REPORT

Study of chronic toxicity of Lithium Ascorbate, “Normopharm” LLC on rabbits with the evaluation of local irritant effect 

Saint Petersburg, 2019

STUDY CHARACTERISTICS

PCS code – 12/18-2

Drug developer – Normopharm LLC, 655750, Republic of Khakassia, Abaza, Lenin St., 3, office 1n.

Organization that arranges the preclinical study – Normopharm LLC, 655750, Republic of Khakassia, Abaza, Lenin St., 3, office 1n.

Executor – FSBSI IT FMBA of Russia, St. Petersburg, 192019, Bekhterev Str., 1.

The experimental part was performed in the period of October 08, 2018 to June 07, 2019 inclusive.

LIST OF EXECUTORS

The work was provided by: K.V. Masterova, M.A. Anisimova.

NOTATIONS AND ABBREVIATIONS

REGULATORY STANDARDS

The studies were carried out in FSBSI Institute of Toxicology of the Federal Medical and Biological Agency of Russia in accordance with the regulatory documentation:

• Federal Law № 61-FZ of 12.04.2010 “On the Circulation of Medicines”;

• Order of the Ministry of Health of the Russian Federation dated 01.04.2016 № 199n “On Approval of the Rules of Good Laboratory Practice”;

• Decree of the Chief State Sanitary Physician of the Russian Federation dated 29.08.2014 № 51 on approval of Sanitary Rules 2.2.1.3218-14 “Sanitary and epidemiological requirements for the design, equipment and maintenance of experimental biological clinics (vivaria)”;

• GOST 33044-2014 dated 01.08.2015 “Principles of Good Laboratory Practice GLP”;

• “Guidelines for studies of general toxic effect of pharmacological substances" (in  book “Guidelines for conducting preclinical studies of drugs”, Moscow, Medicine, 2012);

• Directive 2010/63/EC of the European Parliament and of the Council of 22 September 2010 on the protection of animals used for scientific purposes;

• GOST 32519-2013 dated 01.08.2014 “Test methods for the effect of chemical products on the human body. Study of chronic toxicity following intragastric administration”;

• OECD Test № 452 “Chronic Toxicity Studies”;

• GOST 7.32-2017 “System of Standards for Information, Library and Publishing. R&D report. Structure and Rules of Design”.

ABSTRACT

Report 73 p., 30 tables, 15 sources, 2 annexes. 

The report presents the results of an experimental study to investigate the chronic 180-day toxicity (+30 days of delayed observation) of Lithium Ascorbate, Normopharm LLC on sexually mature rabbits with an evaluation of the local irritant effect.

The drug developer and the organization arranging the preclinical study – Normopharm LLC, 655750, Republic of Khakassia, Abaza, Lenin Str., 3, office 1n. The study was carried out at the Laboratory of Drug Toxicology of the Federal State Budgetary Scientific Institution “Institute of Toxicology of the Federal Medical and Biological Agency” in the period from 03.08.2018 to 21.06.2019  (PCS 12/18-2). 

The experimental part was carried in the period from October 08, 2018 to June 07, 2019 inclusive.

Sexually mature chinchilla rabbits, aged 3 months, were used as a test system. The test substance and the control substance were administered orally through a tube, repeatedly. 

In the chronic toxicity study, the following doses of Lithium Ascorbate were used: 5.0 mg/kg, 50.0 mg/kg, 150 mg/kg. The individual volume of the administered dose for each animal was calculated based on the value of body weight and adjusted after each weighing.

During the study, the clinical picture of intoxication, dynamics of body weight, water and feed consumption, dynamics of physiological values, dynamics of hematological values, dynamics of biochemical values were evaluated; macroscopic and microscopic examinations of internal organs were carried out; mass coefficients of organs were compared; the local irritant action was studied.

As a result of the study, it was established that:

body weight values of experimental animals tended to increase uniformly throughout the study period, both in the control and experimental groups; 

– no significant changes in electrocardiogram or rectal temperature were shown. There were no significant gender (intersexual) differences between animals;

– no changes in urine parameters were shown in the experimental and control groups;

– hematological and biochemical examination did not shown any significant disorders in the cellular metabolism of various organs and systems when Lithium Ascorbate was administered in three doses;

– autopsy performed in the experimental animals did not show any noticeable pathological changes in the internal organs. 

The results of the study of chronic toxicity of substance Lithium Ascorbate,  Normopharm LLC, Republic of Khakassia, allow us to recommend the drug for obtaining approval for clinical trials or registration in the Russian Federation.

All study materials, including the study protocol, source data and the final report will be stored in the archive of FSBSI Institute of Toxicology of FMBA of Russia (office 233, building 2) for 15 years from the end of the study. Samples of test and standard objects and/or their retention samples, as well as histological specimens, should be stored in the archive during three cycles of inspections by regulatory authorities.