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Science Advances Jun 2021The global outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) necessitates the rapid development of new therapies against coronavirus disease 2019...
The global outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) necessitates the rapid development of new therapies against coronavirus disease 2019 (COVID-19) infection. Here, we present the identification of 200 approved drugs, appropriate for repurposing against COVID-19. We constructed a SARS-CoV-2-induced protein network, based on disease signatures defined by COVID-19 multiomics datasets, and cross-examined these pathways against approved drugs. This analysis identified 200 drugs predicted to target SARS-CoV-2-induced pathways, 40 of which are already in COVID-19 clinical trials, testifying to the validity of the approach. Using artificial neural network analysis, we classified these 200 drugs into nine distinct pathways, within two overarching mechanisms of action (MoAs): viral replication (126) and immune response (74). Two drugs (proguanil and sulfasalazine) implicated in viral replication were shown to inhibit replication in cell assays. This unbiased and validated analysis opens new avenues for the rapid repurposing of approved drugs into clinical trials.
Topics: Antiviral Agents; COVID-19; Drug Repositioning; Humans; Neural Networks, Computer; Proguanil; SARS-CoV-2; Sulfasalazine; Virus Replication; COVID-19 Drug Treatment
PubMed: 34193418
DOI: 10.1126/sciadv.abh3032 -
Journal of Molecular Graphics &... Dec 2023In this paper we have studied the density functional theory of four drugs ibuprofen, alendronate, Sulfasalazine and paracetamol with quartz, propylamine, trimethylamine...
In this paper we have studied the density functional theory of four drugs ibuprofen, alendronate, Sulfasalazine and paracetamol with quartz, propylamine, trimethylamine functionalized quartz and carboxyl modified carbon nanotube. The attractive and repulsive interaction energies between drugs and quartz is obtained at various pH values. The attractive and repulsive energies are well correlated with experimental drug loading and releasing behavior by mesoporous silica nanoparticles. Further, a theoretical model is developed that accounts the electrostatic interaction between silica and drug and the model can predict the drug loading and releasing behavior by silica nanoparticles at various pH values. Sulfasalazine can be taken orally and loaded with trimethyl ammonium functionalized mesoporous silica nanoparticles, which keeps the drug in tact with the carrier in the acidic environment of the stomach and releases it into the neutral or basic medium of the small intestine. Alendronate may be loaded and released from propylamine functionalized mesoporous silica nanoparticles in the ranges of 1-5 and > 8, respectively. Ibuprofen is absorbed in an acidic environment and released in basic conditions for carboxyl modified carbon nanotube. The loading and releasing pH ranges for paracetamol in trimethylammonium functionalized mesoporous silica nanoparticles are 4-8 and >8, respectively. We also convert the pH-dependent variant of the diffusion-controlled Higuchi equation. We have changed the original Higuchi equation to produce the pH-dependent variation by incorporating the Nernst-Planck equation into Flick's first law. The updated equation could be used to forecast when medication particles with varying release times will emerge from a nanoparticles matrix.
Topics: Silicon Dioxide; Quartz; Nanotubes, Carbon; Acetaminophen; Alendronate; Ibuprofen; Sulfasalazine; Drug Delivery Systems; Hydrogen-Ion Concentration
PubMed: 37647724
DOI: 10.1016/j.jmgm.2023.108609 -
The Journal of the Royal College of... Sep 2021Conventional disease-modifying antirheumatic drugs (DMARDs) have been used in the management of rheumatoid arthritis for a long time. Whereas methotrexate (MTX) is the... (Review)
Review
Conventional disease-modifying antirheumatic drugs (DMARDs) have been used in the management of rheumatoid arthritis for a long time. Whereas methotrexate (MTX) is the anchor drug, leflunomide, hydroxychloroquine and sulfasalazine are used along with MTX either in combination or sequentially. Together these four drugs are the most commonly used DMARDs. They are also used in combination with biological DMARDs (bDMARDs) to enhance their efficacy and MTX in particular to reduce antibodies against anti-tumour necrosis factor. Despite their widespread use, concerns regarding their safety especially when used long-term hinder their optimum use in clinical medicine. In this narrative review we have critically appraised the available literature regarding the safety of these four DMARDs when used long-term.
Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Humans; Methotrexate; Sulfasalazine; Tumor Necrosis Factor-alpha
PubMed: 34528610
DOI: 10.4997/JRCPE.2021.306 -
Experimental Animals Nov 2018The aim of this study, was to determine the effect of sulfasalazine for different periods of time reduces disseminated intravascular coagulation, inflammation and organ...
The aim of this study, was to determine the effect of sulfasalazine for different periods of time reduces disseminated intravascular coagulation, inflammation and organ damages by inhibiting the nuclear factor kappa beta pathway. The study was performed with 30 Wistar albino rats and the groups were established as Control group, LPS group; endotoxemia was induced with LPS, SL5 group: sulfasalazine (300 mg/kg, single dose daily) was administered for 5 days before the LPS-induced endotoxemia, and LS group: sulfasalazine (300 mg/kg, single dose) was administered similtenously with LPS. Hemogram, biochemical, cytokine (IL-1β, IL-6, IL-10, TNF-α) and acute phase proteins (HPT, SAA, PGE2) analyzes and oxidative status values were measured from blood samples at 3 and 6 h after the last applications in the all groups. The rats were euthanized at 6 h and mRNA levels of BCL2 and BAX genes were examined from liver and brain tissues. Sulfasalazine reduced the increased IL-1β, IL-6, TNF-α and PGE levels and significantly increased anti-inflammatory cytokine IL-10 levels. In addition, decreasing of ATIII level was prevented in the SL5 group, and decreasing of fibrinogen levels were prevented in the LS and SL5 groups within first 3 h. In LPS group, leukocyte and thrombocyte levels were decreased, however sulfasalazine application inhibited decreases of leukocyte levels in LS and SL5 groups. In addition, sulfasalazine inhibited the decrease of total antioxidant capacity and unchanged apoptosis in brain and liver. In conclusion, the use of sulfasalazine in different durations reduce the excessive inflammation of endotoxemia cases.
Topics: Acute-Phase Proteins; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cytokines; Endotoxemia; Inflammation Mediators; Lipopolysaccharides; Male; NF-kappa B; Oxidative Stress; Rats; Rats, Wistar; Signal Transduction; Sulfasalazine
PubMed: 29731490
DOI: 10.1538/expanim.18-0029 -
Biochemical Pharmacology Apr 2019Neuroblastoma (NB) is a tumor arising from the sympathetic nervous system during infancy and early childhood. High-risk patients who relapse often fail to respond to...
Neuroblastoma (NB) is a tumor arising from the sympathetic nervous system during infancy and early childhood. High-risk patients who relapse often fail to respond to further therapy, which results in 5-year survival rate for this patient group below 5%. Therefore, there continues to be an urgent need for innovative treatments. Recently, we found that sulfasalazine (SSZ), an FDA-approved drug for the treatment of rheumatoid arthritis and ulcerative colitis induces anti-proliferative effects in NB tumor cells. SSZ was recently shown to inhibit sepiapterin reductase (SPR), a key enzyme that produces tetrahydrobiopterin (BH4) in the nitric oxide (NO) pathway. Here we tested SSZ against purified SPR in vitro, measured the anti-proliferative effect of SSZ on a panel of MYCN amplified and MYCN non-amplified NB cell lines, and assessed the anti-tumor effect of SSZ in NB tumor-xenografted mice. We found that the expression of both SPR mRNA and SPR protein was significantly higher in cell lines without MYCN amplification. SSZ inhibited SPR enzyme activity in vitro and exhibits anti-proliferative activity in a large number of NB cell lines derived from high-risk tumors. Importantly, oral/intraperitoneal (i.p.) SSZ co-administration resulted in measureable anti-tumor effects in vivo. The FDA-approved drug SSZ, a well-tolerated drug in clinical use, could be repositioned to inhibit tumor growth in NB.
Topics: Alcohol Oxidoreductases; Animals; Antineoplastic Agents; Cell Line, Tumor; Humans; Male; Mice; Mice, Nude; Neuroblastoma; Protein Structure, Secondary; Sulfasalazine; Xenograft Model Antitumor Assays
PubMed: 30639262
DOI: 10.1016/j.bcp.2019.01.007 -
Infection Feb 2023Reactive arthritis is acute aseptic arthritis occurring 1 to 4 weeks after a distant infection in a genetically predisposed individual. It may occur after COVID-19... (Review)
Review
PURPOSE
Reactive arthritis is acute aseptic arthritis occurring 1 to 4 weeks after a distant infection in a genetically predisposed individual. It may occur after COVID-19 infection. We summarize, in this article, the current findings of reactive arthritis following COVID-19 infection.
METHODS
A literature search has been performed from December 2019 to December 2021. We included case reports of reactive arthritis occurring after COVID-19 infection. We collected demographic, clinical, and paraclinical data.
RESULTS
A total of 22 articles were reviewed. There were 14 men and 11 women with a mean age of 44.96 + 17.47 years. Oligoarticular involvement of the lower limbs was the most frequent clinical presentation. The time between arthritis and COVID infection ranged from 6 to 48 days. The diagnosis was based on clinical and laboratory findings. The pharmacological management was based on non-steroidal anti-inflammatory drugs in 20 cases. Systemic or local steroid therapy was indicated in 13 patients. Sulfasalazine was indicated in two cases. Alleviation of symptoms and recovery were noted in 22 cases. The mean duration of the clinical resolution was 16 + 57 days.
CONCLUSION
The diagnosis of reactive arthritis should be considered in patients with a new onset of arthritis following COVID-19 infection. Its mechanism is still unclear.
Topics: Male; Humans; Female; Adult; Middle Aged; Arthritis, Reactive; COVID-19; Anti-Inflammatory Agents, Non-Steroidal; Sulfasalazine
PubMed: 35655110
DOI: 10.1007/s15010-022-01858-z -
The American Journal of Gastroenterology Apr 2020Half of patients with inflammatory bowel disease (IBD) are men, yet less attention has been focused on their sexual issues despite higher rates of sexual dysfunction and... (Review)
Review
Half of patients with inflammatory bowel disease (IBD) are men, yet less attention has been focused on their sexual issues despite higher rates of sexual dysfunction and infertility than the general population. Depression and IBD disease activity are the most consistently reported risk factor for sexual dysfunction among men with IBD. Methotrexate and sulfasalazine have been rarely associated with impotence. Sulfasalazine reversibly reduces male fertility. No other medications used in IBD significantly affect fertility in humans. There is no increase in adverse fetal outcomes among offspring of fathers with IBD. Patients with IBD seem to be at a higher risk for prostate cancer; therefore, screening as recommended for high-risk patients should be considered.
Topics: Depression; Gastrointestinal Agents; Humans; Infertility, Male; Inflammatory Bowel Diseases; Male; Methotrexate; Prostatic Neoplasms; Risk Factors; Sexual Dysfunction, Physiological; Sulfasalazine
PubMed: 32022719
DOI: 10.14309/ajg.0000000000000515 -
Molecules (Basel, Switzerland) Feb 2021Sulfasalazine (SAS), an anti-inflammatory drug with potent cysteine/glutamate antiporter system xc-(SXC) inhibition has recently shown beneficial effects in...
Sulfasalazine (SAS), an anti-inflammatory drug with potent cysteine/glutamate antiporter system xc-(SXC) inhibition has recently shown beneficial effects in brain-related diseases. Despite many reports related to central nervous system (CNS) effect of SAS, pharmacokinetics (PK) and metabolite identification studies in the brain for SAS were quite limited. The aim of this study was to investigate the pharmacokinetics and metabolite identification of SAS and their distributions in mouse brain. Using in vivo brain exposure studies (neuro PK), the PK parameters of SAS was calculated for plasma as well as brain following intravenous and oral administration at 10 mg/kg and 50 mg/kg in mouse, respectively. In addition, in vivo metabolite identification (MetID) studies of SAS in plasma and brain were also conducted. The concentration of SAS in brain was much lower than that in plasma and only 1.26% of SAS was detected in mouse brain when compared to the SAS concentration in plasma (brain to plasma ratio (%): 1.26). In the MetID study, sulfapyridine (SP), hydroxy-sulfapyridine (SP-OH), and N-acetyl sulfapyridine (Ac-SP) were identified in plasma, whereas only SP and Ac-SP were identified as significant metabolites in brain. As a conclusion, our results suggest that the metabolites of SAS such as SP and Ac-SP might be responsible for the pharmacological effect in brain, not the SAS itself.
Topics: Animals; Brain; Male; Mass Spectrometry; Mice; Mice, Inbred ICR; Sulfasalazine; Time Factors
PubMed: 33671835
DOI: 10.3390/molecules26041179 -
Placenta Jun 2020The antiangiogenic factors soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sENG) are elevated in preeclampsia and have been implicated in its...
INTRODUCTION
The antiangiogenic factors soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sENG) are elevated in preeclampsia and have been implicated in its pathogenesis. We have previously demonstrated metformin and sulfasalazine independently reduce antiangiogenic factor secretion. Here we examined whether combining metformin and sulfasalazine may be more effective than either alone in reducing placental expression and secretion of antiangiogenic and angiogenic factors and the expression of markers of endothelial dysfunction.
METHODS
We performed functional experiments using primary human placenta to explore the effect of metformin and sulfasalazine, at lower doses than previously explored, individually and in combination, on sFlt-1 and sENG secretion and placental growth factor (PlGF) and vascular endothelial growth factor (VEGFα) expression. Using primary endothelial cells we induced dysfunction using cytokine tumor necrosis factor-α (TNF-α) and assessed the effect of low dose combination treatment on the expression of vascular cell adhesion molecule-1 (VCAM-1) and Endothelin-1 (a potent vasoconstrictor).
RESULTS
We demonstrated combination metformin and sulfasalazine was additive in reducing sFlt-1 secretion from cytotrophoblasts and placental explants. Combination treatment was also additive in reducing sENG secretion from placental explants. Furthermore, combination treatment increased cytotrophoblast VEGFα mRNA expression. Whilst combination treatment increased PlGF mRNA expression this was similar to treatment with sulfasalazine alone. Combination therapy reduced TNFα induced endothelin-1 mRNA expression however did not change VCAM expression.
DISCUSSION
Low dose combination metformin and sulfasalazine reduced cytotrophoblast sFlt-1 and sENG secretion, increased VEGFα expression and reduced TNFα induced endothelin-1 expression in primary endothelial cells. Combination therapy has potential to treat preeclampsia.
Topics: Drug Therapy, Combination; Endoglin; Endothelin-1; Female; Humans; Metformin; Placenta; Placenta Growth Factor; Pre-Eclampsia; Pregnancy; Sulfasalazine; Vascular Cell Adhesion Molecule-1; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1
PubMed: 32452405
DOI: 10.1016/j.placenta.2020.04.010 -
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