Research and Development of a New Safe Form of Drugs - Aerosols: Measurement, Dosimetry, and Health Effects - page 275

one third of statin's normal dose, symvaglysin is a more eficacious and safer agent as compared
with symvastatin.
Thus, symvaglysine is a noncompetitive inhibitor/proinhibitor of 3HMG-CoA reductase, arresting
the synthesis of cholesterol in the microsomal fraction of rat liver in vitro on par with symvastatin.
At the inhibition constant ranging between 100 and 300 nM, symvaglysine inhibits the formation of
mevalonat by 37.7%-42.0%. After a 14 day course of treatment of hypercholesterolemic rats with sym-
vaglysine at the doses containing one third of symvastatin normal dose, symvaglysine decreases total
cholesterol level by 31%-33%, which is comparable to the effect of symvastatin in the therapeutic dose.
Higher safety of symvaglysine follows from the fact that after 14 days of intake at the doses
containing symvaglysine the content of which was two to ive times lower the increase of creatine
phosphokinase level in blood of hypercholesterolemic rats was two to ive times lower (Ragino
et al., 2008; Vavilin et al., 2008).

11.2.1.11 Antidote and Antiradical Activity of Complexes of
Glycyrrhizic Acid with Uracil Derivatives
GA forms stable complexes with uracil derivatives with the molecular composition 1:1. The complex
with 2-tiouracil is a dehydrate, complexes with salts are crystallized with one molecule of water.
Complexes with 5-oxi-6-methyl-uracil and aminouracil are waterless (Tolstikov et al., 1996). All com-
plexes are 1.8-1.9 times less toxic than uracil and belong to moderately or low toxic substances. By
the range of antidote action determined using the model of male mice poisoning with sodium nitrite,
the complexes exceeded initial uracils on average twice and cystamin—2.6-17.4 times. Complexes
with uracils have a lower value of effective dose (ED 50 ) than cystamin, that is, they are more efica-
cious than the reference drug. Complexes with 2-tiouracil and 5-oxi-6-methyluracil, although having
a higher value of ED 50 as compared with cystamin, exceed it in the range of pharmacological action.
The experiment results were evaluated using the survival and mortality rates in the control and
test groups 48 h after poisoning. The control animals received physiological solution and test ani-
mals were injected complexes of GA and initial uracils at the doses of 6.75, 12.5, 25.0, 50.0, 100.0,
and 200.0 mg/kg.
Antiradical activity of GA complexes in vitro was studied by chemiluminescence method by
determining the reaction rate constant (K 7 ) for the interaction of ethylbenzol peroxide radicals with
the compounds studied. It was found out that the antiradical activity of GA complexes with amino-
pyrimidines and 2-tiouracil was on average 10 times higher than that of ionol (Table 11.7).
High antidote activity of GA complexes with uracil derivatives in combination with their anti-
radical action makes these compounds promising for the development of drugs protecting living
beings from toxic exposures.

TABLE 11.7
Antiradical Activity of Uracils and Their Complexes

Constant K 7 M/l
Complex with GA Uracils Pyrimidine

2-Thiouracil 1.3 ± 0.6 × 105 1.3 ± 0.6 × 105

6-Amino-2-thiouracil 4.3 ± 1.3 × 105 1.3 ± 0.4 × 105

6-Aminouracil 4.3 ± 1.3 × 105 1.3 ± 0.4 × 105

6-Methyl-2-thioutacil 9.1 ± 2.7 × 104 9.1 ± 2.7 × 104

5-Oxi-6-methyluracil 2.6 ± 0.8 × 104 2.6 ± 0.8 × 104

5-Aminouracil 2.0 ± 0.6 × 105 2.0 ± 0.6 × 105

GA 1.3 ± 0.4 × 102

Ionol 2.3 ± 0.6 × 104