FEATURES OF AN INVESTIGATION OF THE GENERAL TOXIC PROPERTIES OF ANTIPSYCHOTICS

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DOI: https://doi.org/None
Issue: 
4
Year: 
2017

O.I. Avdeeva, PhD; M.N. Makarova, MD; V.G. Makarov, MD 1 PHARMACY HOUSE Research-and-Production Association; 245, Kuzmolovsky Settlement, Leningrad Region 188663, Russian Federation

Introduction. Unlike many organs and systems, the brain of humans and animals varies considerably. These features should be taken into account in the preclinical study of antipsychotic drugs. Objective: to comparatively investigate the toxicity of the atypical neuroleptic agent Clozapine repeatedly used in 3 laboratory animal species (rats, rabbits, and miniature pigs) and to assess different dosing regimens of the tested object. Material and methods. The biological models included outbred rats, New Zealand rabbits, and miniature pigs. The following doses of the neuroleptic were investigated: 0.5, 1, and 2.5 (maximum therapeutic dose, MTD) mg/kg for rats, 0.8, 1.6, and 3.2 (MTD) mg/kg for rabbits, and 1.5 and 3 (MTD) mg/kg for miniature pigs. The doses were calculated based on the human MTD, by using the interspecies scaling factors for human/animal dose conversion. Results. A complete picture of the effects of antipsychotics was observed in more highly organized animals (miniature pigs). The rats showed a paradoxical reaction to antipsychotics, which was probably associated with a rapid increase in the density of dopamine receptors. The optimum dosing regimen, a dose escalation method, was established in preclinical studies. The use of interspecies scaling factors for dose conversion in the study of antipsychotics provides false information on the toxicity of the tested objects. Conclusion. The miniature pigs are the optimal biological object for the preclinical studies of antipsychotics; the dose escalation method is optimal for a dosing regimen.
Keywords: 
antipsychotics
general toxicity
miniature pigs
rabbits
rats
References: 
  1. A Roadmap to Key Pharmacologic Principles in Using Antipsychotics. Prim Care Companion J. Clin. Psychiatry., 2007; 9 (6): 444–54.
  2. Spravochnoe rukovodstvo po psihofarmakologicheskim i protivoe`pilepticheskim preparatam, razreshennym k primeneniyu v Rossii. Pod red. S.N. Mosolova. M.: BINOM, 2004. [Reference psychopharmacological and antiepileptic drugs permitted for use in Russia/ Edited byS.N.Mosolov. M.:«Publishing house BINOM», 2004] (in Russian)].
  3. Basu D., Marudkar M., Khurana H. Abuse of neuroleptic drug by psychiatric patients, 2000; 54 (2): 59–62.
  4. Morozov P.V. Aripiprazol (abilifay) - novyy atipichnyy antipsihotik. Psihiatriya i psihofarmakoterapiya. 2006; 8 (4). [Morozov P.V. Aripiprazole (abilifay) – a new atypical antipsychotic. Psichiatrija i psichopharmacoterapiya. 2006; 8 (4)] (in Russian)].
  5. Lieberman J.A. Dopamine partial agonists: a new class of antipsychotic. CNS Drugs. 2004; 18 (4): 251–67.
  6. Snedkov E.V. Invega® (paliperidon): metodicheskie rekomendacii dlya vrachey po ispol`zovaniyu preparata pri lechenii bol`nyh shizofreniey. Obozrenie psihiatrii i medicinskoy psihologii im. V.M. Behtereva, 2008; 4: 41–6. [Snedkov E.V. Invega® (paliperidone): guidelines for physicians on the use of the drug in the treatment of patients with schizophrenia. Obozrenie psichiatrii i medicinskoy psichologii. V.M. Bechtereva. 2008; 4: 41–6] (in Russian)].
  7. Psihiatriya. Nacional`noe rukovodstvo. Pod red. T.B. Dmitrievoy, V.N. Krasnova, N.G. Neznanova, V.Ya. Semke, A.S. Tiganova) M.: GE`OTAR-Media, 2011. [Psychiatry. National leadership. Edited by Dmitrievoj T.B., Krasnova V.N., Neznanova N.G., SemkeV.Ya., Tiganova A.S. Moskva: GEOTAR-Media, 2011] (in Russian)].
  8. Szarfman A., Tonning J.M., Levine J.G., Doraiswamy P.M. Atypical antipsychotics and pituitary tumors: a pharmacovigilance study. Pharmacotherapy, 2006; 26 (6): 748–58.
  9. Stankov A.G. Anatomiya cheloveka. M. 1959. [Stankov A.G. Human Anatomy. M. 1959] (in Russian)].
  10. Nozdrachev A.D., Polyakov E.L. Anatomiya krysy. SPb.: Lan`, 2001; 464. [Nozdraczev A.D., Poljakov E.L. Rat Anatomy. SPb: Publishing house «Lan». 2001; 464 r.] (in Russian)].
  11. Nozdrachev A.D., Polyakov E.L. Anatomiya krolika. SPb: Izdatel`stvo SPbGU. 2009; 356. [Nozdraczev A.D., Poljakov E.L. Rabbit Anatomy. SPb: Publishing house SPbGU. 2009; 356 r.] (in Russian)].
  12. Guidance for Industry. Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers. Pharmacology and Toxicology, 2005; 30.
  13. Frank I. Tarazi et al. Long-term effects of JL 13, a potential atypical antipsychotic, on rat dopamine and serotonin receptor subtypes. Journal of Neuroscience Research., 2006; 84: 675–82.
  14. Van der Staay F.J., Pouzet B., Mahieu M., Nordquist R.E., Schuurman T. The d-amphetamine-treated Göttingen miniature pig: an animal model for assessing behavioral effects of antipsychotics. Psychopharmacology (Berl.), .2009; 206 (4): 715–29.
  15. Minuzzi L., Olsen A.K., Bender D., Arnfred S., Grant R., Danielsen E.H., Cumming P. Quantitative autoradiography of ligands for dopamine receptors and transporters in brain of Göttingen minipig: comparison with results in vivo. , 2006; 15. 59(4): 211–9.
  16. Elman I., Borsook D., Lukas S.E. Food intake and reward mechanisms in patients with schizophrenia: implications for metabolic disturbances and treatment with second-generation antipsychotic agents. Neuropsychopharmacology, 2006; 31: 2091–20.
  17. Haddad P.M., Wieck A. Antipsychotic-induced hyperprolactinaemia: mechanisms, clinical features and management. Drugs, 2004; 64: 2291–314.
  18. Rukovodstvo po provedeniyu doklinicheskih issledovaniy lekarstvennyh sredstv. Ch.1. M.: Grif i K; 2012. [Guidelines for conducting pre-clinical trials of medicinal products. Part one. – M.: Grifi K; 2012] (in Russian)].
  19. OECD (2008) Guideline for testing of chemicals. Acute Oral Toxicity. Up-and-Down-Procedure (UDP), № 425.