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Poster presented by lead author, James R.W. Glanville, MBChB, MRCP, at the PAINWeek Conference in September 2022. Based on a peer-reviewed paper published in the FASEB Journal (Sept 2021): faseb.onlinelibrary.wiley.com/doi/abs/10.1096/fj.201902918RR.
NSAIDs such as naproxen are utilized to treat inflammation and pain; unfortunately, these agents have been associated with increased cardiovascular risk and high incidence of gastrointestinal (GI) upset. A novel model of ultraviolet-killed Escherichia coli-triggered resolving dermal acute inflammation was used to evaluate whether otenaproxesul, while demonstrating lower GI adverse events (AEs), retains its anti-inflammatory effect in humans. This single-blind study recruited 23 healthy, male subjects aged 18-50 years and randomly assigned them to 1 of 3 treatments: naproxen, otenaproxesul, untreated. The novel model was used to evaluate whether otenaproxesul, while demonstrating lower GI adverse events (AEs), retains its anti-inflammatory effect in humans. No AEs were reported in any group. Compared to untreated controls, otenaproxesul significantly inhibited neutrophil infiltration at the site of inflammation at 4 hours. This was also seen to a lesser extent in the naproxen group. Compared to the untreated control group, HLA-DR-T/NK cells were significantly lower in the otenaproxesul group at 48 hours.
NSAIDs represent one of the most widely used classes of drugs and play a pivotal role in the therapy of numerous inflammatory diseases. However, the adverse effects of these drugs, especially when applied chronically, frequently affect gastrointestinal (GI) tract, resulting in ulceration and bleeding, which constitutes a significant limitation in clinical practice. On the other hand, it has been recently discovered that gaseous mediators nitric oxide (NO), hydrogen sulfide (H2S) and carbon monoxide (CO) contribute to many physiological processes in the GI tract, including the maintenance of GI mucosal barrier integrity. Therefore, based on the possible therapeutic properties of NO, H2S and CO, novel NSAIDs with ability to release one or more of those gaseous messengers have been synthesized. Until now, both preclinical and clinical studies have shown promising effects with respect to the anti-inflammatory potency as well as GI-safety of these novel NSAIDs. This review provides an overview of the gaseous mediators-based NSAIDs along with their mechanisms of action, with special emphasis on possible implications for GI mucosal defense mechanisms.
Significant progress has been made in recent years towards targeting H2S in drug design, with translation to human applications on the horizon. This Special Issue highlights the substantial breadth of research related to hydrogen sulfide, elucidating its important roles in a wide range of physiological and pathophysiological processes. (This is the overview editorial — the full issue is linked from this paper.)
The covalent linking of nonsteroidal anti-inflammatory drugs (NSAIDs) to a hydrogen sulfide (H2S)-releasing moiety has been shown to dramatically reduce gastrointestinal (GI) damage and bleeding, as well as increasing anti-inflammatory and analgesic potency. We tested the hypothesis that a H2S-releasing derivative of ketoprofen (ATB-352) would exhibit enhanced efficacy without significant GI damage in a mouse model of allodynia/hyperalgesia. ATB-352 was significantly more potent and effective as an analgesic than ketoprofen, and did not elicit GI damage. In vitro, ATB-352 was substantially more potent than ketoprofen as an inhibitor of fatty acid amide hydrolase, consistent with a contribution of endogenous cannabinoids to the analgesic effects of this drug. Blood anandamide levels were significantly depressed by ketoprofen, but remained unchanged after treatment with ATB-352.
Antibe’s recent Phase 2B GI safety study provides unequivocal evidence for a marked reduction of GI toxicity of its H2S-releasing analgesic/anti-inflammatory drug, ATB-346, as compared to the conventional dose of naproxen that produced equivalent suppression of cyclooxygenase (COX). This peer-reviewed paper was published in one of the world’s leading pharmacology journals and provides a comprehensive summary of the clinical trial results.
Antibe recently concluded a substantive endoscopic Phase 2B clinical trial in 244 healthy volunteers, in which it demonstrated an unequivocal GI safety advantage of ATB-346 as compared to naproxen, the most prescribed NSAID in the United States. This internal paper provides a more in-depth analysis of the data from this clinical trial, including summaries and discussion of the secondary endpoints. A peer-reviewed paper was subsequently published in February 2019 in the British Journal of Pharmacology.
Significant alterations of intestinal microbiota and anemia are hallmarks of inflammatory bowel disease (IBD). It is widely accepted that iron is a key nutrient for pathogenic bacteria, but little is known about its impact on microbiota associated with IBD. We describe an unexpected iron-scavenging property for an experimental hydrogen sulfide-releasing derivative of mesalamine. The findings demonstrate that this new drug reduces the virulence of IBD microbiota biofilms through a direct reduction of microbial iron intake and without affecting bacteria survival or species composition within the microbiota.
H2S-releasing drugs, such as SG1002 for cardiovascular disorders, and ATB-346 for arthritis, have progressed into clinical trials and have shown considerable promise. The proof-of-concept clinical studies reviewed herein pave the way for examination, in a clinical setting, of several other potential applications of H2S-based drugs in a wide range of disorders, including diabetes, hypertension, and cancer chemoprevention.
Proton pump inhibitors (PPIs) represent a milestone in the treatment of acid-related diseases, and are the mainstay in preventing upper GI bleeding in high-risk patients treated with NSAIDs or low-dose aspirin. However, this beneficial effect does not extend to the lower gastrointestinal tract. PPIs do not prevent NSAID or aspirin-associated lower gastrointestinal bleeding (LGB). PPIs may increase both small bowel injury related to NSAIDs and low-dose aspirin treatment and the risk of LGB. Recent studies suggested that altering intestinal microbiota by PPIs may be involved in the pathogenesis of NSAID-enteropathy. An increase in LGB hospitalization rates may occur more frequently in older patients with more comorbidities and are associated with high hospital resource utilization, longer hospitalization, and increased mortality. Preventive strategies for NSAID and aspirin-associated GI bleeding should be directed toward preventing both upper and lower GI damage.
This study explored the possibility that Antibe’s lead drug, ATB-346, would be effective in a murine model of hereditary intestinal cancer (APCMin+ mouse). Daily treatment with ATB-346 was significantly more effective at preventing intestinal polyp formation than naproxen. Significant beneficial effects were seen with a treatment period of only 3–7 days, and reversal of existing polyps was observed in the colon. ATB-346 may represent a promising agent for chemoprevention of tumorigenesis in the GI tract and elsewhere.
Hydrogen sulfide (H2S) has become recognized as an important signalling molecule throughout the body, contributing to many physiological and pathological processes. In recent years, improved methods for measuring H2S levels and the availability of a wider range of H2S donors and more selective inhibitors of H2S synthesis have helped to more accurately identify the many biological effects of this highly reactive gaseous mediator. Animal studies of several H2S-releasing drugs have demonstrated considerable promise for the safe treatment of a wide range of disorders. Several such drugs are now in clinical trials.
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.
This paper provides an overview of some of the mechanisms underlying the anti-inflammatory and cytoprotective actions of hydrogen sulfide. It also gives some examples of hydrogen sulfide-releasing anti-inflammatory drugs, and their actions in terms of reducing inflammation and attenuating the development of cancer in experimental models.
Vitamin B deficiencies, which can lead to hyperhomocysteinemia (Hhcy), are commonly reported in patients with inflammatory bowel disease (IBD) and may be a causative underlying factor. However, the mechanism for this effect is not known. Hydrogen sulfide (H2S) is a gaseous mediator that promotes tissue repair and resolution of inflammation. In experimental colitis, a marked increase in colonic H2S synthesis drives ulcer healing and resolution of inflammation.
This article reviews the latest developments in understanding the pathogenesis, detection and treatment of small intestinal damage and bleeding caused by NSAIDs. With improvements in the detection of NSAID-induced damage in the small intestine, it is now clear that this injury and the associated bleeding occurs more frequently than that occurring in the stomach and duodenum, and can also be regarded as more dangerous. Moreover, recent studies suggest that commonly used drugs for protecting the upper gastrointestinal tract (i.e., proton pump inhibitors) can significantly worsen NSAID-induced damage in the small intestine.
NSAIDs are among the most commonly used drugs worldwide and their beneficial therapeutic properties are thoroughly accepted. However, they are also associated with GI adverse events. NSAIDs can damage the whole GI tract including a wide spectrum of lesions. About 1 to 2% of NSAID users experienced a serious GI complication during treatment. The relative risk of upper GI complications among NSAID users depends on the presence of different risk factors, including older age (>65 years), history of complicated peptic ulcer, and concomitant aspirin or anticoagulant use, in addition to the type and dose of NSAID. Some authors recently reported a decreasing trend in hospitalizations due to upper GI complications and a significant increase in those from the lower GI tract, causing the rates of these two types of GI complications to converge. NSAID-induced enteropathy has gained much attention in the last few years and an increasing number of reports have been published on this issue. Current evidence suggests that NSAIDs increase the risk of lower GI bleeding and perforation to a similar extent as that seen in the upper GI tract. Selective cyclooxygenase-2 inhibitors have the same beneficial effects as nonselective NSAIDs but with less GI toxicity in the upper GI tract and probably in the lower GI tract. Overall, mortality due to these complications has also decreased, but the in-hospital case fatality for upper and lower GI complication events has remained constant despite the new therapeutic and prevention strategies.
Hydrogen sulfide is emerging as an important mediator of many aspects of inflammation, and perhaps most importantly as a factor promoting the resolution of inflammation and repair of injury. Enteric bacteria can be a significant source of H2S, which could affect mucosal integrity; indeed, luminal H2S can serve as an alternative to oxygen as a metabolic substrate for mitochondrial respiration in epithelial cells. Enterocytes and colonocytes thereby represent a ‘‘metabolic barrier’’ to the diffusion of bacteria-derived H2S into the subepithelial space. A compromise of this barrier could result in modulation of mucosal function and integrity by bacterial H2S.
Nonsteroidal anti-inflammatory drugs are among the most commonly used prescription and over-the-counter medications, but they often produce significant gastrointestinal ulceration and bleeding, particularly in elderly patients and patients with certain co-morbidities. Novel anti-inflammatory drugs are seldom tested in animal models that mimic the high risk human users, leading to an underestimate of the true toxicity of the drugs. In the present study we examined the effects of two novel NSAIDs (including ATB-346) and two commonly used NSAIDs in models in which mucosal defence was expected to be impaired.
Proton pump inhibitors (PPIs) and NSAIDs are among the most commonly used classes of drugs, with the former frequently co-prescribed to reduce gastro-duodenal injury caused by the latter. However, suppression of gastric acid secretion by PPIs is unlikely to provide any protection against the damage caused by NSAIDs in the more distal small intestine. As shown here, PPIs exacerbate NSAID-induced intestinal damage at least in part because of significant shifts in enteric microbial populations. Prevention or reversal of this dysbiosis may be a viable option for reducing the incidence and severity of NSAID enteropathy.
Hydrogen sulphide is an important mediator of gastric mucosal defence. The use of non-steroidal anti-inflammatory drugs continues to be limited by their toxicity, particularly in the upper gastrointestinal tract. The ability of ATB-346 versus naproxen to cause gastric damage was evaluated in healthy rats and in rats with compromised gastric mucosal defence. ATB-346 exhibits anti-inflammatory properties similar to naproxen, but with substantially reduced gastrointestinal toxicity.
Gastrointestinal damage caused by nonsteroidal anti-inflammatory drugs (NSAIDs) remains a significant clinical problem. Hydrogen makes an important contribution to mucosal defense, and NSAIDs can suppress its synthesis. In this study, we evaluated the gastrointestinal safety and anti-inflammatory effects of a novel “HS-NSAID” (ATB-337) that consists of diclofenac linked to a hydrogen sulfide–releasing moiety.
The hypothesis that neutrophils play an important role in the pathogenesis of gastric ulceration induced by nonsteroidal anti-inflammatory drugs (NSAIDs) was tested in rats. Rats made neutropenic (i.e., had neutrophils (white blood cells) removed from their bloodstream) by prior treatment with an antibody to rat neutrophils were found to be significantly more resistant to the gastric-damaging actions of indomethacin or naproxen than were control rats or rats treated with serum that did not contain neutrophil antibodies. These results suggest an important role for neutrophils in the pathogenesis of NSAID-induced gastric ulceration. Neutrophils may be important in the vascular injury that occurs early after administration of these compounds.
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