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OBJECTIVES: To assess eligibility criteria that either explicitly or implicitly exclude older patients from randomized controlled trials (RCTs) in RA. METHODS: Our analysis included RCTs of pharmacological interventions registered with ClinicalTrials.gov and started between 2013 and 2022. Co-primary outcomes were proportions of trials with an upper age limit and the eligibility criteria indirectly increasing risk of the exclusion of older adults. RESULTS: A total of 143/290 (49%) trials had an upper age limit of 85 years or less. Multivariable analysis showed that the odds of an upper age limit were significantly lower in trials performed in the USA [adjusted odds ratio (aOR), 0.34; CI, 0.12-0.99; P = 0.04] and intercontinental trials (aOR, 0.4; CI, 0.18-0.87; P = 0.02). In total, 154/290 (53%) trials had at least one eligibility criterion implicitly excluding older adults. These included specific comorbidities (n = 114; 39%), compliance concerns (n = 67; 23%), and broad and vague exclusion criteria (n = 57; 20%); however, we found no significant associations between these criteria and trial characteristics. Overall, 217 (75%) trials either explicitly or implicitly excluded older patients; we also noted a trend towards increasing proportion of these trials over time. Only one trial (0.3%) enrolled solely patients aged 65 and older. CONCLUSION: Older adults are commonly excluded from RCTs in RA based on both age limits and other eligibility criteria. This seriously limits the evidence base for the treatment of older patients in clinical practice. Given the growing prevalence of RA in older adults, relevant RCTs should be more inclusive to them.
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Artritis Reumatoide , Humanos , Anciano , Ensayos Clínicos Controlados Aleatorios como Asunto , Artritis Reumatoide/tratamiento farmacológico , ComorbilidadRESUMEN
The small intestine is a significant site of ulceration and bleeding induced by nonsteroidal anti-inflammatory drugs (NSAIDs). The pathogenesis is poorly understood. The present study explored the roles of bile, bacteria, and enterohepatic circulation to NSAID enteropathy, using both a conventional NSAID (naproxen) and a gastrointestinal-safe naproxen derivative (ATB-346), as well as proton pump inhibitors (PPIs). Rats were treated orally with naproxen or equimolar doses of ATB-346 over a 5-day period, with or without PPI administration, and intestinal damage was quantified. The cytotoxicity of bile from the rats was evaluated in vitro. Biliary excretion of naproxen and ATB-346 was determined. The impact of the NSAIDs and of PPIs on the composition of the intestinal microbiota was examined by deep sequencing of 16s rRNA. Naproxen caused significant intestinal damage and inflammation, whereas ATB-346 did not. Naproxen, but not ATB-346, dose dependently increased the cytotoxicity of bile, and it was further increased by PPI coadministration. Whereas biliary excretion of naproxen was significant in naproxen-treated rats, it was greatly reduced in rats treated with ATB-346. The enteric microbiota of naproxen-treated rats was distinct from that in vehicle- or ATB-346-treated rats, and PPI administration caused significant intestinal dysbiosis. The increase in cytotoxicity of bile induced by naproxen and PPIs may contribute significantly to intestinal ulceration and bleeding. Some of these effects may occur secondary to significant changes in the jejunal microbiota induced by both naproxen and PPIs.
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Antiinflamatorios no Esteroideos/farmacología , Sulfuro de Hidrógeno/farmacología , Enfermedades Intestinales/tratamiento farmacológico , Naproxeno/análogos & derivados , Inhibidores de la Bomba de Protones/farmacología , Animales , Eliminación Hepatobiliar/fisiología , Inflamación/tratamiento farmacológico , Masculino , Naproxeno/farmacología , ARN Ribosómico 16S/genética , Ratas WistarRESUMEN
Understanding how intestinal enteropathogens cause acute and chronic alterations has direct animal and human health perspectives. Significant advances have been made on this field by studies focusing on the dynamic crosstalk between the intestinal protozoan parasite model Giardia duodenalis and the host intestinal mucosa. The concept of intestinal barrier function is of the highest importance in the context of many gastrointestinal diseases such as infectious enteritis, inflammatory bowel disease, and post-infectious gastrointestinal disorders. This crucial function relies on 3 biotic and abiotic components, first the commensal microbiota organized as a biofilm, then an overlaying mucus layer, and finally the tightly structured intestinal epithelium. Herein we review multiple strategies used by Giardia parasite to circumvent these 3 components. We will summarize what is known and discuss preliminary observations suggesting how such enteropathogen directly and/ or indirectly impairs commensal microbiota biofilm architecture, disrupts mucus layer and damages host epithelium physiology and survival.
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Epitelio/fisiología , Giardia/fisiología , Intestinos/fisiopatología , Microbiota/fisiología , Moco/fisiología , Animales , HumanosRESUMEN
Our understanding of polymicrobial gastrointestinal infections and their effects on host biology remains incompletely understood. Giardia duodenalis is an ubiquitous intestinal protozoan parasite infecting animals and humans. Concomitant infections with Giardia and other gastrointestinal pathogens commonly occur. In countries with poor sanitation, Giardia infection has been associated with decreased incidence of diarrheal disease and fever, and reduced serum inflammatory markers release, via mechanisms that remain obscure. This study analyzed Giardia spp. co-infections with attaching and effacing (A/E) pathogens, and assessed whether and how the presence of Giardia modulates host responses to A/E enteropathogens, and alters intestinal disease outcome. In mice infected with the A/E pathogen Citrobacter rodentium, co-infection with Giardia muris significantly attenuated weight loss, macro- and microscopic signs of colitis, bacterial colonization and translocation, while concurrently enhancing the production and secretion of antimicrobial peptides (AMPs) mouse ß-defensin 3 and trefoil factor 3 (TFF3). Co-infection of human intestinal epithelial cells (Caco-2) monolayers with G. duodenalis trophozoites and enteropathogenic Escherichia coli (EPEC) enhanced the production of the AMPs human ß-defensin 2 (HBD-2) and TFF3; this effect was inhibited with treatment of G. duodenalis with cysteine protease inhibitors. Collectively, these results suggest that Giardia infections are capable of reducing enteropathogen-induced colitis while increasing production of host AMPs. Additional studies also demonstrated that Giardia was able to directly inhibit the growth of pathogenic bacteria. These results reveal novel mechanisms whereby Giardia may protect against gastrointestinal disease induced by a co-infecting A/E enteropathogen. Our findings shed new light on how microbial-microbial interactions in the gut may protect a host during concomitant infections.
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Coinfección/metabolismo , Escherichia coli Enteropatógena , Infecciones por Escherichia coli/metabolismo , Giardia lamblia , Giardiasis/metabolismo , Factor Trefoil-3/metabolismo , beta-Defensinas/metabolismo , Animales , Células CACO-2 , Coinfección/microbiología , Coinfección/parasitología , Infecciones por Escherichia coli/microbiología , Infecciones por Escherichia coli/parasitología , Humanos , Masculino , RatonesRESUMEN
BACKGROUND AND PURPOSE: Hydrogen sulphide is an important mediator of gastrointestinal mucosal defence. The use of non-steroidal anti-inflammatory drugs (NSAIDs) is significantly limited by their toxicity in the gastrointestinal tract. Particularly concerning is the lack of effective preventative or curative treatments for NSAID-induced intestinal damage and bleeding. We evaluated the ability of a hydrogen sulphide donor to protect against NSAID-induced enteropathy. EXPERIMENTAL APPROACH: Intestinal ulceration and bleeding were induced in Wistar rats by oral administration of naproxen. The effects of suppression of endogenous hydrogen sulphide synthesis or administration of a hydrogen sulphide donor (diallyl disulphide) on naproxen-induced enteropathy was examined. Effects of diallyl disulphide on small intestinal inflammation and intestinal microbiota were also assessed. Bile collected after in vivo naproxen and diallyl disulphide administration was evaluated for cytotoxicity in vitro using cultured intestinal epithelial cells. KEY RESULTS: Suppression of endogenous hydrogen sulphide synthesis by ß-cyano-L-alanine exacerbated naproxen-induced enteropathy. Diallyl disulphide co-administration dose-dependently reduced the severity of naproxen-induced small intestinal damage, inflammation and bleeding. Diallyl disulphide administration attenuated naproxen-induced increases in the cytotoxicity of bile on cultured enterocytes, and prevented or reversed naproxen-induced changes in the intestinal microbiota. CONCLUSIONS AND IMPLICATIONS: Hydrogen sulphide protects against NSAID-enteropathy in rats, in part reducing the cytotoxicity of bile and preventing NSAID-induced dysbiosis.
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Compuestos Alílicos/uso terapéutico , Hemorragia Gastrointestinal/tratamiento farmacológico , Sulfuro de Hidrógeno/metabolismo , Enfermedades Intestinales/tratamiento farmacológico , Sustancias Protectoras/uso terapéutico , Sulfuros/uso terapéutico , Úlcera/tratamiento farmacológico , Alanina/análogos & derivados , Alanina/farmacología , Animales , Antiinflamatorios no Esteroideos , Bilis/metabolismo , Línea Celular , Ciclooxigenasa 1 , Hemorragia Gastrointestinal/inducido químicamente , Hemorragia Gastrointestinal/metabolismo , Hemorragia Gastrointestinal/microbiología , Hemorragia Gastrointestinal/patología , Humanos , Sulfuro de Hidrógeno/antagonistas & inhibidores , Enfermedades Intestinales/inducido químicamente , Enfermedades Intestinales/metabolismo , Enfermedades Intestinales/microbiología , Enfermedades Intestinales/patología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología , Yeyuno/metabolismo , Yeyuno/microbiología , Yeyuno/patología , Proteínas de la Membrana/antagonistas & inhibidores , Microbiota , Naproxeno , Ratas Wistar , Úlcera/inducido químicamente , Úlcera/metabolismo , Úlcera/microbiología , Úlcera/patologíaRESUMEN
SIGNIFICANCE: There is a rapidly expanding body of evidence for important roles of hydrogen sulfide in protecting against tissue injury, reducing inflammation, and promoting repair. There is also growing evidence that H2S can be successfully exploited in drug development. RECENT ADVANCES: H2S synthesis and degradation are regulated in circumstances of inflammation and injury so as to promote repair and re-establish homeostasis. Novel H2S-releasing drugs exhibit enhanced anti-inflammatory and pro-restorative effects, while having reduced adverse effects in many tissues. CRITICAL ISSUES: H2S is a pleiotropic mediator, having effects on many elements in the inflammatory cascade and promoting the resolution of inflammation and injury. It also contributes significantly to mucosal defence in the gastrointestinal tract, and in host defence against infection. There is strong evidence that novel, H2S-based therapeutics are safe and effective in animal models, and several are progressing through human trials. FUTURE DIRECTIONS: A better understanding of the physiological and pathophysiological roles of H2S continues to be restrained by the lack of simple, reliable methods for measurement of H2S synthesis, and the paucity of highly selective inhibitors of enzymes that participate in endogenous H2S synthesis. On the other hand, H2S donors show promise as therapeutics for several important indications.
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Antiinflamatorios/metabolismo , Sulfuro de Hidrógeno/metabolismo , Sulfuro de Hidrógeno/uso terapéutico , Sustancias Protectoras/metabolismo , Heridas y Lesiones/tratamiento farmacológico , Animales , Antiinflamatorios/química , Antiinflamatorios/uso terapéutico , Humanos , Sulfuro de Hidrógeno/química , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Membrana Mucosa/metabolismo , Sustancias Protectoras/química , Sustancias Protectoras/uso terapéutico , Heridas y Lesiones/metabolismoRESUMEN
Nonsteroidal anti-inflammatory drugs (NSAIDs) remain among the most commonly used medications because of their effectiveness in reducing pain and inflammation. Inhibitors of gastric acid secretion can substantially reduce the damaging effects of NSAIDs in the stomach and duodenum. However, there are no proven effective preventative or curative treatments for NSAID-induced enteropathy. In recent years, substantial progress has been made in better understanding the pathogenesis of NSAID-enteropathy, and in particular the interplay of enteric bacteria, bile and the enterohepatic recirculation of the NSAIDs. Moreover, it is becoming clear that suppression of gastric acid secretion significantly worsens NSAID-enteropathy.