Studying the pharmacokinetic parameters of new normothymic drug based on the complex of lithium citrate, aluminum oxide and polymethylsiloxane

For the treatment of bipolar affective disorders, lithium preparations are the most famous and effective. But the main problem with the use of lithium preparations is the narrow «therapeutic corridor». An urgent task is the creation of dosage forms of lithium with a slow release and a wide therapeutic range. The study object was a new normotymic drug based on lithium, aluminum oxide and polymethylsiloxane. Due to the new carrier matrix lithium is released from its porous structure gradually providing a prolonged effect and maintaining an optimal concentration in the blood which also helps to minimize side effects. The purpose of the study was to explore the pharmacokinetic parameters of a normotymic drug based on a complex lithium citrate, aluminum oxide and polymethylsiloxane (LOAP).Material and methods: for the assessment of pharmacokinetic parameters the method of atomic emission spectrometry with inductively coupled plasma and two-chamber modeling were used.Results and discussion. The pharmacokinetic data showed a linear nature of pharmacokinetics of the drug based on LOAP as the foundation of data of the lithium’s amount in the blood plasma of rabbits after intragastric administration at doses of 200, 400 and 800 mg/kg. The drug with intragastric administration at a dose of 800 mg/kg is well absorbed from the gastrointestinal tract, with bioavailability (F) 74 %. This dose shows the maximum increase of the area under the pharmacokinetic curve (AUC - 32787.1 (ng x h)/ ml), and indicators of elimination constant (Kel - 0.062 h-1), clearance (Cl - 0.09 l/(kg x h)), elimination half-life (T1/2p - 11.436 h) in comparison with other doses remain unchanged

Estimation of acute toxicity of a drug based on the complex of lithium citrate, polymethylsiloxane, aluminum oxide

Research Institute of Clinical and Experimental Lymphology has developed an innovative drug based on a complex of lithium citrate, polymethylsiloxane and aluminum oxide (LOAP). Lithium-based drugs are effective in treating bipolar disorders. However, the toxic effects of lithium cause a “narrow therapeutic window”, which limits its clinical use. The creation of the drug LOAP was aimed at creating a prolonged form with a slow release of lithium to reduce toxic properties and use lithium citrate as an active pharmacological agent. At the moment, the lithium complex has no analogues. The purpose of the study was to study the parameters of acute toxicity of the LOAP. Material and methods. When studying acute toxicity, drugs were administered once intragastrically to mice and rats at doses of 12000, 10000, and 5000 mg/kg. Results. A single administration of drugs intragastrically through a probe in the maximum possible doses to mice and rats did not cause the death of animals and did not cause a locally irritating effect on the gastric mucosa. LOAP can be assigned to hazard class 4 (GOST 12.1.007-76)

STUDYING THE POSSIBLE MUTAGENIC PROPERTIES OF NEW MEDICINE ON THE BASIS OF COMPLEX LITHIUM CITRATE, ALUMINUM OXIDE AND POLYMETHILSILOXANE

Aim of the study was to investigate the possible mutagenic properties of a new drug based on a lithium-containing substance – a complex of lithium citrate, polymethylsiloxane and aluminum oxide. Material and methods. Methods for testing mutagenicity using chromosomal aberrations in the bone marrow cells of CBA mice and somatic recombination in Drosophila melanogaster were used. Results. It was shown that a single intragastric administration of drug at a dose of 5000 mg/kg and a fivefold course of administration at a dose of 400 mg/kg to CBA mice did not increase the level of cytogenetic disorders in bone marrow cells. The study of the lithium complex drug in a somatic mosaicism test revealed that the preparation at a dose of 2000 mg/kg does not increase the frequency of mutations in Drosophila melanogaster. Conclusion. A single intragastric administration of the studied drug at a dose of 5000 mg/kg and its course administration (400 mg/kg × 5) do not increase the level of cytogenetic disorders in the bone marrow cells of CBA mice. In the somatic recombination (mosaicism) test system on D. melanogaster, no increase in the appearance of mutant setae and spots on the body and head was observed when using yellow and singed markers. The results of the study indicate that the studied drug does not have mutagenic properties

STUDY OF DNA DAMAGE by NEW NORMOTHYMIC MEDICINAL ON THE BASIS OF THE COMPLEX OF LITHIUM CITRATE, POLYMETHYLSYLOXANE AND ALUMINUM OXIDE BY DNA COMET ASSAY <i>IN VIVO</i>

The aim of the study was to study the effect of the normotimic drug based on a complex of lithium citrate, polymethylsiloxane and alumina on DNA damage level (DNA comet test) in vivo by alkaline gel electrophoresis. It was shown that at 3 and 18 hours after the drug administration at the highest dose (2000 mg/kg) and therapeutic dose (400 mg/kg), the percentage of DNA in the tail in the cells of the bone marrow does not differ from the negative controls. That may indicate absence of possible carcinogenic action of the lithium-containing drug. On the other hand, the amount of DNA damage in other organs (kidney, liver, large intestine) increased with an exposure time of 3 hours after administration of the drug in a toxic dose. Although, the degree of this effect expression was not high. When the dose was reduced (400 mg/kg) and the duration of the experiment was increased (up to 18 hours), this effect was not detected. That indicates the ability of the drug to enhance DNA damage repair. Given that lithium preparations have a pronounced toxic effect on kidneys, gastrointestinal tract, liver, the increase in the percentage of DNA in the tail in these organs can be a consequence of the cytostatic action of the drug