Research and Development of a New Safe Form of Drugs - Aerosols: Measurement, Dosimetry, and Health Effects - page 269

TABLE 11.4
Uterine Tonic Activity of Prostaglandins and Their Complexes
with GA (1:1) in Rats In Vitro , Phosphate Buffer C = 10 −8 g/mL
(Polyakov et al., 2006): PGE 1 , PGE 2 , SP, PGF 2 α

Change of Uterine
Contraction Amplitude (%)

Changes in
Uterus Tonus (%) Substance P P

GA: PGE1 53.4 ± 5.0 <0.002 49.4 ± 1.2 <0.002

PGE1 24.3 ± 1.5 <0.05 30.7 ± 2.2 <0.05

GA: SP 150.0 ± 11.0 <0.001 135.0 ± 10.0 <0.001

SP 50.0 ± 5.0 <0.001 115.0 ± 9.5 <0.001

GA: PGE2 63.5 ± 6.0 <0.001 40.7 ± 4.0 <0.002

PGE2 20.0 ± 2.8 <0.05 33.5 ± 2.4 <0.05

GA: PGF2α 55.6 ± 5.0 <0.001 61.0 ± 5.6 <0.001

PGF2α 27.8 ± 1.5 <0.05 39.4 ± 5.3 <0.02

In experiments on the uterus of rats and guinea-pigs, complexes GA:PGE 1 (1:1) and GA:PGF 2α
(1:1) double uterine contraction amplitude as compared with sodium PGE 1 at the same concentrations
(10 −8 g/mL). SP and PGE 2 in the form of complexes with GA (1:1) strengthen uterine contraction
amplitude by three times while increasing uterus tonus (Tolstikov et al., 1991b) (Table 11.4).
On the basis of GA complexes with cloprostenol, a known synthetic luteolytic prostaglandin, a
highly effective veterinary drug “Chlatraprostin” was developed, the active agent dosage of which
is ive times lower than that accepted in the world practice. In comparison with imported analogues
the drug is cheaper and its action is more physiological.
“Chlatiram” containing amino acid tyrosine along with GA and cloprostenol is even more efica-
cious (Tolstikov et al., 1997b). Its effect is stronger than that of Estrofan, the well-known veterinar-
ian drug, at a 100 times reduced dose of prostaglandin.

11.2.1.5 Complexes of Glycyrrhizic Acid with Cardiovascular Drugs
The structure and pharmacological properties of GA complexes with antiarrhythmic drugs allap-
inin (hydrobromide of lappaconitine, diterpenoid alkaloid) (LA) and antihypertensive drug nifedip-
ine were investigated.
The process of complexation of lappaconitine with glycyrrhizic acid in solutions was investigated
by photo-CIDNP method (Polyakov et al., 2005; Kornievskaya et al., 2007a,b,c). Photolytic destruc-
tion of lappaconitine, which slows down sharply in the presence of GA, was chosen as a reaction
simulating the complexation effect. The reaction leads to protection of the complex-bonded alka-
loid. The experiment demonstrating that complexation results in the photodestruction slowdown is
a suficiently correct model of pharmacon metabolism in vivo for the complex of glycyrrhizic acid
with lappaconitine base in water-methanol solution (20% MeOH), stoichiometry 1:1, stability con-
stant K s = 2 × 10 5 ± 0.13 × 10 5 M −1 . In pure methanol the constant is lower by an order, K s =1.3 × 10 4
M −1 . Complex of lappaconitine hydrobromide with GA has the stability constant K s = 2.6 × 10 3 M −1 .
It should be noted that the average values of the stability constants of pharmacon complexes with
cyclodextrins are about 10 3 M −1 .
Allapinin has been included in the list of antiarrhythmic drugs. It is recommended at different
forms of cardiac rhythm disturbance, especially in ventricular arrhythmias, paroxysmal atrial ibril-
lation, and monofocus atrial tachycardia (Sadritdinov and Kurmukov, 1980; Mashkovsky, 2005).
The disadvantage of allapinin is its high toxicity.
In a special series of experiments, it was shown that complexes GA:LA produce an effect on
antiarrhythmic activity and that complex GA:LA of composition 4:1, patented as “alaglysine,” has