Insulin-mimetic macromolecular poly-N-vinylpyrrolidone-based  vanadium metallocomplexes. Part 1.  Synthesis of macromolecular vanadium metallocomplex and its acute oral toxicity evaluation

Diabetes mellitus (DM) is a severe chronic disease affecting virtually all kinds of metabolic processes in the human body. As incidence and prevalence of DM are increasing worldwide, WHO estimates the number of people living with diabetes to be as high as half a billion and still rising. Long-term health complications of DM, such as diabetic nephropathy, retinopathy, neuropathy, and cardiovascular pathology, although preven-table in most cases, are known to be severe, potentially life-threatening and often irreversible, which makes the search for new effective antidiabetic drugs a research priority and one of the most pressing issues in health care today. To date, the insulin-mimetic properties of vanadium compounds have been the subject of quite a significant number of studies. In vivo experiments have shown that vanadium, acting in an insulin-like fashion, takes part in the regulation of glucose and lipid metabolism. In particular, vanadium stimulates glucose uptake and metabolism in insulin target tissues, increases the intensity of glycogen and lipid biosynthesis, and inhibits that of gluconeogenesis, glycogenolysis, and lipolysis. Organic vanadium complexes are known to be less toxic than its inorganic salts, which are characterized by a number of potentially serious adverse effects, mainly but not exclusively on the central nervous system and the kidneys; in addition to lower toxicity, organic vanadium compounds have been found to have higher bioavailability when to compared to those of inorganic nature. Such observations clearly hold promise for the development of an entirely novel therapeutic class of antidiabetic drugs. The aims of this study are to obtain new polymeric vanadyl(VO2+) derivatives based on poly-N-vinylpyrrolidone (PVP) that would exert hypoglycemic effect in vivo, and to explore the possibilities of using such compounds or formulations derived thereof for type 2 DM prophylaxis and/or treatment. This work gives a method of obtaining and isolation of an oxovanadium(IV)-polymer metallocomplex, and describes the structural features of said compound, confirmed experimentally. The results of the acute oral toxicity study revealed that the newly synthesized compound is of low toxicity, having a median lethal dose (LD50) that is at a level well above those typical of inorganic vanadium salts.

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QSAR and Classification Study on Prediction of Acute Oral Toxicity of N-Nitroso Compounds

International Journal of Molecular Sciences ◽

10.3390/ijms19103015 ◽

2018 ◽

Vol 19 (10) ◽

pp. 3015 ◽

Cited By ~ 14

Author(s):

Tengjiao Fan ◽

Guohui Sun ◽

Lijiao Zhao ◽

Xin Cui ◽

Rugang Zhong

Keyword(s):

External Validation ◽

Lethal Dose ◽

Nitroso Compounds ◽

Acute Oral Toxicity ◽

Classification Models ◽

Toxicity Data ◽

Oral Toxicity ◽

Qsar Studies ◽

Dragon Descriptors

To better understand the mechanism of in vivo toxicity of N-nitroso compounds (NNCs), the toxicity data of 80 NNCs related to their rat acute oral toxicity data (50% lethal dose concentration, LD50) were used to establish quantitative structure-activity relationship (QSAR) and classification models. Quantum chemistry methods calculated descriptors and Dragon descriptors were combined to describe the molecular information of all compounds. Genetic algorithm (GA) and multiple linear regression (MLR) analyses were combined to develop QSAR models. Fingerprints and machine learning methods were used to establish classification models. The quality and predictive performance of all established models were evaluated by internal and external validation techniques. The best GA-MLR-based QSAR model containing eight molecular descriptors was obtained with Q2loo = 0.7533, R2 = 0.8071, Q2ext = 0.7041 and R2ext = 0.7195. The results derived from QSAR studies showed that the acute oral toxicity of NNCs mainly depends on three factors, namely, the polarizability, the ionization potential (IP) and the presence/absence and frequency of C–O bond. For classification studies, the best model was obtained using the MACCS keys fingerprint combined with artificial neural network (ANN) algorithm. The classification models suggested that several representative substructures, including nitrile, hetero N nonbasic, alkylchloride and amine-containing fragments are main contributors for the high toxicity of NNCs. Overall, the developed QSAR and classification models of the rat acute oral toxicity of NNCs showed satisfying predictive abilities. The results provide an insight into the understanding of the toxicity mechanism of NNCs in vivo, which might be used for a preliminary assessment of NNCs toxicity to mammals.

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In Vivo and In Vitro Toxicity Profiles of Hexane Extract of Alpinia malaccensis Rhizome in Rat and Cell Line Models

Journal of Toxicology ◽

10.1155/2021/9578474 ◽

2021 ◽

Vol 2021 ◽

pp. 1-12

Author(s):

T. Somarathna ◽

M. G. Thammitiyagodage ◽

K. K. D. S. Ranaweera ◽

G. A. S. Premakumara ◽

M. A. Akbarsha ◽

...

Keyword(s):

Body Weight ◽

Biochemical Parameters ◽

Lethal Dose ◽

In Vitro Cytotoxicity ◽

Hexane Extract ◽

Acute Oral Toxicity ◽

Oral Toxicity ◽

Hematological And Biochemical Parameters

The objective of the study was to evaluate the potential toxicity of crude n-hexane extract of Alpinia malaccensis rhizome. The in vivo acute oral toxicity was evaluated by administering a single oral dose of the extract at 0, 300, or 2000 mg/kg body weight to female Wistar rats according to modified OECD Test Guideline 423. For the in vitro cytotoxicity study, A549, HepG2, 3T3, and COS-7 cell lines were exposed to different doses of A. malaccensis extract and cell viability was assessed adopting MTT assay followed by AO/EB staining, Hoechst staining, and comet assay with a view to compare the cellular and molecular mechanisms underlying the toxicity, if any. It was found that administration of 2000 mg/kg bw dose in in vivo oral acute toxicity study did not produce significant toxicity or mortality. No significant ( p < 0.05 ) differences were observed for body weight and hematological and biochemical parameters compared to control after 14 days of treatment. No changes in behavior, body weight, hematological and biochemical parameters, and aspects of histopathology were observed when compared to the control. Thus, the possible oral lethal dose for A. malaccensis extract is above 2000 mg/kg body weight. The in vitro cytotoxicity analysis showed nontoxicity concentrations of the extract to be 2, 1.4, 30, and 1.4 µg/mL for A549, HepG2, 3T3, and COS-7 cells, respectively, where no apoptotic/necrotic cell death and DNA damage were observed. In conclusion, the extract of rhizome of A. malaccensis did not produce apparent cytotoxicity or acute oral toxicity, confirming the scope to use A. malaccensis as a safe food preservative and a natural therapeutic product after further subacute and chronic toxicity studies.

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Acute toxicity of an insecticidal little containing ivermectin and fipronil for white mice

Veterinaria Kubani ◽

10.33861/2071-8020-2020-6-31-32 ◽

2020 ◽

pp. 31-32

Author(s):

Mikhail A. Levchenko ◽

◽

Natalia A. Sennikova ◽

Keyword(s):

Acute Toxicity ◽

Lethal Dose ◽

Live Weight ◽

Acute Oral Toxicity ◽

Oral Toxicity ◽

Toxicological Assessment ◽

Russian Research Institute ◽

Veterinary Entomology ◽

Russian Research

Toxicological assessment is a mandatory research step in the development of new insecticidal drugs. At the All-Russian Research Institute of Veterinary Entomology and Arachnology, a prototype of the insecticidal bait Mukhnet IF was obtained with an active ingredient content of 0.06% ivermectin and 0.015% fipronil, which showed a highly effective effect against houseflies. This work presents the results of the study of acute oral toxicity of the above agent. For this, male white mice with a live weight of 16-26 g were selected. They were kept on a starvation diet for one day in individual houses with water. The drug was given in mg/kg body weight the next day. A total of 33 doses have been tested, ranging from 100 mg/kg to 40,000 mg/kg. The animals were observed for 14 days. According to the research results, it was revealed that at doses up to 20,000 mg/kg there were no signs of intoxication, but when tested at 25,000 mg/kg in some mice, these signs were noted, and at 30,000, 35,000 and 40,000 mg/kg deaths were recorded 20±10, 45±30 and 60±20%, respectively. It was not possible to test the drug over the last above dose due to incomplete eaten by mice. According to the degree of danger for warm-blooded animals, the drug belongs to the 4th class of low-hazard drugs (average lethal dose of 5000 mg/kg or more) in accordance with the classification of GOST 12.1.007-76. When analyzing the literature data on the toxicological characteristics of preparations containing ivermectin and chlorfenapyr, it was revealed that the insecticidal agent in its acute toxicity for warm-blooded animals is comparable to known analogues.

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A New Symmetrical Thiazolidinedione Derivative: In Silico Design, Synthesis, and In Vivo Evaluation on a Streptozotocin- Induced Rat Model of Diabetes

Processes ◽

10.3390/pr9081294 ◽

2021 ◽

Vol 9 (8) ◽

pp. 1294

Author(s):

Samuel Álvarez-Almazán ◽

Gabriel Navarrete-Vázquez ◽

Itzia Irene Padilla-Martínez ◽

José Correa-Basurto ◽

Diana Alemán-González-Duhart ◽

...

Keyword(s):

Rat Model ◽

In Silico ◽

Female Rats ◽

Therapeutic Effects ◽

Acute Oral Toxicity ◽

Oral Toxicity ◽

In Vivo Evaluation ◽

Docking Simulations ◽

Ppar Γ

By activating PPAR-γ, thiazolidinediones normalize glucose levels in animal models of type 2 diabetes and in patients with this pathology. The aim of the present study was to analyze 219 new derivatives in silico and select the best for synthesis, to be evaluated for acute oral toxicity in female rats and for control of diabetes-related parameters in a rat model of streptozotocin-induced diabetes. The best compound was chosen based on pharmacokinetic, pharmacodynamic, and toxicological parameters obtained in silico and binding orientation observed by docking simulations on PPAR-γ. Compound 1G was synthesized by a quick and easy Knoevenagel condensation. Acute oral toxicity was found at a dose greater than 2000 mg/Kg. Compound 1G apparently produces therapeutic effects similar to those of pioglitazone, decreasing glycaemia and triglyceride levels in diabetic animals, without liver damage. Moreover, it did not cause a significant weight gain and tended to reduce polydipsia and polyphagia, while diminishing systemic inflammation related to TNF-α and IL-6. It lowered the level of endogenous antioxidant molecules such as reduced glutathione and glutathione reductase. In conclusion, 1G may be a candidate for further testing as an euglycemic agent capable of preventing the complications of diabetes.

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Sub-acute oral toxicity and in vivo antioxidant properties of Oxalis cernua

South African Journal of Botany ◽

10.1016/j.sajb.2020.07.004 ◽

2020 ◽

Vol 133 ◽

pp. 91-97

Author(s):

Meriama Belghoul ◽

Abderrahmane Baghiani ◽

Seddik Khennouf ◽

Lekhmici Arrar

Keyword(s):

Antioxidant Properties ◽

Acute Oral Toxicity ◽

Oral Toxicity

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Delving into the Antiurolithiatic Potential of Tribulus terrestris Extract Through –In Vivo Efficacy and Preclinical Safety Investigations in Wistar Rats

Scientific Reports ◽

10.1038/s41598-019-52398-w ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Jyoti Kaushik ◽

Simran Tandon ◽

Rishi Bhardwaj ◽

Tanzeer Kaur ◽

Surinder Kumar Singla ◽

...

Keyword(s):

Body Weight ◽

Aqueous Extract ◽

Kidney Stones ◽

Wistar Rats ◽

Lethal Dose ◽

Tribulus Terrestris ◽

Oral Toxicity ◽

Preclinical Safety

Abstract Modern treatment interventions for kidney stones are wrought with side-effects, hence the need for alternative therapies such as plant-based medicines. We have previously documented through in vitro studies that statistically optimized aqueous extract of Tribulus terrestris (Zygophyllaceae family) possesses antiurolithic and antioxidant potential. This provides strong scientific foundation to conduct in vivo efficacy and preclinical safety studies to corroborate and lend further proof to its ability to prevent and cure kidney stones. The preventive and curative urolithiatic efficacy in experimentally induced nephrolithiatic Wistar rats, along with preclinical toxicity was evaluated following oral administration of statistically optimized aqueous extract of T. terrestris. Treatment showed augmented renal function, restoration of normal renal architecture and increase in body weight. Microscopic analysis of urine revealed excretion of small sized urinary crystals, demonstrating that treatment potentially modulated the morphology of renal stones. Tissue enzymatic estimation affirmed the antioxidant efficacy of treatment with reduced free radical generation. Significant upregulation of p38MAPK at both the gene and protein level was noted in hyperoxaluric group and interestingly treatment reversed it. Acute oral toxicity study established the Median Lethal Dose (LD50) to be greater than 2000 mg/kg body weight (b.wt.) No observed adverse effect level (NOAEL) by repeated oral toxicity for 28 days at 750 mg/kg b.wt. was noted. This study lends scientific evidence to the safe, preventive and curative potential of statistically optimized aqueous extract of T. terrestris at a dose of 750 mg/kg b.wt. and suggests that the extract shows promise as a therapeutic antiurolithic agent.

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ACUTE ORAL TOXICITY STUDY OF ETHANOLIC EXTRACT OF ACTINOSCIRPUS GROSSUS (L.F.) GOETGH. AND D.A. SIMPSON

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2018.v11i7.21688 ◽

2018 ◽

Vol 11 (7) ◽

pp. 321

Author(s):

Savin Chanthala Ganapathi ◽

Rajendra Holla ◽

Shivaraja Shankara Ym ◽

Ravi Mundugaru

Keyword(s):

Body Weight ◽

Lethal Dose ◽

Ethanolic Extract ◽

Female Rats ◽

Test Substance ◽

Acute Oral Toxicity ◽

Oral Toxicity ◽

Healthy Female ◽

Ld50 Value ◽

Toxic Potential

Objective: To study the acute oral toxicity of ethanolic extract of Actinoscirpus grossus (L.f.) Goetgh. and D.A. Simpson in Wistar albino rats.Methods: Ethanolic extract of the plant was assessed for single dose acute toxicity by employing Organisation for Economic Co-Operation and Development(OECD) guidelines 425 using Acute Oral Toxicity(AOT) software. The dosed (up or down as per the requirement) rats were observed for 14 days for general appearance, behavior, mortality, and necropsy. A total of 5 healthy female rats of body weight 225±25 g were used.Results: The test substance did not produce any mortality up to the dose of 2000 mg/kg per oral.Conclusion: Test substance is without any toxic potential even at the dose of 2000 mg/kg in animals and the Lethal Dose (LD50) value of A. grossus (L.f.) Goetgh. and D.A. Simpson was found to be more than 2000 mg/kg body weight.

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Acute, Subacute, and Genotoxicity Assessments of a Proprietary Blend of Garcinia mangostana Fruit Rind and Cinnamomum tamala Leaf Extracts (CinDura®)

Journal of Toxicology ◽

10.1155/2020/1435891 ◽

2020 ◽

Vol 2020 ◽

pp. 1-15

Author(s):

Sundararaju Dodda ◽

Venkata Krishnaraju Alluri ◽

Trimurtulu Golakoti ◽

Krishanu Sengupta

Keyword(s):

Body Weight ◽

Wistar Rats ◽

Lethal Dose ◽

Toxicity Study ◽

Mouse Bone Marrow ◽

Acute Oral Toxicity ◽

Oral Toxicity ◽

Garcinia Mangostana ◽

Cinnamomum Tamala ◽

Fruit Rind

The present communication describes a battery of toxicity studies that include an acute oral toxicity, a subacute twenty-eight-day repeated oral dose toxicity, and genotoxicity studies on a herbal formulation CinDura® (GMCT). This proprietary herbal composition contains the extracts of the Garcinia mangostana fruit rind (GM) and the Cinnamomum tamala leaf (CT). The toxicological evaluations were performed following the Organization for Economic Cooperation and Development (OECD) guidelines. The acute oral toxicity study in Wistar rats suggests that the median lethal dose of CinDura® is at least 2000 mg/kg body weight. Acute dermal and eye irritation tests in New Zealand white rabbits indicate that the test item is nonirritant to the skin and eyes. A twenty-eight-day repeated dose oral toxicity study was conducted in male and female Wistar rats using daily doses of 250, 500, and 1000 mg/kg body weight, followed by a fourteen-day reversal period for two satellite groups. The CinDura®-supplemented animals did not show any sign of toxicity on their body weights, organ weights, and on the hematobiochemical parameters. The gross pathology and histopathological examinations indicated no treatment-related changes in the experimental animals. Overall, the no-observed-adverse-effect level (NOAEL) of the herbal blend is 1000 mg/kg body weight, the highest tested dose. Also, the results of the bacterial reverse mutation test and the erythrocyte micronucleus assay in mouse bone marrow suggest that CinDura® (GMCT) is neither mutagenic nor clastogenic.

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In Vivo Wound Healing Activity of Abrus cantoniensis Extract

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2016/6568528 ◽

2016 ◽

Vol 2016 ◽

pp. 1-7 ◽

Cited By ~ 7

Author(s):

Qi Zeng ◽

Hui Xie ◽

Hongjin Song ◽

Fayu Nie ◽

Jiahua Wang ◽

...

Keyword(s):

Wound Healing ◽

Chemical Constituents ◽

Blood Stasis ◽

Acute Oral Toxicity ◽

Test Results ◽

Dermal Toxicity ◽

Oral Toxicity ◽

Incision Wound ◽

Wound Healing Activity

Abrus cantoniensis (Leguminosae sp.) is a traditionally used remedy for treating rheumatism, blood stasis, and internal injuries. In order to reveal a new insight of the utilization of the plant, solvent extraction by ethyl acetate (EA) was performed in order to evaluate the plant extracts’ in vivo excision and incision-wound potentials with models. The contents of the EA fraction, wound healing activity, acute oral toxicity, and acute dermal toxicity were studied. As a result, the main chemical constituents of the EA fraction were alkaloids, flavonoids, and steroids. The acute oral toxicity test results and assessment of skin hypoallergenicity showed that the plant extract was safe at LD50 as high as 5000 mg/kg. Both excision and incision model tests results indicated that the EA fraction of A. cantoniensis showed a significant wound healing capacity at a concentration of 5% (v/w) (p<0.01) as observed by the increased wound contraction, decreased epithelialization time, and increased hydroxyproline content compared to the ones of the controls. The present study showed that the EA fraction of A. cantoniensis possesses potential wound healing activities and provided recent results for the use of A. cantoniensis for wound curing.

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