Subacute toxicity study of the ethanolic extract of Mesua ferrea (L.) flowers in rats.

Mesua ferrea Linn. is used traditionally in India and South East Asian countries as an antiseptic, antidote and a brain tonic. Recent pharmacological studies on the plant have highlighted M. ferrea to be a rich source of secondary metabolites, with proven therapeutic applications. Since the toxicity of a plant following repeated exposure is of higher clinical significance, the present investigation was conducted to establish the subacute toxicity profile of the ethanolic extract of Mesua ferrea flowers (MFE). The study was conducted in accordance with the OECD Guideline 407, wherein MFE was administered orally to groups of male and female rats (n = 5/group/sex) at the doses of 100, 500 and 1000 mg/kg, over a period of 28 days. Repeated administration of MFE had no adverse effect on the growth rate and hematological parameters of the animals. There were no changes in the biochemical parameters, except for a slight decrease in the CHOL (total cholesterol) levels, and an increase in the levels of AST (aspartate aminotransferase) and ALT (alanine aminotransferase), at the highest dose. The latter corroborated with the histopathological findings exhibiting mild lymphocytic infiltration and hepatocyte degeneration observed in the liver tissues of both sexes. According to the study, the no-observed-adverse-effect level (NOAEL) of M. ferrea in the 28-day repeated dose toxicity study in rats was 500 mg/kg. Though the overall effects of the extract at the highest dose did not translate into any serious complications, its effect on hepatic function needs to be established over a longer period of study.

Subacute oral toxicity and bacterial mutagenicity of a mixture of Puerariae radix and Hizikia fusiforme extracts.

The study aims to identify the safety profile of a mixed extract (KGC-02-PS) from two traditional medicinal herbs, Puerariae radix and Hizikia fusiforme. In a subacute oral toxicity study, KGC-02-PS was administered orally for 28 days by gavage to Sprague Dawley rats (both sexes) at a daily dose of 0, 500, 1000, and 2000 mg/kg body weight. Bodyweight, food consumption, and clinical signs were monitored during the experimental period. After administering the final dose, this study conducted hematology, serum biochemistry, and pathological evaluations. In addition, the study performed a bacterial reverse mutation test with varying concentrations of KGC-02-PS (312.5 µg - 5,000 µg/plate) following OECD guideline No. 471, before testing five bacterial strains (Salmonella typhimurium TA98, TA100, TA1535, TA1537, and Escherichia coli WP2) in the presence or absence of metabolic activation. The preclinical evaluation of KGC-02-PS's subacute oral toxicity yielded no associated toxicological effects or any changes in clinical signs, body weight, and food consumption. Moreover, examining KGC-02-PS's hematological and serum biochemical characteristics and pathology yielded no toxicological changes in terms of organ weight measurements and gross or histopathological findings. KGC-02-PS neither increased the number of revertant colonies in all bacterial strains used in the bacterial reverse mutation test, nor did it induce genotoxicity related to bacterial reverse mutations under the study's conditions. Also, KGC-02-PS's no-observed-adverse-effect level was greater than 2000 mg/kg.

Subacute toxicity and toxicokinetics study of DHP107, an oral paclitaxel formulation with once-weekly dosing in mice.

DHP107, an oral formulation of paclitaxel, is effectively and systemically absorbed in intestinal endothelial cells. Although the in vivo efficacy of DHP107 has been reported, the potential toxicity of DHP107 has not been evaluated. Therefore, this study was conducted to evaluate the toxicity and toxicokinetics of DHP107 orally administered to ICR mice at 25, 50, and 100 mg/kg via once-weekly dosing for six weeks. DHP107-related clinical signs were observed in both sexes at 100 mg/kg. There were significant increases in the number of platelets and percentages of reticulocytes and basophils in male mice. Also in males, there was a significant decrease in the absolute and relative weights of testes, epididymides, kidneys, and heart. Relative spleen weights were significantly increased in males treated with doses ≥50 mg/kg which had histopathological correlates. These changes were reversible after a two-week recovery period with the exception of the findings in the reproductive organs. Systemic exposure to paclitaxel increased with DHP107 doses in single and multiple dosing with no marked differences between sexes. In conclusion, the target organs were determined to be the reproductive and hematopoietic organs in male mice, suggesting of sex difference and the NOAEL of DHP107 was established to be < 25 mg/kg for males and 50 mg/kg for females.

Safety assessment of medium- and long-chain triacylglycerols containing 30% (w/w) medium-chain fatty acids in mice and rats.

A novel medium- and long-chain triacylglycerols (MLCT), with 30% (w/w) medium-chain fatty acids (MCFA) was evaluated for its safety as a dietary fat in mice and rats. The subacute oral toxicity study showed that the maximum tolerated dose exceeded 54.33 g/kg body weight (kg bw)/day. In the 90-day feeding study, no dose-related adverse effects were observed in rats administered diets formulated with different levels of MLCT (2.0, 4.0, and 8.0 g/kg bw/day) as compared to the rapeseed oil control diet. Further safety assessment in pregnant rats did not reveal any significant difference relative to the control at a treatment level up to 8.0 g MLCT/kg bw/day. The results from this study indicated the safe use of MLCT with high contents of MCFA in food products for improving human health.

Gallic acid-based indanone derivative interacts synergistically with tetracycline by inhibiting efflux pump in multidrug resistant E. coli.

The purpose of the present study was to study the synergy potential of gallic acid-based derivatives in combination with conventional antibiotics using multidrug resistant cultures of Escherichia coli. Gallic acid-based derivatives significantly reduced the MIC of tetracycline against multidrug resistant clinical isolate of E. coli. The best representative, 3-(3',4,'5'-trimethoxyphenyl)-4,5,6-trimethoxyindanone-1, an indanone derivative of gallic acid, was observed to inhibit ethidium bromide efflux and ATPase which was also supported by in silico docking. This derivative extended the post-antibiotic effect and decreased the mutation prevention concentration of tetracycline. This derivative in combination with TET was able to reduce the concentration of TNFα up to 18-fold in Swiss albino mice. This derivative was nontoxic and well tolerated up to 300 mg/kg dose in subacute oral toxicity study in mice. This is the first report of gallic acid-based indanone derivative as drug resistance reversal agent acting through ATP-dependent efflux pump inhibition.

Subacute Oral Toxicity and Bacterial Mutagenicity Study of a Mixture of Korean Red Ginseng (Panax ginseng C.A. Meyer) and Salvia plebeia R. Br. Extracts.

As various populations are rapidly becoming an aging society worldwide and interest in health issues has increased, demand for functional foods including herbal products has increased markedly to maintain a healthy state which has led to safety issues about their intake as an inevitable result. The objective of this study was to identify the safety profile of a Korean red ginseng and Salvia plebeia R. Br. extract mixture (KGC-03-PS) which is a valuable ingredient that can be used as a functional food. In the present study, the subacute oral toxicity and bacterial reverse mutagenicity of KGC-03-PS were evaluated. Sprague Dawley rats were administered KGC-03-PS orally for 28 days by gavage. Daily KGC-03-PS dose concentrations were 0, 500, 1,000, or 2,000 mg/kg body weight (bw) per day. Bacterial reverse mutation test with KGC-03-PS dose levels ranging from 312.5 to 5,000 µg/plate was carried out by OECD test guideline No. 471. Five bacterial strains (Salmonella typhimurium TA98, TA100, TA1535, TA1537, and Escherichia coli WP2) were tested in the presence or absence of metabolic activation by plate incorporation method. There were no toxicological effects related with test substance in the clinical evaluation of subacute oral toxicity test including clinical signs, body weight, and food consumption. Moreover, no toxicological changes related to KGC-03-PS were observed in the hematological and serum biochemical characteristics as well as in the pathological examinations, which included organ weight measurements and in the gross- or histopathological findings. KGC-03-PS did not induce an increase in the number of revertant colonies in all bacterial strains of the bacterial reverse mutation test. The no-observed-adverse-effect level of KGC-03-PS is greater than 2,000 mg/kg bw/day, and KGC-03-PS did not induce genotoxicity related to bacterial reverse mutations under the conditions used in this study.

Subacute Oral Toxicity Assesment of Ethanol Extract of Mariposa christia vespertilionis Leaves in Male Sprague Dawley Rats.

The term Butterfly tea refers to decoction of Mariposa christia vespertilionis leaves which is widely consumed by cancer patients throughout Malaysia and has gained a huge popularity among Malaysians, not only cancer patients but also researchers to discover the real potential of this plant. Herein, the study is aimed at evaluating the possible toxicity in 28-day subacute oral toxicity of ethanolic extract M. christia vespertilionis in male Sprague Dawley rats. The 28-day subacute toxicity study was conducted to detect the no-observed adverse effect level (NOAEL). In this study, a total of 30 rats were divided into the control, 5% DMSO (vehicle), low dose (75 mg/kg), medium dose (125 mg/kg) and high dose (250 mg/kg) groups. The extract was administered daily from day 1 until day 28. At the end of the study, the animals were humanely sacrificed and assessed for the effect extract of Mariposa christia vespertilionis leaves on body weight and relative organ weights and haematological, biochemical and histopathological parameters. The haematological and serum biochemical parameters for the assessment of kidney and liver injuries were carried out. Results of haematological and serum biochemistry results showed no changes in the control and treated groups. In the histopathology, evaluation of kidney tissues in all treated groups showed no significant (p > 0.05) lesions. In contrast to kidney, liver tissues showed significant differences (p < 0.05) in lesions observed in low dose (430 mg), medium dose (700 mg) and high dose (1480 mg) groups with very mild, mild and mild to moderate lesion of hepatic necrosis, in the respective groups, and very mild hepatic degeneration and hepatitis were scored in all three groups.

Subacute oral toxicity and bacterial mutagenicity study of Korean Red Ginseng oil.

BACKGROUND: Red ginseng oil (RGO) is produced by supercritical CO2 extraction of secondary products derived from Korean Red Ginseng extract. As the use of RGO has increased, product safety concerns have become more important. METHODS: In the present study, the subacute oral toxicity and bacterial reverse mutagenicity of RGO were evaluated. Sprague-Dawley rats were orally administered with RGO for 28 d by gavage. Daily RGO dose concentrations were 0 mg/kg body weight (bw), 500 mg/kg bw, 1,000 mg/kg bw, or 2,000 mg/kg bw per day. Bacterial reverse mutation tests included five bacterial strains (Escherichia coli WP2 and Salmonella typhimurium TA98, TA100, TA1535, and TA1537), which were used in the presence or absence of metabolic activation. The plated incorporation method for mutation test was used with RGO concentrations ranging from 312.5 µg to 5,000 µg per plate. RESULTS: The subacute oral toxicity test results did not reveal any marked changes in clinical characteristics. There were no toxicological changes related to RGO administration in hematological and serum biochemical characteristics in either control or treatment animals. Furthermore, no gross or histopathological changes related to RGO treatment were observed. The bacterial reverse mutation test results did not reveal, at any RGO concentration level and in all bacterial strains, any increase in the number of revertant colonies in the RGO treatment group compared to that in the negative control group. CONCLUSION: The no-observed-adverse-effect level of RGO is greater than 2,000 mg/kg bw and RGO did not induce genotoxicity related to bacterial reverse mutations.

Acute and 28-Day Subacute Toxicity Studies of Hexane Extracts of the Roots of Lithospermum erythrorhizon in Sprague-Dawley Rats.

Lithospermum erythrorhizon has long been used as a traditional oriental medicine. In this study, the acute and 28-day subacute oral dose toxicity studies of hexane extracts of the roots of L. erythrorhizon (LEH) were performed in Sprague-Dawley rats. In the acute toxicity study, LEH was administered once orally to 5 male and 5 female rats at dose levels of 500, 1,000, and 2,000 mg/kg. Mortality, clinical signs, and body weight changes were monitored for 14 days. Salivation, soft stool, soiled perineal region, compound-colored stool, chromaturia and a decrease in body weight were observed in the extract-treated groups, and no deaths occurred during the study. Therefore, the approximate lethal dose (ALD) of LEH in male and female rats was higher than 2,000 mg/kg. In the subacute toxicity study, LEH was administered orally to male and female rats for 28 days at dose levels of 25, 100, and 400 mg/kg/day. There was no LEH-related toxic effect in the body weight, food consumption, ophthalmology, hematology, clinical chemistry and organ weights. Compound-colored (black) stool, chromaturia and increased protein, ketone bodies, bilirubin and occult blood in urine were observed in the male and female rats treated with the test substance. In addition, the necropsy revealed dark red discoloration of the kidneys, and the histopathological examination showed presence of red brown pigment or increased hyaline droplets in the renal tubules of the renal cortex. However, there were no test substance-related toxic effects in the hematology and clinical chemistry, and no morphological changes were observed in the histopathological examination of the kidneys. Therefore, it was determined that there was no significant toxicity because the changes observed were caused by the intrinsic color of the test substance. These results suggest that the no-observed-adverse-effect Level (NOAEL) of LEH is greater than 400 mg/kg/day in both sexes.