Evaluation of acute and sub-acute toxicity profile of 5-methylcoumarin-4β-glucoside in mice

Abubakar, Bilyaminu; Alhassan, Alhassan Muhammad; Malami, Ibrahim; Usman, Dawoud; Uthman, Yaaqub Abiodun; Adeshina, Kehinde Ahmad; Olatubosun, Mutolib Olabayo; Imam, Mustapha Umar

doi:10.1016/j.toxrep.2022.03.013

Cited by 5 publications

(1 citation statement)

References 8 publications

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“…Evaluation of the toxicity profile of a promising ther-apeutic agent is unarguably at the forefront of any drug discovery process. Acute toxicity is generally the first type of toxicity study in vivo during preclinical drug developments (Abubakar et al, 2022). It is aimed at providing a guide for the safe dose range of a new therapeutic agent and providing some preliminary information on the mode of toxic action of the agent in question (Jin et al, 2021;Mohs and Greig, 2017;Takeshita et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

The toxicity assessment of neorudin in cynomolgus monkeys

et al. 2023

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In this study, the toxicity effects on circulatory system and respiratory system, and the acute toxicity test of recombinant neorudin (EPR-hirudin, EH) in cynomolgus monkeys were evaluated to provide reference information for clinical studies. Eighteen cynomolgus monkeys were randomly divided into three groups for single intravenous administration of 3, 30 mg/kg EH and normal saline, respectively. The changes of respiratory frequency, respiratory intensity, blood pressure and electrocardiogram before and after administration were recorded. In acute toxicity test, six cynomolgus monkeys were intravenously received EH at a single dose of 171, 257, 385, 578, 867 and 1300 mg/kg respectively. The vital signs, hematology, serum biochemistry, coagulation indexes and electrocardiogram indexes of the animals were determined before administration and on the 7th and 14th day after administration. As the results showed that there were no significant abnormal changes in respiratory frequency, respiratory intensity, blood pressure or electrocardiogram in cynomolgus monkeys after receiving EH at 3 mg/kg and 30 mg/kg, and there was no statistical difference between the treated groups and normal saline group. In the acute toxicity test, no significant abnormalities were observed in vital signs, hematology, serum biochemistry, coagulation indexes and electrocardiogram indexes of six cynomolgus monkeys at day 7 and 14 after EH administration. Furthermore, autopsies of all cynomolgus monkeys showed no abnormalities. The results of toxicokinetics showed that AUClast of the drug increased in proportion to the EH dose in the range of 171-578 mg/kg, and increased in over proportion to the EH dose in the range of 578-1300 mg/kg. The variation of Cmax was basically consistent with AUClast. In a sum, A single intravenous injection of 3 and 30 mg/kg of EH did not affect the circulatory system and respiratory system in cynomolgus monkeys and the maximum tolerated dose of EH in cynomolgus monkey is over 1300 mg/kg (equivalent to 619-1300 times of the proposed clinical equivalent dose).

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Section: Discussionmentioning

confidence: 99%

The toxicity assessment of neorudin in cynomolgus monkeys

et al. 2023

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Newly synthesized acridone derivatives targeting lung cancer: A toxicity and xenograft model study

Bhusare,

Yadav,

Nandave

et al. 2024

Drug Development Research

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AKT is one of the overexpressed targets in nonsmall cell lung cancer (NSCLC) and plays an important role in its progression and offers an attractive target for the therapy. The PI3K/AKT/mTOR pathway is upregulated in NSCLC. Acridone is an important heterocycle compound which treats cancer through various mechanisms including AKT as a target. In the present work, the study was designed to evaluate the safety profile of three acridone derivatives (AC‐2, AC‐7, and AC‐26) by acute and repeated dose oral toxicity. In addition to this, we also checked the pAKT overexpression and its control by these derivatives in tumor xenograft model. The results from acute and repeated dose toxicity showed these compounds to be highly safe and free from any toxicity, mortality, or significant alteration in body weight, food, and water intake in the rats. In the repeated dose toxicity, compounds showed negligible variations in a few hematological parameters at 400 mg/kg. The histopathology, biochemical, and urine parameters remained unchanged. The xenograft model study demonstrated AC‐2 to be inhibiting HOP‐62 induced tumor via reduction in p‐AKT1 (Ser473) expression significantly. In immunofluorescence staining AC‐2 treated tissue section showed 2.5 fold reduction in the expression of p‐AKT1 (Ser473). Histopathology studies showed the destruction of tumor cells with increased necrosis after treatment. The study concluded that AC‐2 causes cell necrosis in tumor cells via blocking the p‐AKT1 expression. The findings may provide a strong basis for further clinical applications of acridone derivatives in NSCLC.

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