Poisoning Research Articles

Explainable machine learning models for predicting the acute toxicity of pesticides to sheepshead minnow (Cyprinodon variegatus).

A quantitative structure-activity relationship (QSAR) study was conducted on 313 pesticides to predict their acute toxicity to Sheepshead minnow (Cyprinodon variegatus) by using DRAGON descriptors. Essentials accounting for a reliable model were all considered carefully, giving full consideration to the OECD (Organization for Economic Co-operation and Development) principles for QSAR acceptability in regulation during the model construction and assessment process. Nine variables were selected through the forward stepwise regression method and used as inputs to construct both linear and nonlinear models. The obtained models were validated internally and externally. Generally, machine learning-based methods, namely support vector machine (SVM), random forest (RF), and projection pursuit regression (PPR), perform better than the multiple linear regression (MLR) model. The statistical results (R2 = 0.682-0.933, Q2LOO = 0.604-0.659, Q2F1 = 0.740-0.796, CCC = 0.861-0.882) of the developed models show that they are robust, reliable, reproducible, accurate and predictive. Comparatively, the RF model performs best, giving predictive correlation coefficient Q2 of 0.814, root mean squared error (RMSE) of 0.658 and mean absolute error (MAE) of 0.534 for the test set, respectively. The RF model (as well as SVM and PPR models) was visualized and explained by using the SHapley Additive explanation (SHAP) analysis to enhance its transparency and credibility. In addition, the applicability domain (AD) range of the RF model was characterized by the Williams plot and the tree manifold approximation and projection (TMAP) technology was utilized to illustrate similarity and diversity of the entire data space, to assist in the analysis of the outliers. Activity cliff detection was investigated by using Arithmetic Residuals in K-groups Analysis (ARKA) descriptors. It was found that none of the pesticides was identified as an activity cliff in the training set or a potential prediction cliff in the test set. Therefore, the RF model fulfills each OECD principle in regulation for QSAR models. The research in this work will aid in the in silico QSAR prediction of the acute toxicity to Sheepshead minnow (Cyprinodon variegatus) for untested and new toxic pesticides and can also be extended to other studies.

Mesoporous silica nanoparticles based on a dual environmental response corresponding to temperature and α-amylase for the control of Spodoptera litura

The design and development of stimuli-responsive nanocarriers hold the promise of the smart delivery of pesticides to target organisms. Herein, we successfully prepared mesoporous silica nanoparticles using the self-templating method, which were grafted with both N-isopropylacrylamide (NIPAM) and cyclodextrin (CD) and loaded with indoxacarb (IN) to afford a pesticide release system with a dual-stimulated response of temperature and α-amylase, referred to as IN@MSNs@NIPAM@CD. Physicochemical characterisation revealed the successful preparation of IN@MSNs@NIPAM@CD with 46.30 % indoxacarb loading. The results showed that IN@MSNs@NIPAM@CD was able to release IN rapidly in the environment of high temperature and α-Amylase, with excellent dual-responsive property. The UV resistance evaluation showed that IN@MSNs@NIPAM@CD could effectively improve the photodegradation resistance of indoxacarb. Fluorescent inverted microscope showed that FITC@MSNs@NIPAM@CD has excellent uptake and translocation properties in corn plants. Bioactivity tests showed that at 14 d, IN@MSNs@NIPAM@CD (LC50 = 9.83 mg L−1) exhibited higher insecticidal activity and longer effective duration than IN@EC (LC50 = 14.64 mg L−1). Acute toxicity test revealed that the IN@MSNs@NIPAM@CD nanoparticles were less acutely toxic to earthworms, zebrafish, BEAS-2B cells and MSNs@NIPAM@CD nanocarriers were safe for the growth of corn. Thus, the dual-responsive nano-controlled-release formulation of IN@MSNs@NIPAM@CD can provide an effective way of achieving the precise delivery and reduced use of pesticides.

Covalent triazine frameworks as particle electrode for three-dimensional photoelectrocatalytic degradation of oxytetracycline: Synergy effects, pathway, and mechanism.

Photoelectrocatalysis has been widely employed for degrading antibiotics due to its high efficiency. However, the application is significantly impeded by the rapid recombination of photogenerated charge carriers and the limited surface areas of photoelectrodes. In the study, high crystallinity covalent triazine frameworks were fabricated at low temperature of 150°C and firstly used as particle photoelectrode in the three-dimensional photoelectrochemical reactor to degrade oxytetracycline (OTC). SEM, TEM, XRD, XPS, and FT-IR confirmed the successful synthesis of high crystallinity covalent triazine frameworks. Compared to CTF-120 (71.2%) and CTF-180 (46.9%), CTF-150 exhibited excellent OTC removal. Electrochemical impedance, UV-vis absorption spectra, and Mott-Schottky tests showed that CTF-150 demonstrated more wide light absorption range of 501nm and narrow bandgap of 2.52eV, and smaller Rct value under illumination, in comparing to CTF-120 and CTF-180. When the initial concentration of OTC was 50mgL-1, the 86.2% of OTC removal and 62.7% of mineralization were obtained under light irradiation (λ>420nm), current of 10mA, pH of 6.4, electrolyte of 0.1M Na2SO4. The synergy effect between photocatalytic and electrocatalytic processes of CTF-150 not only enhanced by 38.5% current efficiency but also reduced energy consumption to 1.90 kWh m-3. CTF-150 had a wide range of acid-base application and displayed resistance on coexisting ions. Electron spin resonance detection, quenching experiments, and probe experiments illustrated that h+, •O2-, 1O2, and •OH contributed to the degradation of OTC and the generation pathways of •O2-, 1O2, and •OH were verified. Moreover, •O2-, 1O2, and h+ were the main reactive species responsible for OTC removal, while 1O2 was for OTC mineralization. Based on high-performance liquid chromatography-tandem mass spectrometry detection, OTC with benzene ring was decomposed to opening ring products. The acute toxicity, developmental toxicity, bioaccumulation factor and mutagenicity of OTC and its intermediates using T.E.S.T. showed the toxicity of 82.35% degradation products decreased.

Elucidation of molecular mechanisms involved in tadpole toxicity employing QSTR and q-RASAR approach

Tadpoles, as early developmental stages of frogs, are vital indicators of toxicity and environmental health in ecosystems exposed to harmful organic compounds from industrial and runoff sources. Evaluating each compound individually is challenging, necessitating the use of in-silico methods like Quantitative Structure Toxicity Relationship (QSTR) and Quantitative Read-Across Structure Activity Relationship (q-RASAR). Utilizing the comprehensive US EPA's ECOTOX database, which includes acute LC50 toxicity and chronic endpoints, we extracted crucial data such as study types, exposure routes, and chemical categories. Regression-based QSTR and q-RASAR models were developed from this dataset, emphasizing key chemical descriptors. Lipophilicity and unsaturation were significant for predicting acute toxicity, while electrophilicity, nucleophilicity, and molecular branching were crucial for chronic toxicity predictions. Additionally, q-RASAR models integrated with the "intelligent consensus" algorithm were employed to enhance predictive accuracy. The performance of these models was rigorously compared across various approaches. These refined models not only predict the toxicity of untested compounds but also reveal underlying structural influences. Validation through comparison with existing literature affirmed the relevance and robustness of our approach in ecotoxicology.

Stereotactic ablative radiotherapy (SABR) for patients with lung tumor and severe pulmonary function impairment.

To evaluate clinical outcomes after SABR in a cohort of early-stage non-small cell lung cancer (NSCLC) or pulmonary metastases in chronic obstructive pulmonary disease (COPD) patients with forced expiratory volume in the first second predicted (FEV1) ≤ 50%. Retrospective single-center study was performed to analyze clinical outcomes and toxicities in COPD patients with severe lung dysfunction treated with SABR from 1st June 2015 to 31st October 2022. Thirty four patients (forty locations) were enrolled for analysis. Median follow-up was 2.9years. Median age was 73.5years (range, 65.6-80.1). FEV1 was 38% (range, 28.2-50.0) prior to radiotherapy. Median overall survival (OS) was 41.1months (95% CI 38.9-not reached). OS rates at 2-, 3-, and 5- years were 79%, 71%, and 36%, respectively. Cancer-specific survival rates at 2-, 3-, and 5- years were 96%, 96%, and 68%, respectively. Local control rates at 2-, 3-, and 5- years were 88%, 83%, and 83%, respectively. No grade 4 or 5 toxicity was observed. The most common acute toxicity was pneumonitis (38.2%), of which only 1 patient (2.9%) reported grade 3 acute toxicity. Lung SABR in patients with poor pulmonary function may be effective with acceptable toxicity.

Using the Super-learner to Predict the Chemical Acute Toxicity on Rats

With the rapid increase in the number of commercial chemicals, testing methods regarding on median lethal dose (LD50) relying animal experiments face challenges such as high costs and ethical concerns. Classical quantitative structure-activity relationship models relying on single algorithm always lack interpretability and precision, given the complexity of the mechanisms underlying acute toxicity. To address these issues, this study has developed a predictive framework using an ensemble learning model based on Super-learner. Particularly, we first obtained LD50 data for 9,843 compounds and constructed 16 meta models using 4 molecular descriptors and machine learning algorithms. The Super-learner model performed well, achieving R² values of 0.61 and 0.64 in five-fold cross-validation and test sets, respectively, with corresponding root mean square errors of 0.55 and 0.64, significantly outperforming the results of individual model. Additionally, we incorporated data filtering and applicability domain methods, which demonstrated that the Super-learner can mitigate the impact of dataset noise to some extent. The model achieved an R² of 0.76 within an applicability domain, ensuring prediction accuracy within the chemical space. Compared to previous studies, the model developed here using Super-learner generally achieved better performance across a larger applicability domain. Finally, we has launched an online tool (http://sltox.hhra.net), allowing users to quickly predict LD50 of compounds, greatly simplifying the chemical safety assessment process. This study not only provides an effective and cost-efficient method for predicting chemical toxicity but also offers technical support and data for risk assessments of chemicals.

Long-chain perfluoroalkylether carboxylic acids PFO5DoA and PFO4DA alter glucose, bile acid, and thyroid hormone homeostasis in fetal rats from 5-day maternal oral exposure

Chemical monitoring studies in North Carolina, USA and Shandong, China have reported detections of perfluoroalkylether carboxylic acids of increasing chain length with ether bonds between each fluorinated carbon. Despite detection there is limited hazard data available to inform risk assessment. Here, we exposed pregnant Sprague-Dawley rats to two of these compounds, perfluoro-3,5,7,9-butaoxadecanoic acid (PFO4DA) and perfluoro-3,5,7,9,11-pentaoxadodecanoic acid (PFO5DoA), from gestation days 18-22 across a series of doses (0.3-62.5mg/kg/d) via oral gavage. PFO5DoA was acutely toxic to rat dams and fetuses at the top two doses (30 and 62.5mg/kg), while PFO4DA did not cause acute toxicity at any doses tested. PFO5DoA significantly increased maternal liver weight (≥3mg/kg; 28% increase at 10mg/kg) while PFO4DA did not affect maternal liver weight up to 62.5mg/kg. PFO4DA and PFO5DoA both significantly reduced serum total thyroxine in maternal (≥10mg/kg for both) and fetal (≥1mg/kg) rats. Both compounds significantly reduced fetal liver glycogen concentrations, increased fetal serum total bile acids, and altered expression levels of multiple genes associated with glucose metabolism in the fetal liver. Serum concentrations of PFO5DoA were higher than PFO4DA in both rat dams and fetuses at equivalent maternal oral doses indicating greater accumulation. Dose response modelling of several fetal endpoints as a function of serum molar concentration indicates PFO5DoA was ∼3-4-fold more potent than PFO4DA. PFO5DoA and PFO4DA produced maternal and fetal toxicity from short-term oral maternal exposure indicating need for additional toxicity data to evaluate potential human health risks.

Acute Efavirenz Intoxication in a 16-year-old HIV Negative Girl: A Case Report and Literature Review

Acute Efavirenz Intoxication in a 16-year-old HIV Negative Girl: A Case Report and Literature Review

Inhibition of Staphylococcus epidermidis and Pseudomonas aeruginosa biofilms by grape and rice agroindustrial residues

Agroindustrial wastes are generated daily and seem to be rich in bioactive molecules. Thus, they can potentially be used as source of compounds able to control bacterial biofilms. We investigated the potential of extracts from the residues of rice and grape to combat clinically important bacterial biofilms. Extracts of grape pomace and rice bran were obtained using different extractive methodologies and subjected to the evaluation of its antimicrobial and antibiofilm activities. After the in vivo toxicity, the chemical characterization of the most promising extract was assessed. The mass spectrometry analysis revealed the presence of dipeptides, alkaloids and phenolic compounds. Most grape extracts presented antibiofilm and antimicrobial activities against Staphylococcus epidermidis ATCC 35984 and Pseudomonas aeruginosa PA14. The hydromethanolic grape pomace extract obtained by ultrasound assisted extraction (MeOH 80 UAE) presented the most promising activity, being able to inhibit in 99% and 80% the biofilm formation of S. epidermidis and P. aeruginosa, respectively. Against the gram-negative model, this extract eradicated the biofilm by 80%, induced the swarming motility and displayed a physical effect. It also did not present acute or chronic toxicity in Caenorhabditis elegans model. In this way, agroindustrial residues represent a promising source of molecules capable of controlling bacterial biofilms.

Implementation of Silver Nanoparticles Green Synthesized with Leaf Extract of Coccinia grandis as Antimicrobial Agents Against Head and Neck Infection MDR Pathogens.

Head and neck infections (HNI) associated with multidrug resistance (MDR) offer several health issues on a global scale due to inaccurate diagnosis. This study aimed to identify the bacteria and Candidal isolates and implement the silver nanoparticles green synthesized with leaf extract of Coccinia grandis (Cg-AgNPs) as a therapeutic approach against HNI pathogens. The Cg-AgNPs were characterized by the UV-visible spectrophotometer, FT-IR analysis, Zeta particle size, Zeta potential, and field emission scanning electron microscope (FESEM) analysis to validate the synthesis of nanoparticles. Additionally, the antimicrobial activity of Cg-AgNPs was presented by the zone of inhibition (ZOI), minimum inhibitory concentration (MIC), minimum bactericidal/fungicidal concentration (MBC/MFC), and antibiofilm assay. Moreover, the cell wall rupture assay was visualized on SEM for the morphological study of antimicrobial activities, and the in-vivo toxicity was performed in a swiss mice model to evaluate the impact of Cg-AgNPs on various biological parameters. Different bacterial strains (Staphylococcus aureus, Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa) and Candida sp. (Candida albicans, Candida tropicalis, Candida orthopsilosis, and Candida glabrata) were identified. The MIC, MBC, and antibiofilm potential of Cg-AgNPs were found to be highest against A. baumannii: 1.25 μg/ml, 5 μg/ml, and 85.01±5.19% respectively. However, C. albicans and C. orthopsilosis revealed 23 mm and 21 mm of ZOI. Subsequently, the micromorphology of the cell wall rupture assay confirmed the efficacy of Cg-AgNPs, and no significant alterations were seen in biochemical and hematological parameters on the swiss mice model in both acute and subacute toxicity studies. The green synthesized Cg-AgNPs have multifunctional activities like antibacterial, anticandidal, and antibiofilm activity with no toxicity and can be introduced against the HNI pathogens.

Agro-input dealers' perspectives on the design of a certification scheme for pesticide risk reduction.

While pesticides are essential for crop protection and food security, they pose serious risks to human health and the environment. Agro-input dealers can play an important role in mitigating pesticide risks, given that they are a major source of pesticides and plant health information for many developing-country farmers. In this article, we assess the willingness of agro-input dealers to offer integrated pest management-based advisory services and promote pesticide risk reduction through a voluntary certification scheme. Using survey data from 557 agro-input dealers in Uganda and a discrete choice experiment, we find that the proposed certification scheme is significantly valued by agro-input dealers, particularly for its potential to provide training opportunities and ensure safety to human health and the environment. Agro-input dealers have a positive attitude towards a certification scheme that restricts the sale of high-risk pesticide products, especially if it stimulates additional income-generating opportunities. Further analysis shows that preferences for voluntary certification attributes are influenced by certification experience, agro-dealership experience, business ownership status and incidence of acute pesticide poisoning. The study findings demonstrate that agro-input dealers are conscious of pesticide risks to human and environmental health and are keen to participate in a certification scheme promoting safer plant protection products. © 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

The oral acute toxicity of per- and polyfluoroalkyl compounds (PFASs) to Rat and Mouse: a mechanistic interpretation and prioritization analysis of untested PFASs by QSAR, q-RASAR and interspecies modelling methods

Per- and polyfluoroalkyl substances (PFASs) are widely used in modern industry, causing many adverse effects on both the environment and human health. In this study, for the first time, we followed OECD guidelines to systematically investigated the quantitative structure-activity relationship (QSAR) of the oral acute toxicity of PFASs to Rat and Mouse using simple 2D descriptors. The Read-Across similarity descriptors and 2D descriptors were also combined to develop the quantitative-read across structure activity relationship (q-RASAR) models. Interspecies toxicity (iST) correlation was also explored between the two rodent species. All developed QSAR, q-RASAR and iST models met the state-of-the-art validation criteria and were applied for toxicity predictions of hundreds of untested PFASs in true external sets. Subsequently, we performed the priority ranking of the untested PFASs based on the model predictions, with the mechanistic interpretation of the top 20 most toxic PFASs predicted by both QSAR and q-RASAR models. The two univariate iST models were also used for filling the interspecies toxicity data gap. Overall, the developed QSAR, q-RASAR and iST models can be used as effective tools for predicting the oral acute toxicity of untested PFASs to Rat and Mouse, thus being important for risk assessment of PFASs in ecological environment.

Disposable Face Masks into aquatic media: chemical and biological testing of the released compounds during the leaching process

The present study investigated the fate, and the biological effects posed by the presence of Disposable Face Masks (DFMs) into fresh- and saltwater media, using both chemical and biological testing. To this end, slightly fragmented DFMs were maintained in tanks with artificial sea water (ASW) or dH2O (DFMASW and DFMdH2O, respectively) for a period of 20 days (under continuous agitation, oxygen supply, and light/dark ration 1:1) to simulate both fresh- and saltwater natural conditions. Thereafter, DFMs leaching substances were determined, before proceeding to biological testing with the use of the marine bacterium Aliivibrio fischeri (Bioluminescence Inhibition assay), the fresh- and saltwater algal species Chlorococcum sp. and Tetraselmis suecica (algal bioassays), as well as the fairy shrimp Thamnocephalus platyurus, the water flea Daphnia magna, and the rotifer Brachionus calyciflorus (acute toxicity screening tests, in terms of microbiotest). According to the results, once into aquatic media (DFMASW and DFMdH2O) DFMs are subjected to degradation, leading to the release of organic, inorganic, and polymeric compounds (PP microfibers). Considering that possible interactions of the leaching substances could differentially affect the aquatic biota, the present study showed that DFMs leaching substances could be harmful to the fairy shrimp T. platyurus, and the water flea D. magna, with slight to non-toxic effects to be observed in case of Chlorococcum sp. and Tetraselmis suecica, the marine bacterium Aliivibrio fischeri, and the rotifer B. calyciflorus. The present findings showed that the DFMs improper disposal into fresh- and/or saltwater media, followed by their degradation and leaching processes, could lead to the release of substances of great environmental concern, thus promoting awareness about their proper handling and management, as well as the long-term monitoring of their environmental risk.

Functionalisation of chitosan with methacryloyl and crotonoyl groups as a strategy to enhance its mucoadhesive properties

Mucoadhesive polymers are crucial for prolonging drug retention on mucosal surfaces. This study focuses on synthesising and characterising novel derivatives by reacting chitosan with crotonic and methacrylic anhydrides. The structure of the resulting derivatives was confirmed using proton-nuclear magnetic resonance spectroscopy and Fourier-transform infrared spectroscopy. It was established that the degree of substitution plays a crucial role in the pH-dependent solubility profiles and electrophoretic mobility of the chitosan derivatives. Spray-drying chitosan solutions enabled preparation of microparticles, whose mucoadhesive properties were evaluated using fluorescence flow-through studies and tensile test, demonstrating improved retention on sheep nasal mucosa for modified derivatives. Acute toxicity studies conducted in vivo using planaria and in vitro using MTT assay with the Caco-2 cell line, a model of the mucosal epithelium in vitro, showed that the novel derivatives are not cytotoxic. These findings emphasise the potential of tailored chitosan chemical modifications for enhancing transmucosal drug delivery.

Discovery of a novel KV7.2/7.3 channels agonist for the treatment of neuropathic pain

Here, we designed, synthesized and evaluated a series of compounds as KV7.2/7.3 channels (or KCNQ2/3) agonists. The new compounds were assayed in vitro for KCNQ2/3 and other receptors binding affinity. The desired compound 16 showed high activity for KCNQ2/3 (EC50 = 1.03 ± 0.07 μM) without acute liver injury compared to flupirtine. It demonstrated powerful dose-dependent effects in multiple analgesic models, such as chronic constriction injury (CCI, ED50 = 12.02 mg/kg) and streptozotocin-induced diabetic peripheral neuropathic pain (DPNP, ED50 = 9.63 mg/kg) models. Additionally, compound 16 showed low affinity for human ether-a-go-go-related gene (hERG), high thresholds for acute toxicity, good motor performance in the rotarod test and acceptable pharmacokinetic properties. These results suggest the potentiality of compound 16 for the treatment of neuropathic pain.

Pesticide exposure patterns in honey bees during migratory pollination

Monitoring pesticide exposures in honey bees provides fundamental risk information that informs efforts to improve regulatory policy, pesticide use, and beekeeping management so pollinators are protected in realistic field conditions. We investigated pesticide exposures to bee colonies while colonies moved along commercial migratory routes in 2022 and 2023 to pollinate multiple pollinator-dependent, high-value U.S. specialty crops (e.g., almonds in California and apples and cherries in Washington). We found evident pesticide exposure patterns, including increasing exposures (both levels and number of pesticides) to fungicides during almond pollination, higher exposures to insecticides and persistent exposures to fungicides during springtime fruit pollination, and declining exposures in summer. Exposure risk assessment by risk quotient (RQ) model based on residues in bee bread indicates no concern of acute toxicity to adult honey bees during pollination, however, during colony inspections we found severe brood mortality in fields associated with high exposure to buprofezin, an insect growth regulator (IGR) thought to be safe for adult bees, which is permitted for use any time across the season. Our results suggest a need to improve compliance with insecticide label requirements during tree fruit pollination and a need for further research into the negative impacts of IGR on colony health especially on immature bees to inform potential policy changes.

Assessment of protective effect of Vitamin E supplementation on oxidative damage of diabetic rat spleen induced by Streptozotocin

AimsIncreased oxidative stress in diabetes mellitus may lead to splenic damage, contributing to decreased immunity. This study aims to evaluate the potential of vitamin E supplements as a protective agent against spleen injury by examining physiological, hematological, biochemical, and histological changes in diabetic rat model. MethodsDiabetes was induced in male wistar albino rats through an intraperitoneal injection of 50mg/kg Streptozotocin, and the rats were randomly divided into five groups. The rats were then administered varying doses of vitamin E for 14 consecutive days. Assessments included renal function tests, blood glucose levels, complete blood counts, lipid profiles, tissue oxidative stress and spleen histology. An acute toxicity study was also conducted on normal rats. ResultsVitamin E supplementation did not result in any mortality up to 5000mg/kg body weight. The treated diabetic group showed improved metabolic characteristics, such as normal body weight, food and water intake and a reduced spleen index compared to the untreated diabetic group. Significant improvements were observed in hematological parameters like packed cell volume (PCV), hemoglobin concentration, RBC (red blood cells) and WBC (white blood cells) counts. HCA (Hierarchical Cluster Analysis) of these parameters indicated that doses of 100mg/kg and 150mg/kg were most similar to normal condition. Catalase and MDA (Malondialdehyde) assays showed a substantial reduction in oxidative stress in spleen tissue and histopathological examination revealed significant regenerative effects. ConclusionThis study demonstrated that vitamin E supplementation significantly enhanced various metabolic, hematological, biochemical, and histological parameters in the diabetic group compared to those who did not receive the treatment. Among the doses tested, 100mg/kg and 150mg/kg body weight were found to yield the most favorable outcomes.

Holistic characterization analysis of tar waste content from gasification process at Surakarta landfill

Surakarta is facing serious problems related to waste management at the Putri Cempo landfill. PT. Solo Citra Metro Plasma Power with the Surakarta city government built a waste power plant installation with gasification technology. Tar waste is a gasification liquid product that is dangerous if not managed. This study aimed to determine the heavy metal content and toxicity level of gasified tar waste using the atomic absorption spectrometry (AAS) and lethal dose-50 (LD<sub>50</sub>) acute toxicity test. The parameters of heavy metals tested are lead (Pb), copper (Cu), iron (Fe), zinc (Zn), and total chromium (Cr). In the LD<sub>50</sub> test, the animals were divided into 5 groups, namely 1 control group and 4 groups with doses of 0.50 mL, 1 mL, 2 mL, and 4 mL. The results showed that the tar contained 17.4 mg/L of iron, 3.5 mg/L of zinc, and <0.01 mg/L of lead, copper, and chromium. Acute toxicity tests did not cause death in the animals but still showed toxic symptoms, so the LD<sub>50</sub> value is declared pseudo. The content of some heavy metals in tar is within safe limits and the level of toxicity is relatively harmless.

Cleistopholis patens root bark extract exerts cardioprotective effect against doxorubicin-induced myocardial toxicity in rats

Abstract Background Myocardial Infarction still persists as the most prevalent cardiovascular disease and is a top cause of morbidity and mortality in doxorubicin treated cancer patients. This study evaluated the prophylactic effect of the ethanol root bark extract of Cleistopholis patens (ERBECP) against doxorubicin-induced myocardial infarction in wistar rats. Extraction, preliminary phytochemical analysis, acute toxicity study and body weight (b.w.) of ERBECP were achieved using standard methods. Phyto-constituents in ERBECP were indentified using Gas Chromatography-Mass Spectrometry (GC–MS) technique. Thirty (30) male albino Wistar rats of average b.w. ranging between 100 and 130 g were divided into six groups of five rats each. Groups I, II and III served as normal, doxorubicin (DOX) and standard (Vasoprin 150 mg/kg b.w) controls respectively, while groups IV, V and VI were orally pre-treated with the extract (200, 400 and 600 mg/kgb.w) for two weeks prior to intraperitoneal induction of cardiotoxicity with DOX (20 mg/kg bw) on day 14. Results Disturbances in serum cardiac function bio-markers such as; Cardiac Troponin-I (CTnI), Creatine Kinase (CK), Lactate Dehydrogenase (LDH), Aspartate aminotransferase (AST), Alanine aminotransferase (ALT). Lipid profile markers such as; Total cholesterol (TC), Triacylglycerol (TAG), Low Density Lipoprotein (LDL), High Density Lipoprotein (HDL). Oxidative stress markers such as; Malondialdehyde (MDA), Superoxide Dismutase (SOD), Catalase (CAT), Glutathione (GSH) confirmed the induction of myocardial infarction. Histological assessment of heart tissues was performed to validate biochemical results. The GC–MS analysis of ERBECP identified a total of 69 compounds. Safety profile of the aqueous extract was safe for the animals up to the highest dose of 5000 mg/kg b.w. Pre-treatment of DOX group with ERBECP could significantly increase the b.w. compared to the DOX-treated group during the experimental period of 2 weeks. There were significant (p < 0.05) alterations in the levels of CTnI, CK, LDH, AST, ALT and lipid profile indices in the DOX control rats. Also, significant (p < 0.05) increase was observed in MDA and decrease in SOD, CAT and GSH in the DOX control rats. However, administration of the extract significantly (p < 0.05) normalized these alterations and reversed the architectural changes in the heart. The 69 compounds were screened against the target protein (CBR1); we identified seven hits based on the docking score and interactions with the active site residues. All the C. patens constituents had MW (g/mol) less than 500, HBA < 10 and HBD not more than 5. Apart, 9-Octadecenoic acid (Z)-, 2,3-dihydroxy propyl ester and Estra-1,3,5(10)-trien-17. beta. -ol, all the constituents had LD50 lower than 2000 mg/kg. Conclusions The findings reveals ERBECP demonstrated promising potential and can be exploited in the development novel cardiac therapeutic agents.

Clinical Pharmacology of Cytokine Release Syndrome with T-cell Engaging Bispecific Antibodies: Current Insights and Drug Development Strategies

Abstract Cytokine release syndrome (CRS) is a common acute toxicity in T-cell therapies, including T-cell engaging bispecific antibodies (T-BiSp). Effective CRS management and prevention is crucial in T-BiSp development. Required hospitalization for 7 of the 9 approved T-BiSp and the need for clinical intervention in severe cases highlight the importance of mitigation strategies to reduce healthcare burden and improve patient outcome. In this review, we discuss the emerging evidence on CRS mitigation, management, and prediction. We cover different strategies for dose optimization, current and emerging (pre)treatment strategies, quantitative pharmacology tools employed during drug development, and biomarkers and predictive factors. Insights are gleaned on step-up dosing and formulation effects on CRS and CRS relationships with cytokine dynamics and drug levels gathered through review of T-BiSp licensing applications and emerging data from conferences and publications.