Toxicity evaluation induced by single and 28-days repeated exposure of withametelin and daturaolone in Sprague Dawley rats

Abstract

Safe preclinical dose determination is predictive of human toxicity and can have a profound impact on the overall progress of the compound in early drug discovery process. In this respect, current study sought to investigate for the first time the acute and subacute oral toxicity of two pharmacologically active natural compounds i.e., withametelin and daturaolone in Sprague Dawley rats following OECD guideline 420 and 407, respectively. As per acute toxicity studies, withametelin and daturaolone were characterized as Globally Harmonized System (GHS) category 4 and 5 compounds, respectively. Sub-acute daily dose of withametelin was 5, 2.5, and 1.25 mg/kg but, for daturaolone, it was 10, 5, and 2.5 mg/kg. High dose (5 and 2.5 mg/kg) withametelin groups showed dose dependent changes in the general, hematological, biochemical and histopathological parameters in both sexes, the most prominent being hyperthyroidism while no toxicity was observed at lower doses (1.25 and 0.75 mg/kg), No Observable Adverse Effect Level (NOAEL) being 1.25 mg/kg. Daturaolone was comparatively safer and showed dose dependent significant changes in hepatic enzyme (Alanine Transaminase), bilirubin, creatinine, and glucose levels while histological changes in testes were also observed. Lower doses (5, 2.5, and 1.25 mg/kg) of daturaolone showed no significant toxic effects and 5 mg/kg was declared as its NOAEL. Depending upon our findings, starting effective oral dose levels of 1.25 mg/kg/day for withametelin and 5 mg/kg/day for daturaolone are proposed for repeated dose (up to 28 days) preclinical pharmacological evaluation models. Long term studies with more behavioral, biochemical, histopathological and hormonal parameters are proposed to strengthen the findings.

Acute and Subchronic Toxicity Assessment of Conventional Soxhlet Cymbopogon citratus Leaves Extracts in Sprague–Dawley Rats

“…The main transport system of drugs and xenobiotic products is the blood, and the cells of the blood interact with these substances during their stay and transport in the blood, making it one of the most vulnerable systems to pathological substances [ 34 ]. White blood cells are the first line of defense against infection, inflammation, or cellular injury [ 34 ]. Studies have reported that an increase in the level of WBC and its indices in test rats during the herbal extract subchronic administration results from the extract stimulating an immune response or inducing an inflammatory condition in the treated rats.…”

“…Te lack of signifcant diferences in the percentage relative organ weight to body weight afrms the safety profle of C. citratus CSE extracts (Figure 3). Te main transport system of drugs and xenobiotic products is the blood, and the cells of the blood interact with these substances during their stay and transport in the blood, making it one of the most vulnerable systems to pathological substances [34]. White blood cells are the frst line of defense against infection, infammation, or cellular injury [34].…”

Pre-clinical studies comparing the anti-inflammatory potential of artemisinic compounds by targeting NFκB/TNF-α/NLRP3 and Nrf2/TRX pathways in Balb/C mice

“…According to the principles, potentially fatal doses or doses known to cause pain, toxicity, and suffering were avoided. The initial doses chosen for acute toxicity testing studies were 5 and 50 mg/kg ( Baig et al, 2022b ). All the dosing was done by oral gavage in a single dose.…”

“…Alterations in histoarchitecture were evaluated via the paraffin-embedded hematoxylin and eosin (H&E) staining procedure ( Baig et al, 2022b ). Fixation of the tissues was done using 10% formalin buffer.…”