421
12 Consensus Drug Design Using IT Microcosm
As a result of predicting the hypoglycemic activity of mixtures, it was established that the mixture of all of the main components of the extract in equal molar
fractions should show a higher activity than any individual component; excluding
two inactive components (XX, XXI) from the complete mixture should not result
in a higher activity; increasing the ratio of the two most active components (XVI,
XVII) and excluding two inactive compounds (XX, XXI) from the complete mixture should result in a lower activity; combinations of the two most active components (XVI, XVII) should show a considerably lower activity compared with
the complete mixture; and adding a considerable amount of an inactive compound
(XXI) to a combination of the two most active components (XVI, XVII) should not
affect the level of activity [74, 105].
It follows from the data obtained from the prediction that a complex of active
substances in Gymnema sylvestre extract should show a more powerful and, most
likely, a more stable and prolonged hypoglycemic effect than any component of the
extract, either individually or in limited combinations, due to a mutual potentiating
synergistic effect of all of the components [74, 105, 112].
An experimental study of the hypoglycemic activity of hydroalcoholic Gymnema sylvestre extracts at gravimetric concentrations of 25, 50 and 75 % was made
on outbred rats at a dose of 280 mg/kg per os; the glucose content in the blood was
determined by the glucosidase method prior to extract administration and two hours
after the administration. According to the experimental data, a medium reduction in
the glucose concentration was 41, 29 and 26 % for the extracts with concentrations
of 25, 50 and 75 %, respectively [75].
The method of obtaining Gymnema sylvestre extract foresees that, as its gravimetric concentration grows, the portion of the active gymnemic acids and gymnemosides increases, whereas the portion of the inactive components diminishes [76].
Thus, the experimental results confirm the presence of the synergistic effects
predicted with IT Microcosm, which enhance the level of the hypoglycemic activity when administering Gymnema sylvestre extract with a lower content of active
substances but with a more varied composition.
12.5.3.3 Synergism of Antidiabetic Drug Combinations
In this study, we used IT Microcosm for a prediction of the synergism of the hypoglycemic activity shown by Metformin combinations with five other antidiabetic
drugs used in clinical practice for antidiabetic therapy (Fig. 12.8) [114].
Nine Metformin combinations with these drugs were used in protracted antidiabetic therapy in multicenter clinical studies with durations of 16 to 26 weeks and
328 to 1250 patients.
For the purposes of the in silico prediction, the administered doses were translated into molar ratios at a rate of 1 mol of the second agent per corresponding Metformin moles. In all nine cases, we observed a synergism manifested as a considerable
enhancement of the hypoglycemic activity of the mixture, which far exceeded the
effect produced by the portion of the added agent compared with Metformin per se
(Table 12.20).
12 Consensus Drug Design Using IT Microcosm
As a result of predicting the hypoglycemic activity of mixtures, it was established that the mixture of all of the main components of the extract in equal molar
fractions should show a higher activity than any individual component; excluding
two inactive components (XX, XXI) from the complete mixture should not result
in a higher activity; increasing the ratio of the two most active components (XVI,
XVII) and excluding two inactive compounds (XX, XXI) from the complete mixture should result in a lower activity; combinations of the two most active components (XVI, XVII) should show a considerably lower activity compared with
the complete mixture; and adding a considerable amount of an inactive compound
(XXI) to a combination of the two most active components (XVI, XVII) should not
affect the level of activity [74, 105].
It follows from the data obtained from the prediction that a complex of active
substances in Gymnema sylvestre extract should show a more powerful and, most
likely, a more stable and prolonged hypoglycemic effect than any component of the
extract, either individually or in limited combinations, due to a mutual potentiating
synergistic effect of all of the components [74, 105, 112].
An experimental study of the hypoglycemic activity of hydroalcoholic Gymnema sylvestre extracts at gravimetric concentrations of 25, 50 and 75 % was made
on outbred rats at a dose of 280 mg/kg per os; the glucose content in the blood was
determined by the glucosidase method prior to extract administration and two hours
after the administration. According to the experimental data, a medium reduction in
the glucose concentration was 41, 29 and 26 % for the extracts with concentrations
of 25, 50 and 75 %, respectively [75].
The method of obtaining Gymnema sylvestre extract foresees that, as its gravimetric concentration grows, the portion of the active gymnemic acids and gymnemosides increases, whereas the portion of the inactive components diminishes [76].
Thus, the experimental results confirm the presence of the synergistic effects
predicted with IT Microcosm, which enhance the level of the hypoglycemic activity when administering Gymnema sylvestre extract with a lower content of active
substances but with a more varied composition.
12.5.3.3 Synergism of Antidiabetic Drug Combinations
In this study, we used IT Microcosm for a prediction of the synergism of the hypoglycemic activity shown by Metformin combinations with five other antidiabetic
drugs used in clinical practice for antidiabetic therapy (Fig. 12.8) [114].
Nine Metformin combinations with these drugs were used in protracted antidiabetic therapy in multicenter clinical studies with durations of 16 to 26 weeks and
328 to 1250 patients.
For the purposes of the in silico prediction, the administered doses were translated into molar ratios at a rate of 1 mol of the second agent per corresponding Metformin moles. In all nine cases, we observed a synergism manifested as a considerable
enhancement of the hypoglycemic activity of the mixture, which far exceeded the
effect produced by the portion of the added agent compared with Metformin per se
(Table 12.20).