Screening for Susceptibility-Related Biomarkers of Diclofenac-Induced Liver Injury in Rats Using Metabolomics

Early identification of individuals susceptible to idiosyncratic drug-induced liver injury (IDILI) is a challenging unmet demand. Diclofenac, one of the most widely available over-the-counter drugs for pain management worldwide, may induce liver dysfunction, acute liver failure, and death. Herein, we report that diclofenac-related hepatobiliary adverse reactions occurred more frequently in cases with immune activation. Furthermore, experiments with rats demonstrated divergent hepatotoxicity responses in individuals exposed to diclofenac, and modest inflammation potentiated diclofenac-induced liver injury. Susceptible rats had unique plasma metabolomic characteristics, and as such, the metabolomic approach could be used to distinguish susceptible individuals. The 23 identified susceptibility-related metabolites were enriched by several metabolic pathways related to acute-phase reactions of immunocytes and inflammatory responses, including sphingolipid, tyrosine, phenylalanine, tryptophan, and lipid metabolism pathways. This finding implies a mechanistic role of metabolic and immune disturbances affects susceptibility to diclofenac-IDILI. Further nine metabolite biomarkers with potent diagnostic capabilities were identified using receiver operating characteristic curves. These findings elucidated the potential utility of metabolomic biomarkers to identify individuals susceptible to drug hepatotoxicity and the underlying mechanism of metabolic and immune disturbances occurring in IDILI.

Drug Packaging Management Based on the Effect of Medical Images on the Intracellular Polysaccharide Synthesis and Antivertigo Activity of Phalaenopsis

Many clinically important drugs come directly or indirectly from higher plants. People are increasingly aware of the role of the human immune system in maintaining good health. Diseases related to physical dysfunction, such as vertigo, have attracted increasing attention from medical researchers and clinicians. In this paper, some compounds isolated and identified from medicinal fomes showed promising antivertigo properties. Medical images were used to classify and synthesize polysaccharides in the management of drug subpackages of Cladosporium intracellular polysaccharides. The scientific explanation of how these compounds work in animal and human systems is increasing exponentially. Studies have found that all of these compounds can enhance the innate and adaptive immune responses of the host and activate various immune cells that are important for maintaining homeostasis, such as host cells and chemical messengers, triggering complement and acute phase reactions. The antivertigo compounds derived from the intracellular polysaccharides of Phellinus mucronatus had an activity interference of 35% without drug subpackage. Although the antivertigo activity of many intracellular polysaccharides from Fovea xylostella can reach 86%, only a few of them have been proved to have antivertigo activity. In addition, they can be considered as multicytokine inducers that can induce the expression of various immune-regulatory cytokines and cytokine receptor genes. Lymphocytes that control antibody production and cell-mediated cytotoxicity are also stimulated.

Acute Phase Reactions After Intravenous Infusion of Zoledronic Acid in Japanese Patients with Osteoporosis: Sub-analyses of the Phase III ZONE Study

In a clinical trial involving Japanese patients with osteoporosis, post hoc analyses were performed to evaluate the incidence of acute phase reactions (APRs) after infusion of zoledronic acid (ZOL). The results highlighted differences in baseline factors between patients with vs without APRs. Changes in efficacy indicators such as bone turnover markers (BTMs) also showed significant differences. We, therefore, investigated the factors involved in the development of APRs in Japanese patients treated with a once-yearly intravenous infusion of ZOL 5 mg for 2 years by assessing the relation between APRs and efficacy. APRs reported in patients with primary osteoporosis from the ZONE study were analyzed post hoc. Baseline factors were compared in patients with vs without APRs, and changes in BTMs and bone mineral density (BMD) were also investigated. In the ZOL group, 51.2% (169/330) of patients developed APRs after the first infusion and 12.3% (33/268) after the second infusion. Comparison of baseline factors showed that patients without APRs in the ZOL group had a significantly higher neutrophil/lymphocyte ratio, lower serum levels of procollagen type I N-terminal propeptide, older age, and higher likelihood of prior bisphosphonate use vs patients with APRs. Patients with APRs showed significantly higher increases in total hip BMD at 6 and 12 months and larger reductions in BTMs vs patients without APRs. Patient profiles differed significantly between patients with vs without APRs, with APRs after the first infusion of ZOL being related to increases in total hip BMD and suppression of BTMs.This study is registered with ClinicalTrials.gov (identifier: NCT01522521; January 31, 2012).

Hyperferritinemia—A Clinical Overview

Ferritin is one of the most frequently requested laboratory tests in primary and secondary care, and levels often deviate from reference ranges. Serving as an indirect marker for total body iron stores, low ferritin is highly specific for iron deficiency. Hyperferritinemia is, however, a non-specific finding, which is frequently overlooked in general practice. In routine medical practice, only 10% of cases are related to an iron overload, whilst the rest is seen as a result of acute phase reactions and reactive increases in ferritin due to underlying conditions. Differentiation of the presence or absence of an associated iron overload upon hyperferritinemia is essential, although often proves to be complex. In this review, we have performed a review of a selection of the literature based on the authors’ own experiences and assessments in accordance with international recommendations and guidelines. We address the biology, etiology, and epidemiology of hyperferritinemia. Finally, an algorithm for the diagnostic workup and management of hyperferritinemia is proposed, and general principles regarding the treatment of iron overload are discussed.

Keeping an Eye on Bisphosphonate Therapy in Myeloma: A Case Report of Ocular Inflammation Postzoledronic Acid Infusion

Bisphosphonates have evolved over the past decades from oral to more potent intravenous preparations. Along with significant paradigm shift in the management of myeloma over the past years, stronger nitrogen-containing bisphosphonates, due to their antiresorptive action on the bones, have found their way as a key and integral part in the management of bone disease in myeloma. Multiple randomized controlled trials have established efficacy of bisphosphonates in reducing skeletal-related events in myeloma. Some well-documented adverse events include acute-phase reactions, esophageal irritation, and osteonecrosis of the jaw. Across all clinical indications, the incidence of inflammatory eye reactions after bisphosphonate infusion ranges from 0.046% to 1%. However, data from myeloma patients are extrapolated from few reported cases in literature with varying management strategies including discontinuation, switching to different forms, and rechallenging with steroid cover. Inflammatory eye reactions can vary from self-limiting conjunctivitis and episcleritis to serious uveitis and vision-threatening orbital inflammation. We present a similar case of a patient with IgG kappa myeloma who developed flu-like symptoms followed by severe orbital inflammation within 48–72 hours after receiving zoledronic acid infusion. The patient was successfully managed with intravenous methyl prednisolone followed by oral tapering dose of steroids and discontinuation of further bisphosphonate therapy. A complete recovery was noted in a week’s time.

Hemostasis disorders, thrombosis, antiphospholipid antibodies in patients with covid-19

The article provides an overview of main blood clotting disorders in coronavirus infection 2019 (COVID-19), which is associated with several hematological changes. Patients with COVID-19 develop typically two hemostasis disorders – an increased D-dimer levels and moderate thrombocytopenia, which occur in more than 40% of cases. Other hemostasis abnormalities, which are frequently reported in COVID-19, included prolonged prothrombin time (PT), also expressed as international normalized ratio, prolonged thrombin time, and activated partial thromboplastin time (APTT), which were typical acute phase reactions. Prolonged APTT or PT, and thrombocytopenia are common, especially in patients with severe clinical course. It has been hypothesized that increased D-dimer concentration and prolongation of PT, APTT are associated with higher mortality in patients with COVID-19. Disseminated intravascular coagulation occurs most often in severe cases of COVID-19 (about 2% of all hospitalized patients) and indicates a poor prognosis, i.e. about 90% mortality. It remains unclear whether SARS-CoV-2 can induce antiphospholipid antibodies. An increased incidence of positive lupus anticoagulants was observed in patients with COVID-19, it can be assumed that all patients with COVID-19 in whom antiphospholipid antibodies are revealed should be monitored and receive thromboprophylaxis even with no history of thromboembolism. Keywords: coronavirus infection (COVID-19), hemostasis disorder, antiphospholipid antibodies, antiphospholipid syndrome, thrombosis, anticoagulants For citation: Reshetnyak TM, Chel'dieva FA, Lila AM, Nasonov EL. Hemostasis disorders, thrombosis, antiphospholipid antibodies in patients with COVID-19. Consilium Medicum. 2021; 23 (1): 35–42. DOI: 10.26442/20751753.2021.1.200607

Interleukin 6 and Rheumatoid Arthritis

Interleukin-6 (IL-6) is a representative cytokine featuring pleiotropic activity and redundancy. A transient synthesis of IL-6 contributes to host defense against infectious agents and tissue injuries by inducing acute phase reactions and immunological and hematopoietic responses. However, uncontrolled persistent production of IL-6 may lead to the development of several immune-mediated diseases. Rheumatoid arthritis (RA) is a chronic disease with joint and systemic inflammation resulting from immunological abnormalities and it has been found that IL-6 plays a key role in the development of this disease. Clinical trials in various parts of the world of tocilizumab, a humanized anti-IL-6 receptor antibody, have proved its efficacy and tolerable safety either as monotherapy or in combination with disease-modifying antirheumatic drugs. As a result, it is currently used as a first-line biologic for the treatment of moderate-to-severe RA in more than 100 countries. Clarification of the mechanism(s) through which tocilizumab exerts its effect on RA and of the reason(s) why IL-6 is continuously produced in RA can be expected to lead to the best use of this agent for RA patients and aid in investigations into the pathogenesis of RA.