Toxic Doses Research Articles

Case series: star anise toxicity presenting to the emergency department in Eastern Regional Referral Hospital in Bhutan

BackgroundStar anise fruit has been used in spice in Asian cuisine, ingredient for traditional medicines, component for antiviral drugs and as parts of tea and beverage across the globe. Toxicity from these plants has been reported due to adulteration with similar toxic species and from consumption with high toxic dose. Most physician and public are unaware of these adverse effects.CasesWe present two cases of star anise toxicity. Both of the patients presented with gastrointestinal and neurological symptoms after consumption of the said fruit. All of the labs and imaging test was negative for other causes and star anise toxicity diagnosis was made after detailed history, events and related symptoms. They were managed supportively and discharged after 24 h of observation.ConclusionEmergency department doctors should be vigilant about possible star anise toxicity in patient presenting with suggestive symptoms, negative investigation for other possible cause and in area where these plant species is available. A detailed drug and ingestion history is essential.

FZ-AD005, a Novel DLL3-Targeted Antibody-Drug Conjugate with Topoisomerase I Inhibitor, Shows Potent Antitumor Activity in Preclinical Models.

Delta-like ligand 3 (DLL3) is overexpressed in small cell lung cancer (SCLC) and has been considered an attractive target for SCLC therapy. Rovalpituzumab tesirine was the first DLL3-targeted antibody-drug conjugate (ADC) to enter clinical studies. However, serious adverse events limited progress in the treatment of SCLC with rovalpituzumab tesirine. In this study, we developed a novel DLL3-targeted ADC, FZ-AD005, by using DXd with potent cytotoxicity and a relatively better safety profile to maximize the therapeutic index. FZ-AD005 was generated by a novel anti-DLL3 antibody, FZ-A038, and a valine-alanine (Val-Ala) dipeptide linker to conjugate DXd. Moreover, Fc-silencing technology was introduced in FZ-AD005 to avoid off-target toxicity mediated by FcγRs and showed negligible Fc-mediated effector functions in vitro. In preclinical evaluation, FZ-AD005 exhibited DLL3-specific binding and demonstrated efficient internalization, bystander killing, and excellent in vivo antitumor activities in cell line-derived xenograft and patient-derived xenograft models. FZ-AD005 was stable in circulation with acceptable pharmacokinetic profiles in cynomolgus monkeys. FZ-AD005 was well tolerated in rats and monkeys. The safety profile of FZ-AD005 was favorable, and the highest nonseverely toxic dose was 30 mg/kg in cynomolgus monkeys. In conclusion, FZ-AD005 has the potential to be a superior DLL3-targeted ADC with a wide therapeutic window and is expected to provide clinical benefits for the treatment of patients with SCLC.

Toxicological evaluation of combination products containing imidacloprid, moxidectin and pyriproxyfen

The purpose of the research is to investigate subacute cutaneous toxicity in rats, allergenic properties in guinea pigs and tolerance of increased doses of drugs based on imidacloprid, moxidectin and pyriproxyfen by dogs and cats of different age groups.Materials and methods. Toxicological studies (subacute cutaneous toxicity, study of allergenic properties) were conducted in the vivarium of the All-Russian Research Institute of Plant Protection, a branch of the Federal Scientific Center for Experimental Veterinary Medicine of the Russian Academy of Sciences, on male rats and guinea pigs. Experiments on the tolerance of drugs by target animal species (dogs, cats) were conducted in the Podolsk department of the All-Russian Research Institute of Plant Protection. The choice of doses, frequency and methods of administration of the studied drugs were determined in accordance with the Guidelines for Experimental (Preclinical) Study of New Pharmacological Substances. All doses were calculated for the drug taking into account the density (1.08 g/cm3).Results and discussion. When studying the acute cutaneous toxicity of the drug on rats, LD50 exceeded the maximum possible dose of 10 000 mg/kg (hazard class 4 according to GOST 12.1.007-76). In a subacute experiment on rats, it was established that doses of 1000 and 500 mg/kg are ineffective (safe), the threshold and toxic doses could not be established. These drugs, when treating animals 8 times with an interval of 3 days in a three- and five-fold increase in the maximum therapeutic dose during the experimental period, did not have a negative effect on the general condition of the animals, their physiological status and behavior; no statistically significant changes in the morphological and biochemical parameters of the blood, physicochemical parameters of urine were noted in animals from the experimental groups compared to the control. However, in one adult dog from the second experimental group, which was used a five-fold increase in the maximum therapeutic dose of the drug, depression was noted on the 20th day of the experiment. The physiological state of the animal returned to normal within 24 hours voluntarily without the use of symptomatic therapy.

Paracetamol Dosing Errors in People Aged 12 Years and Over: An Analysis of Over 14,000 Cases Reported to an Australian Poisons Information Centre.

Paracetamol dosing errors can cause acute liver injury, with potentially toxic doses only slightly above the therapeutic range. This study aimed to characterise unintentional paracetamol overdose reported to an Australian poisons centre, including time trends, demographics, types of dosing errors, and outcomes. Records regarding paracetamol dosing errors for individuals aged ≥12 years were extracted from the New South Wales Poisons Information Centre database, January 2017 to June 2023. Data from 2021 underwent an in-depth screening of free text case notes to examine: dose, duration, products involved, reasons for ingestion and outcomes including hospitalisation, treatment, liver transplantations and deaths. Where possible, complete outcome data were obtained from medical records of New South Wales hospitalised cases in 2021. There were 14,380 exposures due to paracetamol dosing errors (predominantly self-administered, median age 43 years, 62.6% female), with an average yearly increase of 2.5% (95% CI 1.6-3.8%; p < 0.0001). The in-depth analysis of exposures recorded during 2021 revealed 1899 exposures (median age 46 years, 63.4% female) with 26.8% requiring hospitalisation. Immediate- and modified-release formulations were highly implicated. Multiple paracetamol-containing products were ingested in approximately 20% of exposures. Hospitalised exposures were associated with paracetamol use for dental pain and ingested higher doses for longer durations. Over half of those hospitalised (52%) were treated with the antidote (N-acetylcysteine), and 6% of exposures developed hepatotoxicity. Paracetamol dosing errors continue to occur, with relatively high rates of hospitalisation and liver injury. Many hospitalisations involved use for dental pain. Possible preventative measures include ingredient name prominence and increased education on appropriate dosing.

Advances in the Synthesis and Bioactivity of Polysaccharide Selenium Nanoparticles: A Review.

Selenium, an essential trace element of the human body, is pivotal in human health and disease prevention. Nevertheless, the narrow therapeutic index of selenium, where the toxic and therapeutic doses are close, limits its clinical utility. Significantly, nanoscale selenium synthesized by different methods using polysaccharides as stabilizers has low toxicity properties and exhibits excellent bioactivity. Its biological activities, such as anti-tumor, anti-inflammatory, antioxidant, antibacterial, and immune function enhancement, are improved compared with traditional organic and inorganic selenium compounds, conferring greater potential for application in biomedicine. Therefore, this review evaluates the advancements in various synthesis methodologies for polysaccharide selenium nanoparticles (Se NPs) and their biological activities. It aims to provide a comprehensive theoretical basis and research directions for the future development of highly efficient, minimally toxic, and biocompatible polysaccharide-Se NPs and the application of polysaccharide-Se NPs in biomedicine.

CMG901, a Claudin18.2-specific antibody-drug conjugate, for the treatment of solid tumors

Claudin18.2 has been recently recognized as a potential therapeutic target for gastric/gastroesophageal junction or pancreatic cancer. Here, we develop a Claudin18.2-directed antibody-drug conjugate (ADC), CMG901, with a potent microtubule-targeting agent MMAE (monomethyl auristatin E) and evaluate its preclinical profiles. Invitro studies show that CMG901 binds specifically to Claudin18.2 on the cell surface and kills tumor cells through direct cytotoxicity, antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and bystander killing activity. Invivo pharmacological studies show significant antitumor activity in patient-derived xenograft (PDX) models. Toxicity studies show that the major adverse effects related to CMG901 are reversible hematopoietic changes attributed to MMAE. The highest non-severely toxic dose (HNSTD) is 6mg/kg in cynomolgus monkeys and 10mg/kg in rats once every 3weeks. CMG901's favorable preclinical profile supports its entry into the human clinical study. CMG901 is currently under phase 3 investigation in patients with advanced gastric/gastroesophageal junction adenocarcinoma expressing Claudin18.2 (NCT06346392).

Toxicokinetics, in vivo metabolic profiling and tissue distribution of chlorfenapyr in mice.

Chlorfenapyr is a novel broad-spectrum insecticide derived from natural pyrrole derivatives produced by Streptomyces spp. It acts as a pro-insecticide and is metabolically converted to the active metabolite, tralopyril. Chlorfenapyr poisoning is known for its delayed neurological symptoms and high mortality. Unfortunately, information on the toxicokinetics, metabolism and tissue distribution of chlorfenapyr and tralopyril is still lacking. In this study, the metabolic profile, toxicokinetics and tissue distribution of chlorfenapyr and tralopyril after oral administration at a toxic dose in mice were investigated. Twenty metabolites were identified in plasma, urine and feces, which were mainly formed by dealkylation, oxidative dechlorination and reductive dechlorination. Toxicokinetic results showed that chlorfenapyr was rapidly converted to tralopyril after administration, and the in vivo half-life (t1/2), area under the curve (AUC) and peak concentration (Cmax) values of tralopyril were significantly higher than those of chlorfenapyr (P < 0.05). Tissue distribution experiments confirmed that the metabolite tralopyril had a longer half-life, a lower clearance and a wide distribution in different organs and tissues compared to chlorfenapyr. It was also able to cross the blood-brain barrier, suggesting a potential association with brain lesions. In addition, a sensitive and rapid LC-MS/MS analytical method was established for the detection of chlorfenapyr and tralopyril. In conclusion, this study provided valuable metabolic, toxicokinetic and tissue distribution information, contributing to future risk assessment and forensic identification in cases of chlorfenapyr poisoning. We recommend considering the assessment of tralopyril levels, which may be of greater therapeutic importance in the management of chlorfenapyr poisoning.

Scoping review exploring the evidence base on Vitis vinifera toxicity in dogs after ingestion: Clinical effects, treatments and types of V. vinifera.

Treatment of Vitis vinifera fruit (VVF) ingestion can be challenging due to no clear toxic dose, signalment factors and variable clinical signs. Current treatment guidance is generalised: decontamination, aggressive fluid therapy, monitoring and/or treatment of renal dysfunction. The objective of this study was to conduct a scoping review of scientific evidence regarding the ingestion of VVF in dogs. Three primary areas were reviewed: VVF types ingested, clinical signs reported and treatments given. The inclusion criterion was any paper presenting data on clinical signs or treatments of dogs that had ingested VVF (unprocessed VVF only). The following databases were searched: CAB Abstracts, Medline, Embase and Scopus. No limits were placed on language or date. The review followed the Joanna Briggs Institute scoping review methodology. Twenty-four papers were identified. A wide range of VVF types were ingested, but the toxic dose was difficult to ascertain. The most commonly reported signs were gastrointestinal, renal, neurological and haematological. Treatment commonly consisted of fluid therapy, diuretics and antiemetics. This scoping review neither explored cases of processed VVF ingestion nor did it chart laboratory findings; therefore, potentially clinically significant findings in these areas may have been missed. VVF ingestion typically causes gastrointestinal/renal dysfunction, with no clear toxicity attributable to VVF type. Treatments varied according to the presence/absence of clinical signs, and the prognosis was varied. Further research on current treatment efficacy is warranted, permitting an evidence-based, risk-benefit approach to be adopted by clinicians.

Biogenic zinc oxide nanoregulator determines the quantitative analysis of morpho-anatomical and antioxidant capacity in Lactuca sativa L.

Zinc oxide nanoparticles (ZnO NPs) can possibly serve as a pervasive source of essential nutrient zinc in agricultural crops in the future. The major environmental concerns with ZnO NPs might be their toxicity and incorrect dosage, which might lead to crop damage and environmental pollution. Interplay between ZnO NPs and Lactuca sativa (L. sativa) will be of interest, yet little is known about apropos interaction of these two, which will assist in optimizing the dose of ZnO NPs for their commercial use in agriculture. The current study aimed to investigate the growth, anatomical, and antioxidative responses of L. sativa against ZnO NPs and zinc acetate. ZnO NPs were foliar sprayed with concentrations of 0, 25, 50, and 100 ppm. ZnO NPs remarkably promoted L. sativa growth, leaf water content, and biomass accumulation; however, they declined root growth. The foliar spray of ZnO NPs improved the thickness of the stem hypodermis, cortex, pericycle, and phloem, while decreasing the stem diameter, thickness of the epidermis, and number of vascular bundles. ZnO NPs rigorously declined the cell area of xylem but slightly improved it in phloem. Unlike stem cells' anatomical responses to ZnO NPs, the root cells behaved otherwise. Overall, the antioxidative activity of L. sativa considerably improved at 25 ppm concentration and decreased at 100 ppm. Generally, low and medium concentrations of ZnO NPs promoted plant morphological, anatomical, and antioxidant traits, while higher doses inhibited the same traits. Contrary to this, Zn acetate displayed severe toxic effects on almost all studied anatomical traits.

Accurate Prediction of Rat Acute Oral Toxicity and Reference Dose for Thousands of Polycyclic Aromatic Hydrocarbon Derivatives Based on Chemometric QSAR and Machine Learning.

Acute oral toxicity is currently not available for most polycyclic aromatic hydrocarbons (PAHs), especially their derivatives, because it is cost-prohibitive to experimentally determine all of them. Here, quantitative structure-activity relationship (QSAR) models using machine learning (ML) for predicting the toxicity of PAH derivatives were developed, based on oral toxicity data points of 788 individual substances of rats. Both the individual ML algorithm gradient boosting regression trees (GBRT) and the stacking ML algorithm (extreme gradient boosting + GBRT + random forest regression) provided the best prediction results with satisfactory determination coefficients for both cross-validation and the test set. It was found that those PAH derivatives with fewer polar hydrogens, more large-sized atoms, more branches, and lower polarizability have higher toxicity. Software based on the optimal ML-QSAR model was successfully developed to expand the application potential of the developed model, obtaining reliable prediction of pLD50 values and reference doses for 6893 external PAH derivatives. Among these chemicals, 472 were identified as moderately or highly toxic; 10 out of them had clear environment detection or use records. The findings provide valuable insights into the toxicity of PAHs and their derivatives, offering a standard platform for effectively evaluating chemical toxicity using ML-QSAR models.

Neuroprotective and Nootropic Evaluation of some Important Medicinal Plants in Dementia: A Review

: Dementia is a devitalising decline in neurological acuity, which burdens both high- and lowincome countries due to poor diagnostic systems and high healthcare costs. A growing population and rises in deleterious environmental and genetic anomalies aggravate new and aggressive cases of dementia and neurodegenerative disorders. The unparalleled capability of medicinal plants is constantly explored in treating neurological disorders, and some of these phytocompounds are used for treating diseases. However, some of these metabolites are neurotoxic and disrupt DNA polymerase functions. They possess lifethreatening side effects and are unable to prevent disease progression. Therefore, it is important to focus on discovering novel compounds from new medicinal plants. Our review encompasses some medicinal plant metabolites recently explored in treating this disease. We also summarized the molecular mechanism of action as determined in in-vitro: the toxic dose, nootropic and neuroprotective effects on neurophysiology and neurotransmitter levels, and the antioxidant effects.

Pembelajaran Distribusi Gamma dalam Masalah Biomedis: Tinjauan pada Pengaruh Dosis Beracun pada Tikus

Purpose: The objective of this study is to examine the use of the Gamma function in the Gamma distribution and its application in analyzing the effect of toxic doses on rats. Methodology: The methodology employed in this study utilizes a non-standard Gamma distribution, with a continuous random variable X that has parameters α and β. The research methods employed in this study include a literature review and a case study. Findings: The results of the calculations indicated that the mean time to death for the rats was 50 weeks, with a standard deviation of 22.36 weeks. Significance: It was also found that the probability of rats surviving for more than 60 days was less than 60%. Based on these findings, the study offers recommendations for the teaching of mathematics, particularly in the context of understanding probability distributions and their applications in biological and toxicological contexts. This study underscores the significance of grasping the Gamma distribution in anticipating and interpreting data in the life sciences, as well as the capacity of mathematical concepts to be operationalized in genuine settings.

The domperidone dilemma in Pakistan: Balancing access and safety concerns.

Madam, Domperidone is used in the treatment of nausea and vomiting as an antiemetic and prokinetic drug. Its pro-kinetic effects mainly manifest in the upper gastrointestinal tract by acting as a dopamine receptor antagonist [1]. However, the drug has been banned by the FDA in the USA due to its association with cardiac arrhythmias and cardiac arrest. A recent meta-analysis has shown a statistically significant association between sudden cardiac death [2] and the use of domperidone which raises the question of drug usage in Pakistan as an over-the-counter medication. The meta-analysis considers six different case-control studies, between 2005 and 2016, that have shown an increase in the risk of sudden cardiac death and ventricular arrhythmias associated with domperidone. The observational studies were conducted in North America, Asia, and Europe, proving that it is a global phenomenon, stemming from the use of the drug. The forest plot of the studies has been mentioned later in the abstract showing heterogeneity at 0%, OR ratio 1.69 with 95% CI (1.46-1.95). To further highlight the risks associated with domperidone, another study has reported that the safety index of the drug is 5.25, which is remarkably lower than the international safety ratio of 30[3]. The safety index, or therapeutic index, is the ratio of the toxic dose in 50% of the population (TD50) and the effective dose in 50% of the population (ED50) with the same therapeutic effect. A wider safety index indicates more room for error in the drug's therapeutic effect; essentially a larger barrier before the drug is toxic. With a safety index of 5.25, the action potential duration is markedly increased, resulting in arrhythmias. The author also comments on restricting the drug only to patients where the potential benefit is proven to justify the risks. In Pakistan, Domperidone is readily available as an over-the-counter drug. The casual availability raises the concern that the associated safety issues must be critically evaluated to determine whether the uses of the drug outweigh the risk of sudden cardiac death and ventricular arrhythmias [4] mentioned in these studies.

Human risk assessment through development and application of a physiologically based toxicokinetic model for 4-tert-octylphenol

4-tert-octylphenol (4-tert-OP) is an ecologically hazardous substance, and exposure to it in the environment has been consistently reported in the past. Despite the hazards and widespread exposure to 4-tert-OP, tools for scientific assessment of 4-tert-OP exposure risk level in humans are lacking. The main purpose of this study was to develop a physiologically-based-toxicokinetic (PBTK) model for 4-tert-OP and to perform quantitative risk assessment of 4-tert-OP in various population groups using the established model. Based on the results of toxicokinetic experiments on male rats, the PBTK model for 4-tert-OP was established and verified, and this was converted to a model for humans through interspecies extrapolation. Based on the previously reported no-observed-adverse-effect-levels for rats, it was possible to estimate the 4-tert-OP reference dose in humans through reverse dosimetry using the model. Biomonitoring data derived from various population groups were applied to the human PBTK model to calculate external exposures and margin of safety for 4-tert-OP for each population group. The PBTK model established in this study adequately explained the toxicokinetic experimental values at acceptable levels and was able to quantitatively predict the 4-tert-OP exposure level in the testes related to male reproductive toxicity. In addition, the degree of external exposure to 4-tert-OP could be scientifically estimated based on biomonitoring values derived from various biological matrices. The reference doses for systemic and reproductive toxicity caused by 4-tert-OP in male humans were calculated to be 0.16 and 1.12 mg/kg/day, respectively. The mean external exposure to 4-tert-OP in each population group estimated based on plasma and urine biomonitoring data was 0.04–66.24 mg/kg/day, showing very large exposure diversity between groups. Exposure risks to 4-tert-OP in populations ranged from safe to risky, suggesting the need for continued monitoring and risk management of 4-tert-OP worldwide. This study provides valuable scientific insight regarding the 4-tert-OP human risk assessment.

Relationship between Endotoxin Content in Vaccine Preclinical Formulations and Animal Welfare: An Extensive Study on Historical Data to Set an Informed Threshold.

The most widely known pyrogen impurity in vaccines is the Gram-negative bacterial endotoxin lipopolysaccharide (LPS). When administered at toxic doses, endotoxin triggers inflammatory responses, which lead to endotoxic shock. The literature on endotoxic content (EC) for preclinical vaccines' formulations used in animal studies is very poor, and the recommended thresholds are solely based on commercial vaccine limits set for humans and are, therefore, not connected to the actual impact of EC on animal welfare for species used in preclinical research studies. An extensive study to evaluate the presence of a potential relationship between endotoxin content in formulations administered to mice (the most common species used in preclinical research studies) and their welfare was conducted to calculate an EC threshold for formulations of candidate vaccines. Three years of historical data, from more than 500 formulations of different antigen types (i.e., proteins, glycoconjugates, OMV/GMMA) injected into more than 5000 mice, was evaluated with two alternative statistical methodologies, both demonstrating that there is no significant relationship between actual endotoxin levels and mouse welfare. The calculation of thresholds was, therefore, performed by consistency versus formulations that demonstrated no impact on animal welfare.

Refined Cumulative Risk Assessment of Pb, Cd, and as in TCM Decoction Based on Bioavailability through In Vitro Digestion/MDCK Cells.

In this study, the oral bioavailability of Pb, Cd, and As in three types of traditional Chinese medicines (TCMs) and TCM decoctions were investigated through in vitro PBET digestion/MDKC cell model. Furthermore, a novel cumulative risk assessment model associated with co-exposure of heavy metal(loid)s in TCM and TCM decoction based on bioavailability was developed using hazard index (HI) for rapid screening and target organ toxicity dose modification of the HI (TTD) method for precise assessment. The results revealed that the bioavailability of Pb, Cd, and As in three types of TCM and TCM decoction was 5.32-72.49% and 4.98-51.97%, respectively. After rapid screening of the co-exposure health risks of heavy metal(loid)s by the HI method, cumulative risk assessment results acquired by TTD method based on total metal contents in TCMs indicated that potential health risks associated with the co-exposure of Pb, Cd, and As in Pheretima aspergillum (E. Perrier) and Oldenlandia diffusa (Willd.) Roxb were of concern. However, considering both the factors of decoction and bioavailability, TTD-adjusted HI outcomes for TCMs in this study were <1, indicating acceptable health risks. Collectively, our innovation on cumulative risk assessment of TCM and TCM decoction provides a novel strategy with the main purpose of improving population health.

Recording of hippocampal activity on the effect of convulsant doses of caffeine

Seizures occur when there is a hyper-excitation of the outer layer of the brain, with subsequent excessive synchrony in a group of neurons. According to the World Health Organization (WHO), an estimated 50 million people are affected by this disease, a third of whom are resistant to the treatments available on the market. Caffeine (1,3,7-trimethylxanthine), which belongs to the purine alkaloid family, is the most widely consumed psychoactive drug in the world. It is ingested by people through drinks containing this substance, such as coffee, and as an adjuvant in analgesic therapy with non-steroidal antiflammatory drugs. The present study evaluated the electrocorticographic changes observed in the hippocampus of Wistar rats subjected to acute doses of caffeine (150 mg/kg i.p), which represents a toxic dose of caffeine corresponding to an estimated acute intake of more than 12 cups of coffee to record its convulsant activity. Our results showed, for the first time, that the administration of high doses of caffeine (150 mg/kg i.p.) in rats caused an increase in the spectral distribution of power in all frequency bands and suggested the appearance of periods of ictal and interictal peaks in the electrocorticogram (ECog). We have also shown that the anticonvulsants phenytoin, diazepam and phenobarbital have a satisfactory response when associated with caffeine.

Use of Drug Sensitisers to Improve Therapeutic Index in Cancer.

The clinical management of malignant tumours is challenging, often leading to severe adverse effects and death. Drug resistance (DR) antagonises the effectiveness of treatments, and increasing drug dosage can worsen the therapeutic index (TI). Current efforts to overcome DR predominantly involve the use of drug combinations, including applying multiple anti-cancerous drugs, employing drug sensitisers, which are chemical agents that enhance pharmacokinetics (PK), including the targeting of cellular pathways and regulating pertinent membrane transporters. While combining multiple compounds may lead to drug-drug interactions (DDI) or polypharmacy effect, the use of drug sensitisers permits rapid attainment of effective treatment dosages at the disease site to prevent early DR and minimise side effects and will reduce the chance of DDI as lower drug doses are required. This review highlights the essential use of TI in evaluating drug dosage for cancer treatment and discusses the lack of a unified standard for TI within the field. Commonly used benefit-risk assessment criteria are summarised, and the critical exploration of the current use of TI in the pharmaceutical industrial sector is included. Specifically, this review leads to the discussion of drug sensitisers to facilitate improved ratios of effective dose to toxic dose directly in humans. The combination of drug and sensitiser molecules might see additional benefits to rekindle those drugs that failed late-stage clinical trials by the removal of detrimental off-target activities through the use of lower drug doses. Drug combinations and employing drug sensitisers are potential means to combat DR. The evolution of drug combinations and polypharmacy on TI are reviewed. Notably, the novel binary weapon approach is introduced as a new opportunity to improve TI. This review emphasises the urgent need for a criterion to systematically evaluate drug safety and efficiency for practical implementation in the field.

Metabolomics highlights biochemical perturbations occurring in the kidney and liver of mice administered a human dose of colistin.

Introduction: Colistin (CMS) is used for the curation of infections caused by multidrug-resistant bacteria. CMS is constrained by toxicity, particularly in kidney and neuronal cells. The recommended human doses are 2.5-5mg/kg/day, and the toxicity is linked to higher doses. So far, the in vivo toxicity studies have used doses even 10-fold higher than human doses. It is essential to investigate the impact of metabolic response of doses, that are comparable to human doses, to identify biomarkers of latent toxicity. The innovation of the current study is the in vivo stimulation of CMS's impact using a range of CMS doses that have never been investigated before, i.e., 1 and 1.5mg/kg. The 1 and 1.5mg/kg, administered in mice, correspond to the therapeutic and toxic human doses, based on previous expertise of our team, regarding the human exposure. The study mainly focused on the biochemical impact of CMS on the metabolome, and on the alterations provoked by 50%-fold of dose increase. The main objectives were i) the comprehension of the biochemical changes resulting after CMS administration and ii) from its dose increase; and iii) the determination of dose-related metabolites that could be considered as toxicity monitoring biomarkers. Methods: The in vivo experiment employed two doses of CMS versus a control group treated with normal saline, and samples of plasma, kidney, and liver were analysed with a UPLC-MS-based metabolomics protocol. Both univariate and multivariate statistical approaches (PCA, OPLS-DA, PLS regression, ROC) and pathway analysis were combined for the data interpretation. Results: The results pointed out six dose-responding metabolites (PAA, DA4S, 2,8-DHA, etc.), dysregulation of renal dopamine, and extended perturbations in renal purine metabolism. Also, the study determined altered levels of liver suberylglycine, a metabolite linked to hepatic steatosis. One of the most intriguing findings was the detection of elevated levels of renal xanthine and uric acid, that act as AChE activators, leading to the rapid degradation of acetylcholine. This evidence provides a naïve hypothesis, for the potential association between the CMS induced nephrotoxicity and CMS induced 39 neurotoxicity, that should be further investigated.

Semi-commercial scale fermentation of prawn waste by Exiguobacterium sp. GM010 for bioactive pigment production: Safety and efficacy assessment in Wistar rats

Pigment producing Exiguobacterium sp. GM010 demonstrates utilization of prawn carapace hydrolysate. Accordingly, our investigation was focused to produce cost effective bioactive pigment in 15 L semi-commercial scale. Further acute and subacute toxicities were evaluated as per OECD guidelines for application as nutraceutical. The biomass and pigment extract yield were 28.76 ± 1.78 and 0.82 ± 0.04 g/L, respectively, at 1.5 L of aeration. The UV–visible spectrum of pigment showed absorption peaks at 357, 466, and 491 nm indicating carotenoid like pigment. This was correlated with colour distribution in yellowish-orange region of CIE Lab spectrum. The qualitative and quantitative characteristics of pigment were similar between lab-scale and bioreactor production. The acute toxic dose (2000 mg/kg bw) exhibited the toxicity as determined by haematological analysis. While subacute toxic dose (250, 500, 1000 mg/kg bw) demonstrated no adverse effects on parameters such as food intake, body weight gain, vital organ weight, haematological and histopathological examination. Serum biochemistry results showed significant increase in HDL and decrease in SGPT values in treated groups compared to control. The results revealed that, Exiguobacterium sp. GM010 has efficiently utilised prawn waste to produce bioactive pigment. The dose of Exiguobacterium sp. GM010 pigment lower than 1000 mg/kg bw can be regarded as safe.