Each new drug may have a lot of unfavorable and even dangerous adverse effects. One of these properties of the drug which are of concern to both a physician and a patient is its ability to cause toxic effect on human body. However before the drug may be used in clinical practice, laboratories should check out its safety and conduct the appropriate toxicological studies.
Goals and methods of chemical toxicological studies
It should be understood that not all drugs may cause acute intoxication. Development of sub-acute and chronic toxicity is also possible. Chemical toxicological studies are performed in laboratory animals to reveal the ability of a substance to cause these phenomena.
To evaluate the pathological influence of the drug on the organism of experimental animal the following methods are used:
general blood analysis (hematological and biochemical), urine analysis;
electrocardiography;
nervous system state diagnostics;
identification of locally irritating action;
evaluation of skin-resorptive effect;
determination of general animal state and state of separate organs and systems;
histopathological methods.
After conducting chemical toxicological studies the final decision about drug toxicity and possibility of its usage in clinical practice is made. Then additional chemical toxicological studies are carried out to accurate toxic and lethal doses, adverse effects and other unfavorable effects.
The appropriate chemical toxicological study that was properly conducted allows avoiding the use of toxic drugs in practice and providing complete safety of a patient throughout treatment.
Additional toxicological studies are performed in accordance with OECD protocols for testing of chemicals:
417
Toxicokinetics
424
Neurotoxicity Study in Rodents
426
Developmental Neurotoxicity Study
427
Skin Absorption: In Vivo method
428
Skin Absorption: In Vitro method
432
In Vitro 3T3 NRU Phototoxicity test
435
In Vitro Membrane Barrier Test Method for Skin Corrosion
440
Uterotrophic Bioassay in Rodents: Short-term screening test for the detection of estrogenic properties
441
Hershberger Bioassay in Rats: A Short-term Screening Assay for (Anti)Androgenic Properties
456
H295R Steroidogenesis Assay
Сardiotoxicity assessment in guinea pigs by a method of ECG changes (ICH S7B; Current protocols in pharmacology, 2009)
Electrocardiogram parameters of healthy guinea pigs, М±m
Indicator
males
n=40
females
n=56
HR/min
315±9
324±8
RR, msec
192±5
198±4
P, msec
43±2
45±3
P, mV
0.09±0.01
0.09±0.01
PQ, msec
62±2
64±2
QRS, msec
55±1
53±2
R, mV
0.47±0.03
0.48±0.02
S, mV
0.10±0.01
0.08±0.01
ST, msec
71±2
76±3
ST, mV
0.06±0.01
0.05±0.01
QT, msec
109±2
113±5
Publications by topic:
Kosman V.M., Faustova N.M., Karlina M.V., Pozharitskaya O.N. Immunoassay as analytical method in pharmacokinetic and toxicokinetic invastigations // Abstracts. Phitopharm. 2016. Obzory po klinicheskoj farmacologii i lekarstvennoj terapii. – 2016. – Vol. 14. – P. 28.
Vavilova V.A., Shekunova E.V., Kashkin V.A., Makarova M.N., Makarov V.G. Pharmacological safety of drugs: evaluation of phototoxic effects in vivo // Experimental and clinical pharmacology. -2018 (Appendix). Proceedings of the 5th Congress of Pharmacologists of Russia “Scientific basis for the search and creation of new drugs.” May 14-18, 2018. Yaroslavl. – P. 39. [Full text is available in Russian].
Vavilova V.А., Shekunova E.V., Kashkin V.A., Makarova M.N., Makarov V.G., Khaymenov A.Y. EXPERIMENTAL TESTING OF AN IN VIVO METHOD OF PHOTOTOXICITY EVALUATION // The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products. – 2018. – 8(2). – Р. 115-122. https://doi.org/10.30895/1991-2919-2018-8-2-115-122.ABSTRACT. At present all new medicinal products and cosmetics that absorb medium-wavelength UVB, long-wavelength UVA, or visible light in the range 290–700 nm need to be tested for potential hototoxicity. Phototoxicity is evaluated by both in vitro and in vivo methods. There are guidelines for in vitro phototoxicity evaluation, however, there are no formally validated protocols for in vivo phototoxicity evaluation. The purpose of this study was to test an economically viable and informative method for in vivo evaluation of tetracycline and ketorolac phototoxicity using outbred rats. Two medicinal products potentially capable of causing clinically established phototoxic reactions were used in this study: tetracycline (tablets, 200 mg/kg and 300 mg/kg) and ketorolac (gel, 13.4 mg/kg, 26.8 mg/kg and 40.3 mg/kg). The medicines were administered in both single and multiple doses. Ultraviolet rradiator OUFK-03 (OOO «Solnyshko», Russia) was used as a light source. The UV exposure (5 J/cm2 and 15 J/cm2) was erformed once 1 h after medicine administration. The skin reaction was evaluated 30 minutes and 24 hours after irradiation and then daily for 2 weeks. As a result, the following optimal parameters were determined for in vivo evaluation of phototoxic reactions caused by the medicines: radiation intensity — 15 J/cm2 for single systemic administration and 5 J/cm2 for single topical (dermal) administration; recommended period of skin reaction valuation for outbred rats is not less than 7 days [Full text is available in Russian].
Avdeeva O.I., Makarova M.N., Makarov V.G. Cytostatic drugs effect on hemopoiesis of outbred mice // Farmatsiya, (Pharmacy). – 2019. – 68(2). – С. 50-56.https://doi.org/10/29296/25419218-2019-02-09.SUMMARY. Introduction. Preclinical studies of cytostatics include a bone marrow smear, reflecting the qualitative and quantitative composition of the nucleated cells of myeloid tissue (myelogram). To a certain extent, the state of the bone marrow can be predicted by the hematological analysis of peripheral blood of laboratory animals. Objective: assessment of the feasibility of studying the state of laboratory animals’ bone marrow using the example of 14-day administration effect of cytostatics on the cellularity of peripheral blood and bone marrow of outbred mice. Materials and methods. The objects of study are cytostatics of 3 groups: alkylating compounds of platinum (cisplatin and carboplatin), antimetabolites (methotrexate and cytarabine), and preparations of plant origin (paclitaxel and etoposide). Outbred mice served as biological test system. The study was carried out in accordance with the principles of GLP and the European Convention for the Protection of Vertebrate Animals. Results. An assessment was made of the feasibility of studying the bone marrow state of laboratory animals using the example of the effect of 14-day parenteral administration 3 groups of cytostatic (alkyl platinum compounds, antimetabolites and herbal preparations) in the dose of LD10 on the cellularity of peripheral blood and bone marrow of outbred mice. It was established that the presence of significant changes in the clinical analysis of peripheral blood is a sufficient basis for the analysis of myelograms. When conducting such studies, it is advisable to use animals of both sexes, because of the effect of cytostatics on hematopoiesis, differences in the sensitivity of animals by gender are observed. Conclusion. Analysis of the composition of the bone marrow significantly expands the idea of medicinal substances effect on hemopoiesis, but its implementation must be dictated by considerations of expediency, in particular, significant changes in the clinical analysis of peripheral blood [Full text is available in Russian].
