bizunok, N.A. (2013) Structural determinants of antioxidative activity of the phenols, diphenols and polyphenols at reactive oxygen species generated by macrophages in a different microenvironment circumstances. Military Medicine, 1, 84-94. http://www.bsmu.by/files/vm/1-2013/24.pdf

[20]   Magocsi, M., Vizi, E.S., Selmeczy, Z., Brózik A. and Szelenyi, J. (2007) Multiple G-protein-coupling specificity of β-adrenoreceptor in macrophages. Immunology, 122, 503-513. doi:10.1111/j.1365-2567.2007.02658.x

[21]   García-García, E. and Rosales, C. (2002) Signal transduction during Fc receptor-mediated phagocytosis. Journal of Leukocyte Biology, 72, 1092-1108.

[22]   Luttrell, L.M. and Lefkowitz, R.J. (2002) The role of beta-arrestins in the termination and transduction of G-protein-coupled receptor signals. Journal of Cell Science, 115, 455-465.

[23]   Allanore, Y., Borderie, D., Perianin, A., Lemaréchal, H., Ekindjian, O.G. and Kahan, A. (2005) Nifedipine protects against overproduction of superoxide anion by monocytes from patients with systemic sclerosis. Arthritis Research & Therapy, 7, R93-R100. doi:10.1186/ar1457

[24]   Yurkova, I.L. (2010) Free radical fragmentation in the polar part of the lipids: A new path of destruction and the formation of biologically active compounds. Dissertation for the Degree of Doctor of Chemical Sciences, Belarusian State University, Minsk.

[25]   Tong Mac, I., Arroyo, M.C. and Weglicki, W.B. (1989) Inhibition of sarcolemmal carbon-centered free radical formation by propranolol. Circulation Research, 65, 1151-1156. doi:10.1186/ar1718