Tinospora cordifolia (Guduchi/Giloy)-Induced Liver Injury: A Case Review.

Tinospora cordifolia (Guduchi/Giloy) is a relatively common herbal supplement whose use has recently become prominent in Southeast Asia. It was promoted to the public in India as an immunity booster, especially against the novel COVID-19. There have been reports, mostly from India, of an association between Guduchi/Giloy and liver injury. We present a 50-year-old female with a history of Hashimoto thyroiditis, who presented with abdominal discomfort and nausea of two weeks duration, which coincided with starting HistaEzeTM supplement containing Tinospora cordifolia. The vital signs upon presentation showed no significant abnormalities. Labs were significant for severely elevated transaminases; however, viral panels, autoimmune serologies, and imaging studies were unremarkable. Roussel Uclaf causality assessment method (RUCAM) score was at 6, which was indicative of probable drug/herb-induced liver injury. HistaEzeTM was discontinued, and the patient took a three-day course of oral steroids with significant interval improvement in clinical status, as evidenced by progressive normalization of the transaminases level. The transaminases decreased by greater than 50% within two weeks of discontinuation and trended back to baseline within three months. This case highlights the worldwide availability and use of Tinospora cordifolia, which can cause liver injury that appears to be idiosyncratic and possibly immune-mediated. Further research on the precise mechanism of its hepatotoxicity is warranted.

Liver transaminase concentrations in children with acute SARS-CoV-2 infection.

OBJECTIVE: To evaluate the relationship between SARS-CoV-2 infection and liver injury by comparing transaminase concentrations among children tested for SARS-CoV-2 and other respiratory viruses in pediatric emergency departments. DESIGN & METHODS: Eligible children were <18 years with suspected SARS-CoV-2, tested using molecular approaches in emergency departments between March 7, 2020, and June 15, 2021 (Pediatric Emergency Research Network), and between August 6, 2020, and February 22, 2022 (Pediatric Emergency Research Canada). We compared aspartate (AST) and alanine aminotransferase (ALT) concentrations at presentation for SARS-CoV-2 and other respiratory viruses through a multivariate linear regression model, with the natural log of serum transaminase concentrations as dependent variables. RESULTS: Of 16,892 enrolled children, 2,462 (14.6%) had transaminase concentrations measured; 4318 (25.6%) were SARS-CoV-2 positive, and 3932 (23.3%) were tested for additional respiratory viruses. Among study participants who had additional respiratory virus testing performed, the most frequently identified viruses were enterovirus/rhinovirus [8.7% (343/3,932)], respiratory syncytial virus [4.6% (181/3,932)], and adenovirus [2.6% (103/3,932)]. Transaminase concentrations were elevated in 25.6% (54/211) of children with isolated SARS-CoV-2 detection and 21.6% (117/541) of those with no virus isolated; P = 0.25. In the multivariable model, isolated SARS-CoV-2 detection was not associated with elevated ALT (adjusted geometric mean ratio (IU/L): 0.96; 95%Confidence Interval (CI): 0.84, 1.08) or AST (adjusted geometric mean ratio (IU/L): 1.03; 95%CI: 0.92, 1.16) concentrations, with negative respiratory panel as the referent group. Ninety-day follow-up was completed in 82.2% (3,550/4,318) of SARS-CoV-2 positive children; no cases of new-onset liver disease were reported. CONCLUSION: Among those tested, transaminase concentrations did not vary between SARS-CoV-2-positive children and those with a negative respiratory viral panel. In multivariate analysis, SARS-CoV-2 infection was not associated with increased initial transaminase concentrations compared to other respiratory viruses.

Paracetamol Overdose Induces Acute Liver Injury accompanied by oxidative stress and inflammation

The concept of paracetamol as a safe drug has become very misleading as this has led to a high rate of paracetamol toxicity. Hepatotoxicity and liver failure have been reported even with doses just more than the maximum therapeutic dose, which was obviously noticed in the (COVID-19) pandemic. Oxidative stress plays an important role in paracetamol hepatotoxicity. The current study investigates the mechanism of action through which paracetamol induces hepatotoxicity and implements an alarming sign for the unsupervised use of paracetamol. Twenty albino rats were equally divided into a normal control group and paracetamol treated group where rats received paracetamol at a dose of 2g/kg b.wt once orally for 24 hours. Oral administration of paracetamol resulted in a significant elevation of liver enzymes in serum such as glutamate pyruvate transaminase and glutamate oxaloacetate transaminase when compared with the results of the control group. In terms of oxidative stress biomarkers, the group that received an overdose of paracetamol showed a significant increase in the tissue level of 4-Hydroxynonenal accompanied by a significant decrease in the activity of the anti-oxidant markers Paraoxonase and Catalase. Histopathological examination revealed focal necrosis in the hepatocytes, Centri-lobular necrobiotic changes, and dilated congested portal vein. Immunohistochemical investigation for the Nuclear factor-kappa B showed strong positive expression in the nuclei of the hepatocytes of rats that received an overdose of paracetamol. Our study suggests that an overdose of paracetamol could attenuate the endogenous antioxidant defense mechanisms and augment the hepatic tissue inflammation;both factors may contribute to the observed increase in apoptosis-related signaling and cell death. ©2023 National Information and Documentation Center (NIDOC).

The Problem of Comorbid Socially Significant Infections Under The Conditions of The COVID-19 Pandemic.

The aim of the study. To analyze formation features of the epidemic situation for tuberculosis (TB) in the context of the COVID-19 pandemic in order to predict the further actions of medical organizations. Materials and methods. The data for the region for the last 5 years (2017-2021) were analyzed, including 1,762 newly diagnosed cases of patients with TB and comorbidities (according to the data of the Regional Public Health Organization <<Regional Clinical Anti-Tuberculosis Dispensary>>). All cases were verified using standard diagnostic methods, including molecular genetic methods, to determine the resistance of pathogens to antibacterial drugs. Results. It was revealed that the epidemiological situation in the region was multidirectional: thus, during the COVID-19 epidemic, the most pronounced incidence decrease was observed among cases of chronic course hepatitis (by 16.4 times), while among patients with tuberculosis the incidence decreased by 2.75 times, and among patients with acute hepatitis - only by 1.5 times (P<0.05). Among the cases of comorbid infection, the most severe course was observed in patients with combined (TB + HIV) infection: there was both a more severe general condition, and the development of adverse (undesirable) reactions to anti-TB drugs, which required an extension of maintenance therapy. Conclusions. The results of the study showed that against the background of the COVID-19 pandemic in the region, there was no tendency towards a worsening of the epidemic situation, primarily for the more socially significant infection - tuberculosis. At the same time, there was an increase in the number of cases of comorbid pathology, including HIV + TB. In the treatment of patients with comorbid forms of infection, it is necessary to take into account the possibility of developing hepatotoxic reactions and, as a result, the appointment of accompanying drugs with hepatoprotective and detoxification effects in therapy.Copyright © Team of Authors, 2022.

The Evolving Profile of Idiosyncratic Drug-Induced Liver Injury.

Idiosyncratic drug-induced liver injury (DILI) is an infrequent but important cause of liver disease. Newly identified causes of DILI include the COVID vaccines, turmeric, green tea extract, and immune checkpoint inhibitors. DILI is largely a clinical diagnosis of exclusion that requires evaluation for more common causes of liver injury and a compatible temporal association with the suspect drug. Recent progress in DILI causality assessment includes the development of the semi-automated revised electronic causality assessment method (RECAM) instrument. In addition, several drug-specific HLA associations have been identified that can help with the confirmation or exclusion of DILI in individual patients. Various prognostic models can help identify the 5%-10% of patients at highest risk of death. Following suspect drug cessation, 80% of patients with DILI fully recover, whereas 10%-15% have persistently abnormal laboratory studies at 6 months of follow-up. Hospitalized patients with DILI with an elevated international normalized ratio or mental status changes should be considered for N-acetylcysteine therapy and urgent liver transplant evaluation. Selected patients with moderate to severe drug reaction with eosinophilia and systemic symptoms or autoimmune features on liver biopsy may benefit from short-term corticosteroids. However, prospective studies are needed to determine the optimal patients and dose and duration of steroids to use. LiverTox is a comprehensive, freely accessible Web site with important information regarding the hepatotoxicity profile of more than 1000 approved medications and 60 herbal and dietary supplement products. It is hoped that ongoing "omics" studies will lead to additional insight into DILI pathogenesis, improved diagnostic and prognostic biomarkers, and mechanism-based treatments.

Adverse effects of triclosan exposure on health and potential molecular mechanisms.

With the COVID-19 pandemic, the use of disinfectants has grown significantly around the world. Triclosan (TCS), namely 5-chloro-2-(2,4-dichlorophenoxy) phenol or 2,4,4'-trichloro-2'-hydroxydiphenyl ether, is a broad-spectrum, lipophilic, antibacterial agent that is extensively used in multifarious consumer products. Due to the widespread use and bioaccumulation, TCS is frequently detected in the environment and human biological samples. Accumulating evidence suggests that TCS is considered as a novel endocrine disruptor and may have potential unfavorable effects on human health, but studies on the toxic effect mediated by TCS exposure as well as its underlying mechanisms of action are relatively sparse. Therefore, in this review, we attempted to summarize the potential detrimental effects of TCS exposure on human reproductive health, liver function, intestinal homeostasis, kidney function, thyroid endocrine, and other tissue health, and further explore its mechanisms of action, thereby contributing to the better understanding of TCS characteristics and safety. Moreover, our work suggested the need to further investigate the biological effects of TCS exposure at the metabolic level in vivo.

Highlights of the drug-induced liver injury literature for 2021.

INTRODUCTION: In 2021, over 3,000 articles on Drug-Induced Liver Injury (DILI) were published, nearly doubling the annual number compared to 2011. This review selected DILI articles from 2021 we felt held the greatest interest and clinical relevance. AREAS COVERED: A literature search was conducted using PubMed between 1 March 2021 and 28 February 2022. 86 articles were included. This review discusses new and established cases of hepatotoxins, including new FDA approvals and COVID-19 therapeutics. Developments in biomarkers and causality assessment methods are discussed. Updates from registries are also explored. EXPERT OPINION: DILI diagnosis and prognostication remain challenging. Roussel Uclaf Causality Assessment Method (RUCAM) is the best option for determining causality and has been increasingly accepted by clinicians. Revised Electronic Causality Assessment Method (RECAM) may be more user-friendly and accurate but requires further validation. Quantitative systems pharmacology methods, such as DILIsym, are increasingly used to predict hepatotoxicity. Oncotherapeutic agents represent many newly approved and described causes of DILI. Such hepatotoxicity is deemed acceptable relative to the benefit these drugs offer. Drugs developed for non-life-threatening disorders may not show a favorable benefit-to-risk ratio and will be more difficult to approve. As the COVID-19 landscape evolves, its effect on DILI deserves further investigation.

Can Guduchi (Tinospora cordifolia), a well-known ayurvedic hepato-protectant cause liver damage?

Ayurveda is a centuries old traditional medicine practiced in India even today. There are certain safe medicinal plants with well-established medicinal properties both in clinical practice as well as in modern scientific publications. Guduchi or Tinospora cordifolia (Willd.) Miers (Menispermaceae), is one such medicinal plant that has well known anti-inflammatory, immune-modulatory and other safe therapeutic applications including hepato-protection, because of which it was recommended by the Ministry of AYUSH, Government of India to be used in COVID-19 care. Therefore, Aabha Nagral's article "Herbal Immune Booster-Induced Liver Injury in the COVID-19 Pandemic-a Case Series," published in 2021, was unanticipated. The article recounted histologically documented clinical cases of six patients who developed drug-induced autoimmune-like hepatitis after reported consumption of Guduchi or Guduchi containing formulations during the COVID-19 pandemic. Since the Ayurveda practitioners vouch by the safety of T. cordifolia (TC), it was felt that the story needed to be further scrutinized. This article reviews the botanical entities, the substitutes and adulterants of species used as Guduchi, their pharmacological and toxicological properties. While the authentic botanical entity of Guduchi is TC, Tinospora sinensis and Tinospora crispa are also commonly traded in the Indian subcontinent as Guduchi or Giloy. Among these species, T. crispa is known to induce heapto-toxicity. In Nagral's article, there were variations in the reported six cases in terms of patient history and TC/TC product consumption. More importantly, the botanical authenticity of the consumed products was not investigated. A review of published literature indicates that it is unlikely that the authentic TC could have induced autoimmune-like hepatitis of the patients. It is probable that a wrong species was self-administered by the patients. It is worth following up with the cases (patients), to investigate details of the products, so that other consumers do not suffer. Nagral's article however does highlight the serious issue of adulteration in herbal markets and the need for establishing a robust pharmacovigilant system in India.

Association between COVID-19 and chronic liver disease: Mechanism, diagnosis, damage, and treatment.

As the outbreak evolves, our understanding of the consequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the resulting coronavirus disease 2019 (COVID-19) on the liver has grown. In this review, we discussed the hepatotropic nature of SARS-CoV-2 and described the distribution of receptors for SARS-CoV-2 (e.g., angiotensin-converting enzyme 2) in the vascular endothelium and cholangiocytes of the liver. Also, we proposed mechanisms for possible viral entry that mediate liver injury, such as liver fibrosis. Due to SARS-CoV-2-induced liver damage, many COVID-19 patients develop liver dysfunction, mainly characterized by moderately elevated serum aminotransferase levels. Patients with chronic liver disease (CLD), such as cirrhosis, hepatocellular carcinoma, nonalcoholic fatty liver disease, and viral hepatitis, are also sensitive to SARS-CoV-2 infection. We discussed the longer disease duration and higher mortality following SARS-CoV-2 infection in CLD patients. Correspondingly, relevant risk factors and possible mechanisms were proposed, including cirrhosis-related immune dysfunction and liver deco-mpensation. Finally, we discussed the potential hepatotoxicity of COVID-19-related vaccines and drugs, which influence the treatment of CLD patients with SARS-CoV-2 infection. In addition, we suggested that COVID-19 vaccines in terms of immunogenicity, duration of protection, and long-term safety for CLD patients need to be further researched. The diagnosis and treatment for liver injury caused by COVID-19 were also analyzed in this review.

Effect of Pirfenidone on Risk of Pulmonary Fibrosis in COVID-19 Patients Experiencing Cytokine Storm.

OBJECTIVES: Severe stages of COVID-19 infection have been associated with the excessive discharge of pro-inflammatory mediators such as cytokines, resulting in lung deterioration, which progresses rapidly to lung fibrosis leading to acute respiratory distress syndrome. In this investigation, the efficacy and safety of the novel antifibrotic and anti-inflammatory agent, Pirfenidone, were assessed in COVID-19 patients with pulmonary fibrosis secondary to cytokine storm. In this randomized controlled study, we assigned 100 adult COVID-19 patients cytokine storm and admitted to the intensive care isolation unit into either pirfenidone added to the standard therapy (n = 47), or the standard protocol only (n = 53). High-resolution computed tomography of the chest was performed in all patients to evaluate fibrotic lesions and their progression. The results showed that the percentage of patients who developed pulmonary fibrosis during cytokine storm onset in the pirfenidone group relative to the standard group was 29.8% and 35.8%, respectively, with no significant difference between the two groups; while there was a significant increase in the proportion of patients discharged from the isolation unit with pulmonary fibrosis without progression in fibrotic lesions in the pirfenidone group compared to the standard group (21.3% and 5.7%, respectively). Furthermore, there was a significant difference concerning liver enzyme elevation and GIT disturbance incidences in the studied groups (p = 0.006 and 0.01, respectively). Our findings show that Pirfenidone inhibits fibrosis advancement in COVID-19 patients with pulmonary fibrosis and is associated with hepatotoxicity and GI distress. It may be beneficial in patients with mild to moderate COVID-19-induced pulmonary fibrosis; however, additional research is necessary.

Anti-COVID-19 terpenoid from marine sources: A docking, admet and molecular dynamics study.

Traditional medicines contain natural products (NPs) as main ingredient which always give new direction and paths to develop new advanced medicines. In the COVID-19 pandemic, NPs can be used or can help to find new compound against it. The SARS coronavirus-2 main protease (SARS CoV-2 Mpro) enzyme, arbitrate viral replication and transcription, is target here. The study show that, from the electronic features and binding affinity of all the NPs with the enzyme, the compounds with higher hydrophobicity and lower flexibility can be more favorable inhibitor. More than fifty NPs were screened for the target and one terpenoid (T3) from marine sponge Cacospongia mycofijiensis shows excellent SARS CoV-2 Mpro inhibitory activity in comparison with known peptide based inhibitors. The molecular dynamics simulation studies of the terpenoids with the protein indicates that the complex is stable and hydrogen bonds are involved during the complexation. Considering binding affinity, bioavailability, pharmacokinetics and toxicity of the compounds, it is proposed that the NP T3 can act as a potential drug candidate against COVID-19 virus.

Drug-induced liver injury after covid-19 mRNA vaccine: case report.

Case description: A 22-year-old female patient received the first dose of Pfizer-BioNTech vaccine (RNAm) against COVID-19; 6 days later, she presented abdominal pain located in the right hypochondrium and epigastrium, associated with emetic episodes. Re-consultation 21 days later due to the same symptoms; three days after the second dose of the vaccine was administered. Clinical findings: Pain on palpation in the right hypochondrium. Laboratories reported hepatocellular lesion and cholestasis, with negative amylase, hepatotropic virus and autoimmune hepatitis tests. Liver and biliary tract ultrasound and cholangioresonance were normal. Treatment and Results: Hyoscine and intravenous fluids as support therapy. She presented improvement in abdominal pain and progressive decrease of transaminases and bilirubin levels until normalization, and was discharged on the fifth day of hospitalization. A drug-associated hepatotoxicity (DILI) diagnosis was considered probable, in this case, secondary to vaccination against COVID-19. Clinical Relevance: The current SARS CoV-2 pandemic has spurred the development of new vaccines, the safety of which remains a concern. There is a likely causal relationship between vaccination and liver involvement in this clinical case, rather than simply a sporadic occurrence.

Descripción del caso: Paciente femenina de 22 años, quien recibió primera dosis de vacuna Pfizer-BioNTech (RNAm) contra COVID-19; presenta 6 días después, dolor abdominal localizado en hipocondrio derecho y epigastrio, asociado a episodios eméticos. Reconsulta a los 21 días por la misma sintomatología; tres días posteriores a la aplicación de la segunda dosis de la vacuna. Hallazgos clínicos: dolor a la palpación en hipocondrio derecho. Los laboratorios reportaron lesión hepatocelular y colestasis, con amilasa, estudios para virus hepatotrópos y hepatitis autoinmune negativos. La ecografía de hígado, vías biliares y colangioresonancia fueron normales. Tratamiento y Resultados: hioscina 20 mg vía oral cada 8 horas y líquidos endovenosos como terapia de soporte. Presentó mejoría del dolor abdominal y descenso progresivo de transaminasas y bilirrubinas, hasta su normalización y se dio egreso al quinto día de hospitalización. Se consideró probable diagnóstico de hepatotoxicidad asociada a medicamentos (DILI), en este caso, secundario a la vacunación contra COVID-19. Relevancia Clínica: La pandemia actual por el virus SARS CoV-2 ha impulsado el desarrollo de nuevas vacunas, cuya seguridad sigue siendo un motivo de preocupación. En este caso clínico, hay una probable relación causal entre la vacunación y el compromiso hepático, en lugar de una simple aparición esporádica.

LIVER DAMAGE IN PATIENTS WITH COVID-19

The clinical spectrum of SARS-CoV-2 infection continues to expand, raising important fundamental issues regarding the SARS-CoV-2 cellular tropism and pathogenic mechanisms. Liver damage is observed in patients with all forms of COVID-19, especially severe and critical forms, which could be due to the direct viral damage, immune dysregulation (systemic inflammatory response and cytokine storm), hypoxia-ischemia, drug-induced hepatotoxicity, and concomitant chronic disorders. Liver damage, defined primarily by elevated transaminase levels, is often observed in patients with COVID-19 and correlates with clinical outcomes, including mortality. Diagnostic criteria, pathogenesis, clinical characteristics, treatment, and prognosis of liver injury in COVID-19 should be clarified in further clinical trials. Currently, there is a critical shortage of proven treatment options for patients with COVID-19, resulting in an urgent need to study the multiple organ failure and liver damage pathogenesis in patients with this disease. The review provides information about the pathophysiological mechanisms of the SARS-CoV-2-induced liver damage and the development of liver failure in COVID-19. Information sources were searched in the PubMed database using the keywords “liver damage in COVID-19” and “immune liver damage in COVID-19”. © 2022 Obstetrics, Gynecology and Reproduction. All rights reserved.

Caveolin-1 Alleviates Acetaminophen-Induced Hepatotoxicity in Alcoholic Fatty Liver Disease by Regulating the Ang II/EGFR/ERK Axis.

Acetaminophen (APAP) is a widely used antipyretic analgesic which can lead to acute liver failure after overdoses. Chronic alcoholic fatty liver disease (AFLD) appears to enhance the risk and severity of APAP-induced liver injury, and the level of angiotensin II (Ang II) increased sharply at the same time. However, the underlying mechanisms remain unclear. Caveolin-1 (CAV1) has been proven to have a protective effect on AFLD. This study aimed to examine whether CAV1 can protect the APAP-induced hepatotoxicity of AFLD by affecting Ang II or its related targets. In vivo, the AFLD model was established according to the chronic-plus-binge ethanol model. Liver injury and hepatic lipid accumulation level were determined. The levels of Angiotensin converting enzyme 2 (ACE2), Ang II, CAV1, and other relevant proteins were evaluated by western blotting. In vitro, L02 cells were treated with alcohol and oleic acid mixture and APAP. CAV1 and ACE2 expression was downregulated in APAP-treated AFLD mice compared to APAP-treated mice. The overexpression of CAV1 in mice and L02 cells alleviated APAP-induced hepatotoxicity in AFLD and downregulated Ang II, p-EGFR/EGFR and P-ERK/ERK expression. Immunofluorescence experiments revealed interactions between CAV1, Ang II, and EGFR. The application of losartan (an Ang II receptor antagonist) and PD98059 (an ERK1/2 inhibitor) alleviated APAP-induced hepatotoxicity in AFLD. In conclusion, our findings verified that CAV1 alleviates APAP-aggravated hepatotoxicity in AFLD by downregulating the Ang II /EGFR/ERK axis, which could be a novel therapeutic target for its prevention or treatment.

Impact of Liver Functions by Repurposed Drugs for COVID-19 Treatment.

Liver injury is an important complication that may arise in patients suffering from coronavirus disease 2019 (COVID-19) and is accompanied by a transient increase of transaminases and/or other liver enzymes. Liver function test (LFT) abnormalities generally disappear when the COVID-19 resolves or hepatotoxic drugs are discontinued. The LFT abnormalities are associated with drug-induced liver injury (DILI), due to the overuse of antimalarials, antivirals, and antimicrobials. Studies have reported varying levels of these liver injuries in COVID-19 patients; however, most involve elevated serum aminotransferases. Hepatic dysfunction is significantly high in patients with severe illness and has poor outcome. Normally, the liver is involved in the metabolism of many drugs, including nucleoside analogs and protease inhibitors, which are currently repurposed to treat COVID-19. In addition to the manifestation of COVID-19, drugs implemented in its treatment may aggravate liver injuries. Thus, DILI should be considered especially in those COVID-19 patients with underlying liver disease. It was unclear whether the elevated liver enzymes have originated from the underlying disease or DILI in this population. Furthermore, it is difficult to establish a direct relationship between a specific drug and liver injury. Another possible effect of liver damage may due to inflammatory cytokine storm in severe COVID-19. Liver injury can change metabolism, excretion, dosing, and expected concentrations of the drugs, which may make it difficult to achieve a therapeutic dose of the drug or increase the risk of adverse effects. These repurposed drugs have shown limited efficacy against the virus and the disease itself; however, they still pose risk of adverse effects. Careful and close monitoring of LFTs in COVID-19 patients can provide early diagnosis of liver injury, and the risk of DILI could be reduced. Also, drug interactions in liver-transplanted patients should always be kept in mind for certain immunosuppressive therapies and their known signs of DILI. Altogether, abnormal LFTs should not be regarded as a contraindication to use COVID-19 experimental therapies if needed under emergent status.

Assessment of Liver profile in Multi Drugs Resistant (MDR) Tuberculosis Patients on Treatment

M tuberculosis mainly infects the lungs, which is known as pulmonary tuberculosis, but it can infect other organs also such as the gastrointestinal tract, central nervous system, lymph nodes, bones, joints, urinary tract, and other sites, which is known as extrapulmonary tuberculosis. Drug-resistant M. tuberculosis isolates are a serious threat to TB control because only a few effective drugs are available for the treatment of this disease. Directly observed treatment short course (DOTS) is the main pillar employed for the control of tuberculosis under the National Tuberculosis Elimination Programme (NTEP) in India. Treatment of tuberculosis either drug-sensitive or drug-resistant involves drugs that are potentially hepatotoxic and may lead to drug-induced liver injury (DILI). Research has noticed the inevitability and cyclicity of pandemics during the last two centuries and highlighted it through smallpox, Tuberculosis, Plague, Influenza, HIV/AIDS, Ebola, and COVID-19.(18)

Synthesis, Spectroscopic Studies for Five New Mg (II), Fe (III), Cu (II), Zn (II) and Se (IV) Ceftriaxone Antibiotic Drug Complexes and Their Possible Hepatoprotective and Antioxidant Capacities

Magnesium, copper, zinc, iron and selenium complexes of ceftriaxone were prepared in a 1:1 ligand to metal ratio to investigate the ligational character of the antibiotic ceftriaxone drug (CFX). The complexes were found to have coordinated and hydrated water molecules, except for the Se (IV) complex, which had only hydrated water molecules. The modes of chelation were explained depending on IR, 1HNMR and UV–Vis spectroscopies. The electronic absorption spectra and the magnetic moment values indicated that Mg (II), Cu (II), Zn (II), Fe (III) and Se (VI) complexes form a six-coordinate shape with a distorted octahedral geometry. Ceftriaxone has four donation sites through nitrogen from NH2 amino, oxygen from triazine, β-lactam carbonyl and carboxylate with the molecular formulas [Mg(CFX)(H2O)2]·4H2O, [Cu(CFX)(H2O)2]·3H2O, [Fe(CFX)(H2O)(Cl)]·5H2O, [Zn(CFX)(H2O)2]·6H2O and [Se(CFX)(Cl)2]·4H2O and acts as a tetradentate ligand towards the five metal ions. The morphological surface and particle size of ceftriaxone metal complexes were determined using SEM, TEM and X-ray diffraction. The thermal behaviors of the complexes were studied by the TGA(DTG) technique. This study investigated the effect of CFX and CFX metal complexes on oxidative stress and severe tissue injury in the hepatic tissues of male rats. Fifty-six male rats were tested: the first group received normal saline (1 mg/kg), the second group received CFX orally at a dose of 180 mg/kg, and the other treated groups received other CFX metal complexes at the same dose as the CFX-treated group. For antibacterial activity, CFX/Zn complex was highly effective against Streptococcus pneumoniae, while CFX/Se was highly effective against Staphylococcus aureus and Escherichia coli. In conclusion, successive exposure to CFX elevated hepatic reactive oxygen species (ROS) levels and lipid peroxidation final marker (MDA) and decreased antioxidant enzyme levels. CFX metal complex administration prevented liver injury, mainly suppressing excessive ROS generation and enhancing antioxidant defense enzymes and in male rats.

Diacerein ameliorates acetaminophen hepatotoxicity in rats via inhibiting HMGB1/TLR4/NF-κB and upregulating PPAR-γ signal.

BACKGROUND: Acetaminophen (APAP) is a worldwide antipyretic as well as an analgesic medication. It has been extensively utilized during the outbreak of coronavirus 2019 (COVID-19). APAP misuse would lead to liver injury. Diacerein (DIA), an anthraquinone derivative, has antioxidant and inflammatory properties. Hence, this study attempted to evaluate the impact of DIA treatment on liver injury induced by APAP and its influence on nuclear factor-κB (NF-κB) /toll-like receptor 4 (TLR4)/high mobility group box-1(HMGB-1) signaling as well as the expression of peroxisome proliferator-activated receptor-gamma (PPAR-γ) expression. METHODS: Male albino rats received 25 as well as 50 mg/kg/day DIA orally for seven days. One hour after the last administration, rats received APAP (1gm/kg, orally). For histopathological analysis, liver tissues and blood were collected, immunohistochemical (IHC) assay, biochemical assay, as well as quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: DIA markedly reduced liver injury markers and ameliorated histopathological changes. Moreover, DIA dose-dependently alleviated oxidative stress status caused by APAP administration along with inflammatory markers, including the level of interleukin-1 beta (IL-1ß), myeloperoxidase (MPO), tumor necrosis factor-alpha (TNF-α), and interleukin 6 (IL-6). Furthermore, DIA downregulated protein levels as well as mRNA of HMGB-1, TLR4, NF-κB p65 expression, and enhanced PPAR-γ expression. Moreover, DIA ameliorated apoptotic (Bax) and caspase-3 expressions and increased the anti-apoptotic (Bcl2) expression. CONCLUSIONS: This study demonstrated that DIA exerts anti-apoptotic, anti-inflammatory, and antioxidant properties against liver injury induced by APAP that is attributed to inhibition of the HMGB1/TLR4/NF-κB pathway, besides upregulation of the expression of PPAR-γ.

Dabigatran in patients with atrial fibrillation after COVID-19 hospitalization: an update of the ANIBAL protocol.

COVID-19 increases the risk of atrial fibrillation (AF) and thrombotic complications, particularly in severe cases, leading to higher mortality rates. Anticoagulation is the cornerstone to reduce thromboembolic risk in patients with AF. Considering the risk of hepatotoxicity in patients with severe COVID-19 as well as the risk of drug-drug interactions, drug-induced hepatotoxicity and bleeding, the ANIBAL protocol was developed to facilitate the anticoagulation approach at discharge after COVID-19 hospitalization. However, since the publication of the original algorithm, relevant changes have occurred. First, treatment of COVID-19 pneumonia has been modified with the use of dexamethasone or remdesivir during the first week in patients that require oxygen therapy, and of dexamethasone and/or tocilizumab or baricitinib during the second week in patients that necessitate supplementary oxygen or with a high inflammation state, respectively. On the other hand, metabolic syndrome is common in patients with AF as well as metabolic-associated fatty liver disease, and this could negatively impact the prognosis of patients with COVID-19, including high transaminase levels in patients treated with immunomodulators. The EHRA guidelines update also introduce some interesting changes in drug-drug interaction patterns with the reduction of the level of the interaction with dexamethasone, which is of paramount importance in this clinical context. Considering the new information, the protocol, named ANIBAL II, has been updated. In this new protocol, the anticoagulant of choice in patients with AF after COVID-19 hospitalization is provided according to three scenarios: with/without dexamethasone treatment at discharge and normal hepatic function, transaminases ≤2 times the upper limit of normal, or transaminases >2 times the upper limit of normal.