Hepatic Toxicity Research Articles

Protective effects of Pelargonium graveolens (geranium) oil against cefotaxime-induced hepato-renal toxicity in rats.

Cefotaxime is a broad-spectrum antibiotic targeting Gram-negative bacteria used for diverse infections, but it can be toxic to the stomach, liver, and kidneys. This study explored the protective effects of geranium oil against cefotaxime-induced hepatotoxicity and nephrotoxicity in rats, employing biochemical, histopathological, and immunohistochemical evaluations. Thirty rats were divided into five groups of six animals each one. Group 1 received orally normal saline for 14days, Group 2 was given orally 2.5% DMSO for 14days, Group 3 received cefotaxime (200mg/kg/day IM) for 14days, Group 4 received with cefotaxime (200mg/kg/day IM) and geranium oil (67mg/kg b. w./day orally in DMSO) for 14days, and Group 5 received geranium oil alone (67mg/kg b. w./day orally in DMSO) for 14days. Geranium oil significantly reduced cefotaxime-induced damage, evidenced by lower serum levels of liver enzymes (AST, ALT), renal markers (urea, creatinine), and other indicators (alkaline phosphatase, TNF-alpha, IL-1Beta, MAPK, nitric oxide, MDA). It also increased levels of protective tissue biomarkers such as NrF2, albumin, catalase, Beclin 1, and reduced glutathione (GSH). Histopathological and immunohistochemical analyses revealed significant protective effects in liver and renal tissues in rats treated with Geranium oil. These results suggest that Geranium oil is effective in mitigating cefotaxime-induced hepatotoxicity and renal toxicity.

Pexidartinib and standard neoadjuvant therapy in the adaptively randomized I-SPY2 trial for early breast cancer.

We investigated the small-molecule receptor tyrosine kinase-inhibitor of colony-stimulating factor-1 receptor pexidartinib in the stage II/III breast cancer in the I-SPY2 platform trial. I-SPY2 is an adaptive platform trial that features multiple arms of experimental agents administered on a background of standard neoadjuvant therapy with paclitaxel and adriamycin/cyclophosphamide, followed by definitive surgery. The adaptive randomization engine preferentially assigns patients based upon cumulative performance of each agent in a given breast cancer subtype based on hormone receptor and HER2 receptor status. The study endpoint is pathologic complete response. A total of 9 participants were randomized to receive pexidartinib with neoadjuvant paclitaxel before enrollment was halted due to a serious adverse event of vanishing bile duct syndrome. No participants received a full course of the study drug. Although there remains interest in agents targeting CSF-1, hepatic toxicity appears to be a limiting factor for their use in early breast cancer. NCT01042379 ( www. gov/ct2/show/NCT01042379 ).

Prophylactic administration of naringin prevents anticancer drug 5-fluorouracil-induced hepatorenal toxicity via suppressing lipid peroxidation and oxidative stress in rats

Prophylactic administration of naringin prevents anticancer drug 5-fluorouracil-induced hepatorenal toxicity via suppressing lipid peroxidation and oxidative stress in rats

Comprehensive review on advanced antipyretic and anti-nociceptic agents: Efficacy; safety and emerging therapies

Fever; characterized by an increased core temperature; is a complex physiological reaction to illness involving acute-phase reactants and many physiological; endocrinological; and immunological systems. Antipyretics; chiefly non-steroidal anti-inflammatory Drugs (NSAIDs) and paracetamol; are essential for the management of fever and related discomfort. These medicines primarily function by inhibiting cyclooxygenase enzymes; so diminishing the production of prostaglandin E2 in the hypothalamus and subsequently decreasing the thermal set point. Although paracetamol is acknowledged for its safety when utilized correctly; it presents concerns of hepatic toxicity and overdose; requiring vigilant monitoring; especially in pediatric patients or those with concomitant conditions. Conversely; ibuprofen typically has greater antipyretic efficacy; particularly in pediatric populations; although its application may be constrained by gastrointestinal adverse effects and renal considerations. Recent breakthroughs in this domain concentrate on improving the safety and efficacy of antipyretic drugs; particularly for at-risk populations such as the elderly and children. Innovations like COX-2 selective inhibitors and advanced delivery technologies; including nanomedicine; offer exciting opportunities for enhancing pain management and fever therapy. Future study should emphasize the customization of therapy according to pharmacodynamics; possible drug interactions; and patient attributes to enhance therapeutic results. An interdisciplinary approach is crucial for the appropriate management of fever and pain; enhancing patient welfare and progressing clinical practices in antipyretic and antinociceptive therapies.

Vaginal administration of 17-alpha hydroxyprogesterone caproate appears to be safe in non-pregnant female rats and rabbits

Intramuscular (250 mg once weekly) or subcutaneous (275 mg once weekly) injections of 17-hydroxyprogesterone caproate (17-OHPC) has been utilised to prevent recurent spontaneous preterm birth in pregnant women with a short cervix or those with a prior preterm birth but its efficacy in these conditions has been questioned. It is unclear whether adequate concentrations of 17-OHPC reach the suspected target organs such as the cervix and uterus following either IM or SC administration. The objective of this study was to determine feasibility and safety of vaginal administration of 17-OHPC in adult female Sprague Dawley rats and female New Zealand rabbits. Gels containing 17-OHPC were administered intravaginally to rats and rabbits for 10 consecutive days. After the last dose, serial blood samples and terminal uterine and adipose tissue samples were collected. 17-OHPC concentrations were measured by LC-MS-MS. Tissue histology showed that intravaginal administration of 17-OHPC was safe. There was no renal or hepatic toxicity as measured by liver function and kidney function tests. Intravaginal administration of 17-OHPC resulted in low systemic plasma concentrations but substantially higher uterus and adipose tissue concentrations of 17-OHPC. Composition of the formulation affected the tissue distribution of 17-OHPC. Future studies warrant further evaluation of the effect and safety of daily intravaginal administration of 17-OHPC gel in pregnant animals.

First Cycle Toxicity and Survival in Patients with Rare Cancers Treated with Checkpoint Inhibitors.

Associations between immune-related adverse events (irAEs) from checkpoint inhibitor therapy and outcomes have been previously evaluated, with most prior research finding a positive association between toxicity and survival. This prior research has generally reported on more common tumor types. We use a unique data resource of a federally-funded basket trial ((NCT02834013) for patients with rare cancers (N = 684) to evaluate associations between irAEs and overall survival and progression-free survival. Patients were treated with nivolumab and ipilimumab; the trial was opened at > 1000 sites. Landmark Cox regression models were used to assess first cycle irAE associations with progression-free and overall survival. We found that grade 1-2 treatment-related irAEs in the first cycle of therapy were associated with longer overall survival (OS) (multivariable hazard ratio, 95% confidence interval, p-value: 0.61, 0.49-0.75, p < .001) compared to no treatment-related irAE, while grade 3-4 irAEs were associated with shorter OS (HR = 1.41, 95% CI = 1.04-1.90, p = .025). Similar, but weaker, associations were observed with progression-free survival (PFS) and grade 1-2 treatment-related irAEs: HR = 0.83, 95% CI = 0.67-1.01, p = .067 and grade 3-4: HR = 1.35, 95% CI = 1.02-1.78, p = .037 compared to no treatment-related irAEs. Grade 1-2 dermatologic toxicity was associated with improved OS compared to other grade 1-2 toxicities (HR = 0.67, 95% CI = 0.52-0.85, p = .002). There was no significant OS difference between patients with Grade 1-2 fatigue, gastrointestinal, metabolic, hepatic, endocrine, and thyroid toxicities vs other Grade 1-2 toxicities. In this large cohort of patients with rare tumors receiving checkpoint inhibitor therapy, grade of irAE in the first cycle was predictive for survival.

Paracetamol overdose associated with cortical blindness-complicated acute leukoencephalopathy: a case report

BackgroundParacetamol is one of the most used antipyretics and analgesics among pediatrics, and its overdose is highly encountered among pediatrics especially in the pre-school age. While it is well-known that paracetamol overdose may lead to toxicities including severe hepatic toxicity, some recent reports have highlighted its “in situ” toxicity on brain tissue at high doses, even in the absence of hepatotoxicity. This can result in acute leukoencephalopathy (AL), coma, or even death. This report describes a case of a child who developed cortical blindness-complicated AL, following a paracetamol overdose.Case presentationAn 18-month-old previously healthy girl accidentally ingested 300 mg/kg of paracetamol suspension. After ingestion, the child was in an initial bad condition that has gradually improved. Several days after ingestion, the patient lost her vision, and she remained blind since then despite a newer appreciation to light. The initial brain magnetic resonance imaging (MRI) suggested AL demonstrated as a faint high T2/fluid-attenuated inversion recovery (FLAIR) signal intensity in the cortical and subcortical regions of both parieto-occipital lobes with sulcal effacement and restricted diffusion. After around 3 months, the subsequent brain MRI showed involutional changes that were manifested as a brain volume loss in the same areas with evidence of gyri-form laminar necrosis in both parieto-occipital regions without restricted diffusion. Other brain MRI findings include right cerebral convexity hyperacute subdural hematoma with prominent subarachnoid spaces.ConclusionsThe child developed cortical blindness-complicated AL following a paracetamol overdose. It is well- known that AL may result from several toxins by their direct and/or indirect effect on the cerebral white matter. However, there is still no enough data in the literature clearly explaining the relation of paracetamol overdose to AL. The generally proposed effect of paracetamol on the brain is mainly justified by the excessive oxidative stress. Further studies at the cellular and genetic levels are still needed to investigate the exact association between paracetamol overdose and AL, as well as the underlying mechanisms involved.

Potential role of Azolla pinnata on Abamectin Induced Hepatorenal Toxicity and Oxidative Stress in Nile tilapia

Potential role of Azolla pinnata on Abamectin Induced Hepatorenal Toxicity and Oxidative Stress in Nile tilapia

CTIM-09. INB-200: FULLY ENROLLED PHASE 1 STUDY OF GENE-MODIFIED AUTOLOGOUS GAMMA-DELTA (ΓΔ) T CELLS IN NEWLY DIAGNOSED GLIOBLASTOMA MULTIFORME (GBM) PATIENTS RECEIVING MAINTENANCE TEMOZOLOMIDE (TMZ)

Abstract IN8bio’s DeltEx drug resistant immunotherapy (DRI), comprising TMZ-resistant γδ T cells engineered to express methylguanine-DNA methyltransferase (MGMT), enables γδ T cells to target upregulated NKG2D ligands on tumor cells in real time during alkylating chemotherapy exposure. Updated results from the fully enrolled Phase 1 trial evaluating DRI in adult newly diagnosed GBM subjects with IDH wild type and mutant tumors, adequate organ function and KPS ≥ 70%. Cohorts (C) 1, 2 and 3 received 1, 3 or 6 doses (1 x 107 DRI cells/dose) into the resection cavity with 150 mg/m2 of IV TMZ on Day 1 of each of 6 Stupp maintenance cycles. The primary endpoint is safety and secondary endpoints include survival; immunologic correlative analyses are included. Dose limiting toxicities (DLTs) are defined as treatment related ≥ grade (G) 3 cardiopulmonary or hepatic toxicity, G4 toxicity exceeding 72 hours or neurologic deterioration that exceeds 2 weeks. A total of 23 subjects were enrolled and 13 dosed (61% male; median age 68 (range: 21-74); 92% IDH-WT, 54% MGMT unmethylated). No DLTs, cytokine release syndrome (CRS), neurotoxicity (ICANS) or treatment related deaths were reported. The most common adverse events were decreased WBC/platelet count, asthenia, fatigue, hydrocephalus, headache, decreased appetite, urinary tract infection, thrombosis and balance disorder with ≥G3 platelet count decreased in 23% and WBC/ neutrophil/ lymphocyte count decreased in 7.7% each. Peripheral TMZ-based lymphodepletion was maintained for up to 1 year evidenced by near or below normal range T, B, and NK subsets. With median follow-up of 10.8 months, 83% of subjects exceeded the median 7 month Progression Free Survival (PFS) of the Stupp regimen alone, had manageable toxicity with a continued encouraging trend in PFS. Subject with IDH mutant tumor remains progression free for &amp;gt; 35 months. Long-term follow-up for durability of PFS and OS continues.

Death Due to Homicidal Paraquat Poisnong: A Case Report

Background: Paraquat is a widely used herbicide that raises a significant public health concern due to its extreme toxicity even at low doses and its potential for criminal poisoning. However, most of the research is concentrated on pulmonary toxicity of the compound so far, ignoring its other systemic effects. Moreover, a perfect antidote for this poisoning remains still at large. Case Presentation: In this case report, we present probably the first case of criminal paraquat poisoning in India, involving a 40-year-old man who was poisoned by family members with paraquat-laced alcohol. Although the patient initially appeared to be recovering, his condition worsened, and he died from multi-organ dysfunction syndrome (MODS). Discussion: Paraquat poisoning presents with a spectrum of clinical features, mainly affecting the lungs and kidneys, often leading to respiratory and renal failure. However, its toxicity extends to other organs like liver causing toxic hepatitis that prompts us for a proper diagnosis and management. Current research and management protocols tend to neglect the hepatic and renal toxicities, focusing primarily on pulmonary fibrosis. The manufacture and sale of paraquat in India needs to be reviewed in the light of increasing global bans of this compound. There is also a pressing need for antidote research in dealing with agrochemical substance abuse, particularly paraquat. Conclusion: The emergence of paraquat as a lethal homicidal poison highlights the need for stringent regulations and proactive measures to safeguard public health. The whole saga of chemical/pesticide regulation in our country is very naïve when compared to the global standard. It is time to foster collaboration between regulatory bodies, healthcare professionals, and researchers to address the menace of ‘paraquat deaths’ in India.

Organelle-level toxicity of nanometals relevant to titanium implants. Original research and comprehensive literature overview

ObjectiveThis study analyzed organelle toxicities of nanometals applied as free formulations or titanium rod-coating materials in rats. MethodsAll materials were injected intraperitoneally, including the physiological saline applied to the control group. The first experimental group was implanted with nanosilver-coated titanium rods, and the second, third, and fourth groups received free nanosilver at rising levels. The fifth group was implanted with nanosilver, nanocopper, and nanozinc-coated titanium rods, and the sixth group received the same nanometals as free formulations. Light and electron microscopy and ICP-Mass Spectrometry were utilized to determine the neural, hepatic, and renal toxicities and tissue metal levels. ResultsIn brains, neuropil, myelin, and cellular damages occurred, especially in groups receiving high-dose nanosilver or nanometal combinations. Histiocyte accumulation and dark mitochondria within hepatocytes were discernible in the liver. Kidneys were the organs that were most severely affected by nanometal toxicity. The nephrotoxicity was apparent with the perturbations of the membrane infoldings and mitochondrial damage in the proximal and distal convoluted epithelia. Large angular peroxisomes developed inside the mesangial cells, and Golgi bodies increased in epithelial cells. Systemic metal levels increased on the thirtieth and prominently dropped on the sixtieth day. ConclusionThese results provide insights into the extent of injury and organelle targets of nanometals and will guide optimizing the nanomaterials and implants used in the surgical practice.

Hesperidin mitigates Doxorubicin-induced hepatic toxicity in rats, targeting JAK-STAT signaling pathway

Hesperidin mitigates Doxorubicin-induced hepatic toxicity in rats, targeting JAK-STAT signaling pathway

Protective effect of beta-carotene on hepato-nephrotoxicity of gentamicin in male Wistar rats

BackgroundDespite causing significant tissue damage at the molecular and cellular levels, partly due to its induction of oxidative stress, it remains of interest in medical applications. Beta-carotene, found in fruits and vegetables, is being studied for its antioxidant properties. This study aimed to explore beta-carotene's protective effects against gentamicin-induced hepatorenal toxicity. MethodThirty male Wistar-rats were divided into five groups. Control group received normal-saline, while the canola group received canola oil (beta-carotene solvent). Gentamicin group received 100 mg/kg gentamicin injections for seven days. Beta-carotene groups were treated with beta-carotene at doses of 10 and 20 mg/kg for 10 days, along with gentamicin from the fourth day for 7 days. Serum and tissue hepatorenal function tests were performed at the end of the study. ResultsGentamicin resulted in hepatorenal damage. Beta-carotene alongside gentamicin significantly decreased serum SGOT (152.3 ± 12.7 vs. 264.8 ± 9.3 IU/L), SGPT (65.7 ± 2.5 vs. 98.0 ± 4.8 IU/L), creatinine (0.74 ± 0.0 vs. 1.5 ± 0.1 mg/dL), and urea (78.1 ± 10.7 vs. 207.4 ± 23.6 mg/dL) in comparison to gentamicin alone (p < 0.05). Beta-carotene caused a significant decrease in vacuolar degeneration, interstitial nephritis and infiltration of lymphocytes in kidney, and cell necrosis, vacuolar degeneration and infiltration of leukocytes compared to the gentamicin group; additionally, beta-carotene prevented increase in oxidative stress in gentamicin group. ConclusionAdministration of gentamicin alone resulted in hepatorenal toxicity, whereas beta-carotene could prevent gentamicin-induced oxidative stress imbalance and tissue damage. Therefore, beta-carotene could serve as an adjunctive therapy to mitigate hepatorenal toxicity in patients undergoing gentamicin treatment.

Recent Progress and Future Perspectives on Anti-Hyperuricemic Agents.

Increased biosynthesis or underexcretion of uric acid (UA or urate) in the body ultimately leads to the development of hyperuricemia. Epidemiological studies indicate that hyperuricemia is closely associated with the occurrence of various diseases such as gout and cardiovascular diseases. Currently, the first-line therapeutic medications used to reduce UA levels primarily include xanthine oxidase (XO) inhibitors, which limit UA production, and urate transporter 1 (URAT1) inhibitors, which decrease urate reabsorption and enhance urate excretion. Despite significant progress in urate-lowering therapies, long-term use of these drugs can cause hepatorenal toxicity as well as cardiovascular complications. Therefore, there is an urgent need for novel anti-hyperuricemic agents with better efficacy and lower toxicity. This perspective mainly focuses on the current research progress and design strategy of anti-hyperuricemic agents, particularly those targeting XO and URAT1. It is our hope that this perspective will provide insights into the challenges and opportunities for anti-hyperuricemic drug discovery.

Olive Oil's protective potential against cyclophosphamide-induced nephrotoxicity in Swiss albino rats

Background: Cyclophosphamide is a widely used chemotherapy drug, known for its cytotoxic and mutagenic effects on mammalian tissues and cells. Olive oil, rich in antioxidants, has potential protective effects against drug-induced organ damage. This study investigates the protective role of olive oil against cyclophosphamide-induced toxicity in mice. Objective: To evaluate the protective effects of olive oil against cyclophosphamide-induced kidney toxicity in rats. Material and Method: Male albino mice (n=9) were divided into three groups: Control, Cyclophosphamide (150 mg/kg), and Cyclophosphamide (150 mg/kg) + Olive Oil (200 mg/kg). After one week of treatment, kidney tissues were collected and stained with hematoxylin and Eosin for histopathological analysis. Results: The administration of olive oil led to a significant decrease in cellular damage of the kidney tissue. In this study the histopathological examination revealed marked improvement in kidney tissue architecture, with reduced cellular damage, inflammation, and fibrosis compared to the group treated with cyclophosphamide alone. These findings suggest that olive oil has a protective effect against cyclophosphamide-induced hepatic and renal toxicity in mice. Conclusion: Cyclophosphamide caused significant histopathological damage to kidney tissues in mice. Co-administration of olive oil mitigated these adverse effects, likely due to its antioxidant properties. This suggests that olive oil may serve as a protective adjunct in cyclophosphamide chemotherapy.

Hepatic toxicity assessment in HIV’s interaction with reverse transcriptase and integrase strand transfer inhibitors at a military hospital, southsouth Nigeria

IntroductionThe use of anti-retroviral therapy (ART) has made HIV a manageable condition, but there are risks associated with medications like reverse transcriptase inhibitors (RTIs) and integrase strand transfer inhibitors (INSTIs), such as liver and renal toxicity. It is essential to understand these risks for effective treatment and case management. Investigating liver toxicity related to RTIs and INSTIs in Nigeria is crucial for optimizing HIV treatment. This study aimed to assess the impact of tenofovir lamivudine dolutegravir (TLD) on the liver function of HIV patients at Nigerian Navy Hospital (NNH)-Warri.MethodsThe liver function of 170 participants was assessed, with 120 on ART and the remainder being HIV-negative attendees at NNH-Warri. The study used a cross-sectional design and selected participants through random sampling. We collected data using a semi-structured questionnaire. Blood samples were taken through venipuncture and stored at – 20 °C before analysis. Ethical approval was obtained, and data analysis was conducted using SPSS Statistical Software Version 23, with significance set at p < 0.05.ResultsThe study found significant differences in AST, TP, Alb, and GST levels between HIV-positive subjects receiving TLD and HIV-negative individuals. HIV-positive subjects had lower AST and Alb levels but higher TP and GST levels. Further analysis revealed correlations between age, gender, and liver enzymes, highlighting the complex relationship between HIV, liver function, and treatment outcomes.ConclusionThe study suggests that decreased AST levels may have a protective effect, while ALT activity had minimal impact. Changes in TP, Alb, and GSTs emphasize the importance of monitoring hepatic synthetic function and detoxification pathways in HIV patients taking TLD.

The Effects of Ubiquinone on the Antioxidant System in Male Rats Exposed to Saccharin-Induced the Hepatic Toxicity

Saccharin (Sac) is a widely used artificial sweetener with significant applications in the food industry, pharmaceutical formulations, and tobacco products. Despite its popularity, saccharin has drawn attention due to its potential carcinogenic effects and associations with various health risks, including renal impairment, hepatic dysfunction, obesity, and diabetes. This study aimed to investigate the protective effects of Ubiquinone, or coenzyme Q10 (COQ10), on liver toxicity induced by saccharin, focusing on oxidative stress and antioxidant markers. In this experiment, rats were divided into six groups of ten. The control group received no treatment, while the second group was administered COQ10 at a dosage of 20 mg per kilogram of body weight. The third and fourth groups were given saccharin at 1/10 and 1/20 of the lethal dose 50 (LD50), respectively. The fifth and sixth groups received saccharin at the same dosages as the third and fourth groups, but with additional COQ10 supplementation. All treatments were administered orally for 30 days, after which liver tissues were collected to assess oxidative stress and antioxidant markers. The results revealed that saccharin significantly increased oxidative stress in the liver, as evidenced by elevated levels of malondialdehyde (MDA) and oxidized glutathione (GSSG). Additionally, saccharin-treated groups exhibited a marked decrease in antioxidant markers, including reduced glutathione (GSH) and superoxide dismutase (SOD). However, the groups that received COQ10 alongside saccharin showed significant improvement, with oxidative stress and antioxidant levels nearly returning to those observed in the control group. These findings suggest that saccharin consumption promotes the generation of reactive oxygen species and contributes to liver damage, characterized by necrotic hepatocytes, sinusoidal dilatation, and inflammatory infiltration. The protective effects of COQ10 in mitigating saccharin-induced oxidative stress highlight its potential as a therapeutic agent for preventing liver damage associated with saccharin intake.

Quercetin attenuates cadmium-induced hepatotoxicity by suppressing oxidative stress and apoptosis in rat

BackgroundCadmium (Cd) is considered a major industrial and environmental toxicant, threatening the health of aquatic organisms, plants, animals, and humans. Quercetin (Que) is a natural flavonoid with antioxidant properties. The purpose of this study was to investigate the role of the oxidative stress and apoptosis in Cd-induced hepatotoxicity and the protective effect of Que. MethodologyThirty-six male SD rats were randomly divided into 6 groups: control group, 1 mg/kg Cd group, 2 mg/kg Cd group, 1 mg/kg Cd+Que group, 2 mg/kg Cd + Que group, and a Que group. After a feeding period of 28 days, serum and liver tissue samples were collected to evaluate liver function, oxidative stress levels, liver histology, and apoptosis. ResultsExperimental results confirmed that compared with the control group, the body weights of the Cd group significantly decreased. Additionally, there was a tremendous increased in the levels of ALT, AST, and LDH, and a significant decreased in the activities of SOD, CAT, and GSH content, while the level of MDA increased. Pathological sections of the liver showed that Cd-induced rats had ruptured liver tissue cells, exposed nuclei, and disturbed arrangement of hepatocyte cords. Cd exposure decreased the mRNA and protein expression of Nrf2 and NQO1 while increased the mRNA and protein expression of Keap1, thereby inducing oxidative stress. Meanwhile, Cd exposure increased the mRNA and protein expressions of Cytc, caspase-9, caspase-3, and Bax, while decreased the expression of Bcl-2. Conversely, after Que addition of alleviated liver injury and oxidative stress induced by Cd and inhibited apoptosis. ConclusionIn conclusion, Que alleviates hepatic toxicity induced by Cd through suppression of oxidative stress and apoptosis.

Adverse Impacts of PEGylated Protein Therapeutics: A Targeted Literature Review.

The beneficial effects of polyethylene glycol (PEG)-conjugated therapeutics, such as increased half-life, solubility, stability, and decreased immunogenicity, have been well described. There have been concerns, however, about adverse outcomes with their use, but understanding of those adverse outcomes is still relatively limited. The present study aimed to characterize adverse outcomes associated with PEGylation of protein-based therapeutics on immunogenicity, pharmacologic properties, and safety. A targeted review of English language articles published from 1990 to September 29, 2023, was conducted. Of the 29 studies included in this review, 18 reported adverse safety outcomes such as hematologic complications, hepatic toxicity, injection site reactions, arthralgia, nausea, infections, grade 3 or 4 adverse events (AEs), and AE-related discontinuations and dose modifications. Fifteen studies reported immunogenicity-related outcomes, such as the prevalence of pre-existing antibodies to PEG, treatment-emergent antibody response, and hypersensitivity reactions to PEGylated drugs. Seven studies reported pharmacological outcomes such as increased clearance and reduced activity in response to PEGylated drugs. This review aims to contribute to a balanced view of PEGylated therapies by summarizing the adverse outcomes or lack of benefit associated with PEGylated therapeutics reported in the literature. We identified several studies characterizing adverse outcomes, pharmacological effects, and immunogenicity associated with the use of PEGylated therapeutics. Our findings suggest that using PEGylated therapeutics may require careful monitoring for adverse safety outcomes, including screening and monitoring for pre-existing antibodies and those induced in response to PEGylated therapy, as well as monitoring and adjusting the dosing of PEGylated therapeutics.

Probiotics as Potential Tool to Mitigate Nucleotide Metabolism Alterations Induced by DiNP Dietary Exposure in Danio rerio.

Diisononyl phthalate, classified as endocrine disruptor, has been investigate to trigger lipid biosynthesis in both mammalian and teleostean animal models. Despite this, little is known about the effects of DiNP exposure at tolerable daily intake level and the possible mechanisms of its toxicity. Probiotics, on the other hand, were demonstrated to have beneficial effects on the organism's metabolism and recently emerged as a possible tool to mitigate the EDC toxicity. In the present study, using a metabolomic approach, the potential hepatic sex-related toxicity of DiNP was investigated in adult zebrafish together with the mitigating action of the probiotic formulation SLAB51, which has already demonstrated its ability to ameliorate gastrointestinal pathologies in animals including humans. Zebrafish were exposed for 28 days to 50 µg/kg body weight (bw)/day of DiNP (DiNP) through their diet and treated with 109 CFU/g bw of SLAB51 (P) and the combination of DiNP and SLAB51 (DiNP + P), and the results were compared to those of an untreated control group (C). DiNP reduced AMP, IMP, and GMP in the purine metabolism, while such alterations were not observed in the DiNP + P group, for which the phenotype overlapped that of C fish. In addition, in male, DiNP reduced UMP and CMP levels in the pyrimidine metabolism, while the co-administration of probiotic shifted the DiNP + P metabolic phenotype toward that of P male and closed to C male, suggesting the beneficial effects of probiotics also in male fish. Overall, these results provide the first evidence of the disruptive actions of DiNP on hepatic nucleotide metabolism and mitigating action of the probiotic to reduce a DiNP-induced response in a sex-related manner.