Acute Toxicity Study Research Articles

Evaluation of in silico model predictions for mammalian acute oral toxicity and regulatory application in pesticide hazard and risk assessment

The United States Environmental Protection Agency (USEPA) uses the lethal dose 50% (LD50) value from in vivo rat acute oral toxicity studies for pesticide product label precautionary statements and environmental risk assessment (RA). The Collaborative Acute Toxicity Modeling Suite (CATMoS) is a quantitative structure-activity relationship (QSAR)-based in silico approach to predict rat acute oral toxicity that has the potential to reduce animal use when registering a new pesticide technical grade active ingredient (TGAI). This analysis compared LD50 values predicted by CATMoS to empirical values from in vivo studies for the TGAIs of 177 conventional pesticides. The accuracy and reliability of the model predictions were assessed relative to the empirical data in terms of USEPA acute oral toxicity categories and discrete LD50 values for each chemical. CATMoS was most reliable at placing pesticide TGAIs in acute toxicity categories III (>500–5000 mg/kg) and IV (>5000 mg/kg), with 88% categorical concordance for 165 chemicals with empirical in vivo LD50 values ≥ 500 mg/kg. When considering an LD50 for RA, CATMoS predictions of 2000 mg/kg and higher were found to agree with empirical values from limit tests (i.e., single, high-dose tests) or definitive results over 2000 mg/kg with few exceptions.

Synergy and Antagonism in Antimalarial Crude Extract Combinations

Background Malaria accounts for around 4.8% of all recorded fatalities in Tanzania. Medicinal plants such as Caesalpinia bonducella, Azadirachta indica, and Annickia kummeriae have demonstrated promise in treating many diseases, including malaria. However, their combined activity against malaria has not been documented. Combination therapy using some medicinal plants with antimalarial activities may enhance safety and efficacy and reduce the evolution of parasite resistance. Objectives This study aimed to investigate antiplasmodium activities of different combinations of crude extracts from selected medicinal plants. Azadirachta indica leaves, Annickia kummeriae and Caesalpinia bonducella were extracted using dichloromethane (DCM). Methods An in vivo acute toxicity study of both individual and combined crude extracts was carried out according to Chinedu et al., 2015. The in vivo antiplasmodial activity of individual and combined crude extracts was performed in mice inoculated with Plasmodium berghei (ANKA strain) using Peters’s 4-day suppressive test. Results Individually, Caesalpinia bonducella crude extracts exhibited the highest in vivo antiplasmodial efficacy (91% parasite suppression) than A. kummeriae (73% parasite suppression) and A. indica (60% parasite suppression) at 800 mg/kg/day. The A. indica and A. summarize combinations and A. indica and C. bonducella demonstrated higher antiplasmodial activity (synergism-combination index 0.29 and 0.97, respectively) than their constituents. However, combining A. kummeriae and C. bonducella produced the lowest antiplasmodial activity (antagonism- combination index 40.67) than its extracts. The high antiplasmodial potencies (ED50) demonstrated by AiAk and AiCb are significant and critical results for traditional, complementary and alternative medicine. Conclusion Therefore, these preliminary findings suggest that AiAk and AiCb are potential antiplasmodium herbal therapies. Further research should be undertaken to investigate the antiplasmodium effect of AiAk and AiCb in humans.

Safety profile of Naga Bhasma prepared by two classical methods

Abstract Background: Naga Bhasma (NB) (incinerated lead) has been indicated as a remedy for the treatment of a wide range of diseases including Prameha (diabetes), Kasa (cough), Raktapradara (menorrhagia), Shukradosha (defects in semen), etc., However, improperly prepared NB can cause harmful effects on the human body. In modern science also, lead consumption has been accepted to produce toxicity. Aim: The present study was undertaken to elucidate and compare the toxicity profile of two samples of NB prepared by two different methods to ascertain the safety aspects. Materials and methods: In the first method, NB was prepared by using Parada (mercury), Gandhaka (sulfur), and Nimbu Swarasa (juice of Citrus medica var acida of Watt). In the second method, NB was prepared by using Ashwattha-Twaka-Churna (Ficus religiosa L.), Manahshila (realgar) (Ariloha), and Nimbu Swarasa. In both methods, 30 calcination cycles were given. Charles foster albino rats were used for the pharmacological study. Acute oral toxicity study was carried out as per organization for economic cooperation and development (OECD) 425 and chronic oral toxicity study was carried out as per OECD 408 (90-day oral repeated dose toxicity study). Acute oral toxicity study was conducted at five dose levels, namely 100, 250, 500, 1000, and 2000 mg/kg body weight. Chronic toxicity was carried out at a dose level of 62.5 mg/kg body weight. Animals were sacrificed on the 91st day by cervical dislocation. Blood was collected from the jugular vein and sent for hematological and biochemical investigations were done. Organs were used for histopathological studies. The data were analyzed by unpaired t-test. Results: No mortality was observed in the acute toxicity study. Chronic toxicity study shows that both the test drugs do not produce significant toxicity, but both were not completely free from adverse effects at the dose level studied. Conclusion: The study shows that both the test drugs do not produce significant toxicity, but they are not completely free from adverse effects at the dose level studied.

The protective effects of Zingiber zerumbet rhizome against fevers in rats.

The Zingiber zerumbet rhizomes are traditionally used to treat fever, and the in vitro inhibitory effect of ethyl acetate extract from Zingiber zerumbet rhizomes (EAEZZR) against DENV2 NS2B/NS3 (two non-structural proteins, NS2 and NS3 of dengue virus type 2) has been reported earlier. This study was carried out to establish an acute toxicity profile and evaluate the anti-fever (anti-pyretic) activities of EAEZZR in yeast-induced fever in rats. The major compound of EAEZZR, zerumbone, was isolated using chromatographic methods including column chromatography (CC) and preparative thin-layer chromatography (PTLC). Additionally, the structure of zerumbone was elucidated using nuclear magnetic resonance (NMR), liquid chromatography mass spectrometer-ion trap-time of flight (LCMS-IT-TOF), infrared (IR), and ultraviolet (UV) spectroscopy. The toxicity of EAEZZR was evaluated using Organization for Economic Cooperation and Development Test Guideline 425 (OECD tg-425) with minor modifications at concentrations EAEZZR of 2000 mg/kg, 3000 mg/kg, and 5000 mg/kg. Anti-fever effect was determined by yeast-induced fever (pyrexia) in rats. The acute toxicity study showed that EAEZZR is safe at the highest 5000 mg/kg body weight dose in Sprague Dawley rats. Rats treated with EAEZZR at doses of 125, 250, and 500 mg/kg exhibited a significant reduction in rectal temperature (TR) in the first 1 h. EAEZZR at the lower dose of 125 mg/kg showed substantial potency against yeast-induced fever for up to 2 h compared to 0 h in controls. A significant reduction of TR was observed in rats treated with standard drug aspirin in the third through fourth hours. Based on the present findings, ethyl acetate extract of Zingiber zerumbet rhizomes could be considered safe up to the dose of 5000 mg/kg, and the identification of active ingredients of Zingiber zerumbet rhizomes may allow their use in the treatment of fever with dengue virus infection.

Safety of AYUSH OSTO in experimental animals

Background: AYUSH OSTO is a coded formulation developed by the Central Council for Research in Ayurvedic Sciences for the treatment of bone-related disorders. Aim: The present study focused on evaluating the safety of AYUSH OSTO through acute, 28-day sub-acute, and 90-day sub-chronic repeated dose toxicity studies. Materials and Methods: Acute oral toxicity was tested with doses of 260, 1300, and 2600 mg/kg, and sub-acute, sub-chronic studies were performed with doses of 180, 900, and 1800 mg/kg. During the acute toxicity, the evaluation test compound was administered once orally, whereas in the sub-acute toxicity and sub-chronic studies, the test compound was administered daily for 28 days and 90 days, respectively. Clinical signs of toxicity and mortality were observed in all three studies. Feed intake, changes in body weight, hematological, clinical biochemistry, urine analysis, gross necropsy, and histopathological analysis were performed in sub-acute, sub-chronic studies. Results: There was no mortality, and no clinical signs of toxicity were observed in all three toxicity studies. The weekly feed intake and body weight changes were found to be nonsignificant when compared to the control. The clinical chemistry and hematological profiles of the animals were not altered with the treatment. The histopathological analysis of vital organs at the tested dose levels did not show any organ damage. Conclusions: The findings of the acute toxicity study established the approximate LD50 of >2600 mg/kg and the repeated dose toxicity studies established the no-observed-adverse-effect level of AYUSH OSTO is up to 1800 mg/kg.

Evaluating acute toxicity of amino acid ionic liquids towards Poecilia reticulata fish for designing sustainable chemical processes

An acute toxicity study assessed the LC50 values for eight different amino acid ionic liquids (AAILs), featuring two cations, tetrabutylphosphonium [P4444] and tetrabutylammonium [N4444], coupled with four anions [PHE], [ASP], [SER], and [GLY]. According to the OECD 203 standard for acute fish toxicity tests with guppy fish (Poecilia reticulata, all the AAILs exhibited low toxicity levels, and were practically nontoxic and harmless. The LC50 values surpassed 100 mg/L and 1000 mg/L. This study provides valuable insights for industrial professionals in utilizing tetrabutylphosphonium-based amino acid ionic liquids [P4444] [AA] and tetrabutylammonium-based amino acid ionic liquids [N4444][AA] in chemical processes, indicating their safety in aquatic environments. These promising results highlight the potential of incorporating these AAILs into diverse chemical processes while ensuring minimal ecological impact.

Proximate analysis, total phenolic content, acute toxicity, anti-oxidative and anti-inflammatory studies of Vigna unguiculata and Citrus limon using Wister rat models

Herbal medicines have been in use for thousands of years. It is estimated that 80% of world population rely on traditional herbal medicine for prophylaxis and therapy of different ailments. In recent years, there has been an upsurge in the use of these herbal remedies due to their cultural acceptability, availability, affordability, efficacy and safety claims. This study carried out the proximate analysis, total phenolic and Citric acid contents, acute toxicity, anti-oxidative and anti-inflammatory studies of Vigna unguiculata and Citrus limon using Wister rat models. Wister rats (135 – 140 g) were used for this study. Vigna unguiculata was extracted using ethanol for 72 hours. Proximate analysis, Citric acid content of Citrus limon, total phenolic content, acute toxicities, anti-oxidative and anti-inflammatory studies were done. The yield of the extract was 1.9%. The LD50 was greater than 5,000 mg/kg body weight. The Citric acid content of Citrus limon was 54.2 + 0.003 mg/ml. The proximate analysis showed the presence of protein, fat, carbohydrate, dietary fibre, moisture, and iron while total phenolic contents of Vigna unguiculata and Citrus limon were 15.3 and 19.3 mgGAE/L respectively. The combination of Vigna unguiculata and Citrus limon exhibited greatest anti-oxidation effect and recorded malondialdehyde concentration of 3.66 ± 0.34 nmol/ml as compared to the individual herbs that recorded 6.14 ± 0.38 and 4.28 ± 0.12 nmol/ml respectively. In anti-inflammatory assay, Vigna unguiculata had the best percentage inhibition of heat induced hemolysis of 62.79%. In conclusion, Vigna unguiculata and Citrus limon had synergistic antioxidant and antagonistic anti-inflammatory activities.

Anti-obesity, phytochemical profiling and acute toxicity study of ethanolic extract of saffron (Crocus sativus L.)

IntroductionCrocus sativus (C. sativus), known as saffron, has been recognized for its medicinal benefits since ancient times. The plant was first introduced to the Chongming Island region of Shanghai, China, in 1980. Chinese Saffron, derived from this plant, is one of China's most valuable traditional herbs, yielding about 1 ton in 2013. Traditional Chinese Medicine (TCM) has used this plant as an antianginal for a long time. The plant has been extensively studied for its pharmacological benefits in treating obesity and gastrointestinal problems. This study aimed to conduct a comprehensive phytochemical analysis of C. sativus stigma (saffron) ethanolic extract using LCMS/MS, quantify its major compound, i.e., trans-4-GG-crocin, and study its acute toxicity. In addition, this study aimed to investigate the effect of the extract on anti-obesity in a high-fat diet-induced zebrafish model. MethodsBefore the anti-obesity study, we conducted a comprehensive profiling of saffron ethanolic extract using UHPLC-ESI-MS/MS in both positive and negative modes. Then, the principal constituent, i.e., trans-4-GG-crocin, was quantified using HPLC with a UV detector. The study was followed by an acute toxicity study for 72 h to evaluate the safety profile of this extract using five concentrations of extract, from 93.75–1500 mg/L. Six groups of wild-type zebrafish were then segregated according to food regimen, i.e., (1) control (5 mg artemia/fish/day), (2) overfeeding (60 mg of artemia/fish/day), (3–6) high-fat diet (5 mg artemia+30 mg egg yolk/fish/day), then starting week 9–16, groups 4–6 were received (4) 50 mg/L, (5) 100 mg/L and (6) 200 mg/L of saffron extract. ResultsNegative mode analysis revealed twenty phytoconstituents, while twenty-two were found in positive mode LCMS/MS analysis. The extract contained 536.91 µg/g of trans-4-GG-crocin. The highest concentration tested in the acute toxicity killed 100% of the testing animals within 24 h, and probit analysis showed that the LC50 of the extract was 1021 mg/L. Eight weeks of treatment with 100 and 200 mg/L of saffron significantly reduced the body mass index of the high-fat diet-induced zebrafish model (p<0.0001). ConclusionSaffron ethanolic extract contains mainly flavonoid, carotenoid, and terpenoid compounds. This extract is highly toxic in high concentrations (1500 mg/L), which kills 100% of the tested zebrafish. Eight weeks of treatment with 100 and 200 mg/L of saffron extract via immersion significantly reduced body mass index in the high-fat diet zebrafish model. The findings suggest that Saffron extract could be a promising natural anti-obesity agent that warrants further investigation. The study provides valuable insights into the potential of natural compounds as a source of anti-obesity agents and highlights the need for further research in this area. Even though this plant was studied for anti-obesity in rodent models, its mode of action is still unknown and warrants further investigation, which could be explored more in a cheaper and easier way by using another translational animal model, such as zebrafish.

Acute Inhalation Toxicity Study of 3-Methoxybutyl Acetate in Sprague-Dawley Rats

3-Methoxybutyl acetate is an organic solvent used in a wide range of industrial and consumer applications, such as coatings, adhesives, chemical intermediates, paints, and washing products. We conducted an acute inhalation toxicity study of 3-Methoxybutyl acetate using an inhalation exposure system (nose-only) in Sprague-Dawley rats. Male and female rats were exposed to 3-Methoxybutyl acetate for 4 h/day. The tests were conducted according to the Organisation for Economic Cooperation and Development Guidelines for the Testing of Chemicals (OECD TG) 436. The analytical concentrations of the exposure chamber were 9.76 ± 0.51 mg/L. Clinical signs, mean body weight changes, and gross necropsy results were observed. No deaths, abnormal clinical signs, gross findings at necropsy, or abnormal mean body weight changes related to exposure to the test substance were observed in either sex. Based on these results, we suggested that 3-Methoxybutyl acetate does not have acute toxic effects at the technically acceptable concentration of 10 mg/L.

Leaching of unexpected cyazofamid degradation products into groundwater demonstrates gaps in current pesticide risk assessment

To investigate the formation and leaching potential of degradation products N,N-dimethylsulfamide (DMS) and dimethylsulfamic acid (DMSA) from cyazofamid under real-world agricultural conditions, the fungicide cyazofamid was applied in a potato crop as part of the Danish Pesticide Leaching Assessment Programme (PLAP). Leaching of DMS, DMSA, 4-chloro-5-(4-methylphenyl)-1H-imidazole-2-carbonitrile (CCIM), and 4-chloro-5-(4-methylphenyl)-1H-imidazole-2-carboxylicacid (CTCA) was monitored in water from the variably saturated zone (suction cups) and groundwater for more than two years following the applications. In total, 424 samples were analyzed for the content of the four degradation products. An additional laboratory study was executed in parallel with the field monitoring study. Here, cyazofamid was applied to soil columns and leaching of the four degradation products was studied under controlled conditions.In the EFSA conclusion on cyazofamid, CCIM and CTCA are mentioned as major relevant metabolites; DMS is not mentioned in the risk assessment and DMSA is only included in acute oral toxicity studies and an in vitro bacterial mutation assay. In contrast to the EFSA conclusion on cyazofamid, our studies showed no leaching of the two major metabolites, CTCA and CCIM, but instead, major leaching of DMS and DMSA in both the field and laboratory studies was observed. That is, both DMS and DMSA leached to the groundwater in concentrations >0.1 μg/L for more than half a year. Based on this, we suggest improvements to the current pesticide risk assessment.

&lt;i&gt;In Vivo&lt;/i&gt; Hepatoprotective Activity of Hydroalcohol Extract of &lt;i&gt;Gyrocarpus asiaticus&lt;/i&gt; Willd and &lt;i&gt;Lactuca runcinata&lt;/i&gt; DC

Objective: Investigation of hepatoprotective activity of Gyrocarpus asiaticus Willd (GA) and Lactuca runcinata DC (LR) prepared by hydroalcohol extraction. Methodology: Albino rats were used for the in vivo experiments for the determination of oral acute toxicity study. For these experiments, 6 groups were created of which 5 groups were for each plant extract and 1 group for control. A total of 11 groups were made for the toxicity study. Each group required 2 albino mice. Different doses of 0.025, 0.2, 0.5, 2, and 5 gm/kg body weight were administered orally for each plant extract. For the control group, these were administered with distilled water. For hepatoprotective activity, albino rats were randomly divided into 5 (control, toxic, standard, 2 samples) groups, and 4 animals were randomly divided into each group. For 2 plants, a total of 7 groups were made. 5% gum acacia was used as the vehicle. For induced hepatotoxicity CCl4 and as a standard drug silymarin was used. Result and Discussion: Plant extracts did not show any toxicity, and no histopathological changes were seen in the liver, kidney, or lungs due to toxicity. In the study of GA Willd and LR DC extract prepared by hydroalcohol solution, there was evidence of protection against CCl4-induced hepatotoxicity in the Histopathological study of the liver of albino rats. Conclusion: Hydroalcohol extract of LR DC and GA Willd shows no oral acute toxicity and LR DC shows no significant hepatoprotective activity but GA Willd shows significant hepatoprotective activity

Study of Anti Melancholy Effect of Tridax procumbens Leaf Extracts

The current study was intended to assess the antidepressant action of Successive extraction of Petroleum ether (PEETP), Chloroform (CHETP), ethylacetate (EAETP), Ethanolic (EETP) &amp; Aqueous (AETP) extracts of Tridax procumbens (TP)by Tail suspension test (TST). The 25-30g over night fasted mice were selected and divided into six groups. Dose was fixed as per OECD 425 Guidelines acute toxicity studies. Extracts and standard were administered 1 hr prior to study,time period and percentage diminution of immobility were noted. The CETP &amp; EAETP 200 mg/kg extracts shows significant (p&lt;0.01) reduction of immobility time was observed when compared to control. Both EETP 200 mg/kg effect and escitalopram (10mg/kg) shows the more significant (P&lt;0.001) when compared to negative control. AETP was shows p˂0.05 significant whereas PEETP no significant to negative control, the studies result recommends that ethanol extract pronouncedantidepressant effect. It may be the presences of Phtoconstituents attribute the level of Neurotransmitter like 5 hydroxy tryptamine and noradrenaline.

Characterization of the antioxidant activity, identified free radical-relieving components by LC/QTOF/MS and acute oral toxicity studies of Tri-Tharn-Thip tea

This study assessed the antioxidant activities and bioactive maker of Tri-Than-Thip tea (Tri-TTa) to provide database support for the use of Tri-Than Thip remedy according to the Thai Pharmaceutical Textbook and aims to develop herbal medicine or food from natural products. Tri-TTa and herbal components were tested for antioxidant scavenging activity (DPPH assay, ABTS assay), chain-breaking/iron ion chelating activity (Metal Chelating Activity; MAC, the ferric-reducing antioxidant power activity; FRAP), superoxide anion radical scavenging activity (NBT assay), oxygen radical antioxidant capacity (ORAC assay), total content of Phenolic (TCP) and flavonoid (TCP) substance. The chemical components were separated and investigated by LC/QTOF/MS for safe dosages due to acute oral toxicity in rats. The Tri-TTa showed the strongest inhibition of antioxidant activity with the DPPH, ABTS, and MCA assay, with IC50 values of 0.087 ± 0.003, 0.025 ± 0.000, and 0.012 ± 0.000 mg/mL, respectively. In addition, Tri-TTa can also inhibit superoxide anion radicals, with IC50 values of 158 ± 0.009 mg/mL, and the oxygen radical was 3.47 ± 0.03 μM of TE/g extract. TCP, TCF, and FRAP values of Tri-TTa were 154.123 ± 1.326, 80.233 ± 14.268 mg equivalent/g of extract, and 1092.457 ± 106.024 mM FeSO4/mg, respectively. Additionally, Tri-TTa contains important substances in the phenolic and flavonoid groups that have good antioxidant abilities and were confirmed to be safe through acute oral toxicity testing in rats, which revealed no toxicity-related effects at high doses. Tri-TTa is a strong candidate for use as a natural product with antioxidant activity, suggesting that plant polyphenol content may promote antioxidant activity. These results support further research on Thai folk remedy infusions as promising antioxidant agents that can be developed for food, tea, or tonic drugs from natural.

Pharmacological Evaluation of Sedum lineare Thunb Extract: Acute Toxicity and Anticonvulsant Effects in Swiss Albino Mice

Aim: This study aimed to assess the acute toxicity and anticonvulsant effects of the hydroalcoholic extract of Sedum lineare Thunb in Swiss albino mice. Materials and Methods: Acute toxicity was evaluated by administering a high dose (2000 mg/kg) of the hydroalcoholic extract and monitoring mortality, behavioral changes, body weight, and food/water consumption. Hematological parameters and organ histopathology were analyzed to assess systemic effects. The anticonvulsant activity was explored using pentylenetetrazole (PTZ) and picrotoxin-induced seizure models at various extract doses (100, 250, and 500 mg/kg). Results and Discussion: The acute toxicity study revealed the safety of the hydroalcoholic extract, with no observed mortality, behavioral changes, or adverse effects on body weight and food/water consumption. While hematological changes were statistically significant, their clinical relevance requires further exploration. Histopathological examination confirmed the absence of organ toxicity. In the anticonvulsant assessment, the hydroalcoholic extract exhibited a protective effect against PTZ-induced seizures, significantly delaying jerk onset at the highest dose. Although not prevent clonic convulsions entirely, it dose-dependently reduces mortality rates. In the picrotoxin model, particularly at 250 mg/kg, the extract significantly increased clonic convulsion latency and suppressed mortality, indicating a potential modulatory role against seizures. Conclusion: The hydroalcoholic extract of S. lineare Thunb demonstrated favorable acute toxicity and promising anticonvulsant effects in Swiss albino mice. The observed hematological changes warrant further investigation for clinical relevance, and additional studies, including long-term assessments and biochemical analyses, are recommended to comprehensively evaluate the extract’s safety and therapeutic potential. These findings support further exploration of S. lineare Thunb as a potential candidate for neurological disorder interventions..

Oral acute toxicity study of ethanol extract of Mobe leaves (Artocarpus lacucha Buch-Ham) in Wistar rats

Many medicinal plants are now being chosen because the treatment is safer and cheaper. Artocarpus lacucha Buch-Ham is a plant with many pharmacological activities and is efficacious; its safety has not been studied. Acute oral toxicity evaluation followed Organization for Economic Co-operation and Development guidelines using the fixed dose method. The evaluation began with a preliminary test, then a primary test with three groups: a 2000 mg/Kg BW dose test group, a 5000 mg/Kg BW dose test group, and a control group. The results of visual observations, haematological and clinical examinations, and histological examination of organs (liver, spleen, kidneys, lungs and heart) showed no toxicity in the animals, and they did not die during testing. The findings of this study support the safety of Artocarpus lacucha Buch-Ham leaf ethanol extract, which did not produce harmful results in acute toxicity tests.

In vivo antimalarial effect of 1-hydroxy-5,6,7-trimethoxyxanthone isolated from Mammea siamensis T. Anders. flowers: pharmacokinetic and acute toxicity studies

BackgroundThe potent antiplasmodial activity of 1-hydroxy-5,6,7-trimethoxyxanthone (HTX), isolated from Mammea siamensis T. Anders. flowers, has previously been demonstrated in vitro. However, its in vivo activity has not been reported. Therefore, this study aimed to investigate the antimalarial activity and acute toxicity of HTX in a mouse model and to evaluate the pharmacokinetic profile of HTX following a single intraperitoneal administration.MethodsThe in vivo antimalarial activity of HTX was evaluated using a 4-day suppressive test. Mice were intraperitoneally injected with Plasmodium berghei ANKA strain and given HTX daily for 4 days. To detect acute toxicity, mice received a single dose of HTX and were observed for 14 days. Additionally, the biochemical parameters of the liver and kidney functions as well as the histopathology of liver and kidney tissues were examined. HTX pharmacokinetics after intraperitoneal administration was also investigated in a mouse model. Liquid chromatography triple quadrupole mass spectrometry was used to quantify plasma HTX and calculate pharmacokinetic parameters with the PKSolver software.ResultsHTX at 10 mg/kg body weight significantly suppressed parasitemia in malaria-infected mice by 74.26%. Mice treated with 3 mg/kg HTX showed 46.88% suppression, whereas mice treated with 1 mg/kg displayed 34.56% suppression. Additionally, no symptoms of acute toxicity were observed in the HTX-treated groups. There were no significant alterations in the biochemical parameters of the liver and kidney functions and no histological changes in liver or kidney tissues. Following intraperitoneal HTX administration, the pharmacokinetic profile exhibited a maximum concentration (Cmax) of 94.02 ng/mL, time to attain Cmax (Tmax) of 0.5 h, mean resident time of 14.80 h, and elimination half-life of 13.88 h.ConclusionsHTX has in vivo antimalarial properties against P. berghei infection. Acute toxicity studies of HTX did not show behavioral changes or mortality. The median lethal dose was greater than 50 mg/kg body weight. Pharmacokinetic studies showed that HTX has a long elimination half-life; hence, shortening the duration of malaria treatment may be required to minimize toxicity.

Effects of Ethyl Acetate Fraction of Mangifera haden Seeds on Carbon Tetrachloride Induced Hepatotoxicity in Albino Rats

The present study investigated the effects of ethyl acetate fraction of Mangifera haden seeds on carbon tetrachloride-induced liver damage in wistar albino rats. The phytochemical compositions and acute toxicity studies of crude extract and Mangifera haden seed fraction were determined using standard methods. Albino rats (60) randomly grouped into twelve of five rats each were used for this study. Determination of total bilirubin and protein, lipid peroxidation, liver enzymes marker, antioxidant enzymes, glutathione, lipid profile analysis and histological examination were carried out using standard methods. Phytochemical constituents of crude extract and ethyl acetate fraction of Mangifera haden seed showed that they contain relative amount of flavonoids, phenolics, saponins, tannins, terpenoids, triterpenes, alkaloids and coumarins. Liver injury was induced with carbon tetrachloride (CCl4) at a dose of 1.0 ml/kg body weight of the animals. All the CCl4 intoxicated rats displayed hyperlipidemia as shown by their elevated levels of serum total cholesterol (TC), triacylglycerol (TAG), low density lipoprotein (LDL), and reduction in high density lipoprotein (HDL) levels. The administration of ethyl acetate fraction of Mangifera haden seeds significantly (P = 0.05) lowered the levels of serum TC, TAG, LDL, and increased HDL levels. The level of serum malondialdehyde (MDA) significantly (P = 0.05) increased in the CCl4 group as compared to the normal and treated groups. The elevated level of serum MDA decreased (P = 0.05) significantly at the treatment of rats with 200, 400 and 600 mg/kg of ethyl acetate fraction. The rats treated with CCl4 produced significant (P = 0.05) increase in serum ALT, AST and ALP when compared to the normal group. Animals treated with varying doses of ethyl acetate fraction produced significant (P = 0.05) reduction of serum ALT, AST and ALP activities when compared to the CCl4-untreated group. The activities of hepatic antioxidant enzymes (SOD, CAT and GPx) and glutathione concentration significantly (P = 0.05) decreased in CCl4­-untreated group compared to the normal group. The decreased activities of the antioxidant enzymes and glutathione concentration in CCl4 intoxicated rats were ameliorated/modulated more effectively in rats treated with 200, 400 and 600 mg/kg ethyl acetate fraction of Mangifera haden seed. Total bilirubin (TB) concentrations significantly (P = 0.05) increased in CCl4-untreated group when compared to the normal group. Oral treatment of rats with varying doses (200, 400, 600 mg/kg) of ethyl acetate fraction caused a significant (P = 0.05) decrease in the serum TB levels. Administration of CCl4 showed a reduction in serum total proteins. Treatment of the animals with 200, 400 and 600 mg/kg of ethyl acetate fraction caused significant (P = 0.05) increase in serum total potein. Histological examination showed hepatoprotective properties of plant’s fractions. The compounds found in the different fractions (ethyl acetate and n-hexane) of Mangifera haden seeds are 9-Octadecenoic acid (Z)-, methyl ester, (Z) –Oleic acid and so on. Therefore the medicinal importance of the plant is been established.

Discovery of Novel 4-Hydroxyquinazoline Derivatives: In Silico, In Vivo and In Vitro Studies Using Primary PARPi-Resistant Cell Lines.

A series of novel 4-Hydroxyquinazoline derivatives were designed and synthesized to enhance sensitivity in primary PARPi-resistant cells. Among them, the compound B1 has been found to have superior cytotoxicity in primary PARPi-resistant HCT-15 and HCC1937 cell lines, and dose-dependently suppressed the intracellular PAR formation and enhanced the γH2AX aggregation. Mechanistic study showed that B1 stimulated the formation of intracellular ROS and the depolarization of the mitochondrial membrane, which could increase apoptosis and cytotoxicity. An in vivo study showed that B1 significantly suppressed tumor growth at a dose of 25 mg/kg, and an acute toxicity study confirmed its safety. Molecular docking and dynamics simulations revealed that hydrogen bonding between B1 and ASP766 may be helpful to enhance anti-drug resistance ability. This study suggests that B1 is a potent PARP inhibitor that can overcome PARPi resistance and deserves further investigation.

Anti-inflammatory, anti-diabetic, and biocompatibility properties of aqueous extract of Tamarindus indica L. fruit coat analyses by in-vitro and in-vivo approaches

The anti-inflammatory, anti-diabetic, and biocompatibility nature of Tamarindus indica L. fruit coat aqueous extract were investigated in this research through in-vitro and in-vivo studies. The anti-inflammatory property was determined through albumin denaturation inhibition and antiprotease activities as up to 39.5% and 41.2% respectively at 30 mg mL−1 concentration. Furthermore, the antidiabetic activity was determined through α-amylase and α-glucosidase inhibition as up to 62.15% and 67.35% respectively at 30 mg mL−1 dosage. The albino mice based acute toxicity study was performed by different treatment groups (group I–V) with different dosages of aqueous extract to detect the biocompatibility of sample. Surprisingly, findings revealed that the T. indica L. fruit coat aqueous extract had no harmful impacts on any of the groups. Urine, as well as serum parameter analysis, confirmed this. Moreover, the findings of SOD (Superoxide Dismutase), GST (Glutathione-S-transferase), & CAT (Catalase) as well as glutathione peroxidase as well as reduced glutathione antioxidant enzymes studies stated that the aqueous extract possess high antioxidant ability via a dose-dependent way. These findings indicate that T. indica fruit coat aqueous extract contains medicinally important phytochemicals with anti-inflammatory and anti-diabetic properties, as well as being biocompatible in nature.

In Silico Prediction of Oral Acute Rodent Toxicity Using Consensus Machine Learning.

Acute oral toxicity (AOT) is required for the classification and labeling of chemicals according to the global harmonized system (GHS). Acute oral toxicity studies are optimized to minimize the use of animals. However, with the advent of the three Rs principles and machine learning in toxicology, alternative in silico methods became a reasonable alternative approach for addressing the AOT of new chemical matter. Here, we describe the compilation of AOT data from a commercial database and the development of a consensus classification model after evaluating different combinations of molecular representations and machine learning algorithms. The model shows significantly better performance compared to publicly available AOT models. Its performance was evaluated on an external validation data set, which was compiled from the literature, and an applicability domain was deduced.