Peer-reviewed research by Antibe’s scientists...

 

The following is a selection of papers published by Antibe’s scientists in peer-reviewed journals, including Nature Reviews, the British Journal of Pharmacology and the Proceedings of the National Academy of Sciences (PNAS). Many were written in collaboration with widely respected researchers specializing in highly relevant fields, including cardiology, gastroenterology, pain medicine and pharmacology. Most address the physiological and pharmacological behavior of hydrogen sulfide in a variety of human trials and animal models.

 

Feb 2019

A proof-of-concept, Phase 2 clinical trial of the gastrointestinal safety of a hydrogen sulfide-releasing anti-inflammatory drug

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.

WALLACE ET AL., BRITISH JOURNAL OF PHARMACOLOGY

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Aug 2018

Antibe Therapeutics: Phase 2B Gastrointestinal Safety Clinical Trial

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.

WALLACE, ANTIBE THERAPEUTICS (COMPANY DOCUMENT - NOT PEER-REVIEWED)

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May 2018

Iron Sequestration in Microbiota Biofilms As A Novel Strategy for Treating Inflammatory Bowel Disease

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.

MOTTA ET AL., INFLAMMATORY BOWEL DISEASES

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May 2017

Hydrogen Sulfide-Releasing Therapeutics: Translation to the Clinic

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.

WALLACE ET AL., ANTIOXIDANTS & REDOX SIGNALING

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Feb 2016

Profound Chemopreventative Effects of a Hydrogen Sulfide-Releasing NSAID in the APCMin/+ Mouse Model of Intestinal Tumorigenesis

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.

PAUL-CLARK ET AL., PLOS ONE

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May 2015

Hydrogen sulfide-based therapeutics: exploiting a unique but ubiquitous gasotransmitter

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.

WALLACE & WANG, NATURE REVIEWS

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Nov 2014

H2S-releasing drugs: Anti-inflammatory, cytoprotective and chemopreventative potential

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.

GEMICI ET AL., NITRIC OXIDE

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Aug 2014

Impaired hydrogen sulfide synthesis and IL-10 signaling underlie hyperhomocysteinemia-associated exacerbation of colitis

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.

FLANNIGAN ET AL., PNAS

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Mar 2013

Mechanisms, prevention and clinical implications of nonsteroidal anti-inflammatory drug-enteropathy

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.

WALLACE, WORLD JOURNAL OF GASTROENTEROLOGY

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Jul 2012

Hydrogen Sulfide: An Endogenous Mediator of Resolution of Inflammation and Injury

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.

WALLACE ET AL., ANTIOXIDANTS & REDOX SIGNALING

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Apr 2012

Gastrointestinal-Sparing Effects of Novel NSAIDs in Rats with Compromised Mucosal Defence

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.

BLACKLER ET AL., PLOS ONE

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Oct 2011

PPIs Exacerbate NSAID-Induced Small Intestinal Injury by Inducing Dysbiosis

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.

WALLACE ET AL., GASTROENTEROLOGY

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Feb 2010

Markedly reduced toxicity of a hydrogen sulphide-releasing derivative of naproxen (ATB-346)

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.

WALLACE ET AL., BRITISH JOURNAL OF PHARMACOLOGY

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May 2007

Gastrointestinal Safety and Anti-Inflammatory Effects of a Hydrogen Sulfide–Releasing Diclofenac Derivative in the Rat

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.

WALLACE ET AL., GASTROENTEROLOGY

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Sep 1990

Gastric ulceration induced by nonsteroidal anti-inflammatory drugs is a neutrophil-dependent process

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.

WALLACE ET AL., AMERICAN JOURNAL OF PHYSIOLOGY

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