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the responses at the dose of 3.0 mM. For GA:NF 4:1 complex this effect was found to be manifested
at pharmacon concentration 30 times lower (0.1 mM) than that of the original drug. The blockade of
responses caused by the original drug and their restoration after neurons washing out proceed faster
than in the experiments with the complex. This indicates stronger bonding of the complex with the
receptors and, therefore, the prolonged action of the complex. Comparative study of the effect of
Nifedipine and its complex with GA on the dynamics of calcium current amplitude conirmed the
conclusions on the enhancement of complex-receptor afinity (Tolstikova et al., 2007b).
11.2.1.6 Complex of Glycyrrhizic Acid with Indirect Oral Anticoagulant Warfarin
Warfarin (WF) is widely used in modern medicine as an indirect oral anticoagulant for long-term
administration. The number of applications for the indirect anticoagulants in the world has grown
by 10 times in the last 10 years, which is explained by the large number of indications for their
usage. The main disadvantage of such therapy is the development of hemorrhages, often large ones,
particularly during the induction period (or dose selection), as well as the dificulty of dose control
(Levine et al., 2001; Epstein et al., 2010).
The complex WF:GA with the mass ratio 1:10 was synthesized. This component ratio had
been previously selected in our other works and determined to be optimal for complexes with GA
(Tolstikov et al., 2007b; Tolstikova et al. 2009).
The deinition of solubility is considered to be an indicator of complex stability. In the complex
of glycyrrhizic acid with warfarin, we managed to increase the solubility of the latter by 14 times
(Table 11.5), which indicated the formation of a stable complex.
During the trial experiments with animals we determined the optimal complex dose to be 20 mg/
kg (warfarin dose being 2 mg/kg), which clearly stimulated the increase in prothrombin time (PT).
The irst measurement of PT parameters was performed in 6 h after a single intragastric administra-
tion. This time interval was chosen on the basis of warfarin's pharmacologic properties; namely, the
authors Zhu and Shin (2005) had previously proven that the maximum concentration of warfarin
metabolites in the blood plasma of rats is reached in 6-12 h.
According to our research, PT deinitely alters at this temporal point only in groups of positive
control—WF and WF (Nycomed, tablets) inserted in 2 mg/kg doses, which corresponds with the
content of warfarin in complex with GA. However, this length of PT is not clinically signiicant, as
it does not secure the necessary increase in hemopexis time.
A more signiicant increase in PT was observed in 24 h after a single intragastric administration
of the comparator agents; in case of the examined complex, the PT increased (24.88 ± 1.77 s) only
in 30 h (two administrations) after the start of the experiment and reached the values correspond-
ing to positive control WF (PT 42.0 ± 1.60 s) only in 54 h (three administrations, PT 38.8 ± 1.31 s)
(Figure 11.19).
As a result, the complexation of warfarin with GA did not allow reducing its effective dose,
which may be explained through the complex structure. Using the method of gel-penetrating chro-
matography, we discovered that one of the mechanisms of complexation of pharmacons with GA,
particularly of warfarin, is the involvement of their molecules in micellae/self-associates of GA.
This kind of structure serves as protection from fast metabolism and slows down the binding of
warfarin molecule's active centers with the receptors, and therefore the basic activity manifests
TABLE 11.5
Solubility in Water of the WF:GA (1:10)
Agents
WF Solubility in Water (g/L)
Increase in Solubility (Times)
WF
0.021
—
WF:GA (1:10)
0.295
14
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