Severe Hepatotoxicity Research Articles

Propylthiouracil-induced severe hepatotoxicity in grave's disease: a unique case illustrating complex challenges and therapeutic strategies

Propylthiouracil-induced severe hepatotoxicity in grave's disease: a unique case illustrating complex challenges and therapeutic strategies

Acute Liver Failure in a 10 Months Old Male after Repeated Therapeutic Dosage of Paracetamol

Severe hepatotoxicity caused by paracetamol is not common in infants after administration of therapeutic dose. We report a case of paracetamol-induced acute liver failure in a 10 months old infant after repeated therapeutic dosage of paracetamol.

Composite Plot for Visualizing Aminotransferase and Bilirubin Changes in Clinical Trials of Subjects with Abnormal Baseline Values.

On-treatment excursions of liver laboratory test values in clinical trials involving subjects with underlying liver disease are relevant for the efficacy and safety assessment of drug products and biologics. Existing visualization and analysis tools do not efficiently provide an integrated view of these excursions when baseline liver tests are abnormal. The aim of this study was to develop a composite plot that enables visualization of on-treatment changes in liver test results both as multiples of the upper limit of normal defined by each laboratory's reference population (×ULN) and multiples of the subjects' baseline (×BLN) values. The composite plot approach combines biochemical evaluation for drug-induced severe hepatotoxicity (eDISH) plots sequentially applied to subjects' baseline and peak on-treatment liver test results normalized by ULN and integrates them into a four-panel shift plot of peak on-treatment values normalized by BLN. The composite plot enabled efficient assessment of improvement in liver test values during treatment compared with pretreatment in subjects treated with the investigational drug (or the natural history of placebo-treated subjects) and identified outlier subjects for potential drug-induced liver injury. For studies in subjects with abnormal baseline values, the composite plot has potential application in the assessment of beneficial and concerning on-treatment modifications in liver test values in reference to the individual subject's baseline and population threshold values.

Predictors of severe hepatotoxicity among retroviral infected adults on HAART regimen in Ilubabor Zone, Southwest Ethiopia

Nearly half of the deaths among hospitalized human immuno deficiency virus-infected patients in the highly active antiretroviral therapy era have been attributed to liver disease. This may range from an asymptomatic mild increase of liver enzymes to cirrhosis and liver failure. Different works of literature elucidated both retroviral infection and the adverse effects of highly active antiretroviral therapy as a cause of hepatotoxicity. Individual adaptations to medications and environmental exposures, shaped by cultural norms and genetic predispositions, could potentially modulate the risk and progression of liver disease in this population. Therefore, this study aims to assess the predictors of severe hepatotoxicity in retroviral-infected adults receiving highly active antiretroviral therapy regimens within the Ilubabor Zone, Southwest Ethiopia. A facility-based cross-sectional study was conducted among adult retroviral-infected patients in five selected anti-retro virus therapy clinics from May1 to July 30/2022. A systematic sampling technique was used to select 457 study participants and Binary logistic regression statistical data analysis was used, P value < 0.05 was considered statistically significant. The prevalence of severe hepatotoxicity was 21.44% in the study population. CD+4 count < 200 cells/mm3 (AOR = 2.19, 95% CI 1.04–5.22, P = 0.01), human immunodeficiency virus co-infection with tuberculosis (AOR = 2.82, 95% CI 1.01–8.29, P = 0.03) and human immuno deficiency virus co-infection with hepatitis-B/hepatitis C virus (AOR = 5.02, 95% CI 1.82–16.41) were predictors of severe hepatotoxicity. The magnitude of severe hepatotoxicity was high among adult retroviral-infected patients on highly active anti-retroviral drug regimens. Co-infection of human immuno deficiency virus with hepatitis B virus or hepatitis C virus, tuberculosis and CD4+T-cell count below 200 cells/mm3 were predictors of severe hepatotoxicity. Therefore, HIV patients on highly active antiretroviral therapy require close attention and regular monitoring of their liver function.

Paracetamol-induced hepatotoxicity in a malnourished patient: A case report

Abstract Acetaminophen, an analgesic and antipyretic with a favorable safety profile, is used globally. However, excessive doses can lead to severe hepatotoxicity and acute liver failure. We present a case report that describes the unfortunate demise of a 48-year-old male patient with colon carcinoma who developed severe hepatotoxicity attributed to the administration of paracetamol following right radical hemicolectomy. Despite the patient receiving paracetamol at a dosage below the recommended limit under medical supervision, he experienced a rapid deterioration in liver function, leading to a cascade of life-threatening complications. The intricate interplay between medication administration and patient-specific factors emphasizes the ongoing need for the medical community to evolve and optimize treatment strategies for improved patient outcomes.

Hepatotoxicity in patients with non-small cell lung cancer treated with sotorasib after prior immunotherapy: a comprehensive clinical and pharmacokinetic analysis

Sotorasib given after immunotherapy could put patients at increased risk of hepatotoxicity. Therefore, there is a need to gain insight into the potential correlation between anti-PD-(L)1 treatment, anti-PD-(L)1 concentrations, sotorasib concentrations, and the incidence of hepatotoxicity during sotorasib. Patients with KRASG12C-mutated NSCLC treated with sotorasib were prospectively enrolled in our biomarker cohort study (NCT05221372). Plasma samples were collected prior and during sotorasib treatment for anti-PD-1 and sotorasib concentrations. ALT/AST/ALP/GGT increases were collected prospectively and graded according to CTCAEv5.0. Severe hepatotoxicity was defined as grade ≥3 ALT/AST/ALP/GGT increase. Of the 91 included patients, 80 (88%) received prior anti-PD-(L)1. Prior anti-PD-(L)1 and prior immune-related hepatotoxicity were associated with a higher incidence of severe hepatotoxicity (35% versus 0%, p=0.016 and 75% versus 31%, p=0.019, respectively). Patients with an interval of ≤6 weeks between anti-PD-(L)1 and sotorasib (n=18) had a significantly higher incidence of severe hepatotoxicity than those with a 6-12 week (n=24) and ≥12 week (n=38) interval (83% versus 33% versus 13%, respectively, p<0.0001). Sotorasib trough concentrations did not differ significantly between those with or without severe hepatotoxicity (106 versus 126ng/mL, p=0.16). Pembrolizumab concentrations were higher in those with severe hepatotoxicity versus those without (25.6 versus 6.1μg/mL, p<0.0001). In this preliminary prospective study, sotorasib after PD-(L)1 blockade was associated with severe hepatotoxicity, especially in patients with a short interval between treatments, prior immune-related hepatitis and higher anti-PD-1 plasma concentrations. Our results suggest a minimum interval of 6 weeks between anti-PD-(L)1 and sotorasib to minimize the risk of hepatotoxicity. None.

Toosendanin induces hepatotoxicity by restraining autophagy and lysosomal function through inhibiting STAT3/CTSC axis

Toosendanin (TSN) is the main active component in the traditional herb Melia toosendan Siebold & Zucc, which exhibits promising potential for development due to its diverse pharmacological properties. However, the hepatotoxicity associated with TSN needs further investigation. Previous research has implicated autophagy dysregulation in TSN-induced hepatotoxicity, yet the underlying mechanisms remain elusive. In this study, the mechanisms of signal transducer and activator of transcription 3 (STAT3) in TSN-induced autophagy inhibition and liver injury were explored using Stat3 knockout C57BL/6 mice and HepG2 cells. TSN decreased cell viability, increased lactate dehydrogenase (LDH) production in vitro, and elevated serum aspartate transaminase (AST) and alanine aminotransferase (ALT) levels as well as liver lesions in vivo, suggesting TSN had significant hepatotoxicity. TSN inhibited Janus kinase 2 (JAK2)/STAT3 pathway and the expression of cathepsin C (CTSC). Inhibition of STAT3 exacerbated TSN-induced autophagy inhibition and hepatic injury, whereas activation of STAT3 attenuated these effects of TSN. Mechanistically, STAT3 transcriptionally regulated the level of CTSC gene, which in turn affected autophagy and the process of liver injury. TSN-administered Stat3 knockout mice showed more severe hepatotoxicity, CTSC downregulation, and autophagy blockade than wildtype mice. In summary, TSN caused hepatotoxicity by inhibiting STAT3/CTSC axis-dependent autophagy and lysosomal function.

PROTECTIVE EFFECTS OF VITAMIN C ON ACETAMINOPHEN-INDUCED LIVER AND KIDNEY TOXICITY IN MALE RATS

Acetaminophen (paracetamol) is a widely used over-the-counter analgesic and antipyretic medication known for its efficacy and safety when administered within recommended doses. However, overdose or prolonged use of acetaminophen can lead to severe hepatotoxicity and nephrotoxicity, posing a significant public health concern. This study aims to investigate the protective effects of vitamin C on acetaminophen-induced hepatotoxicity and nephrotoxicity in male Wistar rats. Six rats were randomly assigned to seven groups, with Group 1 designated as the control. Groups 2, 4, and 6 were given daily single oral doses of 100, 200, and 400 mg/kg of acetaminophen, respectively. Meanwhile, Groups 3, 5, and 7 received daily single oral doses of 100, 200, and 400 mg/kg of acetaminophen, followed by intraperitoneal administration of 100 mg/kg of vitamin C daily, for 14 days. Liver function markers (AST, ALT, total bilirubin, and total protein) and renal function indicators (urea and creatinine levels) were assessed, alongside antioxidant status in liver and kidney tissues through antioxidant assays (SOD, CAT, GSH, and MDA). The results demonstrated the protective influence of vitamin C on liver and kidney tissues, as indicated by the modulation of biochemical markers. These findings suggest that vitamin C may play a pivotal role in alleviating acetaminophen-induced liver and kidney damage across different dosage regimens, potentially serving as a therapeutic intervention for preventing or treating drug-induced organ injuries. Further investigations are essential to elucidate the underlying mechanisms and validate the translational potential of vitamin C as a protective agent against acetaminophen toxicity.

Exploring the effect of Wuzhi capsule on the pharmacokinetics of regorafenib and its main metabolites in rat plasma using liquid chromatography-tandem mass spectrometry.

Regorafenib is a small-molecule tyrosine kinase inhibitor with severe hepatotoxicity. It undergoes metabolism mainly by CYP3A4 to generate active metabolites regorafenib-N-oxide (M2) and N-desmethyl-regorafenib-N-oxide (M5). Wuzhi capsule (WZC) is an herbal preparation derived from Schisandra sphenanthera and is potentially used to prevent regorafenib-induced hepatotoxicity. This study aims to explore the effect of WZC on the pharmacokinetics of regorafenib in rats. An efficient and sensitive liquid chromatography-tandem mass spectrometry method was developed to quantitatively determine regorafenib and its main metabolites in rat plasma. The proposed method was applied to the pharmacokinetic study of regorafenib in rats, with or without WZC. Coadministration of regorafenib with WZC resulted in a prolonged mean residence time (MRT) of the parent drug but had no statistically significant difference in other pharmacokinetic parameters. While for the main metabolites of regorafenib, WZC decreased the area under the curve and maximum concentration (Cmax ), delayed the time to reach Cmax , and prolonged the MRT of M2 and M5. These results indicate that WZC delayed and inhibited the metabolism of regorafenib to M2 and M5 by suppressing CYP3A4. Our study provides implications for the rational use of the WZC-regorafenib combination in clinical practice.

Incidence of amoxycillin-clavulanic acid associated hepatotoxicity in an Australian children's hospital.

Amoxycillin/clavulanic acid is the most common antimicrobial cause of drug-induced liver injury in adults. It is a less common cause of severe drug-related hepatotoxicity in children despite its frequent use. We studied the incidence, characteristics and predictive factors for amoxycillin/clavulanic acid hepatoxicity in children. Retrospective cohort study of children who received oral or intravenous amoxycillin/clavulanic acid at a quaternary children's hospital over a 5-year period. Children were included if they had liver function tests (LFTs) determined at baseline, during and within 3 months after the treatment course. Causality was assessed using the Naranjo criteria for adverse drug reactions and Roussel Uclaf Causality Assessment Method. Of 3271 children prescribed amoxycillin/clavulanic acid, 374 were included. Forty-nine (13%) had LFT abnormalities related to amoxycillin/clavulanic acid. Fourteen (3.6%) fulfilled Common Terminology Criteria for Adverse Events (CTCAE) grade 2 criteria with clinically significant hepatotoxicity. Age <2 years, sepsis, post-gastrointestinal surgical indications, prolonged treatment course of >7 days and higher cumulative amoxycillin (>10 g) and clavulanic acid dose (>1 g) were predictive of hepatotoxicity. The median time to resolution of LFT abnormalities was 4 weeks (range 3-7). The incidence of amoxycillin/clavulanic acid related LFT abnormalities (CTCAE Grade 2 or above) in children was 3.6%. A prolonged treatment course >7 days, high cumulative amoxycillin (10 g) and clavulanic acid (>1 g) doses, those aged <2 years, and patients with sepsis or post-gastrointestinal surgery were predictive of a higher likelihood of abnormal LFTs. LFT monitoring should be considered in children receiving ≥7 days of treatment, particularly in those with other predisposing factors.

The Ameliorative Role of Lico A on Aflatoxin B1-Triggered Hepatotoxicity Partially by Activating Nrf2 Signal Pathway.

Aflatoxin B1 (AFB1) is one of the most harmful and toxic mycotoxins in foods and feeds, posing a serious health risk to both humans and animals, especially its hepatotoxicity. Nuclear factor-erythroid 2-related factor 2 (Nrf2), an important nuclear transcription factor, is generally recognized as a potential target for phytochemicals to ameliorate liver injury. The current study sought to elucidate the molecular processes by which licochalcone A (Lico A), a compound derived from Xinjiang licorice Glycyrrhiza inflate, protects against AFB1 toxicity. In vivo, male wild-type (WT) and Nrf2 knockout (Nrf2-/-) C57BL/6 mice were orally administered AFB1 at 1.5 mg/kg body weight (BW) with or without Lico A at 5 mg/kg. In vitro, AML12 cells were utilized to evaluate the protective effect and mechanism of Lico A against the AFB1-induced hepatotoxicity. Our findings demonstrated that AFB1 caused severe hepatotoxicity, while Lico A treatment successfully relieved the toxicity. Meanwhile, Lico A effectively improved liver injury, inflammatory mediators, oxidative insults, apoptosis, liver fibrosis, and pyroptosis, which contributed to the inhibition of toll receptor 4 (TLR4)-NF-κB/MAPK and NOD-like receptors protein 3 (NLRP3)/caspase-1/GSDMD signaling pathway activation. Furthermore, Lico A was able to enhance the Nrf2 antioxidant signaling pathway. Intriguingly, Lico A still had a protective effect on AFB1-caused liver injury in mice via the inhibition of inflammation and pyroptosis, while apoptosis and liver fibrosis were blocked in the absence of Nrf2. To sum up, the present study first elucidated that Lico A ameliorated AFB1-induced hepatotoxic effects and its main mechanism involved the inhibitory effects on oxidative stress, apoptosis, liver fibrosis, inflammation, and pyroptosis, which might be partially dependent on the regulation of Nrf2. The work may enrich the role and mechanism of Lico A's resistance to liver injury caused by various factors, and its application is promising.

Severe Hepatotoxicity in Mushroom Poisoning by Lepiota brunneoincarnata from Complete Recovery to Liver Transplantation: A Case Series with Review on Liver Function Tests and Liver Histopathology.

In spite of the scientific evidence supporting health advantages of mushrooms, some of them are seriously poisonous. The clinical picture of mushroom intoxication ranges from minor gastrointestinal symptoms to organ failure, such as liver failure and death. We provided demographics, clinicopathological characteristics, applied treatments, and outcomes of mushroom poisoning by Lepiota species in a series of 18 cases that were referred from Kermanshah and Lorestan provinces to Abu-Ali-Sina Hospital, Shiraz, Iran. Clinical and paraclinical data were collected by taking history and reviewing of medical documents. Pathologic findings were extracted through a review of hematoxylin and eosin pathologic slides. The patients were between the ages of 18 and 67 years, composed of ten females and eight males. The most frequent clinical manifestations were nausea and vomiting followed by abdominal pain. Four cases presented decreased consciousness on admission. One of them passed away. Three other cases underwent liver transplantation, two of them died after transplantation, and one fully recovered without any major issues. All instances had elevated ALT levels, which ranged from 44 to 9,140 IU/L (mean: 3259 ± 2476), with most of them also having concurrent AST elevations (mean: 1,361 ± 1,532). Only few patients had modest elevations in alkaline phosphatase. Total and direct bilirubin elevations up to 47.6 and 24 mg/dL, respectively, were found in most cases. Decreased total protein and albumin concentrations and increased BUN and creatinine levels were observed in some patients. In addition, some instances revealed increased LDH, increased WBC, decreased hemoglobin, and decreased platelet count. Most patients had increased prothrombin time; hematuria and positive stool occult blood were observed in few patients. Histopathologic examination of three explanted livers revealed massive necrosis with moderate to severe macrovesicular steatosis, significant ductular reaction, and parenchymal inflammation. Other patients followed a recovery process with a considerable drop in liver enzymes, especially ALT, during hospitalization utilizing conservative treatment. They had no liver problems or relevant issues after a two-year follow-up. In our study, highly elevated liver enzymes with a significantly high ALT/AST ratio were observed in cases of mushroom poisoning by Lepiota species, leading to fulminant liver failure and death in some cases. These laboratory findings were correlated with liver necrosis and macrovesicular steatosis in explanted livers.

Assessing immune hepatotoxicity of troglitazone with a versatile liver-immune-microphysiological-system.

Drug-induced liver injury is a prevalent adverse event associated with pharmaceutical agents. More significantly, there are certain drugs that present severe hepatotoxicity only during the clinical phase, consequently leading to the termination of drug development during clinical trials or the withdrawal from the market after approval. The establishment of an evaluation model that can sensitively manifest such hepatotoxicity has always been a challenging aspect in drug development. In this study, we build a liver-immune-microphysiological-system (LIMPS) to fully demonstrate the liver injury triggered by troglitazone (TGZ), a drug that was withdrawn from the market due to hepatotoxicity. Leveraging the capabilities of organ-on-chip technology allows for the dynamic modulation of cellular immune milieu, as well as the synergistic effects between drugs, hepatocytes and multiple immune cells. Through the LIMPS, we discovered that 1) TGZ can promote neutrophils to adhered hepatocytes, 2) the presence of TGZ enhances the crosstalk between macrophages and neutrophils, 3) the induction of damage in hepatocytes by TGZ at clinically relevant blood concentrations not observed in other in vitro experiments, 4) no hepatotoxicity was observed in LIMPS when exposed to rosiglitazone and pioglitazone, structurally similar analogs of TGZ, even at the higher multiples of blood drug concentration levels. As an immune-mediated liver toxicity assessment method, LIMPS is simple to operate and can be used to test multiple drug candidates to detect whether they will cause severe liver toxicity in clinical settings as early as possible.

Selpercatinib-induced hepatotoxicity: A rare case report

Abstract Introduction/Objective Selpercatinib (Retevmo) is a highly selective rearranged during transfection (RET) kinase inhibitor indicated for treatment of solid tumors with RET gene mutation or fusion, such as medullary thyroid carcinoma or non-small cell lung carcinoma. Among selpercatinib’s side effects, severe hepatotoxicity was only seen in 3% of the patients. Here we report a case of selpercatinib-induced hepatotoxicity, which has not been well characterized before. Methods/Case Report The patient was a 56-year-old female who had medullary thyroid carcinoma with RET M918T mutation (pT3aN1b) status post total thyroidectomy. Recurrence occurred and selpercatinib treatment was initiated. Then the patient complained of mouth sores, tongue sensitivity, and lower extremity cramping. The dosage was reduced to half. The magnetic resonance imaging on day 67 of selpercatinib treatment showed heterogeneous enhancement in the right hepatic lobe, compatible with parenchymal liver disease/hepatitis, trace perihepatic ascites, and mild splenomegaly. On day 71, liver function abnormalities were detected (ALK 315 IU/L, ALT 745 IU/L, AST 899 IU/L, total bilirubin 7.7 mg/dL). Workups including autoimmune hepatitis serology, viral hepatitis, or other infections were all negative. She had no history of other drug use. On day 72, a liver biopsy was performed that demonstrated mild to moderate portal lymphocyte-predominant mixed inflammation with interface activity. The lobules showed marked inflammation with hepatocyte disorganization, acidophil bodies, hepatocyte dropout, and rare lipogranulomas. Bile duct injury and patchy canalicular cholestasis were also noted. Trichrome stain showed focal bridging fibrosis. Overall, the histologic findings were acute and chronic hepatitis pattern injury, favor selpercatinib-induced hepatotoxicity. Selpercatinib was discontinued. All liver enzymes gradually returned to normal levels on day 169. Results (if a Case Study enter NA) NA Conclusion Our study suggests that screening patients for abnormal liver function tests prior to and monitoring periodically during selpercatinib treatment is necessary. Based on the severity of hepatotoxicity, withholding, reducing the dose, or permanently discontinuing selpercatinib is recommended.

Molecular Characteristics of Cisplatin-Induced Ototoxicity and Therapeutic Interventions.

Cisplatin is a commonly used chemotherapeutic agent with proven efficacy in treating various malignancies, including testicular, ovarian, cervical, breast, bladder, head and neck, and lung cancer. Cisplatin is also used to treat tumors in children, such as neuroblastoma, osteosarcoma, and hepatoblastoma. However, its clinical use is limited by severe side effects, including ototoxicity, nephrotoxicity, neurotoxicity, hepatotoxicity, gastrointestinal toxicity, and retinal toxicity. Cisplatin-induced ototoxicity manifests as irreversible, bilateral, high-frequency sensorineural hearing loss in 40-60% of adults and in up to 60% of children. Hearing loss can lead to social isolation, depression, and cognitive decline in adults, and speech and language developmental delays in children. Cisplatin causes hair cell death by forming DNA adducts, mitochondrial dysfunction, oxidative stress, and inflammation, culminating in programmed cell death by apoptosis, necroptosis, pyroptosis, or ferroptosis. Contemporary medical interventions for cisplatin ototoxicity are limited to prosthetic devices, such as hearing aids, but these have significant limitations because the cochlea remains damaged. Recently, the U.S. Food and Drug Administration (FDA) approved the first therapy, sodium thiosulfate, to prevent cisplatin-induced hearing loss in pediatric patients with localized, non-metastatic solid tumors. Other pharmacological treatments for cisplatin ototoxicity are in various stages of preclinical and clinical development. This narrative review aims to highlight the molecular mechanisms involved in cisplatin-induced ototoxicity, focusing on cochlear inflammation, and shed light on potential antioxidant and anti-inflammatory therapeutic interventions to prevent or mitigate the ototoxic effects of cisplatin. We conducted a comprehensive literature search (Google Scholar, PubMed) focusing on publications in the last five years.

Compassionate Use of Emapalumab in Children with Life-Threatening Disorders: Real-World Data

Introduction: Life threatening hyperinflammation occurs in hemophagocytic lymphohistiocytosis (HLH) and during acute rejection of hematopoietic stem cell (HSC) grafts. Both conditions reflect acute activation of the immune system, in part due to overproduction of proinflammatory cytokines, particularly interferon gamma (IFNγ). Emapalumab, a fully human monoclonal antibody that binds to IFNγ, is approved by the FDA for refractory or recurrent primary HLH (pHLH) or in patients intolerant to conventional therapy. Off-label use of emapalumab has been reported for treatment of secondary HLH (sHLH) and for HSC graft rejection. The European Medicines Agency did not approve emapalumab for the treatment of HLH and many other regulatory authorities, including the Israeli Ministry of Health, have yet to approve emapalumab for clinical use. Pending such regulatory approval, emapalumab is available in Israel exclusively though the Managed Access Request Program (MAP) on a compassionate basis sponsored by Sobi (Swedish Orphan Biovitrum AB,Reg. no. 556038-9321). Experience that accumulates through on- and off-label use of emapalumab obtained via MAP enriches the knowledge base regarding the uses of this drug in the real-world clinical setting. Methods: We summarized the data of patients receiving emapalumab at our tertiary pediatric center. The medication was received after application to the MAP sponsored by Sobi International with import approval of the Israel Ministry of Health on a named-patient basis. Results: Seven patients (Pt) aged 2.5 months-17.5 years were treated with emapalumab between 3/2020-6/2023. Patients 1-5 fulfilled HLH-2004 diagnostic criteria. Indications for the use of emapalumab included treatment of HLH in a newborn with severe hepatotoxicity after treatment with the standard HLH-94 protocol (Pt. 3), treatment of acute graft rejection with recurrence of HLH in a patient with pHLH (Pt.1), secondary HSC graft failure and disease relapse in a child with pHLH (Pt. 4), sHLH with multi-organ failure (MOF) requiring extracorporeal membrane oxygenation (ECMO) (Pts 2&amp;5) and HSC primary graft rejection with suspected 2 nd rejection (Pts.6&amp;7). Table 1 summarizes the clinical characteristics of all cases. The patient outcomes were closely related to their clinical status at treatment initiation. Pt.3 was able to reach remission and successfully bridge to SCT without complications after only 4 doses of VP-16 with continuation therapy using only dexamethasone and emapalumab. Pt.4, who experienced relapsed pHLH with concomitant HSC graft loss, attained complete remission with emapalumab, dexamethasone and IVIG, facilitating a successful second HSC graft. Pt. 1 expired after initial graft failure, severe sepsis and relapse of pHLH. Pts. 2&amp;5, despite showing improvement of their HLH criteria after treatment with emapalumab, succumbed to MOF that was already present when they were referred to our center for ECMO support. Following unsuccessful emapalumab treatment for primary graft rejection, Pts. 6&amp;7 underwent successful 2 nd HSC transplants with early emapalumab treatment for suspected re-rejection. Conclusions: Emapalumab is a safe, effective, and well tolerated treatment for various HLH scenarios, and for similar hyper-inflammatory medical conditions. Administration of emapalumab early in the disease course is likely to be more effective as compared to administration of the drug when MOF has occurred or when the HSC graft has already been rejected. Since these diseases are life-threatening, eliminating delays in procurement of emapalumab is essential to expedite treatment before irreversible organ failure ensues.

Investigation of the principle of concoction by using the processing excipient Glycyrrhiza uralensis Fisch. juice to reduce the main toxicity of Dioscorea bulbifera L. and enhance its main efficacy as expectorant and cough suppressant

Ethnopharmacological relevanceDioscorea bulbifera L. (Rhizoma Dioscoreae Bulbiferae; RDB) is commonly used as an expectorant and cough suppressant herb but is accompanied by severe hepatotoxicity. Using the juice of auxiliary herbs (such as Glycyrrhiza uralensis Fisch. (Glycyrrhizae Radix et Rhizoma; GRR) juice) in concocting poisonous Chinese medicine is a conventional method to reduce toxicity or increase effects. Our previous study found that concoction with GRR juice provided a detoxifying effect against the major toxic hepatotoxicity induced by RDB, but the principle for the detoxification of the concoction is unknown to date. Aim of the studyThe principle of concoction was investigated by using the processing excipient GRR juice to reduce the major toxic hepatotoxicity of RDB, and the efficacy of RDB as an expectorant and cough suppressant was enhanced. Materials and methodsIn this study, common factors (RDB:GRR ratio, concocted temperature, and concocted time) in the concoction process were used for the preparation of each RDB concocted with GRR juice by using an orthogonal experimental design. We measured the content of the main toxic compound diosbulbin B (DB) and serum biochemical indicators and performed pathological analysis in liver tissues of mice to determine the best detoxification process of RDB concocted with GRR juice. On this basis, the biological mechanisms of target organs were detected by Western blot and enzyme-linked immunosorbent assay at the inflammation and apoptosis levels. Further, the effects of RDB on expectorant and cough suppressant with GRR juice were evaluated by the conventional tests of phenol red expectorant and concentrated ammonia-induced cough. Lastly, the major compounds in the GRR juice introduced to RDB concoction were determined. ResultsRDB concocted with GRR juice significantly alleviated DB content, serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase levels, and improved liver pathological damages. The best detoxification process was achieved by using an RDB:GRR ratio of 100:20 at 120 °C for 20 min. Further, RDB concocted with GRR juice down-regulated the protein levels of nuclear factor kappa B (NF-κB), cyclooxygenase 2 (COX-2), and Bcl-2 related X protein (Bax) in the liver and enhanced the expectorant and cough suppressant effects of RDB. Finally, liquiritin (LQ) and glycyrrhizic acid (GA) in the GRR juice were introduced to the RDB concoction. ConclusionConcoction with GRR juice not only effectively reduced the major toxic hepatotoxicity of RDB but also enhanced its main efficacy as an expectorant and cough suppressant, and that the rationale for the detoxification and/or potentiation of RDB was related to the reduction in the content of the main hepatotoxic compound, DB, the introduction of the hepatoprotective active compounds, LQ and GA, in the auxiliary GRR juice, as well as the inhibition of NF-κB/COX-2/Bax signaling-mediated inflammation and apoptosis.

Fructose as a novel nutraceutical for acetaminophen (APAP)-induced hepatotoxicity.

Acetaminophen (APAP) is the most widely used analgesic in the world. APAP overdose can cause severe hepatotoxicity and therefore is the most common cause of drug-induced liver injury. The only approved treatment for APAP overdose is N-acetyl-cysteine (NAC) supplementation. However, the narrow efficacy window of the drug severely limits its clinical use, prompting the search for other therapeutic options to counteract APAP toxicity. Recent research has pointed to fructose as a novel nutraceutical for APAP-induced liver injury. This review summarizes the current understanding of the molecular mechanisms underlying APAP-induced liver injury, introduces how fructose supplementation could prevent and treat APAP liver toxicity with a focus on the ChREBPα-FGF21 pathway, and proposes possible future directions of study.

Consideration of Nevirapine Analogs To Reduce Metabolically Linked Hepatotoxicity: A Cautionary Tale of the Deuteration Approach.

Idiosyncratic drug reactions (IDRs) in their most deleterious form can lead to serious medical complications and potentially fatal events. Nevirapine (NVP), still widely used in developing countries for combinatorial antiretroviral and prophylactic therapies against HIV infection, represents a prototypical example of IDRs causing severe skin rashes and hepatotoxicity. Complex metabolic pathways accompanied by production of multiple reactive metabolites often complicate our understanding of IDR's origin. While assessment of NVP analogs has helped characterize the pathways involved in IDRs for NVP, which are largely driven by metabolism at the 12-methyl position, it has yet to be investigated if some of these analogs could be valuable replacement drugs with reduced reactive metabolite properties and drug-drug interaction (DDI) risks. Here, we evaluated a set of eight NVP analogs, including the deuterated 12-d3-NVP and two NVP metabolites, for their efficacy and inhibitory potencies against HIV reverse transcriptase (HIV-RT). A subset of three analogs, demonstrating >85% inhibition for HIV-RT, was further assessed for their hepatic CYP induction-driven DDI risks. This led to a closer investigation of the inactivation properties of 12-d3-NVP for hepatic CYP3A4 and a comparison of its propensity in generating reactive metabolite species. The metabolic shift triggered with 12-d3-NVP, increasing formation of the 2-hydroxy and glutathione metabolites, emphasized the importance of the dynamic balance between induction and metabolism-dependent inactivation of CYP3A4 and its impact on clearance of NVP during treatment. Unfortunately, the strategy of incorporating deuterium to reduce NVP metabolism and production of the electrophile species elicited opposite results, illustrating the great challenges involved in tackling IDRs through deuteration.

Evaluation of the nephroprotective properties of silver nanoparticles formulated by Pistacia atlantica aqueous extract under ultrasonic condition in streptozotocin-induced diabetic nephropathy in mice

Green formulated silver nanoparticles offer a great promise in biomedicine. Administration of streptozotocin causes severe hepatotoxicity and nephrotoxicity by increasing the blood glucose. The development of nephroprotective drugs through eco-friendly production routes is a major challenge for current pharmacology and nanotechnology. The creation of cutting-edge technology for the synthesis of effective nephroprotective agents is crucial on a global scale. So in the current study, we report herein the bio-inspired proficient preparation of silver NPs over Pistacia atlantica (P.a.) aqueous extract as natural reducing/capping and stabilizing agent (P.a./Ag NPs) under ultrasonic irradiation. The final hybrid nanocomposite was thereafter characterized by a range advanced analytical methods like, FE-SEM, ICP-OES, EDX, TEM, and elemental mapping. Diabetes was induced by administration of 60 mg/kg of streptozotocin (STZ) intraperitoneally in 100 mature male mice and they were randomly divided into 5 groups. The negative control group received normal saline and treatment groups received glibenclamide with dose 0.5 mg/kg and 10 and 40 μg/kg of P.a./Ag nanocomposite through gavage for 50 days. On the last day, serum levels of samples blood glucose, urea and creatinine were measured. After tissue processing, 5 μm sections of the kidneys were prepared and they were stained by periodic acid Schiff (PAS) and used for stereological analysis. The kidney weight, kidney volume (Volume of cortex, medulla, glomerulus, proximal and distal tubules, collecting ducts, loop of Henle, interstitial tissues, and vessels) and kidney structures length (length of proximal and distal tubules, collecting ducts, loop of Henle, and vessels) decreased significantly (p ≤ 0.05) after treatment with high dose of P.a./Ag NPs nanocomposite (p > 0.05). The increased levels of blood glucose and urea were decreased (p ≤ 0.05) significantly in P.a./Ag nanocomposite-treated groups as compared to the untreated diabetic. This study suggested using from P.a./Ag nanocomposite as an antidiabetic and nephroprotective drug in the developing countries.