-
European Journal of Pharmacology Jun 2022To assess which immunosuppressive drugs have been investigated and proven efficacious in patients with cardiovascular disease (CVD) or type 2 diabetes (T2D) without... (Review)
Review
OBJECTIVE
To assess which immunosuppressive drugs have been investigated and proven efficacious in patients with cardiovascular disease (CVD) or type 2 diabetes (T2D) without preexisting immune mediated disorders to validate in vitro and animal model findings on low grade inflammation (bedside-to-bench).
METHODS
Clinical trials on immunosuppressive drugs in CVD or T2D were found in PubMed. Studies on patients with preexisting immune mediated inflammatory disease were excluded. A total of 19 clinical trials testing canakinumab, anakinra, methotrexate, colchicine, hydroxychloroquine, etanercept and sulfasalazine were found.
RESULTS
Canakinumab and colchicine significantly reduced the risk of CVD, whereas methotrexate did not. Sulfasalazine showed no effect on vascular function. Anakinra and hydroxychloroquine had a positive effect on glycemic control and β-cell function in T2D. Etanercept had no effect in patients with T2D.
CONCLUSION
The observed results indicate that immunosuppressive drugs specifically targeting IL-1β hold promise for dampening CVD and T2D. These findings validate in vitro and animal models showing involvement of the IL-1-axis in the pathogenesis of CVD and T2D. The use of immunosuppressive drugs targeting the chronic inflammation in these diseases could be a possible future treatment strategy as an add-on to the existing pharmacological treatment of CVD and T2D. However, potential treatment effects, adverse events and cost-effectiveness should be carefully considered with importance for drug development.
Topics: Animals; Antibodies, Monoclonal, Humanized; Cardiovascular Diseases; Colchicine; Diabetes Mellitus, Type 2; Etanercept; Humans; Hydroxychloroquine; Immunomodulating Agents; Immunosuppression Therapy; Immunosuppressive Agents; Inflammation; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Interleukin-1beta; Methotrexate; Sulfasalazine
PubMed: 35533739
DOI: 10.1016/j.ejphar.2022.174998 -
International Journal of Clinical... Aug 2022Sulfasalazine has been widely used in treatment of rheumatoid arthritis and spondyloarthritis. This study aims to assess persistence with sulfasalazine and also... (Observational Study)
Observational Study
OBJECTIVES
Sulfasalazine has been widely used in treatment of rheumatoid arthritis and spondyloarthritis. This study aims to assess persistence with sulfasalazine and also frequency and severity of adverse drug reactions (ADRs) encountered with this very well-established disease-modifying anti-rheumatoid drug.
MATERIALS AND METHODS
This retrospective study was done in 1,114 patients from medicine and rheumatology outpatient departments of six centers across India. The inclusion criteria was patients taking sulfasalazine. Patients receiving sulfasalazine for rheumatoid arthritis or spondyloarthritis were selected and details on drugs used, duration of taking sulfasalazine, ADRs to sulfasalazine and whether sulfasalazine had to be stopped due to ADRs were analyzed.
RESULTS
Of the total of patients included in the study, 10.1% had ADRs with sulfasalazine, and stopped the drug. Gastritis, deranged liver enzymes, hepatitis, skin rashes were the most commonly encountered ADRs. Of the total number of patients recruited for the study, 11% were lost to follow-up, as most of the centers were army hospitals and the officers and staff were posted to other places. Sulfasalazine was taken for less than 1 month by 3.8% patients while 12.5% had taken the drug for less than 6 months. Of the study patients, 28.6% had taken the drug for 24 - 60 months and 4.6% (51 patients) had taken it for more than 5 years. It was found that ADRs were most commonly encountered within the first year of using the drug, and persistence was seen in patients on long-term therapy.
CONCLUSION
Sulfasalazine is a safe option in chronic therapy of rheumatoid arthritis and spondyloarthritis. Although frequency of ADRs with patients taking sulfasalazine is minimal, it did necessitate the stoppage of drug. If not well tolerated, sulfasalazine would not have been continued for more than 12 months as evidenced from this study.
Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Humans; Retrospective Studies; Spondylarthritis; Sulfasalazine; Treatment Outcome
PubMed: 35713159
DOI: 10.5414/CP204120 -
Journal of Orthopaedic Research :... Mar 2020Joint stiffness due to fibrosis/capsule contracture is a seriously disabling complication of articular injury that surgical interventions often fail to completely...
Joint stiffness due to fibrosis/capsule contracture is a seriously disabling complication of articular injury that surgical interventions often fail to completely resolve. Fibrosis/contracture is associated with the abnormal persistence of myofibroblasts, which over-produce and contract collagen matrices. We hypothesized that intra-articular therapy with drugs targeting myofibroblast survival (sulfasalazine), or collagen production (β-aminopropionitrile and cis-hydroxyproline), would reduce joint stiffness in a rabbit model of fibrosis/contracture. Drugs were encapsulated in poly[lactic-co-glycolic] acid pellets and implanted in joints after fibrosis/contracture induction. Capsule α-smooth muscle actin (α-SMA) expression and intimal thickness were evaluated by immunohistochemistry and histomorphometry, respectively. Joint stiffness was quantified by flexion-extension testing. Drawer tests were employed to determine if the drugs induced cruciate ligament laxity. Joint capsule fibroblasts were tested in vitro for contractile activity and α-SMA expression. Stiffness in immobilized joints treated with blank pellets (control) was significantly higher than in non-immobilized, untreated joints (normal) (p = 0.0008), and higher than in immobilized joints treated with sulfasalazine (p = 0.0065). None of the drugs caused significant cruciate ligament laxity. Intimal thickness was significantly lower than control in the normal and sulfasalazine-treated groups (p = 0.010 and 0.025, respectively). Contractile activity in the cells from controls was significantly increased versus normal (p = 0.001). Sulfasalazine and β-aminopropionitrile significantly inhibited this effect (p = 0.005 and 0.0006, respectively). α-SMA expression was significantly higher in control versus normal (p = 0.0021) and versus sulfasalazine (p = 0.0007). These findings support the conclusion that sulfasalazine reduced stiffness by clearing myofibroblasts from fibrotic joints. Statement of clinical significance: The results provide proof-of-concept that established joint stiffness can be resolved non-surgically. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:629-638, 2020.
Topics: Aminopropionitrile; Animals; Collagen; Contracture; Disease Models, Animal; Fibrosis; Hydroxyproline; Joint Capsule; Joint Diseases; Male; Muscle Contraction; Myofibroblasts; Rabbits; Stress, Mechanical; Sulfasalazine
PubMed: 31692083
DOI: 10.1002/jor.24499 -
Pregnancy Hypertension Oct 2020Development and repurposing of therapies that show promise in the prevention or treatment of preeclampsia would be a major advance for the obstetrics field. We recently...
Esomeprazole and sulfasalazine in combination additively reduce sFlt-1 secretion and diminish endothelial dysfunction: potential for a combination treatment for preeclampsia.
Development and repurposing of therapies that show promise in the prevention or treatment of preeclampsia would be a major advance for the obstetrics field. We recently identified esomeprazole and sulfasalazine as potential candidates for the treatment of preeclampsia. Both reduce placental and endothelial secretion of sFlt-1 and sENG and mitigate endothelial dysfunction in vitro. Here we assessed whether esomeprazole and sulfasalazine in combination would additively attenuate the elevated release of anti-angiogenic factors and markers of endothelial dysfunction, key characteristics of preeclampsia. Primary placental tissue and cells, and primary endothelial cells were treated with esomeprazole and sulfasalazine alone and in combination. We assessed secretion of sFlt-1 and sENG and performed in vitro assays of endothelial dysfunction. Combining esomeprazole and sulfasalazine in lower concentrations caused an additive reduction in sFlt-1 secretion in primary cytotrophoblasts, placental explants and endothelial cells. No additive reduction was observed in sENG secretion when esomeprazole and sulfasalazine were combined. Together, esomeprazole and sulfasalazine additively reduced TNF-α-induced VCAM and ET-1 mRNA expression, and monocyte adhesion to endothelial cells. In conclusion, combining esomeprazole and sulfasalazine additively reduced secretion of sFlt-1 and markers of endothelial dysfunction. Combined administration of esomeprazole and sulfasalazine may provide a more effective treatment or prevention for preeclampsia compared to either as single agents.
Topics: Case-Control Studies; Drug Therapy, Combination; Esomeprazole; Female; Human Umbilical Vein Endothelial Cells; Humans; Placenta; Pre-Eclampsia; Pregnancy; Sulfasalazine; Vascular Endothelial Growth Factor Receptor-1
PubMed: 32758704
DOI: 10.1016/j.preghy.2020.07.013 -
Gastroenterology Feb 2019Most patients with ulcerative colitis (UC) have mild-to-moderate disease activity, with low risk of colectomy, and are managed by primary care physicians or... (Review)
Review
Most patients with ulcerative colitis (UC) have mild-to-moderate disease activity, with low risk of colectomy, and are managed by primary care physicians or gastroenterologists. Optimal management of these patients decreases the risk of relapse and proximal disease extension, and may prevent disease progression, complications, and need for immunosuppressive therapy. With several medications (eg, sulfasalazine, diazo-bonded 5-aminosalicylates [ASA], mesalamines, and corticosteroids, including budesonide) and complex dosing formulations, regimens, and routes, to treat a disease with variable anatomic extent, there is considerable practice variability in the management of patients with mild-moderate UC. Hence, the American Gastroenterological Association prioritized clinical guidelines on this topic. To inform clinical guidelines, this technical review was developed in accordance with the Grading of Recommendations Assessment, Development and Evaluation framework for interventional studies. Focused questions included the following: (1) comparative effectiveness and tolerability of different oral 5-ASA therapies (sulfalsalazine vs diazo-bonded 5-ASAs vs mesalamine; low- (<2 g) vs standard (2-3 g/d) vs high-dose (>3 g/d) mesalamine); (2) comparison of different dosing regimens (once-daily vs multiple times per day dosing) and routes (oral vs rectal vs both oral and rectal); (3) role of oral budesonide in patients mild-moderate UC; (4) comparative effectiveness and tolerability of rectal 5-ASA and corticosteroid formulations in patients with distal colitis; and (5) role of alternative therapies like probiotics, curcumin, and fecal microbiota transplantation in the management of mild-moderate UC.
Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Colitis, Ulcerative; Disease Management; Disease Progression; Female; Gastroenterology; Humans; Male; Mesalamine; Prognosis; Risk Assessment; Severity of Illness Index; Societies, Medical; Sulfasalazine; Treatment Outcome; United States
PubMed: 30576642
DOI: 10.1053/j.gastro.2018.12.008 -
Biotechnic & Histochemistry : Official... May 2023Increased pro-inflammatory cytokines and oxidative stress contribute to the pathophysiology of ulcerative colitis (UC). is a plant with antioxidant and...
Increased pro-inflammatory cytokines and oxidative stress contribute to the pathophysiology of ulcerative colitis (UC). is a plant with antioxidant and anti-inflammatory properties. We investigated the effect of an ethanolic extract of on an experimental UC model created using acetic acid. Rats were divided into four groups of eight: group 1, control; group 2, 3% acetic acid group; group 3, 100 mg/kg sulfasalazine + 3% acetic acid group; group 4, 400 mg/kg + 3% acetic acid. and sulfasalazine were administered by oral gavage and 3% acetic acid was administered per rectum. We found that treatment decreased colon malondialdehyde, tumor necrosis factor-α, interleukin-1 beta and nuclear factor kappa B levels; it increased reduced glutathione, nuclear factor erythroid 2-related factor 2, heme oxygenase-1 and kelch-like ECH-associated protein 1 levels and glutathione peroxidase enzyme activity. Group 1 colon exhibited normal histological structure. Slight inflammatory cell infiltration and edema and insignificant slight erosion in crypts were detected in colon tissues of group 4. We found that reduced oxidative stress and inflammation, which was protective against UC by inducing the Nrf-2/Keap-1/HO-1 pathway in the colon.
Topics: Rats; Animals; Colitis, Ulcerative; Sulfasalazine; Inula; Acetic Acid; Antioxidants
PubMed: 37165766
DOI: 10.1080/10520295.2023.2176923 -
Immunopharmacology and Immunotoxicology Dec 2023Compared to biological agents, little is known about the impact of sulfasalazine therapy on COVID-19 outcomes in patients with Axial Spondyloarthritis (AxSpA)....
INTRODUCTION
Compared to biological agents, little is known about the impact of sulfasalazine therapy on COVID-19 outcomes in patients with Axial Spondyloarthritis (AxSpA). Therefore, we aimed to evaluate the COVID-19 severity in AxSpAs receiving sulfasalazine and biologic-agent.
MATERIALS AND METHODS
A total of 219 SARS-CoV-2 positive AxSpA patients were retrospectively analyzed. COVID-19 pneumonia, hospitalization rate, and length of stay were used to determine COVID-19 severity. AxSpA patients were mainly grouped and compared as sulfasalazine and non-sulfasalazine. Afterward, we excluded no-treatment patients to reveal the drug's effects more clearly and regrouped AxSpA patients as sulfasalazine-monotherapy (34.3%), biologic-monotherapy (33.7%), and sulfasalazine + biologic (7.3%).
RESULTS
Fifty-nine percent of the patients were male and the mean age was 45.0 years. Peripheral arthritis was 35% and uveitis 15%. In total, 41.5% of them have received sulfasalazine and 41.0% biologic agents, and the remaining patients with no AxSpA-specific treatment. In the first comparison, the sulfasalazine group had a higher age, more frequent COVID-19 pneumonia, hospitalization, and longer hospitalization than a non-sulfasalazine group. In the pairwise comparison of 3 treatment groups, the demographic and clinical features, the hospitalization rate and the length of hospital stay were similar but the sulfasalazine-monotherapy group had a higher frequency of COVID-19 pneumonia than the biologic-monotherapy group (23% vs. 7%, = 0.008).
CONCLUSION
Our results imply sulfasalazine may be related to more severe COVID-19 in AxSpA patients. These patients should be followed more carefully in the presence of COVID-19, regardless of reasons such as age, comorbidity, and extra-axial disease, and consideration of discontinuing sulfasalazine maybe even thought.
Topics: Humans; Male; Middle Aged; Female; Spondylarthritis; Spondylitis, Ankylosing; Sulfasalazine; Retrospective Studies; COVID-19; SARS-CoV-2; Axial Spondyloarthritis; Biological Products
PubMed: 36537308
DOI: 10.1080/08923973.2022.2160729 -
Inflammatory Bowel Diseases Mar 2017Induction treatment of mild-to-moderate Crohn's disease is controversial. (Meta-Analysis)
Meta-Analysis Review
Comparative Effectiveness of Mesalamine, Sulfasalazine, Corticosteroids, and Budesonide for the Induction of Remission in Crohn's Disease: A Bayesian Network Meta-analysis.
BACKGROUND
Induction treatment of mild-to-moderate Crohn's disease is controversial.
PURPOSE
To compare the induction of remission between different doses of mesalamine, sulfasalazine, corticosteroids, and budesonide for active Crohn's disease.
DATA SOURCES
We identified randomized controlled trials from existing Cochrane reviews and an updated literature search in Medline, EMBASE, and CENTRAL to November 2015.
STUDY SELECTION
We included randomized controlled trials (n = 22) in adult patients with Crohn's disease that compared budesonide, sulfasalazine, mesalamine, or corticosteroids with placebo or each other, for the induction of remission (8-17 wks). Mesalamine (above and below 2.4 g/d) and budesonide (above and below 6 mg/d) were stratified into low and high doses.
DATA EXTRACTION
Our primary outcome was remission, defined as a Crohn's Disease Activity Index score <150. A Bayesian random-effects network meta-analysis was performed on the proportion in remission.
DATA SYNTHESIS
Corticosteroids (odds ratio [OR] = 3.80; 95% credible interval [CrI]: 2.48-5.66), high-dose budesonide (OR = 2.96; 95% CrI: 2.06-4.30), and high-dose mesalamine (OR = 2.29; 95% CrI: 1.58-3.33) were superior to placebo. Corticosteroids were similar to high-dose budesonide (OR = 1.21; 95% CrI: 0.84-1.76), but more effective than high-dose mesalamine (OR = 1.83; 95% CrI: 1.16-2.88). Sulfasalazine was not significantly superior to any therapy including placebo.
LIMITATIONS
Randomized controlled trials that use a strict definition of induction of remission and disease severity at enrollment to assess effectiveness in treating mild-to-moderate Crohn's disease are limited.
CONCLUSIONS
Corticosteroids and high-dose budesonide were effective treatments for inducing remission in mild-to-moderate Crohn's disease. High-dose mesalamine is an option among patients preferring to avoid steroids.
Topics: Adrenal Cortex Hormones; Anti-Inflammatory Agents; Bayes Theorem; Budesonide; Comparative Effectiveness Research; Crohn Disease; Humans; Induction Chemotherapy; Mesalamine; Network Meta-Analysis; Odds Ratio; Randomized Controlled Trials as Topic; Sulfasalazine; Treatment Outcome
PubMed: 28146003
DOI: 10.1097/MIB.0000000000001023 -
Oncotarget 2022Glutathione is an antioxidant that has an important role in chemotherapeutic drug resistance in cancer. Cysteine is synthesized from cystine and is transported into the...
Glutathione is an antioxidant that has an important role in chemotherapeutic drug resistance in cancer. Cysteine is synthesized from cystine and is transported into the cell via the xCT antiporter. Another pathway for synthesizing cysteine involves intracellular methionine. We determined whether targeting the xCT represents a promising strategy for the treatment of endometrial cancer and identified factors that predict efficacy of this treatment strategy. In uterine serous carcinoma (USC) cell lines, the combination of cisplatin and the xCT inhibitor, sulfasalazine, significantly inhibited cell growth compared with single-agent cisplatin or sulfasalazine. Sulfasalazine treatment significantly decreased intracellular glutathione levels and induced apoptosis when combined with cisplatin in USC cell lines. On the one hand, the effectiveness of combined cisplatin and sulfasalazine was not evident in endometrioid carcinoma. USC cell lines exhibited increased expression of xCT and decreased expression of cystathionine gamma lyase (CGL), which is an enzyme involved in the synthesis of cysteine from methionine. On the other hand, endometrioid carcinoma cell lines exhibited increased CGL expression or decreased xCT expression. These findings suggest that using a glutathione synthesis pathway-based approach for selecting subjects for sulfasalazine treatment may be an effective strategy for circumventing glutathione-related chemotherapeutic drug resistance in endometrial carcinoma.
Topics: Amino Acid Transport System y+; Antioxidants; Antiporters; Carcinoma, Endometrioid; Cell Line, Tumor; Cisplatin; Cystathionine gamma-Lyase; Cysteine; Cystine; Female; Glutathione; Humans; Methionine; Reactive Oxygen Species; Sulfasalazine
PubMed: 35106124
DOI: 10.18632/oncotarget.28185 -
Epilepsia Jul 2019Currently prescribed antiepileptic drugs (AEDs) are ineffective in treating approximately 30% of epilepsy patients. Sulfasalazine (SAS) is an US Food and Drug...
OBJECTIVE
Currently prescribed antiepileptic drugs (AEDs) are ineffective in treating approximately 30% of epilepsy patients. Sulfasalazine (SAS) is an US Food and Drug Administration (FDA)-approved drug for the treatment of Crohn disease that has been shown to inhibit the cystine/glutamate antiporter system xc- (SXC) and decrease tumor-associated seizures. This study evaluates the effect of SAS on distinct pharmacologically induced network excitability and determines whether it can further decrease hyperexcitability when administered with currently prescribed AEDs.
METHODS
Using in vitro cortical mouse brain slices, whole-cell patch-clamp recordings were made from layer 2/3 pyramidal neurons. Epileptiform activity was induced with bicuculline (bic), 4-aminopyridine (4-AP) and magnesium-free (Mg -free) solution to determine the effect of SAS on epileptiform events. In addition, voltage-sensitive dye (VSD) recordings were performed to characterize the effect of SAS on the spatiotemporal spread of hyperexcitable network activity and compared to currently prescribed AEDs.
RESULTS
SAS decreased evoked excitatory postsynaptic currents (eEPSCs) and increased the decay kinetics of evoked inhibitory postsynaptic currents (eIPSCs) in layer 2/3 pyramidal neurons. Although application of SAS to bic and Mg -free-induced epileptiform activity caused a decrease in the duration of epileptiform events, SAS completely blocked 4-AP-induced epileptiform events. In VSD recordings, SAS decreased VSD optical signals induced by 4-AP. Co-application of SAS with the AED topiramate (TPM) caused a significantly further decrease in the spatiotemporal spread of VSD optical signals.
SIGNIFICANCE
Taken together this study provides evidence that inhibition of SXC by SAS can decrease network hyperexcitability induced by three distinct pharmacologic agents in the superficial layers of the cortex. Furthermore, SAS provided additional suppression of 4-AP-induced network activity when administered with the currently prescribed AED TPM. These findings may serve as a foundation to assess the potential for SAS or other compounds that selectively target SXC as an adjuvant treatment for epilepsy.
Topics: Animals; Anticonvulsants; Brain; Disease Models, Animal; Epilepsy; Excitatory Postsynaptic Potentials; Mice; Mice, Inbred C57BL; Patch-Clamp Techniques; Sulfasalazine
PubMed: 31211419
DOI: 10.1111/epi.16073