Current Topics in Medicinal Chemistry - Volume 5, Issue 5, 2005

COX-2 selective inhibitors were developed in order to provide similar efficacy to traditional nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) but with improved upper gastrointestinal safety. This paper presents an overview of randomized clinical trials demonstrating the efficacy of COX-2 selective inhibitors for the treatment of patients with arthritis, particularly osteoarthritis and rheumatoid arthritis. In osteoarthritis and rheumatoid arthritis, COX-2 selective inhibitors have been shown to be more effective than placebo and similarly effective as standard doses of nonselective NSAIDs. There are currently few randomized clinical trials comparing the efficacy of the 2 first-generation COX-2 selective inhibitors, celecoxib and rofecoxib, in osteoarthritis. Of 4 head-to-head studies comparing the 2 agents, 3 indicated similar efficacy, while the other demonstrated superiority of rofecoxib at a dose of 25 mg qd compared with celecoxib at a dose of 200 mg qd. There are no clinical trials comparing the efficacy of different agents for treatment of patients with rheumatoid arthritis. Some studies have also demonstrated efficacy for COX-2 selective inhibitors in patients with ankylosing spondylitis and gout. In aggregate, these data show that COX-2 selective inhibitors provide effective relief of pain in patients with osteoarthritis and rheumatoid arthritis, with efficacy that is similar to traditional NSAIDs. Costeffectiveness and cost-utility studies suggest, however, that their use should be limited to patients at high risk of serious upper gastrointestinal side effects, including complicated ulcers.

Non-selective NSAIDs enhance the risk of serious ulcer complications (bleeding, perforation, obstruction), hospitalization and death about 3-10-fold. The gastrointestinal side effects of NSAIDs have a considerable economical burden, since they are responsible for 5-10 billion dollars in hospitalization charges and lost work time. NSAIDs cause gastrointestinal damage by both topical and systemic effects. COX-1-mediated inhibition of prostaglandin synthesis is probably the most relevant mechanism, but NSAIDs can cause gastrointestinal injury also by COX-independent pathways. COX-2-selective inhibitors (Coxibs) such as celecoxib, rofecoxib or valdecoxib have been developed to achieve an equal relief of pain and inflammation as classical NSAIDs but without their risk of gastrointestinal side effects. Within the first three months, celecoxib became the fastest selling drug in history. The gastrointestinal safety of classical NSAIDs and Coxibs has been compared in a variety of endoscopic investigations, meta-analyses and outcome studies. In conclusion, these studies have clearly shown, that Coxibs are associated with significantly less dyspeptic symptoms, erosions, ulcers and ulcer complications. In contrast, Coxibs seem to delay gastric ulcer healing to the same extent as traditional NSAIDs. Besides their effects on the upper gastrointestinal tract, NSAIDs can cause small intestinal inflammation, ulcers of the small and large intestine, ileal dysfunction, intestinal strictures, colitis and NSAID enteropathy. In addition, NSAIDs increase the risk of lower gastrointestinal complications including bleeding, perforation and obstruction. Current data suggest, that Coxibs are associated with a significantly lower risk of serious lower GI events than traditional NSAIDs. It is now under debate, who should receive COX-2-selective inhibitors instead of classical NSAIDs, since Coxibs are much more expensive. Data from cost-effectiveness studies suggest, that Coxibs should currently be used only in patients with high risks of GI complications.

Non-steroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase-2 inhibitors (Coxibs) are commonly used for minor pain treatment and chronically in the management of rheumatoid arthritis and osteoarthritis. Three areas of safety concerns are shared by both groups of drugs: Gastrointestinal complications (upper gastrointestinal bleeding, perforations or obstruction), cardiovascular safety (mainly myocardial infarction) and renal safety (acute renal failure, hypertension and electrolyte abnormalities). The incidence of renal complications may be increased two-fold with NSAIDs or coxibs, and there is no evidence for a major difference between the two groups of drugs. Coxibs are clearly associated with improved gastrointestinal safety compared to NSAIDs, but this benefit is reduced and may be lost completely with concurrent low-dose aspirin use. In contrast, coxibs may be associated with a greater incidence of cardiovascular complications, mainly myocardial infarction, especially in comparison to certain NSAIDs such as naproxen. Thus, coxibs are not generally safer than NSAIDs. Rather, their long-term use should be customized to individual patients and their intrinsic baseline risks and other medications required in their management.

This article reviews our recent studies on NSAID-induced gastric damage, focusing on the relation between COX inhibition and pathogenic events. Conventional NSAIDs such as indomethacin, at a dose that inhibits PG production, enhance gastric motility, resulting in an increase in mucosal permeability and MPO activity, and eventually, gastric lesions. The development of these lesions can be prevented by administering PGE2 or antisecretory drugs, and also via an atropine-sensitive mechanism, not related to any antisecretory action. The selective COX-2 inhibitor rofecoxib has no effect on PG production and does not induce damage in the stomach. The selective COX-1 inhibitor SC-560 also does not cause damage, despite evoking a decrease in the PGE2 level. The combined administration of SC-560 and rofecoxib, however, provokes the formation of gastric lesions. SC-560, but not rofecoxib, causes gastric hypermotility and an increase in mucosal permeability, although the level of MPO activity increases only when rofecoxib is co-administered. COX-2 mRNA is expressed in the stomach after administration of SC-560 and indomethacin but not rofecoxib. The upregulation of COX-2 expression in response to indomethacin is prevented by atropine at a dose that inhibits gastric hypermotility but not by omeprazole at an antisecretory dose. We conclude that the gastric ulcerogenic properties of NSAIDs are not accounted for solely by the inhibition of COX-1 and require the inhibition of both COX-1 and COX-2, the inhibition of COX-1 up-regulates COX-2 expression in association with gastric hypermotility, and PGs produced by COX-2 counteract the deleterious influences of the COX-1 inhibition.

Nitric oxide (NO) releasing non-steroidal anti-inflammatory drugs (NSAIDs) are a new class of antiinflammatory agents obtained by adding an NO releasing moiety to existing NSAIDs. They have also christened as COX inhibiting NO-donating drugs (CINOD). Preclinical and clinical studies suggest that CINOD inhibit COX-1 and COX-2 activities while cause less adverse effects on gastrointestinal tract in comparison to conventional NSAIDs and coxibs and reduce systemic blood pressure. A different class of NO-donating drugs has been obtained by coupling NO to aspirin. These NO-releasing aspirins are new chemical entities that maintain and possibly expands the pharmacological properties of aspirin, but spare the gastrointestinal mucosa. Animal studies have shown that CINOD and NO-aspirins maintain gastric mucosal blood flow and reduce leukocyte-endothelial cell adherence.

Chemoprevention of colorectal cancer involves the long-term use of pharmacologic agents that can prevent neoplasms from developing in the large bowel. This new approach requires major funding and human investments. Among the most widely studied agents for the chemoprevention of colorectal cancer, aspirin, the NSAIDs and COX-2 inhibitors seem to be the most promising. A large number of observational epidemiological studies show that regular use of aspirin and other NSAIDs is associated with a reduction in the risk of developing both colorectal adenomas and cancer. In addition, the prodrug sulindac reduces the growth of existing polyps in familial adenomatous polyposis (FAP). However, the dose, duration of effect and length of protection seen after cessation remain to be fully established. Furthermore, in view of previous discrepancies between the results of observational studies and randomized control trials (RCTs), it is crucially important to investigate the effects of aspirin by RCTs. RCTs investigating the effect of chemopreventive agents on adenoma recurrence as an intermediate endpoint for colorectal cancer is a more feasible approach than RCTs to investigate the effect on the incidence if colorectal cancer per se. Four RCTs of the effect of aspirin on adenoma recurrence are available. Other trials are currently underway.

Colorectal cancer is the most common cancer in Western countries and the second leading cause of cancerrelated death. Sporadic lesions represent 75-80% of all colorectal cancer, whereas 20-25% are in younger individuals or in patients with a family history of cancer, suggesting a heritable susceptibility. Persons with germline alterations in cancerpromoting genes, such as those with familial adenomatous polyposis and hereditary non-polyposis colorectal cancer, stand to benefit significantly from chemopreventive interventions, along with those who had already developed any colorectal neoplasia (either adenoma or carcinoma). Among the most promising approaches to chemoprevention is the use of nonsteroidal anti-inflammatory drugs, including both selective and non-selective cyclooxigenase-2 inhibitors. Although the present article is mainly focused on these drugs and their mechanisms of action, other strategies with potential involvement in colorectal cancer chemoprevention such as peroxisome proliferator activated receptor ligands, epithelial growth factor receptor blockers, calcium, vitamin D, folate, and DNA methyltransferase inhibitors are also reviewed.

In the third millennium preventive medicine is becoming a corner stone in our concept of health. Colorectal cancer (CRC) prevention, in particular, has become an important goal for health providers, physicians and the general public. CRC fits the criteria of a disease suitable for chemopreventive interventions. It is a prevalent disease that is associated with considerable mortality and morbidity rates, with more than 1,000,000 new cases and 500,000 deaths expected, worldwide, in 2004. CRC has a natural history of transition from precursor to malignant lesion that spans, on average, 15-20 years, providing a window of opportunity for effective interventions and prevention. A pre-malignant precursor lesion (i.e., adenoma) usually precedes cancer, and helps to identify a subset of the population that is at increased risk of harbouring and developing cancer. Science and technology have evolved to a point where we are able to use our knowledge of cancer biology to identify individuals at risk and interrupt the process of malignant transformation at the level of the pre-cancerous lesion. Recent progress in molecular biology and pharmacology enhances the likelihood that cancer prevention will increasingly rely on chemoprevention. Chemoprevention, a new emerging science, means the use of agents to inhibit, delay or reverse carcinogenesis. Recent observations suggest a number of potential targets for chemoprevention. Many agents have potential benefit, but only modest chemopreventive efficacy in clinical trials. There is much evidence suggesting an inverse relationship between aspirin or NSAIDs consumption and CRC incidence and mortality. However, NSAID consumption is not problem-free, as 1997 data showed 107,000 hospitalisations and 16,500 deaths due to NSAIDs consumption in the US alone. Therefore, although chemoprevention of CRC is already possible, drugs that have more acceptable side-effect profiles than the currently available NSAIDs are required. COX-2-specific inhibitors, which have an improved safety profile, as compared to traditional NSAIDs that inhibit both the COX-1 and COX-2 enzymes, seem to be well suited drug candidates for CRC prevention. The inhibition of the growth of precancerous and cancerous cells without affecting normal cells is the ultimate aim of cancer treatment and is of particular importance in chemoprevention studies, which may be long term in nature, involve healthy subjects and minimal toxicity. Cancer prevention is certain to be a significant focus of research and intervention in the coming years, propelled by the realization that we will be able to identify both individuals susceptible to specific cancers as well as the molecular targets that can alter or stop the carcinogenesis process. Pharmacology and genetics are collaborating to develop new chemoprevention agents designed to affect molecular targets linked to specific pre-malignant or predisposing conditions.