Disease State

There are two major types of acid-dependent diseases of the upper gastrointestinal (GI) tract, peptic ulcer disease (PUD) in the stomach and duodenum and gastroesophageal reflux disease (GERD) in the esophagus. Nocturnal acid secretion can also be related to hoarseness or laryngitis, and even symptoms of asthma. Although these have quite different etiologies, the main therapeutic approach has always been control of gastric acid secretion.

PUD, for most of human history, was the prevalent ailment of this region of the GI tract, and had very significant associated mortality due to perforation and hemorrhage. In the twentieth century, control of acid secretion, first surgically and then medically, became possible, reducing serious outcomes of this disease significantly.1 In the mid-1980s an association with infection by Helicobacter pylori was suggested.2 It is now universally accepted that, in addition to acid, infection by this organism is necessary for the development of PUD. Although PUD is now much less prevalent in developed countries, perhaps due to a decline in infection by H. pylori, it is highly significant in underdeveloped regions of the world, where the infection rate remains at approximately 90%. The mode of transmission of the bacteria remains unknown, but most suspicion has focused on the water supply and its treatment. The modality of treatment of PUD or its symptoms now requires acid suppression as well as confirmed eradication of H. pylori, if active infection is established. Eradication requires acid suppression in combination with at least two antibiotics twice a day for at least

7 days.3

GERD, on the other hand, is increasing in prevalence in the developed countries of the world, and may also predispose to, first, Barrett's esophagus and, then, esophageal cancer.4'5 So, not only is there an emphasis on healing any erosions present in the lower esophagus, but there is also concern that treatment should extend to full symptomatic relief. When histamine (H2) receptor antagonists were introduced, the first being cimetidine, these drugs enabled

8 week healing of peptic ulcers, but had a lesser effect on GERD. With the introduction of proton pump inhibitors (PPIs), such as omeprazole, GERD also became amenable to effective treatment in terms of healing, in that 8 weeks of treatment is usually sufficient. However, complete symptom relief is much more difficult: although healing occurs at a luminal esophageal pH of greater than 4.0,6,7 this pH is still sufficiently high to activate the acid-sensitive ion channels (ASICs) in the nerves of the epithelium, which have an activation threshold of approximately pH 5.0, resulting in pain. Given the mechanism of action of the PPIs, as discussed below, this is particularly true for patients with night-time GERD. Night-time reflux also results in laryngitis and even asthma,8 requiring highly effective acid suppression for treatment. Although treatment of pain with COX-2 inhibitors was thought to be a means to avoid the common gastric symptoms and lesions associated with treatment with COX-1 inhibitors, the nonsteroidal anti-inflammatory drugs (NSAIDs), the cardiac safety of the former class of drugs has been questioned, as have the data indicating an absence of gastric symptoms.9 The combination of a PPI with a COX-1 inhibitor appears to reduce the incidence of gastric side-effects.10'11

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