Novel therapeutic approaches to gastric and duodenal ulcers: an update

Over the last 25 years, a remarkable revolution in the pathophysiology and treatment of gastric and duodenal ulcers has occurred. Effective therapies were developed not only to heal ulcers, but also to cure most patients. The two principal causes for gastric and duodenal ulcers are either infection with Helicobacter pylori or the use of non-steroidal anti-inflammatory drugs (NSAIDs). With H. pylori eradication, gastric and duodenal ulcers 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 gastric and duodenal ulcers. Intense research is currently focused on the development of proton pump inhibitors primarily for the treatment and prevention of gastroesophageal reflux disease. The older proton pump inhibitors, omeprazole and lansoprazole, are effective in healing gastric and duodenal ulcers. Furthermore, both drugs are effective in eradicating H. pylori when given with various antibiotics. Pantoprazole, rabeprazole and esomeprazole are new proton pump inhibitors, which appear to have comparable therapeutic profiles with omeprazole and lansoprazole. Rebamipide is a new mucosal protective drug, which is effective in healing gastric ulcers. 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 H. pylori 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 H. pylori currently happening 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 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.     

Novel therapeutic approaches to gastric and duodenal ulcers: an update

Over the last 25 years, a remarkable revolution in the pathophysiology and treatment of gastric and duodenal ulcers has occurred. Effective therapies were developed not only to heal ulcers, but also to cure most patients. The two principal causes for gastric and duodenal ulcers are either infection with Helicobacter pylori or the use of non-steroidal anti-inflammatory drugs (NSAIDs). With H. pylori eradication, gastric and duodenal ulcers 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 gastric and duodenal ulcers. Intense research is currently focused on the development of proton pump inhibitors primarily for the treatment and prevention of gastroesophageal reflux disease. The older proton pump inhibitors, omeprazole and lansoprazole, are effective in healing gastric and duodenal ulcers. Furthermore, both drugs are effective in eradicating H. pylori when given with various antibiotics. Pantoprazole, rabeprazole and esomeprazole are new proton pump inhibitors, which appear to have comparable therapeutic profiles with omeprazole and lansoprazole. Rebamipide is a new mucosal protective drug, which is effective in healing gastric ulcers. 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 H. pylori 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 H. pylori currently happening 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 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.     

Prophylaxis and treatment of NSAID-induced gastroduodenal disorders.

A significant percentage of patients taking nonsteroidal anti-inflammatory drugs (NSAIDs) experience some type of adverse gastrointestinal symptoms, lesions of the gastroduodenal tract being clinically the most relevant. NSAIDs cause gastrointestinal damage by 2 independent mechanisms: a topical effect, which is pH and pKa related, and a systemic effect mediated by cyclooxygenase (COX) inhibition with a reduction in prostaglandin synthesis. Using endoscopy, gastroduodenal lesions identified include subepithelial haemorrhages, erosions and ulcers. The prevalence of ulceration in NSAID users has been reported as being between 14 and 31% with a 2-fold higher frequency of gastric ulcers compared with duodenal ulcers. Among the strategies used to decrease the risk of ulcer development are: (i) the use of analgesics other than NSAIDs; (ii) use of the lowest possible dosage of NSAID; (iii) the use of a COX-2 selective NSAID; (iv) the use of low doses of corticosteroids instead of NSAIDs; (v) avoidance of concomitant use of NSAIDs and corticosteroids; and (vi) use of preventive therapy. In an attempt to reduce the incidence of NSAID-induced gastrointestinal lesions, the following approaches have been proposed: (i) use of the prostaglandin analogue misoprostol, which is an antiulcer drug which has been proven to be as effective in the prevention of NSAID-induced gastric and duodenal ulcers as in the reduction of serious upper gastrointestinal complications; (ii) histamine H2 receptor antagonists (H2 antagonists), e.g. ranitidine, cimetidine and famotidine, which are useful in the prevention of NSAID-induced duodenal ulcers during long term treatment, but not in the prevention of NSAID-induced gastric ulcers; (iii) proton pump inhibitors, e.g omeprazole, and pantoprazole, whose efficacy in preventing NSAID-associated ulcers has been recently demonstrated; and (iv) barrier agents, e.g. sucralfate, which cannot be recommended as prophylactic agents to prevent NSAID-induced gastropathy. The first step in the treatment of NSAID-associated ulcers lies in a reduction in the dosage of the NSAID or discontinuation of the drug. If NSAID treatment cannot be withdrawn, a proton pump inhibitor appears to be the most effective treatment in healing ulcers, accelerating the slow healing observed with H2 antagonists.     

Is eradication sufficient to heal gastric ulcers in patients infected with Helicobacter pylori? A randomized,controlled, prospective study

BACKGROUND: In Helicobacter pylori infection, the effect of short-term triple therapy with proton pump inhibitor plus two antibiotics on gastric ulcer healing is not well known. AIM: To compare 1-week triple therapy with 8-week proton pump inhibitor therapy on gastric ulcer healing in infected patients. PATIENTS AND METHODS: We randomly assigned 120 patients with H. pylori and gastric ulcers to proton pump inhibitor plus amoxicillin and clarithromycin for 1 week (n = 61) or proton pump inhibitor alone for 8 weeks (n = 59), with endoscopic assessment of ulcer healing 8 weeks after the start of treatment. RESULTS: Triple therapy eradicated H. pylori in 51 patients [intention-to-treat, 84%; 95% confidence interval (CI), 75-93%]. At 8 weeks, gastric ulcers were healed in 30 patients given triple therapy (49%; 95% CI, 37-62%) and in 49 patients given proton pump inhibitor (83%; 95% CI, 73-93%, P < 0.001). Healing rates in the triple therapy and proton pump inhibitor-only groups were 89% and 100%, respectively, for ulcers of < 1.0 cm in diameter, 54% and 77% for ulcers of 1.0 to < 1.5 cm in diameter, and 5% and 77% (P < 0.001) for ulcers of > or = 1.5 cm in diameter. CONCLUSIONS: One-week triple therapy healed most ulcers of < 1.0 cm, but not ulcers of > or = 1.5 cm. Short-term therapy is effective for gastric ulcers of < 1.0 cm, but, for larger ulcers, follow-up therapy to suppress acid is needed.     

NSAID-induced peptic ulcers and Helicobacter pylori infection: implications for patient management.

The conflicting data about the influence of Helicobacter pylori infection on the ulcer risk in patients receiving NSAIDs can be accounted for by the heterogeneity of study designs and the diversified host response to H. pylori. Factors that will affect the outcome include the choice of H. pylori diagnostic tests, previous ulcer complications, concurrent use of acid suppressants, NSAID-naive versus long-term users, low-dose aspirin (acetylsalicylic acid) versus non-aspirin NSAIDs and whether the result was derived from a pre-specified endpoint or post hoc subgroup analysis. Current evidence suggests that H. pylori eradication reduces the ulcer risk for patients who are about to start receiving NSAIDs but not for those who are already on long-term NSAID therapy. Since treatment with a proton pump inhibitor (PPI) worsens H. pylori-associated corpus gastritis, H. pylori should be tested for, and eradicated if present, before starting long-term prophylaxis with PPIs. Patients with H. pylori infection and a history of ulcer complications who require NSAIDs should receive concomitant PPIs or misoprostol after curing the infection. Among patients receiving low-dose aspirin, who have H. pylori infection and previous ulcer complications, long-term treatment with a PPI further reduces the risk of complicated ulcers if H. pylori eradication fails or if patients use concomitant non-aspirin NSAIDs. Current data on the gastric safety of COX-2 selective NSAIDs in H. pylori-infected patients are conflicting. Limited data suggest that the gastroduodenal sparing effect of rofecoxib is negated by H. pylori infection in patients who have had prior upper gastrointestinal events. In light of potential cardiovascular risk with COX-2 selective NSAIDs, it is important to weigh the potential adverse effects against the benefits for an individual patient.     

COX-2 inhibitors vs. NSAIDs in gastrointestinal damage and prevention

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit production of protective gastric mucosal prostaglandins and also have a direct topical irritant effect. In some patients this results in dyspepsia and development of gastroduodenal erosions and ulceration. The risk of ulcer complications, such as bleeding, perforation and death is increased approximately 4-fold in NSAID users. Patients at high risk of ulcer complications include the elderly, those taking anticoagulants, steroids and aspirin, those with a previous history of peptic ulceration and patients with concomitant serious medical problems. The interaction of NSAIDs with Helicobacter pylori (the major cause of peptic ulceration in non-NSAID users) is controversial and some studies suggest that H. pylori infection may even protect against NSAID-induced ulceration. Selective inhibitors of the inducible cyclooxygenase-2 (COX-2) enzyme spare COX-1 in the gastric mucosa and, hence, do not inhibit production of mucosal prostaglandins. COX-2-selective inhibitors are associated with a significant reduction in gastroduodenal damage compared with traditional NSAIDs. Proton pump inhibitors (PPI) are probably the best agents for healing and prevention of NSAID-induced ulcers. Preliminary studies suggest that COX-2 selective inhibitors, like traditional NSAIDs, may prevent lower gastrointestinal cancer. Further studies are needed but they may be useful in individuals at high risk of certain types of lower gastrointestinal malignancy with increased gastrointestinal tolerability and safety.     

Should NSAID/low‐dose aspirin takers be tested routinely for H. pylori infection and treated if positive? Implications for primary risk of ulcer and ulcer relapse after initial healing

Helicobacter pylori infection and the use of nonsteroidal anti-inflammatory drugs (NSAIDs) can each result in gastric or duodenal ulcer(s) and ulcer complications. Together, H. pylori infection and NSAIDs account for approximately 90% of peptic ulcer disease. In 2003, the results of studies suggest, and guidelines recommend, the careful selection of anti-inflammatory drugs - NSAIDs or selective COX-2 inhibitors (coxibs) based upon patients gastrointestinal history and use of aspirin therapy. Testing for, and cure of, H. pylori infection is recommended in patients prior to the initiation of NSAID therapy and in those who are currently receiving NSAIDs and have a history of dyspepsia, peptic ulcer or ulcer complications. For patients who present with peptic ulcer bleeding but require NSAIDs long-term, H. pylori eradication therapy should be considered, followed by continuous proton pump inhibitor prophylaxis to prevent re-bleeding, regardless of which kind of NSAID (nonselective NSAID /coxib) is being prescribed. Routine testing for, and eradication of, H. pylori infection has not been recommended for current takers of NSAIDs with no or low risk of complications. The management of patients taking low-dose aspirin is complex, but eradication of H. pylori infection alone in those with a past history of bleeding does not guarantee complete protection and therefore a proton pump inhibitor should also be given. The success of eradication therapy should always be confirmed, because of the risk of ulcer recurrence and bleeding in H. pylori-infected patients who require anti-inflammatory treatments.     

Influence of nonsteroidal anti-inflammatory drugs on the antiplatelet effects of aspirin in rats

Low-dose aspirin acts by irreversibly acetylating internal cyclooxygenase-1 (COX-1) on platelets, thereby suppressing platelet aggregation. Because nonsteroidal anti-inflammatory drugs (NSAIDs) also inhibit COX-1, the antiplatelet effects of aspirin may be suppressed when it is co-administered with NSAIDs. In this study, the influences of ibuprofen, loxoprofen sodium and etodolac on the antiplatelet effects of aspirin were investigated in male Sprague-Dawley (SD) rats. Aspirin and/or NSAIDs were administered orally at single or multiple daily doses. Platelet aggregation (ADP and collagen were added as stimuli) and serum thromboxane B(2) (TXB(2)) concentrations were measured. The maximum inhibitions of aggregation in the aspirin before ibuprofen group were 41.0±7.8% for ADP and 38.7±5.4% for collagen at 6 h after administration; similar values were seen in the aspirin group; however, percent inhibitions in the aspirin before ibuprofen multiple administration group were lower than those in the aspirin group. Thus, the inhibitory effects of daily low-dose aspirin on platelets are competitively inhibited by the prolonged use of multiple daily doses of ibuprofen. In contrast, serum TXB(2) concentrations in all groups were lower than those in the control group (drug-free). This suggests that the relationship between the inhibition of platelet COX-1 and the suppression of platelet aggregation is nonlinear. When aspirin was administered with loxoprofen sodium, similar effects were observed; however, with etodolac, the antiplatelet effects in all groups were equal to those in the aspirin group. Accordingly, if co-administration with NSAIDs is necessary with low-dose aspirin, a selective COX-2 inhibitor, such as etodolac, should be used.     

Prevention of nonsteroidal anti-inflammatory drug–associated gastrointestinal symptoms and ulcer complications

Nonsteroidal anti-inflammatory drugs (NSAIDs) produce symptoms of dyspepsia and peptic ulcer disease in up to 50% and up to 20%, respectively, of individuals taking them. Risk factors for NSAID-related gastric injury include age >70 years, history of ulcer disease, use of multiple agents (e.g., ≥2 NSAIDs, or an NSAID plus aspirin—even at cardioprotective doses), high doses of an NSAID, and concurrent use of corticosteroids or anticoagulants. In NSAID users, infection with Helicobacter pylori can produce additive or synergistic gastric mucosal injury. Several clinical strategies can decrease the risk for dyspepsia, ulceration, and the more serious complications in NSAID users. Proton pump inhibitor (PPI) co-therapy has been shown to lower the incidence of dyspepsia in those taking NSAIDs. In those with an active ulcer, PPI therapy produces ulcer healing even in “tough-to-treat” individuals who require ongoing NSAID therapy. Maintenance of ulcer healing is significantly greater in those who receive ongoing PPI treatment compared with placebo, and adverse events and treatment withdrawals are fewer compared with their occurrence in persons treated with misoprostol. In those not receiving aspirin therapy, the use of an NSAID that is a selective inhibitor of cyclooxygenase (COX)-2 may result in fewer gastrointestinal symptoms compared with a traditional agent; however, studies have failed to show any decrease in healthcare resource utilization (including outpatient or emergency room visits, hospitalization rate, or use of any resource) with COX-2–selective therapy.     

Impaired gastric ulcer healing in diabetic rats: role of heat shock protein, growth factors, prostaglandins and proinflammatory cytokines

Gastric mucosa of diabetic rats is highly vulnerable to acute injury, but little is known about the influence of diabetic conditions on the healing of gastric ulcers. In this study, streptozotocin (70 mg/kg injected intraperitoneally) was used to induce diabetes mellitus in rats. Four weeks after streptozotocin injection, gastric ulcers were induced using the acetic acid method, and 10 days later, the healing rate and the gastric blood flow (GBF) were measured by planimetry and hydrogen (H(2))-gas clearance method, respectively. Six major groups of rats with gastric ulcers were used: (1) vehicle (saline); (2) streptozotocin alone; (3) insulin (4 IU/day intraperitoneally); (4) streptozotocin plus insulin; (5) pentoxifylline, an inhibitor of synthesis and release of tumor necrosis factor-alpha (TNF alpha); and (6) aspirin, a non-selective inhibitor of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), and rofecoxib, the highly selective COX-2. In the diabetic rats, a significant delay in ulcer healing ( approximately by 300%), accompanied by a decrease in the gastric mucosal blood flow was observed. The prolongation of the healing in diabetic animals was associated with an increase in gastric mucosal expression and release of TNFalpha, interleukin-1 beta (IL-1 beta), suppression of the vascular endothelial growth factor (VEGF), platelet endothelial cell adhesion molecule-1 (PECAM-1) and the mucosal overexpression of heat shock protein 70 (HSP 70). Administration of insulin reversed the delay in ulcer healing and significantly decreased the expression of IL-1 beta and TNF-alpha, while producing the rise in the expression of VEGF and PECAM. Pentoxifylline, an inhibitor of TNF-alpha, which by itself accelerated ulcer healing in non-diabetic rats, counteracted the increase in the area of gastric ulcer induced by streptozotocin, raised significantly gastric blood flow and suppressed the plasma TNF-alpha levels. Aspirin and rofecoxib, that significantly suppressed the mucosal prostaglandin E(2) generation in ulcer area, delayed significantly the rate of ulcer healing and decreased the GBF at ulcer margin in non-diabetic rats, and these changes were significantly augmented in diabetic animals. We conclude that: (1) Experimental diabetes dramatically impairs ulcer healing, depending upon the increased release of proinflammatory cytokines and the attenuation of angiogenesis that can limit the ulcer healing effects of locally produced HSP 70 and TNF-alpha. (2) Insulin reversed this impairment of ulcer healing in diabetic rats, mainly due to the enhancement of angiogenesis and reduction in expression of cytokines in the ulcer area. (3) Classic non-steroidal anti-inflammatory drugs such as aspirin prolonged ulcer healing under diabetic conditions due to suppression of endogenous prostaglandins and the fall in the microcirculation at the ulcer margin and these effects were mimicked by selective, so called "safe" COX-2 inhibitor, rofecoxib, suggesting that both COX isoforms are important sources of prostaglandins that are essential in the ulcer healing in diabetes.     

Therapeutic management of recurrent peptic ulcer disease

The epidemiology of peptic ulcer disease (PUD) has undergone significant changes since the discovery of Helicobacter pylori. Various aetiologies contribute to recurrent PUD. Ulcers related to untreated H. pylori infection tend to recur. Use of NSAIDs, low-dose aspirin and dual anti-platelet therapy have become important risk factors for recurrent ulcers and their complications as the proportion of H. pylori-related ulcers declines. Recent data have shown that H. pylori-negative, NSAID-negative idiopathic peptic ulcers are on the rise and carry a higher risk of recurrent ulcer bleeding and mortality. Effective management of recurrent PUD relies on identification and modification of treatable risk factors. Persistent H. pylori infection should be carefully ruled out. Choice of an effective H. pylori eradication regimen should be based on local antibacterial resistance patterns. For patients who need long-term NSAID therapy, the initial choice of an NSAID relates to a patient's cardiovascular risk, and the need for therapy to decrease gastrointestinal (GI) complications is determined by the severity and number of GI risk factors. For patients on dual anti-platelet therapy, strategies to prevent recurrent ulcer disease and its complications centre on balancing the bleeding and thrombotic risks of individual patients. Long-term proton pump inhibitor maintenance therapy may be necessary to prevent recurrent ulcer bleeding for patients with ulcer bleeding from H. pylori-negative, NSAID-negative ulcers, and for patients who require NSAID or aspirin maintenance therapy.     

Surface phospholipids in gastric injury and protection when a selective cyclooxygenase-2 inhibitor (Coxib) is used in combination with aspirin

BACKGROUND AND PURPOSE: Clinical studies demonstrate that aspirin consumption reverses the gastrointestinal (GI) benefits of coxibs, by an undefined mechanism. EXPERIMENTAL APPROACH: Rodent models were employed to investigate the effects of combinations of celecoxib and aspirin on gastric ulcerogenesis, bleeding, surface hydrophobicity (by contact angle analysis) and ulcer healing. We also evaluated the effects of phosphatidylcholine (PC)-associated aspirin in these rodent models and confirmed its cyclooxygenase (COX)-inhibitory activity by measuring mucosal prostaglandin E(2) (PGE(2)) concentration. We present evidence that aspirin's ability to induce gastric injury and bleeding in rats, was exacerbated in the presence of a coxib and was dependent on its ability to reduce gastric surface hydrophobicity. In contrast, co-administration of phosphatidylcholine (PC)-associated aspirin and celecoxib induced little or no gastric injury/bleeding and maintained the stomach's hydrophobic properties. Interestingly, aspirin and aspirin/PC equally inhibited gastric mucosal PGE(2) concentration. Aspirin in combination with a coxib retarded the healing of experimentally induced gastric ulcers, whereas healing rates of rats treated with celecoxib in combination with aspirin/PC were comparable to controls. CONCLUSIONS AND IMPLICATIONS: Aspirin's gastric toxicity in combination with a coxib can be dissociated from its ability to inhibit COX-1 and appears to be dependent, in part, on its ability to attenuate the stomach's surface hydrophobic barrier. This adverse drug interaction between aspirin and coxibs, which impacts the treatment of osteoarthritic and cardiac patients requiring cardiovascular prophylaxis, can be circumvented by the administration of phosphatidylcholine (PC)-associated aspirin, to maintain the stomach's hydrophobic properties.     

Omeprazole in the treatment of peptic ulcers resistant to H2-receptor antagonist

Thirty patients with peptic ulcers resistant to at least 8 weeks of continuous therapy with full-dose H2-receptor antagonists alone or followed by other anti-ulcer drugs, were treated with the gastric proton pump inhibitor omeprazole (40 mg), administered orally once daily for up to 8 weeks. The study design was non-comparative and open; healing was verified by endoscopy. After only 2 weeks of treatment, 21 out of 23 (91%) duodenal ulcer patients were healed, as well as 2 out of 2 patients with both duodenal and gastric ulcer and 1 out of 3 patients with prepyloric ulcer. After 4 weeks, all duodenal ulcers, 1 out of 2 gastric ulcers and 2 out of 3 pre-pyloric ulcers were healed. A further month of therapy healed the gastric ulcer to give an overall healing rate of 97% and leaving only one patient (pre-pyloric ulcer) unhealed at the end of the study. Of 19 patients suffering ulcer symptoms at entry, only two patients reported any symptoms at 2 weeks and one of these (who remained unhealed) continued to have symptoms throughout the study. One patient reported mild asthenia; otherwise, no clinical or biochemical side-effects were recorded. It is concluded that omeprazole is highly effective in healing refractory peptic ulcers.     

Effect of omeprazole on delayed healing of acetic acid-induced gastric ulcers in rats

Omeprazole, a gastric mucosal proton pump inhibitor, significantly and dose-dependently prevented the delayed healing of acetic acid-induced gastric ulcers in response to repeatedly administered indomethacin to rats. Both basal and histamine-stimulated gastric acid secretions in rats with acetic acid-induced ulcers that were given indomethacin were markedly and persistently (greater than 24 hr) inhibited after 4 weeks treatment with omeprazole. The prevention of delayed ulcer healing by omeprazole appears to be due to its long-lasting antisecretory activity.