Non-steroidal anti-inflammatory drugs (NSAIDs) associate with zwitterionic phospholipids: insight into the mechanism and reversal of NSAID-induced gastrointestinal injury.

The molecular basis of the injurious actions of non-steroidal anti-inflammatory drugs (NSAIDs) on the gastrointestinal (GI) tract is only partly understood. In this study we have obtained evidence, employing both in vitro and in vivo systems, that five NSAIDs have the ability to form a chemical association with zwitterionic phospholipids. Since this same class of phospholipids line the luminal aspects of the mucus gel layer to provide it with non-wettable properties, this intermolecular association may be the mechanism by which NSAIDs attenuate the hydrophobic barrier properties of the upper GI tract. Preassociating a number of NSAIDs with exogenous zwitterionic phospholipids prevented this increase in surface wettability of the mucus gel layer and protected rats against the injurious GI side-effects of these drugs, while enhancing their lipid permeability, antipyretic and anti-inflammatory activity.

Role of surface-active phospholipids in gastric cytoprotection.

Intragastric administration of a liposomal surfactant suspension markedly reduced acid-induced gastric ulcerogenesis and bleeding in rats. The concentration of surface-active molecules intrinsically present in the gastric mucosa was increased two to six times by administration of 16,16-dimethyl prostaglandin E2. Thus, local accumulation of surface-active phospholipids may be an integral component of the cytoprotective mechanism activated by prostaglandin treatment.

Naproxen-PC: a GI safe and highly effective anti-inflammatory.

UNLABELLED: We have been developing a family of phosphatidylcholine (PC)-associated NSAIDs, which appear to have improved GI safety and therapeutic efficacy in both rodent model systems and pilot clinical trials. As naproxen has been demonstrated to be associated with the lowest cardiovascular adverse events in comparison with both COX-2 selective inhibitors and conventional NSAIDs, we have been developing a Naproxen-PC formulation for evaluation in animal models and clinical trials. We have determined that an oil-based formulation of naproxen and triple strength soy lecithin provides excellent GI protection in both: 1) an acute NSAID-induced intestinal bleeding model in rats pretreated with L-NAME that are intragastrically administered a single dose of naproxen (at a dose of 50 mg/kg) vs the equivalent dose of Naproxen-PC; and 2) a more chronic model (at a naproxen dose of 25 mg/kg BID) in rats that have pre-existing hindpaw inflammation (induced with a intradermal injection of Complete Freund's Adjuvant/CFA). Both models demonstrate the superior GI safety of Naproxen-PC vs naproxen while this novel formulation had significant anti-inflammatory efficacy to reduce hindpaw edema and the generation of PGE(2) in the collected joint synovial fluid. CONCLUSION: Naproxen-PC appears to induce significantly less GI injury and bleeding in two rodent model systems while maintaining anti-inflammatory and COX-inhibitory activity.

Surface phospholipids in gastric injury and protection when a selective cyclooxygenase-2 inhibitor (Coxib) is used in combination with aspirin.

BACKGROUND AND PURPOSE: Clinical studies demonstrate that aspirin consumption reverses the gastrointestinal (GI) benefits of coxibs, by an undefined mechanism. EXPERIMENTAL APPROACH: Rodent models were employed to investigate the effects of combinations of celecoxib and aspirin on gastric ulcerogenesis, bleeding, surface hydrophobicity (by contact angle analysis) and ulcer healing. We also evaluated the effects of phosphatidylcholine (PC)-associated aspirin in these rodent models and confirmed its cyclooxygenase (COX)-inhibitory activity by measuring mucosal prostaglandin E(2) (PGE(2)) concentration. We present evidence that aspirin's ability to induce gastric injury and bleeding in rats, was exacerbated in the presence of a coxib and was dependent on its ability to reduce gastric surface hydrophobicity. In contrast, co-administration of phosphatidylcholine (PC)-associated aspirin and celecoxib induced little or no gastric injury/bleeding and maintained the stomach's hydrophobic properties. Interestingly, aspirin and aspirin/PC equally inhibited gastric mucosal PGE(2) concentration. Aspirin in combination with a coxib retarded the healing of experimentally induced gastric ulcers, whereas healing rates of rats treated with celecoxib in combination with aspirin/PC were comparable to controls. CONCLUSIONS AND IMPLICATIONS: Aspirin's gastric toxicity in combination with a coxib can be dissociated from its ability to inhibit COX-1 and appears to be dependent, in part, on its ability to attenuate the stomach's surface hydrophobic barrier. This adverse drug interaction between aspirin and coxibs, which impacts the treatment of osteoarthritic and cardiac patients requiring cardiovascular prophylaxis, can be circumvented by the administration of phosphatidylcholine (PC)-associated aspirin, to maintain the stomach's hydrophobic properties.

Bioavailability of aspirin in rats comparing the drug's uptake into gastrointestinal tissue and vascular and lymphatic systems: implications on aspirin's chemopreventive action.

Aspirin is an effective analgesic and antiplatelet drug that in addition to its ability to reduce pain, inflammation and fever, appears to have efficacy in the prevention/treatment of a range of diseases including heart disease, numerous cancers and Alzheimer's. It is important to understand the bioavailability of aspirin and its major metabolite, salicylic acid, since dosage and route of administration can vary for treating differing diseases, and the major side-effects of aspirin, upper gastrointestinal ulceration and bleeding, are dose-dependent. We examined the time course for gastroduodenal uptake of aspirin and the appearance of its major metabolite salicylic acid in blood and lymph after intragastric (to simulate oral) and intraduodenal (to simulate enteric-coating) dosing in rats. Results show that after intragastric dosing, intact aspirin is absorbed primarily by the gastric mucosa and to a lesser extent by the duodenal mucosa. When aspirin is dosed intragastrically or intraduodenally, a much greater concentration of aspirin enters the lymph than the blood. In contrast, the concentration of salicylic acid was higher in blood than in lymph. Lymph levels of both aspirin and salicylic acid were sufficiently high so as to perform a pharmacologic function there, possibly as a chemopreventive agent against colon cancer and potentially the metastatic spread of non-gastrointestinal cancers.

Formula Feeding Predisposes Gut to NSAID-Induced Small Intestinal Injury.

OBJECTIVES: Breast feeding protects infants from many diseases, including necrotizing enterocolitis, peptic ulceration and infectious diarrhea. Conversely, maternal separation stress and Non-Steroidal Anti-Inflammatory Drugs (NSAID's) can induce intestinal injury and bleeding. This study aimed to evaluate in suckling rats if maternal separation/formula feeding leads to increased intestinal sensitivity to indomethacin (indo)-induced intestinal injury and to look at potential mechanisms involved. METHODS: Nine-day-old rats were dam-fed or separated/trained to formula-feed for 6 days prior to indo administration (5 mg/kg/day) or saline (control) for 3 days. Intestinal bleeding and injury were assessed by measuring luminal and Fecal Hemoglobin (Hob) and jejunal histology. Maturation of the intestine was assessed by measuring luminal bile acids, jejunal sucrase, serum corticosterone, and mRNA expression of ileal Apical Sodium-Dependent Bile Acid Transporter (ASBT). RESULTS: At 17 days, formula-fed indo-treated pups had a 2-fold increase in luminal Hb compared to formula-fed control pups and had evidence of morphological injury to the small intestinal mucosa as observed at the light microscopic level, whereas indo had no effect on dam-fed littermates. In addition, formula-fed rats had significant increases in luminal bile acid, sucrase specific activity, serum corticosterone, and expression of ASBT mRNA compared to dam-fed rats. CONCLUSION: Maternal separation stress may cause early intestinal maturational changes induced by corticosteroid release, including increased epithelial exposure to bile acids. These maturational changes may have a sensitizing rather than protective effect against indo-induced injury in the new-born.

Comparison of the gastrointestinal growth- promoting effects of rat colostrum and mature milk in newborn rats in vivo.

The purpose of this study was to compare the effects of rat colostrum and mature milk on newborn rat gastrointestinal growth under conditions that controlled the possible confounding effects of energy intake and mode of feeding. Newborn Sprague-Dawley rat pups were tubefed equicaloric amounts of rat colostrum or mature rat milk for 40 h before they were killed. Compared to littermates that were killed immediately after birth, both groups of fed rats demonstrated increases in the weights of stomach and intestine, but there was no organ weight difference detected between colostrum-fed and mature milk-fed rat pups. However, both the concentration of DNA and the rate of synthesis of DNA in the intestines were greater in rats fed colostrum than in those at birth or those mature milk. Although the pancreas exhibited no detectable increase in weight by 41 h, the DNA concentration and total DNA content increased and RNA/DNA ratio decreased in both fed groups, also without apparent difference between rats fed colostrum and those fed mature milk. The rate of 3H-thymidine incorporation into DNA in pancreas, however, was greater in colostrum-fed pups than in mature milk-fed pups. These differences at 40 h age in intestinal and pancreatic cell replication activity, but not organ weights, can be ascribed to feeding colostrum.

Localization of phospholipid-rich zones in rat gastric mucosa: possible origin of a protective hydrophobic luminal lining.

Mammalian gastric mucosa is unusually hydrophobic or nonwettable, which may be an essential biophysical characteristic of the gastric mucosal barrier. Since this property may be attributable to an adsorbed layer of surface-active phospholipids (SAPL), we investigated the distribution of SAPL in rat oxyntic mucosa. Ferric hematoxylin (FH) and iodoplatinate (IP), selective histochemical stains for phospholipids (as confirmed by spot tests), were used to detect SAPL in frozen sections and aldehyde-fixed tissue, respectively. Using FH staining in conjunction with extraction procedures that either solvate or preserve SAPL, we determined that positive reactivity was the greatest in the apical third of the oxyntic mucosa between the glandular neck region and the surface. IP reactivity appeared to parallel the FH staining pattern. Mucous cells, especially the surface epithelial cells, were heavily stained. Electron microscopic examination revealed that these cells contain inclusion bodies associated with various subcellular organelles, e.g., nuclear envelope, endoplasmic reticulum, Golgi apparatus and its vesicles, and mucous secretory granules. Vesicles and myelin figures, which resembled those found in lung surfactant, were observed extracellularly in close association with the surface mucous cells. Our findings suggest that mucous cells are actively involved in synthesis and storage of SAPL, which may be an essential component of the stomach's protective hydrophobic lining.

A method to preserve extracellular surfactant-like phospholipids on the luminal surface of rodent gastric mucosa.

Previous results from our laboratory employing the phospholipid-selective cytochemical stain iodoplatinate (IP) suggest that surfactant-like phospholipids (SLPL) are intracellularly contained within rodent gastric mucous cells and are occasionally seen extracellularly within the mucous gel layer. This hydrophobic lipid coating may provide the stomach with a protective water-repellent lining against the corrosive gastric juice in the lumen. Extracellular SLPL are frequently removed during tissue processing for electron microscopy. In this study, we developed a simple method employing an agarose-embedding technique to retain these extracellular SLPL in gastric mucosa excised from rats pre-treated with prostaglandin (to stimulate gastric surfactant/mucus secretion). With the help of polypropylene supporting screens and cassette carriers, thin slices of agarose-embedded gastric mucosa were well preserved and uniformly stained with IP. Extracellular myelin figures were well retained over the interfoveolar surface as well as in the pit region. The IP-reactive substances were seen within or coating the surface of the mucous gel. Our results also indicate that agarose is useful not only for supporting soft tissue while preparing sections with a microslicer but also for preservation of extracellular lipoidal material for electron microscopic observation.

Where is the evidence that cyclooxygenase inhibition is the primary cause of nonsteroidal anti-inflammatory drug (NSAID)-induced gastrointestinal injury? Topical injury revisited.

In this commentary, we take a critical look at the concept that the gastrointestinal (GI) side-effects of nonsteroidal anti-inflammatory drugs (NSAIDs) are due to the ability of these drugs to inhibit cyclooxygenase-1 (COX-1) that is constitutively expressed in the GI mucosa. Indeed, development of the new "super aspirins," such as Celebrex and Vioxx, that selectively inhibit the inducible COX-2, expressed in areas of inflammation, is a direct outgrowth of this concept. We discuss evidence from both the laboratory and the clinic that appears to be inconsistent with the above concept, and cite a number of examples where the depletion of mucosal prostaglandin levels and the development of GI injury can be dissociated. Instead, we revisit the possibility that NSAID-induced GI side-effects are mostly due to the ability of these drugs to topically injure the GI mucosa. We devote the remainder of the commentary to presenting evidence from our and other laboratories that NSAIDs can directly attenuate the surface hydrophobic barrier of the GI mucosa due to their ability to bind to zwitterionic phospholipids, and that even systemically administered NSAIDs that are secreted into the bile may induce GI ulceration and/or bleeding due to phospholipid interactions and the development of topical mucosal injury.

Interaction of indomethacin and naproxen with gastric surface-active phospholipids: a possible mechanism for the gastric toxicity of nonsteroidal anti-inflammatory drugs (NSAIDs).

The possibility that the molecular mechanism underlying the topical gastric irritancy of nonsteroidal anti-inflammatory drugs (NSAIDs) may involve alterations in the surface-active properties of gastric phospholipids was investigated. Indomethacin and naproxen were intragastrically administered to rats and the hydrophobicity of the luminal surface of the stomach wall was assessed by contact angle analysis. Both NSAIDs have the ability to attenuate the phospholipid-related hydrophobic properties of the gastric mucosa by more than 80-85% in a dose-dependent fashion. Potential molecular interactions between both NSAIDs and surface-active phospholipids were analyzed using fluorescent probes. Indomethacin has the ability to displace, in a dose-dependent manner, ANS (1-anilino-8-naphthalene sulphonate), a fluorescent anionic probe previously bound to the head group of phosphatidylcholine molecules. Estimations of the resonance fluorescence transfer between naproxen and the surface probe ANS or the hydrophobic probe, pyrene, bound to dipalmitoylphosphatidylcholine (DPPC) vesicles revealed that naproxen diffuses within the phospholipid bilayers. The dynamic of the gastric lipid material extracted from the surface scraping material (SSM) of the mucosa was altered by the NSAID as shown by the increase in the steady-state fluorescence anisotropy of 1,6-diphenyl-1,3,5-hexatriene (DPH) (at 25 degrees, rSSM = 0.106+/-0.006, rssM + indomethacin = 0.137+/-0.005, and rSSM + naproxen = 0.133+/-0.007, P < 0.001). The thermodynamic behavior of a model bilayer containing DPPC was also perturbed by the NSAIDs tested. These results provide evidence that NSAIDs may reduce the ability of gastric surface-active phospholipids to form a hydrophobic protective layer.

Effect of ranitidine bismuth citrate on the phospholipase A2 activity of Naja naja venom and Helicobacter pylori: a biochemical analysis.

BACKGROUND: Helicobacter pylori has become recognized as a fundamental pathogen in the development of gastritis and peptic ulcer disease. Bismuth compounds in combination with antibiotics are widely used to treat H. pylori associated peptic ulcer disease. METHODS: In this study we measured and analysed the inhibitory effect of ranitidine bismuth citrate (RBC, Pylorid, Tritec) on the activity and kinetics of phospholipase A2 (PLA2) (E.C.3.1.1.4) of commercial cobra (Naja naja) venom and H. pylori (French press lysates) using L-alpha-dipalmitoyl-(2[1-14C]palmitoyl)-phosphatidylcholine as substrate. RESULTS: Our data suggest that RBC might exert a dose-dependent uncompetitive inhibition on PLA2 activity of both H. pylori and Naja naja venom. the inhibitory effect of RBC on the PLA2 activity cannot be abolished by the optimal concentration of calcium (10 mM), indicating its mechanism to be unrelated to the displacement of calcium from the activation site of the enzyme. CONCLUSION: Our results suggest that one of the mechanisms by which bismuth compounds are therapeutically effective in the treatment of H. pylori associated gastritis is by inhibiting the activity of the degradative PLA2 enzyme secreted by H. pylori. As a consequence of the inhibitory action of RBC on PLA2 of the bacteria, the extracellular and/or intracellular phospholipid components of the gastric mucosal barrier are preserved.

Effect of pepper and bismuth subsalicylate on gastric pain and surface hydrophobicity in the rat.

BACKGROUND: The mechanism by which dietary pepper causes dyspepsia and epigastric pain is poorly understood, as is the ability of bismuth subsalicylate (BSS) to relieve these symptoms. AIM: To investigate the ability of black pepper, red pepper and BSS to affect gastric surface hydrophobicity and induce/relieve visceral pain in rat model systems. METHODS: Fasted rats were administered intragastrically Vivonex containing varying concentrations of either black or red pepper (0-200 mg/mL) and gastric contact angles were read after 1-24 h. Some rats were post-treated with BSS (2.0-17.5 mg/mL) and contact angles were read after 2-18 h. To study pain sensitivity in rats treated with pepper/BSS, we compared tail-flick latencies after the application of radiant heat. RESULTS: Both black and red pepper rapidly (< 1 h) induced a decrease in gastric surface hydrophobicity in a dose-dependent fashion. This spice-induced increase in surface wettability was long-lasting, could be enhanced in the presence of ethanol and reversed by post-treating the rats with BSS. Both black and red pepper induced an increase in pain sensitivity, consistent with the presence of gastric pain, which could also be reversed by post-treating the rats with BSS. CONCLUSION: Both black and red pepper may induce epigastric pain by removing the stomach's hydrophobic lining and activating intramucosal pain receptors. BSS may provide relief from postprandial dyspepsia by restoring the stomach's non-wettable properties.

Effect of omeprazole on the bioavailability of unmodified and phospholipid-complexed aspirin in rats.

BACKGROUND: Treatment and prevention of non-steroidal anti-inflammatory drug-induced gastropathy involve the concurrent use of antisecretory drugs. Recently, we have shown that the ability of these drugs to increase the intragastric pH to values > > pKa of NSAIDs compromises their therapeutic activity. In the present study, we evaluated the potential of omeprazole to interfere with the bioavailability of aspirin administered to rats either alone or complexed with the zwitterionic phospholipid, dipalmitoylphosphatidylcholine (DPPC). METHODS: Aspirin or aspirin/DPPC was administered intragastrically to rats pre-dosed with either saline or omeprazole. Concentrations of aspirin and salicylic acid in the blood and the gastric mucosa were assessed by HPLC and the 6-keto-PGF1 alpha gastric mucosal concentration by radioimmunoassay. RESULTS: Gastric absorption of aspirin and its relative bioavailability were reduced by an antisecretory dose of omeprazole; its inhibitory effect on gastric prostaglandin synthesis was consequently attenuated. However, these effects could be partly overcome if aspirin was administered as a complex with DPPC. CONCLUSIONS: These observations suggest that: (i) DPPC increases the lipid solubility and gastric permeability of NSAIDs; and (ii) neutralization of the gastric pH results in a shift of aspirin absorption toward the intestine where it could be degraded to salicylic acid.

Failure to isolate Helicobacter pylori from stray cats indicates that H. pylori in cats may be an anthroponosis--an animal infection with a human pathogen.

The recent isolation of Helicobacter pylori from cats obtained from a commercial supplier has potentially important public health implications. The present study investigated whether H. pylori infection was common in stray cats. Twenty-five cats were examined for the presence of H. pylori by histological examination, culture and two polymerase chain reaction (PCR) assays. Histologically, the gastric biopsy specimens from all cats showed large spiral organisms typical of H. felis and not H. pylori. Samples from 23 cats yielded bacterial growth and two had no growth. Colonies grossly similar to H. pylori were tested for catalase, oxidase, urease and Gram's stain reactions. None was H. pylori. All samples tested as positive by the Helicobacter 16S rRNA genus-specific PCR assay and only six cats and a mouse stomach infected with H. heilmannii gave positive results with the adhesin subunit A (hpaA)-specific PCR assay, which is consistent with either H. pylori or H. heilmannii. The helicobacters identified in these samples by PCR were not cultivable and hence were probably H. heilmannii. H. pylori infection is uncommon in stray cats and owning pet cats should not be a threat to public health in relation to H. pylori infection.

Recombinant human lactoferrin is effective in the treatment of Helicobacter felis-infected mice.

Recombinant human lactoferrin possesses in-vitro antibiotic and anti-inflammatory activity similar to the native form. It was tested for in-vivo activity in mice infected with the gastritis-inducing bacterium Helicobacter felis. A two-week course of treatment with lactoferrin was sufficient to partially reverse both infection-induced gastritis and the infection rate, and fully reverse gastric surface hydrophobicity changes. A comparison of lactoferrin with amoxicillin and standard triple therapy revealed no differences in infection rate. These results show that recombinant human lactoferrin is effective in a mouse model of Helicobacter infection, and support further testing of this promising agent for this application.

Aspirin's ability to induce intestinal injury in rats is dependent on bile and can be reversed if pre-associated with phosphatidylcholine.

Clinical evidence suggests that aspirin and particularly enteric-coated aspirin induce significant injury to the lower gut. We have reported that NSAID injury to the small bowel is exacerbated by bile acids and that phosphatidylcholine (PC) can protect against this damage. Using a recently described method, we intra-duodenally administered either: saline, aspirin or aspirin pre-associated with PC. The rats were euthanized 90 minutes later at which time we assessed: tissue injury morphologically, vascular permeability with i.v. administered Evan's blue and intestinal bleeding by measuring luminal hemoglobin. In a separate experiment, aspirin-induced injury was studied in rats whose bile duct was ligated either alone or in the presence of rat bile (collected from donor animals). Intra-duodenal administration of aspirin induced mucosal injury (observed histologically), an increase in vascular permeability and blood loss into the intestinal lumen, all of which could be attenuated if the NSAID was pre-associated with PC. Furthermore, using 100 mg/kg dose of aspirin it was determined that bile duct ligation (BDL) significantly reduced aspirin-induced intestinal bleeding which was not different from control rats. Lastly, it was determined that intestinal bleeding was significantly increased in rats with BDL if the aspirin was administered in rodent bile. Aspirin-induced intestinal injury and bleeding in the rat is dependent on the presence of luminal bile, which is likely attributable to it's constituent bile acids. Pre-association of aspirin with PC provides a novel therapeutic approach to significantly reduce aspirin-induced small intestinal injury and bleeding, as may occur with enteric-coated aspirin.

Gastrointestinal safety and therapeutic efficacy of parenterally administered phosphatidylcholine-associated indomethacin in rodent model systems.

BACKGROUND AND PURPOSE: Indomethacin is a non-steroidal anti-inflammatory drug (NSAID) that is limited in its enteral or parenteral use by side effects of gastroduodenal bleeding and ulceration. We have investigated the ability of phosphatidylcholine associated with indomethacin to form a therapeutically effective drug (INDO-PC) with reduced gastrointestinal (GI) toxicity for parenteral use. EXPERIMENTAL APPROACH: Rats were treated acutely by intravenous or chronically with subcutaneous injection of vehicle, indomethacin or INDO-PC using three related protocols. We then evaluated the following properties of these parenterally administered test drugs: (i) GI toxicity (luminal and faecal haemoglobin; intestinal perforations and adhesions; and haematocrit); (ii) bioavailability (plasma indomethacin); and (iii) therapeutic efficacy (analgesia from sensitivity to pressure; anti-inflammatory from ankle thickness; cyclo-oxygenase (COX) inhibition from synovial fluid prostaglandin E(2) concentration) in rats with adjuvant-induced joint inflammation. KEY RESULTS: Acute and chronic dosing with INDO-PC produced less GI bleeding and intestinal injury than indomethacin alone, whereas the bioavailability, analgesic, anti-inflammatory and COX inhibitory activity of INDO-PC were comparable to indomethacin. CONCLUSIONS AND IMPLICATIONS: The chemical association of phosphatidylcholine with indomethacin appears to markedly reduce the GI toxicity of the NSAID while providing equivalent therapeutic efficacy in a parenteral INDO-PC formulation.

Clinical trial: comparison of ibuprofen-phosphatidylcholine and ibuprofen on the gastrointestinal safety and analgesic efficacy in osteoarthritic patients.

BACKGROUND: Chronic use of NSAIDs is associated with gastrointestinal (GI) toxicity that increases with age. AIM: To evaluate the GI safety and therapeutic efficacy of ibuprofen chemically associated with phosphatidylcholine (PC) in osteoarthritic (OA) patients. METHODS: A randomized, double-blind trial of 125 patients was performed. A dose of 2400 mg/day of ibuprofen or an equivalent dose of ibuprofen-PC was administered for 6 weeks. GI safety was assessed by endoscopy. Efficacy was assessed by scores of analgesia and anti-inflammatory activity. Bioavailability of ibuprofen was pharmacokinetically assessed. RESULTS: Ibuprofen-PC and ibuprofen provided similar bioavailability/therapeutic efficacy. In the evaluable subjects, a trend for improved GI safety in the ibuprofen-PC group compared with ibuprofen that did not reach statistical significance was observed. However, in patients aged >55 years, a statistically significant advantage for ibuprofen-PC treatment vs. ibuprofen in the prevention of NSAID-induced gut injury was observed with increases in both mean Lanza scores and the risk of developing >2 erosions or an ulcer. Ibuprofen-PC was well tolerated with no major adverse events observed. CONCLUSION: Ibuprofen-PC is an effective osteoarthritic agent with an improved GI safety profile compared with ibuprofen in older OA patients, who are most susceptible to NSAID-induced gastroduodenal injury.

The hydrophobic barrier properties of gastrointestinal mucus.

Impressive evidence has accumulated over the past 12 years indicating that one of the potentially important biophysical characteristics of mucus relates to its hydrophobic character. This surface property is region specific and reaches high values in the stomach and colon, where barrier properties against noxious agents in the lumen are most important. The hydrophobic properties of mucus appear to be related to its lipidic constituents and specifically to the presence of phospholipid surfactants that are synthesized, stored, and secreted by GI mucus cells in a regulated fashion.