Specific Manifestations of Neurotoxicity of Some Drug Combinations for Treatment of Drug Resistant Tuberculosis from the Perspective of Experimental Studies

The objective: to evaluate comparative neurotoxicity of combinations of anti-tuberculosis and antimicrobial drugs with different and similar toxic potentials assessing behavioral changes in rats.

Subjects and Methods: non-linear female rats divided in 3 groups were used in this study. For 14 days, the rats received a daily combinations of drugs: Group 1 – Mxf + Lzd + Cs + Pto, Group 2 – Mxf + Bdq + Cs + Z , and Group 3 – Bdq + Lzd + Cfz + Z. Neurotoxicity was assessed by changes in behavioral responses using Open Field Test. The number of crossed squares and racks was recorded which characterized horizontal and vertical activity, also peeping into burrows (exploratory activity), the number of groomings (washing and scratching) and physiological functions were registered.

Results. In rats of Group 1 versus baseline parameters, we observed a significant limitation of horizontal motor activity and a sharp decrease (by 5 times) in exploratory activity, a 2.8-fold decrease in the number of groomings which indicated emotional suppression. In rats of Groups 2 and 3, the decrease in motor and exploratory activity was insignificant but there was a more pronounced emotional depression. The use of the Mxf + Lzd + Cs + Pto combination in which all drugs possessed a neurotoxic potential, led to diverse and profound changes in behavioral responses which indicated a pronounced neurotoxic effect.

1. Ivanova D.A., Borisov S.E., Rodina O.V., Filippov A.V., Ivanushkina T.N., Litvinova N.V. Safety of treatment regimens for multiple drug resistant tuberculosis patients compiled as per the new WHO recommendations as of 2019. Tuberculosis and Lung Diseases, 2020, vol. 98, no. 1, pp. 5-15. (In Russ.)

2. Mozhokina G.N., Zyuzya Yu.R., Petrova L.Yu., Samoilova A.G., Vasilyeva I.A. Toxicity of treatment regimens for drugresistant tuberculosis. Antibiotiki i Khimioterapiya, 2021, vol. 66, no. 11-12, pp. 25-30. (In Russ.) https://doi.org/10.37489/0235-2990-2021-66-11-12-25-30.

3. Mozhokina G.N., Samoylova A.G., Vasilyeva I.A. The problem of neurotoxicity of drugs in the treatment of tuberculosis patients. Tuberculosis and Lung Diseases, 2020, vol. 98, no. 10, pp. 58-63. (In Russ.) http://doi.org/10.21292/2075-1230-2020-98-10-58-63.

4. Russkikh A.E., Kutuzova D.M., Lovacheva O.V., Samoylova A.G., Vasilyeva I.A. Short course treatment of pulmonary tuberculosis patients suffering from multiple drug resistance. The current situation and future perspectives. Tuberculosis and Lung Diseases, 2020, vol. 98, no. 12, pp. 57-66. (In Russ.) https://doi.org/10.21292/2075-1230-2020-98-12-57-66.

5. Toktogonova A.A. Frequency and characteristics of adverse reactions to second line anti-tuberculosis drugs in those ill with multiple drug resistant tuberculosis. Tuberculosis and Lung Diseases, 2017, vol. 95, no. 10, pp. 63-67. (In Russ.)

6. Schegertsov D.Yu., Filinyuk O.V., Buynova L.N., Zemlyanaya N.A., Kabanets N.N., Alliluev A.S. Adverse events during treatment of patients suffering from multiple drug resistant tuberculosis. Tuberculosis and Lung Diseases, 2018, vol. 96, no. 3, pp. 35-43. (In Russ.)

7. Bressler A.M., Zimmer S.M., Gilmore J.L., Somani J. Peripheral neuropathy associated with prolonged use of linezolid. Lancet Infect. Dis., 2004, no. 4, pp. 528-531.

8. Hurkacz M., Dobrek L., Wiela-Hojeńska A. Antibiotics and the nervous system-which face of antibiotic therapy is real, Dr. Jekyll (Neurotoxicity) or Mr. Hyde (Neuroprotection)? Molecules, 2021, no. 26 (24), pp. 7456.

9. Jaspard M., Butel N., El Helali N., Marigot-Outtandy D., Guillot H., Peytavin G., Veziris N., Bodaghi B., Flandre P., Petitjean G., Caumes E., Pourcher V. Linezolid-associated neurologic adverse events in patients with multidrug-resistant tuberculosis, France. Emerg. Infect. Dis., 2020, vol. 26, no. 8, pp. 1792-1800.

10. Kass J.S., Shandera W.X. Nervous system effects of antituberculosis therapy. CNS Drugs, 2010, no. 24, pp. 655-667.

11. Nambiar S., Rellosa N., Wassel R.T., Borders-Hemphill V., Bradley J.S. Linezolid-associated peripheral and optic neuropathy in children. Pediatrics, 2011, no. 127, pp. e1528-e1532.

12. Rezaei N.J., Bazzazi A.M., Alavi S.A.N. Neurotoxicity of the antibiotics: A comprehensive study. Neurol. India, 2018, no. 66, pp. 1732-1740.

13. Scavone C., Mascolo A., Ruggiero R., Sportiello L., Rafaniello C., Berrino L., Capuano A. Quinolones-induced mesculoskeletal,neurological, and psychiatric ADRs: A pharmacovigilance study based on data from the Italian Spontaneous Reporting System. Front. Pharmacol., 2020, no. 11, pp. 428.

14. Vinh D.C., Rubinstein E. Linezolid: a review of safety and tolerability. J. Infect., 2009, no. 59, suppl. 1, pp. S59-S74.

15. Yang T.W., Park H.O., Jang H.N., Yang J.H., Kim S.H., Moon S.H., Byun J.H., Lee C.E., Kim J.W., Kang D.H. Side effects associated with the treatment of multidrug-resistant tuberculosis at a tuberculosis referral hospital in South Korea: a retrospective study. Medicine (Baltimore), 2017, no. 96, pp. e7482.