During the last twenty-five years, a remarkable revolution in the pathophysiology and treatment of gastric (GU) and duodenal (DU) ulcers has occurred. Effective therapies were developed not only to heal ulcers but also to cure most patients. The two principal causes for GU and DU are either infection with Helicobacter pylori (HP) or the use of nonsteroidal anti-inflammatory drugs (NSAIDs). With HP eradication, GU and DU are rapidly becoming historical diseases. This communication reviews the salient pharmacology of the novel anti-ulcer drugs currently in development with particular emphasis on the treatment of DU and GU.
Intense research is currently focused on the development of proton pump inhibitors (PPIs) primarily for the treatment and prevention of gastroesophageal reflux disease (GERD). The older PPIs omeprazole and lansoprazole are effective in healing GU and DU. Furthermore, both drugs are effective in eradicating HP when given with various antibiotics. Pantoprazole, rabeprazole and esomeprazole are new PPIs, which appear to have comparable therapeutic profile to omeprazole and lansoprazole.
Rebamipide is a new mucosal protective drug, which is effective in healing GU. Polaprezinc and nocloprost are also mucosal protective drugs which, are in clinical development. However, none of these three cytoprotective drugs have been evaluated for their efficacy in eradicating HP when given in combination with antibiotics. Likewise, no published literature exists on the use of these drugs for preventing NSAID-induced ulcers.
With the rapid eradication of HP currently experienced in the developed world, the therapeutic challenge is now directed toward preventing NSAID-associated ulcer. Significant reduction of NSAID-induced ulcers is achieved by using continuous prophylactic anti-ulcer therapy (misoprostol or omeprazole) or by using NSAIDs possessing selective cyclooxygenase-2 (COX-2) inhibitory activity. However, outcome clinical studies are needed to compare the adjuvant anti-ulcer therapies given with COX-1 inhibitors versus the selective COX-2 inhibitors given alone.
A remarkable revolution in the pathophysiology and pharmacology of peptic ulcer disease has been witnessed during the past 25 years. In the 1970's, both GU and DU were common illness affecting about 10 % of the population . Furthermore, GU and DU accounted for significant loss in productivity and decreased quality of life. Prior to 1970's, the medical management of peptic ulcers consisted of prescribing bland diet, milk or cream, antacids and anti-cholinergics, which did not consistently work. However, discoveries made during the last 25 years clarified the cellular mechanisms controlling gastric acid secretion and mucosal defense. Furthermore, the discovery and wide implementation of upper gastrointestinal (GI) endoscopy was also most crucial for the diagnosis and objective documentation of ulcer healing.
The development of effective and well tolerated gastric anti-secretory drugs (histamine (H2) antagonists and PPIs) were major milestones for the treatment and prevention of GU and DU. Likewise, the development of misoprostol, was a major advance for the prevention of gastric and duodenal ulcer induced by NSAIDs. However, the beneficial anti-ulcer actions of these drugs were maintained as long as the gastric anti-secretory or cytoprotective therapies were continued. Moreover, ulcer recurrences were thought to be part of ulcer natural history. Without continuous anti-ulcer therapy, ulcers recurred in 35-80 % of patients within 6-12 months after healing . The discovery of the important role of HP in the pathogenesis of peptic ulcers led to the development of effective antibiotic combination therapies for its eradication and for curing ulcers in most patients [2,3].
The therapeutic use of NSAIDs represents the second major cause of ulceration [4,5]. Subsequently, the recent discovery and introduction of NSAIDs with high selectively for the inhibition of COX-2 enzyme afforded drugs which are considerably less ulcerogenic than traditional NSAIDs possessing COX-1 inhibitory activity .
Gastric and duodenal ulcers are principally caused by an imbalance between excessive aggressive factors (acid, pepsin, bile and H. pylori) and diminished mucosal defense (mucus, bicarbonate, blood flow and endogenous prostaglandins). The goals of therapy of peptic ulcers are the relief of pain, promotion of healing, prevention of recurrences and curing the disease, whenever possible. Treatment of peptic ulcers consisted of reducing aggressive factors and/or increasing defensive factors affecting the mucosa.
Prior to the discovery of the role of HP in the pathogenesis of GU and DU, ulcers were effectively treated either with selective inhibitors of gastric acid secretion (H2 receptor antagonists or PPIs) or with cytoprotective drugs (sucralfate or misoprostol). Unfortunately, such ulcers always recurred following stopping the gastric anti-secretory or cytoprotective drugs as discussed below.
Overwhelming evidence supports a casual relationship between HP infection and the development of gastric and duodenal ulcers [7,8]. H. pylori infection disturbs the gastric mucus gel and causes injury to the gastroduodenal mucosa through the production of ureases, cytotoxins, proteases, adhesins, and/or phopholipids [9,10]. Furthermore, HP incites an intense immune response, which also contribute to this injury . Several studies indicate that 95 % of patients with DU and 80 % of patients with GU are infected with HP [12,13]. The most convincing evidence for a casual association between H. pylori and peptic ulcer disease is derived from studying ulcer recurrence rates in patients treated with antibiotics effective for eradicating HP. Compared with patients whose ulcers were healed by H2 antagonists, the patients in whom HP was eradicated by antibiotics showed much lower rate of duodenal ulcer recurrence [14-17]. The median ulcer recurrence rates were 70% in patients with persistent HP infection and 0-22% in patients whose infection with HP had been eradicated.
Several antibiotic therapeutic regimens were studied with varying results for HP eradication. Effective regimens include quadruple therapy consisting of a bismuth preparation, an anti-secretory drug (PPI or H2 antagonist) and two antibiotics (tetracycline and metronidazole) administered for 14 days. In addition, a triple therapy consisting of a PPI or H2 antagonist plus clarithromycin and amoxycillin given for 14 days provides the best results for eradication . Triple and quadruple drug regimens are more likely to eradicate HP and less likely to generate resistant strains among surviving organisms [16-17]. Graham et al  provides excellent review of drug regimens for HP eradication particularly with regard to specific antibiotics, dosages, treatment duration and posttreatment follow-up.
With the introduction of effective antibiotic regimens in the 1990's, the incidence of GU and DU is now much reduced in clinical practice. Unfortunately, there are no well-documented epidemiological studies examining the prevalence of peptic ulcers in the post H. pylori era.
Nonsteroidal anti-inflammatory drugs are the most widely used analgesic and anti-inflammatory agents throughout the world. However, it is also well established that the use of NSAIDs increases the vulnerability of the GI mucosa for the development of peptic lesions (erosions, inflammation and ulceration) and serious ulcer complications (bleeding and perforation). In fact, in the United States alone, a total of 16,500 patients with rheumatoid arthritis or osteoarthritis died during 1997 from the GI toxicity of NSAIDs . Of interest is the observation that NSAIDs are associated with a higher frequency of injury to the stomach than the duodenum and this observation has major therapeutic implication [4, 19]. NSAIDs inhibit duodenal mucosal bicarbonate and mucus secretion and reduce mucosal blood flow as a consequence of their inhibitory effects on the biosynthesis of endogenous prostaglandins . NSAIDs also prevent the increase in cell replication at the ulcer margins, an action that has obvious effects on mucosal repair and ulcer healing .
The mechanism of GI injury by NSAIDs has both topical and systemic components . Topical mucosal injury usually occurs after the ingestion of aspirin and other weakly acidic NSAIDs. Weak acids are not ionized in the acid environment of the stomach, freely penetrate the gastric barrier and increase the back diffusion of gastric acid across the mucosa causing further aggravation of the injury. The chronic administration of a prodrug, such as sulindac, produces ulcers, even though its acute topical damaging action on the gastric mucosa is at minimum. Furthermore, enteric-coated preparations of aspirin and other NSAIDs are also ulcerogenic when administered chronically even though such preparations have minimum topical injury following acute administration. The chronic administration of sulindac and enteric-coated preparations is associated with GI ulcerogenic actions. Such lines of evidence suggest that the topical injurious effect of NSAIDs is probably of limited pathophysiologic importance.
The principal mechanism of the GI injury induced by NSAIDs is a consequence of the inhibition of the COX enzymes, which mediate both the efficacy and the GI toxicity of NSAIDs . Recent research has disclosed at least two types of COX enzymes: COX-1 is a constitutive enzyme responsible for housekeeping functions in organs such as the stomach, kidney, intestine and platelets, while COX-2 is an inducible enzyme exerting its action at inflammatory sites of the joints and muscles [20,21]. Such important findings led to the development and subsequent introduction of the selective COX-2 inhibitors celecoxib and rofecoxib, which have considerably reduced GI ulcerogenicity potential when compared with the older, non-selective NSAIDs .
This pharmacological class of drug is currently under extensive investigations by several pharmaceutical companies. Proton pump inhibitors (PPIs) constitute a family of substituted benzimidazoles, which irreversibly inhibit the H+, K+-ATPase enzyme system ("proton pump") located at the apical membrane of the parietal cell. The introduction of omeprazole in the late 1980's was a major therapeutic milestone for the treatment of peptic ulcers. Subsequently, lansoprazole, rabeprazole and pantoprazole were also introduced to human therapeutics [22-27]. Pumaprazole , YJA-20379-8  and esomeprazole  are experimental PPIs currently in clinical development primarily for their potential use in the treatment of GERD. Omeprazole is a racemic mixture of two optical isomers, S-omeprazole (esomeprazole) and R-omeprazole.
At neutral pH, omeprazole and lansoprazole are lipid soluble weak bases that are devoid of gastric acid inhibitory effect. Following their systemic absorption, the PPIs reach the parietal cell, become protonated (ionized) and therefore become trapped into the parietal cells. The protonated drugs rearrange to form a sulfenic acid and sulfenamide . The sulfenamide reacts covalently with the sulfhydryl group of the H+, K+- ATPase enzyme to inhibit gastric acid secretion. The reactions of the PPIs with the enzyme is permanent, and new H+, K+- ATPase enzyme needs to be formed to allow the resumption of gastric acid secretion. In contrast to omeprazole and lansoprazole, the drug pantoprazole is activated at higher pH but could be less acid stable than other PPIs . Some PPIs are being developed in several pharmaceutical dosage forms including intravenous formulations for use in critically ill patients.
PPIs exhibit prolonged and profound inhibition of gastric acid output (90%) and volume (50% to 60 %) in man. The anti-secretory activity is delayed for a few hours, stabilizes after 3 to 4 days, and lasts 24 hours after therapy is stopped. Older PPIs such as omeprazole and lansoprazole had been shown to heal gastric and duodenal ulcers and to prevent ulcer recurrence when therapy is maintained. However, for patients with history of ulcer recurrence due to HP infection, PPIs are usually administered with antibiotics, which cure ulcer disease in most patients.
Given their potent gastric anti-secretory action, the older PPIs omeprazole and lansoprazole were shown to be effective for the treatment and prevention of GU and DU. The newer PPIs, however, were not extensively studied for the treatment of GU and DU because these drugs were primarily developed for the treatment GERD. However, the salient pharmacology of PPIs for the treatment of GERD, which is well described in the literature, parallels their efficacy for the treatment and prevention of DU and GU. For the treatment of GERD, PPIs are much more effective than H2 receptor antagonists given at dosages effective for healing DU and GU  are. However at higher dosages than that used for the treatment of GU and DU, H2 antagonists provides healing rates of reflux esophagitis comparable to PPIs [33, 34]. PPIs are effective in relieving GERD symptoms, healing erosive esophagitis and maintaining remission. However, no head-to-head comparative trials have yet been conducted to determine major advantages/disadvantages of the new PPIs versus omperazole. Clearly, additional clinical studies are needed to provide information about therapeutics and costs of treatment with various PPIs.
PPIs have also been investigated for the treatment and prevention of NSAID associated ulcers [4,35]. The mechanism of the anti-ulcer action of PPIs against NSAIDs is not fully known but appears to be mediated via their potent gastric anti-secretory action. For example, omeprazole had been found to be significantly more effective than ranitidine for healing and preventing ulcers associated with NSAIDs . Studies comparing omeprazole to misoprostol or ranitidine in true NSAID ulcer have shown that omeprazole is equal to full-dose misoprostol for ulcer healing and to the lowest useful dose of misoprostol for ulcer prevention [37-38]. In contrast with misoprostol, which produces transient diarrhea in patients, omeprazole is much better tolerated. Available clinical data do not support the use of H2 antagonists for NSAID ulcer healing or prevention . In preliminary studies published as abstracts, lansoprazole has also been found effective for the prevention of NSAID associated ulcer. Currently, there are no published studies examining the efficacy of the newer PPIs for the prevention of NSAID-induced ulcers. However, most of the clinical studies with omeprazole for the prevention of NSAID-induced ulcers did not examine its relative efficacy against GU and DU associated with NSAIDs. In the United States, misoprostol is the only drug approved for the prevention of NSAID-induced ulcers. Clearly, additional studies are needed to address the anti-ulcer action of PPIs against both GU and DU associated with NSAIDs. Furthermore, the therapeutic efficacy of PPIs has not been determined with respect to the reduction of serious GI complications associated with NSAIDs. Unlike PPIs, misoprostol has been shown to significantly reduce the serious upper GI complications in arthritic patients who were receiving continuous NSAIDs [39,40]. Therefore, we must await the conduct of outcome studies with PPIs in order to determine their effectiveness or cost-effectiveness for the treatment and prevention of NSAID-induced GU and DU in comparison with established adjuvant therapy with misoprostol. Furthermore, outcome studies are also needed to determine the cost effectiveness of adjuvant anti-ulcer therapies versus highly selective COX-2 antagonists.
PPIs are generally well tolerated; diarrhea and headaches are the most common adverse reactions occurring in 5% of the patients [41,42]. All PPIs share many similar pharmacokinetics features following oral administration of single dose [43,44]. With multiple dosing, rabeprazole differs from omeprazole and esomepdrazole in that its pharmacokinetics profile does not change significantly over the course of the therapy [30,45]. All PPIs are metabolized by hepatic cytochrome P450 pathway and may affect the metabolism of some drugs such as warfarin, theophylline, diazepam and phenytoin. Omeprazole inhibits the metabolism of warfarin, diazepam and phenytoin. Lansoprazole induces the metabolism of theophylline. Both rabeprazole and pantoprazole do not appear to interact with cytochrome P450 system. All PPIs raise gastric pH and may thus impair the absorption of weak acids, weak bases and the pH dependent controlled released formulations of some drugs. Because of their potent gastric anti-secretory effects, all PPIs could interfere with the absorption of digoxin and ketoconazole . However, the extent of drug interactions with PPIs appears to be of minimum clinical importance . Although minor differences exist in the metabolisms of PPIs in patients with moderate renal and hepatic disease, no dosage adjustment is required in these special populations.
Although short-term administration of PPIs has an acceptable risk-to-benefit ratio, their lifelong use, which is especially needed for the management of GERD, is subject to debate. Clearly, one of the early and major therapeutic concerns associated with long-term use of PPIs is their potential for inducing hypergastrinemia and enterochromaffin-like (ECL) cell hyperplasia. However, no carcinoid tumors have been observed in man [41,42]. In addition, the potential for altered microbial flora by PPIs, resulting from their potent acid inhibition, had not been widely manifested during their therapeutic use.
Given the comparable therapeutic and safety profiles of PPIs, it would be difficult to recommend a particular drug over another on therapeutic ground. However, the acquisition costs of the PPIs vary nationally and internationally and this could be a critical factor in formulary inclusion decisions . In addition, some PPIs have parenteral dosage forms, which may be useful for the prevention of stress ulcer in critically ill patients and for the treatment of complicated ulcers and upper GI bleeding . However, none of the PPIs currently marketed in the United States are approved for the treatment of upper GI bleeding and stress ulcers. Clearly, additional studies are needed to establish their role for the prevention of stress ulcers and for the treatment of upper GI bleeding.
To promote patient compliance for H. pylori eradication, several fixed drug combinations became commercially available worldwide in convenient, easy to use packages. The packages usually contain antibiotics and detailed instructions to the patients. For example, Helidac presents a combination of bismuth subsalicylate, metronidazole and tetracycline. Helidac is usually prescribed with an H2 antagonist or a PPI for the relief of dyspeptic pain and for promoting ulcer healing. Ranitidine bismuth citrate (Tritec) is a novel drug specifically developed for the treatment of H. pylori associated ulcer and is usually prescribed in combination with clarithromycin and amoxicillin. In the stomach, ranitidine bismuth citrate hydrolyzes to form bismuth citrate and ranitidine hydrochloride. Similarly, Prevac is a fixed combination of lansoprazole, clarithromycin and amoxicillin for the treatment of HP infection. All such drug combinations provide convenience and low cost in the United States. However in other countries, such fixed drug combinations may cost more than generic equivalent of the individual drugs.
Several interesting mucosal protective drugs were in active clinical development in the 1990's. However, interest in developing these drugs had greatly diminished, as the role of HP in the pathogenesis of gastric and duodenal ulcers had become evident. In addition, the development of effective therapeutic regimen for the eradication of HP had decreased the incidence of both GU and DU in clinical practice in developed countries, which clearly decreased the interest for developing these drugs. Furthermore, it is not known at this time whether these mucosal protective drugs are being considered for development for the prevention and treatment of NSAID associated ulcer or complications of GU and DU. Furthermore, not much literature exists on rebamipide, polaprezinc and nocloprost during the last two years. Listed below is a brief discussion regarding these novel mucosal protective drugs.
Rebamipide (2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl)] proprionic acid; Mucosta) is a drug, which stimulates the generation of endogenous prostaglandins in the gastric mucosa and improve the speed and the quality of ulcer healing . In animals, rebamipide protects the gastric mucosa against injury induced by noxious and ulcerogenic factors. Furthermore, rebamipide may also enhance the eradication of HP infection in man using standard eradication therapy . Rebamipide has been approved in Japan and Korea for the treatment of gastric ulcer and gastritis.
Polaprezinc [N-(3-aminopropionyl)-L-histadinazinc] is a chelate compound consisting of zinc ion and L-carnosine, which is being developed in Japan. Polaprezinc has been shown to prevent and heal gastric lesions in various animal models [49,50]. Its mechanism of action is not totally known, but it had been shown to stimulate mucus production and to maintain the integrity of the gastric mucosal barrier .
Nocloprost is a stable prostaglandin E2 derivative with gastroprotective and ulcer healing properties. Nocloprost was superior to ranitidine for healing chronic gastric ulcer following 4 weeks of therapy . The beneficial effect of nocloprost on ulcer healing is partly mediated via the release of epidermal growth factor (EGF). Patients treated with nocloprost had significantly higher EGF output in saliva and higher EGF concentration in plasma throughout the anti-ulcer therapy . Growth factors, especially EGF and transforming growth factor-alpha (TGF alpha) are crucial in the reconstruction of the damaged mucosal structures.
With effective HP eradication, gastric and duodenal ulcers are rapidly disappearing and would soon become historical diseases . Active drug development is currently focused on the identification of new PPIs primarily for the treatment of GERD. All PPIs have comparable pharmacology and efficacy and it is difficult choose among them based strictly on therapeutic consideration. Clearly, head-to-head comparative clinical studies of all new PPIs are needed to determine advantages and disadvantages versus omeprazole. In the post HP era, H2 receptor antagonists are now available, over-the-counter, in many countries, as self-medication for the treatment of heartburn rather than for their previous widespread use as a primary treatment for GU and DU.
The mucosal protective drugs rebamipide, polaprezinc and nocloprost, which had showed good prospect for the treatment of GU and DU, have neither been studied in combination with antibiotic therapy for HP eradication nor investigated for their action, if any, towards preventing NSAID-associated ulcers.
Misoprostol and omeprazole are effective for the treatment and prevention of NSAID-induced ulcers. Omeprazole appears to have a better GI tolerance than misoprostol, however, specific clinical investigations are needed to define the role of PPIs for the treatment and prevention of GU and DU associated with NSAIDs. The availability of the selective COX-2 inhibitors (celecoxib and rofecoxib) would lessen the need for prescribing prophylactic anti-ulcer therapies for patients requiring the chronic use of NSAIDs. The selective COX-2 inhibitors are associated much reduced upper GI ulcerogenicity potential than the traditional COX-1 NSAIDs However, no outcome studies have yet been performed with selective COX-2 inhibitors similar to the MUCOSA study performed with misoprostol . Furthermore, we do not know whether an adjuvant anti-ulcer therapy with either misoprostol or PPIs has advantage of disadvantages versus the selective COX-2 inhibitors administered alone. Clearly, additional prospective clinical studies are needed to address these unresolved questions.
Considerable advance has recently been made in understanding the pathophysiology and therapeutics of GU and DU. Gastric antisecretory and mucosal protective drugs are effective in healing ulcers but not in curing this disease. The eradication of HP essentially eliminated one of the principal causes of ulcers. The major therapeutic challenge today is the elimination of NSAID-associated ulcers. The development of prophylactic anti-ulcer therapies and the recent introduction of selective COX-2 were major advances against NSAID-induced ulcers. Intense drug development activities are currently focused on the development of new PPIs primarily for the treatment of GERD.
Papers of special note have been highlighted as: * Of interest ** Of Considerable interest
Dr. Esam Z. Dajani, Ph.D., FACG has over 30 years of experience in Pharmaceutical Research & Development with expertise in Clinical Pharmacology, Toxicology, Drug Development, Regulatory Affairs, Pharmaceutical Patents and Contract Research Organizations (CROs). Dr. Dajani has directed worldwide clinical research at major pharmaceutical companies and led the research teams that discovered & developed misoprostol (Cytotec), a worldwide anti- ulcer drug. He has 10 pharmaceutical patents. He is a licensed Pharmacist.
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