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As a key feature of human physiology, pain typically serves as a signal that a body part has sustained damage. Often termed “nociceptive pain”, it is triggered at the site of injury primarily by prostaglandin production, and is regulated by cyclooxygenase (COX) enzymes, comprising two subtypes: COX-1 and COX-2 (NSAIDs function by inhibiting COX enzymes). The biological purpose of inflammation is to enable efficient and rapid cellular repair. However, many types of inflammation—especially when arising from long-term conditions like osteoarthritis—can cascade into a medical problem in themselves, leading to further tissue damage, fever and chronic pain.
The NSAID category includes aspirin and well-known consumer brands like Advil (ibuprofen) and Aleve (naproxen), as well as prescription-only medicines like celecoxib (Celebrex), ketoprofen, ketorolac and meloxicam. Given their ability to reduce both pain and inflammation, NSAIDs’ non-addictive nature and well-established efficacy have made them drugs of choice for physicians and consumers alike.
However, NSAIDs also cause clinically significant gastrointestinal ulcers and bleeding in approximately 25% of users, a problem that has resisted solution since aspirin was introduced more than 100 years ago. As first documented by Dr John L. Wallace and his colleagues in 1990, the root of this problem is that NSAIDs impair the body’s ability to maintain the mucosal layer that ordinarily protects the lining of the digestive organs. This issue is highly consequential—adverse reactions to NSAIDs are a leading cause of hospital deaths. Several approaches have been attempted to address this widespread problem, but all have proved unsatisfactory.
While traditional NSAIDs block both COX-1 and COX-2 enzymes, the late 1990s saw the introduction of NSAIDs that specifically inhibit COX-2, on the premise that stomach damage was primarily due to the effects of suppressed COX-1. Although COX-2 selective NSAIDs were outstandingly successful commercially, the FDA eventually removed the majority from the market (e.g., Vioxx, Bextra), due to increased risk of cardiovascular events. A few COX-2 selective NSAIDs, principally celecoxib, continue to be available. To counteract cardiovascular concerns, they are often administered with low-dose aspirin, nullifying their gastroprotective advantage—while intensifying damage to the small intestine.*
* Damage to most of the small intestine was hidden from researchers until the recent availability of capsule endoscopy, a method of viewing the digestive tract via a swallowed capsule that contains a miniaturized camera. Traditional endoscopes are only able to inspect the stomach/duodenum or the large intestine.
Enterically-coated NSAIDs were introduced to prevent the digestion of the NSAID tablet by the stomach, thereby protecting that organ from damage. However, these coatings necessarily deliver intact pills (now absent their protective coating) into the more easily-damaged small intestine. As such, they can cause more serious injury than they prevent. Moreover, enteric coatings reduce the efficacy of NSAIDs, necessitating increased dosages to achieve intended therapeutic effects.
PPIs and H2 antagonists (e.g., esomeprazole and ranitidine; branded as Nexium and Zantac) are often co-prescribed with NSAIDs to protect the stomach. However, this treatment strategy dramatically increases intestinal bleeding, ulcers, and risk of perforation, as observed in rising rates of hospitalization and mortality. Notably, reduced stomach acidity can enable the survival of dangerous microbes, including C. difficile, with resulting opportunistic infections compounding the damage caused by the NSAIDs themselves.
As depicted in the accompanying chart, intestinal damage in rats caused by naproxen (dark blue bars) and celecoxib (light blue bars) is worsened significantly when omeprazole (“Omep”), a common PPI, or low-dose aspirin (for cardiovascular protection), is given at the same time. These results have been replicated in human studies. When co-administered with PPIs, ATB-346 remained gastrointestinal-safe (although there is no need for PPIs or other acid-reduction medication to be co-administered with ATB-346) .
Overall, intestinal injury is more difficult to diagnose and treat than stomach damage, and symptoms correlate poorly with the severity of tissue injury, complicating medical assessment. By focusing on the stomach, physicians may be inadvertently placing their patients at risk of serious, difficult-to-diagnose injury—with no proven-effective therapies and significantly higher rates of morbidity and mortality. Moreover, many current solutions do not even adequately protect the stomach.