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Methotrexate (MTX) is the standard of care in the treatment of rheumatoid arthritis (RA), a common autoimmune disease that is characterized by chronic inflammation in the synovial membrane of joints. Unfortunately, MTX suffers from high discontinuation rates due to a large variability in efficacy and, in particular, adverse effects. As inflammation is associated with elevated levels of reactive oxygen species (ROS) like HO, we propose to improve treatment through site-selective delivery of MTX to inflammatory tissue by use of a HO sensitive MTX prodrug. To establish proof proof-of-concept, two novel HO sensitive, thiazolidinone-based MTX prodrugs were synthesized and evaluated for this purpose. MTX-γ-thiazolidinone (MTX-γ-TZ) exhibited the most promising properties - good to high chemical and metabolic stability, excellent aqueous solubility, while being activated when subjected to patho-physiological concentrations of HO. In vivo, MTX-γ-TZ exhibited comparable efficacy to MTX in a murine collagen type II-induced arthritis (CIA) model while treated mice showed indications of reduced toxicity as their body weight decreased less towards the end of the study, compared to the MTX-treated group.
This article was published in the following journal.
Name: European journal of medicinal chemistry
Methotrexate has been used in treatment of rheumatoid arthritis (RA) since the 1980s and to this day is often the first line medication for RA treatment. In this review, we examine multiple hypotheses...
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Molecules or ions formed by the incomplete one-electron reduction of oxygen. These reactive oxygen intermediates include SINGLET OXYGEN; SUPEROXIDES; PEROXIDES; HYDROXYL RADICAL; and HYPOCHLOROUS ACID. They contribute to the microbicidal activity of PHAGOCYTES, regulation of signal transduction and gene expression, and the oxidative damage to NUCLEIC ACIDS; PROTEINS; and LIPIDS.
A technique for causing a targeted loss of molecular function from REACTIVE OXYGEN SPECIES that are formed by the illumination of dyes placed in the immediate vicinity of the target molecule.
Oxygenated derivatives of cholesterol or its sterol precursors. They are generated from sterol metabolism and the interaction of cholesterol with REACTIVE OXYGEN SPECIES.
A species of gram-negative, anaerobic, rod-shaped bacteria originally classified within the BACTEROIDES genus. This bacterium produces a cell-bound, oxygen-sensitive collagenase and is isolated from the human mouth.
A mitochondrial uncoupling protein that is expressed in many tissues and exhibits the greatest expression in SKELETAL MUSCLE. It regulates mitochondrial ATP production and the generation of REACTIVE OXYGEN SPECIES.
Arthroplasty Joint Disorders Orthopedics Spinal Cord Disorders Orthopedics is the science or practice of correcting deformities caused by disease or damage to the bones and joints of the skeleton. This specialized branch of surgery may ...
Autoimmune disorders are conditions that occurs when the immune system mistakenly attacks and destroys healthy body tissue. There are more than 80 different types of autoimmune disorders. Normally the immune system's white blood cells help protect ...