Increase In Aminotransferase Research Articles

Oral Toxicity of Magnesium Oxide Nanoparticles, MgO NPs on Liver in Male Rats

Nanotechnology is an emerging technology that has led to the nanomedicine development, which involves nanoparticles that exist in the natural world. Nanoparticle is an ultrafine unit with dimensions measured in nanometers. They are created as a result of human activities, and have recently been used in various biomedical applications, consumer products, and commercially, etc. Magnesium oxide nanoparticles (MgO NPs), among the known metal oxides, have attracted a vast scientific interest. Therefore, human health can be at risk of continuous exposure. However, the toxic effects of MgO NPs should be assessed with their increased applications. The present study aimed to investigate the physiological and histological, alterations induced by the MgO nanoparticles in hepatocytes of male rats through oral route with (250, and 1000) mg/kg for (14, 28, and 56) days. Fifty-four male mature rats, (2.5 - 3 months old) were divided randomly into nine groups of six rats each, gavaged with MgO NPs (which were purchased from US Research Nanomaterials, Inc). The results obtained revealed highly significant increase (p<0.01) in aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), and total bilirubin. The histopathological examinations showed sinusoidal dilatation, atrophy of hepatocytes, depletion of glycoprotein, focal area of necrosis, inflammatory cells infiltration and apoptosis. MgO NPs demonstrated potential harm to liver tissue, and human health.

Detection of Some Heavy Metals (Mercury and Lead) Pollutants and their Association with Type 2 Diabetes Mellitus (T2DM) in Baghdad, Iraq

Due to the increased use of products carrying heavy metals caused by human factors in the streets of the city of Baghdad and their direct impact on the air, water quality and soil pollution, heavy metals pollution is one of the important environmental problems. As heavy metals cannot be degraded, they accumulate biologically, and, therefore, can directly threaten higher organisms including humans. The current study focused on detecting heavy metals (mercury and lead) to determine the adverse effects and risk of developing type 2 diabetes mellitus (T2DM) in humans. One hundred total blood samples were collected from healthy people and the patients of both sexes who were suffering from T2DM, with mean age of 31 to 75 years, after 8 to 12 hours of fasting. The first group - G1 the control group consisted of 20 health people (6 males and 14 females). The second group - G2 included 40 patients (20 males and 20 females) who had T2DM and were not exposed to any pollutants. The third group - G3 included 40 males with T2DM and also who were exposed to smoke from local electricity generators, as these samples were collected from workers or living near generators and were exposed to air pollution for a long time. Blood samples were collected from each individual by drawing blood from a vein to evaluate each of the biochemical tests, as well as detecting of some heavy metals such as mercury and lead. The results showed that there was a highly significant increase (p≤0.01) when both fasting blood sugar (FBS) and HbA1c were analysed. As for the results of the analysis of the types of lipid profile, there is no significant difference in cholesterol, while there was a significant increase (p≤0.05) in both low-density lipoprotein (LDL) cholestrol and very low density lipoprotein (VLDL) cholestrol and a highly significant increase (p≤0.01) for both triglyceride and high density lipoporotein cholesterol (HDL) cholestrol. The results of the liver function analysis showed that there was no significant difference in the results of the enzyme serum glutamic oxaloacetic transaminase (SGOT) as well as total bilirubin, while there was a significant increase (p≤0.05) in serum glutamate pyruvate transaminase (SGPT). Significant increase (p≤0.01) was detected in the alkaline phosphatase (ALP) enzyme for each of the studied groups. The results of the detection of the presence of heavy metals using the atomic absorption spectrophotometer showed that there was a significant increase (p≤0.01) in lead, and as for mercury, no significant difference was noticed.

Histological and Enzymatic Changes of the Liver in Common Carp(Cyprinus carpio L. 1758) After Chronic Exposure to A Mixture of Goldate and Alexander Pesticides

Pesticides are man-made chemical compounds, widely used in agriculture to control different types of pests, product crops and prevent diseases which damage them. This experiment used herbicide Goldate, insecticide Alexander and their mixture with different concentrations exposed to common carp in 40L glass aquaria. The results showed that there was a significant increase in the alanine aminotransferase (ALT) and aspartate aminotransferase (AST) means value of mixture pesticides compared with control. The liver tissues of the fish exposure to pesticides groups G1, A1, M1 and M2 showed different degrees of jaundice, cellular swelling, necrosis hepatocytes and vascular degeneration of pancreatic acini and aggregation of bile pigments. These effects increased with the increase in pesticides concentrations and exposure time. These effects also increased when exposure was to more than one pesticide at the same time. The study aimed to evaluate the effects of two pesticides as mixture, study the chronic toxicity of Goldate, Alexander and their mixture by assessing ALT, AST and liver histological changes. This study concluded that the Goldate + Alexander mixture had adverse effects more than each one alone.

Potential of dehydroepiandrosterone and quercetin to ameliorate copper oxide nanoparticles induced hepatotoxicity in albino wistar rats.

The current investigation was designed as an experimental endeavor to explore the protective efficacy of dehydroepiandrosterone (DHEA) and quercetin against hepatotoxicity induced by copper oxide (CuO) nanoparticles. Rats were subjected to CuO nanoparticle intoxication through intraperitoneal injection of 150mg/kg b.w. for three weeks, followed by the administration of the aforementioned antioxidants for an additional three weeks. This study systematically tracked alterations in liver enzymatic activity, antioxidant levels, apoptotic markers, and histopathological changes using the comet assay. CuO nanoparticle-intoxicated rats exhibited a significant increase in serum alanine transaminase aspartate aminotransferase (AST), and bilirubin levels, coupled with a noteworthy reduction in serum albumin. Moreover, there was a marked rise in serum tumor necrosis factor-alpha levels, concomitant with a significant decline in serum hepatocyte growth factor (HGF). Caspase-3 and Bax mRNA levels in the serum showed a substantial increase, while serum Bcl-2 mRNA levels witnessed a significant decrease. Liver tissue levels of malondialdehyde (MDA) and nitric oxide (NOx) experienced a significant elevation, and DNA damage was observed through the comet assay. Histopathological examination of the liver tissue substantiated these aforementioned findings. Administration of the antioxidants DHEA or quercetin, either individually or in combination, mitigated the parameters of hepatotoxicity to varying extents. In summary, the hepatic genotoxicity induced by CuO nanoparticles demonstrated improvement following the administration of either DHEA or quercetin. Additionally, their combined administration exhibited a more potent protective potential.

Sarkome: Neue Kombinationstherapie mit günstigerem Nebenwirkungsprofil

Purpose: While cytotoxic chemotherapy is the standard first-line treatment for patients with metastatic soft-tissue sarcoma (STS), clinical outcomes remain suboptimal. Our prior study showed lurbinectedin plus doxorubicin is well tolerated with promising clinical activity in STS. We designed this phase 1b trial to optimize dosing as the basis for a randomized trial in leiomyosarcoma and to further explore the safety profile and efficacy signal. Patients and methods: Patients had advanced/metastatic STS and no prior anthracycline/lurbinectedin/trabectedin. Escalation followed a 3 + 3 design with 3-week cycles: lurbinectedin (3.2 mg/m2 day 1) and two doxorubicin levels (DL1, 25 mg/m2 day 1; DL2, 25 mg/m2 days 1 and 8). The primary objectives were to identify the maximum tolerated dose and recommended dose for subsequent randomized trials. Results: Ten patients were enrolled in a 6-month period. The most common treatment-emergent adverse events were grade (G) 2 fatigue and nausea, and G2 cytopenias with no febrile neutropenia events. There were two dose-limiting toxicities (DLTs) at DL2 [day 8 (G2 alanine aminotransferase [ALT]/aspartate aminotransferase increase, G3 neutropenia)], and one DLT in DL1 (G3 ALT increase). These were reversible and all patients continued the study. DL1 was chosen for further study. At the time of data cutoff, the estimated median progression-free survival is 16.5 months [95% confidence interval (CI), 6.0-ND]. The objective response rate was 60% (6/10 confirmed partial responses).

Toxicity and Anti-Trypanosomal Studies of Aqueous and Methanol Leaf Extracts of Acacia Nilotica on Trypanosoma Brucei-Induced Infection in Mice

African Animal Trypanosomiasis constitutes one of the greatest threats to the health of animals and socioeconomic status of people, particularly in developing countries. Chemotherapy, the main means of controlling the disease is limited due to parasite resistance and toxicity of the current anti-trypanosomal drugs. The development of a vaccine has been thwarted by antigenic variation of the parasite. Thus, plant extracts are one of the strategies being explored to address some of the problems encountered. The main objective of the current study was to investigate the toxicity and anti-trypanosomal activity of methanol and aqueous extracts of Acacia nilotica through in vivo assays against Trypanosoma brucei brucei. The chosen plants' healthy, fresh, matured leaves were air dried under shade, pulverized with mortar and pestle into powder, and passed through a 0.5mm mesh to standardize their particles. The plant samples were extracted using aqueous, methanol solvents. Qualitative and quantitative phytochemical analysis of the active chemical constituents of the extracts was conducted to determine saponins, flavonoids, tannins, terpenoids, steroids, and cardiac glycosides according to standard procedure. It was established that aqueous and methanol leaf extracts of the selected plants were safe in rats at dose levels of 1000, 3000, and 5000 mg/kg body weight for 72 hours. However, Sedation and abnormal movement were observed for both A. nilotica and Z. mucronata as manifestations of clinical toxicity at 5000mg/kg body weight. The fatal dose of all extracts exceeds the maximum dose of 5000mg/kg. Prolonged oral administration of the extracts for 21 days with A. nilotica extracts did not reveal major changes in body and organs weights, liver and kidney functions, the biochemical analysis showed a slight, non-significant increase in Alanine transaminase, Aspatate transaminase, and Alkaline phosphatase at (4000mg/kg) in rats, the average creatinine and urea levels were within the normal range, the relative organ weight and isolated organ are within the normal reference value. The photomicrographs of the liver and kidney sections showed mild histological changes. The in vivo assay showed the aqueous and methanol extracts from A. nilotica at 200mg/kg, 100mg/kg, and positive control (diminazine aceturate 3.5mg) reduced parasitaemia (p < 0.05), improved anaemia (p < 0.05), prevented body weight loss (p < 0.05) compared to the negative control. This study showed that the leaf of A. nilotica is safe and possess antitrypanosomal properties, suggesting that they may be a source of novel drugs for treatment of tropical diseases caused by trypanosomes.

Population Pharmacokinetics of Intravenous Paracetamol and Its Metabolites in Extreme Preterm Neonates in the Context of Patent Ductus Arteriosus Treatment.

Our aim was to describe the pharmacokinetics of paracetamol and its metabolites in extreme preterm neonates in the context of patent ductus arteriosus treatment. Factors associated with inter-individual variability and metabolic pathways were studied. The association between drug exposure and clinical outcomes were investigated. Preterm neonates of 23-26 weeks' gestational age received paracetamol within 12 h after birth. Plasma concentrations of paracetamol and its metabolites were measured throughout 5 days of treatment. Clinical success was defined as ductus closure on two consecutive days or at day 7. Aspartate aminotransferase and alanine aminotransferase levels were used as surrogates for liver damage. Data from 30 preterm neonates were available for pharmacokinetic analysis. Paracetamol pharmacokinetics were described using a two-compartment model with significant positive effects of weight on clearance and of birth length on peripheral compartment volume. Paracetamol was mainly metabolised into sulphate (89%) then glucuronide (6%), and the oxidative metabolic pathway was reduced (4%). The glucuronidation pathway increased with gestational age, whereas the sulfation pathway decreased. No difference was observed in drug exposure between successful and unsuccessful patients. No increase in aspartate aminotransferase and alanine aminotransferase levels were observed during treatment, and no association was found with either paracetamol or oxidative metabolite exposures. The relative proportions of the metabolic pathways were characterised with gestational age. In the range of observed drug exposures, no association was found with clinical response or liver biomarkers. These findings may suggest that paracetamol concentrations were within the range that already guarantee a maximum effect on ductus closure.

Results of monitoring probable cases of acute severe hepatitis of unknown etiology in children in Мoscow in 2022

In the spring 2022, the number of cases of severe acute hepatitis of unknown etiology was unusual increased in Europe. As an immediate response, the World health organization recommended active efforts to identify such cases at the international level. For monitoring of acute hepatitis in Moscow, patients with suspected liver disease were sent to Infectious Diseases Clinical Hospital No. 1. The goal: study of the structure of diseases occurring with liver damage in children hospitalized in 2022. Materials and methods: analysis of medical records of children hospitalized with a diagnosis of hepatitis from May 1 to December 31, 2022. Еpidemiological data (age, gender, parenteral manipulations, contacts with patients, travel abroad), clinical (fever, jaundice, etc.), laboratory parameters were assessed. Results: A total of 164 completed cases of hepatitis in children aged 5 months to 17 years were analyzed. 36 children met the criteria for probable severe acute hepatitis of unknown etiology. Age median was 7 years [2.25;11]. Girls made up more than half (21 (58.3%). Non-infectious genesis was established in 15 (41.6%). The infectious disease was verified in 11 (30.5%), of which adenoviral infection was detected in 2 children. In 9 (25%) children the etiology of hepatitis was not established. Conclusion. Various infectious and non-infectious diseases among hospitalized children lead to a significant increase in liver transaminases. Most acute hepatitis with unspecified etiology proceeded as an acute infectious disease and ended in recovery. The role of adenoviruses in the development of severe hepatitis in children was not confirmed in our study.

PROTECTIVE EFFECT OF COMBINATION OF ETHANOLIC EXTRACTS OF XIMENIA AMERICANA AND TERMINALIA MACROPTERA AGAINST ALCOHOL-INDUCED HEPATOTOXICITY IN RATS

Objective: The aim of this study was to evaluate the hepatoprotective effect of the combination. Methods: Serum liver markers, tissue antioxidant activity, and histological changes in the livers of rats from the blank, negative (distilled water), positive (silymarin 100 mg/kg bw), and test (combination 500 mg/kg bw) groups were measured after 7 days of pretreatment and induction of hepatotoxicity by 10 g/kg bw alcohol every 12 h for 48 h. Results: Rats in the negative control group showed a highly significant (p<0.001) increase in aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin (BT) levels by 281.13%, 221.7%, and 93.44%, respectively, compared to rats in the blank group. Pretreatment with the combination resulted in a highly significant (p<0.001) decrease in AST, ALT, and BT levels of 69.19%, 62.24%, and 41.52%, respectively. The study of tissue oxidative stress parameters revealed a very significant (p<0.01) increase in superoxide dismutase (123.08%), glutathione (131.66%), and catalase (49.01%) activities and a significant (p<0.05) decrease in malondialdehyde concentration (59.72%) in the group pretreated with the combination compared with the negative control group. Steatosis and necrosis estimated at 50% were observed in rats in the negative control group. In contrast, necrosis observed in the group pre-treated with the combination was <10%. Conclusion: These data suggest that the combination is effective in preventing the elevation of biochemical markers and the imbalance of enzymatic and non-enzymatic antioxidant systems caused by alcohol.

Beyond soybean meal: investigating the effects of dietary protein alternatives on gut health, liver function and microbiota in traditional slow-growing chicken breeds

The use of soybean meal in animal feed is crucial for nutrition but has a significant environmental impact, especially related to deforestation and biodiversity loss. With the increasing demand for sustainable agricultural practices, it becomes essential to explore alternatives to soybean meal. This study evaluated the effect of a soy-free diet, replaced with fava beans and pea protein, on an Italian slow-growing chicken breed: the Bianca di Saluzzo. The results indicate that the experimental diet did not compromise the growth, final weight or intestinal health of the animals, demonstrating a good tolerance and adaptability of the breed to these alternative ingredients. Furthermore, the analysis of the intestinal microbiota showed a positive impact, with an increase in organic acids such as succinic and citric, which could improve intestinal health and metabolic efficiency. Some changes in liver enzyme levels were observed, such as the increase in glutamate-oxaloacetate transaminase, an enzyme involved in amino acid metabolism. This increase could indicate a higher efficiency in protein metabolism, suggesting that the diet based on alternative ingredients could support an improvement in liver metabolism. Although this aspect deserves further investigation, it could represent a positive effect of the diet on liver function and overall health of the animals. Further studies are needed to fully understand the long-term implications of these dietary modifications, particularly in relation to the gut microbiota and metabolism.

Effect of ethyl acetate extract from Usnea longissima on chemotherapy-associated multiple organ dysfunction in rats

BackgroundThe toxic effects of doxorubicin and cisplatin in various organs have been associated with oxidative stress. Studies have shown that Usnea longissima has strong antioxidant effects. This study aimed to investigate the protective effect of ethyl acetate extract from Usnea longissima (ULE), which is known to have strong antioxidant effects, on chemotherapeutic-induced heart, kidney, liver, and ovarian toxicity. MethodsAlbino Wistar female rats were divided into five groups (12 rats per group): healthy (HG), doxorubicin (DOX), Cisplatin (CIS), Doxorubicin+ ULE (DULE), Cisplatin+ ULE (CULE). In this experiment, ULE was given 100 mg/kg orally. After 1 hour, 2.5 mg/kg doxorubicin and 2.5 mg/kg cisplatin were administered intraperitoneally. Drug treatments continued once a day for seven days. At the end of seven days, six rats from each group were euthanized and heart, kidney, liver, and ovary tissues were analyzed biochemically. The remaining rats were left in the laboratory with male rats for 45 days for reproduction. ResultsULE inhibited chemotherapeutic-induced increase in malondialdehyde, tumor necrosis factor-alpha, and interleukin 6 and a decrease in total glutathione in liver, kidney, and ovarian tissues. ULE also inhibited the increase of blood urea nitrogen, creatinine, alanine aminotransferase, and aspartate aminotransferase in serum. ULE treatment had no protective effect against doxorubicin and cisplatin cardiac toxicity. On the other hand, ULE also decreased the delay in pregnancy induced by chemotherapy. ConclusionULE may be considered an adjuvant therapy in patients receiving chemotherapy to reduce liver, kidney, and ovarian toxicity.

Investigation of hematological, biochemical and coagulological markers, their diagnostic effectiveness in toxic hepatitis in patients with COVID‑19

This article discusses hematological, biochemical and coagulological markers for the diagnosis of toxic hepatitis in patients with COVID-19. The analysis of the effectiveness of these markers in a large sample of patients confirmed their importance for the early detection of toxic hepatitis b in patients with COVID-19. Blood parameters such as platelets, ALT, AST, bilirubin, as well as coagulograms and markers of protein metabolism (albumin) conducted among patients divided into control and experimental groups were analyzed. It was found that in patients with concomitant toxic hepatitis c COVID-19, the tendency of thrombocytopenia is most common in clinical blood analysis. Among the biochemical parameters of blood, liver markers increase (ALT, GGT, alkaline phosphatase, etc.). It should be noted that in 1/3 of patients, the activity of liver enzymes alanine aminotransferase and aspartate aminotransferase increases, which indicates a violation of liver function.The analysis of these data using ROC analysis showed high diagnostic accuracy of these markers in the detection of toxic hepatitis in patients with COVID-19. These studies may be important for more effective screening and further monitoring of appropriately selected treatment in such clinical situations and contributes to more effective management of this condition, leading to an improved prognosis of this disease. This study is important in the context of understanding the effects of COVID-19 on liver function.

Long-Term Impact of Lumacaftor/Ivacaftor Treatment on Cystic Fibrosis Disease Progression in Children 2-5 Years of Age Homozygous for F508del-CFTR: A Phase 2, Open-Label Clinical Trial.

Rationale: Clinical trials show that lumacaftor/ivacaftor (LUM/IVA) treatment has the potential to modify early cystic fibrosis (CF) disease progression in children as young as 2 years of age. Objectives: To assess the long-term impact of LUM/IVA treatment on CF disease progression in children aged 2-5 years. Methods: This phase 2 trial had two parts: part 1, a 48-week, randomized, double-blind, placebo-controlled study of LUM/IVA in children aged 2-5 years (previously reported) was followed by a 48-week open-label treatment period in which all children received LUM/IVA (part 2; reported here). Endpoints assessed in part 2 included absolute changes from baseline in chest magnetic resonance imaging (MRI) global score at Week 96; weight-for-age, stature-for-age, and body mass index (BMI)-for-age z-scores at Week 96; lung clearance index based on lung volume turnover required to reach 2.5% of starting N2 concentration (LCI2.5) through Week 96; chest MRI morphological score, chest MRI perfusion score, weight, stature, BMI, and microbiology cultures (oropharyngeal swabs) at Week 96; sweat chloride, amount of immunoreactive trypsinogen, fecal elastase-1 concentration, and fecal calprotectin through Week 96; and number of pulmonary exacerbations, time to first pulmonary exacerbation, and number of CF-related hospitalizations. Results: Forty-nine children received one or more doses of LUM/IVA in the open-label period (33 in the LUM/IVA to LUM/IVA group and 16 in the placebo to LUM/IVA group), with a mean exposure of 47.1 (standard deviation [SD], 5.2) weeks. The mean absolute change in MRI global score (negative value indicates improvement) from baseline at Week 96 was -2.7 (SD, 7.0; 95% confidence interval [CI], -5.2 to -0.1) in the LUM/IVA to LUM/IVA group and -5.6 (SD, 6.9; 95% CI, -9.2 to -1.9) in the placebo to LUM/IVA group. Improvements in LCI2.5, sweat chloride concentration, and markers of pancreatic function and intestinal inflammation were also observed in both groups. Growth parameters remained stable in both groups. The majority of children had adverse events considered mild (38.8%) or moderate (40.8%). Two (4.1%) children discontinued LUM/IVA treatment because of adverse events (distal intestinal obstruction syndrome [n = 1] and alanine aminotransferase increase [n = 1]). Conclusions: These findings confirm the potential for early LUM/IVA treatment to alter the trajectory of CF disease progression, including CF lung disease, in children as young as 2 years of age. Clinical trial registered with ClinicalTrials.gov (NCT03625466).

Zinc oxide nanoparticle biofortification of lentil seedlings enhances plant growth and zinc bioavailability in rats

This study aimed to evaluate the potential of zinc oxide nanoparticles (ZnO NPs) in the biofortification of lentil seedlings and subsequently improve the Zn status in rats. In the first phase of the study, the effects of various ZnO NPs concentrations (0, 10, 20, 40, 80, and 160 ppm) on the lentil growth, Zn accumulation, and other physiological parameters were investigated. Subsequently, the rats were fed ZnO NP-biofortified lentil seedlings (20 and 160 ppm) to assess their impact on animal health and Zn status. The results highlighted a concentration-dependent response of lentil seedlings to ZnO NPs, with optimal growth observed at 20 ppm, whereas higher concentrations inhibited lentil growth. Pigment and biochemical analyses revealed a complex interplay between chlorophyll, carotenoids, soluble sugars, and proteins with distinct responses to nanoparticle concentrations. Elevated levels of hydrogen peroxide and malondialdehyde of lentil seedlings at high concentrations of ZnO NPs suggest oxidative stress, countered by the upregulation of antioxidant enzymes and increased phenolic compounds. On the other hand. animal studies have showed that ZnO NP-biofortified lentil seedlings enhance serum zinc and magnesium levels in rats without affecting body weight. While serum triglyceride levels of rats decreased in both treatment groups, an elevation in creatinine and a marked increase in aspartate aminotransferase (AST) levels were observed at a higher ZnO NP concentration (160 ppm), indicative of potential kidney and liver stress. Paradoxically, serum iron levels were lower in all groups consuming lentil seedlings than in the control group, suggesting a potential interaction between lentil components and iron metabolism. These findings suggest that ZnO NP-biofortified lentils may be a promising approach to enhance Zn nutrition; however, further investigation is needed to optimize ZnO NPs concentration and assess long-term safety.

The benefit and risk of addition of chemotherapy to EGFR tyrosine kinase inhibitors for EGFR-positive non-small cell lung cancer patients with brain metastases: a meta-analysis based on randomized controlled trials.

Combining epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) with chemotherapy (ETC) offers more advantages for patients with EGFR-positive non-small cell lung cancer (NSCLC) than using EGFR TKIs alone (ET). However, whether this conclusion applies to patients with brain metastases (BM) remains controversial. This meta-analysis was performed to evaluate the benefits and risks of the two groups. Six databases were systematically searched for relevant literatures comparing ETC versus ET in treating EGFR-positive NSCLC patients with BM. The primary outcome assessed was overall survival (OS), while secondary outcomes included progression-free survival (PFS), and central nervous system (CNS)-PFS, responses, progression status and safety. Seven studies based on five randomized clinical trials with 550 patients were included. The ETC group exhibited better OS (hazard ratio [HR]: 0.64 [0.48, 0.87]), PFS (HR: 0.42 [0.34, 0.52]), and CNS-PFS (HR: 0.42 [0.31, 0.57]). The benefits in survival for OS, PFS, and CNS-PFS were validated in nearly all subgroups. Meanwhile, the overall objective response rate (ORR) (risk ratio [RR]: 1.25 [1.02, 1.52]) and CNS-ORR (RR: 1.19 [0.93, 1.51]) also tended to favor the ETC group. However, the addition of chemotherapy also brought about more grade 3-5/serious adverse events (AEs). The top five grade 3-5 AEs in the ETC group were alanine aminotransferase increase (11.25%), neutropenia (7.5%), nausea (7.5%), anorexia (5%), and diarrhea (5%). ETC appears to be better than ET in treating EGFR-positive NSCLC patients with BM, with better OS, PFS, CNS-PFS, and responses. However, its poorer safety profile also needs to be taken into consideration. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024551073.

Efficacy evaluation of extending or switching to tenofovir amibufenamide in patients with chronic hepatitis B: a phase Ⅲ randomized controlled study

Objective: In chronic hepatitis B (CHB) patients with previous 96-week treatment with tenofovir amibufenamide (TMF) or tenofovir disoproxil fumarate (TDF), we investigated the efficacy of sequential TMF treatment from 96 to 144 weeks. Methods: Enrolled subjects who were previously assigned (2:1) to receive either 25 mg TMF or 300 mg TDF with matching placebo for 96 weeks received extended or switched TMF treatment for 48 weeks. Efficacy was evaluated based on virological, serological, biological parameters, and fibrosis staging. Statistical analysis was performed using the McNemar test, t-test, or Log-Rank test according to the data. Results: 593 subjects from the initial TMF group and 287 subjects from the TDF group were included at week 144, with the proportions of HBV DNA<20 IU/ml at week 144 being 86.2% and 83.3%, respectively, and 78.1% and 73.8% in patients with baseline HBV DNA levels ≥8 log10 IU/ml. Resistance to tenofovir was not detected in both groups. For HBeAg loss and seroconversion rates, both groups showed a further increase from week 96 to 144 and the 3-year cumulative rates of HBeAg loss were about 35% in each group. However, HBsAg levels were less affected during 96 to 144 weeks. For patients switched from TDF to TMF, a substantial further increase in the alanine aminotransferase (ALT) normalization rate was observed (11.4%), along with improved FIB-4 scores. Conclusion: After 144 weeks of TMF treatment, CHB patients achieved high rates of virological, serological, and biochemical responses, as well as improved liver fibrosis outcomes. Also, switching to TMF resulted in significant benefits in ALT normalization rates (NCT03903796).

Nonclinical Profile of PF-06952229 (MDV6058), a Novel TGFβRI/Activin Like Kinase 5 Inhibitor Supports Clinical Evaluation in Cancer.

The development of transforming growth factor βreceptor inhibitors (TGFβRi) as new medicines has been affected by cardiac valvulopathy and arteriopathy toxicity findings in nonclinical toxicology studies. PF-06952229 (MDV6058) selected using rational drug design is a potent and selective TGFβRI inhibitor with a relatively clean off-target selectivity profile and good pharmacokinetic properties across species. PF-06952229 inhibited clinically translatable phospho-SMAD2 biomarker (≥60%) in human and cynomolgus monkey peripheral blood mononuclear cells, as well as in mouse and rat splenocytes. Using an optimized, intermittent dosing schedule (7-day on/7-day off/cycle; 5 cycles), PF-06952229 demonstrated efficacy in a 63-day syngeneic MC38 colon carcinoma mouse model. In the pivotal repeat-dose toxicity studies (rat and cynomolgus monkey), PF-06952229 on an intermittent dosing schedule (5-day on/5-day off cycle; 5 cycles, 28 doses) showed no cardiac-related adverse findings. However, new toxicity findings related to PF-06952229 included reversible hepatocellular (hepatocyte necrosis with corresponding clinically monitorable transaminase increases) and lung (hemorrhage with mixed cell inflammation) findings at ≥ targeted projected clinical efficacious exposures. Furthermore, partially reversible cartilage hypertrophy (trachea and femur in rat; femur in monkey) and partially to fully reversible, clinically monitorable decreases in serum phosphorus and urinary phosphate at ≥ projected clinically efficacious exposures were observed. Given the integral role of TGFβ in endochondral bone formation, cartilage findings in toxicity studies have been observed with other TGFβRi classes of compounds. The favorable cumulative profile of PF-06952229 in biochemical, pharmacodynamic, pharmacokinetic, and nonclinical studies allowed for its evaluation in cancer patients using the intermittent dosing schedule (7-day on/7-day off) and careful protocol-defined monitoring. SIGNIFICANCE STATEMENT: Only a few TGFβRi have progressed for clinical evaluation due to adverse cardiac findings in pivotal nonclinical toxicity studies. The potential translations of such findings in patients are of major concern. Using a carefully optimized intermittent dosing schedule, PF-06952229 has demonstrated impressive pharmacological efficacy in the syngeneic MC38 colon carcinoma mouse model. Additionally, a nonclinical toxicology package without cardiovascular liabilities and generally monitorable toxicity profile has been completed. The compound presents an acceptable International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use S9-compliant profile for the intended-to-treat cancer patients.

Extracorporeal membrane oxygenation ameliorate hepatic injury in brain death rat donors with hemodynamic instability.

Donation after brain death (DBD) serves as the primary source for liver transplantation. However, livers obtained through DBD often incur damage due to unstable hemodynamics, potentially impacting transplantation outcomes. Extracorporeal Membrane Oxygenation (ECMO) emerges as an optimal technique for donor liver retrieval and has found application in clinical settings. Despite its clinical implementation, the precise mechanisms through which ECMO enhances liver functions remain elusive. This study aims to investigate the mechanisms underlying how ECMO ameliorates liver function in brain-dead donors. We randomly assigned 18 male Sprague-Dawley (SD) rats (350 ± 50 g) into three groups: Con (n = 6), DBD-assisted drug (n = 6), and DBD-assisted ECMO (n = 6). After 3 h of ECMO, the rats were sacrificed. We assessed and compared changes in heart rate, blood pressure, cumulative liver damage (evaluated through HE and TUNEL staining), serum levels of AST and ALT, alterations in serum oxidative stress factors (MDA, H2O2, SOD, and 8-OHdG), and serum concentrations of related inflammatory factors (interleukin [IL]-1β, IL-6, IL-8, and TNF-α) among rats in the Con, DBD-assisted drug, and DBD-assisted ECMO groups. Subsequently, we established a rat orthotopic liver transplantation (OLT) model and transplanted livers obtained through the aforementioned methods. The post-transplantation status of the livers was observed. After 3 h of brain death, liver injury worsened, accompanied by a significant increase in serum transaminases, inflammatory responses, oxidative stress, and TUNEL staining. Strikingly, ECMO not only stabilized hemodynamics after DBD but also mitigated liver damage, leading to an alleviated status post liver transplantation. ECMO stabilizes hemodynamics, attenuates inflammatory responses and oxidative stress, thereby enhancing the quality of liver grafts for transplantation.

Hyperbilirubinemia and Hepatic Dysfunction in Patients Undergoing Cardiac Surgery: Predictors and Outcome - A single Centre Prospective Study

Background: We aim to assess the incidence and perioperative risk factors for hyperbilirubinemia and hepatic dysfunction after cardiac surgery and determine its influence on early operative outcome. Methods: This prospective observational study was conducted on 485 patients who underwent cardiac surgical procedures from June 2022 to October 2023. Postoperative hyperbilirubinemia was defined as serum total bilirubin &gt;2.0 mg/dl. Results: The overall incidence of post operative hyperbilirubinemia was 24.5% (119 patients). Total and indirect bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase was measured preoperatively and at day 1, day 2 and day 5. Patients undergoing valve repair or replacement had the highest incidence of hyperbilirubinemia (37.1%), followed by coronary artery bypass grafting with concomitant valve surgery (35.3%), congenital heart surgery (24.5%), and coronary artery bypass alone (12.4%). Post operative hyperbilirubinemia was associated with increased duration of inotropic support (p=0.0001), mechanical ventilation (p=0.0001), intensive care unit stay (p=0.001), hospital stay (p=0.006), and mortality (p=0.014). The perioperative factors associated with postoperative hyperbilirubinemia were increased preoperative bilirubin level (p&lt;0.0001), preoperative prothrombin time (p&lt;0.0001), cardiopulmonary bypass time (p=0.026), aortic cross clamp time (p=0.004), and blood transfusion units (p=0.0001). A significant increase of total bilirubin, aspartate aminotransferase, and alkaline phosphatase were noted in the second postoperative day. Significant relation was seen between hypotension and alkaline phosphatase, and aspartate aminotransferase change but hypothermia had not affected alanine aminotransferase, total bilirubin and indirect bilirubin change. Conclusions: Post operative hyperbilirubinemia is seen in patients undergoing cardiopulmonary bypass and is associated with high hospital mortality. The factors associated with its occurrence are increased preoperative bilirubin level, preoperative prothrombin time, cardiopulmonary bypass time, aortic cross clamp time, and blood transfusion units. Persistent hyperbilirubinemia is associated with a worse outcome than early transient hyperbilirubinemia.

Astilbin alleviates hepatic fibrosis through PXR-PINK1/Parkin pathway: A new strategy by regulating hepatic stellate cells-macrophage crosstalk

BackgroundAstilbin (ATB), a natural dihydroflavonol compound, exists in many plants, processed and functional foods. ATB has multiple pharmacological effects, such as antioxidant, lipid-lowering, and hepatoprotective. However, its anti-hepatic fibrosis and mechanisms remain unclearly elucidated. PurposeThis study explored the effect of ATB against the hepatic fibrosis and its regulation of hepatic microenvironment by regulating hepatic stellate cells-macrophage crosstalk. MethodThioacetamide (TAA) was intraperitoneal injected to establish hepatic fibrosis mice, and treated with ATB or curcumin by gavage, respectively. Hepatic stellate cells (HSCs) were stimulated with TGF-β or conditioned medium (CM) from LPS-induced THP-1, then cultured with ATB, PXR agonist or antagonist. ResultsIn TAA-induced mice, ATB improved histopathological changes, serum transaminases increase; alleviated extracellular matrix (ECM) deposition, epithelial-mesenchymal transformation (EMT), inflammatory infiltration, PTEN induced kinase 1 (PINK1)/Parkin-mediated mitophagy and activated pregnane X receptor (PXR) expression. In vitro, ATB significantly reduced ECM, inflammatory cytokines release, mitophagy, EMT, and activated PXR expression. ATB could increase PXR and decrease PINK1/Parkin, functioning as a PXR agonist. PXR deficiency in LX-2 could degrade the regulation of ATB on ECM, inflammation, EMT, and mitophagy. CM from LPS-induced THP-1 activated LX-2 and resulted in PXR decreasing, while ATB could regulate the crosstalk between HSCs and macrophages. Deficiency of PXR, whether in LX-2 or in macrophages, all weakened the inhibitory effect of ATB on α-SMA, EMT, inflammatory cytokines, and PINK1/Parkin signaling. ConclusionATB ameliorated hepatic fibrosis by inhibiting HSCs activation, inflammation and EMT through PXR-mediated PINK1/Parkin signaling. Especially, ATB targeted the hepatic microenvironment between hepatic stellate cells and macrophages, which might be a promising strategy for the treatment of hepatic fibrosis.