Leflunomide an immunomodulator with antineoplastic and antiviral potentials but drug-induced liver injury: A comprehensive review

Autor: Sabah H. El-Ghaiesh, Sarah Majed A. Alquayr, Samaher S Alsubhi, Ghadeer Abdullah Albalawi, Raghad Dhafer E. ALamri, Mazen A Elmeligy
Rok vydání: 2021
Předmět:
0301 basic medicine
Drug-induced liver injury
Bcl2
B-cell lymphoma 2 protein
medicine.medical_treatment
Review
Pharmacology
0302 clinical medicine
PIM1 kinase
proto-oncogene serine/threonine protein kinase Pim-1
Immunology and Allergy
media_common
Leflunomide
Liver injury
Clinical Trials as Topic
AMPK
adenosine monophosphate-activated protein kinase
LDH
lactate dehydrogenase
biology
JNK
c-Jun N-terminal kinases
Immunosuppression
Antineoplastic
030220 oncology & carcinogenesis
sEphrin-A1
soluble ephrin-A1
iNOS
inducible nitric oxide synthase
Immunomodulator
Chemical and Drug Induced Liver Injury
Antibody
Tyrosine kinase
medicine.drug
Drug
ERK1/2
extracellular signal-regulated kinases
CCL4
carbon tetrachloride
media_common.quotation_subject
PCNA
proliferating cell nuclear antigen
Immunology
Antineoplastic Agents
P56Lck
T-lymphocyte-specific protein tyrosine kinase
Antiviral Agents
03 medical and health sciences
PGE2
prostaglandin E2
medicine
Humans
Immunologic Factors
Antiviral
NO
nitric oxide
SARS-CoV-2
Cell growth
business.industry
COVID-19
TAK1
transforming growth factor β-activated kinase 1
Eph-A2
ephrin-A2
medicine.disease
COVID-19 Drug Treatment
Bax
Bcl-2-associated X protein
030104 developmental biology
COX2
cyclo-oxygenase 2
AMP
adenosine monophosphate
biology.protein
Dihydroorotate dehydrogenase
ULK1
Unc-51-like autophagy activating kinase
Anti-inflammatory
business
Zdroj: International Immunopharmacology
ISSN: 1567-5769
DOI: 10.1016/j.intimp.2021.107398
Popis: Leflunomide (LF) represents the prototype member of dihydroorotate dehydrogenase (DHODH) enzyme inhibitors. DHODH is a mitochondrial inner membrane enzyme responsible for catalytic conversion of dihydroorotate into orotate, a rate-limiting step in the de novo synthesis of the pyrimidine nucleotides. LF produces cellular depletion of pyrimidine nucleotides required for cell growth and proliferation. Based on the affected cells the outcome can be attainable as immunosuppression, antiproliferative, and/or the recently gained attention of the antiviral potentials of LF and its new congeners. Also, protein tyrosine kinase inhibition is an additional mechanistic benefit of LF, which inhibits immunological events such as cellular expansion and immunoglobulin production with an enhanced release of immunosuppressant cytokines. LF is approved for the treatment of autoimmune arthritis of rheumatoid and psoriatic pathogenesis. Also, LF has been used off-label for the treatment of relapsing-remitting multiple sclerosis. However, LF antiviral activity is repurposed and under investigation with related compounds under a phase-I trial as a SARS CoV-2 antiviral in cases with COVID-19. Despite success in improving patients' mobility and reducing joint destruction, reported events of LF-induced liver injury necessitated regulatory precautions. LF should not be used in patients with hepatic impairment or in combination with drugs elaborating a burden on the liver without regular monitoring of liver enzymes and serum bilirubin as safety biomarkers. This study aims to review the pharmacological and safety profile of LF with a focus on the LF-induced hepatic injury from the perspective of pathophysiology and possible protective agents.
Databáze: OpenAIRE
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