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RMD Open Mar 2024Sulfasalazine-induced cytopenia, nephrotoxicity and hepatotoxicity is uncommon during long-term treatment. Some guidelines recommend 3 monthly monitoring blood tests...
BACKGROUND
Sulfasalazine-induced cytopenia, nephrotoxicity and hepatotoxicity is uncommon during long-term treatment. Some guidelines recommend 3 monthly monitoring blood tests indefinitely during long-term treatment while others recommend stopping monitoring after 1 year. To rationalise monitoring, we developed and validated a prognostic model for clinically significant blood, liver or kidney toxicity during established sulfasalazine treatment.
DESIGN
Retrospective cohort study.
SETTING
UK primary care. Data from Clinical Practice Research Datalink Gold and Aurum formed independent development and validation cohorts.
PARTICIPANTS
Age ≥18 years, new diagnosis of an inflammatory condition and sulfasalazine prescription.
STUDY PERIOD
1 January 2007 to 31 December 2019.
OUTCOME
Sulfasalazine discontinuation with abnormal monitoring blood-test result.
ANALYSIS
Patients were followed up from 6 months after first primary care prescription to the earliest of outcome, drug discontinuation, death, 5 years or 31 December 2019. Penalised Cox regression was performed to develop the risk equation. Multiple imputation handled missing predictor data. Model performance was assessed in terms of calibration and discrimination.
RESULTS
8936 participants were included in the development cohort (473 events, 23 299 person-years) and 5203 participants were included in the validation cohort (280 events, 12 867 person-years). Nine candidate predictors were included. The optimism adjusted R and Royston D statistic in the development data were 0.13 and 0.79, respectively. The calibration slope (95% CI) and Royston D statistic (95% CI) in validation cohort was 1.19 (0.96 to 1.43) and 0.87 (0.67 to 1.07), respectively.
CONCLUSION
This prognostic model for sulfasalazine toxicity uses readily available data and should be used to risk-stratify blood-test monitoring during established sulfasalazine treatment.
Topics: Humans; Adolescent; Sulfasalazine; Prognosis; Retrospective Studies
PubMed: 38453215
DOI: 10.1136/rmdopen-2023-003980 -
Biomedicines Feb 2022Approximately 25% of colorectal cancer (CRC) patients will develop metastatic (m)CRC despite treatment interventions. In this setting, tumor cells are attracted to the...
Approximately 25% of colorectal cancer (CRC) patients will develop metastatic (m)CRC despite treatment interventions. In this setting, tumor cells are attracted to the epidermal growth factor receptor () oncogene. Kirsten rat sarcoma (RAS) 2 viral oncogene homolog () mutations were reported to drive CRC by promoting cancer progression in activating Wnt/β-catenin and RAS/extracellular signal-regulated kinase (ERK) pathways. In addition, is associated with almost 40% of patients who acquire resistance to EGFR inhibitors in mCRC. Multiple studies have demonstrated that cancer stem cells (CSCs) promote tumorigenesis, tumor growth, and resistance to therapy. One of the most common CSC prognostic markers widely reported in CRC is a cluster of differentiation 44 (CD44), which regulates matrix metalloproteinases 7/9 (MMP7/9) to promote tumor progression and metastasis; however, the molecular role of CD44 in CRC is still unclear. In invasive CRC, overexpression of MMP7 was reported in tumor cells compared to normal cells and plays a crucial function in CRC cetuximab and oxaliplatin resistance and distant metastasis. Here, we utilized a bioinformatics analysis and identified overexpression of oncogenic signatures in CRC tumor tissues compared to normal tissues. In addition, a high incidence of mutations in and were associated with some of the top tumorigenic oncogene's overexpression, which ultimately promoted a poor response to chemotherapy and resistance to some FDA-approved drugs. Based on these findings, we explored a computational approach to drug repurposing of the drug, sulfasalazine, and our in silico molecular docking revealed unique interactions of sulfasalazine with the oncogenes, resulting in high binding affinities compared to those of standard inhibitors. Our in vitro analysis demonstrated that sulfasalazine combined with cisplatin reduced cell viability, colony, and sphere formation in CRC cell lines. In addition, sulfasalazine alone and combined with cisplatin suppressed the expression of in DLD-1 and HCT116 cell lines. Thus, sulfasalazine is worthy of further investigation as an adjuvant agent for improving chemotherapeutic responses in CRC patients.
PubMed: 35203586
DOI: 10.3390/biomedicines10020377 -
Medical Sciences (Basel, Switzerland) Aug 2023IBD consists of two diseases-CD and UC-that affect the digestive tract, with a greater affinity for the large bowel. In this case report, we focus on one of its most...
IBD consists of two diseases-CD and UC-that affect the digestive tract, with a greater affinity for the large bowel. In this case report, we focus on one of its most common complications. CDI is a pathology that is mostly secondary to UC. Another cause of this bacterial infection is established after the use of antibiotics, most commonly at the hospital level. Around 20 percent of CDI persists because of a chronic dysbiosis of the microbiota and low levels of antibodies against CD toxins. In this case report, we demonstrated mdCDI in a young woman after treatment with multiple drug therapies as well as with semi-invasive procedures as follows: antibiotics (vancomycin, fidaxomicin), anti-inflammatory agents (mesalamine, sulfasalazine), corticosteroids (budesonide, prednisone), integrin receptor antagonists (vedolizumab), several semi-invasive procedures such as fecal transplant microbiota (FMT), aminosalicylates (5-ASA), treatment with tumor necrosis factor (TNF) blockers (adalimumab, golimumab), and immunomodulators (upadcitinib, tofacitinib). This leads us to establish how rCDI and its resistance to different treatments make this a challenge for the health system, both for hospitals and for outpatients, as well as how time-consuming each treatment is from the first intake of the drug until its total efficacy or until patients reach a dose-response and time-response to the disease. Accordingly, this case report and other similar cases reflect the need for randomized control trials or meta-analyses to establish therapeutic guidelines for cases of mdCDI in the near future.
Topics: Female; Humans; Colitis, Ulcerative; Clostridium Infections; Mesalamine; Adalimumab; Anti-Bacterial Agents
PubMed: 37606431
DOI: 10.3390/medsci11030052 -
Oxidative Medicine and Cellular... 2020Ferroptosis is an atypical form of regulated cell death, which is different from apoptosis, necrosis, pyroptosis, and autophagy. Ferroptosis is characterized by... (Review)
Review
Ferroptosis is an atypical form of regulated cell death, which is different from apoptosis, necrosis, pyroptosis, and autophagy. Ferroptosis is characterized by iron-dependent oxidative destruction of cellular membranes following the antioxidant system's failure. The sensitivity of ferroptosis is tightly regulated by a series of biological processes, the metabolism of iron, amino acids, and polyunsaturated fatty acids, and the interaction of glutathione (GSH), NADPH, coenzyme Q10 (CoQ10), and phospholipids. Elevated oxidative stress (ROS) level is a hallmark of cancer, and ferroptosis serves as a link between nutrition metabolism and redox biology. Targeting ferroptosis may be an effective and selective way for cancer therapy. The underlying molecular mechanism of ferroptosis occurrence is still not enough. This review will briefly summarize the process of ferroptosis and introduce critical molecules in the ferroptotic cascade. Furthermore, we reviewed the occurrence and regulation of reduction-oxidation (redox) for ferroptosis in cancer metabolism. The role of the tumor suppressor and the epigenetic regulator in tumor cell ferroptosis will also be described. Finally, old drugs that can be repurposed to induce ferroptosis will be characterized, aiming for drug repurposing and novel drug combinations for cancer therapy more efficiently and economically.
Topics: Acetaminophen; Antineoplastic Agents; Antioxidants; Apoptosis; Artemisinins; Auranofin; Cell Death; Cisplatin; Epigenesis, Genetic; Fatty Acids; Ferroptosis; Haloperidol; Humans; Indoles; Iron; Lapatinib; Mevalonic Acid; NADP; Neoplasms; Oxidation-Reduction; Oxidative Stress; Oxygen; Quinolines; Reactive Oxygen Species; Sorafenib; Spiro Compounds; Sulfasalazine; Trigonella
PubMed: 33425217
DOI: 10.1155/2020/8810785 -
The Antioxidant and Anti-Inflammatory Effects of Extract on TNBS-Induced Ulcerative Colitis in Rats.Evidence-based Complementary and... 2021Ulcerative colitis is a common subtype of persistent inflammatory bowel disease with high morbidity consequences. Despite unknown definite pathogenesis, multiple...
OBJECTIVES
Ulcerative colitis is a common subtype of persistent inflammatory bowel disease with high morbidity consequences. Despite unknown definite pathogenesis, multiple anti-inflammatory medications are used for its treatment. Traditionally, (QB), mostly available in the Middle East, has been used for gastrointestinal disorders. Other beneficial effects associated with QB include reduction of oxidative stress, inflammations, homeostatic instability, and improvement in clinical conditions.
MATERIALS AND METHODS
This experimental study was designed to assess the possible therapeutic effects of QB on UC and compare its effects with those of sulfasalazine. Of the 70 Wistar rats clustered in seven groups, ten received only alcohols and sixty were confirmed to be suffering from trinitrobenzene sulfonic acid- (TNBS-) induced colitis. Four groups received different dosages of QB extract via oral and rectal routes, one received sulfasalazine, and the other remaining two groups received nothing. The effects of QB were evaluated by assessing macroscopic and histologic scoring, measuring inflammatory mediators, and determining oxidative stress markers.
RESULTS
Comparing to the untreated TNBS-induced control groups, QB-treated groups showed a dose- and route-dependent improvement comparable with sulfasalazine. Treating rats with QB reduced the microscopic and macroscopic damage, decreased TNF-, IL-6, NO, MPO activity, and MDA content, increased superoxide dismutase (SOD) activity, and reduced body weight loss.
CONCLUSIONS
Our data recommended the anti-inflammatory and antioxidant effects of QB extract in a dose-dependent manner.
PubMed: 33505492
DOI: 10.1155/2021/3075973 -
Theranostics 2020Loss of iron-sulfur cluster function predisposes cancer cells to ferroptosis by upregulating iron-starvation response, but the role of glutaredoxin 5 (GLRX5) silencing...
Loss of iron-sulfur cluster function predisposes cancer cells to ferroptosis by upregulating iron-starvation response, but the role of glutaredoxin 5 (GLRX5) silencing in ferroptosis remains unknown. We examined the role of GLRX5 functional loss in promoting ferroptosis in cisplatin-resistant head and neck cancer (HNC) cells. The effects of sulfasalazine treatment and GLRX5 gene silencing were tested on HNC cell lines and mouse tumor xenograft models. These effects were analyzed concerning cell viability and death, lipid reactive oxygen species (ROS) and mitochondrial iron production, labile iron pool, mRNA/protein expression, and malondialdehyde assays. Cyst(e)ine deprivation, erastin, or sulfasalazine induced ferroptosis in HNC cells, which was relatively less sensitive in cisplatin-resistant HNC cells. Sulfasalazine or cyst(e)ine deprivation-induced ferroptosis resulted from increased lipid peroxidation and intracellular free iron, which were significantly promoted by short-interfering RNA or short hairpin RNA (shRNA) targeting GLRX5 (<0.05). GLRX5 silencing activated iron-starvation response and boosted up intracellular free iron through the iron-responsive element-binding activity of increased iron regulatory protein (increased transferrin receptor and decreased ferritin). These effects were rescued by resistant GLRX5 cDNA but not by catalytically inactive mutant GLRX5 K101Q. The same results were noted in an mouse model transplanted with vector or shGLRX5-transduced HNC cells and treated with sulfasalazine. Our data suggest that inhibition of GLRX5 predisposes therapy-resistant HNC cells to ferroptosis.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cisplatin; Drug Resistance, Neoplasm; Ferroptosis; Glutaredoxins; Head and Neck Neoplasms; Humans; Iron; Male; Mice; Mitochondria; Mutation; RNA Interference; Sulfasalazine; Xenograft Model Antitumor Assays
PubMed: 32685019
DOI: 10.7150/thno.46903 -
Pharmaceutics Mar 2021The simultaneous administration of sulfasalazine and folic acid is regular practice in the therapy of inflammatory bowel diseases in order to maintain sufficient folate...
The simultaneous administration of sulfasalazine and folic acid is regular practice in the therapy of inflammatory bowel diseases in order to maintain sufficient folate concentration in patients. Having multiple drugs in the therapy increases the possibility of patients failing adherence, thus unintentionally endangering their health. A fixed-dose combination of sulfasalazine and folic would simplify the classical polytherapeutic approach; however, the physicochemical compatibility investigation of two active pharmaceutical ingredients plays an important role in the development of such a product. In this work, various analytical tools were used to determine the physicochemical compatibility of sulfasalazine and folic acid. For the evaluation of chemical compatibility, infrared spectroscopy in combination with advanced statistical methods, such as the principal component analysis and cluster analysis, were used, whilst a simultaneous thermogravimetry/differential thermal analysis gave us an insight into the physical compatibility of two drugs. Isothermal stress testing, forced degradation and dissolution studies, followed by the analysis with a developed chromatographic method for the monitoring of folic acid, sulfasalazine and two of its related impurities, sulfapyridine and salicylic acid, gave us an insight into its chemical compatibility. The combination of the results obtained from the used techniques implies a satisfactory physicochemical compatibility between sulfasalazine and folic acid, which opens the path to the development of the proposed fixed-dose combination.
PubMed: 33802955
DOI: 10.3390/pharmaceutics13030400 -
Biomedicines Jan 2023Inflammatory bowel disease (IBD) has become a global concern. Proanthocyanidin-rich red rice extract (PRRE) has been shown to suppress the inflammatory response in...
Inflammatory bowel disease (IBD) has become a global concern. Proanthocyanidin-rich red rice extract (PRRE) has been shown to suppress the inflammatory response in cellular cultures. However, the anti-colitis effect of PRRE has never been investigated in animals. This study aimed to examine the protective effect of the PRRE against dextran sulfate sodium (DSS)-induced colitis in mice. Male mice were orally administrated with PRRE of 50, 250 and 500 mg/kg/day for 21 days. Acute colitis was subsequently induced by administrated 2.5% DSS in drinking water for the final seven days. Sulfasalazine-treated mice were the positive group. All doses of PRRE and sulfasalazine significantly ameliorated DSS-induced severity of colitis, as indicated by decreasing daily activity index and restoring colon shortening. Treatments with PRRE, but not sulfasalazine, significantly reduced the histopathological index and infiltration of inflammatory cells. Furthermore, the PRRE treatments effectively improved mucous in colonic goblet cells using PAS staining, and suppressed the production of pro-inflammatory cytokines TNF-α, IL-1β and IL-6 induced by DSS, while sulfasalazine reduced only IL-1β and IL-6. This study suggested that PRRE had a greater anti-colitis effect than sulfasalazine. Thus, PRRE has a potential anti-colitis effect, and should be developed in a clinical trial as a natural active pharmaceutical ingredient for IBD.
PubMed: 36830802
DOI: 10.3390/biomedicines11020265 -
Cellular and Molecular Gastroenterology... 2019Many differentiated epithelial cell types are able to reprogram in response to tissue damage. Although reprogramming represents an important physiological response to...
BACKGROUND & AIMS
Many differentiated epithelial cell types are able to reprogram in response to tissue damage. Although reprogramming represents an important physiological response to injury, the regulation of cellular plasticity is not well understood. Damage to the gastric epithelium initiates reprogramming of zymogenic chief cells into a metaplastic cell lineage known as spasmolytic polypeptide-expressing metaplasia (SPEM). The present study seeks to identify the role of xCT, a cystine/glutamate antiporter, in chief cell reprogramming after gastric injury. We hypothesize that xCT-dependent reactive oxygen species (ROS) detoxification is required for the reprogramming of chief cells into SPEM.
METHODS
Sulfasalazine (an xCT inhibitor) and small interfering RNA knockdown were used to target xCT on metaplastic cells in vitro. Sulfasalazine-treated wild-type mice and xCT knockout mice were analyzed. L635 or DMP-777 treatment was used to chemically induce acute gastric damage. The anti-inflammatory metabolites of sulfasalazine (sulfapyridine and mesalazine) were used as controls. Normal gastric lineages, metaplastic markers, autophagy, proliferation, xCT activity, ROS, and apoptosis were assessed.
RESULTS
xCT was up-regulated early as chief cells transitioned into SPEM. Inhibition of xCT or small interfering RNA knockdown blocked cystine uptake and decreased glutathione production by metaplastic cells and prevented ROS detoxification and proliferation. Moreover, xCT activity was required for chief cell reprogramming into SPEM after gastric injury in vivo. Chief cells from xCT-deficient mice showed decreased autophagy, mucus granule formation and proliferation, as well as increased levels of ROS and apoptosis compared with wild-type mice. On the other hand, the anti-inflammatory metabolites of sulfasalazine did not affect SPEM development.
CONCLUSIONS
The results presented here suggest that maintaining redox balance is crucial for progression through the reprogramming process and that xCT-mediated cystine uptake is required for chief cell plasticity and ROS detoxification.
Topics: Amino Acid Transport System y+; Animals; Azetidines; Cell Line; Cell Plasticity; Cellular Reprogramming; Chief Cells, Gastric; Gastric Mucosa; Gene Knockout Techniques; Humans; Mice; Parietal Cells, Gastric; Piperazines; Reactive Oxygen Species; Sulfasalazine; Up-Regulation
PubMed: 31071489
DOI: 10.1016/j.jcmgh.2019.04.015 -
International Journal of Preventive... 2023Ulcerative colitis is one of the major phenotypic forms of inflammatory bowel diseases. The present study aimed to investigate the effect of force swimming exercise on...
BACKGROUND
Ulcerative colitis is one of the major phenotypic forms of inflammatory bowel diseases. The present study aimed to investigate the effect of force swimming exercise on clinical symptoms (disease activity index; DAI), colon histopathology, inflammation and fibrosis, and oxidant/antioxidant balance in dextran sulfate sodium (DSS)-induced colitis mice.
METHODS
Male C57BL6 mice were randomly divided into five groups ( = 6 each): control, exercise, colitis, colitis + sulfasalazine, and colitis + exercise. Exercise was performed by forced swimming six weeks before and during the experiment. Colitis was induced by 1.5% DSS in drinking water. The animals were evaluated for body weight changes and DAI (including changes of body weight, stool consistency, rectal bleeding, and prolapse) during the induction of colitis and treatment. At the end of experiment, colons and spleens were evaluated by H and E and Masson Trichrome stainings. Oxidant (Malon dialdehyde; MDA), and antioxidant markers [total thiol groups, superoxide dismutase (SOD), and catalase activity] were also measured in colon tissue.
RESULTS
Results indicated that exercise in colitis mice significantly improved DAI, colon length, spleen weight, and histological injury score and alleviated fibrotic changes in colon tissue that were comparable to sulfasalazine group. Exercise also restored the oxidant/antioxidant balance in colitis mice by reducing MDA and increasing antioxidative markers including total thiol groups, SOD, and catalase activity.
CONCLUSIONS
Taken together, aerobic exercise could improve clinical symptoms and colonic inflammation through, at least, the balancing the oxidative stress markers. Thus, it can be considered in management of colitis patients as effective method.
PubMed: 37351030
DOI: 10.4103/ijpvm.ijpvm_162_22