Understanding nonsteroidal antiinflammatory drug (NSAID) use and impact on common rheumatic and arthritic conditions is critical to reconciling their appropriate use with their potentially serious adverse effects. NSAIDs have a profound impact on the treatment of connective tissue disorders because of their ability to address the underlying cause with specific benefits of decreasing stiffness and inflammation, and improving mobility. NSAID use is twice as common as opioid use, and inappropriate use of NSAIDs is widespread. NSAID use should be monitored and the impact understood to mitigate the risks. NSAID discontinuation should be evidence based and individualized to specific requirements.

The present studies were designed to evaluate inhalatory microparticles carrying indomethacin (IN) for potential local (specific and non-specific bronchial inflammatory asthma responses) and systemic treatments (joint inflammation, rheumatoid arthritis and osteoarthritis pain) by optimizing microparticle properties, characterizing their lung deposition, drug release, evaluating cytotoxicity and also pharmacological effect in vitro. The acidic groups of IN were complexed with the cationic groups of the polyelectrolyte polylysine in order to increase the drug water compatibility. The polylysine/indomethacin ratio was fixed and the pH was adjusted in different formulations. Microparticles were obtained by spray drying using a relatively high atomization air flowrate (742 L/min) and a high-performance cyclone in order to optimize the production of microparticles with adequate attributes for inhalatory delivery. The produced microparticles exhibited high process yield and IN loading, volumetric mean diameters smaller than 5 μm and narrow particle size distributions. According to demonstrated aerosolization performance, the powders were suitable for inhalatory indomethacin local and systemic treatments. Emitted fraction was higher than 90%, the MMAD was around 3 μm and the GSD lower than 3. The respirable fraction for particles with aerodynamic diameters smaller than 5 μm was around 29% while for particles with aerodynamic diameters smaller than 3 μm the value was around 17%. The addition of lactose as carrier worsened the aerodynamic performance of the microparticles. The developed powdered systems got wet and dissolved quickly and presented higher release rates respect to pure IN in simulated lung physiological conditions. Furthermore, the assays performed in RAW 264.7 cell line showed that the microparticles exhibited the same anti-inflammatory capability as the pure drug. The developed particles did not affect the RAW 264.7 cell viability. In conclusion, a promising powder formulation for DPIs has been developed to treat, locally and systemically, inflammatory diseases.

The skin is a formidable diffusion barrier that restricts passive diffusion to small (<500 Da) lipophilic molecules. Methods used to permeabilize this barrier for the purpose of drug delivery are maturing as an alternative to oral drug delivery and hypodermic injections. Ultrasound can reversibly and non-invasively permeabilize the diffusion barrier posed by the skin. This review discusses the mechanisms of ultrasound-permeability enhancement, and presents technological innovations in equipment miniaturization and recent advances in permeabilization capabilities. Additionally, potentially exciting applications, including protein delivery, vaccination, gene therapy and sensing of blood analytes, are discussed. Finally, the future challenges and opportunities associated with the use of ultrasound are discussed. It is stressed that developing ultrasound for suitable applications is key to ensure commercial success.

Complex secondary metabolites, some of which are highly toxic to mammals, are produced by many marine organisms. Some of these organisms are important food sources for marine animals and, when ingested, the toxins that they produce may be absorbed and stored in the tissues of the predators, which then become toxic to animals higher up the food chain. This is a particular problem with shellfish, and many cases of poisoning are reported in shellfish consumers each year. At present, there is no practicable means of preventing uptake of the toxins by shellfish or of removing them after harvesting. Assessment of the risk posed by such toxins is therefore required in order to determine levels that are unlikely to cause adverse effects in humans and to permit the establishment of regulatory limits in shellfish for human consumption. In the present review, the basic principles of risk assessment are described, and the progress made toward robust risk assessment of seafood toxins is discussed. While good progress has been made, it is clear that further toxicological studies are required before this goal is fully achieved.

In the last years a large variety of drug delivery systems have been developed to improve bioavailability of therapeutics in oral administration. An increasing interest has arisen in reservoir-based microdevices designed for active ingredients like water insoluble compounds and fragile biomolecules. Such microdevices are designed to protect the active ingredient against degradation and deactivation, and to allow cytoadhesion and unidirectional drug release. There are few works which optimize the drug loading step and often therapeutics are dosed in the microdevices through laborious and time consuming procedures. This work proposes an effective loading technique for a poorly soluble model drug in microcontainers, by combining inkjet printing and supercritical fluid impregnation. Well defined quantities of poly(vinyl pyrrolidone) (PVP) solutions are dispensed into microcontainers by inkjet printing with a quasi-no-waste performance. Then ketoprofen is impregnated in the polymer matrix by using supercritical carbon dioxide (scCO2) as loading medium. The amount of polymer is controlled by the volume and the number of droplets of dispensed polymer and drug loading is tuned by varying the impregnation parameters. Compared to solid dispersions of the same drug and polymer, scCO2-impregnated microcontainers exhibit a more reproducible drug loading and a faster dissolution rate of the active compound which allows drug release to be modulated. The combination of these loading techniques potentially allows the high throughput fabrication of microdevices for oral drug delivery with a safe and solvent-free solution.

Cyclooxygenase (COX) catalyzes the conversion of arachidonic acid into prostaglandins (PGs), which play a significant role in health and disease in the gastrointestinal tract (GI) and in the renal, skeletal, and ocular systems. COX-1 is constitutively expressed and found in most normal tissues, whereas COX-2 can be expressed at low levels in normal tissues and is highly induced by pro-inflammatory mediators. Inhibitors of COX activity include: (1) conventional nonselective, nonsteroidal anti-inflammatory drugs (ns-NSAIDs) and (2) COX-2 selective nonsteroidal anti-inflammatory drugs (COX-2 s-NSAIDs). Inhibition of COX-1 often elicits GI toxicity in animals and humans. Therefore, COX-2 s-NSAIDs were developed to provide a selective COX-2 agent, while minimizing the attendant COX-1-mediated GI toxicities. Rats and dogs overpredict COX inhibition for renal effects such as renal handling of electrolytes in humans. COX inhibitors are shown to have both beneficial and detrimental effects, such as on healing of ligament or tendon tears, on the skeletal system in animal models. Certain ophthalmic conditions such as glaucoma and keratitis are associated with increased COX-2 expression, suggesting a potential role in their pathophysiology.

The effect of Quebrachitol (2-O-methyl-L-inositol), a bioactive component from Magonia glabrata fruit extract was investigated against gastric damage induced by absolute ethanol (96%, 0.2 ml/animal) and indomethacin (30 mg/kg, p.o.), in mice. Quebrachitol at oral doses of 12.5, 25, and 50mg/kg markedly attenuated the gastric lesions induced by ethanol to the extent of 69%, 64%, and 53% and against indomethacin by 55%, 59%, and 26%, respectively. While pretreatment with TRPV1 antagonist capsazepine (5mg/kg, i.p.) failed to block effectively the gastroprotective effect of quebrachitol (25mg/kg) against ethanol damage, the non-selective cyclooxygenase inhibitor indomethacin (10mg/kg, p.o.), almost abolished it. Furthermore, quebrachitol effect was significantly reduced in mice pretreated with L-NAME, or glibenclamide, the respective inhibitors of nitric oxide synthase and K(+)(ATP) channel activation. Thus we provide the first evidence that quebrachitol reduces the gastric damage induced by ethanol and indomethacin, at least in part, by mechanisms that involve endogenous prostaglandins, nitric oxide release, and or the activation of K(+)(ATP) channels.

Probably all non-steroidal anti-inflammatory drugs (NSAIDs) increase the risk of gastrointestinal (GI) mucosal injury. The most frequent lesions are gastric erosions in the pre-pyloric region. Non-steroidal anti-inflammatory drugs also increase the incidence of peptic ulcers, although it is not yet clear whether more gastric ulcers or more duodenal ulcers are produced. Gastrointestinal symptoms are prevalent during NSAID treatment, but there is no correlation between symptoms and lesions. Clinical presentation may therefore vary considerably: many symptomatic patients will have no lesions, whereas others will present with complications but no symptoms. Blood loss is the most frequent complication of NSAID-induced GI lesions. Bleeding is usually 'silent' and occult. Overt haemorrhage, though rare, is more frequent in patients taking NSAIDs. Other complications, such as penetration and perforation, may also occur. Endoscopy is the diagnostic method of choice, as this method can detect even superficial mucosal lesions. However, because of the lack of correlation between symptoms and lesions, it is difficult to ascertain which patients are at risk and thus to avoid unnecessary diagnostic procedures. Future efforts should therefore be directed towards the prevention of NSAID-induced GI lesions.

Concepts are reviewed of the effects of anti-ulcer agents in counteracting the biochemical and cellular pathology of gastrointestinal injury by non-steroidal anti-inflammatory drugs (NSAIDs). While some measure of control of NSAID-induced mucosal damage is achieved in the upper gastrointestinal tract by the currently available anti-ulcer drugs, none can effectively counteract the major biochemical changes induced by NSAIDs. Some experimental approaches, which have been developed from recent studies in laboratory animals, are considered as a possible basis towards developing improvements in preventive procedures against NSAID-induced gastrointestinal injury in man.

Cyclooxygenase (COX) is a rate-limiting enzyme that catalyzes the conversion of arachidonic acid, an essential fatty acid present in cell membrane phospholipids and liberated by phospholipase, into prostaglandins (PGs) and prostanoids. COX has two distinct membrane-anchored isoenzymes; COX-1 and COX-2. COX-1 is a constitutively expressed and found in most normal body tissues; COX-2 is expressed in normal tissues at low levels and is highly induced by pro-inflammatory mediators in the setting of inflammation, injury, and pain. Inhibitors of COX activity include: (1) conventional non-selective non-steroidal anti-inflammatory drugs (ns-NSAIDs); (2) selective COX-2 inhibitors (COXIBs); and (3) COX-1 inhibitors. Non-selective NSAIDs, at therapeutic doses, inhibit both COX-1 and COX-2. The anti-inflammatory benefits of these drugs are primarily derived from COX-2 inhibition, while inhibition of COX-1 often elicits gastrointestinal (GI) toxicity. Therefore, COXIBs were developed to provide a selective COX-2 agent, i.e., one, that at fully therapeutic doses demonstrated comparable therapeutic benefit to non-selective NSAIDs, without the attendant COX-1-mediated GI toxicities. In this review, we evaluate available literature describing the pathophysiologic role of cyclooxygenases and the effects of their inhibition in GI system in experimental and domestic animal species.

In this study the antinociceptive and the gastroprotective effects of orally administered or inhaled Lavandula hybrida Reverchon "Grosso" essential oil, and its principal constituents linalool and linalyl acetate were evaluated in rodents. Either when orally administered (100 mg/kg) or inhaled for 60 min lavender essential oil significantly reduced the acetic acid-writhing response in a naloxone-sensitive manner. In the hot plate test, analgesic activity observed after oil inhalation was inhibited by naloxone, atropine, mecamylamine pretreatment suggesting the involvement of opioidergic as well as cholinergic pathways. Regardless of the administration route and the experimental model used both linalool and linalyl acetate did not produce significant analgesic response. Oral or inhalatory treatment with analgesic doses of essential oil did not affect mice spontaneous locomotor activity. Concerning the gastric effects, lavender oil, linalool and linalyl acetate oral administration protected against acute ethanol-induced gastric ulcers but did not prevent indomethacin-induced lesions indicating no interference with arachidonic acid metabolic cascade. In conclusion, besides this gastroprotection, lavender oil reveals an interesting analgesic activity mainly relevant after inhalation, at doses devoid of sedative side effect, suggesting the interest for potential application of this oil in aromatherapy.

Nonsteroidal anti-inflammatory drugs (NSAIDs) induced formation of intestinal ulcers as side effects, in which an unbalanced increase in the number of gram-negative bacteria in the small intestine plays an important role. To clarify how intestinal microflora are influenced by NSAIDs, we examined the effects of 5-bromo-2-(4-fluorophenyl)-3-(4-methylsulfonylphenyl) thiophene (BFMeT), an NSAID, on intestinal motility and on the growth of Escherichia coli and Lactobacillus acidophilus. Transit index, a marker of peristalsis, was not different in BFMeT-treated and solvent-treated rats, indicating that BFMeT increased the number of gram-negative bacteria without suppression of peristalsis. The factors that affect the growth of intestinal bacteria were not found in intestinal contents of BFMeT-treated rats, because the growth of E. coli and that of L. acidophilus in the supernatants of small intestinal contents of BFMeT-treated rats and solvent-treated rats were not different. The mechanism of the increase in the number of gram-negative bacteria is still unclear, but heat-killed E. coli cells and their purified lipopolysaccharide (LPS) caused deterioration of BFMeT-induced ileal ulcers, while they could not cause the ulcers by themselves without the NSAID. Concentration of LPS and myeloperoxidase activity level were elevated correlatively in the intestinal mucosa of rats treated with LPS and BFMeT. These results suggest that an increase in the number of gram-negative bacteria and their LPS in the mucosa induces activation of neutrophils together with the help of NSAID action and causes ulcer formation.

The aim of this experimental study was to investigate the effect of diclofenac sodium and ketoprofen, two non-steroidal anti-inflammatory drugs (NSAIDs) with different excretion pathways, and the role of other enteric factors during simultaneous administration of these drugs on the development of mucosal lesions of the small intestine in canines. Twenty-five animals were divided into three groups. Group I included 10 canines, 5 with diclofenac sodium (group Ia) and 5 with ketoprofen administration (group Ib). Group II included 5 animals in which a segment of ileum was surgically isolated from the rest of the small intestine. Group III included 10 animals in two subgroups of 5; a segment of ileum was surgically isolated in both subgroups; groups IIIa received diclofenac and group IIIb ketoprofen. Histological examination of the specimens taken revealed macroscopic and microscopic mucosal lesions in 5/5 animals in group Ia, whereas none of the 5 animals in group Ib had any lesions. Group II did not reveal any mucosal lesions. Three out of 5 animals (60%) administered diclofenac in group IIIa had intestinal mucosal lesions, but none of the 5 revealed lesions in the isolated loop of ileum. No lesions were observed in the isolated loop or in the rest of the intestinal mucosa in the animals in group IIIb. Our results suggest that NSAIDs produce intestinal mucosal lesions not only when administered per mouth but also after intramuscular administration. Diclofenac, unlike ketoprofen, was responsible for the development of lesions in the intestinal mucosa. The role of drugs and/or their metabolites in the intestine and certain other factors must still be determined.

Ileal ulcers and thiobarbituric acid (TBA)-reactive substances in the ileal mucosa were induced in rats treated with a nonsteroidal antiinflammatory drug, 5-bromo-2-(4-fluorophenyl)-3-(4-methylsulfonylphenyl)thiophene (BFMeT), at a dose of 1,000 mg/kg administered with tap water as drinking water. However, the formation of ileal ulcers and TBA-reactive substances in the ileal mucosa was repressed by giving the animals a culture supernatant of Lactobacillus acidophilus as drinking water. We measured the antioxidative activity of the culture supernatant and found that the supernatant inhibited the formation of t-butyl hydroperoxide-induced TBA-reactive substances in erythrocyte membrane ghosts. Therefore, the effects of various known antioxidative compounds on the ileal ulcer formation induced by BFMeT were investigated. While alpha-tocopherol, t-butyl-1,4-hydroxyanisole and allopurinol did not repress ulcer formation after BFMeT treatment, ascorbic acid, dimethyl sulfoxide, glutathione and beta-carotene significantly inhibited formation. Among these compounds, ascorbic acid was the most effective. Accumulation of TBA-reactive substances in the ileal mucosa after BFMeT treatment also decreased significantly in rats treated with ascorbic acid. In addition, the percentage of gram-negative rods in the ileal contents of rats treated with BFMeT and tap water was dramatically increased, but it was not increased in rats treated with BFMeT and these antioxidants. A positive correlation between the percentage of gram-negative rods and the number of ileal ulcers was also observed. These results suggest that lipid peroxidation mediated by oxygen radicals plays an important role in the induction of ileal ulcers by BFMeT in rats, and that lipopolysaccharide-activated neutrophils probably produce highly reactive hypochlorous acid and hydrogen peroxide, which are inactivated by ascorbic acid and glutathione, respectively.

A nonsteroidal antiinflammatory drug, 5-bromo-2-(4-fluorophenyl)-3-(4-methylsulfonylphenyl) thiophene (BFMeT), induced ileal ulcers in rats after oral administration, while no ulcers were observed after subcutaneous injection. The ileal ulcer formation in BFMeT-treated rats was examined to correlate the administration of cultures of Lactobacillus acidophilus or Bifidobacterium adolescentis with intestinal bacteria in the ileal contents and lipid peroxidation of the small intestinal mucosa. Ileal ulcers were observed in more than 85% of the rats treated with BFMeT at a dose of 1,000 mg/kg when they were given tap water as drinking water. The incidence of ulcer formation was repressed by giving culture supernatants of L. acidophilus or B. adolescentis as drinking water, but not by giving the cell suspension as drinking water. Gram staining of the ileal contents of normal rats revealed that 97% of the stained bacteria were gram-positive rods and only 1.5% were gram-negative rods. The percentage of gram-negative rods 72 hr after BFMeT administration was 49.8% and increased over 30-fold in BFMeT-treated rats. However, the percentage of gram-negative rods was 9.7 % or 16%, respectively, in rats taking culture supernatants of L acidophilus or B. adolescentis. In addition, thiobarbituric acid-reactive substances in the ileal mucosa increased significantly in the rats given tap water for 72 hr after BFMeT treatment, but not in rats given the culture supernatants of L. acidophilus or B. adolescentis. Since BFMeT induced an unbalanced intestinal microflora, the effect of antibiotic treatment on ulcer formation in rats was examined. The magnitude of the ulcer formation in the antibiotic-treated rats was, in decreasing order, metronidazole >none > kanamycin > a mixture (bacitracin, neomycin and streptomycin). These results suggest that the intestinal microflora plays an important role in ulcer formation and that a metabolite(s) of L. acidophilus and B. adolescentis inhibits ileal ulcer formation by repressing changes in the intestinal microflora and lipid peroxidation in BFMeT-treated rats.

Intrapleural injection of carrageenan in rats increased prostaglandin E2 (PGE2) production and induced newly synthesized cyclooxygenase-2 (COX-2) in pleural exudate cells without affecting COX-1 levels. Nimesulide, a preferential inhibitor of COX-2, reduced pleural PGE2 production and was almost as active as indomethacin and 10 times more active than ibuprofen. Only COX-1, and nc COX-2, was detected in gastric mucosal cells, and PGE2 concentration of gastric mucosa was significantly decreased by indomethacin and ibuprofen. The decrease in gastric PGE2 production induced by indomethacin and ibuprofen was enhanced in stressed rats, resulting in aggravation of stress-induced gastric lesions at anti-inflammatory doses. However, nimesulide did not produce stress-induced gastric lesions even at 30 times the anti-inflammatory dose. This supports the hypothesis that inhibition of COX-1 causes unwanted side effects and inhibition of COX-2 produces anti-inflammatory effects.

Adverse GI effects of NSAIDs include dyspepsia, occult bleeding, overt bleeding and ulcer disease. Consequences of NSAID-induced GI toxicity include anemia, hospitalization, and death. External factors, such as drugs and alcohol, can disrupt the gastric barrier that protects the GI tract from erosive substances. Pharmacists should counsel patients who frequently use non-prescription analgesics and determine whether further medical evaluation is needed. In contrast to NSAIDs, acetaminophen has not been associated with GI toxicity of increased risk of GI tract bleeding.

The role of intestinal bacteria in induction and repression of ulcer formation in the ileum of rats treated with one of the nonsteroidal antiinflammatory drugs (NSAIDs), 5-bromo-2-(4-fluorophenyl)-3-(4-methylsulfonylphenyl) thiophene (BFMeT), was examined in this study. BFMeT was administered by intragastric gavage once at doses of 500-1,500 mg/kg of body weight to Wistar rats treated with and without antibiotics (bacitracin, neomycin, streptomycin), germ-free rats and gnotobiotic rats, and 72 hr later their gastrointestinal tracts were examined for ulcer formation. A single oral administration of BFMeT induced ileal ulcers in specific pathogen-free rats. However, the rats given antibiotics to reduce the intestinal bacteria had no ulcers. BFMeT-treated germ-free rats and gnotobiotic rats mono-associated with Bifidobacterium adolescentis or Lactobacillus acidophilus also had no intestinal ulcers. However, the drug induced ileal ulcers in gnotobiotic rats mono-associated with Eubacterium limosum or Escherichia coli. An overnight culture of B. adolescentis or L. acidophilus or yogurt containing Bifidobacterium breve and Streptococcus thermophilus, when given as drinking water, inhibited ulcer formation in the ileum of rats treated with BFMeT. Gram staining of the ileal contents of normal rats revealed that 97.4% of the stained microorganisms were Gram-positive rods and only 1.2% were Gram-negative rods. In the group of rats with ulcers induced by BFMeT, the Gram-positive rods decreased by 56.4% and the Gram-negative rods including Escherichia coli, Klebsiella, Proteus and Bacteroides increased by 37.3%. However, in the group of rats administered the Bifidobacterium culture, the Lactobacillus culture or yogurt, the percentages of the Gram-negative rods were decreased. Although Lactobacillus was a major bacterium in the ileum of normal rats, the Gram-negative facultatively anaerobic rods E.coli, Klebsiella and Proteus were increased in the ulcerated ileum of rats treated with BFMeT, suggesting that these bacteria are associated with ulcer formation in rats treated with NSAIDs, and that Lactobacillus and Bifidobacterium inhibit it by repressing the growth of ulcer-inducing bacteria.

Constitutive cyclooxygenase (COX-1; prostaglandin-endoperoxide synthase, EC 1.14.99.1) is present in cells under physiological conditions, whereas COX-2 is induced by some cytokines, mitogens, and endotoxin presumably in pathological conditions, such as inflammation. Therefore, we have assessed the relative inhibitory effects of some nonsteroidal antiinflammatory drugs on the activities of COX-1 (in bovine aortic endothelial cells) and COX-2 (in endotoxin-activated J774.2 macrophages) in intact cells, broken cells, and purified enzyme preparations (COX-1 in sheep seminal vesicles; COX-2 in sheep placenta). Similar potencies of aspirin, indomethacin, and ibuprofen against the broken cell and purified enzyme preparations indicated no influence of species. Aspirin, indomethacin, and ibuprofen were more potent inhibitors of COX-1 than COX-2 in all models used. The relative potencies of aspirin and indomethacin varied only slightly between models, although the IC50 values were different. Ibuprofen was more potent as an inhibitor of COX-2 in intact cells than in either broken cells or purified enzymes. Sodium salicylate was a weak inhibitor of both COX isoforms in intact cells and was inactive against COX in either broken cells or purified enzyme preparations. Diclofenac, BW 755C, acetaminophen, and naproxen were approximately equipotent inhibitors of COX-1 and COX-2 in intact cells. BF 389, an experimental drug currently being tested in humans, was the most potent and most selective inhibitor of COX-2 in intact cells. Thus, there are clear pharmacological differences between the two enzymes. The use of such models of COX-1 and COX-2 activity will lead to the identification of selective inhibitors of COX-2 with presumably less side effects than present therapies. Some inhibitors had higher activity in intact cells than against purified enzymes, suggesting that pure enzyme preparations may not be predictive of therapeutic action.

This double-blind, parallel group study was conducted to evaluate the gastroduodenal safety and antiarthritic efficacy of a fixed combination of diclofenac sodium 50 mg and misoprostol 200 mcg, compared with a combination of diclofenac 50 mg and placebo. Three hundred and thirty-nine patients with rheumatoid arthritis and no significant gastric or duodenal mucosal damage were enrolled and received study medication (diclofenac/misoprostol, 164; diclofenac/placebo, 175) BID or TID for 12 weeks. Posttreatment gastroduodenal endoscopic examinations revealed ulcers in 11% of the diclofenac/placebo group, compared with only 4% of the diclofenac/misoprostol group (p = 0.034). Four-weekly assessments of arthritic condition revealed no clinically or statistically significant treatment differences. It was concluded that diclofenac/misoprostol caused significantly less gastroduodenal damage than diclofenac, but was as effective as diclofenac alone in the treatment of rheumatoid arthritis.

Epidemiological evidence consistently indicates that aspirin or non-aspirin non-steroidal anti-inflammatory drug use is associated with the occurrence of gastric ulceration, gastric and ulcer bleeding, and ulcer death. Evidence on duodenal ulcer occurrence conflicts, possibly because of differences in study populations. A wide range of mechanisms could explain the occurrence of non steroidal-induced damage. These include inhibition of bicarbonate secretion, effects on mucus formation, and vascular actions. Not all effects are dependent on cyclo-oxygenase inhibition. Short-term studies in humans provide indications of likely therapeutic effects, but cannot demonstrate clinical efficiency. Although anti-secretory drugs and prostaglandins can protect patients against the development of duodenal or gastric ulcers, but not both, there is no clinical evidence which bears upon the critical issue of protection against complications.

Addition of glucose and sodium citrate to azapropazone, in proportions of 1:1:1 by weight reduced gastric mucosal damage in rats and there was a trend towards reduction in radiolabelled faecal red cell loss in human volunteers compared with that with azapropazone alone. The glucose and citrate did not affect the pharmacokinetics of azapropazone, or its therapeutic efficacy. While no difference was observed in endoscopic injury and in symptomatic gastrointestinal complaints in a multicentre comparison in rheumatic patients, a striking reduction in symptoms was observed in those patients with a history of severe gastrointestinal intolerance to non-steroidal anti-inflammatory drugs.

The elderly are most susceptible to pharmacokinetic drug interactions between various NSAIDs and anticoagulants, sulphonylurea hypoglycaemic agents, certain anticonvulsants, methotrexate, digoxin, aminoglycosides and lithium. Pharmacodynamic interactions between some NSAIDs and antihypertensive drugs, anticoagulants, sulphonylurea agents and other NSAIDs are also potentially significant in the elderly. Despite the finding that mean therapeutic responses of large groups of patients have been generally equivalent for the wide range of NSAIDs studied thus far, it is also apparent that marked variability exists in the response of individual patients to different NSAIDs. Subsequent dosage increments may predispose 'nonresponders' and some less sensitive 'responders' to toxicity from NSAIDs. This interindividual variability in response to NSAIDs may be contributed to by the differing physicochemical properties of NSAIDs, physician prescribing habits and patient expectations, variations in NSAID pharmacokinetics, and the differing effects of NSAIDs other than their common ability to inhibit prostaglandin synthesis. The principles for drug prescribing in the elderly are no different from those that should be applied to the prescribing of medication in any patient. The clinician should strive to make a diagnosis and should avoid treating symptoms in isolation. Critical assessment of the indication for prescribing NSAID therapy must include consideration of the available effective and safe alternatives. If an NSAID is commenced the lowest effective dose should be the desired goal, but after an appropriate trial it is acceptable clinical practice to employ an alternative NSAID. There is no justification for combination NSAID therapy. The progress of each patient must be carefully monitored, particularly during the first few months of treatment, while periodic review of the ongoing need for the NSAID is essential.

A double-blind, crossover study was undertaken to compare the efficacy and tolerability of a novel enteric coated 500 mg naproxen tablet with normal release 500 mg naproxen in patients with osteoarthritis. Eighty-eight patients were randomly allocated to receive enteric coated naproxen as a single daily dose of 2 tablets at night or 1 normal release naproxen tablet twice daily for a period of 3 weeks, followed by the alternative treatment for a further period of 3 weeks. The results of patient and doctor assessments showed that both treatments were increasingly efficacious, with a significant period effect found in the measures for pain on passive movement and duration of morning stiffness. No significant treatment differences were seen in any of the measures of efficacy and tolerability, although there were more withdrawals on normal release than on enteric coated naproxen (p = 0.07). It was concluded that enteric coated naproxen given as a single 1 g dose at night and normal release 500 mg naproxen given twice daily are equally efficacious and well tolerated.

Gastric biopsy specimens from patients who have undergone gastric surgery frequently exhibit foveolar hyperplasia, oedema, vasodilatation and congestion, and a paucity of inflammatory cells as consequences of entero-gastric reflux. Similar, albeit generally milder, changes were found in 47 of 316 (15%) non-surgical patients undergoing endoscopy for dyspeptic symptoms. To relate these changes to bile reflux or other potential gastric irritants the total bile acid concentration was measured in samples of fasting gastric juice, and the use of a symptom questionnaire ascertained the patients' cigarette consumption, use of non-steroidal anti-inflammatory drugs (NSAIDs), and alcohol intake. When patients with reflux gastritis were compared with normal controls (n = 91), significant increases in associated peptic ulceration and NSAID use were found in the group with reflux, but no increases in bile acid concentrations. Indeed, only one patient had evidence of duodenogastric reflux. It is concluded that most cases of "reflux gastritis" in the intact stomach are not due to reflux of bile. Our findings indicate an important pathogenic role for long term NSAID use, in what might be usefully termed type C or "chemical" gastritis.

Aspirin, diclofenac, diflunisal, ibuprofen and indomethacin were given orally or intravenously to fasted or fed rats. The resulting gastric and intestinal damage was assessed using standard methods. The same drugs were administered to rats with biliary fistulas, and the fraction of drug excreted in bile was quantified using HPLC methods. We found that gastric damage occurred only in the fasted animals and was found to be dose-dependent and related to the amount (r = 0.871) and solubility (r = 0.909) of the individual drug. As far as acute gastric toxicity is concerned, neither the potency of a drug as an inhibitor of cyclo-oxygenase nor the fraction of unchanged or conjugated agent excreted in bile appeared to be relevant. Secondly, ulcerations of the small intestine occurred in fed animals only. The degree of damage was related to the amount of unchanged or conjugated drug excreted in bile and cyclo-oxygenase inhibitory potency (r = 0.873). The administered dose (within the range investigated) and drug solubility appeared not to contribute to intestinal toxicity. It is concluded that, in the rat, acute gastric and intestinal toxicity of non-steroidal anti-inflammatory drugs are due to different mechanisms. Whereas gastric toxicity is strongly influenced by the amount of drug dissolved under the pH conditions in the stomach, intestinal toxicity appears to depend on biliary excretion and enterohepatic circulation of a drug as well as on its potency as an inhibitor of prostaglandin synthesis.

A proposed framework for integrated research in ulcer epidemiology is presented. This framework entails the integration of ulcer epidemiology information from national data sets and regional or specialized data sources to produce an organized sequence of studies. National data sets are used to determine the descriptive characteristics of ulcer epidemiology in terms of person, place, and time. Once subpopulations with high or low rates of ulcer disease are identified, hypotheses are generated to explain subpopulation differences. These etiologic hypotheses are then tested in regional or specialized study populations such as the Adventist Health Study, the Rand Health Insurance Study, or the American Rheumatism Association Medical Information System.

The intestinal ulcerogenic activity of the weak prostaglandin synthesis inhibitor drug Wy-41,770 [5H-dibenzo(a,d)-cyclohepten-5-ylidine] was contrasted with the potent synthesis inhibitor, indomethacin, in rats to establish the relationship of inhibition of prostaglandin synthesis to the intestinal damage. Wy-41,770 induced superficial erosions only in the cecum 26 hr after a single oral dose of 250 or 500 mg/kg of the drug, progressing to ulcers after 5 days dosing with ultrastructural evidence of bacteria in the mucosa. Indomethacin (5 or 10 mg/kg po) induced mucosal erosions in the ileum, initially at 26 hr progressing to ulcers after 5 days. Fewer bacteria were seen in the ileal mucosa of indomethacin-treated rats. Both drugs reduced prostaglandin E in those regions of the intestine coincident with the known accumulation of these drugs at sites of mucosal injury. Site-specific intestinal damage from these 2 drugs is associated with inhibition of the synthesis of mucosal-protective prostanoids, followed by pronounced bacterial invasion through the damage mucosae with consequent appearance of local immuno-inflammatory reactions.

The gastrointestinal toxicity of a single oral administration of five nonsteroidal anti-inflammatory agents (NSAIDs) to rats was compared, by a method using 51Cr-labeled red blood cells (RBC), and by macroscopic and microscopic examination. From the profile of gastrointestinal bleeding, the NSAIDs could be divided into a group consisting of aspirin (ASA), oxaprozin (OXP) and 2-[4-(3-methyl-2-butenyl)phenyl]propionic acid (TA), which caused only a transient increase in fecal blood loss based on a gastric lesion, and another group including indomethacin (IM) and ibuprofen (IP), which produced a biphasic increase in the blood loss. The initial phase was caused not only by a gastric lesion but also an intestinal lesion, and the secondary phase originated only in the intestinal lesion. The order of potency causing blood loss was IM much greater than IP greater than ASA much greater than TA greater than OXP. The safety ratio of OXP and TA was shown to be more favorable than that of the other three drugs.

Previous work has shown repeated low doses of flunixin meglumine (FM) inhibit thromboxane production in normal horses. Enhanced concentrations of thromboxane in serum occurred after the drug therapy was discontinued. Our study was performed to evaluate the effects of low doses of FM in horses repeatedly challenged with endotoxin. Group I horses received E. coli endotoxin (0.1 microgram/kg IV) at 0 and 90 h. Group II horses received endotoxin and were also treated with FM (0.25 mg/kg IV) at 2, 10, 18, 26, 34, and 42 h after the initial administration of endotoxin. Clinical signs of endotoxemia were observed in all horses, but FM treated horses recovered more rapidly. The leukopenic response after endotoxin was attenuated in Group II following the second dose. Serum thromboxane (TxB2) decreased after the initial administration of endotoxin and remained below baseline values throughout the study. Serum TxB2 concentrations were not different between the groups. Plasma TxB2 and 6-keto-PGF1 alpha concentrations were increased after the initial endotoxin injection. In Group II, plasma TxB2 levels declined rapidly after FM administration and remained low. After the second dose of endotoxin, Group I horses had a mild rise and decline in TxB2 and 6-keto-PGF1 alpha concentrations, respectively. Thromboxane B2 levels in Group II changed little after the second dose of endotoxin, but a dramatic increase in 6-keto-PGF1 alpha concentrations occurred. These results suggest that multiple low doses of FM to horses with endotoxemia cause a selective and sustained suppression of TxB2 production and an enhancement of 6-keto-PGF1 alpha.

The administration of non-steroidal anti-inflammatory drugs (NSAIDs) leads to mucosal lesions in the upper gastrointestinal tract. Furthermore, NSAIDs increase the risk of ulcer bleeding and perforation, but the overall risk of fatal complications is relatively small (about 21 per one million prescriptions). Therefore, in asymptomatic patients, it is not justified to prescribe NSAIDs together with gastroprotective agents. The following recommendations can be given with respect to the management of peptic lesions in patients taking NSAIDs: (i) Fibre endoscopy should be performed even when there are relatively mild symptoms since mucosal lesions in rheumatic patients under NSAIDs produce minor or no symptoms. (ii) "Modern" NSAIDs might produce less gastric lesions than aspirin. (iii) Rheumatic patients with peptic disorders should be treated with an H2-antagonist. (iv) After complications such as ulcer bleeding or after rapid recurrence of peptic lesions, maintenance treatment with an H2-antagonist is advisable.