ABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: The bark of Canarium schweinfurthii is used in ethnomedicine for the treatment of diabetes, pain, malaria, fever and diarrhoea. AIM OF THE STUDY: The chemical phytoconstituents, antidiarrheal, anti-inflammatory and antinociceptive effects and safety profile of the aqueous extract of Canarium schweinfurthii bark (AECSB) were investigated. MATERIALS AND METHODS: Gas chromatography-mass spectrometry (GC-MS) was used to analyse the phytochemical composition. In the acute toxicity test, AECSB were administered up to 2 g/kg by oral gavage. For the subacute toxicity test (28 days), rats in group 1 (control) received no AECSB, while rats in groups 2-4 were administered different doses of AECSB. Charcoal meal transit and castor oil-induced diarrhoea models were used to study the antidiarrheal effect, while egg albumin/carrageenan and acetic acid/tail immersion models were used for the anti-inflammatory and antinociceptive studies, respectively. With the exception of the acute toxicity experiment, AECSB was administered orally at doses of 200, 400 and 800 mg/kg. RESULTS: Bioactive phytoconstituents identified include p-cymene, δ-terpinene, linalool and phytol. No adverse effects or mortality were observed in acute and subacute studies. Treatment with AECSB (28 days) had no significant effect on organ weight, biochemical, hematologic and histopathologic parameters compared to the control groups (p > 0.05). Comparable antidiarrheal and antinociceptive effects were observed in both AECSB- and standard drug-treated groups, while the 400 and 800 mg/kg AECSB-treated groups showed remarkable anti-inflammatory effects compared to the standard drug-treated and control groups (p < 0.05). CONCLUSION: AECSB has antidiarrheal, antinociceptive and anti-inflammatory effects and can be safely used for therapeutic purposes.
Subject(s)
Analgesics , Anti-Inflammatory Agents , Antidiarrheals , Burseraceae , Diarrhea , Plant Bark , Plant Extracts , Animals , Analgesics/pharmacology , Analgesics/toxicity , Plant Bark/chemistry , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/toxicity , Plant Extracts/pharmacology , Plant Extracts/toxicity , Plant Extracts/chemistry , Male , Antidiarrheals/pharmacology , Antidiarrheals/toxicity , Antidiarrheals/therapeutic use , Diarrhea/drug therapy , Diarrhea/chemically induced , Rats , Female , Burseraceae/chemistry , Rats, Wistar , Toxicity Tests, Acute , Toxicity Tests, Subacute , Pain/drug therapy , Pain/chemically induced , Phytochemicals/analysis , Phytochemicals/pharmacology , Phytochemicals/toxicity , MiceABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Mucuna pruriens L is a wild and cultivated leguminous plant which have been used as an aphrodisiac, diuretic, nerve tonic, and antiarthritic agent. AIM: To evaluate the toxicity, antinociceptive, and anti-inflammatory activities of M. pruriens (EEMP) ethanol extract in experimental models. METHODS: M. pruriens dried leaves were extracted using aqueous ethanol (30:70). Tests for acute and subacute toxicity were conducted on rats and mice. Mice were used in hotplate, acetic acid, and formalin models to test the antinociceptive activity of EEMP. The anti-inflammatory properties of EEMP (25, 100, and 400 mg/kg) were assessed egg albumin, carrageenan, and formalin-induced oedema models. The study examined the anti-inflammatory mechanism of EEMP (25-400 mg/kg) in rats with an air pouch caused by carrageenan. Air pouch exudates were tested for total leucocytes and differential cell counts, TNF-α, IL-6, myeloperoxidase activity, malondialdehyde, nitrites, and reduced glutathione (GSH). RESULTS: The acute oral toxic dose of EEMP is greater than 2000 mg/kg. There were no significant behavioral, hematological or biochemical alterations seen after 14-days repeated administration of EEMP (200, 400 and 800 mg/kg) in mice. The EEMP demonstrated significant antinociceptive activity in hotplate, acetic acid and formalin-induced nociception in mice. The EEMP significantly and dose dependently reduced paw oedema at 2, 4 and 96 h in the egg-albumin, carrageenan- and formalin-induced paw oedema, respectively. Exudates volume, inflammatory cell counts, TNF-α, IL-6, myeloperoxidase, malondialdehyde and nitrites were significantly reduced, while GSH increased in carrageenan-air pouch of EEMP-treated rats. CONCLUSION: Mucuna pruriens leaves ethanol extract demonstrated good safety profile as well as antinociceptive and anti-inflammatory activity through mechanisms related to inhibition of oxidative stress and pro-inflammatory cytokines as well as lysosomal membrane stability.
Subject(s)
Analgesics , Anti-Inflammatory Agents , Edema , Mucuna , Plant Extracts , Plant Leaves , Animals , Plant Extracts/pharmacology , Analgesics/pharmacology , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/isolation & purification , Male , Mice , Edema/drug therapy , Edema/chemically induced , Rats , Mucuna/chemistry , Female , Pain/drug therapy , Pain/chemically induced , Carrageenan , Rats, Wistar , Dose-Response Relationship, Drug , Rats, Sprague-Dawley , Disease Models, Animal , Formaldehyde/toxicity , Toxicity Tests, SubacuteABSTRACT
BACKGROUND: Lepidium sativum (LS) seed extract has various pharmacological properties, such as antioxidant, hepatoprotective, and anticancer activities. However, the translation of L. sativum seed extract to the clinical phase is still tedious due to its bioavailability and stability issues. This problem can be solved by encapsulating it in a nanodelivery system to improve its therapeutic potency. METHODS: In this study, we have determined and compared the in vivo toxicity of ethanolic extracts of L. sativum seeds (EELS) and solid lipid nanoparticles (SLNs). To conduct toxicity (acute and subacute toxicity) assessments, EELS and SLNs were orally administered to Swiss albino mice. Animal survival, body weight, the weight of vital organs in relation to body weight, haematological profile, biochemistry profile, and histopathological alterations were examined. RESULTS: Animals administered with 2000 mg/kg and 5000 mg/kg in an acute toxicity study exhibited no toxicological symptoms regarding behaviour, gross pathology, and body weight. As per a study on acute toxicity, the LD50 (lethal dose) for SLNs and EELS was over 400 mg/kg and over 5000 mg/kg, respectively. When animals were given SLNs (50 and 100 mg/kg, orally) and EELS (250, 500, and 1000 mg/kg, orally) for 28 days, subacute toxicity study did not exhibit any clinical changes. There were no differences in weight gain, haematological parameters, or biochemical parameters compared to the control groups (p > 0.05). The organs of the treated animals showed no abnormalities in the histological analysis (liver, heart, kidney, and spleen). CONCLUSION: The result confirms ethanolic extracts of L. sativum seeds and their SLNs to not have harmful effects following acute and subacute administration to mice. For further studies, patents available on Lepidium may be referred for its preclinical and clinical applications.
Subject(s)
Lepidium sativum , Nanoparticles , Plant Extracts , Seeds , Animals , Mice , Plant Extracts/toxicity , Plant Extracts/chemistry , Plant Extracts/administration & dosage , Seeds/chemistry , Administration, Oral , Nanoparticles/chemistry , Nanoparticles/toxicity , Toxicity Tests, Acute , Male , Female , Lethal Dose 50 , Toxicity Tests, SubacuteABSTRACT
Nanodrugs offer promising alternatives to conventionally used over the counter drugs. Compared to its free form, therapeutic benefits, and gastric tissue safety of naproxen sodium nanoformulation (NpNF) were recently demonstrated. Essential regulatory safety data for this formulation are, however, not available. To address this, male and female BALB/c mice were subjected to acute and 14-day repeated-oral dose assessments. Our data indicate that NpNF was well tolerated up to 2000 mg/kg b.w. A 14-day subacute toxicity testing revealed that the oral administration of low dose (30 mg/kg) NpNF did not produce any adverse effects on blood profile and serum biochemical parameters. Levels of oxidative stress markers and antioxidant enzymes neared normal. Histology of selected tissues also showed no evidence of toxicity. In contrast, a ten-fold increase in NpNF dosage (300 mg/kg), demonstrated, irrespective of gender, mild to moderate toxicity (p < 0.05) in the brain, stomach, and heart tissues, while ROS, LPO, CAT, SOD, POD, and GSH levels remained unaffected in the liver, kidney, spleen, testis, and seminal vesicles. No effect on serum biochemical parameters, overall indicated a no-observed-adverse-effect level (NOAEL) is 300 mg/kg. Further increase in dosage (1000 mg/kg) significantly altered all parameters demonstrating that high dose is toxic.
Subject(s)
Mice, Inbred BALB C , Naproxen , Toxicity Tests, Acute , Toxicity Tests, Subacute , Animals , Female , Naproxen/toxicity , Naproxen/administration & dosage , Male , Anti-Inflammatory Agents, Non-Steroidal/toxicity , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Mice , Administration, Oral , Oxidative Stress/drug effects , Nanoparticles/toxicity , Dose-Response Relationship, Drug , No-Observed-Adverse-Effect LevelABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Traditionally, the Morus mesozygia tree leaf has been used to manage maladies such as peptic ulcer, hyperglycemia, dermatitis, rheumatism, stomach-ache, arthritis, cough, malignancies, and malaria in parts of Africa. AIM OF THE STUDY: The study aimed to evaluate the potential of ethanol leaf extract of Morus mesozygia (EEMm) to induce toxicity by employing both acute and sub-acute oral toxicity experimental models. MATERIAL AND METHODS: The extract's cytotoxicity was studied using brine shrimps (Artemia salina) lethality assay (BSLA), while in the acute toxicity test, male and female mice were administered a single oral dose of EEMm (2000 mg/kg). Male and female Wistar rats received repeated doses of 100 or 500 mg/kg EEMm orally for 28 days in the sub-acute toxicity experiment. The phytochemical analysis of EEMm was done using the HPLC. RESULTS: The BSLA revealed a moderate cytotoxic potential of the extract, with an LC50 of 567.13 ± 0.27 µg/mL. All the animals survived the acute toxicity test, with no significant changes in the relative organ weights, suggesting that LD50 is greater than 2000 mg/kg. The animal weights did not vary significantly in the sub-acute toxicity test neither were the alterations in biochemical and hematological tests pronounced, although the histoarchitectures of the kidney, liver and spleen indicated slight anomalies in the evaluated animals. The HPLC analysis revealed the presence of quercetin, ferulic acid, rutin, caffeic acid, morin and gallic acid. CONCLUSIONS: Ethanol leaf extract of Morus mesozygia demonstrated a safe toxicity profile in rodents, supporting its broad folkloric use in African ethnomedicine.
Subject(s)
Moraceae , Morus , Rats , Mice , Animals , Ethanol , Rats, Wistar , Rodentia , Plant Extracts/toxicity , Plant Extracts/analysis , Toxicity Tests, Acute , Artemia , Toxicity Tests, SubacuteABSTRACT
PURPOSE: There is very little information about the toxicological and pathological effects of synthetic cannabinoids, which have cannabis-like properties. This study was carried out to histopathologically, hematologically, and biochemically determine the toxic effects of acute and subacute exposure to a novel synthetic cannabinoid 1-(4-cyanobutyl)-N-(2-phenylpropan-2-yl)indazole-3-carboxamide in internal organs of adult male rats. METHODS: The cannabinoid was injected intraperitoneally at three doses (0.5, 1.0, and 2.0 mg/kg, body weight). The cannabinoid was administered to acute groups for 2 days and to subacute groups for 14 days. Observations were made for 14 days and various changes such as mortality, injury, and illness were recorded daily. Hematological and biochemical changes were evaluated and histopathological analyses in lung, liver, and kidney tissues were also performed. RESULTS: No mortality was observed. It was observed that there were fluctuations in hematological and serum biochemical parameters. Among the oxidative stress parameters, significant decreases in superoxide dismutase, catalase levels and significant increases in lipid peroxidation levels were determined. Serious pathological changes such as necrosis, vacuolation, congestion, and fibrosis were observed in the internal organs in a dose-dependent and time-dependent manner. It was also found that the synthetic cannabinoid triggered apoptosis in the organs. The results demonstrated that the most affected organ by the cannabinoid was the kidney. CONCLUSION: This study showed for the first time that CUMYL-4CN-BINACA adversely affects healthy male albino rats. It can be estimated that the abuse of the cannabinoid may harm human health in the same way.
Subject(s)
Cannabinoids , Kidney , Lipid Peroxidation , Liver , Lung , Oxidative Stress , Animals , Male , Kidney/drug effects , Kidney/pathology , Kidney/metabolism , Cannabinoids/toxicity , Rats , Liver/drug effects , Liver/pathology , Lung/drug effects , Lung/pathology , Lung/metabolism , Lipid Peroxidation/drug effects , Oxidative Stress/drug effects , Superoxide Dismutase/metabolism , Indazoles/toxicity , Catalase/metabolism , Dose-Response Relationship, Drug , Toxicity Tests, Subacute , Rats, Wistar , Toxicity Tests, AcuteABSTRACT
European cranberrybush (ECB) (Viburnum opulus L.) fruits are abundant in phenolic compounds associated with various health benefits. However, the toxicity and safety of ECB juice have not been systematically studied. In the present study, acute and subacute oral toxicities of ECB fruit juice were evaluated on Sprague-Dawley rats and BALB/c mice to establish a toxicity profile. In acute tests, a single administration of 2000 mg/kg body weight of extract to rats exhibited no clinical signs of toxicity or mortality, indicating that the lethal dose (LD50) was over 2000 mg/kg. In subacute tests, repeated administration for 28 days at 0 (control), 500, and 2000 mg/kg doses of extract in mice did not display adverse clinical signs or deaths. However, in the 2000 mg/kg subacute group, platelet counts were significantly high, which correlated with histopathological analyses revealing that ECB extract at 2000 mg/kg was toxic to the kidney, liver, and adipose tissue. The NOAEL value of ECB extract was found as 500 mg/kg/day, but further sub-chronic and chronic toxicity studies are warranted to comprehensively evaluate the long-term safety implications. The study's results emphasize the importance of considering the dosage of dietary supplements containing high levels of phenolic compounds over an extended period to avoid potential cumulative effects from prolonged consumption of high doses.
Subject(s)
Plant Extracts , Viburnum , Rats , Mice , Animals , Rats, Sprague-Dawley , Plant Extracts/toxicity , Fruit and Vegetable Juices , Fruit , Phenols/toxicity , Toxicity Tests, Acute , Toxicity Tests, SubacuteABSTRACT
Pesticide pollution is one of the most important factors for global bee declines. Despite many studies have revealed that the most important Chinese indigenous speciesï¼Apis cerana, is presenting a high risk on exposure to neonicotinoids, the toxicology information on Apis cerana remain limited. This study was aimed to determine the acute and chronic toxic effects of thiacloprid (IUPAC name: {(2Z)-3-[(6-Chloro-3-pyridinyl)methyl]-1,3-thiazolidin-2-ylidene}cyanamide) on behavioral and physiological performance as well as genome-wide transcriptome in A. cerana. We found the 1/5 LC50 of thiacloprid significantly impaired learning and memory abilities after both acute and chronic exposure, nevertheless, has no effects on the sucrose responsiveness and phototaxis climbing ability of A. cerana. Moreover, activities of detoxification enzyme P450 monooxygenases and CarE were increased by short-term exposure to thiacloprid, while prolonged exposure caused suppression of CarE activity. Neither acute nor chronic exposure to thiacloprid altered honey bee AChE activities. To further study the potential defense molecular mechanisms in Asian honey bee under pesticide stress, we analyzed the transcriptomes of honeybees in response to thiacloprid stress. The transcriptomic profiles revealed consistent upregulation of immune- and stress-related genes by both acute or chronic treatments. Our results suggest that the chronic exposure to thiacloprid produced greater toxic effects than a single administration to A. cerana. Altogether, our study deepens the understanding of the toxicological characteristic of A. cerana against thiacloprid, and could be used to further investigate the complex molecular mechanisms in Asian honey bee under pesticide stress.
Subject(s)
Bees , Insecticides , Neonicotinoids , Thiazines , Animals , Bees/genetics , Bees/metabolism , Bees/physiology , Insecticides/toxicity , Neonicotinoids/toxicity , Thiazines/toxicity , Toxicity Tests, Subacute , Toxicity Tests, Chronic , China , Acetylcholinesterase/genetics , Acetylcholinesterase/metabolism , Stress, Physiological/geneticsABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Toxicity studies in appropriate animal models are an integral and very important component of pre-clinical studies in drug development. Brugmansia aurea lagerh. is used for both medicinal and non-medical purposes, including treating skin infections, different types of physical discomfort, inflammation, cough, hallucinations, and evil protection. AIM OF THE STUDY: This study was designed to detect any hazardous effects of B. aurea on animals and find out its LD50. MATERIALS & METHODS: An acute toxicity study was performed to find out the LD50 value and sub-acute toxicity study was performed to find out the toxicity on repeated dose administration till 28 days. Both studies were performed according to the organization of economic cooperation and development (OECD) 425 and 407 respectively. For the acute oral toxicity study, animals were divided into two groups, group I normal control (NC) and group II received a 2000mg/kg dose of B.aurea leaves extract. In the sub-acute toxicity study, male and female animals were divided into eight groups, I-IV for males and V-VIII for females received control, 100, 200 & 400mg/kg B. aurea leaves extract respectively. Hematological and biochemical markers were estimated at the end of each study. RESULTS: Results revealed that no mortality and morbidity were observed in acute oral as well as sub-acute toxicity studies. Oxidative stress markers were increased significantly in all organs of the treatment groups in both studies. Animals significantly decreased their food and water intake in an acute oral toxicity study. A slight difference in renal function tests was observed in the acute oral toxicity study when compared with the normal control group. No significant change in histopathology was observed in both studies on selected organs. CONCLUSION: This study concluded that B. aurea can be safely used for pharmacological purposes.
Subject(s)
Plant Extracts , Plant Leaves , Rats , Male , Female , Animals , Toxicity Tests, Acute , Plant Extracts/toxicity , Lethal Dose 50 , Toxicity Tests, SubacuteABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Currently, there is a remarkable increase in the consumption of microgreens, (young edible vegetables or herbs), as potential nutraceuticals for the management of diseases. Brassica carinata A. Braun is one of the traditional leafy vegetables cultivated in various parts of Sub- Saharan Africa. The plant is revered for its efficacy in the treatment of wounds and gastrointestinal disorders among other medicinal benefits. It is therefore crucial to characterize Brassica carinata microgreens for their phytoconstituents and ascertain their safety for use. AIM OF THE STUDY: The study evaluated the oral acute and subacute toxicity of Brassica carinata microgreens ethanol extract (BMEE) in Wistar rats and identification of its chemical composition and profile. MATERIALS AND METHODS: For acute toxicity (14 days), rats were grouped into four and received a single oral dose, the control group received distilled water, while others received 500 mg/kg, 1000 mg/kg, and 2000 mg/kg of BMEE. For the subacute toxicity (28 days), rats in four groups received daily doses of 250 mg/kg, 500 mg/kg or 1000 mg/kg and distilled water. Daily clinical observations like lethargy and mortality were conducted. Hematological, biochemical, and histopathological evaluations were performed at the end of each experiment. Phytochemical profile was determined using a UV-VIS spectrophotometer and Gas Chromatography coupled to Mass Spectrometry (GC-MS) analysis determined the potential bioactive components in the microgreens extract. RESULTS: In both acute and sub-acute toxicity studies, no mortalities, indications of abnormality, or any treatment related adverse effects were observed at doses of 2000 mg/kg, 1000 mg/kg, 500 mg/kg, and 250 mg/kg. The LD50 of BMEE was above 2000 mg/kg. No significant (p > 0.05) changes in the hematological and biochemical parameters of the treated groups compared to the control groups in both studies. Histopathological examination of the liver, kidney, lungs, and heart revealed a normal architecture of the tissues in all the treated animals. Phytochemical analyses revealed the presence of flavonoids (most abundant), phenols and alkaloids. Phytol, linoleic acid, and 9,12,15-octadecatrienoic acid, among other compounds, were identified by GC-MS analysis. CONCLUSION: The results showed that B. carinata microgreens ethanol extract is nontoxic and found to have several compounds with reported pharmacological significance suggesting safety for use.
Subject(s)
Brassica , Plant Extracts , Rats , Animals , Rats, Wistar , Plant Extracts/chemistry , Toxicity Tests, Acute , Ethanol , Phytochemicals/toxicity , Water , Toxicity Tests, SubacuteABSTRACT
The toxicological potential of the ethanolic extract from Gomphrena celosioides (EEGC), a medicinal plant used as a natural analgesic, was investigated in acute and subacute toxicity models in rodents. For the acute toxicity test, 2000 mg/kg of EEGC was administered orally to male and female Wistar rats, while Swiss mice received 75, 150 or 300 mg/kg of EEGC for the subacute toxicity test. Animals treated with an only dose of 2000 mg/kg EEGC showed no clinical signs of toxicity, indicating that the LD50 is higher than this dose. The repeated treatment with EEGC did not cause adverse clinical signs, or lesions in target tissues. According to the Globally Harmonized System of classification, the EEGC dosages can be in Category 5 which is the least toxic or non-toxic one.
Subject(s)
Amaranthaceae , Rodentia , Animals , Ethanol , Female , Male , Mice , Plant Components, Aerial , Plant Extracts/therapeutic use , Plant Extracts/toxicity , Rats , Rats, Wistar , Toxicity Tests, Acute , Toxicity Tests, SubacuteABSTRACT
Artemisinin-hydroxychloroquine sulfate tablets (AH) are considered a relatively inexpensive and novel combination therapy for treating all forms of malaria, especially aminoquinoline drugs-resistant strains of P.falciparum. We aim to carry out acute and subacute oral toxicity studies in rats to acquire preclinical data on the safety of AH. Acute toxicity was evaluated in Sprague-Dawley (SD) rats at a single dose of 1980, 2970, 4450, 6670, and 10000 mg/kg. A 14-days subacute toxicity was assessed in SD rats at doses of 0, 146, 219, 328, and 429 mg/kg. The median lethal dose (LD50) of acute oral administration of AH in rats is found to be 3119 mg/kg, and toxic symptoms include decreased spontaneous activity, dyspnea, bristling, soft feces, spasticity, and convulsion. Repeated doses of AH have toxic effects on the nervous system, skin, blood system, liver, kidney, and spleen in rats. The main toxic reactions include epilation, emaciation, mental irritability, decreased body weight gain and food consumption, changes in the hematological and biochemical parameters, especially pathological lesions in the liver, kidney, and spleen. The no-observed-adverse-effect level (NOAEL) and lowest-observed-adverse-effect level (LOAEL) of AH are considered to be 219 mg/kg and 328 mg/kg, respectively.
Subject(s)
Antimalarials/toxicity , Artemisinins/toxicity , Hydroxychloroquine/toxicity , Administration, Oral , Animals , Antimalarials/administration & dosage , Antimalarials/pharmacology , Artemisinins/administration & dosage , Artemisinins/pharmacology , Dose-Response Relationship, Drug , Drug Combinations , Female , Hydroxychloroquine/administration & dosage , Hydroxychloroquine/pharmacology , Lethal Dose 50 , Male , No-Observed-Adverse-Effect Level , Random Allocation , Rats , Rats, Sprague-Dawley , Toxicity Tests, Acute , Toxicity Tests, SubacuteABSTRACT
Piper amalago L. (Piperaceae) is traditionally used due to its anti-inflammatory, analgesic, diuretic, and antiparasitic properties. However, few studies have focused on its adverse effects, compromising its safe use. This study evaluated the toxicological safety of ethanolic extract from Piper amalago leaves (EEPA), through subacute toxicity and genotoxicity assays in rodents. In subacute toxicity, 100, 200 or 300 mg/kg of EEPA were tested in female Wistar rats, by gavage, for 28 days. For genotoxicity test, female Swiss mice were orally treated with 17.5, 175 or 1750 mg/kg of EEPA and the comet, micronucleus, and splenic phagocytic assays were evaluated. In subacute toxicity, the extract induced an increase in the food and water intakes, as well as in the liver absolute weight, and in the heart and kidney relative weights. EEPA also provoked alterations in histopathological analysis of liver and in hemato-biochemical parameters, evidenced by a decrease in hematocrit levels and albumin levels, and an increase in the number of platelets and in alkaline phosphatase and cholesterol levels. However, EEPA did not presented genotoxic nor mutagenic properties. EEPA showed hemato-biochemical toxicity profile in rats and should be used with caution, especially when for prolonged period.
Subject(s)
Piper , Plant Extracts/pharmacology , Animals , Blood/drug effects , Blood Chemical Analysis , DNA Damage/drug effects , Dose-Response Relationship, Drug , Female , Liver/drug effects , Mice , Mutagenicity Tests , Plant Leaves , Random Allocation , Rats , Rats, Wistar , Toxicity Tests, SubacuteABSTRACT
BACKGROUND: Several local communities in Central, Western, Eastern, and Northern regions of Uganda have been using the whole leaf extracts of Aloe vera (L.) Burm. f. (Asphodelaceae) in the treatment of various ailments. Also, several commercial companies sell A. vera as soft drinks in Uganda. However, there are inadequate reports on the toxicities of such preparations. This paper reports the acute and sub-acute oral toxicity of aqueous extracts of whole leaf and green rind of A. vera in Wistar rats. METHODS: Acute oral toxicity test was carried out in female Wistar rats at doses of 175, 550, 1750, and 5000 mg/kg, p.o. The animals were observed for signs of toxicity for 14 days. Similarly, a sub-acute oral toxicity test was performed in both sexes of rats at doses of 200, 400, and 800 mg/kg, p.o. daily for 28 days. All the groups of animals were monitored for behavioral, morphological, biochemical, and physiological changes, including mortality and compared with respective controls. Body weights were measured weekly while the animals' relative organ weights, hematological, biochemical, gross, and microscopic pathology were examined on day 29. RESULTS: There was no mortality or apparent behavioral changes at the doses tested in acute and sub-acute oral toxicity tests. Thus, the Median Lethal Dose (LD50) of green rind and whole leaf aqueous extracts was above 5000 mg/kg. Gross anatomy revealed that the rats' relative spleen weight in green rind extract at 200 mg/kg significantly decreased compared to the control group. The creatinine levels in female rats that received green rind extract and the chloride ion levels in male rats administered whole leaf extract were significantly elevated. Conversely, Mean Corpuscular Hemoglobin Concentration (MCHC) levels significantly decreased at lower doses of the green rind extract compared to the control. Histopathology of the kidney revealed the renal interstitium's inflammation at doses of 200 and 800 mg/kg of the whole leaf extract. CONCLUSION: The findings demonstrated that A. vera green rind and whole leaf extracts are non-toxic at relatively high doses when used for a short duration. Prolonged use of the aqueous whole leaf extract might be associated with kidney toxicity.
Subject(s)
Aloe/toxicity , Plant Extracts/toxicity , Animals , Female , Lethal Dose 50 , Male , Rats , Rats, Wistar , Toxicity Tests, Acute , Toxicity Tests, Subacute , UgandaABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Syzygium cumini (L.) Skeels has been extensively used in the ancient medical system of Pakistan, India, Bangladesh, and Sri Lanka to combat diabetes, inflammation, and renal disorders. These health-promoting aspects of S. cumini are related to bioactive metabolites such as phenolic acids, anthocyanins, tannins, and flavonoids. AIM OF THE STUDY: Earlier to this study, we have reported S. cumini extracts as potential sources of bioactive compounds bearing antioxidant and anti-inflammatory properties. However, prior further suggesting S. cumini fruit extracts for consumption against inflammatory disorders, it was mandatory to validate the claim and explore toxicity of the extracts. This study aims to determine the in vivo anti-nociceptive, anti-inflammatory, acute, and subacute toxicity properties of S. cumini crude extracts, followed by identifying and quantifying bioactive metabolites. MATERIAL AND METHODS: In the present study, the anti-nociceptive and anti-inflammatory potential of S. cumini sequential crude extracts were evaluated using formalin and glutamate-induced paw licking method in mice. The acute and sub-acute toxicity assessment of active extract was performed by oral administration in rats. An acute toxicity trial was performed with two different doses, i.e., 2000 mg/kg and 3000 mg/kg for consecutive 14 days, whereas a sub-acute toxicity study was conducted at doses of 750 mg/kg and 1500 mg/kg for the next 28 days. Identification of bioactive compounds was performed using HPLC, and at the end, in silico docking calculations of identified compounds were performed. RESULTS: The 100% methanolic extract (SCME) protected the mice from painful stimulation of formalin and glutamate in a dose-dependent manner with the maximum effect of 49% and 67% at 200 mg/kg, respectively, followed by moderate and non-influential effects of 50% methanolic extract and dichloromethane (DCM) extracts when compared to control, i.e., normal saline. The results of acute toxicity recorded LD50 of SCME over 3000 mg/kg, and no antagonistic effects were recorded during the subacute study when SCME dispensed at the rate of 750 mg/kg and 1500 mg/kg. SCME was found to induce no adverse effects to kidney, heart, liver, spleen, and paired lungs examined by hematological, serum biochemical, histological analysis. HPLC analysis of S. cumini 100% methanolic extracts revealed the presence of delphinidin 3-glucoside, peonidin-3,5-diglucoside, scopoletin, and umbelliferone at the concentration of 127.4, 2104, 31.3, 10.4 µg/g whereas in 50% methanolic extract, the quinic acid, catechin, and myricetin were present at the concentration of 54.9, 63.7, 12.3 µg/g, respectively. Umbelliferone and scopoletin are newly reported compounds in the present study. In silico docking calculations of these compounds indicated the potential of anti-nociceptive and anti-inflammatory activities. CONCLUSIONS: These findings validate that S. cumini fruit extracts are a rich source of bioactive compounds that needs to be considered to enhance biological activities with lesser side effects.
Subject(s)
Analgesics/pharmacology , Anti-Inflammatory Agents/pharmacology , Plant Extracts/pharmacology , Syzygium/chemistry , Analgesics/administration & dosage , Analgesics/isolation & purification , Animals , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/isolation & purification , Chromatography, High Pressure Liquid , Disease Models, Animal , Dose-Response Relationship, Drug , Female , Male , Mice , Molecular Docking Simulation , Plant Extracts/administration & dosage , Plant Extracts/toxicity , Rats , Rats, Sprague-Dawley , Toxicity Tests, Acute , Toxicity Tests, SubacuteABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Sanren decoction (SRD) is a well-known traditional Chinese medicine prescription containing eight kinds of materials. SRD has been used mainly in China for more than 200 years for the treatment of respiratory disorders that co-occur with a bad fever after midday. AIM OF THE STUDY: To evaluate the acute and 28-day subacute toxicity of an aqueous extract of SRD using in vivo methods. MATERIALS AND METHODS: To determine acute toxicity, SRD was administered by gavage at a dosage of 58.5 g/kg/day to male and female mice for 7 days. To determine subacute toxicity, SRD was administered at 3.3, 6.5, or 13 g/kg/day to male and female rats for 28 days. The general behavior, body weight, biochemical and hematological parameters, organ coefficients and pathological morphology of the treated animals were analyzed. RESULTS: Neither acute nor subacute concentrations of SRD caused significant changes in the body weights, general behavior, hematology and biochemical parameters, organ weights, or histopathological appearances of the liver, kidney, spleen, brain, lung or heart in mice or rats. CONCLUSIONS: The administration of SRD can be considered safe within the conditions of this study.
Subject(s)
Body Weight/drug effects , Drugs, Chinese Herbal/toxicity , Organ Size/drug effects , Animals , Animals, Outbred Strains , Dose-Response Relationship, Drug , Drugs, Chinese Herbal/administration & dosage , Female , Male , Mice , Rats , Rats, Sprague-Dawley , Toxicity Tests, Acute , Toxicity Tests, SubacuteABSTRACT
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.
Subject(s)
Flowers , Magnoliopsida , Plant Extracts , Animals , Aspartate Aminotransferases/metabolism , Female , Flowers/chemistry , Liver , Magnoliopsida/chemistry , Male , Plant Extracts/toxicity , Rats , Toxicity Tests, SubacuteABSTRACT
Peganum harmala (P. harmala) belongs to the family Zygophyllaceae, and is utilized in the traditional medicinal systems of Pakistan, China, Morocco, Algeria, and Spain to treat several chronic health disorders. The aim of the present study was to identify the chemical constituents and to evaluate the antioxidant, anti-inflammatory, and toxicity effects of P. harmala extracts both in vitro and in vivo. Sequential crude extracts including 100% dichloromethane, 100% methanol, and 70% aqueous methanol were obtained and their antioxidant and anti-inflammatory effects evaluated both in vitro and in vivo. The anti-inflammatory effect of the extract was investigated using the carrageenan-induced paw edema method in mice, whereas the toxicity of the most active extract was evaluated using an acute and subacute toxicity rat model. In addition, we have used the bioassay-guided approach to obtain potent fractions, using solvent-solvent partitioning and reversed phase high performance liquid chromatography from active crude extracts; identification and quantification of compounds from the active fractions was achieved using electrospray ionization mass spectrometry and high performance liquid chromatography techniques. Results revealed that the 100% methanol extract of P. harmala exhibits significant in vitro antioxidant activity in DPPH assay with an IC50 of 49 µg/mL as compared to the standard quercetin with an IC50 of 25.4 µg/mL. The same extract exhibited 63.0% inhibition against serum albumin denaturation as compared to 97% inhibition by the standard diclofenac sodium in an in vitro anti-inflammatory assay, and in vivo anti-inflammatory against carrageenan-induced paw edema (75.14% inhibition) as compared to 86.1% inhibition caused by the standard indomethacin. Furthermore, this extract was not toxic during a 14 day trial of acute toxicity when given at a dose of 3 g/kg, indicating that the lethal dose (LD50) of P. harmala methanol extract was greater than 3 g/kg. P. harmala methanolic fraction 2 obtained using bioassay-guided fractionation showed the presence of quinic acid, peganine, harmol, harmaline, and harmine, confirmed by electrospray ionization mass spectrometry and quantified using external standards on high performance liquid chromatography. Taken all together, the current investigation further confirms the antioxidant, anti-inflammatory, and safety aspects of P. harmala, which justifies its use in folk medicine.
Subject(s)
Anti-Inflammatory Agents/administration & dosage , Antioxidants/administration & dosage , Carrageenan/adverse effects , Edema/drug therapy , Peganum/chemistry , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Antioxidants/chemistry , Antioxidants/pharmacology , Disease Models, Animal , Edema/chemically induced , Indomethacin/pharmacology , Lethal Dose 50 , Mice , Plant Extracts/chemistry , Quercetin/pharmacology , Rats , Toxicity Tests, Acute , Toxicity Tests, SubacuteABSTRACT
The discovery of the expression of opioid receptors in the skin and their role in orchestrating the process of tissue repair gave rise to questions regarding the potential effects of clinical morphine treatment in wound healing. Although short term treatment was reported to improve tissue regeneration, in vivo chronic administration was associated to an impairment of the physiological healing process and systemic fibrosis. Human mesenchymal stem cells (hMSCs) play a fundamental role in tissue regeneration. In this regard, acute morphine exposition was recently reported to impact negatively on the functional characteristics of hMSCs, but little is currently known about its long-term effects. To determine how a prolonged treatment could impair their functional characteristics, we exposed hMSCs to increasing morphine concentrations respectively for nine and eighteen days, evaluating in particular the fibrogenic potential exerted by the long-term exposition. Our results showed a time dependent cell viability decline, and conditions compatible with a cellular senescent state. Ultrastructural and protein expression analysis were indicative of increased autophagy, suggesting a relation to a detoxification activity. In addition, the enhanced transcription observed for the genes involved in the synthesis and regulation of type I collagen suggested the possibility that a prolonged morphine treatment might exert its fibrotic potential risk, even involving the hMSCs.
Subject(s)
Mesenchymal Stem Cells/drug effects , Morphine/toxicity , Wound Healing/drug effects , Autophagy/drug effects , Cell Differentiation/drug effects , Cell Survival/drug effects , Collagen Type I/analysis , Collagen Type I/metabolism , Fibrosis , Humans , Mesenchymal Stem Cells/physiology , Primary Cell Culture , Toxicity Tests, SubacuteABSTRACT
Regulatory limits for shellfish toxins are required to protect human health. Often these limits are set using only acute toxicity data, which is significant, as in some communities, shellfish makes up a large proportion of their daily diet and can be contaminated with paralytic shellfish toxins (PSTs) for several months. In the current study, feeding protocols were developed to mimic human feeding behaviour and diets containing three dose rates of saxitoxin dihydrochloride (STX.2HCl) were fed to mice for 21 days. This yielded STX.2HCl dose rates of up to 730 µg/kg bw/day with no effects on food consumption, growth, blood pressure, heart rate, motor coordination, grip strength, blood chemistry, haematology, organ weights or tissue histology. Using the 100-fold safety factor to extrapolate from animals to humans yields a dose rate of 7.3 µg/kg bw/day, which is well above the current acute reference dose (ARfD) of 0.5 µg STX.2HCl eq/kg bw proposed by the European Food Safety Authority. Furthermore, to reach the dose rate of 7.3 µg/kg bw, a 60 or 70 kg human would have to consume 540 or 630 g of shellfish contaminated with PSTs at the current regulatory limit (800 µg/kg shellfish flesh), respectively. The current regulatory limit for PSTs therefore seems appropriate.