Increase In AST Research Articles

A First-in-Human Phase 1 Study of the Menin-KMT2A (MLL1) Inhibitor JNJ-75276617 in Adult Patients with Relapsed/Refractory Acute Leukemia Harboring KMT2A or NPM1 Alterations

Background: Relapsed/refractory (R/R)acute leukemia withalterations in KMT2A (also called MLL1; 9-15% of adult AML, 10% of ALL) or NPM1 (30% of adult AML) are often associated with poor outcomes. Pre-clinical studies demonstrated the relevance of the menin-KMT2A protein-protein interaction in sustaining leukemic cells with KMT2A and NPM1 alterations (Kuhn 2016). JNJ-75276617 is a potent and selective inhibitor of the interaction between the scaffolding protein menin and the methyltransferase KMT2A with preclinical activity in KMT2A-rearranged or NPM1-mutated leukemic cell lines and primary leukemia patient samples in vitro and in vivo (Kwon 2022). We report initial data investigating JNJ-75276617 in adult participants (pts) with R/R acute leukemia harboring KMT2A alterations (rearrangements, amplifications, or partial tandem duplications) or NPM1 mutations. Methods: 75276617ALE1001 (NCT04811560) is an ongoing Phase 1, multicenter, open-label, dose-finding study. Pts in dose escalation receive JNJ-75276617 orally on a 28-day cycle. As of 8 April 2023, multiple dose levels ≥15 mg have been explored on either a daily or twice daily (BID) dosing schedule. AEs were graded by CTCAE v5.0. Responses were investigator-assessed per ELN2017. Preliminary safety, efficacy and PD data are reported herein, with a focused review of the efficacy in higher dose levels with ≥3 pts dosed. Results: Fifty-eight pts received JNJ-75276617. The median age was 63 (range: 19-83) years; 56 pts (97%) had R/R AML and 2 (3%) had R/R ALL. The median number of prior lines of treatment was 2 (range: 1-7), including 10 (17%) pts with a prior allogeneic stem cell transplant. A KMT2A or NPM1 alteration was present in 33 (57%) and 25 (43%) pts, respectively. Thirty (52%) pts experienced ≥1 treatment-related AE (TRAE); most commonly differentiation syndrome (DS) (8 [14%]). Grade ≥3 TRAEs were observed in 17 (29%) pts; those reported in ≥2 pts were neutropenia (6 [10%]), anemia and thrombocytopenia (4 [7%] each), DS (3 [5%]), and ALT and AST increase (2 [3%] each). Dose limiting toxicities (DLTs) were observed in 5 (9%) pts, with DS (2 [3%]) as the only DLT reported in ≥2 pts. In 26 (63%) of the 41 pts with disease evaluation data, there was a reduction in bone marrow (BM) disease burden ( Figure 1). Of these, a ≥50% decrease in BM blasts was observed in 16 (39%) pts. In the highest dose level with ≥3 pts (90 mg BID; n=8), the ORR (≥PR) was 50% (n=4), with all responders ongoing ( Figure 2). These responders (2 NPM1-, 2 KMT2A-altered) achieved CR (1 pt), CRh (1 pt), and CRi (2 pts). In a review of higher dose levels with ≥3 pts (≥45 mg BID; n=20), the ORR was 40% (n=8), with 7 responders ongoing ( Figure 2). These responders (5 NPM1-, 3 KMT2A-altered) achieved CR (3 pts), CRh (1 pt), CRi (3 pts), and PR (1 pt); median (range) time to first response (≥PR) 1.81 mos (1.0-3.3; n=8); time to CR, CRh, or CRi 1.77 mos (1.0-3.3; n=7); and time to CR 2.79 mos (1.8-2.9; n=3). Across all cohorts there were 12 responders, including 1 MRD negative CR. One responder discontinued treatment for allogeneic transplant; however, 8 responders continue on treatment, including 2 pts in cycle 9. Preliminary PD data from unfractionated BM and/or PBMCs in paired samples among responders (n=12) show biologic activity as indicated by reduction in expression (mean fold change from baseline calculated as [on-tx-baseline]/baseline [range]) of menin-KMT2A target genes ( MEIS1 -0.42 [-1.0-9.0]; HOXA9 -0.03 [-1.0-21.7]; FLT3 18.6 [-1.0-425]) and induction of genes associated with differentiation ( ITGAM 55.0 [-0.93-1467]; MNDA 5.9 [-1.0-83.5]). Compared to baseline, the percentage of KMT2A-altered cells or NPM1 variant allele frequency (VAF) was reduced in responders, with a decrease in KMT2A-altered cells by break-apart FISH probe from 59.2% at baseline to 8.1% post-treatment and in NPM1 VAF using a myeloid gene NGS panel from 13.1% at baseline to 2.8% post-treatment. Conclusions: Dose escalation in 75276617ALE1001 is ongoing with the RP2D(s) yet to be determined. Pts in dose expansion will receive JNJ-75276617 at the identified RP2D(s). Preliminary results of this FIH Phase 1 study demonstrate that JNJ-75276617 monotherapy has an acceptable safety profile, encouraging antileukemic activity, and emerging biologic activity consistent with the proposed mechanism of action in pts with R/R acute leukemia harboring KMT2A or NPM1 alterations.

Impact of MTHFR Polymorphisms C677T and A1298C in Acute Lymphoblastic Leukemia and Burkitt Lymphoma Patients Exposed to Methotrexate and Asparaginase

Background: Asparaginase (Asp) and high-dose methotrexate (HDMTX) are pivotal drugs in the treatment of aggressive hematological malignancies as acute lymphoblastic leukemia (ALL) and Burkitt lymphoma (BL). Asp and MTX present specific drug-related toxicities; for Asp, prothrombotic alteration of the coagulation profile, hepatobiliary and pancreatic toxicities, for MTX, renal, hepatobiliary, hematologic, gastro-intestinal and neuro- toxicity. The 5,10-methylenetetrahydrofolate reductase (MTHFR) is the enzyme involved in conversion of homocysteine into methionine. MTHFR most frequent single nucleotide polymorphisms C677T and A1298C are associated with reduced enzymatic activity up to 60%, that implies hyperhomocysteinemia and increased toxicity of MTX. Numerous studies have explored the relationship between C677T and A1298C polymorphisms of MTHFR and MTX toxicity and/or outcome in children ALL, but results are controversial. Nevertheless, it is common practice to reduce MTX dosage in adult patients in homozygosis. Aims: To explore the relationship between the MTHFR C677T and A1298C polymorphisms in homozygosis and development of MTX toxicity in a cohort of adult patients; furthermore, to evaluate the relationship with thrombotic risk in patients exposed to Asp. Materials and Methods: Data from consecutive adult onco-hematologic patients for whom MTHFR C677T and A1298C polymorphism analysis was available, treated with chemotherapeutic regimens containing HDMTX and/or Asp was retrospectively collected at a single center Italian institution. Adverse events (AEs) were graded according to CTCAE 5.0. Statistical analysis was performed with R language. The impact of MTHFR polymorphisms was evaluated by mean of a multivariate analysis adjusting Odds Ratio (OR) estimates for drug dosage and disease status. Results: Data from 78 patients, 57 affected by ALL, 3 by mixed phenotype leukemia (MPAL) and 18 by BL, was retrospectively collected. Overall, 13 (16.7%) of patients were 677TT and 8 (10.3%) were 1298CC. Patients with ALL/MPAL received mostly pediatric-inspired chemotherapy regimens (containing MTX 2.5 - 5 g/m 2 and Asp 1000-2000 UI/m 2), patients with BL received modified Rituxumab (R)-BFM protocol (MTX 1.5 g/m2); age/comorbidities-adjusted dose reduction was performed according to institutional guidelines. Median age for ALL and BL patients was 37.5 (IQR 27.0-54.2) and 33.5 (26.0-49.7) years, respectively; 54/78 (69.2%) of patients were male. Patients received a median of 3 (IQR 2-6) cycles containing HDMTX and/or Asp, for a total number of 299 cycles (94 containing Asp, 184 HDMTX and 24 both); 142 (48.0%) cycles were administered for active disease (AD), at diagnosis/relapse, and 154 (52.0%) in complete remission (CR). The impact of different dosages of Asp < 1000 UI/m 2 and ≥ 1000 UI/m² and of HDMTX <1.5 g/m 2 and ≥ 1.5 g/m 2 as well as the impact of disease status (AD vs CR) on AEs was explored. Concerning Asp therapy and thrombotic risk, 13 deep vein thrombosis (DVT) were observed, but no association between 677TT nor 1298CC was appreciated. AD status was strongly related to DVT (21.4% vs 1.8%, p 0.003). Coherently with the MTHFR-independent drug's mechanism of action, the polymorphisms had no impact on the development of Asp-related toxicities. Diversely, concerning HDMTX, in multivariate analysis, patients with 677TT were more likely to experience AST increase grade ≥3 (OR 10.55, 95%CI 1.34-83.09) while a protective role versus any grade GGT increase was observed (OR 0.09, 95%CI 0.01-0.71) (Figure 1A). Patients with 1298CC exhibited a superior incidence any grade AST/ALT increase, not confirmed for grade ≥3 (Figure 1B). No significant superior toxicity was observed in terms of renal, gastro-intestinal, hematologic AEs. The impact of a MTX dose reduction >25% of expected dose was then explored in a homogeneous population of 45 front-line pediatric-regimen treated ALL patients (35 received MTX dose ≥75% and 10 < 75%) and no impact in terms of OS and RFS was appreciated. Conclusions: The analysis ofMTHFR polymorphisms in adult patients is useful in identifying patients at higher risk for transaminitis, providing a biological parameter to integrate with hepatosteatosis, liver stiffness evaluation and BMI, for a comprehensive hepatic baseline evaluation. Patients at higher risk for hepatic complications may benefit from MTX dose reduction with no impact on disease outcome.

Effect of Vitamins A, E, D3 Supplemented with Omega3 and Vitamins A, E, D3 (without Omega -3) on Biochemical Blood Parameters of Females Awassi Lamb

This study was conducted in the animal field of the University of Anbar College of Agriculture from 15/December/2021 to 15/February/2022. Twelve Iraqi Awassi female lambs were used in the experiment, at ranged of ages 2-3 months with average body weight 16.737 kg. The experimental animals were randomly divided into three groups, each group consisted of four lambs. The first group (G1) was considered the control group and left without any treatment, while the second group (G2) was treated with omega-3 supplemented with vitamins A, D3 and E of 1.5 CC, whilst the third group (G3) was treated with vitamins A, D3 and E of 1.5 CC by intramuscular injection, the lambs were injected with 6 times, the interval between each injection was 15 days. The lambs were nourished on the same concentrated diet, alfalfa hay, minerals bloke and water given adliptum. The result showed that G2 had significant increased (P≤0.05) on glucose concentration level as comported with G1. G3 had significant increase (P≤0.05) in urea concentration level as comported with G1 and G2. G3 had significant increased (P≤0.05) in Cholesterol and Triglyceride concentration level as comported with G1and G2. G1 had significant increase in LDL concentration level as comported with G2 and G3. T1 had significant increase in AST in G1, G2 and G3 as comported with T2 and T3. In conclusion, that treat a lamb with vitamins A, E, D3 supplemented with omega3 and vitamins A, E, D3 (without omega -3) led to improve lipid profile, liver enzyme activity and public health of lambs.

Effect of high-sucrose diet on liver enzymes and serum protein levels of Wistar albino rats

A global change in dietary habits has led to the introduction of sweeteners in foods. This study investigated the effect of concentrations of sucrose on liver enzymes and serum protein levels in Wistar rats. Thirty-five (35) Wistar rats were equally randomized into seven groups and fed with a rat diet mixed with sucrose at concentrations of 10, 20, 40, 60, 80, and 100% w/w, while the control group was fed on a normal diet without sucrose. Their blood samples were analyzed for total protein, albumin, ALT, AST, ALK phosphatase, and gamma-glutamyl transpeptidase (ƔGT) levels. The results indicated that there was a significant (p<0.05) increase in AST (16.00-82.00 µ/L), ALT (44.00-90.80 µ/L), ALK Phos (44.00-90.80 µ/L), and a corresponding decrease in total proteins (69.80-61.39 g/L), albumin (36.00-34.00 g/L) and ƔGT (493.00-191.00 µ/L) levels as the concentration of sucrose increased. Rats fed with sucrose diets had higher levels of AST (39.27 µ/L), ALT (14.50 µ/L), and ALK Phos (68.47 µ/L) than rats fed with normal diets. Therefore, high doses of sucrose can cause increases in serum liver enzymes and total proteins that are suggestive of liver necrosis. Hence, by decreasing the concentrations of sucrose, the liver may be protected.

Nesfatin-1 is a biomarker that plays a role in the inflammatory process of coronary artery diseases in Iraqi patients with non-alcoholic fatty liver disease.

Amis: NAFLD is considered to be the most common cause of liver conditions worldwide. Also, it is a primary reason that leads to coronary artery diseases, limiting blood flow to the heart. Therefore, This study aimed to evaluate the serum level of Nesfatin-1 and its ability to indicate the prognosis of CAD in patients with NAFLD. Material & Methods: one-hundred eighty Individuals were enrolled in the study, including In both genders, blood was collected from each Individual and sent to the laboratory for biochemical tests. Findings: Data from the current study showed a significant increase in Nesfatin-1 in the CAD group and a significant decrease in Nesfatin-1 in the NAFLD group compared to the control group. In addition, there was also a significant increase in both cardiac parameters and AST in the CAD group compared to the NAFLD group and the control group. Conclusion: Patients with coronary artery disease have higher Nesfatin-1 Concentration due to Nesfatin-1 having anti-inflammatory properties that raise the level of Nesfatin-1. In addition, Data from the current study showed a significant positive correlation between Nesfatin-1 and (ALT and AST) in NAFLD patients. However, further studies are needed to confirm this conclusion. Keywords: Coronary Artery Disease, Non-alcoholic fatty liver disease, Nesfatin1, Troponin-I

The Influence of Exposure to Pesticides on Plasma Cholinesterase Levels and Hepatic, and Renal Functions among Farmers in Khan Yunis Governorate, Palestine

Background: An increase in acute intoxication signs/symptoms indicates a serious public health problem among farmers who use organophosphate (OP) pesticides. This study aimed to assess the health effects of OP pesticides on farm workers who deal with pesticides in Khan Yunis Governorate, Palestine. Methods: A comparative cross-sectional study started in March and finished in September 2021 on a total of 120 randomly selected farmers, out of them 60 subjects that used pesticides (cases group) for six months or more. The other 60 were not exposed to pesticides (controls group), aged between 20-50 years old. Sociodemographic data, health-related data, and working-related data habits of the study population were taken by interview questionnaire. Biochemical evaluations were carried out. Collected data were analyzed using SPSS 22. Results: The prevalence of abnormal plasma cholinesterase (PChE) activity among the cases group due to chemical poisoning was significantly higher as compared to those in the control group (p ≤ 0.05). The case group has higher levels of serum liver enzymes (AST, ALT, & ALP) when compared with the control group (p ≤ 0.05 for all). The kidney function indicators (creatinine and urea) were significantly higher among the cases group as compared to the control group (p ≤ 0.05 for all). The occurrence of headaches is associated with abnormal PCHE activity among farmers who on pesticides. Conclusion: The decrease in PCHE activity and increase in serum AST, ALT, ALP, urea & creatinine that were observed among farmers who were on pesticides-using in the current study indicate the adverse and toxic effects of pesticides on the liver and kidney functions among them, so these observations should be of interest to health and environmental policymakers in Palestine.

Evaluation of the Effects of Green Tea (Camellia sinensis) on Markers of Liver Function and Liver Histology in Wistar Rats

Background: Green tea is rich in flavonoids and catechins, compounds reported to have antioxidant, anti-inflammatory, and anticancer properties. However, there is a need to evaluate the effects of green tea on vital organs like the liver. This study aimed to investigate the effects of Camellia sinensis on markers of liver function, and liver histology in Wistar rats.
 Methods: Forty-eight adult male Wistar rats were divided into four equal groups and orally administered 250mg/kg, 500mg/kg and 1000mg/kg of Camellia sinensis extract or 1ml of distilled water for up to 28 days. AST, ALT, ALP, TP, ALB, TB, and CB levels were measured at various time points. Effect on liver histology was also assessed using haematoxylin and eosin staining. Results: Camellia sinensis had varying effects on biomarkers of liver injury in a dose-dependent manner. Higher doses (500mg/kg and 1000mg/kg) of Camellia sinensis led to significant increases in AST, ALT, and ALP levels when consumed for up to 21 days. TP and ALB levels were not significantly altered. TB levels significantly increased in the highest dose group while CB levels did not significantly change at any time point studied. Also, higher doses of Camellia sinensis were associated with the development of fatty liver and mild inflammation from the histology. Conclusion: Camellia sinensis extract at low dose may not be harmful to the liver, however, the potential toxicity of green tea on the liver (at higher doses) should be further studied. Moderate use of green tea is therefore, recommended to ensure its safe and beneficial effects on liver health.

Clinical and hematological сhanges in viral panleukopenia in cats

Cat infectious diseases have become widespread due to the increase in the number of stray cats; feline viral panleukopenia is no exception. It is caused by a single-stranded DNA virus of feline parvovirus, characterized by high contagiousness, fever, damage to the gastrointestinal tract, respiratory organs, heart, general intoxication, and body dehydration. The research aimed to study the hematological indices of blood and biochemical indices of plasma in viral panleukopenia of cats. During the development of intestinal panleukopenia syndrome in animals, vomiting and diarrhea were noted. The development of inflammatory processes in the digestive organs causes pain in the abdominal cavity, due to which a specific “sitting posture” occurs. An acute course was most frequently noted, characterized by a sudden increase in temperature to 42 °C, vomiting, diarrhea, and cachexia. Studies of hematological indices of blood indicate the development of thrombocytosis, neutrophilia, monocytosis, and lymphocytosis, which corresponds to the acute course of the disease with a focal inflammatory process. Erythropenia leads to systemic disorders of the cardiovascular system, which provoke the weakening of the body, accompanied by cachexia. Studies of biochemical parameters of plasma indicate systemic disorders of organs developing in the body. Thus, an increase in total protein indices and globulin fractions indicates inflammatory processes in the body, particularly the digestive and urinary organs. In addition, one of the renal impairment indices was an increase in creatinine and urea, and an increase in glucose, total bilirubin, AST, and α-amylase indicates liver and pancreas dysfunction. In some cases, hepatitis and infectious toxicosis may develop. The study of hematological indices of blood and biochemical indices of plasma will ensure a complex picture of morphological changes that develop in the body of cats with panleukopenia. The obtained data will permit the monitoring of an animal's condition with the applied therapeutic scheme and the form of a prognosis.

Melatonin associated with a high-fat diet during pregnancy and lactation prevents liver changes in the offspring

In the present study, we set out to determine whether melatonin combined with a high-fat diet during pregnancy and lactation can prevent liver disorders in offspring. Forty rats were divided into four groups: DC - pregnant rats submitted to the standard diet; DC + Mel - pregnant rats submitted to the standard diet combined with melatonin; HFD - pregnant rats submitted to a high-fat diet; HFD + Mel - pregnant rats submitted to a high-fat diet combined with melatonin. Morphophysiological and biochemical parameters were analyzed. Melatonin (5 mg/kg) was administered intraperitoneally. The HFD group offspring showed an increase in AST, ALT, alkaline phosphatase, cholesterol, triglycerides, LDL and glucose levels, and a reduction in HDL and lipase levels. In the liver obseved steatosis, hepatocellular ballooning, increased lobular parenchyma and reduced non-lobular parenchyma, beside reduced liver glycogen and fibrosis. These changes were not observed in the HFD + Mel group. In conclusion, melatonin combined with a high-fat diet preserves the liver architecture and function in the offspring.

Toxic effects of AB-CHMINACA on liver and kidney and detection of its blood level in adult male mice

BackgroundAB-CHMINACA is a cannabimimetic indazole derivative. In 2013, it was reported in different countries as a substance of abuse.PurposeThis study evaluated the subacute toxic effects of AB-CHMINACA on the liver and kidneys and measured its blood level in adult male mice.MethodsThe histological and biochemical subacute toxic effects on the liver and kidneys were assessed after four weeks of daily intraperitoneal injections of one of the following doses: 0.3 mg/kg, 3 mg/kg, or 10 mg/kg as the highest dose in adult male albino mice. In addition, the blood concentration level of AB-CHMINACA was determined by GC–MS-MS.ResultsThe histological effects showed congestion, hemorrhage, degeneration, and cellular infiltration of the liver and kidney tissues. Considering the control groups as a reference, biochemical results indicated a significant increase in the serum AST only in the highest dose group, while the ALT and creatinine levels did not significantly change. The mean values of AB-CHMINACA blood levels were 3.05 ± 1.16, 15.08 ± 4.30, and 54.43 ± 8.70 ng/mL for the three treated groups, respectively, one hour after the last dose of intraperitoneal injection. The calibration curves were linear in the 2.5–500 ng/mL concentration range. The intra-assay precision and accuracy of the method were less than 7.0% (RSD) and ± 9.2% (Bias).ConclusionThis research supports the available case reports on AB-CHMINACA toxicity that it has low lethality; still, the chronic administration causes evident liver and kidney histotoxic effects even at low doses with unnoticeable clinical effects in mice.

Intermittent hypoxia induces hepatic senescence through promoting oxidative stress in a mouse model.

Metabolic-associated fatty liver disease (MAFLD) is an aging-related disease. Obstructive sleep apnea (OSA) may cause MAFLD. This study aimed to explore whetheror not intermittent hypoxia (IH), the hallmark of OSA, induces liver aging through oxidative stress. C57BL/6J male mice were administered normal air (control), IH, or antioxidant tempol + IH daily for 6 weeks before the collection of serum and liver tissue samples. A histological examination was conducted to assess liver aging. ELISA was performed to measure liver function indicator levels in the serum and oxidative stress indicator activities in the liver. Western blot analysis was carried out to determine the protein expression of the markers related to oxidative stress, inflammation, and senescence. Compared with control, IH resulted in significant increases in serum ALT, AST, and TG levels in mice (all P < 0.001), along with lobular inflammation and accumulation of collagen and fat in the liver. The protein levels of inflammatory factors and senescent markers were significantly increased in the IH mouse liver compared with those in the control mouse liver. Meanwhile, IH significantly reduced SOD and CAT activities while enhancing p22phox and Nrf2 protein expression in mouse liver compared with control. Importantly, antioxidant therapy with tempol effectively abrogated the effects of IH on oxidative stress response and aging-related liver injury. Our findings suggest that IH induces liver inflammation and aging through oxidative stress. OSA mayexacerbate target organ aging and participate in target organ damage. Strategies targeting oxidative stress may prevent and treat OSA-related MAFLD.

Effect of Mining Activities on Some Biochemical Parameters of Opanda-Ugya Inhabitants, Toto Local Government of Nigeria

Mining activities are usually associated with environmental pollution and the infiltration of toxic heavy metals into waterways which could be absorbed by plants or used by inhabitants. The aim of this research was to determine the effect of mining activities on some biochemical parameters of Opanda-Ugya inhabitants, Toto Local government of Nigeria. Four hundred and fifty (450) people were interviewed using questionnaires. Eighty (80) of them were carefully grouped into four: Group 1(20 Control), Group 2 (20 inhabitants), Group 3 (20 indirect miners) Group 4 (20 direct miners). The Survey discovered some symptoms that could be associated with heavy metal toxicity among the inhabitants. Biochemical assay of blood samples revealed no significant (P ˃0.05) increase in Serum ALT, AST and Total bilirubin in groups 2, 3 and 4 when compared to control, but a decrease in TP. Serum creatinine levels increased significantly in group 3 when compared to the control. Both creatinine and urea levels elevated significantly in group 2 and group 4 when compared with the control. The result of Oxidative stress markers has indicated a significant increase in the levels of MDA with a concomitant decrease in the levels of GSH in groups 2, 3 and 4 compared to the control. The AChE activity in groups 2, 3 and 4 significantly increased when compared to the control. The levels of CRP increased significantly in groups 3 and 4 when compared to the control. We conclude that the neurological and other disorders observed in some participants could be attributed to chronic inflammation and oxidative stress induced by heavy metal toxicity, thus something should be done by the necessary authority to curtail the long-time effect of Mining activities in this community.

Efficacy and safety of the siRNA JNJ-73763989 and the capsid assembly modulator JNJ-56136379 (bersacapavir) with nucleos(t)ide analogues for the treatment of chronic hepatitis B virus infection (REEF-1): a multicentre, double-blind, active-controlled, randomised, phase 2b trial

JNJ-73763989 (JNJ-3989), a small interfering RNA, targets all hepatitis B virus (HBV) RNAs, reducing all HBV proteins. JNJ-56136379 (JNJ-6379; also known as bersacapavir), a capsid assembly modulator, inhibits HBV replication. We aimed to evaluate the efficacy (ie, antiviral activity) and safety of these therapeutics in combination with nucleos(t)ide analogues in patients with chronic hepatitis B. The REEF-1 multicentre, double-blind, active-controlled, randomised, phase 2b study was done at 108 hospitals or outpatient centres across 19 countries in Asia, Europe, and North and South America. We included patients aged 18-65 years with chronic hepatitis B (defined as HBsAg positivity at screening and at least 6 months before screening or alternative markers of chronicity [eg, HBV DNA]), including those not currently treated, virologically suppressed, HBeAg positive, and HBeAg negative. Patients were randomly assigned (1:1:2:2:2:2) via permuted block randomisation according to a computer-generated schedule to receive oral nucleos(t)ide analogues once per day plus placebo (control group); oral JNJ-6379 250 mg daily plus nucleos(t)ide analogues (JNJ-6379 dual group); nucleos(t)ide analogues plus subcutaneously injected JNJ-3989 at doses of 40 mg (JNJ-3989 dual 40 mg group), 100 mg (JNJ-3989 dual 100 mg group), or 200 mg (JNJ-3989 dual 200 mg group) every 4 weeks; or JNJ-6379 250 mg plus JNJ-3989 100 mg every 4 weeks plus nucleos(t)ide analogues (triple group) for 48 weeks followed by a follow-up phase. An interactive web response system provided concealed treatment allocation, and investigators remained masked to the intervention groups until the primary analysis at week 48. The primary endpoint was the proportion of patients meeting predefined nucleos(t)ide analogue-stopping criteria (alanine aminotransferase <3 × upper limit of normal, HBV DNA below the lower limit of quantitation, HBeAg negative, and HBsAg <10 IU/mL) at week 48. All patients who received at least one dose of study drug were included in the analysis population used for primary efficacy assessment, excluding those who withdrew because of COVID-19-related reasons, withdrew before week 44, or had no efficacy data (ie, the modified intention-to-treat population). Safety was assessed in all participants who received at least one dose of study drugs. This trial is registered with ClinicalTrials.gov, NCT03982186. The study has been completed. Between Aug 1, 2019, and April 26, 2022, 470 patients (310 [66%] male and 244 [52%] White) were randomly assigned: 45 to the control group, 48 to the JNJ-6379 dual group, 93 to the JNJ-3989 dual 40 mg group, 93 to the JNJ-3989 dual 100 mg group, 96 to the JNJ-3989 dual 200 mg group, and 95 to the triple group. At week 48, five (5%; 90% CI 2-11) of 91 patients in the JNJ-3989 dual 40 mg group, 15 (16%; 10-24) of 92 in the JNJ-3989 dual 100 mg group, 18 (19%; 13-27) of 94 in the JNJ-3989 dual 200 mg group, eight (9%; 4-15) of 94 in the triple group, and one (2%; 0-10) of 45 in the control group met nucleos(t)ide analogue stopping criteria. No patients in the JNJ-6379 dual group met stopping criteria. 38 (81%) patients who met nucleos(t)ide analogue-stopping criteria at week 48 were virologically suppressed and HBeAg negative at baseline. Ten (2%) of 470 patients had serious adverse events during the treatment phase, and two patients (one each from the JNJ-3989 dual 200 mg group [exercise-related rhabdomyolysis] and the triple group [increase in ALT or AST]) had serious adverse events related to study treatment. During follow-up, 12 (3%) of 460 patients had a serious adverse event; one (<1%), a gastric ulcer, was considered to be related to nucleos(t)ide analogues and occurred in a patient from the JNJ-3989 dual 200 mg group. 29 (6%) of 460 patients in the treatment phase and in ten (2%) of 460 patients in the follow-up phase had grade 3 or 4 adverse events. Five (1%) of 470 patients discontinued treatment due to adverse events, and there were no deaths. Although treatment with JNJ-3989 led to a dose-dependent response for meeting nucleos(t)ide analogue-stopping criteria, it rarely led to HBsAg seroclearance. However, most patients treated with JNJ-3989 had clinically meaningful reductions in HBsAg that might contribute to a liver environment conducive to better immune control and, in turn, might improve the response to immune-modulating therapies. Janssen Research and Development.

Benchmark Dose Approach to DNA and Liver Damage by Chlorpyrifos and Imidacloprid in Male Rats: The Protective Effect of a Clove-Oil-Based Nanoemulsion Loaded with Pomegranate Peel Extract.

Pesticides are widely used around the world to increase crop production. They also have negative impacts on animals, humans, and the ecosystem. This is the first report evaluating a novel pomegranate-extract-loaded clove-oil-based nanoemulsion (PELCN) and its potential for reducing oxidative stress and DNA damage, as well as its hepatoprotective effects against imidacloprid (IM) and chlorpyrifos (CPF) toxicity in male rats. The benchmark dose (BMD) approach was also used to study the dose-response toxicity of IM and CPF. IM and CPF were administered daily for 28 days at doses of 14, 28, and 54 mg/kg body weight (bw) of IM and 1, 2, and 4 mg/kg bw of CPF via drinking water. The PELCN was administered orally at a dose of 50 mg/kg bw/day of pomegranate extract, 500 mg/kg bw of the clove oil nanoemulsion, and IM or CPF at high doses in the drinking water. In male rats, IM and CPF caused a reduction in body weight gain and hepatotoxic effects as evidenced by increases in the liver enzymes AST, ALT, and ALP. They caused oxidative damage in the liver of male rats as indicated by the decreased liver activity of the GST, GPX, SOD, and CAT enzymes and decreased serum TAC. IM and CPF produced a significant dose-dependent increase in DNA damage in hepatocyte cells, resulting in moderate to severe liver damage with cells that are more inflammatory and have enlarged sinusoids and compacted nuclei. IM had a higher BMD than CPF for both body and liver weight, suggesting that CPF was more dose-dependently toxic than IM. Albumin was a highly sensitive liver biomarker for IM, while total protein was a biomarker for the CPF-treated rats. GPx was an extremely sensitive biomarker of oxidative stress in the IM treatment, while CAT and GPx were highly sensitive parameters in the CPF-treated rats. Therefore, at comparable doses, CPF has a higher potential to cause liver damage and oxidative stress than IM. The hepatotoxicity of IM and CPF can be mitigated by administering a nanoemulsion containing clove oil and pomegranate extract. The nanoemulsion acts as a protector against the oxidative stress caused by these insecticides, especially at high doses. The nanoemulsion based on clove oil increases the bioavailability and stability of the pomegranate extract, which has antioxidant properties.

Subacute Toxicity, Subacute Anti-inflammatory and Anti-arthritic Activities of Combination of Hydroethanolic Extract of Terminalia macroptera and Ximenia americana In-vivo

The aim of this study was to assess the anti-inflammatory effects of a combination of medicinal plants on two models of inflammation. Subacute toxicity was assessed by daily oral administration of 2000 mg/kg body weight (bw). Subacute inflammation and arthritis were induced using the carrageenan air pouch granuloma model and Complete Freund's Adjuvant (CFA) respectively. After 28 days of administration, the combination at 2000 mg/kg proved to be non-toxic and induced a significant reduction (p&lt;0.05) in transaminases and total cholesterol. The combinations C3 (150 mg/kg of T. macroptera + 250 mg/kg of X. americana), C2 ((250 mg/kg of T. macroptera + 150 mg/kg of X. americana) and C1 (250 mg/kg of T. macropteria + 250 mg/kg of X. americana) inhibited fresh granuloma formation by 40.37, 45.63 and 58.32% and dry granulomas by 47.77, 55.08 and 61.24% respectively. The combinations significantly (p&lt;0.001) reduced air pouch fluid volume and massive leukocytes infiltration compared with the control group. With regard to the anti-arthritic effect, the combination C1 showed significant inhibition (p&lt;0.05) of primary and secondary lesions compared with the control CFA. The increase in serum ALT, AST and uric acid concentrations observed in the CFA control group was significantly reduced (p&lt;0.001) by the combination C1. An antioxidant effect was observed with the administration of the combination C1 and prednisone, which resulted in a significant increase (P&lt;0.01) in GSH, SOD and catalase activity and a decrease in MDA concentration (P&lt;0.001) compared with the CFA control group.The results suggest that the combination C1 has anti-inflammatory and anti-arthritic effects and prevents oxidative stress in arthritic rats.

Alteration of Liver and Kidney Specific Biomarkers in Indigenous Ducks Infected with Duck Plague Virus

Duck plague is an economically devastating viral disease prevalent in ducks which causes massive loss of duck populations annually. High morbidity and mortality are characteristic of the infection and outbreaks. Duck plague is reported from time to time from different parts of our country including Assam. The infected ducks manifest clinical signs like photophobia, partially or completely closing of eyelids, excessive thirst, nasal discharge, anorexia, drooped plumage, ataxia, diarrhea with soiled vents along with tremors in the head, neck and body. Present study was aimed to evaluate the deleterious effects of duck plague virus on liver and kidney condition by estimating liver and kidney specific biomarkers from indigenous ducks, namely Pati, Nageswari and Cinahanh of Assam from different agroclimatic zones. Study revealed significant increase of AST, ALT, ALP, uric acid and creatinine which is indicative of disruption of healthy function of liver and Kidney due to duck plague virus infection.

Acute deltamethrin intoxication in a cat – a case report

Deltamethrin is a synthetic type II pyrethroid insecticide that is widely used to protect vegetables, fruits and agricultural crops against pests such as mites, ants, beetles and weevils. Moreover, it is used in veterinary practice as an ectoparasiticide, but it is not approved for feline use. To my knowledge, deltamethrin intoxication in cats has never been reported before. For the first time, this report aimed to report clinical, haematological and biochemical changes due to deltamethrin intoxication in a cat. The cat had complaints of involuntary movements and difficulty in standing because the owner sprayed his kittens to treat lice infestation with a watery solution of a pesticide containing deltamethrin, and the mother cat licked its kittens. In the clinical examination of the cat – incoordination, spontaneous contractions, ataxia, hyperesthesia, hypothermia (T: 37.2°C), bradycardia (128/bpm), tachypnea, mydriasis and erosive lesions in the tongue – were detected. Hematologic examination revealed leukocytosis and neutrophilia. Biochemical analysis showed an increase in AST, LDH and CK-MB activities and potassium levels. Given that there is no specific antidote to deltamethrin toxicity, symptomatic treatment was given. Fluid therapy (0.9% NaCl and 5% dextrose solution at a dose of 40 ml/kg, IV) was administered for the elimination of the toxin from the body and coping with septic shock. Diazepam (0.5 mg/kg, IV) was administered to alleviate neurological signs. Enrofloxacin (5 mg/ kg, SC) was administered for three days due to sepsis, leukocytosis and neutrophilia. In the treatment of hypothermia, blankets and hot water bottles were used. After this treatment, the cat recovered. This case report, confirms that deltamethrin, like other pyrethroids, is quite toxic to cats, the clinical findings appeared in a short time, and neurological findings, especially choreoathetosis, were dominant. Consequently, this study demonstrated that deltamethrin causes neutrophilia, leukocytosis, hyperkalaemia, and heart and skeletal muscle damage in cats.

The Influential Antioxidant Role Of Coenzyme Q10 and Dehydroepiandrosterone against Carbon Tetrachloride Induced Liver Damage In Male Rats

This study evaluated the protective role of exogenous CoQ10 and DHEA and their combination on CCl4-induced hepatotoxicity in adult male rats. Thirty adult male rats 225-250 grams, 12-14 weeks old, were used in this study and randomly divided into five equal groups, 6 animals each as in the following: Control group (G1): 6 male rats received DMSO 0.5ml/ animal/day orally, First treated group (T1): 6 male rats received daily CCl4 1ml/kg (1:1 olive oil, IP), Second treated group (T2): 6 male rats received CCl4 1ml/ kg and after 1hour injected daily with CoQ10 200 mg/kg IP, Third treated group (T3): 6 male rats received CCl4 1ml/kg and after 1hour injected daily with DHEA 25 mg/kg IP, Fourth treated group (T4): 6 male rats received CCl4 1ml/kg and after 1hour injected daily with a combination of CoQ10 200 mg/kg + DHEA 25 mg/kg IP. The experiment lasted for 28 successive days. The obtained results illustrated that male rats received CCl4 (1ml/kg) caused a significant increase in hepatic enzyme function AST, ALT and ALP, as well as MDA levels, and caused a significant decrease in antioxidant enzyme activity GPx, SOD and CAT levels. In addition, CCl4 also caused various degrees of liver damage, such as dilation and congestion of the central vein with hemorrhage, apparent fatty degeneration and infiltration of inflammatory cells compared to the control group. Whereas, the group treated with CoQ10 200 mg/kg and DHEA 25 mg/kg showed a significant decrease (P&lt; 0.05) in serum AST, ALT and ALP as well as MDA value, and significantly increased in GPx, SOD with the decline in CAT levels compared to the group treated with CCl4 intoxication. It is also observed from the results that the combination of CoQ10 and DHEA caused a highly significant (P &lt; 0.05) decline in AST, ALT and ALP as well as MDA levels, and a significant elevate in GPx, SOD and decline in CAT, and almost return to average level compared to control. As well as, the histopathological examination of the liver revealed that rats treated with CoQ10 and DHEA and their combination had usual central veins and hepatocytes compared to groups treated with CCl4 due to antioxidant, anti-inflammatory and anti-apoptotic properties. It has been concluded that CoQ10 and DHEA have a protective effect against liver damage induced by CCl4 through improving antioxidant enzyme activity in CCl4 treated group leading to a declined MDA level and reduced lipid peroxidation. Thus, CoQ10 and DHEA are potential therapeutic antioxidant agents on hepatotoxicity by suppressing hepatic oxidative stress. Keywords: CoQ10, DHEA, antioxidant, CCl4, hepatic damage, male rat.

Population pharmacokinetic and exposure-response safety analyses of mecbotamab vedotin (BA3011) in patients with advanced solid tumors.

e15010 Background: Mecbotamab vedotin (BA3011) is antibody-drug conjugate (ADC) consisting of a conditionally active biologic (CAB) anti-AXL humanized (IgG1) monoclonal antibody conjugated to monomethyl auristatin E (MMAE) using a cleavable linker. BA3011 is being developed for the treatment patients with advanced solid tumors including sarcoma with AXL expression. Methods: As of data cutoff date 19 April 2022, BA3011 was administered by intravenous infusion to 67 patients, with doses ranged from 0.3 to 3 mg/kg once every three weeks (Q3W), 1.2 to 1.8 mg/kg once every two weeks (Q2W) and 1.8 mg/kg twice every three weeks (2Q3W). Population pharmacokinetics (popPK) analysis was performed using sequential modeling approach, where a PK model was first developed for BA3011 ADC alone, and then an integrated model was developed for BA3011 ADC and MMAE. The popPK base model for BA3011 ADC and MMAE was used to generate empirical Bayes estimates of PK parameters for patients in Study BA3011-001 and used for the exposure-response (E-R) safety analysis. E-R time-to-event models were developed to characterize the relationship between BA3011 ADC or MMAE exposure and the time to first incidence of adverse events (AEs). Results: A popPK model with two-compartment disposition and parallel linear and nonlinear elimination of BA3011 ADC, formation of MMAE from ADC, and two-compartment disposition and linear elimination of MMAE, adequately described the PK profiles of BA3011 ADC and MMAE in patients based on model evaluation using prediction-corrected visual predictive checks. Key PK parameter estimates are summarized in the table below. In the E-R safety analysis, statistically significant correlations were demonstrated between BA3011 ADC exposure and all safety endpoints explored (TEAE Grade ≥3, neutropenia Grade ≥3, increase in AST or ALT Grade ≥1, anemia Grade ≥2, and peripheral neuropathy Grade ≥1). Correlations were statistically significant between MMAE exposure and TEAE Grade ≥3, neutropenia Grade ≥3, increase in AST or ALT Grade ≥1, but not anemia Grade ≥2 or peripheral neuropathy Grade ≥1. Time-varying Cmax was selected as the most appropriate exposure metric for each model developed, calculated over the past 24 hours, 1 week, or 3 weeks, depending on the model. Conclusions: The popPK relationship between ADC and MMAE were adequately characterized using a sequential modeling approach. BA3011 ADC exposure was correlated with all safety endpoints evaluated whereas MMAE exposure did not demonstrate correlations with anemia or peripheral neuropathy. These models are essential to generate predictions of exposure and safety for dosing regimens to be evaluated in a planned Phase 2 clinical trial. Clinical trial information: NCT03425279 . [Table: see text]

A prospective, open-label, randomized, controlled trial of radiofrequency ablation versus stereotactic body radiation therapy for recurrent small hepatocellular carcinoma.

4096 Background: Effective treatments are urgently needed to improve the prognosis of patients with recurrent hepatocellular carcinoma (HCC). Previous studies demonstrated that both radiofrequency ablation (RFA) and stereotactic body radiation therapy (SBRT) were promising therapies for recurrent small HCC. This trial was designed to compare the efficacy and safety of RFA versus SBRT in patients with recurrent small HCC. Methods: This is a prospective, open label, randomized controlled trial, in which patients aged between 18 and 75 years with recurrent small HCC (occurred more than 3 months after hepatectomy or RFA, a solitary HCC ≤5.0 cm in diameter without vascular invasion or extrahepatic metastasis), KPS score ≥90, Child-Pugh score ≤6, adequate organ function, and estimated life expectancy ≥6 months were considered eligible. All patients were assigned 1:1 to RFA or SBRT group, and stratification was performed according to tumor size (≤ 2.0 cm or 2.1-5.0 cm). The primary endpoint was 2-year local progression-free survival. Secondary endpoints were progression-free survival, locoregional control, overall survival, and safety. Results: A total of 170 patients were recruited during August 2019 to May 2022 (83 in RFA arm and 87 in SBRT arm). In the ITT population, median age was 56 (range, 33-75) and 15 were female. Baseline characteristics were well balanced between treatment arms. Adverse events occurred in RFA and SBRT were mainly grade 1 or grade 2 in severity, and were gastrointestinal and constitutional symptoms, or abnormal laboratory investigations. The most common adverse events were bilirubin increase（14.6%）and AST increase (13.3%) in RFA group vs ALT increase (20.0%) and AST increase (15.3%) in SBRT group. No Grade 3-4 adverse events or mortality were noted. Late adverse events were hardly observed after 3 months. The follow-up of survival data is ongoing. Conclusions: Both RFA and SBRT are tolerable and safe for patients with recurrent small HCC. This randomized controlled trial will report the survival outcomes in 2024, which will make an important contribution in clinical decision-making for recurrent small HCC. Clinical trial information: NCT04047173 .