Primary Acute Toxicity Screen for Biomaterials: Rationale, In Vitro/In Vivo Relationship and Interlaboratory Performance

2009 ◽  
pp. 51-51-20 ◽  
Author(s):  
EO Dillingham
Keyword(s):  
Acute Toxicity

Evaluation of the In Vivo Acute Toxicity and In Vitro Hemolytic and Immunomodulatory Activities of the Moringa oleifera Flower Trypsin Inhibitor (MoFTI)

2020 ◽  
Vol 27 ◽  
Author(s):  
Leydianne Leite de Siqueira Patriota ◽  
Dayane Kelly Dias do Nascimento Santos ◽  
Bárbara Rafaela da Silva Barros ◽  
Lethícia Maria de Souza Aguiar ◽  
Yasmym Araújo Silva ◽  
...  
Keyword(s):  
Acute Toxicity ◽  
Trypsin Inhibitor ◽  
Hemolytic Activity ◽  
Moringa Oleifera ◽  
Biological Activities ◽  
Hematological Parameters ◽  
Behavioral Alterations ◽  
Female Mice

Background: Protease inhibitors have been isolated from plants and present several biological activities, including immunomod-ulatory action. Objective: This work aimed to evaluate a Moringa oleifera flower trypsin inhibitor (MoFTI) for acute toxicity in mice, hemolytic activity on mice erythrocytes and immunomodulatory effects on mice splenocytes. Methods: The acute toxicity was evaluated using Swiss female mice that received a single dose of the vehicle control or MoFTI (300 mg/kg, i.p.). Behavioral alterations were observed 15–240 min after administration, and survival, weight gain, and water and food consumption were analyzed daily. Organ weights and hematological parameters were analyzed after 14 days. Hemolytic activity of MoFTI was tested using Swiss female mice erythrocytes. Splenocytes obtained from BALB/c mice were cultured in the absence or presence of MoFTI for the evaluation of cell viability and proliferation. Mitochondrial membrane potential (ΔΨm) and reactive oxygen species (ROS) levels were also determined. Furthermore, the culture supernatants were analyzed for the presence of cytokines and nitric oxide (NO). Results: MoFTI did not cause death or any adverse effects on the mice except for abdominal contortions at 15–30 min after administration. MoFTI did not exhibit a significant hemolytic effect. In addition, MoFTI did not induce apoptosis or necrosis in splenocytes and had no effect on cell proliferation. Increases in cytosolic and mitochondrial ROS release, as well as ΔΨm reduction, were observed in MoFTI-treated cells. MoFTI was observed to induce TNF-α, IFN-γ, IL-6, IL-10, and NO release. Conclusion: These results contribute to the ongoing evaluation of the antitumor potential of MoFTI and its effects on other immunological targets.

Chemosensitizing Activity of Histone Deacetylases Inhibitory Cyclic Hydroxamic Acids for Combination Chemotherapy of Lymphatic Leukemia

2018 ◽  
Vol 18 (4) ◽  
pp. 365-371 ◽  
Author(s):  
Denis V. Mishchenko ◽  
Margarita E. Neganova ◽  
Elena N. Klimanova ◽  
Tatyana E. Sashenkova ◽  
Sergey G. Klochkov ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Acute Toxicity ◽  
Histone Deacetylases ◽  
Hydroxamic Acids ◽  
Water Soluble ◽  
Male Rat ◽  
Hybrid Male ◽  
Cyclic Hydroxamic Acids

Background: Anti-tumor effect of hydroxamic acid derivatives is largely connected with its properties as efficient inhibitors of histone deacetylases, and other metalloenzymes involved in carcinogenesis. Objective: The work was aimed to (i) determine the anti-tumor and chemosensitizing activity of the novel racemic spirocyclic hydroxamic acids using experimental drug sensitive leukemia P388 of mice, and (ii) determine the structure-activity relationships as metal chelating and HDAC inhibitory agents. Method: Outbreed male rat of 200-220 g weights were used in biochemical experiments. In vivo experiments were performed using the BDF1 hybrid male mice of 22-24 g weight. Lipid peroxidation, Fe (II) -chelating activity, HDAC fluorescent activity, anti-tumor and anti-metastatic activity, acute toxicity techniques were used in this study. Results: Chemosensitizing properties of water soluble cyclic hydroxamic acids (CHA) are evaluated using in vitro activities and in vivo methods and found significant results. These compounds possess iron (II) chelating properties, and slightly inhibit lipid peroxidation. CHA prepared from triacetonamine (1a-e) are more effective Fe (II) ions cheaters, as compared to CHA prepared from 1- methylpiperidone (2a-e). The histone deacetylase (HDAC) inhibitory activity, lipophilicity and acute toxicity were influenced by the length amino acids (size) (Glycine < Alanine < Valine < Leucine < Phenylalanine). All compounds bearing spiro-N-methylpiperidine ring (2a-e) are non-toxic up to 1250 mg/kg dose, while compounds bearing spiro-tetramethylpiperidine ring (1a-e) exhibit moderate toxicity which increases with increasing lipophility, but not excite at 400 mg/kg. Conclusion: It was shown that the use of combination of non-toxic doses of cisplatin (cPt) or cyclophosphamide with CHA in most cases result in the appearance of a considerable anti-tumor effect of cytostatics. The highest chemosensitizing activity with respect to leukemia Р388 is demonstrated by the CHA derivatives of Valine 1c or 2c.

In-vitro and in-vivo evaluation of antidiabetic activity of Withania coagulans extract

2019 ◽  
Vol 09 ◽  
Author(s):  
Tejas Patel ◽  
B.N. Suhagia
Keyword(s):  
Blood Glucose ◽  
Acute Toxicity ◽  
Aqueous Extract ◽  
Pancreatic Beta Cell ◽  
Toxicity Study ◽  
Acute Toxicity Study ◽  
Withania Coagulans ◽  
Study Results

Background: Diabetes mellitus is major issue to public health as its prevalence is rising day by day. Synthetic agents available for the diabetic treatment are expensive or produce undesirable side effect on chronic use and some of them are not suitable during pregnancy. Herbal medicines accepted widely due to side effects and low cost. Objective: The aim of present study was to evaluate the activity of Withania coagulans extract using In-vitro and In-vivo model. Methods: Different three types of Withania coagulans extract were prepared using aqueous (W1), Alcohol (W2) and hydro-alcoholic (50:50) mixture (W3). In-vitro Anti-diabetic activity of the all three extracts evaluated using RINm5F Pancreatic beta cells.Further, n-vivo anti-diabetic evaluation performed by administering 50 mg/kg (p.o) aqueous extract for 7 days in Streptozotocin (STZ)-induced mice. Body weight of the animals was also determined to perform acute toxicity study. Results: The results of in –vitro cell based study indicated that among all three extract, aqueous extract (W1) of Withania coagulans showed potential increase in inulin release. The EC50 of the W1 (249.6 µg/L) which is compared with standard (Glibenclamide) EC50. From the results of In-vitro study, W1 subjected for acute toxicity study and the acute toxicity study results indicated LD50 of 50mg/kg. Diabetic rats treated with W1 extract at oral dose of 50 mg/kg for 7 days showed 34.17% reduction in blood glucose in comparison to untreated diabetic (STZ-induced) rats. Blood glucose levels of Standard treated (Glibenclamide) and control untreated. Conclusion: In conclusion, results of pancreatic beta cell based study showed increase in insulin release by administration of extract. Further aqueous extract (W1) was potentially reduced blood glucose level in STZ induced diabetic mice.

scholarly journals Preparation and Evaluation of Topically Applied Azithromycin Based on Sodium Hyaluronate in Treatment of Conjunctivitis

Pharmaceutics ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 183
Author(s):  
Chen ◽  
Yin ◽  
Ma ◽  
Tu ◽  
Shen
Keyword(s):  
Acute Toxicity ◽  
Hydroxypropyl Methylcellulose ◽  
Sodium Hyaluronate ◽  
Drug Formulation ◽  
Resonance Spectroscopy ◽  
Eye Drops ◽  
Scanning Calorimetry ◽  
Eye Irritation

Azithromycin (AZI) eye drops containing sodium hyaluronate (SH) were developed to improve the bioavailability of AZI. Interaction between AZI and SH in the AZI-SH formulation was investigated by differential scanning calorimetry, X-ray diffraction, and 1H-nuclear magnetic resonance spectroscopy analyses. Moreover, advantages of using SH as an excipient were investigated by comparing physiological properties and pharmacokinetic behaviors of SH-containing AZI eye drops with that of hydroxypropyl methylcellulose (HPMC)-containing formulation. In addition, safety of the developed AZI-SH eye drops was evaluated by in vitro 3-(4,5-dimethyl-2-Thiazyl)-2, 5-diphenyl-2H-tetrazolium bromide assay (MTT assay) and neutral red uptake assay as well as in vivo eye irritation test and acute toxicity test. The results indicated that AZI formed a complex with SH under a slightly acidic condition. The area under the curve (AUC) of AZI in SH-containing formulation was 1.58-fold higher (P<0.01) than that in HPMC-containing formulation due to the interaction between the amine group of AZI and the carboxyl group of SH, despite of the higher viscosity of HPMC-containing formulation. Safety evaluation showed that AZI-SH eye drops caused no obvious eye irritation and acute toxicity. In conclusion, the developed SH-containing AZI formulation possessing advantages of longer retention time and higher drug availability was a promising drug formulation for topical ocular therapy.

scholarly journals ACUTE TOXICITY STUDY OF THE LEAVES ETHANOLIC EXTRACT OF PICRIA FEL-TERRAE LOUR.

2018 ◽  
Vol 11 (13) ◽  
pp. 55
Author(s):  
Popi Patilaya ◽  
Dadang Irfan Husori ◽  
Imam Bagus Sumantri ◽  
Simon Sihombing
Keyword(s):  
Acute Toxicity ◽  
Plant Extract ◽  
Aspartate Aminotransferase ◽  
Alanine Aminotransferase ◽  
Ethanolic Extract ◽  
Male Mice ◽  
Plant Leaves ◽  
Liver And Kidney

 Objective: Picria fel-terrae belongs to family Linderniaceae is also known as Pugun tano by Indonesian people. The ethanolic extract of plant leaves has several potential pharmacological activities including antidiabetic, anthelmintic, and antioxidant. However, the toxicity of the plant extract is rarely explored. This work was to investigate toxicity of the leaf ethanolic extract of P. fel-terrae on Artemia salina and male mice.Methods: Acute toxicity of the plant extract was studied by in vitro and in vivo methods. In vitro study was carried out by exposing nauplii to the plant extract at concentrations of 10, 100, 200, 500, and 1000 μg/ml for 48 h. In vivo study was performed on male mice that divided into four groups. Groups I, II, III, and IV were treated with sodium carboxymethyl cellulose 0.5%, the ethanolic extract of plant leaves at doses of 1000, 2000, and 5000 mg/kg bw, respectively. The animal toxic symptoms were observed every day for 14 days. On day 15, the blood of mice was collected to measure alanine aminotransferase, aspartate aminotransferase, and creatinine levels. The effects of plant extract on vital animal organs such as heart, liver, and kidney were also studied. Statistical analysis of data was performed using analysis of variance and followed by Tukey post hoc.Results: The results showed that the leaf ethanolic extract of P. fel-terrae to have weakly toxicity on A. salina with the LC50 of 768.07 μg/ml. At in vivo studies, the toxic symptoms of mice were not identified during experiment with all doses of the plant extract for 14 days. In addition, aspartate aminotransferase and creatinine levels were no significantly different between control and all treatment groups (p>0.05). However, alanine aminotransferase level changed when mice were exposed by the plant extract at the doses of 2.000 and 5.000 mg/kg bw. Although the mice were not dead during experiment, the animal organs such as heart, liver, and kidney were histologically changed.Conclusion: This study suggests that the ethanolic extract of P. fel-terrae leaves has weakly toxicity on A. salina and causes histological changes on male mice organs at the high doses.

Novel amidino substituted 2-phenylbenzothiazoles: Synthesis, antitumor evaluation in vitro and acute toxicity testing in vivo

2010 ◽  
Vol 18 (3) ◽  
pp. 1038-1044 ◽  
Author(s):  
Livio Racané ◽  
Marijeta Kralj ◽  
Lidija Šuman ◽  
Ranko Stojković ◽  
Vesna Tralić-Kulenović ◽  
...  
Keyword(s):  
Acute Toxicity ◽  
Toxicity Testing ◽  
Antitumor Evaluation ◽  
Acute Toxicity Testing

scholarly journals Evaluation of Eucalyptus citriodora essential oil on goat gastrointestinal nematodes

2011 ◽  
Vol 20 (3) ◽  
pp. 223-227 ◽  
Author(s):  
Iara Tersia Freitas Macedo ◽  
Claudia Maria Leal Bevilaqua ◽  
Lorena Mayana Beserra de Oliveira ◽  
Ana Lourdes Fernandes Camurça-Vasconcelos ◽  
Luiz da Silva Vieira ◽  
...  
Keyword(s):  
Acute Toxicity ◽  
Essential Oil ◽  
Larval Development ◽  
Anthelmintic Activity ◽  
Gastrointestinal Nematodes ◽  
Gastrointestinal Parasites ◽  
Eucalyptus Citriodora ◽  
Egg Hatching

Phytotherapy may be an alternative strategy for controlling gastrointestinal parasites. This study evaluated the anthelmintic efficacy of Eucalyptus citriodora essential oil (EcEO). The in vitro effects of EcEO were determined through testing the inhibition of egg hatching and larval development of Haemonchus contortus. EcEO was subjected to acute toxicity testing on mice, orally and intraperitoneally. The in vivo effects of EcEO were determined by the fecal egg count reduction test (FECRT) in goats infected with gastrointestinal nematodes. The results showed that 5.3 mg.mL-1 EcEO inhibited egg hatching by 98.8% and 10.6 mg.mL-1 EcEO inhibited H. contortus larval development by 99.71%. The lethal doses for 50% of the mice were 4153 and 622.8 mg.kg-1, for acute toxicity orally and intraperitoneally. In the FECRT, the efficacy of EcEO and ivermectin was 66.25 and 79.16% respectively, on goat gastrointestinal nematodes eight days after treatment. EcEO showed in vitro and in vivo anthelmintic activity.

scholarly journals Acute Toxicity, Antioxidant, and Antifatigue Activities of Protein-Rich Extract from Oviductus ranae

2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Yang Zhang ◽  
Yang Liu ◽  
Kun Zhu ◽  
Yao Dong ◽  
Hao Cui ◽  
...  
Keyword(s):  
Amino Acids ◽  
Acute Toxicity ◽  
Mice Model ◽  
Sod Activity ◽  
Antioxidant Power ◽  
Safety Property ◽  
Protein Rich ◽  
Oviductus Ranae

The paper investigated the preparation, amino acid composition, acute toxicity, and in vitro and in vivo antioxidant, coupled with in vivo antifatigue activities of protein-rich extract of Oviductus ranae (PEOR). The results indicated that PEOR possesses high-safety property with maximum tolerated dose (MTD) higher than 20 g/kg in mice, shows weak scavenging capacities against hydroxyl, superoxide anion, and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals, as well as ferric-reducing antioxidant power in vitro, but exerts strong antioxidant effect in ethanol-induced oxidative stress mice model; it can decrease malonaldehyde (MDA) and protein carbonyl (PCO) formation and increase total superoxide dismutase (T-SOD) activity and glutathione (GSH) synthesis. Besides the strong in vivo antioxidant activity, PEOR in a dose of 400 mg/kg also has antifatigue effect in mice, and it can prolong the exhaustive swimming time, reduce the elevated blood urea nitrogen (BUN) and blood lactic acid (BLA) caused by intense exercise. The in vivo activity of PEOR may be contributed by its absorbed amino acids, due to the fact that eight antioxidant amino acids and twelve glucogenic ones were found in it. This study will provide an evidence for the clinical use of PEOR as a dietary supplement for antioxidant and antifatigue in the same oral dose (400 mg/kg).

scholarly journals Zebrafish toxicological screening could aid Leishmaniosis drug discovery

2021 ◽  
Vol 37 (1) ◽  
Author(s):  
Hirla Costa Silva Fukushima ◽  
Ricardo Lacava Bailone ◽  
Tatiana Corrêa ◽  
Helena Janke ◽  
Luís Kluwe De Aguiar ◽  
...  
Keyword(s):  
Acute Toxicity ◽  
Zebrafish Embryo ◽  
New Drugs ◽  
Toxicological Screening ◽  
Cell Models ◽  
Clinical Tests ◽  
Teratogenic Effects ◽  
Complex Interactions

Abstract Background Recently a screen from a library of 1.8 million compounds identified in vitro a potent activity of the 2-aminobenzimidazoles series against Leishmania infantum, the etiological agent responsible by over 20.000 deaths each year. Several analogs were synthesized and in vitro tested through an optimization program, leading to a promising 2-aminobenzimidazoles derived compound (2amnbzl-d) that was progressed to in vivo mice studies. However, the not expected toxic effects prevented its progression to more advanced preclinical and clinical phases of drug development. Due to limitations of cell models in detecting whole organism complex interactions, 90% of the compounds submitted to pre-clinical tests are reproved. The use of Zebrafish embryo models could improve this rate, saving mammals, time and costs in the development of new drugs. To test this hypothesis, we compared 2amnbzl-d with two compounds with already established safety profile: carbamazepine and benznidazole, using an embryo Zebrafish platform based on acute toxicity, hepatotoxicity, neurotoxicity and cardiotoxicity assays (Pltf-AcHpNrCd). Results Tests were performed blindly, and the results demonstrated the presence of lethal and teratogenic effects (CL50%: 14.8 µM; EC50%: 8.6 µM), hepatotoxic in concentrations above 7.5 µM and neurotoxic in embryos exposed to 15 µM of 2amnbzl-d. Nevertheless, benznidazole exposition showed no toxicity and only the 100 µM of carbamazepine induced a bradycardia. Conclusions Results using Pltf-AcHpNrCd with zebrafish reproduced that found in the toxicological tests with mammals to a portion of the costs and time of experimentation.

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