Experimental study of the toxic effect of a drug based on lithium citrate on cardiovascular and central nervous system

Aim. To study the toxic effect of a drug product (DP) based on a complex of lithium citrate, aluminum oxide and polymethylsiloxane on the cardiovascular and central nervous systems of experimental animals.

Materials and methods. The drug was administered intragastrically once a day for 90 days in the morning from 10:00 to 11:00. Experimental animals were divided into 4 groups: three experimental (administration of the studied DP at doses of 400, 2000 and 4000 mg/kg respectively) and one control (administration of the medium). The assessment of the drug effect on the central nervous system was carried out by examining the exploratory behavior of rats in the Open Field test. Emotional response was assessed by the Brady and Nauta method (1953). The assessment of the functional state of the rat cardiovascular system was performed using the electrocardiography (ECG).

Results. After a course of the DP based on the complex of lithium citrate, aluminum oxide and polymethylsiloxane, no significant changes in the exploratory behavior in the Open Field test were observed. The Emotional Response test also did not show any differences in the parameters of the experimental groups and the control one. In rats of all experimental groups with repeated intragastric administration of the DP, neither cardiac rate and conduction disturbances, nor changes in the amplitude of the ECG waves and the duration of intervals in comparison with the control group were found. The mean ECG values in animals of all groups did not go beyond the physiological norms for this type of animals.

Conclusion. The absence of toxicity of the drug based on the lithium complex with regards to the central nervous and cardiovascular systems was found after its prolonged administration (90 days). The data obtained represent the necessary fragment of the preclinical study of the DP for the subsequent obtaining permission to conduct clinical trials.

1. Rybakowski J.K. (2018, Oct 2). Challenging the negative perception of lithium and optimizing its long-term administration. Front. Mol. Neurosci., 11, 349. doi: 10.3389/fnmol.2018.00349.

2. Rybakowski J.K. (2020, Mar 24). Lithium treatment in the era of personalized medicine. Drug Dev. Res. doi: 10.1002/ddr.21660.

3. Haggarty S.J., Karmacharya R., Perlis R.H. (2020, Jul 7). Advances toward precision medicine for bipolar disorder: mechanisms & molecules. Mol. Psychiatry. doi: 10.1038/s41380-020-0831-4.

4. Ohlund L., Ott M., Oja S. et al. (2018). Reasons for lithium discontinuation in men and women with bipolar disorder: a retrospective cohort study. BMC Psychiatry, 18 (1), 37. doi: 10.1186/s12888-018-1622-1.

5. Zolezzi M., Eltorki Y.H., Almaamoon M., Fathy M., Omar N.E. (2018). Outcomes of patient education practices to optimize the safe use of lithium: A literature review. Ment. Health Clin., 8 (1), 41-48. doi: 10.9740/mhc.2018.01.041.

6. Nederlof M., Kupka R.W., Braam A.M., Egberts A., Heerdink E.R. (2018). Evaluation of clarity of presentation and applicability of monitoring instructions for patients using lithium in clinical practice guidelines for treatment of bipolar disorder. Bipolar Disord., 20 (8), 708-720. doi: 10.1111/bdi.12681.

7. Manchia M., Pisanu C., Squassina, A., Carpiniello B. (2020). Challenges and future prospects of precision medicine in psychiatry. Pharmgenomics Pers. Med., 13, 127-140. doi: 10.2147/PGPM.S198225.eCollection2020.

8. Pronin A.V., Gromova O.A., Torshin I.Yu. et al. (2016). Study of the pharmacokinetics and compartmentalization of lithium ascorbate. Young Scientist, (119), 547555. In Russ.

9. Russell D., Con R. (2012). Lithium Preparations. In Russ.