RESUMEN
Incorporating 5-aminosalicylic acid (5-ASA) into a colon-specific carrier is crucial for treating inflammatory bowel diseases (IBD), as it enhances therapeutic efficacy, targets the affected regions directly, and minimizes side effects. This study evaluated the impact of incorporating cellulose nanofibers (CNF) on the in vitro and in vivo biological performance of retrograded starch/pectin (RS/P) microparticles (MPs) containing 5-ASA. Using Fourier Transform Infrared (FTIR) Spectroscopy, shifts in the spectra of retrograded samples containing CNF were observed with increasing CNF proportions, suggesting the establishment of new supramolecular interactions. Liquid absorption exhibited pH-dependent behaviors, with reduced absorption in simulated gastric fluid (â¼269 %) and increased absorption in simulated colonic fluid (â¼662 %). Increasing CNF concentrations enhanced mucoadhesion in porcine colonic sections, with a maximum force of 3.4 N at 50 % CNF. Caco-2 cell viability tests showed biocompatibility across all tested concentrations (0.0625-2.0000 mg/mL). Evaluation of intestinal permeability in Caco-2 cell monolayers demonstrated up to a tenfold increase in 5-ASA permeation, ranging from 29 % to 48 %. An in vivo study using Galleria mellonella larvae, with inflammation induced by LPS, showed reduction of inflammation. Given the scalability of spray-drying, these findings suggest the potential of CNF-incorporated RS/P microparticles for targeted 5-ASA delivery in IBD.
Asunto(s)
Enfermedades Inflamatorias del Intestino , Mesalamina , Nanofibras , Pectinas , Almidón , Mesalamina/química , Mesalamina/farmacología , Mesalamina/administración & dosificación , Animales , Células CACO-2 , Humanos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Nanofibras/química , Nanofibras/toxicidad , Porcinos , Pectinas/química , Almidón/química , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos , Supervivencia Celular/efectos de los fármacos , Colon/efectos de los fármacos , Colon/metabolismo , Colon/patología , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/administración & dosificaciónRESUMEN
PURPOSE: This study aimed to assess the efficacy and safety of berberine(BBR) plus 5-aminosalicylic acid (5-ASA) for treating ulcerative colitis (UC). METHODS: A comprehensive search was conducted in electronic databases, including Medline/PubMed, Sinomed, Embase, CNKI, Wanfang, and VIP, through January 2024 to identify all randomized controlled trials (RCTs) that administered BBR conjunction in standard therapy(5-ASA) for to support the treatment of UC. The data were synthesized using a meta-analysis approach with RevMan 5.4.1. The primary endpoint was the clinical efficacy rate. In contrast, the secondary endpoints included the Baron score, disease activity index (DAI) score, symptom relief latency, inflammatory markers, immunological indicators, and adverse events. RESULTS: In this analysis, 10 RCTs comprising 952 patients with UC were examined. BBR considerably improved the clinical efficacy rate (RR = 1.22, 95% CI [1.15, 1.30], P < 0.00001), attenuated the Baron score (SMD = -1.72, 95% CI [-2.30, -1.13], P < 0.00001) and reduced the DAI score (SMD = -2.93, 95% CI [-4.42, -1.43], P < 0.00001). Additionally, it ameliorated clinical symptoms (SMD = -2.74, 95% CI [-3.45, 2.02], P < 0.00001), diminished inflammatory responses (SMD = -1.59, 95% CI [-2.14, 1.04], P < 0.00001), and modulated immune reactions (SMD = 1.06,95% CI [0.24,1.87], P <0.00001). Nonetheless, the impact of BBR on reducing adverse reactions was not statistically significant (RR = 0.75, 95% CI [0.42, 1.33], P > 0.05). CONCLUSION: BBR demonstrates substantial efficacy in treating UC without causing severe adverse reactions and may serve as a viable complementary therapy. However, its clinical application warrants confirmation by additional high-quality, low-bias RCTs.
Asunto(s)
Berberina , Colitis Ulcerosa , Mesalamina , Colitis Ulcerosa/tratamiento farmacológico , Humanos , Berberina/uso terapéutico , Berberina/administración & dosificación , Berberina/efectos adversos , Mesalamina/uso terapéutico , Mesalamina/efectos adversos , Mesalamina/administración & dosificación , Resultado del Tratamiento , Ensayos Clínicos Controlados Aleatorios como Asunto , Quimioterapia Combinada , Antiinflamatorios no Esteroideos/uso terapéutico , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/efectos adversosRESUMEN
The mechanism underlying intestinal fibrosis, the main complication of inflammatory bowel disease (IBD), is not yet fully understood, and there is no therapy to prevent or reverse fibrosis. We evaluated, in in vitro cellular models, the ability of different classes of drugs currently used in IBD to counteract two pivotal processes of intestinal fibrosis, the differentiation of intestinal fibroblasts to activated myofibroblasts using CCD-18Co cells, and the epithelial-to-mesenchymal transition (EMT) of intestinal epithelial cells using Caco-2 cells (IEC), both being processes induced by transforming growth factor-ß1 (TGF-ß1). The drugs tested included mesalamine, azathioprine, methotrexate, prednisone, methylprednisolone, budesonide, infliximab, and adalimumab. The expression of fibrosis and EMT markers (collagen-I, α-SMA, pSmad2/3, occludin) was assessed by Western blot analysis and by immunofluorescence. Of the drugs used, only prednisone, methylprednisolone, budesonide, and adalimumab were able to antagonize the pro-fibrotic effects induced by TGF-ß1 on CCD-18Co cells, reducing the fibrosis marker expression. Methylprednisolone, budesonide, and adalimumab were also able to significantly counteract the TGF-ß1-induced EMT process on Caco-2 IEC by increasing occludin and decreasing α-SMA expression. This is the first study that evaluates, using in vitro cellular models, the direct antifibrotic effects of drugs currently used in IBD, highlighting which drugs have potential antifibrotic effects.
Asunto(s)
Budesonida , Transición Epitelial-Mesenquimal , Fibrosis , Enfermedades Inflamatorias del Intestino , Factor de Crecimiento Transformador beta1 , Humanos , Células CACO-2 , Transición Epitelial-Mesenquimal/efectos de los fármacos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/patología , Enfermedades Inflamatorias del Intestino/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Budesonida/farmacología , Adalimumab/farmacología , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Metilprednisolona/farmacología , Mesalamina/farmacología , Prednisona/farmacología , Miofibroblastos/efectos de los fármacos , Miofibroblastos/metabolismo , Antiinflamatorios/farmacología , Infliximab/farmacología , Infliximab/uso terapéutico , Azatioprina/farmacología , Metotrexato/farmacología , Intestinos/efectos de los fármacos , Intestinos/patología , Diferenciación Celular/efectos de los fármacosRESUMEN
Ulcerative colitis (UC) is a challenging inflammatory gastrointestinal disorder, whose therapies encounter limitations in overcoming insufficient colonic retention and rapid systemic clearance. In this study, we report an innovative polymeric prodrug nanoformulation for targeted UC treatment through sustained 5-aminosalicylic acid (5-ASA) delivery. Amphiphilic polymer-based 13.5 nm micelles were engineered to incorporate azo-linked 5-ASA prodrug motifs, enabling cleavage via colonic azoreductases. In vitro, micelles exhibited excellent stability under gastric/intestinal conditions while demonstrating controlled 5-ASA release over 24 h in colonic fluids. Orally administered micelles revealed prolonged 24-h retention and a high accumulation within inflamed murine colonic tissue. At an approximately 60% dose reduction from those most advanced recent studies, the platform halted DSS colitis progression and outperformed standard 5-ASA therapy through a 77-97% suppression of inflammatory markers. Histological analysis confirmed intact colon morphology and restored barrier protein expression. This integrated prodrug nanoformulation addresses limitations in colon-targeted UC therapy through localized bioactivation and tailored pharmacokinetics, suggesting the potential of nanotechnology-guided precision delivery to transform disease management.
Asunto(s)
Colitis , Colon , Preparaciones de Acción Retardada , Mesalamina , Micelas , Nitrorreductasas , Polímeros , Profármacos , Animales , Profármacos/química , Profármacos/farmacocinética , Mesalamina/química , Mesalamina/farmacocinética , Nitrorreductasas/metabolismo , Ratones , Colon/metabolismo , Colon/patología , Polímeros/química , Colitis/tratamiento farmacológico , Colitis/metabolismo , Preparaciones de Acción Retardada/química , NADH NADPH Oxidorreductasas/metabolismo , Ratones Endogámicos C57BL , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/metabolismo , MasculinoRESUMEN
Epigallocatechin gallate (EGCG)-based nanosystems have garnered significant attention for their ability to alleviate inflammation due to their excellent anti-inflammatory properties and enhanced drug delivery capabilities. However, the degradation of EGCG in strongly acidic environments poses a challenge for potential administration, particularly in oral formulations, where gastric resistance is essential. In this study, we develop a "disintegration and reorganization" strategy to create acid-resistant antioxidant nanoparticles (EGA NPs) based on EGCG and 5-aminosalicylic acid (5-ASA) for mitigating inflammation in colitis and acute kidney injury. At acidic pH, the ester bond in EGCG breaks down, producing two building blocks. These, together with 5-ASA and formaldehyde, form oligomers through a combination of phenol-aldehyde condensation and the Mannich reaction. The resulting oligomers self-assemble into EGA NPs, which exhibit significant stability under both acidic and neutral pH conditions. This stability makes them suitable for oral administration, allowing them to withstand harsh gastric conditions, as well as for intravenous injection. Importantly, these oligomers retain the antioxidant and anti-inflammatory properties of EGCG, effectively scavenging reactive oxygen species and reducing intracellular oxidative stress. Additionally, EGA shows potential as a drug carrier, efficiently loading the anti-inflammatory agent curcumin (Cur) to form Cur@EGA NPs. In vivo studies demonstrate the efficacy of Cur@EGA and EGA in alleviating acute colitis and kidney injury following oral and intravenous administration, respectively. These nanoparticulate formulations exhibit superior inflammation reduction compared to free Cur in vivo. Overall, our findings introduce a novel acid-resistant nanoplatform based on EGCG for the treatment of acute inflammation.
Asunto(s)
Lesión Renal Aguda , Antioxidantes , Catequina , Nanopartículas , Catequina/análogos & derivados , Catequina/química , Catequina/farmacología , Animales , Antioxidantes/química , Antioxidantes/farmacología , Ratones , Nanopartículas/química , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/patología , Colitis/tratamiento farmacológico , Colitis/patología , Inflamación/tratamiento farmacológico , Concentración de Iones de Hidrógeno , Mesalamina/química , Mesalamina/farmacología , Estrés Oxidativo/efectos de los fármacos , Antiinflamatorios/química , Antiinflamatorios/farmacología , Masculino , Portadores de Fármacos/química , HumanosRESUMEN
BACKGROUND/AIMS: This study aimed to investigate the possible positive effects of arbutin in a trinitrobenzene sulfonic acid (TNBS)- induced experimental colitis model, to compare it with mesalazine, which is used in treating inflammatory bowel disease and to observe the effect of its concomitant use. MATERIALS AND METHODS: Forty Wistar albino species male rats were randomized into 5 groups as control, colitis, colitis+arbutin (Arb), colitis+mesalazine (Mes), and colitis+mesalazine+arbutin (M+A). Proinflammatory cytokines [interleukin (IL)-6, IL-1ß, tumor necrosis factor alpha (TNF-α)] and oxidant/antioxidant parameters [malondialdehyde (MDA), superoxide dismutase inhibition (SOD) inhibition, myeloperoxidase (MPO), and catalase, glutathione peroxidase (GPx)] were processed from the samples. Histopathological evaluation evaluated goblet cell reduction, cellular infiltration, and mucosal loss. RESULTS: When the treatment groups and the TNBS group were compared, statistical significance was achieved in MDA, MPO, SOD inhibition, GPx values, IL-6, IL-1ß and TNF-α levels. Histopathological evaluation revealed a statistically significant decrease in the mucosal loss value in the group where mesalazine and arbutin were used together compared to the TNBS group. CONCLUSION: Our study's results elaborated that using arbutin alone or in combination with mesalazine produced positive effects in colitis-induced rats.
Asunto(s)
Arbutina , Colitis , Modelos Animales de Enfermedad , Mesalamina , Peroxidasa , Ratas Wistar , Ácido Trinitrobencenosulfónico , Animales , Masculino , Arbutina/farmacología , Arbutina/uso terapéutico , Ratas , Colitis/tratamiento farmacológico , Colitis/inducido químicamente , Ácido Trinitrobencenosulfónico/toxicidad , Mesalamina/farmacología , Mesalamina/uso terapéutico , Peroxidasa/metabolismo , Superóxido Dismutasa/metabolismo , Citocinas/metabolismo , Malondialdehído/metabolismo , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Factor de Necrosis Tumoral alfa , Distribución Aleatoria , Glutatión Peroxidasa/metabolismo , Interleucina-1beta/metabolismo , Estrés Oxidativo/efectos de los fármacos , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/uso terapéuticoRESUMEN
The therapeutic effect of 5-amino salicylic acid (5-ASA), a first-line therapeutic agent for the treatment of ulcerative colitis (UC), is limited by the modest bioavailability afforded by its oral administration. In this study, a 5-ASA oral delivery system was developed using Eudragit S100-coated iron oxide-chitosan nanocomposites (ES-IOCS/5-ASA) to address this issue. According to drug release studies in vitro, ES-IOCS/5-ASA only released a small amount of drug in simulated gastric fluid with a pH of 1.2. However, in a medium with a pH of 7.5, a relatively rapid and complete release was noted. 5-ASA-loaded iron oxide-chitosan nanocomposites (IOCS/5-ASA) could be effectively taken up by NCM460 cells and performed better anti-inflammatory effects than free 5-ASA. At the same time, IOCS/5-ASA improved barrier damage in DSS-induced NCM460 cells. In vivo models of dextran sulphate sodium (DSS)-induced colitis were used to assess the therapeutic efficacy of oral administration of ES-IOCS/5-ASA. ES-IOCS/5-ASA significantly relieved DSS-induced colitis and enhanced the integrity of the intestinal epithelial barrier. ES-IOCS/5-ASA also reduced the expression of NLRP3, ASC and IL-1ß. Additionally, iron oxide nanoparticles used as nanozymes could alleviate inflammation. In summary, this study indicates that ES-IOCS/5-ASA exert anti-inflammatory effects on DSS-induced colitis by improving intestinal barrier function and inhibiting NLRP3 inflammasome expression, presenting a viable therapeutic choice for the treatment of UC.
Asunto(s)
Quitosano , Colitis Ulcerosa , Colon , Inflamasomas , Mesalamina , Proteína con Dominio Pirina 3 de la Familia NLR , Nanocompuestos , Ácidos Polimetacrílicos , Quitosano/química , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Animales , Mesalamina/uso terapéutico , Mesalamina/farmacología , Mesalamina/administración & dosificación , Mesalamina/química , Colitis Ulcerosa/tratamiento farmacológico , Inflamasomas/metabolismo , Nanocompuestos/química , Humanos , Ácidos Polimetacrílicos/química , Colon/efectos de los fármacos , Colon/patología , Colon/metabolismo , Ratones , Compuestos Férricos/química , Sulfato de Dextran , Línea Celular , Ratones Endogámicos C57BL , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Masculino , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/uso terapéutico , Funcion de la Barrera IntestinalRESUMEN
Chemically modified mandua starch was successfully synthesized and applied to coat mesalamine-loaded matrix tablets. The coating material was an aqueous dispersion of mandua starch modified by sodium trimetaphosphate and sodium tripolyphosphate. To investigate the colon-targeting release competence, chemically modified mandua starch film-coated mesalamine tablets were produced using the wet granulation method followed by dip coating. The effect of the coating on the colon-targeted release of the resultant delivery system was inspected in healthy human volunteers and rabbits using roentgenography. The results show that drug release was controlled when the coating level was 10% w/w. The release percentage in the upper gastric phase (pH 1.2, simulated gastric fluid) was less than 6% and reached up to 59.51% w/w after 14 h in simulated colonic fluid. In addition to in vivo roentgenographic studies in healthy rabbits, human volunteer studies proved the colon targeting efficiency of the formulation. These results clearly demonstrated that chemically modified mandua starch has high effectiveness as a novel aqueous coating material for controlled release or colon targeting.
Asunto(s)
Liberación de Fármacos , Mesalamina , Almidón , Comprimidos , Mesalamina/química , Mesalamina/farmacocinética , Conejos , Almidón/química , Animales , Humanos , Concentración de Iones de Hidrógeno , Fosforilación , Preparaciones de Acción Retardada/química , Colon/metabolismoRESUMEN
Mesalazine represents a key treatment for intestinal bowel diseases and only in rare cases produces cardiac toxicity, with a not completely known mechanism. We report a case of a 25-year-old man with a first episode of myocarditis after 2 weeks from the first mesalazine intake, documented also by a characteristic cardiac magnetic resonance pattern. Then, after less than 1 month, he suffered myocarditis recurrence and so, guided by a multidisciplinary team evaluation, in the suspicion of mesalazine-induced myocarditis, the drug was promptly stopped, with consequent recovery of cardiac damage. In our patient, the recurrence of myocarditis because of the non-interruption of the drug is very peculiar (only three cases described in literature) and definitively confirms the diagnosis.
This paper reports an exemplary case of cardiac toxicity induced by mesalazine, a key treatment for inflammatory bowel diseases such as Crohn's disease and ulcerative colitis. In rare cases, this drug can lead to cardiac impairment, with a mechanism not yet clarified. The young patient described experiencing a first episode of myocarditis (inflammation of the heart muscle cells) after 2 weeks of starting mesalazine. The diagnosis was possible thanks to cardiac magnetic resonance, a noninvasive exam providing high-definition images associated with tissue characterization. Mesalazine was not discontinued because drug-induced etiology was not suspected, due to its rarity. Consequently, the patient suffered a second episode of myocarditis, diagnosed by endomyocardial biopsy, an invasive technique that can accurately assess the etiology of myocardial damage, leading to prompt cessation of treatment. Since myocarditis can have various causes, diagnosis was also facilitated through a multidisciplinary team, which ruled out other possible causes for this condition. This case report is highly educational and underscores the importance of clinicians being vigilant about this side effect and considering it in patients taking mesalazine who present with myocarditis, to promptly discontinue the treatment. Mesalazine interruption is otherwise the only effective therapy for this condition, in addition to anti-inflammatory and analgesic drugs. Furthermore, this paper highlights the increasing importance of multidisciplinary teams, comprising various specialists, for accurate diagnosis and therapeutic decisions. The authors also propose an algorithm for diagnosing mesalazine-induced myocarditis, with certainty derived from recurrence after drug rechallenge, either voluntarily or accidentally, as demonstrated in this case.
Asunto(s)
Antiinflamatorios no Esteroideos , Imagen por Resonancia Cinemagnética , Mesalamina , Miocarditis , Recurrencia , Humanos , Miocarditis/inducido químicamente , Miocarditis/diagnóstico , Masculino , Mesalamina/efectos adversos , Adulto , Antiinflamatorios no Esteroideos/efectos adversos , Imagen por Resonancia Cinemagnética/métodos , Imagen por Resonancia Magnética/métodosRESUMEN
AIM: Colorectal cancer is an extremely aggressive form of cancer that often leads to death. Lactoferrin shows potential for targeting and treating colorectal cancer; however, oral delivery faces hurdles hampering clinical applications. We engineered dual-responsive lactoferrin nanostructured microbeads to overcome delivery hurdles and enhance drug targeting. METHODS: The hydrophobic drug mesalazine (MSZ) was coupled to lactoferrin to form amphiphilic conjugate nanoparticles, dispersed in water. The lipid-soluble polyphenolic drug resveratrol (RSV) was then encapsulated into the hydrophobic core of LF-MSZ nanoparticles. To impart thermoresponsive properties, the dual-payload NPs were coupled with a PNIPAAm shell; finally, to further endow the nanoparticles with gastrointestinal resistance and pH responsiveness, the nanoparticles were microencapsulated into ionically cross-linked pectin-alginate beads. RESULTS: The nanoparticles showed enhanced internalization and cytotoxicity against HCT colon cancer cells via LF-receptor-mediated endocytosis. Thermal triggering and tuned release were conferred by the temperature-sensitive polymer. The coatings protected the drugs from degradation. Orally delivered microbeads significantly reduced tumor burden in a mouse colon cancer model, lowering carcinoembryonic antigen and elevating antioxidant enzymes. Apoptotic pathways were stimulated, indicated by heightened Bax/Bcl2 ratio and caspase-3/9 expression. CONCLUSION: Overall, we propose the innovative lactoferrin nanostructured microbeads as a paradigm shift in oral colorectal cancer therapeutics.
Asunto(s)
Neoplasias Colorrectales , Lactoferrina , Lactoferrina/química , Lactoferrina/farmacología , Lactoferrina/administración & dosificación , Animales , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Administración Oral , Humanos , Ratones , Concentración de Iones de Hidrógeno , Microesferas , Nanoestructuras/química , Mesalamina/farmacología , Mesalamina/química , Mesalamina/administración & dosificación , Mesalamina/uso terapéutico , Resveratrol/farmacología , Resveratrol/química , Resveratrol/administración & dosificación , Nanopartículas/química , Temperatura , Sistemas de Liberación de Medicamentos/métodos , Portadores de Fármacos/químicaRESUMEN
BACKGROUND: Banxia Xiexin decoction (BXD) can control irinotecan (CPT-11)-caused delayed diarrhea, but the corresponding mechanism remains undefined. AIMS: This paper aimed to uncover the mechanism of BXD in regulating CPT-11-caused delayed diarrhea. MATERIALS & METHODS: Sprague-Dawley (SD) rats were assigned into the control, model, BXD low-dose (BXD-L, 5 g/kg), BXD medium-dose (BXD-M, 10 g/kg), BXD high-dose (BXD-H, 15 g/kg), 5-aminosalicylic acid (5-ASA, 10 mL/kg), and BXD-M + 5-ASA groups. Rats were injected intraperitoneally with 150 mg/kg CPT-11 at Day 4 and Day 5 to induce delayed diarrhea, and later treated with various doses (low, medium, and high) of BXD and 5-ASA for 9 days, except for rats in control group. The body weight of rats was measured. The rat colon tissue injury, inflammatory cytokine levels, and the activation of toll-like receptor 4/nuclear factor-κB (TLR4/NF-κB) signaling pathway were detected. RESULTS: BXD (5, 10, or 15 g/kg) or 5-ASA (10 mL/kg) alleviated body weight loss and colon tissue injury, decreased levels of inflammatory cytokines, and inactivated TLR4/NF-κB signaling pathway in CPT-11-induced model rats. BXD at 10 g/kg (the optimal concentration) could better treat CPT-11-induced intestinal dysfunction, as evidenced by the resulting approximately 50% reduction on injury score of model rats. Moreover, BXD-M (10 g/kg) synergistic with 5-ASA (10 mL/kg) further strengthened the inhibition on rat body weight loss, colon tissue injury, inflammatory cytokine levels, and TLR4/NF-κB signaling pathway. CONCLUSION: To sum up, BXD has a protective effect against CPT-11-induced intestinal dysfunction by inhibiting inflammation through inactivation TLR4/NF-κB signaling pathway. In particular, the combined use of BXD and 5-ASA holds great promise for treating CPT-11-induced delayed diarrhea.
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Diarrea , Medicamentos Herbarios Chinos , Irinotecán , Mesalamina , FN-kappa B , Ratas Sprague-Dawley , Transducción de Señal , Receptor Toll-Like 4 , Animales , Receptor Toll-Like 4/metabolismo , FN-kappa B/metabolismo , Ratas , Transducción de Señal/efectos de los fármacos , Irinotecán/efectos adversos , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/administración & dosificación , Diarrea/tratamiento farmacológico , Diarrea/inducido químicamente , Diarrea/prevención & control , Masculino , Mesalamina/farmacología , Mesalamina/administración & dosificación , Modelos Animales de Enfermedad , Quimioterapia CombinadaRESUMEN
While mesalamine, a 5-aminosalicylic acid (5-ASA), is pivotal in the management of inflammatory bowel disease (IBD) through both step-up and top-down approaches in clinical settings, its widespread utilization is limited by low bioavailability at the desired site of action due to rapid and extensive absorption in the upper gastrointestinal (GI) tract. Addressing mesalamine's pharmacokinetic challenges, here, we introduce nanoassemblies composed exclusively of a mesalamine prodrug that pairs 5-ASA with a mucoadhesive and cathepsin B-cleavable peptide. In an IBD model, orally administered nanoassemblies demonstrate enhanced accumulation and sustained retention in the GI tract due to their mucoadhesive properties and the epithelial enhanced permeability and retention (eEPR) effect. This retention enables the efficient uptake by intestinal pro-inflammatory macrophages expressing high cathepsin B, triggering a burst release of the 5-ASA. This cascade fosters the polarization toward an M2 macrophage phenotype, diminishes inflammatory responses, and simultaneously facilitates the delivery of active agents to adjacent epithelial cells. Therefore, the nanoassemblies show outstanding therapeutic efficacy in inhibiting local inflammation and contribute to suppressing systemic inflammation by restoring damaged intestinal barriers. Collectively, this study highlights the promising role of the prodrug nanoassemblies in enhancing targeted drug delivery, potentially broadening the use of mesalamine in managing IBD.
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Enfermedades Inflamatorias del Intestino , Macrófagos , Mesalamina , Profármacos , Mesalamina/química , Mesalamina/farmacología , Profármacos/química , Profármacos/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Animales , Ratones , Humanos , Nanopartículas/química , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efectos de los fármacos , Ratones Endogámicos C57BL , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/administración & dosificaciónRESUMEN
BACKGROUND: The impact of continuing or stopping 5-aminosalicylates (5-ASA) after commencing anti-tumour necrosis factor (anti-TNF) therapy in patients with inflammatory bowel disease (IBD) remains unclear. AIMS: To compare the outcomes of patients with IBD who stopped or continued 5-ASA after starting anti-TNF therapy. METHODS: We analysed data from the Korean National Health Insurance claims database between 2007 and 2020. We compared the clinical outcomes of patients who stopped or continued 5-ASA within 90 days of anti-TNF initiation. The primary outcome was any adverse clinical event defined as a composite of new corticosteroid use, IBD-related hospitalisation, or intestinal surgery. RESULTS: Among 7442 patients included for analysis (4479 [60.2%] with Crohn's disease [CD] and 2963 [39.8%] with ulcerative colitis [UC]), 1037 (13.9%) discontinued 5-ASA within 90 days of starting anti-TNF therapy. During a median 4.3-year follow-up, discontinuation of 5-ASA was not associated with an increased risk of adverse clinical events (adjusted hazard ratio 1.01, 95% confidence interval 0.93-1.10). The cumulative incidence of each adverse clinical event and the composite outcome were not significantly different between groups (all, p > 0.05). Additionally, separate analyses in CD and UC cohorts revealed no differences in adverse clinical outcomes between the 5-ASA continuation and discontinuation groups. Subgroup analyses by presumed risk factors for disease relapse showed no significant differences in the risk of adverse events between groups. CONCLUSIONS: In this nationwide population-based study, discontinuing 5-ASA after starting anti-TNF therapy was not associated with an increased risk of adverse events in patients with IBD.
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Mesalamina , Humanos , Femenino , Masculino , Adulto , Mesalamina/uso terapéutico , Mesalamina/efectos adversos , Persona de Mediana Edad , República de Corea/epidemiología , Enfermedad de Crohn/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Antiinflamatorios no Esteroideos/uso terapéutico , Antiinflamatorios no Esteroideos/efectos adversos , Colitis Ulcerosa/tratamiento farmacológico , Adulto Joven , Anciano , Estudios RetrospectivosRESUMEN
BACKGROUND: Ulcerative colitis (UC) is a type of inflammatory bowel disease associated with persistent inflammation. Animal studies proved the efficacy of metformin in UC. AIM: To investigate the potential role of metformin and its protective pathways in patients with UC. METHODS: This is a randomized, controlled, and double-blinded clinical trial that included 60 participants with mild to moderate UC and was divided randomly into two groups (n = 30). For 6 months, the mesalamine group received 1 g of mesalamine three times daily (t.i.d.). For six months, the metformin group received mesalamine 1 g t.i.d. and metformin 500 mg twice daily. A gastroenterologist evaluated patients at baseline and 6 months after starting the treatment in order to measure serum levels of zonulin, sphingosine 1 phosphate (S1P), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). Biopsies from the colon were used to measure gene expression of zonula occuldin-1 (ZO-1), signal transducer and activator of factor-3 (STAT-3), and intracellular adhesion molecule-1 (ICAM-1). The numeric pain rating scale (NRS) and partial Mayo score were also assessed for each patient. RESULTS: When compared to the mesalamine group, the metformin group demonstrated a statistical decrease in serum IL-6, zonulin, TNF-α, SIP, gene expression of ICAM-1 and STAT-3, and a significant increase in colonic ZO-1 when compared to the mesalamine group. The metformin group also showed a significant decrease in NRS and partial Mayo score index in comparison with the mesalamine group. CONCLUSION: Metformin may be a promising additional therapy for UC patients. Trial registration identifier: NCT05553704.
Asunto(s)
Colitis Ulcerosa , Mesalamina , Metformina , Humanos , Metformina/uso terapéutico , Colitis Ulcerosa/tratamiento farmacológico , Mesalamina/uso terapéutico , Método Doble Ciego , Masculino , Femenino , Adulto , Persona de Mediana Edad , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/genética , Reposicionamiento de Medicamentos , Haptoglobinas/metabolismo , Interleucina-6/sangre , Proteína de la Zonula Occludens-1/metabolismo , Proteína de la Zonula Occludens-1/genética , Toxina del Cólera , Molécula 1 de Adhesión Intercelular/sangre , Molécula 1 de Adhesión Intercelular/genética , Molécula 1 de Adhesión Intercelular/metabolismo , Antiinflamatorios no Esteroideos/uso terapéutico , Factor de Necrosis Tumoral alfa/sangre , Colon/patología , Colon/efectos de los fármacos , Resultado del Tratamiento , Adulto Joven , Quimioterapia Combinada , Precursores de ProteínasRESUMEN
5-Aminosalicylic acid (5-ASA) is a first-line agent in both remission and maintenance therapy for ulcerative colitis (UC). However, the mucosal concentration of 5-ASA was significantly lower in patients with severe histological inflammation, which further led to a poor response to 5-ASA treatment. Our study aimed to clarify the mechanism of 5-ASA uptake into colonic epithelial cells and to further explore the reason for the decreased colonic mucosal 5-ASA concentration in UC patients. Our results demonstrated that the colonic 5-ASA concentration was notably reduced in DSS-induced colitis mice and inversely correlated with colonic inflammation. 5-ASA was not a substrate of carnitine/organic cation transporter 1/2 (OCTN1/2) or multidrug resistance protein 1 (MDR1), whereas organic anion transporting polypeptide 2B1 (OATP2B1) and sodium-coupled monocarboxylate transporter 1 (SMCT1) mediated the uptake of 5-ASA, with a greater contribution from OATP2B1 than SMCT1. Inhibitors and siRNAs targeting OATP2B1 significantly reduced 5-ASA absorption in colonic cell lines. Moreover, OATP2B1 expression was dramatically downregulated in colon tissues from UC patients and dextran sodium sulfate (DSS)-induced colitis mice, and was also negatively correlated with colonic inflammation. Mechanistically, mixed proinflammatory cytokines downregulated the expression of OATP2B1 in a time- and concentration-dependent manner through the hepatocyte nuclear factor 4 α (HNF4α) pathway. In conclusion, OATP2B1 was the pivotal transporter involved in colonic 5-ASA uptake, which indicated that inducing OATP2B1 expression may be a strategy to promote 5-ASA uptake and further improve the concentration and anti-inflammatory efficacy of 5-ASA in UC.
Asunto(s)
Colitis Ulcerosa , Citocinas , Regulación hacia Abajo , Mesalamina , Transportadores de Anión Orgánico , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/patología , Animales , Humanos , Regulación hacia Abajo/efectos de los fármacos , Transportadores de Anión Orgánico/metabolismo , Ratones , Mesalamina/farmacología , Mesalamina/uso terapéutico , Citocinas/metabolismo , Masculino , Sulfato de Dextran , Ratones Endogámicos C57BL , Colon/metabolismo , Colon/patología , Colon/efectos de los fármacos , Femenino , Antiinflamatorios no Esteroideos/farmacologíaRESUMEN
Medical therapy is the cornerstone of ulcerative colitis (UC) management and aims to induce and maintain remission. In case of mild-to-moderate UC, mesalamine (5-ASA) is the first-line option. 5-ASA requires local release at the level of the inflamed mucosa to exert its therapeutic action. While rectal preparations are useful in distal colitis, in cases of UC of at least rectosigmoid extent, guidelines suggest the association of oral and rectal 5-ASA. Mesalamine with Multi Matrix System® technology (MMX mesalamine) is an oral, high-strength (1.2 g/tablet), once-daily formulation of 5-ASA, designed to provide delayed and prolonged release throughout the entire colon. Clinical trials demonstrated a strong efficacy in inducing and maintaining clinical and endoscopic remission in active mild-to-moderate UC. The efficacy is related to specific colonic drug-delivery, to its high-dosage and once-daily administration, thus improving patients' adherence and outcomes. The specific colonic-delivery is also associated with very low rates of systemic absorption and adverse events (AEs). With this comprehensive review we aimed to summarize current knowledge on MMX mesalamine in mild-to-moderate UC, in terms of clinical pharmacology, efficacy and safety, also compared to other 5-ASA products. In addition we provided an expert opinion on the topic, examining the implications on clinical practice.
Asunto(s)
Antiinflamatorios no Esteroideos , Colitis Ulcerosa , Mesalamina , Colitis Ulcerosa/tratamiento farmacológico , Mesalamina/administración & dosificación , Mesalamina/uso terapéutico , Humanos , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/uso terapéutico , Preparaciones de Acción Retardada , Administración Oral , Administración RectalRESUMEN
Inflammatory bowel disease (IBD) is rapidly emerging in the Asia Pacific region. However, there are many challenges in the diagnosis and management of this condition. The Asian Pacific Association of Gastroenterology (APAGE) Working Group on IBD conducted a round table meeting to identify 10 common mistakes in the management of IBD in Asia. To summarize, many physicians still over rely on a definitive histological diagnosis before starting treatment and do not fully establish disease extent such as perianal and proximal gastrointestinal involvement in Crohn's disease (CD) or extent of involvement in ulcerative colitis (UC). It is also essential to actively look for evidence of extra-intestinal manifestations, which may influence choice of therapy. In terms of conventional therapy, underuse of topical 5 aminosalicylates (5-ASAs) in UC and inappropriate dosing of corticosteroids are also important considerations. Acute severe UC remains a life-threatening condition and delay in starting rescue therapy after inadequate response to intravenous steroids is still common. Anti-tumor necrosis factors should be considered first line in all cases of complex perianal fistulizing CD. Most patients with IBD are on potent immunosuppressive therapy and should be screened for latent infections and offered vaccinations according to guidelines. Under-recognition and management of significant complications such as anemia, osteoporosis, malnutrition, and thromboembolism should also be addressed. Colonoscopy is still not properly performed for dysplasia/cancer surveillance and for evaluating post-op recurrence of CD. Another common misstep is inappropriate withdrawal of medications during pregnancy leading to increased complications for the mother and the newborn.
Asunto(s)
Gastroenterología , Enfermedades Inflamatorias del Intestino , Humanos , Asia/epidemiología , Gastroenterología/normas , Enfermedades Inflamatorias del Intestino/complicaciones , Enfermedades Inflamatorias del Intestino/diagnóstico , Enfermedades Inflamatorias del Intestino/terapia , Colitis Ulcerosa/complicaciones , Colitis Ulcerosa/diagnóstico , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/terapia , Femenino , Enfermedad de Crohn/diagnóstico , Enfermedad de Crohn/terapia , Enfermedad de Crohn/complicaciones , Enfermedad de Crohn/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Inmunosupresores/efectos adversos , Inmunosupresores/administración & dosificación , Corticoesteroides/administración & dosificación , Corticoesteroides/uso terapéutico , Embarazo , Mesalamina/uso terapéutico , Mesalamina/administración & dosificaciónAsunto(s)
Colitis Ulcerosa , Humanos , Masculino , Adolescente , Colitis Ulcerosa/tratamiento farmacológico , Ustekinumab/uso terapéutico , Ustekinumab/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Infliximab/uso terapéutico , Infliximab/administración & dosificación , Quimioterapia Combinada , Mesalamina/uso terapéutico , Mesalamina/administración & dosificación , Resultado del Tratamiento , Trombosis de la Vena/tratamiento farmacológico , Trombosis de la Vena/etiología , Inmunosupresores/uso terapéutico , Inmunosupresores/administración & dosificación , Azatioprina/uso terapéutico , Azatioprina/administración & dosificaciónRESUMEN
5-Aminosalicylic acid (5-ASA) is recommended for managing ulcerative colitis. Common adverse effects associated with 5-ASA include gastrointestinal disorders, headaches, and skin rashes. Perimyocarditis induced by 5-ASA is a rare adverse effect, with only a limited number of cases reported. This paper presents a case of 5-ASA-induced perimyocarditis in a 29-year-old female who had been taking 5-ASA for three weeks. The patient was admitted to the emergency department with dyspnea, chest discomfort, and fever. She subsequently underwent laboratory investigations, including electrocardiography, transthoracic echocardiography, chest computed tomographic angiography, cardiac magnetic resonance imaging, and heart biopsy. Intravenous steroid was administered, and 5-ASA was discontinued. The patient's signs and symptoms improved significantly within a few days of discontinuing 5-ASA, leading to her subsequent discharge. This case highlights the importance of considering perimyocarditis in patients exhibiting cardiac symptoms during 5-ASA therapy, despite it being a rare adverse effect. Drug withdrawal in such cases may lead to rapid clinical improvement.