scholarly journals PRECLINICAL STUDY OF INDOLOCARBAZOLES N-GLYCOSIDES DERIVATIVE LCS-1208 ANTITUMOR ACTIVITY. REPORT I

2015 ◽  
Vol 14 (2) ◽  
pp. 71-77 ◽  
Author(s):  
M. P. Kiseleva ◽  
Z. S. Shprakh ◽  
L. M. Borisova ◽  
I. Yu. Kubasova ◽  
A. V. Lantsova ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Intravenous Administration ◽  
Dosage Form ◽  
Antitumor Effect ◽  
Preclinical Study ◽  
Tumor Growth Inhibition ◽  
Pharmaceutical Dosage Form ◽  
Established Tumor ◽  
End Of Treatment ◽  
Activity Report

This article presents the results of preclinical study of antitumor activity of indolo[2,3-a]carbazoles N-glycosides derivative (LCS-1208) in pharmaceutical dosage form for intravenous administration - lyophilisate for injection. LCS-1208 high antitumor efficiency has been shown by different regimens of administration on tumors of diverse histogenesis: LCS-1208 exhibited increase of life span (ILS) 76% on lympoblastosis P-388 and ILS 76 % and 33 % recovery of Fisher lympadenosis L5178Y by 25 mg/kg daily intravenous administration during 5 days. Whereas LCS-1208 demonstrated high antitumor efficiency on solid tumors by 150 mg/kg single intravenous dosing: on LLC - tumor growth inhibition (TGI) 95% - 81% during 9 days and on RShM-5 (TGI 74% - 56% during 9 days). LCS-1208 appeared statistically significant TGI 51 % and 47 % on 3rd and 7th days after 150 mg/kg single intravenous dosing on established tumor. Comparative study of LCS-1208 substance and dosage form by intraperitoneal injection has shown that decrease of therapeutic dose to 110 mg/kg, which doesn’t induce death of animals, resulted only in dosage form antitumor effect (TGI 74-75 % during 8 days after the end of treatment).

Strong Antitumor Activity of Bevacizumab and Aflibercept in Neuroendocrine Carcinomas: In-Depth Preclinical Study

2019 ◽  
Vol 110 (1-2) ◽  
pp. 50-62 ◽  
Author(s):  
María Rodríguez-Remírez ◽  
Laura del Puerto-Nevado ◽  
María Jesús Fernández Aceñero ◽  
Hakimeh Ebrahimi-Nik ◽  
Marlid Cruz-Ramos ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Tumor Growth ◽  
Therapeutic Option ◽  
Human Cell Line ◽  
Preclinical Study ◽  
Tumor Control ◽  
Tumor Growth Inhibition ◽  
Bevacizumab Treatment ◽  
Strong Antitumor Activity

Background: Neuroendocrine carcinoma (NEC) is a rare and very aggressive tumor. It has been greatly understudied, and very little is known about optimal treatment strategy for patients with this disease. The purpose of this study was to evaluate in vivo whether anti-vascular endothelial growth factor (VEGF) drugs could be a therapeutic alternative for these tumors with a poor prognosis. Methods: We have developed 2 xenograft models using either human cell line derived from lung (H460) or from colon (COLO320) NEC to assess the effect of 2 antiangiogenic drugs, aflibercept and bevacizumab, on tumor growth and their pathological characteristics. Additionally, tumors were subjected to immunohistochemistry staining and proteins were measured with Western blot and ELISA. Results: Both aflibercept and bevacizumab showed significant antitumor activity (p < 0.001). In the H460 model, aflibercept resulted in 94% tumor growth inhibition (TGI) and bevacizumab treatment resulted in 72.2% TGI. Similarly, in the COLO320 model, aflibercept and bevacizumab resulted in 89.3 and 84% TGI, respectively. Moreover, antitumor activity occurs early after treatment initiation. Using Tumor Control Index score, which address the kinetics of tumor growth in a way comparable to the methods used in human clinical studies, we confirmed that both drugs inhibit significantly tumor growth. When tumor stabilization was evaluated, aflibercept shows higher ability to stabilize NEC tumors than bevacizumab. Conclusion: Results derived from this study strongly support anti-VEGF therapies, especially aflibercept, as a novel therapeutic option in NECs. Further studies are necessary, but our observations encourage the evaluation of antiangiogenics in clinical trials combined with standard chemotherapy.

The Changes of Fibrinolytic Activity of Nattokinase in Artificial Gastrointestinal Environment and Human Digestive Juice

2012 ◽  
Vol 581-582 ◽  
pp. 1145-1150
Author(s):  
Yong Liang Zhao ◽  
Ya Nan Gu ◽  
Wei Guo Wang ◽  
Ling Guang Du ◽  
Li Chuang Tang ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Oral Administration ◽  
Gastric Juice ◽  
Fibrinolytic Activity ◽  
Dosage Form ◽  
Fine Powder ◽  
Pharmaceutical Dosage Form ◽  
Digestive Juice ◽  
End Of Treatment ◽  
Artificial Gastric Juice

Purpose: To search for the change of fibrinolytic activity of different forms of nattokinase when they were treated in human digestive juice, artifical gastric and intestinal juice differently, and to lay the foundation of a proper pharmaceutical dosage form of nattokinase. To provide direct evidences that Nattokinase products can be administered orally and to screen a suitable dosage form for oral administration of nattokinase.Methods: The non-crushed sample was prepared through the solid fermentation of soybean meal at 37°C for 36 h, and evaporation at 70°C for 8 h, The fine and ultra-fine powder were gotten from the non-crushed sample by the micronizer and ultra micronizer. Nattokinase extract was the supernatant liquid of 0.9% saline of non-crush samples. The nattokinase’s fibrinolytic activity of non-crushed sample, fine powder, ultra-fine powder and extract treated in artifical and human digestive were measured by the Fibrin plate method. Results: Three kind of solid form samples still remain about 80% fibrinolytic activity in artificial gastric juice for 4 h, and the fibrinolytic activity of nattokinase extract is 48.7% at the end of treatment. Treated in artificial gastric juice for 4 hours, then handled in artificial intestinal fluid for 4 h, the final fibrinolytic activity of fine and ultra fine powder is 47.0% and 51.0%. The fibrinolytic activity of extract is 79.8% at the end of treatment in human digestive juice for 4 h. At the beginning of treatment in human digestive juice the enzyme activity of fine and ultra fine powder is 130.8U/mL and 132.1U/mL, however, after treatment for 4 h the enzyme activity is 158.7U/mL and159.6U/mL, which is near to the total enzyme activity of sample. Conclusion: Nattokinase products can be administered orally, and solid preparations of nattokinase are more suitable for oral route. The optimum dosage form for oral administration of nattokinase is enteric-coated capsules containing ultra fine powder.

scholarly journals ANTITUMOR ACTIVITY OF SOME DERIVATIVES OF INDOLO[2,3-A]CARBAZOLES N-GLYCOSIDES WITH XYLOSE CARBOHYDRATE RESIDUE

2020 ◽  
Vol 19 (4) ◽  
pp. 86-93
Author(s):  
I. S. Golubeva ◽  
N. P. Yavorskaya ◽  
L. V. Ektova ◽  
M. V. Dmitrieva ◽  
L. M. Borisova ◽  
...  
Keyword(s):  
Nitrogen Atom ◽  
Antitumor Activity ◽  
Tumor Growth ◽  
Growth Inhibition ◽  
Antitumor Effect ◽  
Breast Adenocarcinoma ◽  
Tumor Growth Inhibition ◽  
Carbohydrate Residue ◽  
National Medical ◽  
Derivatives Of

Introduction. The search for new antineoplastic agents in a series of indolo[2,3-a]-carbazole derivatives is an urgent and promising direction, since compounds with antitumor activity have been found in this class. In the chemical fusion laboratory, N.N. Blokhin National Medical Research Center оf the Ministry of Health of Russia has developed an original and effective method for the synthesis of glycosides of indolo[2,3-a]-pyrrolo[3,4-c]carbazoles, which makes it possible to synthesize derivatives of N-glycosides of indolo[2,3-a]carbazoles with different substituents in the heterocyclic parts including at the maleimide nitrogen atom and with different carbohydrate residues.The purpose of the study – the primary assessment of the antitumor activity of new derivatives of indolocarbazoles with a carbohydrate residue xylose in models of tumor growth mice.Materials and methods. The compounds studied at transplanted tumors of mice: the Lewis epidermoid carcinoma (LLC), colon cancer ACATOL, cervical cancer RSHM-5, breast adenocarcinoma CA-755. Studies were performed on immunocompetent mice: males and females of BDF1 hybrids (C57Bl/6 × DBA/2), females CBA/Lac and Balb/c. Compound solutions were prepared ex tempore and administered to the mice intraperitoneally at a dose of 60 mg/kg daily for five days. The antitumor effect was evaluated as to of tumor growth inhibition and increase of life span of the treated animals as compared with the control ones.Results. Eight compounds studied, containing D-xylose as a carbohydrate component and various substituents at the maleimide nitrogen atom, showed different degrees of antitumor activity. Two derivatives have been identified: N-[5,7-dioxo-12-(β-D-xylopyranosyl)-indole[2,3-a]pyrrolo[3,4-c]carbazol-6-il]benzamide (compound 4) and N-[5,7-dioxo-12-(β-D-xylopyranosyl)-5,7,12,13-tetrahydro-6H-indole[2,3-a]pyrrolo[3,4-c]carbazole-6-il]pyridin-2-carboxamide (compound 8), which showed high antitumor activity on 4 solid tumors of mice with a duration of effect of 12 days or more. The most pronounced antitumor effect was obtained in compounds 4 and 8 in RSHM-5 and Ca-755, tumor growth inhibition was amounted, respectively: in RSHM-5 – 68–82 % and 80–72 %; for Ca-755 – 57–62 % and 86–68 % (p <0.05).Conclusion. For further research, we chose the compound (N-[5,7-dioxo-12-(β-D-xilopiranosil)-5,7,12,13-tetrahydro-6H-indole[2,3-a] pyrrolo[3,4-c]carbazol-6-il]pyridin-2-carboxamide).

scholarly journals 3‑HYDROXYQUINAZOLINE DERIVATIVE, AN ANALOGUE OF ERASTIN, INDUCES FERROPTOSIS IN METASTATIC MELANOMA CELLS

2021 ◽  
Vol 20 (1) ◽  
pp. 67-73
Author(s):  
L. M. Borisova ◽  
V. N. Osipov ◽  
D. V. Gusev ◽  
I. S. Golubeva ◽  
M. Р. Kiseleva ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Metastatic Melanoma ◽  
Phase Contrast ◽  
Antitumor Effect ◽  
Antitumor Agent ◽  
Melanoma Cells ◽  
Tumor Growth Inhibition ◽  
Published Data ◽  
Clinical Progression ◽  
Antitumor Therapy

Introduction. The main cause of clinical progression of tumor under the conditions of treatment is the resistance. Reactivate apoptosis in resistant to chemotherapy cells is impossible, the tumor grows into an irreversible growth phase. Recently published data on the ability of ferroptosis inducers to induce the death of resistant cells opens up new possibilities for improving the effectiveness of antitumor therapy.The purpose of the study – assessment of the mechanism of ferroptosis induction of the synthesized analogue of erastin OVN‑002 on Mel Z melanoma cells and investigation of its antitumor activity on transplanatated B‑16 melanoma of mice.Materials and methods. In this study 2D cultivation of metastatic Mel Z melanoma cells, phase‑contrast and fluorescence microscopy, and a model of experimental growth of B‑16 melanoma in female hybrids of immu‑ nocompetent mice F1 (C57Bl/6 × DBA / 2) were used. The antitumor effect was evaluated by measurement of tumor growth inhibition (TGI,  %) and increase of life span of the treated animals as compared to the control ones.Results. The cytotoxic activity of OVN‑002 was equal to the activity of erastin on metastatic melanoma cells Mel Z: 744 ± 20 and 719 ± 20 a. u., respectively. OVN‑002 at a dose 50 mg / kg reduced the growth of experimental melanoma B‑16 about 81 % (TGI 81–57 %, p <0.05). The effect was stable up to 7th day, while erastin showed only a direct antitumor effect (TGI 65 %, p <0.05).Conclusion. The data obtained suggest that OVN‑002 might be considered as a novel antitumor agent.

scholarly journals Antitumor activity of ormustine against transplantable solid murine tumors. Part I

2017 ◽  
Vol 16 (4) ◽  
pp. 55-60 ◽  
Author(s):  
N. S. Saprykina ◽  
L. M. Borisova ◽  
M. P. Kiseleva ◽  
V. P. Krasnov ◽  
G. L. Levit ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Lung Carcinoma ◽  
Lewis Lung Carcinoma ◽  
Antitumor Effect ◽  
Antitumor Agents ◽  
Tumor Growth Inhibition ◽  
Lewis Lung ◽  
Reference Drug ◽  
Murine Tumors ◽  
Melanoma B16

Background. Drugs of nitrosourea class are actively and successfully administered in oncology practice. However, at present, the search for new antitumor agents of this class is very urgent. Objective: to examine in vivo antitumor activity of ormustine, a new Russian drug from alkylnitrosourea class, against solid transplantable murine tumors: melanoma B16 and epidermoid Lewis lung carcinoma. Materials and methods. The assessment of antitumor activity of ormustine and a reference drug mustophoran (Les Labolatories Servier, France) was carried out in B6D2F1 mice. Ormustine was administered intravenously at a single dose of 50-135 mg/kg. Mustophoran was administered intravenously at a dose of 32 mg/kg twice (on days 2 and 9) and 3 times at a dose of 25 mg/kg (on days 2, 6 and 9). The follow-up period lasted till the death of animals. The antitumor effect of agents was assessed by the tumor growth inhibition and increase in life span of experimental mice compared to control animals. Results. It has been defined that the single intravenous dose of ormustine (125 mg/kg) is therapeutic for mice bearing melanoma B16 and epidermoid Lewis lung carcinoma. Conclusions. Ormustine possesses high antitumor effect against solid transplantable murine tumors. Ormustine is not inferior to mustophoran in the therapeutic effect against melanoma B16.

Significance of In-Vitro and In-Vivo Correlation in Drug Delivery System

2018 ◽  
Vol 4 (4) ◽  
pp. 523-531
Author(s):  
Hina Mumtaz ◽  
Muhammad Asim Farooq ◽  
Zainab Batool ◽  
Anam Ahsan ◽  
Ashikujaman Syed
Keyword(s):  
Dosage Form ◽  
Pharmaceutical Preparations ◽  
Pharmacokinetic Profile ◽  
In Vitro Dissolution ◽  
Time Saving ◽  
Pharmaceutical Dosage Form ◽  
Short Period ◽  
Form Development

The main purpose of development pharmaceutical dosage form is to find out the in vivo and in vitro behavior of dosage form. This challenge is overcome by implementation of in-vivo and in-vitro correlation. Application of this technique is economical and time saving in dosage form development. It shortens the period of development dosage form as well as improves product quality. IVIVC reduce the experimental study on human because IVIVC involves the in vivo relevant media utilization in vitro specifications. The key goal of IVIVC is to serve as alternate for in vivo bioavailability studies and serve as justification for bio waivers. IVIVC follows the specifications and relevant quality control parameters that lead to improvement in pharmaceutical dosage form development in short period of time. Recently in-vivo in-vitro correlation (IVIVC) has found application to predict the pharmacokinetic behaviour of pharmaceutical preparations. It has emerged as a reliable tool to find the mode of absorption of several dosage forms. It is used to correlate the in-vitro dissolution with in vivo pharmacokinetic profile. IVIVC made use to predict the bioavailability of the drug of particular dosage form. IVIVC is satisfactory for the therapeutic release profile specifications of the formulation. IVIVC model has capability to predict plasma drug concentration from in vitro dissolution media.

Simultaneous Estimation of Ilaprazole and Domperidone in Pharmaceutical Dosage Form

2016 ◽  
Vol 9 (6) ◽  
pp. 3549-3555
Author(s):  
Gopi Patel ◽  
Kiral M Prajapati ◽  
Bhavesh Prajapati ◽  
Samir K Shah
Keyword(s):  
Dosage Form ◽  
Ammonia Solution ◽  
Hplc Method ◽  
Simultaneous Estimation ◽  
Control Analysis ◽  
Linear Calibration ◽  
Pharmaceutical Dosage Form ◽  
Stability Indicating ◽  
Water Ph ◽  
Alkali Hydrolysis

A simple, accurate and precise stability-indicating RP-HPLC method was developed and subsequently validated for simultaneous determination of ilaprazole and domperidone in bulk and pharmaceutical dosage form. The proposed HPLC method utilizes  C18  (250 mm × 4.6 mm × 5 µm) column with mobile phase comprising of 0.5 % glacial acetic acid in water pH 5.5 adjusted with ammonia solution: methanol in the ratio 45:55 v/v at a flow rate of 1.0 ml/min. Quantitation was achieved with UV detection at 286 nm based on peak area with linear calibration curves at concentration  ranges 80-120µg/ml for ilaprazole and 240-360 µg/ml for domperidone  with correlation coefficient of 0.999.The retention times of ilaprazole and domperidone  were found to be 3.0 min, 5.4 min respectively. The mean recoveries obtained for ilaprazole and domperidone were found to be 99.76 ± 0.6463 % and 100.7 ± 0.2424 % respectively. Stress testing which covered acid, alkali hydrolysis, and peroxide, photolytic, thermal degradation was performed to prove the specificity of the proposed method and degradation was achieved. The proposed method was successfully applied for the stability indicating simultaneous estimation of ilaprazole and domperidone in routine quality control analysis in bulk and pharmaceutical formulation.

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