Acute Toxicity Study
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2022 ◽  
Vol 41 ◽  
pp. 096032712110628
Yu-Juan Li ◽  
Kun Yang ◽  
Xue-Ming Long ◽  
Gang Xiao ◽  
Si-Juan Huang ◽  

Background Gelsenicine, one of the most toxic alkaloids of Gelsemium elegans Benth ( G. elegans), causes severe respiratory depression. However, its toxicity mechanisms are yet to be elucidated and no effective antidotes are available. Objective This study aimed to analyse the toxicity characteristics of gelsenicine. Methods Both acute and sub-acute toxicities were evaluated. Gelsenicine distribution and elimination in the central nervous system (CNS) and blood were observed. Effective antidotes for gelsenicine poisoning were screened. Results In the acute toxicity study, gelsenicine was highly toxic, and female rats exhibited greater sensitivity to gelsenicine than male rats (LD50 0.520 mg/kg vs 0.996 mg/kg, respectively). Death was primarily caused by respiratory failure. However, in the sub-acute toxicity study, no significant organ damage was observed. Gelsenicine was easily absorbed from the gastrointestinal tract and penetrated the blood–brain barrier, reaching peak concentrations in the CNS within 15 min and rapidly decreasing thereafter. Flumazenil or diazepam combined with epinephrine reversed gelsenicine toxicity and significantly improved survival rate in mice. Conclusions Gelsenicine is a highly toxic substance that affects nerve conduction without causing damage; the potential toxic mechanism is possibly associated with GABAA receptors. Our findings provide insights into the clinical treatment of gelsenicine -related poisoning and its toxicity mechanisms.

July Silva Ferreira ◽  
Alanne Lucena de Brito ◽  
Silvana Tavares Paz ◽  
Humberto de Moura Barbosa ◽  
Jeymesson Raphael Cardoso Vieira ◽  


Objective: This work aimed to study the acute toxicity of β-chitin extracted from crab shells in Bal b/c mice. Method: The acute toxicity test was performed by following the OECD guidelines. Female mice were given single or divided doses of β-chitin (maximum 24 h) with doses of 500, 1000, 2000, 4000, and 6000 mg/kg of BW. Observations were made for 14 d, including behaviour, body weight, organ weight, and histopathology of vital organs (stomach, heart, liver, kidney, and lung). Results: During 14 d, no deaths and no abnormalities in behaviour, bodyweight or organ weight were observed. Qualitative histopathological observations at the highest dose showed abnormalities of the liver and kidney compared to those of the control group. Nevertheless, the abnormalities did not affect the organ function. Conclusion: This acute toxicity study reveals that β-chitin up to a dose of 6000 mg/kg of BW is not toxic, as proved by the normal behaviour, body weight, and vital organ weight of the animals. Further chronic toxicities study is needed to confirm its safety.

2021 ◽  
Vol 17 (40) ◽  
pp. 178
Kablan Kassi Jean Jacques ◽  
Blahi Adelaïde Nadia, ◽  
Kouakou Koffi Roger ◽  
Diby Yao Seraphin ◽  
Siapo Yao Martin ◽  

The present study is part of a vast program of the valorization of the medicinal flora and to help the populations to make a real profit from the use of plants in order to avoid any problem of poisoning. Petroselinum crispum Mill. (Apiaceae) is a plant, whose therapeutic virtues are diverse. The toxicological aspect of the aqueous extract of Petroselinum crispum leaves in male and female rats was investigated. The acute toxicity study with the single dose of 5000 mg/Kg body weight shows that the aqueous extract from the leaves of Petroselinum crispum is not toxic orally. According to Organisation for Economic Cooperation and Development (OECD) Guideline 423, the oral LD50 for this extract is greater than 5000 mg/kg body weight. In addition, the sub-acute toxicity study (OECD 407) showed that the aqueous extract from the leaves of Petroselinum crispum did not show any toxic effects at doses 50,100 and 200 mg/kg body weight and would have an orexigenic effect after 28 days of treatment. The different histological sections showed that the aqueous extract of Petroselinum crispum is not toxic on the vital organs and appears to be hepatoprotective.

Tanuja Yadav ◽  
Sachin Rohane

Acute toxicity study describes the adverse effects of a substance that result either from a single exposure or from multiple exposures in a short period of time. Whenever an investigator administered a chemical substance or herbal drug to a biological system different types of interactions can occur and a series of dose-related responses result. In most cases these responses are desired and useful, but there are a number of other effects which are not advantageous. These may or may not be harmful to the patient. Acute toxicity study is involved in estimation of LD50. Also it determines the therapeutic index i.e ratio between the lethal dose and the pharmacologically effective dose in the same strain and species. This article Review the methods so for utilized for the determination of acute toxicity.

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Yared Andargie Ferede ◽  
Woretaw Sisay Zewdu ◽  
Mulugeta Molla Zeleke ◽  
Muluken Adela Alemu

Background. Diarrheal disease is a major cause of morbidity and mortality throughout the world, particularly in developing countries. Currently available drugs are linked with adverse effects, contraindications, and risk of resistance. Traditionally, the leaf concoction of Cordia africana is claimed to be used for diarrhea. However, the safety and efficacy of the leaf extract have not been scientifically approved yet. Therefore, the study was conducted to validate its antidiarrheal activity and safety profile in mice. Method. The hydromethanolic extract was obtained by the cold maceration technique in 80% methanol. Phytochemical screening tests were done for secondary metabolites by using standard tests. The antidiarrheal activity of the test extract at the doses of 100, 200, and 400 mg/kg was evaluated by using castor oil-induced diarrheal, gastrointestinal transit, and enteropooling models in mice. Result. In an acute toxicity study, there were no visible signs of toxicity and mortality following a single oral administration of 2000 mg/kg. Phytochemical screening tests revealed the presence of alkaloids, saponins, flavonoids, terpenoids, phenols, and tannins. The hydromethanolic extract significantly prolonged the onset of diarrhea and reduced the weight of wet and total feces at 100 ( P < 0.01 ), 200 ( P < 0.001 ), and 400 mg/kg ( P < 0.001 ) in the castor oil-induced diarrheal model. However, in the gastrointestinal transit model, a significant ( P < 0.001 ) reduction in the charcoal meal travel was observed in the middle (200 mg/kg) and higher (400 mg/kg) test doses. Similarly, the extract produced a significant ( P < 0.001 ) reduction in the weight and volume of intestinal contents at the aforementioned doses. Conclusion. The study demonstrated that the test extract showed promising antidiarrheal activity. Hence, this study supports its antidiarrheal use in Ethiopian folklore medicine.

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4919-4919
Soumika Sengupta ◽  
Mainak Biswas ◽  
Khushboo Gandhi ◽  
Vikram Gota ◽  
Avinash Sonawane

Abstract Introduction Acute Lymphoblastic Leukemia (ALL) accounts for 20% of all hematological malignancies. L-Asparaginase has been a mainstay of ALL for the last 6 decades and is also included in the WHO list of essential medicines for ALL. Escherichia coli L-asparaginase (EcA) was the first asparaginase to be approved for clinical use. However being isolated from bacteria, EcA has many side-effects which in turn affects the tolerability and efficacy of the drug. EcA administration may cause strong immunogenic and hypersensitive reactions in the patients, necessitating withdrawal of the drug. Sensitive individuals react to repeated EcA administration with formation of anti-drug antibodies (ADAs) that bind to and inactivate the enzyme leading to inadequate plasma levels of EcA. Another serious drawback of EcA is the glutaminase activity which leads to neurotoxicity. Other side effects include hepatotoxicity, thromboembolism and pancreatitis. Although a number of attempts have been made to alleviate these problems by rational protein engineering, the optimization of therapy with EcA for ALL patients still remains a challenge. In an attempt to deal with these problems, we created several EcA mutants. On the basis of their activity, stability and antigenicity we short-listed four EcA mutants (Mutant A, B, C and D) having favourable properties for further development. Methods We identified and mutated several B-cell epitopes and amino acid residues at the EcA interface that are responsible for activity, stability and antigenicity. Enzyme activity was measured at 37 oC (optimum temperature for EcA). Glutaminase activity of the mutants was measured and compared to the wild type EcA. The cytotoxicity of the EcA variants was verified in ALL sensitive REH cell lines by performing MTT assay after 24 h incubation. Further the antigenicity of the mutants was assessed by performing indirect ELISA where the binding of the mutants to the commercially available l-asparaginase antibody was analysed. Further, in vivo immunogenicity was evaluated by immunizing Balc C mice with primary and booster doses of EcA mutants over 66 days followed by the measurement of IgG and IgM titers. In addition, the binding of wild-type EcA and mutants to pre-existing anti-asparaginase antibodies in serum isolated from primary and relapsed ALL patients receiving asparaginase therapy was studied by indirect ELISA. Pharmacokinetics of the mutants was evaluated in female Balb C mice by plotting the asparaginase activity-time curve till 24 h following administration of a single i.v. dose of 50 IU/kg and compared with the wildtype. Finally the safety of the EcA mutants was determined by performing single-dose acute toxicity study at 3 dose levels in Balb C mice. Results At 37 oC, we did not find any significant difference in asparaginase activity of any EcA variant with the wild-type. All four variants showed markedly reduced glutaminase activity as compared to wild-type EcA (P&lt;0.05). In MTT assay Mutant D showed 34.02%, Mutant B (32.4%), Mutant C (31.4%), Mutant A (24.22%), and wild type EcA (24.37%) reduction in REH cell viability in comparison to untreated cells. Binding to commercially available anti-asparaginase antibody was 49.09%, 32.63%, 27.43% less for Mutant D, Mutant B and Mutant C respectively compared to wild type EcA. Mice immunized with Mutant D showed 5-fold lower titres of IgG and 4-fold lower titres of IgM in comparison to wild type. Similarly, when compared to wild type, mice immunized with Mutant C showed 2.5-fold lower titres of IgG and 3.5-fold lower titres of IgM. At the same time Mutants B, C and D showed 2-3 fold less binding to pre-existing anti-asparaginase antibodies in samples collected from primary ALL patients undergoing asparaginase therapy. Similarly mutants B, C and D showed approximately 2-fold less binding to pre-existing anti-asparaginase antibodies in samples collected from relapsed ALL patients. Pharmacokinetic profiling showed that half life of Mutant A (267.28 ± 9.74), Mutant B (213.29 ± 6.53) and Mutant D (273.83 ± 35.45) was significantly longer than the wild type (102.17 ± 7.7). In acute toxicity study, we did not observe any significant toxicity of the mutants over the wildtype EcA. The findings are summarized in the figure. Conclusion Considering the immunogenicity, antigenicity and pharmacokinetics, mutant D emerged as a potent drug candidate for further development in the treatment of ALL. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

2021 ◽  
Vol 104 (4) ◽  
pp. 003685042110042
Abdullahi Aliyu ◽  
Mohd Rosly Shaari ◽  
Nurul Syahirah Ahmad Sayuti ◽  
Farhan Hanif Reduan ◽  
Shanmugavelu Sithambaram ◽  

Moringa oleifera (M. oleifera) Lam belongs to the family Moringaceae. It is an important multipurpose tree that is largely distributed globally and has been used almost in every aspect of traditional medicine for the treatment of various illnesses including cancers, diabetes mellitus, asthma, arthritis, etc. This study investigated the effects of oral acute and sub-acute administration of M. oleifera hydroethanolic leaf extract (MOHE) in ICR-mice. Its major phenolic compounds were also determined. Ten (10) female, 8-week old mice were grouped into control and treatment groups for acute toxicity study. A dose of 2000 mg/kg MOHE was given once to the treatment group via oral gavage. However, for the sub-acute toxicity study, 25 mice were grouped into groups A (control), B (125 mg/kg), C (250 mg/kg), D (500 mg/kg) and E (1000 mg/kg). MOHE was given via oral gavage to groups B, C, D and E daily for 28 days. Group A received only distilled water. The mice were sacrificed at the end of the experiments and samples were collected for evaluation. The results of the chemical profiling of MOHE revealed the presence of glucomoringin, niaziminine, quercetin and kaempferol as the major compounds. The treated mice in the acute toxicity study were slightly anaemic and showed evidence of stress leukogram. Moreover, a slight increase in creatinine, significant increases in AST and CK, hepatic degeneration and necrosis, none-obstructive sinusoidal dilatation, renal tubular necrosis, interstitial nephritis and renal interstitial oedema were observed. It is concluded that the LD50 of MOHE is higher than 2000 mg/kg. However, oral administration of MOHE causes acute mild anaemia and moderate hepato-nephrotoxicity in ICR-mice. Its major phenolic compounds are glucomoringin, niaziminine, quercetin and kaempferol.

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