Research and Development of a New Safe Form of Drugs - Aerosols: Measurement, Dosimetry, and Health Effects - page 270

the most potent antiarrhythmic effect (Bryzgalov et al., 2005). In the calcium chloride and aconite
arrhythmia models, alaglysine demonstrated high antiarrhythmic activity and the antiarrhythmic
index (LD 50 /ED 50 ) higher than that of all known antiarrhythmic drugs. Alaglysine is 10 times less
toxic than allapinin. In an extended study of alaglysine antiarrhythmic activity using the calcium
chloride and aconite arrhythmia models, the complex at the doses of 0.125 and 0.250 mg/kg as such
did not affect the ECG parameters. Intravenous injection of the agent at the dose of 0.125 mg/kg
before the injection of calcium chloride lethal dose blocked the development of arrhythmia in 80%
of the rats. When administrated after the arrhythmogen (CaCl 2 ), alaglysine at the dose of 0.250 mg/
kg reverses the arrhythmia development in 50% of the animals. In the adrenaline arrhythmia model,
a single administration of alaglysine at the doses of 0.125 and 0.250 mg/kg prevents the development
of profound arrhythmia. The ECG parameters reverse to norm in 50% (dose 0.125 mg/kg) and in
100% (dose 0.250 mg/kg) of the animals. In the model, ED 50 is 0.125 mg/kg for alaglysine and 0.290
for allapinine, as follows from the effective dose of alaglysine, it contains 15 times less lappaconi-
tine than the effective dose of allapinine.
Nifedipine (NF) (2.6-dimethyl-3.5-dicarbomethoxy-4-(2′-nitrophenyl)-1.4-dihydropyridine) belongs
to calcium antagonists. It dilates coronary and peripheral (primarily arterial) vessels and diminishes
myocardial oxygen need. Nifedipine produces an insigniicant negative inotropic effect and a very
weak antiarrhythmic effect. The lukewarm attitude of physicians to this drug has recently changed into
a revived interest. This is substantially due to the appearance of novel dosage forms of Nifedipine and
to additional data characterizing the drug as an affordable and active agent for arresting hypertensive
crises. The mere fact of the continuing development of novel dosage forms of Nifedipine indicates that
as the simplest derivative of 1.4-dihydropyridine with proven production technology Nifedipine will
be used in the future as a reliable alternative of more expensive drugs of this type (Pogosova, 2006).
The study of complexation of GA with Nifedipine using NMR method showed the existence of
complex with the molecular composition GA:NF = 2:1 in water-alcohol solutions at the concentra-
tions of GA ≤ 0.5 mM. At higher GA concentrations associates are formed, which include equal
number of molecules of both substances. The complex is highly stable as indicated by its stability
constant ( K s = 1.2 × 10 5 M −1 ) (Polyakov et al., 2006).
Nevertheless, the preliminary study of hypertensive activity of Nifedipine convincingly dem-
onstrated that GA:NF = 4:1 is an optimal composition. The complex synthesized by the mechano-
chemical activation method is an amorphous substance consisting of 20-50 μm vitreous particles.
Complexation was also conirmed by radiographic and thermogravimetric data, according to which
traces of crystalline phase of both reagents disappear. Water-solubility of Nifedipine in the complex
increases 8.5 times.
The study of antihypertensive action showed that at intravenous administration of the complex in
water solution to rats the desired effect is manifested at the dose of Nifedipine 10 times lower than
usual dose (Tolstikova et al., 2006).
As stated earlier, an important consequence of complexation could be the enhancement of pleio-
tropic properties of a pharmacon. For Nifedipine this is its antiarrhythmic action. However, the use
of Nifedipine as an antiarrhythmic drug at an effective dose to achieve the desired positive effect
on cardiac rhythm is impossible, for at this dose Nifedipine provokes a decrease in arterial pressure
and may cause hypotensive crisis. The study of antiarrhythmic action of GA: NF complex showed
that a protective antiarrhythmic effect can be reached at a dose 29 times lower than that providing
antihypertensive effect.
Thus, GA: NF 4:1 complex is promising for the development of the irst universal drug capable
of arresting hypertension and arrhythmia and safe at parenteral administration.
In the comparative study of the mechanisms of action of Nifedipine and its complex with GA,
the complexation effect was conirmed in vitro experiments with the use of isolated neurons of peri-
pharyngeal ganglia of mollusk Lymnaea stagnalis . The neuron technique allows tracing the effect
of the agents introduced in the intercellular space on the transport of Ca +2 ions using generation of
calcium channels action potentials (Zapara et al., 1988, 1999). Nifedipine was found to fully block