Logical Therapeutics: Better medicine. It's only logical.

NSAID Prodrug Platform

NSAID-induced Gastrointestinal complications

Non-steroidal anti-inflammatory drugs (NSAIDs) are the most common medications taken worldwide for the treatment of pain and inflammation. The use of NSAIDs is associated with serious side effects, the most frequent being an increased rate of gastric and duodenal ulcers. In the United States alone, the direct costs of treating ulcer complications associated with NSAID use exceed $4 billion a year. Despite the availability of gastro-protective agents, serious NSAID-induced gastrointestinal (GI) complications, such as hemorrhage and perforation, persist and are directly responsible for approximately 20,000 deaths per year in the United States. Older age, a past history of ulcer disease, the use of anticoagulants including low dose aspirin, and potentially use of corticosteroids magnify the risk of bleeding peptic ulcers in patients taking NSAIDs. Introduction of the COX-2 selective NSAIDs, which touted an improved GI safety profile, resulted in annual sales in excess of $6 billion before public concern over serious cardiovascular (CV) risks led to the withdrawal of both rofecoxib and valdecoxib. Coxib usage has been severely restricted and the coxib pipeline evaporated. As a result, patients are again receiving nonselective NSAIDs and facing GI toxicity risks. Prescribing NSAID therapy has become a complex balancing act as physicians evaluate a patient's CV and GI risks. Current recommendations suggest naproxen for patients with high CV risks. A non-selective NSAID, celecoxib with PPI or misoprostil, is recommended when GI risk is predominant. Logical Therapeutics' investigational product LT-NS001 is being developed as an alternative to either naproxen or celecoxib. LT-NS001 is being developed to reduce the risk of gastric ulcers in patients who require an NSAID for the treatment of rheumatoid arthritis, osteoarthritis and ankylosing spondylitis.  LT-NS001 is the first in a family of bio-activated prodrugs designed to to reduce the risk of gastric ulcers in patients who require regular NSAID therapy.

The Scientific Rationale for an NSAID Prodrug

The problem of NSAID-induced damage to the GI mucosa has been studied extensively for many years, and the underlying mechanisms still are not completely understood. It is clear, of course, that one important factor is decreased production of vasodilating and cytoprotective prostaglandins (PGs), notably PGE2and PGI2, due to inhibition of COX-1 in the mucosa. But, other "off-target" effects of NSAIDs appear to be important as well. Moreover, inhibition of COX-1 in the epithelium of the GI tract can occur because the NSAID is ingested orally and the mucosa is directly exposed to high luminal concentrations of the drug. Alternatively, after the NSAID is absorbed into the circulation, the epithelium in the GI tract can be exposed to the drug via diffusion from the blood stream back into the mucosa. There is yet another mechanism that also may be important. According to this mechanism, the drug—or more likely, pharmacologically active metabolites of the drug—can be delivered to the mucosa via the biliary tract after the drug is metabolized by the liver.
Although multiple mechanisms probably contribute to NSAID-induced GI mucosal damage, various "local" effects seem likely to be more important than "systemic" ones. Several lines of evidence can be mustered to support this view.

1. Enteric-coated aspirin causes less gastric mucosal damage than conventional aspirin.

   An enteric coating is a coating put on a pill or capsule so that it does not dissolve (or release the pharmacologically active compound) until it reaches the small intestine. If the "local" hypothesis is correct, we would predict that enteric-coated aspirin would be associated with less gastric mucosal damage than conventional aspirin, although enteric-coated aspirin would still cause aspirin-induced mucosal damage to the small intestine.
   
   Enteric-coated aspirin has been available for a number of years and the efficacy of this formulation, with regard to decreasing the risk of gastric mucosal damage, has been evaluated extensively. Banoob et al. reviewed numerous studies and concluded that "most of these studies suggest that the use of enteric-coated aspirin was associated with less mucosal damage compared with buffered or plain aspirin. Furthermore, endoscopic evaluations in these trials show that the enteric-coated formulations produce significantly less gastric mucosal damage." (Banoob DW et al. Risk of gastric injury with enteric- versus nonenteric-coated aspirin. Ann Pharmacother 2002;36:163-166).
   
   It is important to emphasize that enteric-coated aspirin does not protect against the development of mucosal lesions in the intestine (where the pill is intended to dissolve and where high local concentrations of the drug will be present). In a trial by Petroski, enteric coating decreased the risk of gastric but not duodenal ulcers (Petroski D. Endoscopic comparison of three aspirin preparations and placebo. Clin Ther 1993;15:314-320). Furthermore, in another recent paper, among 40 patients with endoscopically verified ileal ulcers, 19 admitted to taking enteric-coated aspirin (Lengling RW, et al. Ulcerative ileitis encountered at ileo-colonoscopy: likely role of nonsteroidal agents. Clin Gastroenterol Hepatol 2003;1:160-169]. In another study of intestinal NSAID-induced ulcerations, most cases were associated with a "slow-release" formulation of diclofenac (Puspok A, et al. Clinical, endoscopic, and histologic spectrum of nonsteroidal anti-inflammatory drug-induced lesions in the colon. Dis Colon Rectum 2000;43:685-691).

2. Nabumetone, an NSAID prodrug, causes fewer GI ulcers than conventional NSAIDs.

   Nabumetone is a prodrug, which exerts its pharmacological effects via its active metabolite, 6-methoxy-2-naphthylacetic acid (6-MNA). Nabumetone is pharmacologically inactive as a COX inhibitor and is converted to 6-MNA in the liver via oxidative metabolism. 6-MNA is a non-selective COX inhibitor. The IC50 (concentration that produces half-maximal inhibition) for COX-1 inhibition by 6-MNA is 149 _M and the IC50 for COX-2 inhibition by 6-MNA is 230 _M (Kato M, et al. Cyclooxygenase-1 and cyclooxygenase-2 selectivity of non-steroidal anti-inflammatory drugs: investigation using human peripheral monocytes. J Pharm Pharmacol 2001;53:1679-1685).

   If the "systemic" hypothesis is correct, then one would expect that a balanced COX-1/COX-2 inhibitor like 6-MNA would be associated with a rate of gastroduodenal ulceration not significantly different from other isoform-nonselective NSAIDs. On the other hand, if the "local" hypothesis is correct, then nabumetone, being a prodrug, should have a better GI safety profile than classical NSAIDs used for comparison. It is noteworthy, therefore, that four randomized controlled clinical trials indicate that nabumetone has a more favorable GI safety profile than classical NSAIDs, such as naproxen (Bianchi Porro G, et al. Gastroduodenal tolerability of nabumetone versus naproxen in the treatment of rheumatic patients. Am J Gastroenterol 1995; 90:1485-1488; Greb WH, et al. Endoscopic studies of nabumetone in patients with rheumatoid arthritis. A comparative endoscopic and histologic evaluation. Am J Med 1987; 83(4B):19-24; Roth SH. Endoscopy-controlled study of the safety of nabumetone compared with naproxen in arthritis therapy. Am J Med 1987;30(4B):25-30) or ibuprofen [Roth SH, et al. A controlled study comparing the effects of nabumetone, ibuprofen, and ibuprofen plus misoprostol on the upper gastrointestinal tract mucosa. Arch Intern Med 1993;153:2565-2571).

3. NSAIDs when administered by rectal suppository are associated with rectal (not gastroduodenal) ulcers.

   Support for the idea that high local concentrations of NSAID can cause mucosal damage comes from case reports of rectal mucosal damage associated with the use of suppositories containing drugs, such as ASA (Van Gossum A, et al. Anorectal stenosis in patients with prolonged use of suppositories containing paracetamol and acetylsalicylic acid. Dig Dis Sci 1993; 38:1970-1977; D'Haens G, et al. Proctitis and rectal stenosis induced by nonsteroidal antiinflammatory suppositories. J Clin Gastroenterol 1993; 17:207-212). Obviously, in the case of administration via a suppository, the high local concentration is not in the stomach or proximal GI tract but rather in the rectal mucosa.

   Even more impressive are data from a study by Lipscomb and Rees, who randomized 24 healthy volunteers to treatment with either oral or rectal naproxen 500 mg twice daily (Lipscomb GR, Rees WD. Gastric mucosal injury and adaptation to oral and rectal administration of naproxen. Aliment Pharmacol Ther 1996;10:133-138). The subjects underwent gastroduodenal endoscopy before treatment and on days 1, 7 and 28 of dosing. Maximal gastric damage occurred during the first 24 h in the oral naproxen group. No macroscopic damage or significant changes in mucosal blood flow were observed during rectal administration. There was no significant difference between gastric mucosal PGE2 concentrations in those receiving oral or rectal naproxen, falling from an initial level of 335±29 to 155±49 pg/mg at day 1 (P = 0.06) in those receiving oral naproxen and from 235±55 to 107±31 pg/mg at day 1 (P = 0.1) in those receiving rectal naproxen, and remaining suppressed throughout the study in both groups. Based on these findings, the authors of this study concluded "that acute mucosal damage and changes in mucosal blood flow are caused by the topical rather than systemic actions of naproxen."

4. Intravenous aspirin does not cause gastric mucosal damage in man.

   In one series of clinical studies, acute intravenous administration of aspirin "caused no significant histological damage" to the gastric mucosa of human volunteers (Ivey KJ, et al. Acute effect of systemic aspirin on gastric mucosa in man. Dig Dis Sci 1980;25:97-99). In contrast, oral administration of a dose of aspirin that resulted in comparable blood levels of the drug produced damage to about 25% of the mucosal surface of the stomach (Baskin WN, et al. Aspirin-induced ultrastructural changes in human gastric mucosa: correlation with potential difference. Ann Intern Med 1976;85:299-303]. These observations support the view that high local concentrations of aspirin are essential for the development of gastric mucosal damage induced by this drug.