Current Topics in Medicinal Chemistry, Volume 5, No. 5, 2005
Contents
Benefits,
Problems and Alternatives to COX-2 Inhibition
Guest
Editor: Angel Lanas
Editorial Pp. 441-442
Angel Lanas
COX-2 Selective
Inhibitors in the Treatment of Arthritis: A Rheumatologist Perspective Pp. 443-448
Marc C. Hochberg
Impact of COX-2
Inhibitors in Common Clinical Practice a Gastroenterologist’s Perspective Pp. 449-464
Frank Serge Lehmann and Christoph Beglinger
Global Safety
of Coxibs and NSAIDs Pp.
465-473
Kevin Pham and Raimund Hirschberg
COX Inhibition and
NSAID-Induced Gastric Damage - Roles in Various Pathogenic Events Pp. 475-486
Koji Takeuchi, Akiko Tanaka, Yujiro Hayashi and Aya
Yokota
Dual
COX-Inhibitors: The Answer is NO? Pp. 487-492
Stefano Fiorucci and Elisabetta Antonelli
Low Dose
Aspirin, COX-Inhibition and Chemoprevention of Colorectal Cancer Pp. 493-503
Robert Benamouzig, Bernard Uzzan, Julian Little and
Stanislas Chaussade
Mechanisms of
Colon Cancer Prevention with and Beyond COX-2 Inhibition Pp. 505-516
F. Rodriguez-Moranta and A. Castells
Chemoprevention
of Colorectal Cancer: Ready for Routine Use? Pp. 517-525
Nadir Arber and Bernard Levin
Abstracts
[Back to top] Editorial
Angel Lanas
Benefits, Problems and Alternatives to COX-2 Inhibition
Since the development of drugs which are selective inhibitors of the COX-2 isoenzyme, our understanding of the roles or the involvement of COX-1 and COX-2 in both physiology and pathological conditions has greatly increased. In the same way, the experience with COX-2 inhibitors in clinical practice is now extensive and many questions we had a few years ago have been answered, but new, interesting and challenging questions have been raised. This issue of Current Pharmaceutical Design reviews current evidence and summarizes current clinical experience with the use of COX-2 inhibitors. From this perspective the review is focused not only on the benefits but also on the side effects outside the gastrointestinal tract which are now in the center of the scientific debate and where more data and clarification is needed.
From a rheumatologist’s perspective, Mark C. Hochberg [1] starts this issue by reviewing the evidence available in the efficacy of both older and the newest COX-2 inhibitors. The overview is focused on randomized clinical trials comparing the efficacy of these agents in patients suffering from osteoarthritis, rheumatoid arthritis and on some studies that have also demonstrated efficacy for COX-2 selective inhibitors in patients with ankylosing spondylitis and gout. This chapter is followed by an extensive review from a gastroenterologist’s perspective which is carried out by Frank Serge Lehmann and Christoph Beglinger regarding the safety of NSAIDs and COX-2 selective inhibitors in clinical practice [2]. Their review of the safety of these drugs is not only focused on the upper but also on the lower GI tract. This is a relevant aspect that is being studied more extensively now than before [3], and that may be of interest when the potential differences between the two strategies available to reduce the side effects of NSAIDs (dual COX inhibition plus gastroprotective drugs vs. COX-2 selective inhibition alone) are analysed. Additional commentaries from a cost-effectiveness perspective ends the review indicating that all the evidence suggests that coxibs should currently be used only in patients with high risk of GI complications.
A new area of intense debate in the scientific community is focused on the global (non-GI) safety approach of COX-2 inhibition in clinical practice. This area has been reviewed by Kevin Pham and Raimund Hirschberg who have mainly focused on cardiovascular safety (mainly myocardial infarction) and renal safety (acute renal failure, hypertension and electrolyte abnormalities) [4]. These authors indicate that current evidence from randomised controlled trials suggests that the incidence of renal complications may be increased two-fold with NSAIDs or coxibs, and that there is no evidence for a major difference between the two groups of drugs. In contrast, coxib use is associated with a greater incidence of cardiovascular complications, when compared to placebo and some NSAIDs (e.g. full anti-inflammatory dose of naproxen). Based on these data the authors conclude that long-term use of coxibs should be customized to individual patients and their intrinsic baseline risks and other medications required in their management.
Since COX-2 selective inhibition is not devoid of side effects, new areas of drug development are being considered. One of the most challenging ones is that focused on selective COX-1 inhibition. The article from Japan written by Koji Takeuchi and colleagues [5] is an excellent review of their recent experimental studies on NSAID-induced gastric damage, focused on the relation between COX inhibition and pathogenic events. Their studies indicate that conventional NSAIDs at a dose that inhibits prostaglandin production enhance gastric motility and result in an increase in mucosal permeability, mieloperoxidase activity and gastric lesions. On the contrary, the administration of selective COX-2 inhibitor rofecoxib and the selective COX-1 inhibitor SC-560 does not induce damage in the stomach. Rofecoxib does not inhibit mucosal prostaglandins, but the COX-1 selective inhibitor decreases mucosal PGE2 level, causes gastric hypermotility and increases mucosal permeability, but not mieloperoxidase activity. The combined administration of SC-560 and rofecoxib induces gastric lesions and increases mieloperoxidase activity. COX-2 mRNA is expressed in the stomach after administration of SC-560 and indomethacin but not rofecoxib. The authors conclude that the gastric lesions induced by NSAIDs are not accounted for solely by the inhibition of COX-1 and require the inhibition of both COX-1 and COX-2 and that inhibition of COX-1 up-regulates COX-2 expression and prostaglandin produced by COX-2 counteract the deleterious influences of the COX-1 inhibition.
Another approach to reducing GI lesions-associated with NSAID use different from the inhibition of COX-2 is based on the addition of a nitric oxide moiety to the parent NSAID. The group of Stephano Fiorucci have conducted a large number of experiments and studies in animals and humans with this compound and are the most relevant authorities in this field. NO-releasing NSAIDs exhibit greatly reduced gastrointestinal and renal toxicity and have comparable anti-inflammatory and anti-pyretic activity to the parent drugs with enhanced analgesic and anti-thrombotic properties. These derivatives retain the ability of the parent drugs to inhibit cyclo-oxygenase activity (types 1 and 2) and prostaglandin synthesis, but they have a much better side-effect profile than the parent drugs. Clinical trials have confirmed the data obtained in animal studies, suggesting a potential role of these compounds in chronic inflammatory disease [6]. Whether these compounds will fulfil the promise of being very effective in treating pain, fever and inflammation, as safe as coxibs or gastropective agents in the prevention of NSAID-induced GI damage and safer than NSAIDs and COX-2 selective inhibitors at renal and CV levels remains to be shown in the near future, but the hypothesis is attractive and deserves to be fully explored.
Finally, the other area where new data are available is focused on the effects and mechanisms of COX inhibition involved in the neoplastic transformation and/or tumor progression of lesions of the gastrointestinal tract. Epidemiological studies had shown that NSAIDs and aspirin use was associated with reduction of the risk of developing or dying from colorectal cancer. Now some randomised clinical trials looking at the secondary prevention of recurrence of colonic polyps with low-dose aspirin have been published. Robert Benamouzig and colleagues [7] review in this issue the available evidence underlying this approach, which in their opinion requires major funding and human investment. Furthermore they think that, in view of previous discrepancies between the results of observational studies and randomised control trials, it is important to investigate the effects of aspirin in randomised control trials. However, having this type of studies with colorrectal cancer as an endpoint is a very difficult task and would need a very long follow-up. Investigating the effect of chemopreventive agents on adenoma recurrence as an intermediate endpoint for colorectal cancer is a more feasible approach than randomised control trials to investigate the effect on the incidence of colorectal cancer per se. The authors review the four trials of the effect of aspirin on adenoma recurrence that are now available. The positive results of these studies have opened an exciting debate as to whether low-dose aspirin benefits may outweigh the risks associated with GI toxicity and whether other safer GI agents (e.g. COX-2 selective inhibitors) may have a better profile in this regard. Castell and Rodriguez-Moranta [8] review the mechanisms of action involved in the antitumorigenic action of COX-inhibition and 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. This “in depth” review of the mechanisms of action of these drugs in colorectal cancer treatment and prevention will keep the reader updated in this fascinating area which has undergone an intense change over the last 5 years. Since in the third millennium preventive medicine is becoming a corner stone in our concept of health, the issue ends with another extensive review carried by 2 experts in the field of colorectal cancer, Nadir Narber and Bernard Levine [9], who respond to the question as to whether we are now ready for chemoprevention of colorectal cancer since colorectal cancer fits the criteria of a disease suitable for chemopreventive interventions. The authors state that science and technology have evolved to a point where we can identify individuals at risk and interrupt the process of malignant transformation at the level of the pre-cancerous lesion. They review a number of potential targets for chemoprevention including aspirin, NSAIDs and COX-2 selective inhibitors. They think that COX-2-specific inhibitors seem to be well-suited drug candidates for CRC prevention and that pharmacology and genetics are collaborating to develop new chemoprevention agents designed to affect molecular targets linked to specific pre-malignant or predisposing conditions. These agents must have a good profile regarding the potential incidence of side effects since they may be used long-term.
REFERENCES
[1] Hochberg, M.C. COX-2 Selective Inhibitors in the Treatment of Arthritis: A rheumatologist perspective. Curr. Topics Med. Chem. (in press).
[2] Lehmann, F.S., Beglinger, C. Impact of COX-2 inhibitors in common clinical practice. A gastroenterologist's perspective. Curr. Topics Med. Chem. (in press).
[3] Lanas, A., Panes, J., Pique, J.M.. Clinical implications of COX-1 and/or COX-2 inhibition for the distal gastrointestinal tract. Curr. Pharm. Des. 2003; 9 (27), 2253-66.
[4] Pham, K., Hirschberg, R. Global Safety of Coxibs and NSAIDs. Curr. Topics Med. Chem. (in press).
[5] Takeuchi, K., Tanaka, A., Hayashi, Y., Yokota, A. COX Inhibition and NSAID-Induced Gastric Damage. Roles in Various Pathogenic Events. Curr. Topics Med. Chem. (in press).
[6] Fiourucci, S., Antonelli, E. Dual COX-inhibition: The answer is NO? Curr. Topics Med. Chem. (in press).
[7] Rodriguez-Moranta, F., Castell, A. Mechanisms of Colon Cancer Prevention with and beyond COX-2 inhibition. Curr. Topics Med. Chem. (in press).
[8] Benamouzig, R., Uzzan, B., Little, J., Chaussade, S. Low-dose aspirin, COX inhibition and Colorectal Cancer Prevention. Curr. Topics Med. Chem. (in press).
[9] Arber, N., Levin, B. Chemoprevention of Colorectal Cancer: Ready for Routine Use? Curr. Topics Med. Chem. (in press).
[Back to top] COX-2 Selective
Inhibitors in the Treatment of Arthritis: A Rheumatologist Perspective
Marc C. Hochberg
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.
[Back to top] Impact of
COX-2 Inhibitors in Common Clinical Practice a Gastroenterologist’s Perspective
Frank Serge Lehmann and Christoph Beglinger
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.
[Back to top] Global Safety of
Coxibs and NSAIDs
Kevin Pham and Raimund Hirschberg
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.
[Back to top] COX Inhibition and
NSAID-Induced Gastric Damage - Roles in Various Pathogenic Events
Koji Takeuchi, Akiko Tanaka, Yujiro Hayashi and Aya
Yokota
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 up-regulation 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.
[Back to top] Dual
COX-Inhibitors: The Answer is NO?
Stefano Fiorucci and Elisabetta Antonelli
Nitric oxide (NO) releasing non-steroidal anti-inflammatory drugs (NSAIDs) are a new class of anti-inflammatory 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.
[Back to top] Low Dose Aspirin,
COX-Inhibition and Chemoprevention of Colorectal Cancer
Robert Benamouzig, Bernard Uzzan, Julian Little and Stanislas Chaussade
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.
[Back to top] Mechanisms of
Colon Cancer Prevention with and Beyond COX-2 Inhibition
F. Rodriguez-Moranta and A. Castells
Colorectal cancer is the most common cancer in Western countries and the second leading cause of cancer-related 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 cancer-promoting 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 non-steroidal 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.
[Back to top] Chemoprevention of
Colorectal Cancer: Ready for Routine Use?
Nadir Arber and Bernard Levin
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 pre-cancerous 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.