Abstract
Background. Currently, the drugs, acting directly on tumor molecular or cellular targets, are actively designed. Target antitumor drug aimpila is atractyloside alpha-fetoprotein noncovalent complex. The development of this formulation is based on the ability of alpha-fe-toprotein, as a transport protein, to deliver cytotoxic agents into the cells that have alpha-fetoprotein receptors. Objective: to investigate the toxicity of aimpila in chronic experiment on rabbits. Materials and methods. The study was performed in male and female “Soviet chinchilla” rabbits. Final drug formulation (aimpila in gelatin capsules) was administrated per os at 1 and 10 therapeutic doses (0.05 and 0.5 mg/kg respectively) for 30 days with interval of 24 h. During the study dynamics of body weight, hematological parameters, blood biochemical parameters, electrocardiography and urinalysis were performed for all animals. Five animals in each group were sacrificed in days 1 and 30 post treatment, then their internal organs were subjected to histological evaluation. Results. The study demonstrates that the treatment with aimpila for 30 days in single therapeutic dose of 0.05 mg/kg had no effect on the clinical and laboratory parameters or the morphological structure of the internal organs of rabbits. Signs of hepato-, nephro-, cardio-and gastrointestinal toxicity were found in group of rabbits, treated with high dose of drug. The structural damages in liver were clinically supported with a significant increase of aspartate aminotransferase level in serum. Pathological changes in the kidneys were accompanied by a significant increase of urobilinogen and ketone bodies levels in the urine. Signs of cardio- and gastrointestinal toxicity were documented only by microscopic pathology observation. These abnormalities were reversible within 30 days. Conclusions. Aimpila formulation displayed dose-dependent and reversible toxicity and can be recommended to further investigation.
Highlights
Target antitumor drug aimpila is atractyloside alpha-fetoprotein noncovalent complex. The development of this formulation is based on the ability of alpha-fetoprotein, as a transport protein, to deliver cytotoxic agents into the cells that have alpha-fetoprotein receptors
Five animals in each group were sacrificed in days 1 and 30 post treatment, their internal organs were subjected to histological evaluation
The study demonstrates that the treatment with aimpila for 30 days in single therapeutic dose of 0.05 mg/kg had no effect on the clinical and laboratory parameters or the morphological structure of the internal organs of rabbits
Summary
1; 2ООО «Фармацевтический научный центр “ФармАксесс”»; Россия, 127322 Москва, ул. Таргетный противоопухолевый препарат аимпила представляет собой нековалентный комплекс альфа-фетопротеина (АФП) с атрактилозидом. Цель исследования – изучение токсичности препарата аимпила в хроническом эксперименте на кроликах. Препарат в виде готовой лекарственной формы – желатиновых капсул – вводили перорально в 1 и 10 терапевтических дозах (0,05 и 0,5 мг / кг соответственно) ежедневно в течение 30 сут. Исследование показало, что ежедневное пероральное применение аимпилы в течение 30 сут в дозе, эквивалентной 1 терапевтической, не оказывает влияния на клинико-лабораторные показатели и структуру органов и тканей кроликов. У животных, получавших высокую дозу препарата, были обнаружены признаки гепато-, нефро-, кардио- и гастроинтестинальной токсичности. Признаки кардио- и гастроинтестинальной токсичности выявлялись только при патоморфологическом исследовании органов. Обнаруженные изменения были обратимы в течение 30 сут.
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