Bacillus subtilis ZB423: 90-Day repeat dose oral (gavage) toxicity study in Wistar rats.

The novel genetically modified probiotic Bacillus subtilis ZB423 was assessed in a 90-day repeated-dose oral toxicity study adhering to Good Laboratory Practice (GLP) and Organization for Economic Cooperation and Development (OECD) guidelines. Spray-dried spores at a concentration of 1.1E12 CFU/g were administered at doses of 130, 260, and 519 mg/kg body weight/day correlating to 1.43 × 1011, 2.86 × 1011, and 5.71 × 1011 CFU/kg/day, respectively, by oral gavage to Wistar rats for a period of 90 consecutive days. Results showed no toxicologically relevant findings for B. subtilis ZB423 from measured parameters. The no observed adverse effect level (NOAEL) of B. subtilis ZB423 is 519 mg/kg body weight/day corresponding to 5.71 × 1011 CFU/kg/day for lyophilized B. subtilis ZB423 spores under the test conditions employed.

Safety assessment of crude aqueous methanol extract of Annona senegalensis stem bark: acute and sub-chronic toxicity studies.

Annona senegalensis Pers., (wild custard apple), is a shrub used traditionally to treat respiratory and skin diseases. Previous studies have demonstrated its anti-malaria, anti-snake envenomation and anti-cancer activities. However, its toxicological profile remains limited, particularly in male and female animals. This study aims to evaluate the safety of crude aqueous methanol extract of Annona senegalensis stem bark (AMEAS) through acute and sub-chronic toxicity studies. The stem bark of A. senegalensis was collected, air-dried, pulverized, and extracted using 70% methanol. Phytochemical screening, elemental analysis, and acute toxicity evaluation were carried out on AMEAS. Sub-chronic toxicity study was conducted on Wistar rats of both sexes at different doses administered orally for 28 days. Elemental analysis revealed the presence of heavy metals and essential mineral elements with the highest contents being calcium (59.88%) and potassium (25.39%). Acute toxicity testing showed no mortality up to 5000 mg/kg, suggesting an LD50 greater than 5000 mg/kg. In the sub-chronic toxicity study, no mortality or significant harmful effects were observed. The blood glucose decreased from 13.68 mMol/L at 250 mg/kg to 10.71 mMol/L at 1000 mg/kg, much lower than the distilled water group (17.06 mMol/L). In conclusion, the extract appeared to be well-tolerated, with no obvious adverse effects. AMEAS is rich in Calcium (Ca) and potassium (K). It has been shown to have LD50 greater than 5000 mg/kg and is assumed to be safe. On repeated use, AMEAS may cause hypoglycemia and weight loss which may be useful in managing diabetes and obesity respectively.

Assessment of Biological Activities, Acute and Sub-chronic Toxicity of Liang (Gnetum gnemon var. tenerum) Leaves Powder, a Natural Product.

Gnetum gnemon var. tenerum (Gnetaceae) is a shrub plant native to South-East Asia. In Thailand, Liang leaves are commonly consumed in South of Thailand as vegetable. According to literature, they have an antihyperglycemic capacity because of their rich chlorophyll, fiber, and protein. However, there is need to assess the safety since natural food products are not completely devoid of toxicity. This study aimed to assess the biological activities as well as the acute and sub-chronic oral toxicity of Liang leaves powder (LLP). The evaluation of LLP for acute oral toxicity was performed at dose level 2000 mg/kg body weight in Wistar rats while the sub-chronic oral toxicity of LLP was performed at the effective dose (1.47 g/kg) for antihyperglycemic property according to Organisation for Economic Co-operation and Development (OECD)-425. The results showed that LLP demonstrated anti-inflammatory activities. It also showed no clinical signs of toxic effects and mortality in rats throughout 90 d. Thus, LLP could be classified in GHS category 5 which are of relatively low acute toxicity and then the lethal dose, 50% (LD50) cut off at 5000 mg/kg body weight to infinity (∞). Administration of LLP to the experimental rats significantly increased (p < 0.05) the concentration of triglyceride and increased concentration of creatinine as a result of kidney malfunction was also noticed in the experimental rats. Hematological alteration was not noticed in the treated female rats, but red blood cell, hemoglobin and hematocrit concentrations significantly increased in the treated male rats. The study concludes that sub-chronic administration of 1.47 g/kg LLP is relatively safe.

Safety evaluation of rare ginsenosides of stems and leaves from American ginseng: 90-day exposure toxicity study combined with intestinal flora analysis and metabonomics in rats.

Rare ginsenosides have already been widely applied in many fields, including health food and bio-medicine. The human being can expose to rare ginsenosides directly or indirectly increasingly. However, there are few studies on the safety assessment of rare ginsenoside mixtures. In the present study, the sub-chronic toxicity of rare ginsenosides for 90 days on SD rats was performed by combining the intestinal flora analysis and urine metabonomics aiming to illustrate the safety of long-term consumption of rare ginsenosides and the potential damage for liver and intestinal. 48 adult rats were divided into four groups: control (0 mg/kg), low-dose (60 mg/kg), medium-dose (200 mg/kg), and high-dose (600 mg/kg). Rats in the high-dose group showed inflammatory changes in their livers and intestines. The strong bactericidal effect of rare ginsenosides caused intestinal flora disorder and changed the structure of intestinal flora in rats, thus inducing intestinal damage in rats. In the high-dose group, levels of alanine aminotransferase (ALT), lactate dehydrogenase (LDH), and alkaline phosphatase (AKP) increased significantly. As a result of the high-dose treatment, certain metabolic pathways were altered, such as vitamin B6 metabolism, methionine metabolism, glutathione metabolism, and others. These results indicated that high doses of rare ginsenosides induced liver injury by affecting the above metabolic pathways. Rare ginsenosides with no observed adverse effect level (NOAEL) were below 200 mg/kg/day in vivo. Thus, this present study provides insight into the rational use of rare ginsenosides.

Biochemical and histopathological analysis after sub-chronic administration of oxyresveratrol in Wistar rats.

Oxyresveratrol (OXY) is a naturally occurring phenolic compound; however, there are no toxicity studies reported on its long term use. The aim of our work was to demonstrate the evaluation of acute and sub-chronic toxicity of oxyresveratrol in rats to assess its safety profile. To evaluate the LD50 value, 2000 mg/kg of oxyresveratrol was administered to Wistar rats by oral gavage. For sub-chronic toxicity assessment, 80 Wistar rats were randomly divided into four groups (10 animal/sex/group) and oxyresveratrol administered at a dose of 50, 100, 150 mg/kg/day by oral gavage. Bodyweight, food, and water consumption were monitored every week. At the end of the experiments, biochemical and hematological parameters were analyzed. Gross and microscopic organ analyses were also carried out. LD50 of oxyresveratrol was greater than 2000 mg/kg sub-chronic administration of oxyresveratrol did not influence any mortality. Doses of 50 and 100 mg/kg of oxyresveratrol did not produce any sign of toxicity. However, the 150 mg/kg oxyresveratrol group depicted changes in multiple biochemical and hematological parameters with changes in the pathology of cardiac, hepatic, and renal tissues when compared with control. Therefore, no observed adverse effect level (NOAEL) of oxyresveratrol was observed to be 100 mg/kg per day for both male and female rats.

Safety assessment of MPTA: An oral acute and 90-day sub-chronic toxicity study in Sprague-Dawley rats.

MPTA is a novel extract product derived from Macleaya cordata (Willd.) R. Br., which has good anti-inflammatory and antioxidant activity. The aim of this study was to investigate the acute oral toxicity and 90-day sub-chronic oral toxicity of MPTA. In the acute toxicity study, 50 SD rats of both sexes were randomly divided into 5 groups and dosed in a gradient from 197.53 mg/kg to 1000.00 mg/kg bw. Toxic effects were observed up to 14 days and LD50 was calculated. In a subchronic toxicity test, male and female SD rats were orally dosed repeatedly with 96.40, 19.28, 3.86 mg/kg bw of MPTA for 90 days. In addition, a control group was set up in the subchronic study. The acute toxicity test showed that the oral LD50 of MPTA was 481.99 mg/kg with a 95% confidence interval of 404.24-574.70 mg/kg. MPTA did not appear to induce toxic effects in the longer term in terms of food and water consumption, weight gain, haematological and clinical biochemical parameters and pathological examination. The first data on the potential toxicity of MPTA was provided to highlight the safety of short-term to longer-term oral administration of MPTA, and the experimental results yield and establish a NOEAL of 96.40 mg/kg/d for MPTA.

Sub-chronic and chronic toxicity evaluation of 7-methylxanthine: a new molecule for the treatment of myopia.

Myopia (nearsightedness) is a vision disorder with a blurring of far objects, affect millions worldwide. 7-methylxanthine (7-MX) is a molecule that is presently under clinical investigation for the treatment of myopia. In the present study, we have investigated sub-chronic and chronic toxicity of 7-MX in comparison to other clinically used methylxanthines i.e., caffeine and theobromine as per OECD guidelines 408 and 452. 7-MX was administered orally for 90 days at three different doses of 250, 500, and 1000 mg/kg for sub-chronic toxicity evaluation, and at a limit dose of 1000 mg/kg in 180 days chronic toxicity evaluation in rats. In sub-chronic treatment, 7-MX showed no mortality and signs for toxicity in any group, whereas 10% and 40% mortality with signs for toxicity were observed in caffeine and theobromine treated groups, respectively. A similar, safety profile was observed with 7-MX in 180 days of chronic toxicity study. Further, to confirm any morphological changes in organs; ultrasound and X-rays analysis were performed and no changes in the size of organs, cyst formation, fluid retention, or crystal formation was observed. Thus, the repeated dose study of 7-MX for 180 days may augment the possibility of using 7-MX clinically for the safe and effective treatment of myopia.

Sub-chronic and developmental toxicity of transdermal delivery of Renzhu ointment in young SD rats.

Purpose: Renzhu ointment (Renzhuqigao, RZQG) is a patented herbal drug derived from Chinese traditional medicine formula and modern clinical experience for the transdermal treatment of non-infectious infantile diarrhoea. The safety of RZQG in preclinical studies has not been reported.Materials and methods: In this study, the pups of parent rats were examined for sub-chronic toxicity and developmental toxicity. After 21 days of birth, they were exposed to RZQG through their abdominal skin at doses of 0.1, 0.3, and 0.9 g/kg/day for 4 weeks and then were observed for another four weeks during their recovery period.Results: During the administration period, RZQG had no significant toxicological effect on body weight, food consumption, external eye examination, urinalysis, bone marrow examination, histopathology, central nervous system, reproductive system, or skeletal development. However, in the 0.9 g/kg/day group, the skin of some rats became dry and cracked, red and swollen, forming a white scab, while the white blood cells (WBC) count in female rats was lower and cholesterol (CHOL), triglycerides (TG), and glutamyl-transferase (GGT) were higher (p < 0.05).Conclusions: Rats receiving 0.9 g/kg/day exhibited skin irritation and were suspected to have a mild liver injury. There was no evidence of delayed toxicity four weeks after withdrawal. Therefore, the no-observed adverse effect level of RZQG was 0.3 g/kg/day (30 times the clinical dose planned and 4.92 times the human equivalent dose).

Safety assessment of a novel, dietary pyrroloquinoline quinone disodium salt (mnemoPQQ®).

Pyrroloquinoline quinone (PQQ), a potent coenzyme antioxidant naturally occurring in foods, has been demonstrated to protect brain cells by enhancing the expression of nerve growth factors (NGF) and NGF receptors, and suppressing the fibril formation and aggression of amyloid ß. We developed mnemoPQQ®, a novel PQQ disodium salt and assessed its safety in GLP compliant toxicity studies. Acute toxicity studies of mnemoPQQ® in Wistar rats revealed that its LD50 was 1825- and 1410 mg/kg body weight (bw) in male and female rats, respectively, whereas its acute dermal LD50 was >2000 mg/kg bw. mnemoPQQ® was found to be nonirritant to the skin of rabbit in an acute dermal irritation/corrosion study, and classified mnemoPQQ® as a nonirritant to the eye of rabbit in an acute eye irritation/corrosion study. Ames bacterial reverse mutation assay and in vitro Mammalian cell gene mutation test exhibited its non-mutagenic potential. In mammalian in vivo erythrocyte micronucleus test, mnemoPQQ® was classified as non-clastogenic and non-mutagenic. A 90-day sub-chronic toxicity study, conducted at and up to the highest daily dose of 600 mg/kg body weight, revealed no evidence of systemic toxicity. All rats survived the treatment without any significant abnormal clinical signs and alterations in hematology, clinical chemistry, neurological evaluation, thyroid functions, reproductive hormone levels, sperm evaluations, vaginal cytology, endocrine functions, organ weight and gross and microscopic pathology findings. No observed adverse effect level (NOAEL) of mnemoPQQ® was found to be greater than 600 mg/kg body weight. These studies affirm that mnemoPQQ® has broad spectrum safety for human consumption.

Regulatory safety pharmacology and toxicity assessments of a standardized stem extract of Cassia occidentalis Linn. in rodents.

Cassia occidentalis Linn (CO) is an annual/perennial plant having traditional uses in the treatments of ringworm, gastrointestinal ailments and piles, bone fracture, and wound healing. Previously, we confirmed the medicinal use of the stem extract (ethanolic) of CO (henceforth CSE) in fracture healing at 250 mg/kg dose in rats and described an osteogenic mode of action of four phytochemicals present in CSE. Here we studied CSE's preclinical safety and toxicity. CSE prepared as per regulations of Current Good Manufacturing Practice for human pharmaceuticals/phytopharmaceuticals and all studies were performed in rodents in a GLP-accredited facility. In acute dose toxicity as per New Drug and Clinical Trial Rules, 2019 (prior name schedule Y), in rats and mice and ten-day dose range-finding study in rats, CSE showed no mortality and no gross abnormality at 2500 mg/kg dose. Safety Pharmacology showed no adverse effect on central nervous system, cardiovascular system, and respiratory system at 2500 mg/kg dose. CSE was not mutagenic in the Ames test and did not cause clastogenicity assessed by in vivo bone marrow genotoxicity assay. By a sub chronic (90 days) repeated dose (as per OECD, 408 guideline) study in rats, the no-observed-adverse-effect-level was found to be 2500 mg/kg assessed by clinico-biochemistry and all organs histopathology. We conclude that CSE is safe up to 10X the dose required for its osteogenic effect.

The effect of Dolichandrone serrulata (wall. ex DC.) Seem. flower extract containing antioxidant capacity and terpenoids on the male reproductive system.

Although the fruit extract of Dolichandrone genus was shown to inhibit spermatogenesis, the reproductive toxicity of Dolichandrone serrulata flowers (DSFs) is not documented. Recent study aimed to evaluate the sub-chronic toxicity of DSF on male reproductive system. Antioxidant capacity and total phenolic contents of DSF extract were determined using Folin-Ciocalteu's, 2,2-diphenyl-1-picrylhydrazyl and ferric reducing antioxidant power assays. The terpenoid components were determined using nuclear magnetic resonance spectrum. Adult male rats were treated orally with DSF (100, 300 or 600 mg/kg) for 48 days. Histopathology of testis and epididymis was observed. Sperm concentration, viability, acrosome status and morphology were also examined. Expressions of heat shock protein 70 (Hsp70), tyrosine-phosphorylated (TyrPho) proteins, androgen receptor (AR) and steroidogenic acute regulatory (StAR) protein in testis were investigated. Results showed that DSF contained phenolic compounds and terpenoids (phytoandrogens; rengyolone and cleroindicin B). No reproductive histopathology was observed in DSF-treated rats. Although DSF decreased the serum testosterone level, the sperm qualities were not affected. Particularly, sperm concentration of DSF-treated animals was significantly increased. DSF changed the testicular TyrPho proteins but the expression of AR, StAR or Hsp70 was not altered. In conclusion, DSF possesses antioxidant capacity with no toxicity on male reproductive system.

Toxicological evaluation of a flavonoid, chrysin: morphological, behavioral, biochemical and histopathological assessments in rats.

Nowadays, medicines from plant sources play a vital role in healthcare management. Chrysin, a plant flavonoid, possesses a wide range of pharmacological activities. The aim of present investigation was to evaluate the safety of chrysin by determining toxicity after acute and sub-chronic oral administration in rats. Acute oral toxicity (AOT) and sub-chronic oral toxicity studies of chrysin were carried out according to OECD 425 and OCED 408 in Sprague Dawley rats. In AOT, oral administration of chrysin (5000 mg/kg) showed 40% mortality. In the sub-chronic toxicity study, daily oral administration of chrysin (1000 mg/kg) showed significantly decreased body weight whereas liver weight was increased significantly in male rats. A significant alteration in the hematology (RBC, MCH, MCHC, TLC, lymphocytes, and neutrophil) and blood chemistry (albumin, bilirubin, ALT, AST, creatinine, and GGT) were found in chrysin (1000 mg/kg) treated rats which were either limited to one sex or lacked dose-response or were within the normal laboratory ranges. There was a significant increase in hepatic and renal oxido-nitrosative stress in chrysin (1000 mg/kg) treated rats. There was no significant change in electrocardiographic (except heart rate), hemodynamic, the left ventricular function, and lung function test. Renal and hepatic histological aberrations were induced in chrysin (1000 mg/kg) treated rats. In conclusion results of the present investigation determined the LD50 value of chrysin to be 4350 mg/kg whereas NOAEL and LOAEL of chrysin was found to be 500 and 1000 mg/kg, respectively for both the sexes.

The anti-tussive, anti-inflammatory effects and sub-chronic toxicological evaluation of perilla seed oil.

BACKGROUND: Perilla seed oil (PSO) is the main constituent of perilla seeds currently being used in the food industry, however it also has great clinical potential in the regulation of lung function as a nutrition supplement because of the high content of α-linolenic acid (ALA). In this study, the pharmacological activities including anti-tussive, expectorant and anti-inflammatory effect of PSO were performed. Furthermore, the 90-day sub-chronic oral toxicity with a 30 day recovery period was evaluated in Wistar rats. RESULTS: The pharmacological studies demonstrated that PSO inhibited cough frequency induced by capsaicine in mice. PSO also inhibited the leukotriene B4 (LTB4) release from the calcium ionophore A23187-induced polymorphonuclear neutrophils (PMNs) to some extent. In this sub-chronic toxicity study, mortality, clinical signs, body weight, food consumption, hematology, serum biochemistry, urinalysis, organ weight, necropsy, and histopathology were used to evaluate the toxicity of PSO. Lower body weight and various negative impacts on liver related parameters without histopathological lesion were observed in the 16 g kg-1 groups. No clinically significant changes were discovered in the 4 g kg-1 group during the test period. CONCLUSION: In summary, PSO exhibited anti-tussive and anti-inflammatory activities in vivo and in vitro. These sub-chronic toxicity studies inferred that the 'no-observed adverse effect level' (NOAEL) of PSO in Wistar rats was determined to be 4 g kg-1 . These results may provide a safety profile and a valuable reference for the use of PSO. © 2020 Society of Chemical Industry.

Acute and sub-chronic toxicity studies of Benincasa hispida (Thunb.) cogniaux fruit extract in rodents.

The objective of the present study was to evaluate the safety of standardized 70% ethanolic extract of Benincasa hispida fruit pulp (HABH) in rodents. Chemical characterization of HABH has been done by GC-MS and dimethylsulfoxonium formyl methylide, l-(+)-ascorbic acid and 2,6-dihexadecanoate were identified as major compounds in the extract. Acute oral toxicity study of HABH was done according to the Organization for Economic Cooperation and Development (OECD) guideline, by 'up and down' method, using the limit test at 2000 mg/kg, body weight in mice and were observed up to 14 days. In sub-chronic oral toxicity study, HABH was administered to Wistar rats at doses of 1000, 200 and 40 mg/kg b. w. per day for 90 days. In acute toxicity study, there was no mortality and no behavioural signs of toxicity at the limit test dose level (2000 mg/kg b. w.). In sub-chronic oral toxicity study, there was no significant difference observed in the consumption of food and water, body weight and relative organ weights. Haematological, serum biochemical and urine analysis revealed the non-adverse effects of prolonged oral consumption of HABH. The histopathologic examination did not show any differences in vital organs. Based on our findings, HABH, at dosage levels up to 1000 mg/kg b. w., is non-toxic and safe for long term oral consumption.

Analysis and reflection on the role of the 90-day oral toxicity study in European chemical risk assessment.

The 90-day toxicity study is one of the studies used in the safety assessment of food ingredients, medicines or other chemical substances. This paper reviews the current role of the 90-day oral toxicity study in European regulatory dossiers of chemicals by reviewing EU legislation and EU and OECD guidance documents. Regulatory provisions with regard to necessity, objectives and design of such 90-day toxicity studies vary between the different sectors addressed in this review. Most often the 90-day study is expected to be part of the standard test battery used for chemical risk assessment, without necessarily being a legal requirement and its objectives may vary between regulatory domains. Exceptions, when a 90-day study is not required are spelled out in the chemicals legislation and for food contact materials. The sectorial study design requirements of the 90-day toxicity study are very often embedded in the OECD TG 408 protocol. Differences in study objectives are not necessarily reflected in specific study designs. Considering the call for the reduction of using experimental animals for scientific purposes and the fact that a 90-day study may serve different purposes, consistency between the necessity to conduct such a study, its objectives and the study design to achieve these objectives may improve judicious use of laboratory animals. Thus there may be an opportunity to reflect and further optimise the design of in vivo toxicology studies, such as the 90-day study. This should be based on a systematic analysis of past studies and risk assessments.

Acute and sub-chronic 90-day oral toxicity study of Perilla seed oil in rodents and Beagle dogs.

Perilla seeds are used as food and traditional medicine in China. This study aimed to investigate the toxicity profile of Perilla seed oil (PSO), which is the main constituent of Perilla seeds in rodents and Beagle dogs. No significant treatment-associated toxicity or mortality was observed at PSO dosages of up to 50 g/kg and 20 g/kg in KM mice and Wistar rats, respectively, suggesting that PSO was well tolerated by the experimental rodents. Sub-chronic oral toxicity of PSO was studied in dogs at doses of 3, 6 and 12 g/kg/d for 90 days followed by a 30 day recovery period. The results indicated that the body weight increased in all-dose groups more than control group, typical of animals on diets rich in fatty acids. Treatment-related side effects, including changes in hematology and serum biochemistry parameters, histopathology of liver and lymph glands, were observed in the high and moderate-dose dogs. However, these changes disappeared after the doses were withdrawn during the recovery period, except for alteration of liver in the high-dose group. In conclusion, the "no observed adverse effect level" (NOAEL) of oral administration of PSO for 90 days in Beagle dogs was considered to be 3 g/kg/d.

Acute and sub-chronic oral toxicity studies of hesperidin isolated from orange peel extract in Sprague Dawley rats.

Citrus sinensis contains glycoside hesperetin-7-rhamnoglucoside (hesperidin) which harbor an array of therapeutic potentials including antioxidant, anticancer, and anti-inflammatory. However, a systematic examination of safety is needed before its utilization. Hence, the present investigation is aimed to evaluate acute and sub-chronic toxicity of hesperidin isolated from the citrus fruit. Hesperidin (73%) was isolated from a methanolic extract of dried peel of the citrus fruit, characterized using FTIR, and standardized by HPLC. Its acute oral toxicity (AOT) and sub-chronic toxicity studies were carried out in Sprague-Dawley rats. Hesperidin (5000 mg/kg) showed 10% mortality in AOT. In sub-chronic toxicity study, hesperidin (250 and 500 mg/kg) did not induce any abnormalities in body weight, food consumption, clinical signs, ophthalmological and neurological observations, urine analysis, hematology, clinical chemistry, organ weights, and gross pathology. However, hesperidin (1000 mg/kg) showed significant (p < 0.05) alterations in body and organ weights, hematology, clinical chemistry, and tissue histopathology. To conclude, hesperidin has median lethal dose (LD50) of 4837.5 mg/kg, and Low Observed Adverse Effect Level (LOAEL) at 1000 mg/kg for both male and female Sprague-Dawley rats. Thus, hesperidin isolated from citrus fruit showed a good safety profile in animal study.

Evaluation of the antidepressant- and anxiolytic-like effects of a hydrophilic extract from the green seaweed Ulva sp. in rats.

OBJECTIVES: The green seaweed Ulva sp. contains a large amount of ulvans, a family of sulphated polysaccharides. The present study was designed to investigate in rats the antidepressant- and anxiolytic-like effects of a hydrophilic extract of Ulva sp. (MSP) containing about 45% of ulvans. METHODS: After a 14-day administration of MSP at doses of 10, 20 and 40 mg/kg/day, 48 and 60 male adult Wistar rats were respectively tested in the elevated plus-maze (EPM) and the forced swimming test (FST). In the FST, MSP effects were compared to the reference antidepressant drug imipramine (IMI) (10 mg/kg/day). Acute and sub-chronic toxicities of the extract were also assessed in male and female rats following OECD guidelines. RESULTS: MSP treatment did not modify anxiety-related behaviour in the EPM. In contrast, MSP induced a dose-dependent reduction of immobility behaviour in the FST. At the highest tested dose of 40 mg/kg, MSP displayed a significant antidepressant-like effect similar to IMI. MSP did not modify the exploratory behaviour of rats in the open field test and did not produce any toxic effect. DISCUSSION: MSP may potentially represent a good adjunct or alternative to existing antidepressant therapeutics. Further studies are necessary to confirm the mechanism of action of MSP and its modulation of brain functioning.

Sub-chronic toxicopathological study of lantadenes of Lantana camara weed in Guinea pigs.

BACKGROUND: In the field conditions, animals regularly consume small quantities of lantana leaves either while grazing or due to mixing with regular fodder. The hypothesis of this study was that consumption of lantana toxins over a long period of time leads to progression of sub-clinical disease. Toxicopathological effects of sub-chronic (90 days) administration of lantadenes of L. camara were investigated in guinea pigs. For this, a total of 40 animals were divided into 5 groups whereby groups I, II, III and IV were orally administered lantadenes, daily at the dose of 24, 18, 12, and 6 mg/kg bw, respectively while group V was control. The animals were evaluated by weekly body weight changes, haematology, serum liver and kidney markers, tissue oxidative markers and histopathology. RESULTS: The results of significant decrease in weekly body weights, haematology, liver and kidney marker enzymes (alanine aminotransaminase, aspartate aminotransaminase, acid phosphatase and creatinine), oxidation stress markers (lipid peroxidation, reduced glutathione, superoxide dismutase and catalase) in liver and kidneys, histopathology, and confirmation of fibrous collagenous tissue proliferation by Masson's Trichome stain showed that lantadenes led to a dose-dependent toxicity in decreasing order with the highest dose (24 mg/kg bw) producing maximum lesions and the lowest dose (6 mg/kg bw) producing minimum alterations. CONCLUSIONS: The study revealed that lantadenes which are considered to be classical hepatotoxicants in acute toxicity produced pronounced nephrotoxicity during sub-chronic exposure. Further studies are needed to quantify the levels of lantadenes in blood or serum of animals exposed to lantana in field conditions which would help to assess the extent of damage to the vital organs.

Acute and sub-chronic toxicological studies of the iridoid glycosides extract of Lamiophlomis rotata (Benth.) Kudo in rats.

Lamiophlomis rotata(Benth.) Kudo is widely used in traditional Chinese medicine and its iridoid glycosides extract (IGLR) was the main active ingredient with hemostatic, antinociceptive and anti-inflammatory effects. This study was aimed to evaluate the safety of IGLR using acute and sub-chronic toxicity study methods on Sprague-Dawley rats. In acute toxicity test, IGLR caused slight diarrhea in three dose groups and a decreased of RBC and increased of MCH and Ret (P < .05) were observed in 16 g/kg group. In sub-chronic toxicity study, unscheduled deaths occurred in 1 and 3 rats at 0.40 and 1.00 g/kg groups, respectively. A slight diarrhea was observed in 1.00 g/kg group. Hemolytic anemia was the main toxicity effects of IGLR found in 0.40 and 1.00 g/kg groups, with a significant decrease of RBC, HGB (P < .05) and increase of Ret, MCV, MCH (P < .05) in hematological parameters, a significant decrease of ALT, Crea (P < .05) and increase of TBIL (P < .05) in biochemical parameters, and a significant increase of the percentage of rubricyte, normoblast (P < .05) in bone marrow. Overall, this study found IGLR has a potential toxicity considering with hemolytic anemia and diarrhea to rat. These results provide an important reference for further IGLR-related drug exploration.