Adverse effects of conventional non-steroidal anti-inflammatory drugs on the upper gastrointestinal tract

This article reviews the clinical and epidemiological features of conventional non-steroidal anti-inflammatory drug (NSAID) related peptic ulcer complications, and the associated risk factors. The degree of gastrointestinal toxicity varies widely between the available drugs and with dose of each. The risk of ulcer complications can however be reduced, and perhaps completely removed, by using the lowest dose of the least toxic member of the class. Enteric coating and other delayed release formulations have not been shown to reduce risk. Estimates of the imposed disease burden have varied widely, in part through assuming that risks in selected patient groups will necessarily translate to the general population. Nevertheless, the imposed disease burden is one of the largest associated with current drug treatment. Associated risk factors such as prior ulcer, corticosteroid use and concurrent aspirin as well as general cardiovascular disease will raise the likelihood of an ulcer complication in NSAID takers and non-takers. Therefore, strategies dependent on substituting COX-selective drugs will then be only partially successful.     

Recombinant factor VIIa use in refractory ulcer bleeding in uremic patient

Peptic ulcer bleeding is thought to be a major cause of bleeding in patients with end-stage renal disease and is more complicated in uremic patients. We described a 41-year-old man with end-stage renal disease who underwent hemodialysis with refractory ulcer bleeding, failure to all traditional peptic ulcer treatments, and correction of uremic component, who has been successfully treated by using recombinant factor VIIa. There have been few case reports in dealing refractory upper gastrointestinal bleeding in uremic patients in the literature; and in this case report, we demonstrates that recombinant factor VIIa could be used as a rescue therapy in these high–surgical risk patients when medical therapy fails.     

Ulcers and gastritis

Significant advances continue to be made in the area of gastritis and ulcer disease. Studies to identify the most appropriate use of capsule endoscopy have now confirmed that it is superior to other methods for identifying small-bowel mucosal pathology and sites of obscure gastrointestinal bleeding. It has increasingly been recognized that the complications of ulcer disease are secondary to the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and to interactions between NSAIDs and Helicobacter pylori. Effective prophylaxis for NSAID ulcers in H. pylori-negative individuals continues to be a challenge, as it has become clear that conclusions from studies focusing on "endoscopic ulcers" in patients whose H. pylori status was unknown provided a false sense of security. The concept of multifocal atrophic gastritis has been challenged. The precursor lesion to gastric cancer now appears to be a sheet of pseudopyloric metaplasia advancing into the gastric body with islands of intestinal metaplasia embedded within it. Multifactorial models such as those proposed for understanding periodontal disease, including the organism, environmental factors, and host factors, appear particularly applicable to understanding the pathogenesis of H. pylori-associated gastric cancer.     

Prostaglandin therapy for peptic ulcer disease

The demonstration of inhibition of acid secretion in man or cytoprotection in animals is not proof of efficacy in clinical disease. Indeed, there has been continued debate up to now as to whether any of our previous standard therapies for peptic ulcer disease did more than alleviate symptoms. The use of the fiberoptic endoscope to locate and measure ulcers precisely and evaluate the progress of ulcer healing may finally allow us to assess the efficacy of new therapy. Several endoscopically controlled studies abroad have found PG analogs to be effective in both gastric and duodenal ulcer disease. Clearly, well-controlled, large clinical trials are needed to assess the efficacy of these compounds when compared to placebo and other modes of therapy. A close watch must be kept to detect the possible development of toxicity or other unwanted effects. We are still at an early stage in the development of the specific PG molecule that will affect only the stomach and duodenum in a favorable way, while having no effect on other tissues. When we come close enough to this goal, a PG may be the drug of choice for peptic ulcer disease in man.     

Medical treatment of peptic ulcer disease.

Our understanding of PUD and its treatment has improved dramatically during the past 15 years. During this time, many new effective drugs have been approved by the FDA, and possibly even more potent and effective therapies are now being evaluated. The H2-blockers, sucralfate, and antacids heal over 90% of duodenal ulcers in 6 to 8 weeks, and H2-blockers heal about 80% of gastric ulcers by 8 weeks and over 90% by 12 weeks. The new, more potent pump blockers (omeprazole) promise to be even more effective drugs, even for the healing of patients who are taking NSAIDS. However, the potential hazards of marked, long-term acid suppression must still be evaluated. Maintenance therapy with H2-blockers or sucralfate, ideally used for patients who would otherwise have frequent symptomatic recurrences of duodenal ulcer disease or who have had complications, reduces the relapses, especially symptomatic relapses. Maintenance therapy with H2-blockers also seems to reduce the recurrences of GUD, but this use has not yet received FDA approval. Elimination of H. pylori infection with antibiotics may prove to reduce recurrent ulcer disease and negate the need for maintenance therapy. Colloidal bismuth subcitrate alone, which suppresses but does not eradicate H. pylori infection, seems to be an effective ulcer drug and may even reduce the rate of early recurrences. Effective ulcer therapy, especially if it prevents recurrent disease, may reduce the complications of PUD, but this expectation has yet to be established. The use of prophylactic cytoprotective prostaglandins (misoprostol) reduces the incidence of NSAID-induced GUD.     

Diet and nutrition in ulcer disease

In this era of H2-inhibitors, the available evidence does not support the need to place peptic ulcer disease patients on restrictive diets. The major goal of diet is to avoid extreme elevations of gastric acid secretion and the direct irritation of gastric mucosa. In view of this, only slight modifications in the patient's usual diet are recommended. Table 1 depicts a sample menu for chronic peptic ulcer disease. Frequent milk ingestion as previously prescribed is not encouraged. This is owing to the transient buffering effect and significant gastric acid secretion effect of milk. The fat content of milk has no influence on these effects. Spices, in particular black pepper, red pepper, and chili powder, may produce dyspepsia. One study shows red chili powder to have no detrimental effect on duodenal ulcer healing. It has also been proposed that daily pepper ingestion may have a beneficial adaptive cytoprotective response. While still controversial and under evaluation, peptic ulcer patients should avoid any spice that causes discomfort, especially during exacerbation of peptic disease. Currently, studies indicate that it is prudent to avoid alcohol. This is especially true for the concentrated forms, such as 40% (80 proof) alcohol. Coffee should be avoided on the basis of its strong acid secretagogue property. Coffee can induce dyspepsia. Whether noncoffee caffeine-containing beverages (tea, soft drinks) induce peptic ulcer is unknown, but they are acid secretion stimulators. Decaffeinated coffee has an acid stimulating effect as well. It is reasonable to have peptic ulcer patients restrict decaffeinated coffee and all caffeine-containing beverages. There appears to be no evidence to restrict dietary fiber. Some fiber-containing foods may possess factors that are protective against ulcer disease. According to the Mayo Clinic Diet Manual, previously recommended small frequent feedings have not been shown to be more effective than three meals per day in the treatment of chronic peptic ulcer disease. This reference cites authorities advising against extra feedings because of increased acid secretion and unnecessary complication of eating patterns. However, some patients claim to be relieved of symptoms with more frequent feedings, especially during acute phases. Citric acid juices may induce reflux and cause discomfort in selective patients. Stomach distention with large quantities of food should be discouraged. Although there is now little role for dietary therapy, one should note that bland and ulcer diets probably are not detrimental to most persons if they are used for a short time and may have some psychological benefit.(ABSTRACT TRUNCATED AT 400 WORDS)     

Future for basic and clinical studies on peptic ulcer disease

Since the discovery of H. pylori, various causes of peptic ulcer disease is reevaluated, and only four factors are now considered most important; H. pylori infection, gastric acid, NSAID administration, and mental and physical stress. Among them, gastric acid is an aggravating factor, and gastric acid alone can hardly develop peptic ulcers. The relationship between H. pylori infection and stress has been studied at Hanshin-Awaji great earthquake occurred in 1995. Immediately after the earthquake, the number of patients with peptic ulcer disease has been greatly increased, and those patients were considered to be typical cases of stress ulcers. Interestingly, however, it was found that 83.2% of the patients were infected with H. pylori. The data suggested that stress ulcer developed in those infected with H. pylori. In contrast, the relationship between H. pylori infection and NSAID in the development of ulcer disease is more complex. It is still unclear whether H. pylori infection is an additive effect for development of peptic ulcer disease by NSAID administration or not.     

Effects of Helicobacter pylori(Hp) eradication on gastric mucosal pathophysiology in Hp-positive, NSAIDs-induced gastric ulcer

It has been suggested that the mechanisms of NSAIDs-induced peptic ulcer disease are totally different from those induced by Hp. Although a number of studies have examined the effects of Hp eradication on pathophysiology of NSAIDs-induced ulcer diseases, the results have been controversial. At present, therefore, we do not know whether Hp should be eradicated in Hp-positive NSAIDs-induced ulcer patients. Recent studies have shown that both Hp eradication and NSAIDs treatment increases gastric acid secretion, and often causes mucosal lesions in upper GI tract. Based on this back ground, we have decided to review pathophysiology of the Hp-dependent ulcer, and the NSAIDs-induced ulcer. We also discussed the merit and demerit of Hp eradication on gastric mucosal pathophysiology in Hp-positive, NSAIDs-induced ulcer.     

Nonsteroidal anti-inflammatory drugs and peptic ulcer disease. An overview

Evidence is accumulating that use of nonsteroidal anti-inflammatory drugs (NSAIDs) is linked to ulceration of the stomach and duodenum and can cause significant, life-threatening ulcer complications. The mechanism of action seems to be both topical damage to the mucosal barrier and the systemic effect of a reduction in levels of mucosal prostaglandins. Patients especially at risk are the elderly, those with concomitant debilitating disease, those with a history of ulcers, and those taking corticosteroids. Histamine2 blockers are reported to significantly reduce the incidence of NSAID-induced duodenal ulcer, and misoprostol (Cytotec) has been shown to significantly reduce the incidence of NSAID-induced gastric ulcer. Prophylaxis with these agents should be considered for high-risk patients who need NSAID therapy to maintain a reasonable life-style.     

Treatment of Helicobacter pylori infection

Helicobacter pylori infection has been shown to be the principal cause of peptic ulcer disease and has been associated with MALT lymphoma and gastric cancer. Eradication of H. pylori has been shown to change the natural history of peptic ulcer disease by preventing relapse and to reduce health care expenditures when compared with traditional therapy. Two-drug regimens have been superceded by three-drug regimens because they are more effective in eradication. Therapies with the highest efficacy are cost-effective because failed eradication is associated with high costs.     

Prevention and treatment of low-dose aspirin induced gastric ulcer in coronary artery disease after coronary intervention

Low-dose aspirin has been increasingly used to prevent cardiovascular and cerebrovascular disease through its antiplatelet effect, mainly in the patients with ischemic heart disease, but aspirin has been associated with gastrointestinal injuries, especially peptic ulcer bleeding. However, discontinuation of aspirin may cause cardiovascular and cerebrovascular events. Therefore, high-risk patients for peptic ulcers should be prevented with anti-secretory drugs, such as proton pump inhibitor of H2-receptor antagonists, because ulcer bleedings in patients with treatment of low-dose aspirin can be serious.     

Long-term management of peptic ulcer disease

Maintenance therapy to reduce the risk of ulcer relapse and subsequent ulcer complications should be offered to patients who are likely to suffer a relapse by virtue of their past history or current risk factors. The most effective form of ulcer maintenance therapy appears to be continuous low-dose nocturnal therapy with H2-receptor antagonists. Patients who are observed expectantly and develop recurrent ulcer symptoms can be treated with full-strength therapy on an intermittent basis. Patients with a definite seasonal trend to their ulcer disease may benefit from a seasonal approach to therapy. Ulcer surgery is reserved for patients with ulcer complications or severe symptoms unresponsive to standard maintenance therapy. Just how long continuous low-dose maintenance therapy can or should be continued remains unclear. Whether ulcer disease is ever truly cured (never to recur again), as suggested by pre-endoscopic studies, is a matter of conjecture. Nevertheless, the use of maintenance-dose therapy appears to be safe over relatively long periods of time, and it appears that cumulative ulcer relapse rates decline with continued use of such therapy. The risk of recurrent symptoms, hemorrhage, and other complications is also reduced by maintenance therapy, and the economic aspects of ulcer disease are influenced in a positive fashion by these regimens. The role that C. pylori will ultimately play in the etiology and pathogenesis of peptic ulcers and their relapse is still not known with any certainty, although it appears to represent an important marker (if not an important pathogenetic cause) for ulcer disease. As such, it may be considered a risk factor to be eliminated.(ABSTRACT TRUNCATED AT 250 WORDS)     

Base line tenting: A sign of duodenal ulcer disease

Indirect signs such as clover-leaf deformity, pseudodiverticulum formation, eccentric location of pyloric channel, and flattening of the fornix are of considerable value in the radiologic detection of an ulcer crater. We have found another indirect sign, base line tenting (BLT) to be very useful in the detection and diagnosis of duodenal ulcer disease. This is characterized by interruption of the base line of the bulb, with 2 associated perpendicular lines extending from the base and converging to a point in the duodenal bulb. After we observed this sign in various patients with peptic ulcer disease, a prospective investigation was performed involving 62 patients with duodenal ulcer disease over a period of 2 years. We found the BLT sign in 52 (83.8%). To date, no false-positive incidence has been identified. We concluded that BLT is a most valuable sign in the radiologic identification of duodenal ulcer disease.     

Aciclovir,herpes viruses and HIV: a never-ending story

Evaluation of: Delany S, Mlaba N, Clayton T et al. Impact of aciclovir on genital and plasma HIV-1 RNA in HSV-2/HIV-1 co-infected women: a randomized placebo-controlled trial in South Africa. AIDS 23, 461–469 (2009).

HIV infection continues to be among the leading causes of morbidity and mortality, especially in Africa. The prevalence of herpes simplex virus type 2 (HSV-2) has already reached high seroprevalence of up to 90% in HIV-seropositive individuals, and HSV-2 is now the leading cause of genital ulcer disease in both developing and developed countries. The role of HSV-2 as a biological cofactor in HIV acquisition and transmission may have contributed substantially to HIV diffusion, also facilitating HIV spread among the low-risk population who have stable long-term sexual partnerships. To date, no vaccine to prevent HSV-2 acquisition or reactivation has been developed, although antivirals have been shown to be safe and effective in reducing HSV-2 shedding frequency and the duration of genital ulcer disease. The paper under evaluation confirms the favorable effect of therapies aimed at suppressing HSV-2 reactivation in HIV-seropositive patients on HIV plasma and vaginal load. In this study, aciclovir 400 mg twice daily was able to significantly reduce plasma and genital HIV RNA, the frequency of HIV shedding, genital HSV-2 DNA and the frequency of genital ulcerations. These results suggest that HSV-2 control with low-cost aciclovir can play an important role in reducing HIV spread, mainly in developing countries, where costs limit the use of highly active antiretroviral therapy.     

Ulcer and gastritis

As in previous years, developments in the field of ulcers and gastritis have been dominated by new findings related to Helicobacter pylori. With the decrease in the frequency of H. pylori infection, the relative proportion of non-H. pylori ulcers has increased. Attempts to reduce the endoscopy workload by H. pylori or CagA screening have not been successful, and are probably ill-advised. It has become increasingly clear that curing H. pylori infection will not automatically lead to complete relief of symptoms in patients with duodenal ulcer disease. Post-therapy confirmation of cure will probably become the norm. Studies comparing omeprazole to misoprostol or ranitidine for nonsteroidal anti-inflammatory drug (NSAID) ulcer prevention in true NSAID ulcers have shown that omeprazole is equal to full-dose misoprostol for ulcer healing and to the lowest useful dose of misoprostol for ulcer prevention. H2-receptor antagonists cannot be recommended for NSAID ulcer healing or prevention. Elimination of H. pylori increases the prevalence of gastroesophageal reflux disease in a population in such a way that superficially, there appears to be a choice between more gastroesophageal reflux disease or multifocal atrophic gastritis. The risk of developing adenocarcinoma of the esophagogastric junction is many times (10-fold to 60-fold) less than the risk of developing gastric cancer from CagA-positive H. pylori infection with multifocal atrophic gastritis - the "protective" lesion.     

From costly treatment to cost-effective prevention: using Waterlow

The Waterlow pressure ulcer risk assessment system has been in use for 20 years. In this article, Judy Waterlow describes how it can be used in the community, discusses the recent update to the system and explains how pressure ulcer risk assessments should be conducted.     

NSAID ulcer (H. pylori, treatment, prevention)

Although it has been reported that NSAID ulcer has been increasing in western countries, the epidemiology and treatment or prevention of this type of peptic ulcer have not been fully studied. Recently 'Guideline for the treatment of gastric ulcer' has been published in Japan. Based on the data described in the guideline, at present it is recommended to use misoprostol, protonpump inhibitor, or high dose of H2 receptor in the prevention of NSAID ulcer. In the treatment of NSAID ulcer, to stop NSAID and/or to use misoprostol or protonpump inhibitor are recommended.     

The prognosis of the course and outcome in gastric peptic ulcer

A universal system for forecasting gastric ulcer has been devised. It ensures high reliability of the forecasting of uncomplicated or frequently relapsing disease, development of long non-healing or callous gastric ulcer, occurrence of ulcerous hemorrhage, perforation, penetration, stenosis or malignization. The system is designed for the use in the computer mode or in the form of the tabular prognosis method to be employed in hospitals and in ambulatory-polyclinical practice.     

The proton-pump inhibitors: similarities and differences

OBJECTIVE: This paper examines the clinical pharmacology of the proton-pump inhibitors (PPIs) and briefly reviews some comparative studies of these agents. BACKGROUND: PPIs have emerged as the treatment of choice for acid-related diseases, including gastroesophageal reflux disease (GERD) and peptic ulcer disease. Although these drugs-omeprazole, lansoprazole, pantoprazole, and rabeprazole-share a common structure (all are substituted benzimidazoles) and mode of action (inhibition of H+,K+-adenosine triphosphatase [ATPase]), each differs somewhat in its clinical pharmacology. RESULTS: In comparative clinical trials found in MEDLINE, PPIs administered once daily produced endoscopic evidence of healing in >90% of patients with duodenal ulcer after 4 weeks of treatment, in >90% of those with gastric ulcer after 6 weeks of treatment, and in >90% of those with ulcerative or erosive GERD after 8 weeks of treatment. Maintenance therapy with daily doses of a PPI has been shown to be an effective means of preventing GERD relapse. PPIs also inhibit the growth of Helicobacter pylori, now recognized as an important factor in peptic ulcer disease, and, when administered in combination with antibiotics, provide the best treatment for eradication of the bacterium. Rabeprazole has a more rapid onset of H+,K+-ATPase inhibition than the other PPIs and, compared with omeprazole, a greater effect on intragastric pH after the first dose. Omeprazole and lansoprazole have a greater potential for drug-drug interactions than do pantoprazole and rabeprazole. CONCLUSION: Although the individual PPIs have similar efficacy in many cases, differences between them should be considered when choosing a treatment regimen.