Obviously, fundamental knowledge, elucidation of the mechanism of the effect of dilute aqueous solutions with low concentrations of solutes on living systems, and the substantiation and prediction of their bioeffects is required for the scientific explanation of the observed phenomena. The experimentally established synergism of action of the solutions prepared with high and low concentrations of the same substance (i.e., a more pronounced effect of a combination of such solutions than the simple sum of the effects of each of them) can be used as the basis for increasing of efficiency, reduction of toxicity, as well as the possibility of expansion of the action spectrum of the drugs ( Marotta et al., 2003 Pal'mina et al., 2003). ( Mark and Edward, 2009 Shimanovsky et al., 2010).
Pharmacological profiles of solutions of therapeutic substances are usually complex within the range of low concentrations and characterized by a number of peculiarities: nonmonotonic dose-effect relationship, existence of the “silence zones” where biosystems are practically insensitive to the substance, and change in the direction of the bioeffect, etc. However, it has been established that the effect of many drugs at low concentrations can significantly differ from their effects at therapeutic doses, both in the direction of the effect and in the mechanism of action. It is thought that lower doses can ensure drug selectivity and make it possible to avoid adverse side effects with a comparable therapeutic efficacy ( Mark and Edward, 2009 Shimanovsky et al., 2010). Reduction in the therapeutic dose is one of the ways to improve drug tolerability and reduce their negative effects on the organism. The demand in such studies is due to the problem of significant side effects arising from the use of drugs by the population in high doses. Studies of the phenomena of nonmonotonic concentration dependences of the bioeffects of diluted aqueous solutions of biologically active substances (BAS) are of current interest ( Mark and Edward, 2009 Shimanovsky et al., 2010 Tarasova and Makarova, 2016). This finding demonstrates a significant modifying effect of self-organized dispersed systems of 4-AP in low concentrations on the neurons’ sensitivity to 4-AP. It was found that the pre-incubation of neurons in the 4-AP system with a concentration of 1♱0 −12 M led to a 17.0% synergistic decrease in the membrane potential after a subsequent treatment with 1♱0 −2 M 4-AP solution. An analysis of the obtained results and published data allows for a conclusion that a consistent change in the nature and parameters of the dispersed phase, as well as the pH of the medium, apparently determines the nonmonotonic nature of the effect of the 4-AP systems in a 1♱0 −20–1♱0 −6 M concentration range on the resting membrane potential of neurons.
Incubation of neurons in the 4-AP systems for which the formation of domains and nanoassociates had been established lead to a nonmonotonic decrease of the resting potential by 7–13%. The impact of these diluted aqueous systems on the electrical characteristics of identified neurons of Helix lucorum snails was studied. This allows us to predict the bioeffects of the 4-AP systems at low concentrations. An interrelation between the non-monotonic concentration dependencies of the size of the dispersed phase, the fluorescence intensity ( λ ex 225 nm, λ em 340 nm), specific electrical conductivity, and pH has been established. Using the dynamic light scattering method, it was shown that 4-AP solutions at concentrations in the range of 1♱0 −20–1♱0 −6 M are dispersed systems in which domains and nanoassociates of hundreds of nm in size are formed upon dilution. A variety of physicochemical methods were used to examine the self-organization, physicochemical, UV absorption, and fluorescent properties of diluted aqueous solutions (calculated concentrations from 1♱0 −20 to 1♱0 −2 M) of the membrane voltage-dependent potassium channels blocker 4-aminopyridine (4-AP).
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