RESUMEN
RATIONALE: Rheumatoid arthritis (RA) is a systemic inflammatory disease characterized by joint inflammation and various extra-articular manifestations, including rheumatoid nodules (RNs). This case study aims to explore the effectiveness of alternative treatments for RNs, particularly highlighting the therapeutic potential of sulfasalazine. PATIENT CONCERNS: A 52-year-old male with established RA presented with worsening joint pain and firm nodules on his elbows, feet, and fingers. DIAGNOSES: The patient fulfilled the diagnostic criteria for RA and was diagnosed with methotrexate-induced RNs based on their temporal association with methotrexate initiation. INTERVENTIONS: Methotrexate was discontinued and a combination of leflunomide and sulfasalazine was initiated. Sulfasalazine led to improvement in both joint pain and nodule size. However, due to cost concerns, the patient discontinued sulfasalazine, resulting in a resurgence of both symptoms and nodule enlargement. Reintroduction of methotrexate resulted in significant improvement in joint inflammation, and notably, no new nodules developed at 6 months follow-up. OUTCOMES: Sulfasalazine demonstrated efficacy in managing RA nodules, suggesting a potential alternative therapy. LESSONS: The case highlights the complex etiology of nodules in RA and emphasizes the importance of individualized treatment approaches and close monitoring for optimal management.
Asunto(s)
Antirreumáticos , Artritis Reumatoide , Nódulo Reumatoide , Sulfasalazina , Humanos , Sulfasalazina/uso terapéutico , Persona de Mediana Edad , Masculino , Nódulo Reumatoide/tratamiento farmacológico , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Metotrexato/uso terapéuticoRESUMEN
Through molecular recognition, drugs can interact and complex with macromolecules circulating in the body. The serum albumin transport protein, found in several mammals, has several interaction sites where these molecules can be located. The drug sulfasalazine (SSZ) is known in the literature to complex at drug site 1 (DS1) in human serum (HSA) and bovine serum (BSA) proteins. This complexation can be studied using various spectroscopic techniques. With the techniques used in this work, absorption in the ultraviolet and visible regions (UV-Vis) and electronic circular dichroism (ECD), a significant difference was observed in the results involving HSA and BSA. The application of theoretical methodologies, such as TD-DFT and molecular docking, suggests that the conformation that SSZ assumes in DS1 of the two proteins is different, which exposes it to different amino acid residues and different hydrophobicities. This difference in conformation may be related to the location of DS1 where the drug interacts or to the possibility of SSZ moving in the BSA site, due to its larger size, and moving less freely in HSA.
Asunto(s)
Simulación del Acoplamiento Molecular , Albúmina Sérica Bovina , Sulfasalazina , Sulfasalazina/química , Albúmina Sérica Bovina/química , Humanos , Bovinos , Animales , Estereoisomerismo , Dicroismo Circular , Albúmina Sérica Humana/química , Teoría Funcional de la DensidadRESUMEN
Chemodynamic therapy (CDT) is a promising strategy for cancer treatment, however, its application is restricted by low hydrogen peroxide (H2O2) concentration, insufficient reactive oxygen species (ROS) generation, and high glutathione (GSH) levels. Here, we developed an injectable thermosensitive hydrogel (DSUC-Gel) based on "sea urchin-like" copper sulfide nanoparticles (UCuS) loaded with dihydroartemisinin (DHA) and sulfasalazine (SAS) to overcome these limitations of CDT. DSUC was cleaved to release DHA, SAS and Cu2+ under acidic tumor microenvironment to enhance CDT. DHA with peroxide bridge responded to intracellular Fe2+ to alleviate H2O2 deficiency. SAS prevented GSH synthesis by targeting SLC7A11 and inhibited glutathione peroxidase (GPX4) activity to induce endogenous ferroptosis. ROS produced by Fenton-like reaction of Cu2+ promoted lipid peroxidation (LPO) accumulation to promote ferroptosis. Enhanced CDT and ferroptosis induced immunogenic cell death (ICD), promoted dendritic cells (DCs) maturation and cytotoxic T lymphocytes (CTLs) infiltration. As a result, DSUC-Gel significantly inhibited tumor growth both in vitro and in vivo. Our study provides a novel approach for enhancing anti-tumor efficacy by combining CDT, endogenous ferroptosis and ICD.
Asunto(s)
Artemisininas , Cobre , Ferroptosis , Hidrogeles , Especies Reactivas de Oxígeno , Sulfasalazina , Ferroptosis/efectos de los fármacos , Animales , Cobre/química , Ratones , Especies Reactivas de Oxígeno/metabolismo , Artemisininas/farmacología , Artemisininas/administración & dosificación , Artemisininas/química , Línea Celular Tumoral , Sulfasalazina/farmacología , Sulfasalazina/administración & dosificación , Humanos , Sulfuros/farmacología , Sulfuros/administración & dosificación , Sulfuros/química , Nanopartículas , Microambiente Tumoral/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Peroxidación de Lípido/efectos de los fármacos , Femenino , Peróxido de Hidrógeno , Glutatión/metabolismo , Ratones Endogámicos BALB CRESUMEN
BACKGROUND: Treatments for rheumatoid arthritis (RA) are associated with complex changes in lipids and lipoproteins that may impact cardiovascular (CV) risk. The objective of this study was to examine lipid and lipoprotein changes associated with two common RA treatment strategies, triple therapy or tumor necrosis factor inhibitor (TNFi), and association with CV risk. METHODS: In this secondary data analysis of the TARGET trial, methotrexate (MTX) inadequate responders with RA were randomized to either add sulfasalazine and hydroxychloroquine (triple therapy), or TNFi for 24-weeks. The primary trial outcome was the change in arterial inflammation measured in the carotid arteries or aorta by FDG-PET/CT at baseline and 24-weeks; this change was described as the target-to-background ratio (TBR) in the most diseased segment (MDS). Routine lipids and advanced lipoproteins were measured at baseline and 24-weeks; subjects on statin therapy at baseline were excluded. Comparisons between baseline and follow-up lipid measurements were performed within and across treatment arms, as well as change in lipids and change in MDS-TBR. RESULTS: We studied 122 participants, 61 in each treatment arm, with median age 57 years, 76% female, and 1.5 year median RA disease duration. When comparing treatment arms, triple therapy had on average a larger reduction in triglycerides (15.9 mg/dL, p = 0.01), total cholesterol to HDL-C ratio (0.29, p-value = 0.01), and LDL particle number (111.2, p = 0.02) compared to TNFi. TNFi had on average a larger increase in HDL particle number (1.6umol/L, p = 0.006). We observed no correlation between change in lipid measurements and change in MDS-TBR within and across treatment arms. CONCLUSIONS: Both treatment strategies were associated with improved lipid profiles via changes in different lipids and lipoproteins. These effects had no correlation with change in CV risk as measured by vascular inflammation by FDG-PET/CT. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT02374021.
Asunto(s)
Antirreumáticos , Artritis Reumatoide , Quimioterapia Combinada , Hidroxicloroquina , Lípidos , Metotrexato , Humanos , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/sangre , Femenino , Persona de Mediana Edad , Masculino , Antirreumáticos/uso terapéutico , Hidroxicloroquina/uso terapéutico , Lípidos/sangre , Metotrexato/uso terapéutico , Anciano , Sulfasalazina/uso terapéutico , Adulto , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Resultado del Tratamiento , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Vasculitis/tratamiento farmacológico , Vasculitis/sangreRESUMEN
Although only Saccharomyces boulardii has been studied for ulcerative colitis (UC), probiotic yeasts have immense therapeutic potential. Herein, we evaluated the kefir yeast Kluyveromyces marxianus A4 (Km A4) and its anti-inflammatory effect with sulfasalazine in BALB/c mice with dextran sulfate sodium (DSS)-induced colitis. Oral administration continued for 7 days after the mice were randomly divided into seven groups: control (CON, normal mice administered with saline), DSS-induced colitis mice administered saline (DSS), and DSS-induced colitis mice administered sulfasalazine only (S), Km A4 only (A4), Km A4 plus sulfasalazine (A4 + S), S. boulardii ATCC MYA-796 (Sb MYA-796) only (Sb), and Sb MYA-796 plus sulfasalazine (Sb + S). The ß-glucan content of Km A4 was significantly higher than that of Sb MYA-796 (P < 0.05). Body weight gain (BWG) significantly correlated with colon length, cyclooxygenase-2 (Cox-2) levels, and Bacteroides abundance (P < 0.05). In colitis-induced mice, the A4 + S group had the lowest histological score (6.00) compared to the DSS group (12.67), indicating the anti-inflammatory effects of this combination. The A4 + S group showed significantly downregulated expression of interleukin (Il)-6, tumor necrosis factor-α (Tnf-α), and Cox-2 and upregulated expression of Il-10 and occludin (Ocln) compared to the DSS group. Mice treated with A4 + S had enhanced Bacteroides abundance in their gut microbiota compared with the DSS group (P < 0.05). Bacteroides were significantly correlated with all colitis biomarkers (BWG, colon length, Il-6, Tnf-α, Il-10, Cox-2, and Ocln; P < 0.05). The anti-inflammatory effects of Km A4 could be attributed to high ß-glucan content and gut microbiota modulation. Thus, treatment with Km A4 and sulfasalazine could alleviate UC.
Asunto(s)
Antiinflamatorios , Colitis Ulcerosa , Microbioma Gastrointestinal , Kluyveromyces , Ratones Endogámicos BALB C , Probióticos , Sulfasalazina , Animales , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/microbiología , Colitis Ulcerosa/inducido químicamente , Microbioma Gastrointestinal/efectos de los fármacos , Sulfasalazina/farmacología , Ratones , Antiinflamatorios/farmacología , Probióticos/farmacología , Masculino , Kéfir/microbiología , Sulfato de Dextran/efectos adversos , Humanos , Colon/microbiología , Colon/metabolismo , Colon/efectos de los fármacos , Colon/patología , Modelos Animales de Enfermedad , FemeninoRESUMEN
BACKGROUND: Despite the high prevalence of neuropathic pain, treating this neurological disease remains challenging, given the limited efficacy and numerous side effects associated with current therapies. The complexity in patient management is largely attributed to an incomplete understanding of the underlying pathological mechanisms. Central sensitization, that refers to the adaptation of the central nervous system to persistent inflammation and heightened excitatory transmission within pain pathways, stands as a significant contributor to persistent pain. Considering the role of the cystine/glutamate exchanger (also designated as system xc-) in modulating glutamate transmission and in supporting neuroinflammatory responses, we investigated the contribution of this exchanger in the development of neuropathic pain. METHODS: We examined the implication of system xc- by evaluating changes in the expression/activity of this exchanger in the dorsal spinal cord of mice after unilateral partial sciatic nerve ligation. In this surgical model of neuropathic pain, we also examined the consequence of the genetic suppression of system xc- (using mice lacking the system xc- specific subunit xCT) or its pharmacological manipulation (using the pharmacological inhibitor sulfasalazine) on the pain-associated behavioral responses. Finally, we assessed the glial activation and the inflammatory response in the spinal cord by measuring mRNA and protein levels of GFAP and selected M1 and M2 microglial markers. RESULTS: The sciatic nerve lesion was found to upregulate system xc- at the spinal level. The genetic deletion of xCT attenuated both the amplitude and the duration of the pain sensitization after nerve surgery, as evidenced by reduced responses to mechanical and thermal stimuli, and this was accompanied by reduced glial activation. Consistently, pharmacological inhibition of system xc- had an analgesic effect in lesioned mice. CONCLUSION: Together, these observations provide evidence for a role of system xc- in the biochemical processes underlying central sensitization. We propose that the reduced hypersensitivity observed in the transgenic mice lacking xCT or in sulfasalazine-treated mice is mediated by a reduced gliosis in the lumbar spinal cord and/or a shift in microglial M1/M2 polarization towards an anti-inflammatory phenotype in the absence of system xc-. These findings suggest that drugs targeting system xc- could contribute to prevent or reduce neuropathic pain.
Asunto(s)
Sistema de Transporte de Aminoácidos y+ , Neuralgia , Enfermedades Neuroinflamatorias , Animales , Femenino , Ratones , Sistema de Transporte de Aminoácidos y+/antagonistas & inhibidores , Sistema de Transporte de Aminoácidos y+/deficiencia , Sistema de Transporte de Aminoácidos y+/genética , Sistema de Transporte de Aminoácidos y+/metabolismo , Biomarcadores/metabolismo , Proteína Ácida Fibrilar de la Glía/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Gliosis/complicaciones , Gliosis/tratamiento farmacológico , Gliosis/fisiopatología , Ácido Glutámico/metabolismo , Hiperalgesia/tratamiento farmacológico , Ratones Transgénicos , Microglía/efectos de los fármacos , Microglía/metabolismo , Microglía/patología , Neuralgia/complicaciones , Neuralgia/tratamiento farmacológico , Neuralgia/fisiopatología , Neuralgia/prevención & control , Enfermedades Neuroinflamatorias/complicaciones , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/fisiopatología , Enfermedades Neuroinflamatorias/prevención & control , Fenotipo , Reproducibilidad de los Resultados , ARN Mensajero/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Neuropatía Ciática/complicaciones , Neuropatía Ciática/fisiopatología , Médula Espinal/efectos de los fármacos , Médula Espinal/patología , Médula Espinal/fisiopatología , Sulfasalazina/farmacología , Sulfasalazina/uso terapéuticoRESUMEN
BACKGROUND: Etanercept has been studied in doses up to 0.8 mg/kg/week (max 50 mg/week) in juvenile idiopathic arthritis (JIA) patients. In clinical practice higher doses are used off-label, but evidence regarding the relation with outcomes is lacking. We describe the clinical course of JIA-patients receiving high-dose etanercept (1.6 mg/kg/week; max 50 mg/week) in the BeSt for Kids trial. METHODS: 92 patients with oligoarticular JIA, RF-negative polyarticular JIA or juvenile psoriatic arthritis were randomised across three treat-to-target arms: (1) sequential DMARD-monotherapy (sulfasalazine or methotrexate (MTX)), (2) combination-therapy MTX + 6 weeks prednisolone and (3) combination therapy MTX + etanercept. In any treatment-arm, patients could eventually escalate to high-dose etanercept alongside MTX 10mg/m2/week. RESULTS: 32 patients received high-dose etanercept (69% female, median age 6 years (IQR 4-10), median 10 months (7-16) from baseline). Median follow-up was 24.6 months. Most clinical parameters improved within 3 months after dose-increase: median JADAS10 from 7.2 to 2.8 (p = 0.008), VAS-physician from 12 to 4 (p = 0.022), VAS-patient/parent from 38.5 to 13 (p = 0.003), number of active joints from 2 to 0.5 (p = 0.12) and VAS-pain from 35.5 to 15 (p = 0.030). Functional impairments (CHAQ-score) improved more gradually and ESR remained stable. A comparable pattern was observed in 11 patients (73% girls, median age 8 (IQR 6-9)) who did not receive high-dose etanercept despite eligibility (comparison group). In both groups, 56% reached inactive disease at 6 months. No severe adverse events (SAEs) occurred after etanercept dose-increase. In the comparison group, 2 SAEs consisting of hospital admission occurred. Rates of non-severe AEs per subsequent patient year follow-up were 2.27 in the high-dose and 1.43 in the comparison group. CONCLUSIONS: Escalation to high-dose etanercept in JIA-patients who were treated to target was generally followed by meaningful clinical improvement. However, similar improvements were observed in a smaller comparison group who did not escalate to high-dose etanercept. No SAEs were seen after escalation to high-dose etanercept. The division into the high-dose and comparison groups was not randomised, which is a potential source of bias. We advocate larger, randomised studies of high versus regular dose etanercept to provide high level evidence on efficacy and safety. TRIAL REGISTRATION: Dutch Trial Register; NTR1574; 3 December 2008; https://onderzoekmetmensen.nl/en/trial/26585 .
Asunto(s)
Antirreumáticos , Artritis Juvenil , Quimioterapia Combinada , Etanercept , Metotrexato , Humanos , Artritis Juvenil/tratamiento farmacológico , Etanercept/administración & dosificación , Etanercept/uso terapéutico , Etanercept/efectos adversos , Femenino , Masculino , Niño , Antirreumáticos/administración & dosificación , Antirreumáticos/uso terapéutico , Metotrexato/administración & dosificación , Metotrexato/uso terapéutico , Preescolar , Relación Dosis-Respuesta a Droga , Resultado del Tratamiento , Prednisolona/administración & dosificación , Sulfasalazina/administración & dosificación , Sulfasalazina/uso terapéuticoRESUMEN
Drug metabolism by human gut microbes is often exemplified by azo bond reduction in the anticolitic prodrug sulfasalazine. Azoreductase activity is often found in incubations with cell cultures or ex vivo gut microbiome samples and contributes to the xenobiotic metabolism of drugs and food additives. Applying metagenomic studies to personalized medicine requires knowledge of the genes responsible for sulfasalazine and other drug metabolism, and candidate genes and proteins for drug modifications are understudied. A representative gut-abundant azoreductase from Anaerotignum lactatifermentan DSM 14214 efficiently reduces sulfasalazine and another drug, phenazopyridine, but could not reduce all azo-bonded drugs in this class. We used enzyme kinetics to characterize this enzyme for its NADH-dependent reduction of these drugs and food additives and performed computational docking to provide the groundwork for understanding substrate specificity in this family. We performed an analysis of the Flavodoxin-like fold InterPro family (IPR003680) by computing a sequence similarity network to classify distinct subgroups of the family and then performed chemically-guided functional profiling to identify proteins that are abundant in the NIH Human Microbiome Project dataset. This strategy aims to reduce the number of unique azoreductases needed to characterize one protein family in the diverse set of potential drug- and dye-modifying activities found in the human gut microbiome.
Asunto(s)
Microbioma Gastrointestinal , NADH NADPH Oxidorreductasas , Nitrorreductasas , Humanos , Nitrorreductasas/metabolismo , Nitrorreductasas/genética , NADH NADPH Oxidorreductasas/metabolismo , NADH NADPH Oxidorreductasas/genética , NADH NADPH Oxidorreductasas/química , Colorantes/metabolismo , Simulación del Acoplamiento Molecular , Especificidad por Sustrato , Sulfasalazina , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/química , Cinética , Clostridiales/enzimología , Clostridiales/genética , Compuestos Azo/metabolismo , Compuestos Azo/químicaRESUMEN
OBJECTIVE: There are various combination conventional synthetic disease-modifying-antirheumatic drug (csDMARD) treatment strategies used in rheumatoid arthritis (RA). A commonly used csDMARD combination is triple therapy with methotrexate (MTX), sulfasalazine (SSZ) and hydroxychloroquine (HCQ). Another approach is double therapy with MTX and leflunomide (LEF). We compared the real-world retention of these two treatment combinations. METHODS: Patients with RA from the Ontario Best Practices Research Initiative (OBRI) who received triple or double therapy on or after OBRI enrolment were included. Retention rates were compared between these two groups. We also analyzed which medication in the combination was discontinued and the reasons for treatment discontinuation. Disease activity was assessed at baseline, 6 and 12 months after treatment initiation as well as at time of discontinuation. Risk factors for treatment discontinuation were also examined. RESULTS: Six hundred and ninety-two patients were included (258 triple and 434 double therapy). There were 175 (67.8%) discontinuations in the triple therapy group and 287 (66.1%) discontinuations in patients on double therapy. The median survival for triple therapy was longer (15.1 months; 95% CI: 11.2-21.2) compared to double therapy (9.6 months; 95%CI: 7.03-12.2). However, this was not statistically significant. Disease activity at 6 and 12 months, measured by 28-joint count Disease Activity Score based on erythrocyte sedimentation rate (DAS28-ESR) was lower with triple therapy (mean DAS28 at 6 months 3.4 vs. 3.9, P<0.0001 and at 12 months 3.2 vs. 3.5, P=0.0005). CONCLUSION: Patients on triple therapy remained on treatment longer than patients on double therapy. However, this difference was not statistically significant.
Asunto(s)
Antirreumáticos , Artritis Reumatoide , Quimioterapia Combinada , Hidroxicloroquina , Leflunamida , Metotrexato , Sulfasalazina , Humanos , Artritis Reumatoide/tratamiento farmacológico , Hidroxicloroquina/uso terapéutico , Hidroxicloroquina/administración & dosificación , Leflunamida/uso terapéutico , Leflunamida/administración & dosificación , Sulfasalazina/uso terapéutico , Sulfasalazina/administración & dosificación , Metotrexato/uso terapéutico , Metotrexato/administración & dosificación , Femenino , Masculino , Persona de Mediana Edad , Antirreumáticos/uso terapéutico , Antirreumáticos/administración & dosificación , Anciano , Resultado del Tratamiento , Adulto , Estudios Retrospectivos , Isoxazoles/uso terapéutico , Isoxazoles/administración & dosificación , Índice de Severidad de la EnfermedadRESUMEN
We report a 9-year-old Japanese girl with chronic non-bacterial osteomyelitis (CNO) accompanied by recurrent erythema nodosum (EN) which was successfully treated with salazosulfapyridine (SASP). She was referred to our hospital because of recurrent erythema on her lower extremities and persistent knee and ankle arthralgia, which had been present for approximately 1 year. Although naproxen, a nonsteroidal anti-inflammatory drug, was initiated, her symptoms frequently recurred. Magnetic resonance imaging demonstrated multiple distinct high-intensity signals in the talus bones suggestive of multiple bone oedemas. Additionally, a histological examination of erythematous lesions was consistent with the histopathological findings of EN. She was diagnosed as having CNO complicated by EN, and received 250 mg/day of SASP as a second-line treatment, which showed partial response of both skin and bone lesions. Following increase in the dose of SASP to 500 mg/day resulted in complete remission of her skin and bone lesions. In conclusion, our findings suggest that SASP is effective not only for CNO bone lesions but also for EN. SASP could serve as a second-line therapeutic option at least for some cases of CNO complicated by EN refractory to nonsteroidal anti-inflammatory drugs.
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Eritema Nudoso , Osteomielitis , Sulfasalazina , Humanos , Femenino , Eritema Nudoso/tratamiento farmacológico , Eritema Nudoso/diagnóstico , Eritema Nudoso/etiología , Osteomielitis/tratamiento farmacológico , Osteomielitis/diagnóstico , Osteomielitis/etiología , Niño , Resultado del Tratamiento , Sulfasalazina/uso terapéutico , Sulfasalazina/administración & dosificación , Enfermedad Crónica , Imagen por Resonancia MagnéticaRESUMEN
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is characterized by a widespread maculopapular rash, lymphadenopathy, fever, and multisystem involvement. Conversely, hemophagocytic lymphohistiocytosis (HLH) is an infrequent yet critical condition presenting with fever, hepatosplenomegaly, cytopenias, coagulation abnormalities, and elevated inflammatory markers. The overlapping clinical and laboratory features between DRESS and HLH poses a significant diagnostic challenge. Secondary HLH (sHLH) typically occurs in adults triggered by viral infections, malignancies, rheumatologic diseases, or immune deficiencies. Recently, COVID-19 has also been identified as one of the triggers for sHLH. Herein, we present a case of Sulfasalazine-induced DRESS coinfected with COVID-19 that subsequently progressed into HLH. Our patient exhibited common hepatorenal and splenic involvement along with rare cholecystitis and appendicitis. However, a significant improvement was observed upon the addition of etoposide and azathioprine. We hypothesize that excessive activation of the immune system and cytokine storm due to DRESS combined with COVID-19 infection led to more extensive systemic damage resulting in HLH development. This highlights the potential for severe consequences when DRESS coincides with HLH during a COVID-19 infection.
Asunto(s)
COVID-19 , Coinfección , Síndrome de Hipersensibilidad a Medicamentos , Linfohistiocitosis Hemofagocítica , SARS-CoV-2 , Sulfasalazina , Humanos , Linfohistiocitosis Hemofagocítica/etiología , Linfohistiocitosis Hemofagocítica/diagnóstico , Linfohistiocitosis Hemofagocítica/tratamiento farmacológico , COVID-19/complicaciones , COVID-19/inmunología , Síndrome de Hipersensibilidad a Medicamentos/etiología , Síndrome de Hipersensibilidad a Medicamentos/diagnóstico , Sulfasalazina/efectos adversos , Coinfección/tratamiento farmacológico , Masculino , Persona de Mediana Edad , FemeninoRESUMEN
Successful treatment of ulcerative colitis (UC) is highly dependent on several parameters, including dosing regimen and the ability to deliver drugs to the disease site. In this study two strategies for delivering mesalazine (5-aminosalicylic acid, 5-ASA) to the colon were compared in an advanced in vitro model of the human gastrointestinal (GI) tract, the SHIME® system. Herein, a prodrug strategy employing bacteria-mediated drug release (sulfasalazine, Azulfidine®) was evaluated alongside a formulation strategy that utilised pH and bacteria-mediated release (5-ASA, Octasa® 1600 mg). SHIME® experiments were performed simulating both the GI physiology and colonic microbiota under healthy and inflammatory bowel disease (IBD) conditions, to study the impact of the disease state and ileal pH variability on colonic 5-ASA delivery. In addition, the effects of the products on the colonic microbiome were investigated by monitoring bacterial growth and metabolites. Results demonstrated that both the prodrug and formulation approaches resulted in a similar percentage of 5-ASA recovery under healthy conditions. On the contrary, during experiments simulating the GI physiology and microbiome of IBD patients (the target population) the formulation strategy resulted in a higher proportion of 5-ASA delivery to the colonic region as compared to the prodrug approach (P < 0.0001). Interestingly, the two products had distinct effects on the synthesis of key bacterial metabolites, such as lactate and short chain fatty acids, which varied according to disease state and ileal pH variability. Further, both 5-ASA and sulfasalazine significantly reduced the growth of the faecal microbiota sourced from six healthy humans. The findings support that the approach selected for colonic drug delivery could significantly influence the effectiveness of UC treatment, and highlight that drugs licensed for UC may differentially impact the growth and functioning of the colonic microbiota.
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Antiinflamatorios no Esteroideos , Colon , Microbioma Gastrointestinal , Mesalamina , Sulfasalazina , Mesalamina/administración & dosificación , Mesalamina/farmacología , Humanos , Colon/microbiología , Colon/metabolismo , Colon/efectos de los fármacos , Microbioma Gastrointestinal/efectos de los fármacos , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/farmacología , Sulfasalazina/administración & dosificación , Profármacos/administración & dosificación , Sistemas de Liberación de Medicamentos , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/microbiología , Concentración de Iones de Hidrógeno , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/microbiología , Liberación de FármacosRESUMEN
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 R2 D 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.
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Sulfasalazina , Humanos , Adolescente , Sulfasalazina/efectos adversos , Pronóstico , Estudios RetrospectivosRESUMEN
BACKGROUND: Inflammatory bowel disease (IBD) is a type of immune-mediated condition associated with intestinal homeostasis. Our preliminary studies disclosed that Cichorium intybus L., a traditional medicinal plant, also known as Chicory in Western countries, contained substantial phenolic acids displaying significant anti-inflammatory activities. We recognized the potential of harnessing Chicory for the treatment of IBD, prompting a need for in-depth investigation into the underlying mechanisms. METHODS: On the third day, mice were given 100, 200 mg/kg of total phenolic acids (PA) from Chicory and 200 mg/kg of sulfasalazine (SASP) via gavage, while dextran sodium sulfate (DSS) concentration was 2.5 % for one week. The study measured and evaluated various health markers including body weight, disease activity index (DAI), colon length, spleen index, histological score, serum concentrations of myeloperoxidase (MPO), nitric oxide (NO), superoxide dismutase (SOD), lipid oxidation (MDA), and inflammatory factors. We evaluated the TRP family and the NLRP3 inflammatory signaling pathways by Western blot, while 16S rDNA sequencing was used to track the effects of PA on gut microbes. RESULTS: It was shown that PA ameliorated the weight loss trend, attenuated inflammatory damage, regulated oxidative stress levels, and repaired the intestinal barrier in DSS mice. Analyses of Western blots demonstrated that PA suppressed what was expressed of transient receptor potential family TRPV4, TRPA1, and the expression of NLRP3 inflammatory signaling pathway, NLRP3 and GSDMD. In addition, PA exerted therapeutic effects on IBD by regulating gut microbiota richness and diversity. Meanwhile, the result of the KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichment analysis showed that gut microbiota was mainly related to Membrane Transport, Replication and Repair, Carbohydrate Metabolism and Amino Acid Metabolism. CONCLUSION: PA derived from Chicory may have therapeutic effects on IBD by regulating the TRPV4/NLRP3 signaling pathway and gut microbiome. This study provides new insights into the effects of phenolic acids from Chicory on TRP ion channels and gut microbiota, revealing previously unexplored modes of action.
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Cichorium intybus , Colitis , Sulfato de Dextran , Microbioma Gastrointestinal , Hidroxibenzoatos , Raíces de Plantas , Transducción de Señal , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Cichorium intybus/química , Transducción de Señal/efectos de los fármacos , Hidroxibenzoatos/farmacología , Colitis/tratamiento farmacológico , Colitis/inducido químicamente , Raíces de Plantas/química , Masculino , Ratones , Antiinflamatorios/farmacología , Ratones Endogámicos C57BL , Colon/efectos de los fármacos , Colon/metabolismo , Extractos Vegetales/farmacología , Sulfasalazina/farmacología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Modelos Animales de Enfermedad , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/inducido químicamente , Canales Catiónicos TRPV/metabolismoRESUMEN
Using a rat autologous orthotopic liver transplantation (AOLT) model and liver cold ischemia-reperfusion (I/R)-induced intestinal injury, we clarified whether ferroptosis occurred in rat AOLT cold I/R-induced intestinal injury. Additionally, the role and possible mechanism of the ferroptosis activator sulfasalazine (SAS) in intestinal injury-induced ferroptosis in rats with AOLT liver cold I/R were investigated. Sixty specific pathogen free (SPF)-grade adult male SpragueâDawley (SD) rats were randomly divided into 5 groups using the random number table method (n = 12). Six rats were randomly selected at 6 hour (h) and 24 h after I/R. Inferior vena cava blood specimens were collected from the portal vein (PV) opening at 6 h and 24 h. The concentrations of serum malondialdehyde (MDA), serum interleukin 6 (IL-6) were determined by enzyme-linked immunosorbent assay (ELISA). Ileal tissue was obtained from the PV opening in rats in each group at 6 h and 24 h, and ileal tissue sections were observed under light microscopy. The contents of intestinal MDA, superoxide dismutase (SOD), glutathione(GSH), glutathione peroxidase 4 (GPX4), and tissue iron were determined by ELISA, and the expression of GPX4 and the cysteine glutamate reverse transporter light chain protein (xCT) was determined by Western blot. The experimental results show that ferroptosis is involved in the pathophysiological process of intestinal injury induced by cold hepatic ischemia-reperfusion in AOLT rats. In addition, SAS (500 mg/kg) may inhibit the cystine/glutamate antiporters (System Xc¯)/GSH/GPX4 signal axis in intestinal injury induced by cold I/R in rat AOLT liver, or iron overload after reperfusion, causing a massive accumulation of L-ROS and activating cellular ferroptosis, further aggravate the intestinal injury.
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Ferroptosis , Trasplante de Hígado , Daño por Reperfusión , Ratas , Masculino , Animales , Ratas Sprague-Dawley , Trasplante de Hígado/efectos adversos , Sulfasalazina/farmacología , Daño por Reperfusión/metabolismo , Glutatión/metabolismo , GlutamatosRESUMEN
BACKGROUNDS: Acute anterior uveitis (AAU) is the most common extra-musculoskeletal manifestation in axial spondyloarthritis (axSpA). OBJECTIVES: The aim of the study is to evaluate the factors associated with AAU attacks in patients with axSpA during a 36-month follow-up period. METHODS: In total, 469 patients with axSpA were included in this observational study. Demographic data, clinical characteristics, disease activity measurements, and treatment patterns were compared between patients with and without a history of AAU. The development of AAU and its related factors were investigated using generalized estimating equations, which is a technique for longitudinal data analysis. RESULTS: Overall, 99 (21%) out of 469 patients experienced at least one AAU attack, with 77 patients (78%) having a history of AAU and 53 patients (58% of whom had a history of AAU) experiencing AAU attacks during the follow-up period. At baseline, patients with a history of AAU were found to be older (p = .001), be more likely to have peripheral arthritis (p < .001), have higher serum CRP levels (p = .016), have a higher frequency of sulfasalazine (SLZ) and tumor necrosis factor inhibitors (TNFi) use (p < .001 and p < .001, respectively). In the longitudinal analysis, having a history of AAU was identified as the only independent determinant of the development of AAU. CONCLUSIONS: AAU history might be a risk factor for the development of AAU attacks in patients with axSpA. Although TNFi and SLZ were prescribed more frequently to patients with a history of AAU, the effectiveness of these agents in preventing further AAU attacks was not demonstrated.