Advent of Novel Phosphatidylcholine-Associated Nonsteroidal Anti-Inflammatory Drugs with Improved Gastrointestinal Safety
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The mucosa of the gastrointestinal (GI) tract exhibits hydrophobic, nonwettable properties that protect the underlying epithelium from gastric acid and other luminal toxins. These biophysical characteristics appear to be attributable to the presence of an extracellular lining of surfactant-like phospholipids on the luminal aspects of the mucus gel layer. Phosphatidylcholine (PC) represents the most abundant and surface-active form of gastric phospholipids. PC protected experimental rats from a number of ulcerogenic agents and/or conditions including nonsteroidal anti-inflammatory drugs (NSAIDs), which are chemically associated with PC. Moreover, preassociating a number of the NSAIDs with exogenous PC prevented a decrease in the hydrophobic characteristics of the mucus gel layer and protected rats against the injurious GI side effects of NSAIDs while enhancing and/or maintaining their therapeutic activity. Bile plays an important role in the ability of NSAIDs to induce small intestinal injury. NSAIDs are rapidly absorbed from the GI tract and, in many cases, undergo enterohepatic circulation. Thus, NSAIDs with extensive enterohepatic cycling are more toxic to the GI tract and are capable of attenuating the surface hydrophobic properties of the mucosa of the lower GI tract. Biliary PC plays an essential role in the detoxification of bile salt micelles. NSAIDs that are secreted into the bile injure the intestinal mucosa via their ability to chemically associate with PC, which forms toxic mixed micelles and limits the concentration of biliary PC available to interact with and detoxify bile salts. We have worked to develop a family of PC-associated NSAIDs that appear to have improved GI safety profiles with equivalent or better therapeutic efficacy in both rodent model systems and pilot clinical trials.
Abstract
The mucosa of the gastrointestinal (GI) tract exhibits hydrophobic, nonwettable properties that protect the underlying epithelium from gastric acid and other luminal toxins. These biophysical characteristics appear to be attributable to the presence of an extracellular lining of surfactant-like phospholipids on the luminal aspects of the mucus gel layer. Phosphatidylcholine (PC) represents the most abundant and surface-active form of gastric phospholipids. PC protected experimental rats from a number of ulcerogenic agents and/or conditions including nonsteroidal anti-inflammatory drugs (NSAIDs), which are chemically associated with PC. Moreover, preassociating a number of the NSAIDs with exogenous PC prevented a decrease in the hydrophobic characteristics of the mucus gel layer and protected rats against the injurious GI side effects of NSAIDs while enhancing and/or maintaining their therapeutic activity. Bile plays an important role in the ability of NSAIDs to induce small intestinal injury. NSAIDs are rapidly absorbed from the GI tract and, in many cases, undergo enterohepatic circulation. Thus, NSAIDs with extensive enterohepatic cycling are more toxic to the GI tract and are capable of attenuating the surface hydrophobic properties of the mucosa of the lower GI tract. Biliary PC plays an essential role in the detoxification of bile salt micelles. NSAIDs that are secreted into the bile injure the intestinal mucosa via their ability to chemically associate with PC, which forms toxic mixed micelles and limits the concentration of biliary PC available to interact with and detoxify bile salts. We have worked to develop a family of PC-associated NSAIDs that appear to have improved GI safety profiles with equivalent or better therapeutic efficacy in both rodent model systems and pilot clinical trials.
참고문헌 (64)
- Scarpignato C, "Nonsteroidal antiinflammatory drug-related injury to the gastrointestinal tract: clinical picture, pathogenesis, and prevention", Gastroenterol Clin North Am, 39, pp.433~464 (2010)
- Watson DJ, "Gastrointestinal tolerability of the selective cyclooxygenase-2 (COX-2) inhibitor rofecoxib compared with nonselective COX-1 and COX-2 inhibitors in osteoarthritis", Arch Intern Med, 160, pp.2998~3003 (2000)
- Lichtenberger LM, "Non-steroidal anti-inflammatory drugs (NSAIDs) associate with zwitterionic phospholipids: insight into the mechanism and reversal of NSAID-induced gastrointestinal injury", Nat Med, 1, pp.154~158 (1995)
- Lichtenberger LM, "The hydrophobic barrier properties of gastrointestinal mucus", Annu Rev Physiol, 57, pp.565~583 (1995)
- Lichtenberger LM, "Where is the evidence that cyclooxygenase inhibition is the primary cause of nonsteroidal anti-inflammatory drug (NSAID)-induced gastrointestinal injury? Topical injury revisited", Pharmacol, 61, pp.631~637 (2001)
- Lichtenberger LM, "Effect of bisphosphonates on surface hydrophobicity and phosphatidylcholine concentration of rodent gastric mucosa", Dig Dis Sci, 45, pp.1792~1801 (2000)
- Barrios JM, "Role of biliary phosphatidylcholine in bile acid protection and NSAID injury of the ileal mucosa in rats", Gastroenterology, 118, pp.1179~1186 (2000)
- Giraud MN, "Interaction of indomethacin and naproxen with gastric surface-active phospholipids: a possible mechanism for the gastric toxicity of nonsteroidal anti-inflammatory drugs (NSAIDs)", Biochem Pharmacol, 57, pp.247~254 (1999)
- Lichtenberger LM, "Nonsteroidal anti-inflammatory drug and phospholipid prodrugs: combination therapy with antisecretory agents in rats", Gastroenterology, 111, pp.990~995 (1996)
- Lichtenberger LM, "Insight into NSAID-induced membrane alterations, pathogenesis and therapeutics: characterization of interaction of NSAIDs with phosphatidylcholine", Biochim Biophys Acta, 1821, pp.994~1002 (2012)
- Kao YC, "Localization of phospholipid-rich zones in rat gastric mucosa: possible origin of a protective hydrophobic luminal lining", J Histochem Cytochem, 35, pp.1285~1298 (1987)
- Anand BS, "Phospholipid association reduces the gastric mucosal toxicity of aspirin in human subjects", Am J Gastroenterol, 94, pp.1818~1822 (1999)
- Lanza FL, "Clinical trial: comparison of ibuprofen-phosphatidylcholine and ibuprofen on the gastrointestinal safety and analgesic efficacy in osteoarthritic patients", Aliment Pharmacol Ther, 28, pp.431~442 (2008)
- Lichtenberger LM, "Gastroduodenal mucosal defe", Curr Opin Gastroenterol, 15, pp.463~472 (1999)
- Kao YC, "Morphological effects of aspirin and prostaglandin on the canine gastric mucosal surface. Analysis with a phospholipid-selective cytochemical stain", Gastroenterology, 98, pp.592~606 (1990)
- Goddard PJ, "Luminal surface hydrophobicity of canine gastric mucosa is dependent on a surface mucous gel", Gastroenterology, 98, pp.361~370 (1990)
- Dial EJ, "Surface hydrophobicity of the gastric mucosa in the developing rat. Effects of corticosteroids, thyroxine, and prostaglandin E2", Gastroenterology, 94, pp.57~61 (1988)
- Kao YC, "Phospholipid- and neutral lipid-containing organelles of rat gastroduodenal mucous cells. Possible origin of the hydrophobic mucosal lining", Gastroenterology, 101, pp.7~21 (1991)
- Lichtenberger LM, "Gastric protective activity of mixtures of saturated polar and neutral lipids in rats", Gastroenterology, 99, pp.311~326 (1990)
- Kao YC, "A method to preserve extracellular surfactant-like phospholipids on the luminal surface of rodent gastric mucosa", J Histochem Cytochem, 38, pp.427~431 (1990)
- Ottlecz A, "Helicobacter infection and phospholipase A2 enzymes: effect of Helicobacter felis-infection on the expression and activity of sPLA2 enzymes in mouse stomach", Mol Cell Biochem, 221, pp.71~77 (2001)
- Lichtenberger LM, "Attenuation of hydrophobic phospholipid barrier is an early event in Helicobacter felis-induced gastritis in mice", Dig Dis Sci, 44, pp.108~115 (1999)
- Giraud MN, "Effect of omeprazole on the bioavailability of unmodified and phospholipid-complexed aspirin in rats", Aliment Pharmacol Ther, 11, pp.899~906 (1997)
- Serna JH, "Invasive Helicobacter-like organisms in feline gastric mucosa", Helicobacter, 2, pp.40~43 (1997)
- Lichtenberger LM, "Effect of ammonium ion on the hydrophobic and barrier properties of the gastric mucus gel layer: implications on the role of ammonium in H. pylori-induced gastritis", J Gastroenterol Hepatol, (9 Suppl 1), pp.S13~S19 (1994)
- Ottlecz A, "Phospholipase activity of Helicobacter pylori and its inhibition by bismuth salts. Biochemical and biophysical studies", Dig Dis Sci, 38, pp.2071~2080 (1993)
- Go MF, "Gastric mucosal hydrophobicity and Helicobacter pylori: response to antimicrobial therapy", Am J Gastroenterol, 88, pp.1362~1365 (1993)
- Dial EJ, "A direct role for secretory phospholipase A2 and lysophosphatidylcholine in the mediation of LPS-induced gastric injury", Shock, 33, pp.634~638 (2010)
- Dial EJ, "Oral phosphatidylcholine preserves the gastrointestinal mucosal barrier during LPS-induced inflammation", Shock, 30, pp.729~733 (2008)
- Zayat M, "Pathophysiology of LPS-induced gastrointestinal injury in the rat: role of secretory phospholipase A2", Shock, 30, pp.206~211 (2008)
- Dial EJ, "Lipopolysaccharide-induced gastrointestinal injury in rats: role of surface hydrophobicity and bile salts", Shock, 17, pp.77~80 (2002)
- Dial EJ, "Role of phosphatidylcholine saturation in preventing bile salt toxicity to gastrointestinal epithelia and membranes", J Gastroenterol Hepatol, 23, pp.430~436 (2008)
- Schmitz MG, "Phospholipids from rat, human, and canine gastric mucosa. Composition and metabolism of molecular classes of phosphatidylcholine", Gastroenterology, 99, pp.1292~1296 (1990)
- Zhou Y, "The role of membrane cholesterol in determining bile acid cytotoxicity and cytoprotection of ursodeoxycholic acid", Biochim Biophys Acta, 1788, pp.507~513 (2009)
- Dial EJ, "Importance of biliary excretion of indomethacin in gastrointestinal and hepatic injury", J Gastroenterol Hepatol, 23(8 Pt 2), pp.e384~e389 (2008)
- Zhou Y, "Effect of indomethacin on bile acid-phospholipid interactions: implication for small intestinal injury induced by nonsteroidal anti-inflammatory drugs", Am J Physiol Gastrointest Liver Physiol, 298, pp.G722~G731 (2010)
- Graham DY, "Visible small-intestinal mucosal injury in chronic NSAID users", Clin Gastroenterol Hepatol, 3, pp.55~59 (2005)
- Maiden L, "A quantitative analysis of NSAID-induced small bowel pathology by capsule enteroscopy", Gastroenterology, 128, pp.1172~1178 (2005)
- Lanas A, "Nonsteroidal anti-inflammatory drugs and lower gastrointestinal complications", Gastroenterol Clin North Am, 38, pp.333~352 (2009)
- Bjarnason I, "Side effects of nonsteroidal anti-inflammatory drugs on the small and large intestine in humans", Gastroenterology, 104, pp.1832~1847 (1993)
- Wallace JL, "Proton pump inhibitors exacerbate NSAID-induced small intestinal injury by inducing dysbiosis", Gastroenterology, 141, pp.1314~1322 (2011)
- Watanabe T, "Non-steroidal anti-inflammatory drug-induced small intestinal damage is Toll-like receptor 4 dependent", Gut, 57, pp.181~187 (2008)
- Lichtenberger LM, "Aspirin’s ability to induce intestinal injury in rats is dependent on bile and can be reversed if pre-associated with phosphatidylcholine", J Physiol Pharmacol, 62, pp.491~496 (2011)
- Lichtenberger LM, "NSAID injury to the gastrointestinal tract: evidence that NSAIDs interact with phospholipids to weaken the hydrophobic surface barrier and induce the formation of unstable pores in membranes", J Pharm Pharmacol, 58, pp.1421~1428 (2006)
- Zhou Y, "The anti-inflammatory drug indomethacin alters nanoclustering in synthetic and cell plasma membranes", J Biol Chem, 285, pp.35188~35195 (2010)
- Zhou Y, "The nonsteroidal anti-inflammatory drug indomethacin induces heterogeneity in lipid membranes: potential implication for its diverse biological action", PLoS One, 5, pp.e8811~ (2010)
- Lichtenberger LM, "Association of phosphatidylcholine and NSAIDs as a novel strategy to reduce gastrointestinal toxicity", Drugs Today (Barc), 45, pp.877~890 (2009)
- Yamada T, "Bile secretion in rats with indomethacin-induced intestinal inflammation", Am J Physiol, 270(5 Pt 1), pp.G804~G812 (1996)
- Cryer B, "Low-dose aspirin-induced ulceration is attenuated by aspirin-phosphatidylcholine: a randomized clinical trial", Am J Gastroenterol, 106, pp.272~277 (2011)
- Lichtenberger LM, "Gastrointestinal safety and therapeutic efficacy of parenterally administered phosphatidylcholine-associated indomethacin in rodent model systems", Br J Pharmacol, 157, pp.252~257 (2009)
- Lichtenberger LM, "Zwitterionic phospholipids enhance aspirin’s therapeutic activity, as demonstrated in rodent model systems", J Pharmacol Exp Ther, 277, pp.1221~1227 (1996)
- Kurinets A, "Phosphatidylcholine-associated aspirin accelerates healing of gastric ulcers in rats", Dig Dis Sci, 43, pp.786~790 (1998)
- Lichtenberger LM, "Naproxen-PC: a GI safe and highly effective anti-inflammatory", Inflammopharmacology, 17, pp.1~5 (2009)
- Billiau A, "Modes of action of Freund’s adjuvants in experimental models of autoimmune diseases", J Leukoc Biol, 70, pp.849~860 (2001)
- Lichtenberger LM, "Phosphatidylcholine association increases the anti-inflammatory and analgesic activity of ibuprofen in acute and chronic rodent models of joint inflammation: relationship to alterations in bioavailability and cyclooxygenase-inhibitory potency", J Pharmacol Exp Ther, 298, pp.279~287 (2001)
- Wallace JL, "New pharmacologic therapies in gastrointestinal disease", Gastroenterol Clin North Am, 39, pp.709~720 (2010)
- Scheiman JM, "Prevention of damage induced by aspirin in the GI tract", Best Pract Res Clin Gastroenterol, 26, pp.153~162 (2012)
- Darling RL, "The effects of aspirin on gastric mucosal integrity, surface hydrophobicity, and prostaglandin metabolism in cyclooxygenase knockout mice", Gastroenterology, 127, pp.94~104 (2004)
- Laine L, "Ulcer formation with low-dose enteric-coated aspirin and the effect of COX-2 selective inhibition: a double-blind trial", Gastroenterology, 127, pp.395~402 (2004)
- Lichtenberger LM, "Surface phospholipids in gastric injury and protection when a selective cyclooxygenase-2 inhibitor (Coxib) is used in combination with aspirin", Br J Pharmacol, 150, pp.913~919 (2007)
- Mizuno H, "Induction of cyclooxygenase 2 in gastric mucosal lesions and its inhibition by the specific antagonist delays healing in mice", Gastroenterology, 112, pp.387~397 (1997)
- Schmassmann A, "Role of the different isoforms of cyclooxygenase and nitric oxide synthase during gastric ulcer healing in cyclooxygenase-1 and -2 knockout mice", Am J Physiol Gastrointest Liver Physiol, 290, pp.G747~G756 (2006)
- Rahme E, "NSAIDs and risk of lower gastrointestinal bleeding", Lancet, 376, pp.146~148 (2010)
- Hackelsberger A, "Age and Helicobacter pylori decrease gastric mucosal surface hydrophobicity independently", Gut, 43, pp.465~469 (1998)
