Clinical Symptoms Of Toxicity Research Articles

Acute toxicity assessment of bioactive constituents from Salvia algeriensis (Desf.) extracts: a promising natural agent against clinical bacterial isolates and pathogenic fungi

Salvia species are emerging as promising therapeutic agents due to their diverse bioactivity against various pathologies. This study was conducted to investigate the phytochemical profile, antimicrobial activity, and acute Toxicity of hydromethanolic extracts from Salvia algeriensis (Desf.) leaves, flowers, and roots. Chemical reaction tests and chromatographic analysis were employed to determine the chemical composition, while microdilution was used to determine the tested microorganisms' minimum inhibitory concentration (MIC). The acute Toxicity of the leaf extract was carried out following the rules and guidelines of OECD 425. Toxicity parameters in Swiss albino mice were evaluated after a single dose of 500 mg/kg and 2000 mg/kg. According to the preliminary phytochemical screening results, terpenoids and polyphenols (flavonoids and tannins) were found in all plant parts, but coumarins were only found in the root extract. The HPLC-DAD analysis revealed the presence of 16 phenolic compounds in varying amounts across the three extracts, of which rosmarinic acid, quercetin, caffeic acid, and 3-hydroxybenzoic acid were the most abundant. Selective antimicrobial activity was noticed, with the root extract demonstrating the most substantial effect against the two fungal strains tested. MIC values ranged from 0.3 to 10 mg/mL, and Gram-positive bacteria generally showedgreater susceptibility compared to Gram-negative bacteria. The LD50 was found to be greater than 2000 mg/kg. There were no overt clinical symptoms of Toxicity. Body weights, organ weights, and temperatures were not significantly altered, and hematological analysis showed no significant differences. Salvia algeriensis (Desf.) extracts emerge as potential candidates for natural, non-toxic antimicrobial agents. Keywords: Acute Toxicity; antimicrobial; HPLC-DAD; polyphenols; Salvia

Isolation, In-silico Studies, and Biological Evaluation of Higenamine from Annona squamosa L. against Breast Cancer

The efficacy of Annona squamosa L. in cancer treatment has been documented, inspiring the authors to investigate the plant further for potential novel anticancer compounds. Therefore, the current study aimed to isolate and characterize Higenamine from leaves extract of A. squamosa L. and studied for the in-vitro cancer cell line and molecular docking. The high performance liquid chromatography (HPLC) and thin layer chromatography (TLC) method development of A. squamosa L. leaves extract furnished Higenamine of which characterization was established by HPLC, infrared radiation (IR), liquid chromatography-mass spectrometry (LC-MS) and its acute toxicity study and cytotoxic properties using MCF-7 cell lines by MTT assay were assessed. Molecular docking was done using Auto Dock Vina software to validate the anticancer activity. The extraction batches by ultrasonication and maceration methods showed good results using 80% methanol. Acute toxicity studies, after a single dose (2000 mg/kg) administration of methanolic extract don’t show clinical symptoms of toxicity and mortalities. From the extract, Higenamine was eluted and the dried fraction showed 66% of enrichment of Higenamine. The developed HPLC and TLC methods showed Higenamine (HGN) peak at 6.21 minutes band at Rf 0.61, respectively. The isolated compound was identified as Higenamine with FTIR spectroscopic analysis which revealed various characteristic band values with functional groups. HPLC-MS showed m/z at 272.1 (M+H+) corresponding to the molecular formula C16H17NO3. The IC50 value for Higenamine was 42.39 μg/mL were observed in MCF-7 breast cancer which was better than 5-Fluorouracil having 39.22 μg/mL. In-silico studies explored that higenamine showed good binding affinity to breast cancer PDBIDs and forms a stable complex. Furthermore, absorption, distribution, metabolism, and excretion (ADME) properties of isolated compound was calculated using the Swiss ADME online tool in which higenamine was found to have a good pharmacokinetic profile as compared with 5-fluorouracil and doxorubicin. Higenamine has been isolated and identified as a potential anticancer agent. Further research can explore its effectiveness through pharmaceutical formulation and in vitro cell line studies.

Herbal formulation: Constac plus granules for severe constipation; an acute oral toxicity study

The main aim of this study was to evaluate the acute oral toxicity of Constac® Plus granules. Twelve rats were randomized into four groups of three at random. Groups 2 and 3 received doses of 2000 mg/kg body weight of Constac Plus granules, while group 4 received doses of 5000 mg/kg body weight of Constac Plus granules. Group 1 served as the control and merely received distilled water. For 14 days, the rats were closely monitored for any indications of toxicity. At the end of the study, all rats underwent necropsy and gross pathology was noted. The results demonstrated that during the 14-day observation period, none of the rats in the control or treatment groups showed any clinical symptoms of toxicity or mortality. It was determined that the LD50 value was more than 5000 mg/kg body weight. The acute oral toxicity study of Constac Plus granules in wistar rats concluded that there was no toxicity at dosages up to 5000 mg/kg body weight. These results proved that the usage of Constac Plus granules administered orally is safe.

Acute and Repeated Dose 28-Day Oral Toxicity Studies of Phlorotannin Rich Fraction of <i>Sargassum tenerrimum</i>, A Marine Brown Algae

Sargassum tenerrimum is a marine brown algae rich in phlorotannins, a class of marine polyphenols with significant biological activities. The present study aimed to prepare a phlorotannin-rich fraction from S. tenerrimum (PST) and evaluate its acute and subacute oral toxicity in Wistar albino rats according to the procedures and methods of the OECD test guidelines for acute and repeated dose 28-day oral toxicity studies. S. tenerrimum powder was extracted with ethanol and further fractionated with ethylacetate, 1-butanol, and water. The ethyl acetate fraction was found to have the highest total phlorotannin concentration and was evaluated for its safety. In the acute oral toxicity study, a single dose of PST at 2000 mg/kg body weight did not result in any treatment-related clinical symptoms of toxicity or mortality. Therefore, the median lethal dose (LD50) of PST was identified as greater than 2000 mg/kg. The subacute oral toxicity investigation at 200, 400, and 800 mg/kg doses administered for 28 days with a 14-day recovery period revealed no treatment-related adverse clinical symptoms or mortality/morbidity. The treated animals exhibited normal weight gain, feed intake and did not result in clinically significant toxicity as measured by clinical blood chemistry and hematological markers. Gross and histological examinations of selected tissues did not reveal any notable adverse alterations associated with the intervention. Under the study's findings, the LD50 for PST was determined to be >2000 mg/kg b.wt. and No Observed Adverse Effect Level (NOAEL) to be 800 mg/kg rat b.wt.

Acute and subchronic toxicity of multicomponent antiparasitic drugs Insaсar Total C Plus, Insaсar Total K Plus

The purpose of the research is to study acute oral toxicity in mice, and acute dermal and subchronic toxicity in rats of multicomponent antiparasitic Insacar Total C Plus (for dogs) and Insacar Total K Plus (for cats).Materials and methods. The toxicity of the drugs was studied in September-April 2020–2021 at the premises of the VNIIP – FSC VIEV Vivarium. To determine acute oral toxicity, 80 outbred mice weighing 20 g were used, of which 7 test and one control group were formed. The drugs were administered once in a 1 : 3 dilution with polyethylene glycol as a solution through an intragastric tube and an automatic controller. The control animals were intact. After a single administration, the physical condition of the test mice was monitored within 14 days; weight gain, expected clinical toxicity symptoms and possible death were assessed. Before and on days 1, 3, 7, 11 and 14 of the experiment, the test and control mice’s weight gain were evaluated. The toxicity parameters were calculated by the methods of Pershin, Miller and Taintner. In a subchronic experiment, the study drugs were tested on 80 outbred white rats divided into 6 test and 2 control groups. The rats’ coat was also shaved on the back. The solution was applied to the shaved skin area once a day for 7 days at doses of 1,000 mg/kg (0.1 mL/100 g), 500 mg/kg (0.05 mL/100 g) and 200 mg/kg (0.02 mL/100 g) of the animal weight. On day 8 of the experiment, 5 rats from each group were euthanized; their blood samples were taken, and the internal organs were examined. On day 21 of the experiment, the second part of the animals was euthanized to analyze the reversibility of potential pathoanatomical changes after prolonged repeated application of the drug. The results were processed statistically.Results and discussion.The half-lethal dose (LD 50) after oral administration of the drug for dogs to the mice was 2,475 by the Pershin method, and 2,500±388 mg/kg by the Miller and Taintner method. LD50 of the drug for cats when administered into the mice’s stomach was 2,713 by the Pershin method, and 2,650±403 mg/kg by the Miller and Taintner method (hazard class 3). LD 50 when applied to the rats’ skin was more than 10,000 mg/kg (hazard class 4). When applied once to the rats’ skin, the drugs had a slightly irritating effect. In subchronic experiment on the rats with daily drug application on their skin at doses of 1,000 mg/kg, 500 and 200 mg/kg, no negative effects on the general condition or death of the animals were observed during the entire study. Hematological and biochemical parameters of the test rats that were treated with the drug for dogs at a dose of 200 mg/kg, an increased content of lymphocytes up to 83.40% was observed on day 8 of the experiment, and up to 74.20 % in the control; and an increased glucose level up to 6.08±1.23 mmol/L, and up to 4.82±0.70 mmol/L in the control; LDH was up to 766.00±264.19 U/L, and up to 434.80±525.89 U/L in the control.

Updates in Digoxin Toxicity and Outcome of Management: A Review

Cardiac glycosides, including digitalis and digoxin, have long-standing use in clinical practice. Digoxin has a half-life that varies from 36 to 48 hours, which may increase in cases of renal failure. Approximately 1% of Congestive Heart Failure patients treated with digoxin develop toxicity. The clinical features of toxicity are often non-specific. Diagnosis is difficult and usually made clinically, as levels of digoxin in the blood do not necessarily correlate with toxicity. Treatment involves early recognition and the administration of antibodies specifically against digoxin also known as Fab fragments. Digoxin concentration does not necessarily correlate with clinical symptoms of toxicity however digoxin concentrations may be used for calculating the amount of antidote therapy. Digoxin-specific antibody fragments are used when there is a risk of a life-threatening arrhythmia.

Transcriptome, Spliceosome and Editome Expression Patterns of the Porcine Endometrium in Response to a Single Subclinical Dose of Salmonella Enteritidis Lipopolysaccharide.

Endometrial infections at a young age can lead to fertility issues in adulthood. Bacterial endotoxins, such as lipopolysaccharide (LPS), can participate in long-term molecular changes even at low concentrations. Lipopolysaccharide plays a crucial role in the progression of septic shock, inflammation and auto-immune diseases. The aim of this study was to describe transcriptomic modulations in the porcine endometrium, induced in vivo by a single subclinical dose of LPS from Salmonella Enteritidis. which did not produce clinical symptoms of toxicity. The RNA-seq methodology was applied to reveal 456 differentially expressed regions, including 375 genes, four long noncoding RNAs, and 77 other unclassified transcripts. Two independent methods confirmed 118 alternatively spliced genes that participate i.a., in the formation of the MHC-I complex and the adaptive immune response. Single nucleotide variant-calling algorithms supported the identification of 3730 allele-specific expression variants and 57 canonical A-to-I RNA editing sites. The results demonstrated that the differential expression of genes involved in inflammation, immune response, angiogenesis and endometrial development may be maintained for up to 7 days after exposure to LPS. RNA editing sites and long noncoding RNAs (lncRNAs) play an important role in transcriptional regulatory machinery in the porcine endometrium in response to LPS administration.

Acute and Subchronic Toxicity Study of the Ethanol Extracts from Ficus deltoidea Leaves in Male Mice

BACKGROUND: Ficus deltoidea Jack. leaves have a great potential as traditional medicine, but the safety level of its use is still unknown.
 AIM: This study aimed to determine the phytochemical contents of the ethanol extract of F. deltoidea leaves and evaluate the level of safety and toxicity through acute and subchronic toxicity tests in mice (Mus musculus).
 METHODS: The ethanol extract of F. deltoidea leaves was determined for phytochemical contents such as alkaloids, phenolics, flavonoids, coumarin, steroids, saponins, carotenoids, and tannins. In the acute toxicity test, 10 male mice were divided into a control group and the extract treatment group with 2000 mg/kg body weight (BW) dose for 14 days to identify signs of toxicity and mortality. Meanwhile, in the subchronic toxicity test, 25 male mice were divided into control and four treatment groups with various doses (125, 250, 500, and 1000 mg/kg BW), respectively, for 28 days. The toxicological effect was evaluated by observing behavior, signs of toxicity, and changes in BW. At the end of the treatment, hematological and biochemical evaluations were also measured.
 RESULTS: The results showed that the ethanol extract of F. deltoidea Jack leaves qualitatively contains alkaloids, phenolic, flavonoids, coumarin, and steroids, whereas quantitatively total phenolics, flavonoids, and IC50 were 107.6583211 μg GA/mg, 175.9103641 μg CE/mg, and 103.7484 μg/mL. Moreover, 2000 mg/kg BW dose resulted in no symptoms of toxicity and mortality, indicating that the 50% lethal dose (LD50) was above 2000 mg/kg BW. Meanwhile, there were no behavioral changes, significant differences in weight changes, hematological parameters, and serum biochemistry of mice in subchronic toxicity tests.
 CONCLUSION: The present study shows that acute and subchronic oral administration of the ethanol extract of F. deltoidea leaves for male mice does not induce clinical symptoms of toxicity or mortality. The LD50 of the ethanol extract of F. deltoidea leaves for mice >2000 mg/kg is considered as practically non-toxic.

Enhancement of solubility and bioavailability of ambrisentan by solid dispersion using Daucus carota as a drug carrier: formulation, characterization, in vitro, and in vivo study

Ambrisentan is an US FDA approved drug, it is the second oral endothelin A receptor antagonist known for the treatment of pulmonary arterial hypertension, but its oral administration is limited due to its poor water solubility. Hence, the objective of the investigation was focused on enhancement of solubility and bioavailability of ambrisentan by solid dispersion technique using natural Daucus carota extract as drug carrier. Drug carrier was evaluated for solubility, swelling index, viscosity, angle of repose, hydration capacity, and acute toxicity test (LD50). Ambrisentan was studied for the saturation solubility, phase solubility, and Gibbs free energy change. Compatibility of drug and the natural carrier was confirmed by DSC, FTIR, and XRD. Solid dispersions were evaluated for drug content, solubility, morphology, in vitro, and in vivo study. Screening of the natural carrier showed the desirable properties like water solubility, less swelling index, less viscosity, and acute toxicity study revealed no any clinical symptoms of toxicity. Drug and carrier interaction study confirmed the compatibility to consider its use in the formulation. Formed particles were found to be spherical with smooth surface. In vitro studies revealed higher drug release from the solid dispersion than that of the physical mixture. Bioavailability study confirms the increased absorption and bioavailability by oral administration of solid dispersion. Hence, it can be concluded that the natural Daucus carota extract can be the better alternative source for the preparation of solid dispersion and/or other dosage forms for improving solubility and bioavailability.

Potential Lipid-Lowering Effects of Eleusine indica (L) Gaertn. Extract on High-Fat-Diet-Induced Hyperlipidemic Rats.

Background:To date, anti-obesity agents based on natural products are tested for their potential using lipase inhibition assay through the interference of hydrolysis of fat by lipase resulting in reduced fat absorption without altering the central mechanisms. Previous screening study had indicated strong anti-obesity potential in Eleusine indica (E. indica), but to date, no pharmacologic studies have been reported so far.Objective:This study was performed to investigate the lipid-lowering effects of E. indica using both in vitro and in vivo models.Methods:The crude methanolic extract of E. indica was fractionated using hexane (H-Ei), dichloromethane (DCM-Ei), ethyl acetate (EA-Ei), butanol (B-Ei), and water (W-Ei). All the extracts were tested for antilipase activity using porcine pancreatic lipase. Because H-Ei showed the highest inhibition, it was further subjected to chemical profiling using high-performance liquid chromatography. Subsequently, oral toxicity analysis of H-Ei was performed [Organization for Economic Cooperation and Development guidelines using fixed dose procedure (No. 420)]; efficacy analysis was performed using high-fat diet (HFD)-induced hyperlipidemic female Sprague–Dawley rats.Results:According to the toxicity and efficacy analyses, H-Ei did not demonstrate any noticeable biochemical toxicity or physiologic abnormalities and did not cause any tissue damage as per histologic analysis. Furthermore, H-Ei significantly reduced body weight and improved serum profile and did not show hepatotoxicity and nephrotoxicity based on the serum profile. Moreover, H-Ei alleviated HFD-induced hepatosteatosis and ameliorated induced adiposity in both visceral and subcutaneous adipose tissue.Conclusion:Our results demonstrate that H-Ei effectively improved hyperlipidemia. Further studies to explore its possibility as an alternative pharmacologic agent to treat obesity are warranted.SUMMARY Hexane extract of Eleusine indica (H-Ei) showed strong potential in the inhibition of porcine pancreatic lipase (27.01 ± 5.68%).The acute oral toxicity of E. indica hexane extract on animal model falls into Globally Harmonized System Category 5 (low hazard), since mortality, clinical toxicity symptoms, gross pathologic, or histopathologic damage was not observed.The hexane extract of E. indica had significantly reduced the body weight and improved serum lipid profile, with reduction in serum triglycerides, total cholesterol, low-density lipoprotein, and elevation in high-density lipoprotein when comparing against the high-fat diet control group.Microscopic evaluation on histologic slides of liver and adipose tissues suggested that E. indica hexane extract had greatly improved liver steatosis and adipose tissue hypertrophy in high-fat diet control group. Abbreviation used: ALT: Alanine transaminase; AST: Aspartate transaminase; B-Ei: Butanol extract of E. indica; DCM-Ei: Dichloromethane extract of E. indica; EA-Ei: Ethyl acetate extract of E. indica; GHS: Globally Harmonized System; HDL: High-density lipoprotein; H-Ei: Hexane extract of E. indica; HFD: High-fat diet; HPLC: High-performance liquid chromatography; LDL: Low-density lipoprotein; NFD: Normal fed diet; PPL: Porcine pancreatic lipase; SEM: Standard error of mean; SD: Standard deviation; TC: Total cholesterol; TG: Triglycerides; W-Ei: Water extract of E. indica.

LBPS 01-04 SUB CHRONIC TOXICITY EVALUATION OF POLYSACCHARIDE PEPTIDE GANODERMA LUCIDUM IN AORTA

Objective: Atherosclerosis as bakbone of Cardiovascular disease have increase burdenly in world wide. Dyslipidemia, oxidative process and inflammation either free radical were cornerstone to advancing atherosclerotic process. Ganoderma Lucidum has acceptance and widely use since 2000 years ago in asia. Polysaccharide peptide Ganoderma Lucidum have numerous effect as anti inflammation, anti oxidant, anti lipidemia, and anti diabetic. The aim for this study is to determined and examined sub chronic toxicity of Polysaccharide peptide administration in aorta rattus novergicus strain wistar. Design and Method: This study design as animal experimental study with control in 4 group of rattus novergicus strain wistar both male and female rats and give Polysaccharide peptide with dose of 0, 300, 600 and 1200 mg/kg once daily for 90 days. Parameter measured were clinical symptoms of toxicity, evaluation of histopathological structure and blood chemistry with descriptive statistic with t-test and non parametric with ANOVA One way with p < 0.05 was significant. Furthermore Tuckey test is used to determine between 2 groups. Results: Polysaccharide Peptide Ganoderma Lucidum affect in physical obervation clinical symptoms of toxixity and gross organ were no significant toxicity symptoms and from gross examination found that condition of aortic organ remain unchanged and from organ pathology found no change in histopathological aortic organ even after a dose of 1200 mg/kg. Conclusions: Polysaccharide peptide ganoderma lucidum has negatve toxicity in sub chronic test and there are not found any changes in morphology of both group. Polysaccharide peptide has good safety profile to next use in human trial.

Abstract 2095: Toxicity of selective allosteric FGFR2 inhibition in preclinical studies

Abstract Alofanib (RPT835, Ruspharmtech LLC) is a novel selective allosteric inhibitor binding to the extracellular domain of FGFR2. Alofanib had no direct effect on activation of FGFR1 and FGFR3 in vitro. Selective effect of the compound may reduce toxicity compared to multi-targeted VEGFR/FGFR or pan-FGFR inhibitors. This study characterizes the organ toxicity of alofanib in Sprague-Dawley rats and Chinchilla rabbits, and the reversibility of any treatment-induced effects. 240 rats and 30 rabbits received alofanib (0-40.5 and 0-21.6 mg/kg/day, respectively) intravenously on a consecutive daily dosing schedule for thirteen weeks. Clinical observations and laboratory parameters were recorded. Necropsy was conducted following treatment/recovery periods, and histologic examinations were performed. There was no treatment-related mortality, severe toxicity and significant changes in organs in the thirteen-week study. Alofanib was well-tolerated in vivo. Clinical signs of first injection (8.1 mg/kg) included moderate local irritative reaction and decreased activity during hour in rats. Clinical symptoms of toxicity were not observed over study. Animals were active. Body weight remained stable and it was comparable to vehicle groups. Abnormal electrocardiogram findings and blood pressure changes were not detected. It was notable that in the study, none of the hematologic changes was present at the end of the recovery period. Minimal significant decrease in ALT/AST, slight increase in alkaline phosphatase in male rats and mild increase in urea, decrease in chlorine in female rats were found throughout treatment period. Minimal significant decrease in albumin and chlorine was identified in rabbits. Rate of hyperphosphatemia, an on-target side-effect of pan-FGFR inhibitors, will be presented at the AACR Meeting. We conclude that toxicity of alofanib was mild in the thirteen-week study. Slight decrease of chlorine in blood was most common side effect. The final conclusion will be made after six-month study. This study was supported by a grant from the Skolkovo Foundation. Citation Format: Nataliya V. Lapina, Marina V. Melikhova, Olga A. Vakunenkova, Vadim A. Kashuro. Toxicity of selective allosteric FGFR2 inhibition in preclinical studies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2095.

Abstract 17521: Safety and Efficacy of Centhaquin as a Novel Resuscitative Agent for Hypovolemic Shock

Centhaquin (PMZ-2010) is a cardiovascular active agent (0.01 to 0.05 mg/kg) which has been shown to have resuscitative effect in a (1) rat model of fixed pressure blood loss, (2) rabbit model of uncontrolled bleeding with trauma, and (3) pig model of massive blood loss. PMZ-2010 produced a decrease in heart rate and vascular resistance; however, it increased mean arterial pressure by increasing cardiac output. We embarked on studies to develop PMZ-2010 as a resuscitative agent for hypovolemic shock. Toxicological studies were carried out and intravenous injection of PMZ-2010 in mice, rats and rabbits showed LD50 &gt;100 mg/kg, 79.43 mg/kg and 9.55 mg/kg, respectively. The No Observed Adverse Effect Level (N.O.A.E.L.) of PMZ-2010 determined after repeated (28 days) intravenous injections of different doses in mice, rats and rabbits was found to be 1.0 mg/kg. A 14 day repeated dose toxicity study of PMZ-2010 (0.01, 0.10 and 1.0 mg/kg, iv) in canine model (beagle dog) was conducted and there were no clinical symptoms of toxicity in low and middle whereas in high dose (1.0 mg/kg) temporary sluggishness, shivering and salivation was observed, while biochemical profile was normal in all groups. We conducted a single center randomized, double-blind, placebo-controlled, single and multiple-ascending dose phase I study in healthy male subjects to evaluate the safety of PMZ-2010 (NCT02408731). The study population comprised 6 cohorts of 4 subjects each, which were randomized so that 3 subjects received the active drug and 1 subject received placebo. For single ascending dose cohorts, the initial dose of PMZ-2010 was 0.005 mg/kg, iv infusion. Based on the safety and tolerability of the administered dose, subsequent escalation of doses 0.01, 0.05 0.10 and 0.15 mg/kg was performed and maximum tolerated dose (MTD) was found to be 0.10 mg/kg. For multiple-ascending dose cohorts, the initial dose/day of PMZ-2010 was equal to maximum tolerated dose (MTD) 0.10 mg/kg (3 X 0.033 mg/kg/day) for 2 days. Subsequent escalation of dose was done up to 2 times MTD 0.20 mg/kg (3 X 0.067 mg/kg/day) for 2 days. It is concluded that MTD of PMZ-2010 in humans is 0.10 mg/kg and can be safely used for its resuscitative effect. (Mr. Tajuddin and Dr. D. Chilkoti are acknowledged for assisting in clinical studies).

Clinical and biochemical analysis of acute paint thinner intoxication in adults: a retrospective descriptive study

Context: Paint thinner contains a mixture of various aromatic hydrocarbons. A few studies have reported biochemical abnormalities and clinical symptoms of paint thinner intoxication among adult patients.Objective: We aimed to design a retrospective descriptive study to evaluate clinical and laboratory biochemistry abnormalities due to paint thinner intoxication among adult patients.Methods: Data were obtained by using questionnaires from paint thinner-intoxicated patients recruited at the Loghman-Hakim General Teaching Hospital Poison Center.Results: Clinical and paraclinical data from a total of 37 patients, 24 males (64.86%) and 13 females (35.14%) with the mean age of 34.35 ± 14.15 years and mode of 22 years, was obtained and analyzed. Patients’ ages ranged between 15 and 70 years. The estimated mean consumed dose was 246.70 ± 390.72 ml with a mode of 60 ml (range of 1–1500 ml). Nausea, vomiting, asthma, sore throat, stomach ache, drowsiness, dizziness, agitation, cough and diarrhea were the most frequent clinical features, respectively. Reported tissue damage biomarkers were alkaline phosphatase (ALP, 233.84 ± 122.06) and lactate dehydrogenase enzymes (LDH, 749.33 ± 471.03 IU/l). They reflected development of liver and pulmonary toxicities. Arterial blood gas (ABG) showed acidosis without hypoxia in adult paint thinner-intoxicated patients.Discussion and conclusion: Focusing on biochemical abnormalities and clinical toxicity symptoms is essential for screening organs in paint thinner toxicity. In addition, they provide good information for physicians/clinical toxicologists to perform appropriate conservative treatments in adult paint thinner-intoxicated patients.

Effects of Angiotensin-Converting Enzyme Inhibitor Derived from Tropaeolum majus L. in Rat Preimplantation Embryos: Evidence for the Dehydroepiandrosterone and Estradiol Role.

Although several studies have shown the inhibitory effects of Tropaeolum majus extracts (HETM) on angiotensin-converting enzyme (ACE) activity, no studies have been carried out during the beginning of pregnancy, when humoral and hormonal imbalance may affect zygote and early embryo transport. This study investigates whether HETM can affect embryonic development when administered during the one-cell-blastocyst period. Pregnant Wistar rats received orally the HETM (3, 30, and 300 mg/kg/day) from the 1st to the 7th gestational day. Rats were killed on the 8th day of pregnancy and the following parameters were evaluated: clinical symptoms of toxicity (including organ weights), number of corpora lutea, implants per group, preimplantation losses ratio, and the serum levels of dehydroepiandrosterone (DHEA), estradiol, and progesterone. No clinical symptoms of maternal toxicity were evidenced. On the 8th day of pregnancy, the levels of DHEA and estradiol were increased and significant preimplantation losses were observed at all doses used. The present study reveals that the HETM can raise levels of DHEA and estradiol and induce difficulty in the embryo implantation in the early stages of pregnancy. The data contributes significantly to the safety aspects of using this natural product when trying to get pregnant or during pregnancy.

On-target off-tumor toxicity; when enhancing an NKG2D-based CAR in vitro led to severe toxicities in vivo

Engineering T cells with chimeric antigen receptors (CARs) has emerged as a promising approach to adoptive T cell therapy for cancer. We have been studying CARs that employ the ligand-binding domain of the NKG2D receptor to target tumors. NKG2D ligand expression is increased on the surface of stressed cells, like tumor cells, making this family of ligands a target of interest for cancer immunotherapies. Two CARs were constructed: 1) a fusion of the full-length NKG2D receptor and CD3z (NKG2Dζ) and 2) the extracellular domain of NKG2D fused to a second-generation CAR scaffold composed of transmembrane and intracellular domains from CD28 and the signaling domain of CD3z (NKG2D28ζ). Since surface expression of NKG2D is limited by the presence of DAP10, we also created a vector where DAP10 was co-expressed with NKG2Dζ (NKG2Dζ10). Indeed, NKG2Dζ10-CAR-T cells displayed a greater than 10-fold increase in CAR expression compared to NKG2Dζ; NKG2D28ζ showed an intermediate level of expression. T cells expressing any of the NKG2D CARs produced IFNg and TNFa in response to NKG2D ligand stimulation and efficiently killed tumor targets in vitro. However, following infusion into syngeneic hosts, we observed significant toxicity in vivo with these CAR constructs. Signs of toxicity, including poor body condition, hunched posture, labored breathing, and decreased core body temperature were observed in tumor-bearing and tumor-free mice treated with NKG2D-based CAR-T cells as compared to control mice. The severity of NKG2D CAR-T cell toxicity varied, with NKG2Dζ10 being severely toxic, NKG2D28ζ showing intermediate toxicity, and NKG2Dζ being tolerable. Clinical symptoms of toxicity and mortality rates were exacerbated when mice received chemotherapy prior to adoptive transfer of T cells expressing any of the NKG2D CARs. These observations were consistent between BALB/c and C57BL/6 hosts. Further characterization revealed that the toxicity coincided with a systemic cytokine storm and lethal levels of inflammation within the lungs. These data warn that extreme caution should be taken when using NKG2D ligands for targeted immunotherapy and demonstrate that enhancing T cell expression of strongly activating CARs can be detrimental in vivo when the CAR target is not uniquely expressed on the tumor. This research was supported by the CIHR and the TFRI.

High Efficacy in Hyperthermia-associated with Polyphosphate Magnetic Nanoparticles for Oral Cancer Treatment

Nanotherapy applied to cancer treatment is constantly evolving, and new approaches to current techniques, such as magnetohyperthermia, are being implemented to solve and minimize the limitations of conventional therapeutic strategies. The purpose of this study was to investigate the action of polyphosphate-coated maghemite nanoparticles (MNPs) on oral squamous cell carcinoma. Human oral cancer cells (UM-SCC14A) were incubated with MNPs at various concentrations and subjected to cell proliferation tests (MTT), apoptosis assays and transmission electron image analysis. Viability and apoptotic events were time and dose dependent. These in vitro tests showed that at the intermediate concentration tested there is no significant toxicity, as confirmed by transmission electron microscopy. For this reason this MNPs concentration was chosen for the subsequent in vivo tests. Oral tumor induction was performed by applying the carcinogen DMBA to Syrian hamsters. Animals were then treated by magnetohyperthermia using MNPs. No signs of general clinical symptoms of toxicity or abnormal behavioral reactions were observed. However, animals treated with MNPs and exposed to the alternating magnetic field in the hyperthermia procedure exhibited a significant and time dependent cancer regression, as confirmed by histopathological analyses and immunohistochemistry. Actually, in quantitative terms of the magnetotherapy efficacy involving these polyphosphate-coated MNPs, 100% recovery (12/12) was observed in the oral cancer tumor bearing Syrian hamsters seven days after the treatment with the magnetohyperthermia procedure. Data supports the suggestion that the MNPs-mediated hyperthermia represents a promising strategy for the treatment of oral cancer.

Gastrointestinal and Hepatotoxicity Assessment of an Anticancer Extract from Muricid Molluscs

Marine molluscs from the family Muricidae are under development as a potential medicinal food for the prevention of colon cancer and treatment of gynaecological cancers. Here we report the outcome of the first in vivo toxicity assessment on an anticancer extract from a muricid mollusc containing brominated indole derivatives. Mice received the concentrated lipophilic extract by daily oral gavage over a two-week period. Mortality or clinical toxicity symptoms resulting from the extract were not detected during the trial, and there was no difference in the body weight of treated and control mice at the end of the trial. Histological analysis revealed some evidence for mild, idiosyncratic effects on the gastrointestinal tract and liver, including necrosis, fatty change, and inflammation in a small proportion (<40%) of mice. This is likely to result from first-pass hepatic metabolism of tyrindoxyl sulphate combined with second-pass metabolism of indoles. Overall however, oral administration of muricid extract containing brominated indoles does not result in severe clinical toxicity.

Long-term effects of environmentally relevant doses of 2,2',4,4',5,5' hexachlorobiphenyl (PCB153) on neurobehavioural development, health and spontaneous behaviour in maternally exposed mice

BackgroundPolychlorinated biphenyls (PCBs) are widespread in the environment, human food and breast milk. Seafood is known to contain nutrients beneficial for the normal development and function of the brain, but also contaminants such as PCBs which are neurotoxic. Exposure to non-coplanar PCBs during brain development can disrupt spontaneous behaviour in mice and lead to hyperactive behaviour. Humans are chronically exposed to the highest relative levels of organochlorines in early childhood during brain development, though usually at doses which do not give clinical symptoms of toxicity. This study aimed to elucidate the developmental and behavioural effects of 2,2',4,4',5,5' hexachlorobiphenyl (PCB153) in mice, mimicking human exposure during gestation and lactation.MethodsEnvironmentally relevant doses of PCB153 were added to the experimental diets. Feed concentrations were approximately 0.5, 6.5, and 1500 μg PCB153/kg feed, representing a realistic and a worst case scenario of frequent consumption of contaminated fish. The study also investigated the effects of maternal nutrition, i.e. a standard rodent diet versus a high inclusion of salmon. Mice pups were examined for physical- and reflex development, sensorimotor function and spontaneous behaviour from five days after birth until weaning. A selection of pups were followed until 16 weeks of age and tested for open field behaviour and the acoustic startle response (ASR) with prepulse inhibition (PPI). Blood thyroid hormones and liver enzymes, blood lipids and PCB153 content in fat were examined at 16 weeks. Statistical analyses modelled the three way interactions of diet, PCB exposure and litter size on behaviour, using generalized linear models (GLM) and linear mixed effect models (LME). The litter was used as a random variable. Non-parametric tests were used for pair wise comparisons of biochemical analyses.ResultsLitter size consistently influenced pup development and behaviour. Few lasting PCB153 related changes were observed, but results indicated effects on synchronization of physical development. Perinatal PCB153 exposure appeared to reduce habituation and cause aggression in males, though not statistically significant.ConclusionsLitter size and maternal diet influenced physical development and function more than PCB153 in perinatally exposed mouse pups and supports the developmental importance of maternal care and the social environment.

Ivermectin effects on motor coordination and contractions of isolated rat diaphragm

Ivermectin, the antiparasitic drug from the macrocyclic lactones class raises attention due to its high efficiency against nematodes and arthropods and very specific toxic and side effects that it may produce in host. Dominant clinical symptoms of adverse effects and toxicity of ivermectin in animals are tremor, ataxia, CNS depression and coma which often results in mortality. In our study increasing intravenous doses of ivermectin, (6 or more times higher than therapeutic dose: 1.25, 2.5, 3.75, 5.0, 6.25 and 7.5 mg/kg), caused dose-dependent disturbance of motor coordination in treated rats. The median effective dose (ED50) that was able to impair the rota-rod performance in rats treated 3 min before testing was 2.52 mg/kg. This effect weakens over time, while in the rats treated 60 min before the rota-rod test, ED50 of ivermectin was 4.21 mg/kg. Whereas, all tested doses of ivermectin did not cause any other clinical symptoms of toxicity. Ivermectin has no effect on the contractions of isolated diaphragm caused by the EFS, which effectively blocked mecamylamine (100 μM) and pancuronium (1 and 2 μM). Effect on motor coordination is the first detectable clinical symptom of ivermectin toxicity and apparently is a result of its central effects.