Discovery of Novel 2,3-Dihydro-1H-indene-5-sulfonamide NLRP3 Inflammasome Inhibitors Targeting Colon as a Potential Therapy for Colitis.

The NLRP3 inflammasome is a multiprotein complex that plays a crucial role in the pathophysiology of multiple inflammation-related diseases. In this study, we designed and synthesized a series of novel 2,3-dihydro-1H-indene-5-sulfonamide analogues as NLRP3 inflammasome inhibitors, and then identified compound 15z as a potent and specific inhibitor (IC50: 0.13 µM) with low toxicity. Mechanistic studies indicate that 15z binds directly to NLRP3 protein (KD: 102.7 nM), blocking the assembly and activation of the NLRP3 inflammasome and effectively inhibiting cell pyroptosis. Given the notable distribution of 15z in the colon, the DSS-induced colitis model was employed to evaluate its in vivo effectiveness. 15z significantly impacted NLRP3 inflammasome activation and relieved inflammatory bowel disease symptoms in this model. Acute and subacute toxicity studies suggested that 15z has a favorable safety profile. Our results indicate that 15z has great potential to be further developed as a candidate for the treatment of inflammatory bowel disease.

[Stevens-Johnson syndrome in a patient with positive lymphocyte transformation test]. / Síndrome de Stevens-Johnson en una paciente con prueba positiva de transformación linfocitaria.

BACKGROUND: Stevens-Johnson syndrome is a severe drug reaction. Sulfonamides have been associated with drug reactions, complications, sequelae, even death. CASE REPORT: A 40-year-old female patient with a medical history of endometriosis and recently diagnosed chronic inflammatory ulcerative colitis. She was treated at the Allergology service of the San Juan de Dios Hospital of the Costa Rican Social Security Fund, and after 20 days of treatment with sulfasalazine she had a severe drug reaction on the skin, compatible with Stevens-Johnson syndrome. The lymphocyte transformation test was positive, confirming sulfasalazine as the causative agent. CONCLUSION: The lymphocyte transformation test is a useful method that can confirm the causative agent and prevent important complications in the future.

ANTECEDENTES: El síndrome de Stevens-Johnson es una reacción medicamentosa severa. Las sulfamidas se han asociado con reacciones medicamentosas, complicaciones, secuelas, incluso la muerte. REPORTE DE CASO: Paciente femenina de 40 años, con antecedentes médicos de endometriosis y colitis ulcerativa crónica inflamatoria de reciente diagnóstico. Fue atendida en el servicio de Alergología del Hospital San Juan de Dios de la Caja Costarricense del Seguro Social, y luego de 20 días de tratamiento con sulfasalazina tuvo una reacción medicamentosa severa en la piel, compatible con síndrome de Stevens-Johnson. La prueba de transformación linfocitaria resultó positiva, con lo que se confirmó la sulfasalazina como el agente causal. CONCLUSIÓN: La prueba de transformación linfocitaria es un método útil que puede confirmar el agente causal y prevenir complicaciones importantes a futuro.

The Impact of Patient Age and Corticosteroids in Patients With Sulfonamide Hepatotoxicity.

INTRODUCTION: Sulfonamides are widely used to treat and prevent various bacterial and opportunistic infections. The aim of this study was to describe the clinical presentation and outcomes of a large cohort of patients with sulfonamide hepatotoxicity. METHODS: Between 2004 and 2020, 105 patients with hepatotoxicity attributed to trimethoprim/sulfamethoxazole (TMP-SMZ) (n = 93) or other sulfonamides (n = 12) were enrolled. Available liver biopsies were reviewed by a single hepatopathologist. RESULTS: Among the 93 TMP-SMZ cases, 52% were female, 7.5% younger than 20 years, and the median time to drug-induced liver injury (DILI) onset was 22 days (range: 3-157). Younger patients were significantly more likely to have rash, fever, eosinophilia, and a hepatocellular injury pattern at onset that persisted at the peak of liver injury compared with older patients ( P < 0.05). The 18 (19%) TMP-SMZ patients treated with corticosteroids had more severe liver injury and a higher mortality but a trend toward more rapid normalization of their laboratory abnormalities compared with untreated patients. During follow-up, 6.2% of the TMP-SMZ patients died or underwent liver transplantation. Chronic DILI developed in 20% and was associated with cholestatic injury at onset and higher peak total bilirubin levels. DISCUSSION: Sulfonamide hepatotoxicity is characterized by a short drug latency with frequent hypersensitivity features at onset. Subject age is an important determinant of the laboratory profile at presentation, and patients with cholestasis and higher total bilirubin levels were at increased risk of developing chronic DILI. Corticosteroids may benefit a subgroup of patients with severe injury, but further studies are needed.

Presumed Sulfonamide-Associated Uveitis With Stevens-Johnson Syndrome in a Quarter Horse Mare.

We describe the case of a four-year-old Quarter Horse mare that presented with fever, respiratory infection with productive cough, disorientation, and bilateral anterior uveitis with discharge that had been previously treated with trimethoprim-sulfadiazine (TMPS). Acinetobacter johnsonii was cultured from an endoscopic tracheal wash. Treatment was initiated with cefquinome, systemic flunixin-meglumine, local ocular atropine, and corticosteroids. On subsequent days, the mare exhibited bilateral edematous, painful swelling of the face, primarily affecting the eyelids and lips. There were neither swellings nor pulsations of the metatarsal arteries. On day five of treatment, the facial swelling disappeared, the uveitis improved markedly, and the mare's periorbital skin, muzzle, and vulva began to slough, revealing underlying, nonpigmented skin. Although systemic use of sulfonamides has been associated with bilateral anterior uveitis and Stevens-Johnson syndrome (SJS or erythema multiforme major) in humans, these conditions are rare in horses. Stevens-Johnson syndrome has been associated most commonly with sulfonamide use but also with a range of other medications, including anti-infectives, anti-inflammatories, anticonvulsants, analgesics, and infections. A possible pathway for sulfonamide-induced SJS is discussed. To our knowledge, this is the first reported case of sulfonamide-associated uveitis and SJS in the horse.

Impacts of sulfanilamide and oxytetracycline on methane oxidation and methanotrophic community in freshwater sediment.

Methanotrophs are of great significance for the abatement of methane emission from anoxic environments. Antibiotics are ubiquitous in the environment and can affect microbial activity and community density and composition. However, information about the effect of antibiotics on methanotrophs is still lacking. The current study explored the influences of sulfonamides and tetracyclines on methane oxidation potential (MOP) and methanotrophic density and community structure in freshwater sediment microcosms. The addition of both sulfanilamide (SA) and oxytetracycline (OTC) could increase MOP and particulate methane monooxygenase subunit A (pmoA) gene density but decrease the number of pmoA transcripts. Both SA and OTC could also have impacts on sediment methanotrophic community structure. The antibiotic effects on MOP and methanotrophs were found to depend on the dosage and type of antibiotics. This work could provide some new insights towards the links between methane oxidation and antibiotics.