Interleukin-2 therapy is not clearly effective against breast cancer both in mouse models and in human patients. However, the study of IL-2 therapy of breast cancer remains important, as 3,700 women died from this malignancy in the Netherlands in 2000. Previously we have shown the therapeutical efficacy of a single peritumoural IL-2 application in different experimental models and in veterinary patients. Here we apply this mode of IL-2 therapy to advanced mouse mammary carcinoma models, i.e., severe metastasised tumours in A/Sn mice and non-metastasised carcinomas in BALB/c mice. Mice with advanced transplanted mammary carcinomas were given a single peritumoural treatment with 2.5 x 10(6) IU IL-2 at days 10-14 after i.p. or s.c. inoculation of 10(6) carcinoma cells. Within each experiment it was always possible to distinguish relatively slowly and fast growing tumours which allows the therapeutical effect of IL-2 in tumours with different growth rates to be studied. A new approach to analyse results enabled us to show that survival of mice with transplanted, advanced metastasised breast cancer can be significantly improved after a single local treatment with IL-2. Advanced relatively fast i.p and s.c. growing mammary carcinomas seem to be more sensitive to a single IL-2 treatment than relatively slowly growing tumours. IL-2 was most effective against non-metastasised mouse breast cancer.
Introduction . The appearance of high-quality and effective generics can significantly reduce the cost of health care for the drug supply of the population of Russia. According to expert estimates, the cost of treatment of cancer patients with generics of domestic can be 30– 40 % cheaper as compared to the original drugs. In Russia the pharmaceutical production company “Ozon” created by the domestic analogue of the original anticancer drug hydrea – hydroxycarbamide.Objective: comparative study of chronic toxicity of the drug hydroxycarbamide (“Ozon”, Russia) and registered reference drug hydrea (Corden Pharma Latina S. p. A., Italy) on rats.Materials and methods . A comparative study of the toxicity of drugs was carried out on 70 non-inbred white male rats weighing 220– 250 g obtained from the accredited laboratory animal nursery of LLC “Krolinfo”. Both drugs were administered in parallel daily orally 5-fold in 3 doses. As a solvent, 1 % starch paste was used. Doses were calculated according to the literature data on the basis of maximum tolerated dose. Standard methods of evaluation of chronic toxicity of drugs in rats were used.Results . The obtained data on chronic toxicity of the compared forms of the domestic drug hydroxycarbamide and the reference drug hydrea do not differ significantly in terms of quantitative and qualitative toxicity (lethality, biomarkers of toxicity, morphometry of organs). Conclusion . The compared generic and commercial preparations are practically equitoxic by 5 times oral administration to rats.
In accordance with Russian Federal program of import substitution of foreign medicines quality of Russian drugs in the N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia, played vincristine-RONC (VC-RONC), which as a drug – the generic’s passed preclinical pharmacological and toxicological testing in comparison with foreign firms vincristine Teva of Israel (VC-Teva). The aim. The aim of present study was the comparative pathomorphological evaluation of the effect of VC-RONC and VC-Teva on the internal organs of rats. Materials and methods. Used 50 weinbrenner male rats, at 10 rats per group. VC-RONC and VC-Teva rats were administered intravenously 3 times daily at aquatoxicity total dose corresponding to the MTD and 1/2 MTD. Control rats in the same regime intravenously administered of 0,9 % sodium chloride solution. Rats were deduced from the experience of 3 and 30 days after the end of administration of the drugs. Conducted macroscopic and histological examination of internal organs by conventional methods, including fixation of the material in 10 % formalin and coloring sections with hematoxylin and eosin. The micropreparations of the internal organs was analyzed under light microscope at magnifications of 100, 400, 1000. Results. VC-RONC, as VC-Teva in cumulative doses of 0,5 and 0,25 mg/kg in 3 days after the end of introductions in the internal organs of rats cause similar slightly pronounced morphological changes: hypoplasia in the bone marrow and spleen, destructive changes in the testes, focal degenerative changes in the kidney and liver of individual rats. On the 30th day after the application of both drugs, some rats regardless of the dose occurred similar symptoms residual morphological changes in the bone marrow, testes, kidneys and liver. Conclusion. Based on the results of macroscopic and histological examination the conclusion about the similarity of the influence of VC-RONC and VC-Teva on the internal organs of rats was made.
Результаты. В результате изучения острой токсичности на мышах и крысах-самках и самцах-при введении ЦФ в максимально возможной концентрации и максимально возможных объемах препарат не вызывал гибели животных, не оказывал влияния на общее состояние животных, не вызывал внешних проявлений токсичности, не изменял поведенческие реакции животных. При изучении хронической токсичности ЦФ на крысах и собаках при ежедневном пероральном применении в течение 15 дней во всех исследованных дозах также не наблюдалось гибели животных, препарат не вызывал каких-либо внешних проявлений токсичности. Лимитирующий вид токсичности не установлен, так как препарат вызывает незначительные морфофункциональные изменения различной степени обратимости практически во всех органах и системах организма крыс и собак. На основании полученных на экспериментальных животных данных о функциональных и морфологических изменениях в органах и тканях показано, что самки более чувствительны к препарату, чем самцы. Заключение. С учетом функциональных и морфологических изменений во внутренних органах как крыс, так и собак изученные дозы ЦФ охарактеризованы как дозы, вызывающие слабые незначительные изменения-низкие токсические дозы. На основании анализа данных определена начальная (стартовая) безопасная доза для человека на I фазу клинических испытаний, которая проводится в настоящее время.
Thus, the PBF as a prolong drug needs to correct its parameters for further drug formulation development.
Введение. В ФГБУ «НМИЦ онкологии им. Н. Н. Блохина» Минздрава России проведены доклинические токсикологические исследования лиофилизированной лекарственной формы ормустина (Ормустин)-нового противоопухолевого препарата из класса нитрозоалкилмочевин. В работе представлены результаты изучения субхронической токсичности Ормустина на крысах. Цель исследования-изучение субхронической токсичности Ормустина на крысах при ежедневном 3-кратном внутривенном введении. Материалы и методы. Исследование проведено на 40 неинбредных крысах-самцах. Ормустин вводили внутривенно ежедневно 3-кратно в суммарных дозах 300, 200 и 100 мг/кг. Срок наблюдения-45 сут. На протяжении всего срока наблюдения проводили необходимые клинико-лабораторные исследования. Для изучения повреждающего действия Ормустина на органы и ткани проводили патоморфологическое исследование на 3-и и 45-е сутки наблюдения. Результаты. Установлено, что Ормустин при многократном применении у крыс в 3 исследованных дозах обладает гемато-, нефро-, кардио-и гастроинтестинальной токсичностью. Глубина и степень повреждений, а также их обратимость зависят от величины примененной дозы Ормустина. Выводы. На основании полученных данных определены уровни токсических доз Ормустина, а именно: суммарная доза 300 мг/кг охарактеризована как высокая токсическая доза, суммарные дозы 200 и 100 мг/кг-как низкие токсические дозы. Это позволило рекомендовать Ормустин для дальнейшего исследования.
The aim of our study was to evaluate implantation efficacy and safety across various occluder types and to identify factors determining device selection.Methods. This single-site prospective observational study included patients above the age of 40 years with non-valvular atrial fibrillation (AF) and high thromboembolic risk, undergoing endovascular isolation of the left atrium appendage (LAA) with Watchman or Amplatzer Cardiac Plug/Amulet devices. Occluders were implanted to patients without either had contraindications to anticoagulant therapy (ACT) or refused ACT. We evaluated technical aspects of device implantation, short- and long-term outcomes of the intervention over 3 years of follow-up.Results. 90 patients were enrolled in the study (62 into the Watchman arm and 28 into the Amplatzer arm). Interventions were technically successful in 89 cases. In 1 patient (1/90, 1.1%) technical success was not achieved due to device migration (Amplatzer Amulet). The incidence of early (occurring within˂ 24 hours) implantation complications was 0% in the Watchman arm, and 3.6% in the Amplatzer arm (1/28) (р=0.135) (device migration). The cumulative incidence of all in-hospital complications was 11.3% and 14.3%, respectively (р=0.734). No significant differences between arms were found in the incidence of device thrombosis within 90 days post-implantation (3.3% in the Watchman’s arm and 8.3% in the Amplatzer arm, р=0.316). During the observation period, there were no significant differences in comparison groups in the incidence of net clinical efficacy endpoint events (р=0.58). The bleeding rate was 17.7% and 14.3%, respectively, р=0.769. No factors influencing the choice of the device could be identified reliably; however, there was a trend towards Watchman preference for appendage anatomic variants such as broccoli and cactus. Amplatzer was preferred in patients with contraindications to ACT.Conclusion. Implantation of Watchman and Amplatzer Amulet occluders is equally effective and safe in preventing thromboembolism in patients with AF not receiving ACT for various reasons. The individual choice of a device may be influenced by appendage anatomy and indications to occluder implantation.
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