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Biomedical subjects

D J Fitzgerald

Publications and source records attributed to D J Fitzgerald.

At least 19 recordsLinked to original sources
PubMed2004

Cyclooxygenase-2 expression in primary human colorectal cancers and bone marrow micrometastases.

BACKGROUND: Both the expressions of the inducible form of cyclooxygenase-2 and the presence of bone marrow micrometastases are poor prognostic markers in patients with colorectal carcinoma. AIMS: As cyclooxygenase-2 expression in these tumours is associated with increased metastatic potential in vitro, our objectives were to determine the relationship between cyclooxygenase-2 and haematogenous spread to bone marrow. PATIENTS AND METHODS: Thirty-two patients with resection of colorectal carcinoma were evaluated (median age: 69.5 years). Bone marrow was obtained from all patients from both iliac crests before manipulation of the primary tumour. The tumours were of varying stages at diagnosis (5 Dukes' A, 14 Dukes' B, 11 Dukes' C and 2 Dukes' D). Tumour sections were stained for cyclooxygenase-2 using the avidin-biotin immunohistochemical technique. Extent of staining was graded depending on the percentage of epithelial cells staining positive for cyclooxygenase-2. Micrometastases were detected by staining contaminant cytokeratin-18 positive cells in the bone marrow aspirates by either immunohistochemical (ARAAP) or immunological (flow cytometry) methods. Fisher's exact probability test was used to calculate statistical significance. RESULTS: Cyclooxygenase-2 expression in the primary tumour was detected in 72% of the patients. Twelve (38%) patients had bone marrow micrometastases detected by either immunohistochemistry or flow cytometry. Of the 12 patients who had bone marrow micrometastases, 8 tumours demonstrated increased expression of cyclooxygenase-2 protein (66.6%). In contrast, 9 out of the 20 (45%) patients in whom micrometastases were not detected expressed increased levels of cyclooxygenase-2 (P = 0.29). When dividing the patients into subgroups of localised (Dukes' A and B) versus disseminated (Dukes' C and D) disease, there was no further association between cyclooxygenase-2 expression and bone marrow micrometastases (P = 0.179 and 1.0). CONCLUSION: In this pilot study, there was no association between cyclooxygenase-2 expression and bone marrow micrometastases in patients with otherwise localised or disseminated disease.

Aged↗
PubMed2004

Mode of antimicrobial action of vanillin against Escherichia coli, Lactobacillus plantarum and Listeria innocua.

AIMS: To investigate the mode of action of vanillin, the principle flavour component of vanilla, with regard to its antimicrobial activity against Escherichia coli, Lactobacillus plantarum and Listeria innocua. METHODS AND RESULTS: In laboratory media, MICs of 15, 75 and 35 mmol l(-1) vanillin were established for E. coli, Lact. plantarum and L. innocua, respectively. The observed inhibition was found to be bacteriostatic. Exposure to 10-40 mmol l(-1) vanillin inhibited respiration of E. coli and L. innocua. Addition of 50-70 mmol l(-1) vanillin to bacterial cell suspensions of the three organisms led to an increase in the uptake of the nucleic acid stain propidium iodide; however a significant proportion of cells still remained unstained indicating their cytoplasmic membranes were largely intact. Exposure to 50 mmol l(-1) vanillin completely dissipated potassium ion gradients in cultures of Lact. plantarum within 40 min, while partial potassium gradients remained in cultures of E. coli and L. innocua. Furthermore, the addition of 100 mmol l(-1) vanillin to cultures of Lact. plantarum resulted in the loss of pH homeostasis. However, intracellular ATP pools were largely unaffected in E. coli and L. innocua cultures upon exposure to 50 mmol l(-1) vanillin, while ATP production was stimulated in Lact. plantarum cultures. In contrast to the more potent activity of carvacrol, a well studied phenolic flavour compound, the extent of membrane damage caused by vanillin is less severe. CONCLUSIONS: Vanillin is primarily a membrane-active compound, resulting in the dissipation of ion gradients and the inhibition of respiration, the extent to which is species-specific. These effects initially do not halt the production of ATP. SIGNIFICANCE AND IMPACT OF THE STUDY: Understanding the mode of action of natural antimicrobials may facilitate their application as natural food preservatives, particularly for their potential use in preservation systems employing multiple hurdles.

Adenosine Triphosphate↗
PubMed2004

Inhibition of Bacillus subtilis and Listeria innocua by nisin in combination with some naturally occurring organic compounds.

The application of combined preservative factors (hurdle technology) is very effective in controlling the growth of food spoilage and foodborne pathogenic bacteria. Antimicrobial activity of nisin alone and in combination with some natural organic compounds (carvacrol, cinnamic acid, eugenol, diacetyl, and thymol) on the growth of gram-positive bacteria Bacillus subtilis and Listeria innocua was-investigated. All the organic compounds tested exhibited antimicrobial activity against the microorganisms used; however, the MICs varied between 0.8 and 15.0 mM depending on the potency of the compound or the sensitivity of the target strain. Investigation of the interaction between the organic compounds and nisin against the test organisms revealed different patterns, varying from synergistic to antagonistic. Combinations of nisin with carvacrol, eugenol, or thymol resulted in synergistic action against both test organisms. Activity of nisin and cinnamic acid together was synergistic against L. innocua, but only additive against B. subtilis. In contrast, the combination of diacetyl and nisin resulted in an antagonistic effect against both test organisms. This study highlights the potential of the combination of these compounds with nisin to inhibit pathogen growth in food.

Anti-Bacterial Agents↗
PubMed2003

Integration of proteomics and genomics in platelets: a profile of platelet proteins and platelet-specific genes.

Platelets, while anucleate, contain RNA, some of which is translated into protein upon activation. Hypothesising that the platelet proteome is reflected in the transcriptome, we identified 82 proteins secreted from activated platelets and compared these, as well as published proteomic data, to the transcriptional profile. We also compared the transcriptome of platelets to other tissues to identify platelet-specific genes and used ontology to determine gene categories over-represented in platelets. RNA was isolated from highly pure platelet preparations for hybridization to Affymetrix oligonucleotide arrays. We identified 2,928 distinct messages as being present in platelets. The platelet transcriptome was compared with the proteome by relating both to UniGene clusters. Platelet proteomic data correlated well with the transcriptome, with 69% of secreted proteins detectable at the mRNA level, and similar concordance was obtained using two published datasets. While many of the most abundant mRNAs are for known platelet proteins, messages were detected for proteins not previously reported in platelets. Some of these may represent residual megakaryocyte messages; however, proteomic analysis confirmed the expression of many previously unreported genes in platelets. Transcripts for well-described platelet proteins are among the most platelet-specific messages. Ontological categories related to signal transduction, receptors, ion channels, and membranes are over-represented in platelets, while categories involved in protein synthesis are depleted. Despite the absence of gene transcription, the platelet proteome is mirrored in the transcriptome. Conversely, transcriptional analysis predicts the presence of novel proteins in the platelet. Transcriptional analysis is relevant to platelet biology, providing insights into platelet function and the mechanisms of platelet disorders.

Blood Platelets↗
PubMed2003

Effect of H. pylori infection on the expression of cyclooxygenase-2 in human gastric mucosa.

Cyclooxygenase-1 is the primary isoform responsible for the production of cytoprotective prostaglandins (PGE(2) and PGI(2)) in the stomach. In contrast COX-2 is induced at the sites of inflammation. Using Helicobacter pylori infection as a model of inflammation, this study was designed to evaluate the effects of H. pylori infection on prostanoid synthesis and expression of COX-2 in human gastric mucosa. Prostaglandin (PGE(2)) and prostacyclin (PGI(2)) synthesis in gastric biopsies obtained from 21 patients undergoing diagnostic endoscopy, were determined. H. pylori was detected by CLO test, histology and culture. Biopsy samples were incubated either with NS-398, selective COX-2 inhibitor or aspirin. Samples were also treated with endotoxin (LPS) in order to induce COX-2 expression. Tissue was also analysed for COX-2 expression in vivo by immunohistochemistry. In 15 out of 21 patients, H. pylori was detected by at least two of the three methods. Higher levels of PGE(2) and PGI(2) were seen in patients infected with H. pylori (191+/-30 and 245+/-88ng/mg protein, respectively) compared with non-infected patients (77+/-17 and 120+/-36ng/mg protein, respectively). There was significant inhibition of PGE(2) and PGI(2) with aspirin in both H. pylori infected (28+/-6.6 and 53+/-43ng/mg, respectively) and in non-infected patients (16+/-7 and 12.5+/-3.5ng/mg protein, respectively). However, NS-398 and LPS did not alter prostaglandin function significantly. Immunohistochemistry in all patients irrespective of Hp status demonstrated expression of COX-2.Lower concentration of constitutive expression of COX-2 was detected in human gastric mucosa by immunohistochemistry, however, H. pylori infection failed to induce COX-2 protein. In addition, increased prostaglandin synthesis in Hp-infected patients appears to be COX-1 mediated rather than COX-2. Furthermore, failure of endotoxaemia-treated sample to produce more PGE(2) in the face of enhanced COX-2 expression in gastric mucosa further suggests that increased prostanoids in human gastric stomach are COX-1 mediated.

6-Ketoprostaglandin F1 alpha↗
PubMed2003

Activity of natural antimicrobial compounds against Escherichia coli and Salmonella enterica serovar Typhimurium.

AIMS: The objective of this study was to evaluate the inhibitory activity of several natural organic compounds alone or in combination with nisin against Escherichia coli and Salmonella Typhimurium. METHODS AND RESULTS: The minimum inhibitory concentration (MIC) of five natural organic compounds were determined, and the effect of their combinations with nisin was evaluated by the checkerboard assay using the Bioscreen C. As expected, nisin by itself showed no inhibition against either of the Gram-negative bacteria. Thymol was found to be the most effective with the lowest MIC values of 1.0 and 1.2 mmol 1-1 against Salm. Typhimurium and E. coli, respectively. After thymol, the antimicrobial order of the natural organic compounds was carvacrol > eugenol > cinnamic acid > diacetyl. However, the combination of nisin with the natural organic compounds did not result in the enhancement of their antimicrobial activities. On the contrary, combination of nisin with diacetyl against Salm. Typhimurium resulted in an antagonism of diacetyl activity. CONCLUSIONS: While the individual natural organic compounds showed inhibitory activity against the two Gram-negatives, their combinations with nisin showed no improvement of antimicrobial activity. SIGNIFICANCE AND IMPACT OF THE STUDY: This study shows the potential of the natural organic compounds to control E. coli and Salm. Typhimurium.

Anti-Bacterial Agents↗
PubMed2003

Platelet proteomics.

As anucleate cell particles, platelets do not lend themselves to analysis by traditional cell and molecular biology techniques. Moreover, while valuable information may be gleaned from studies of messenger RNA in platelets, the rapid events in platelets are not governed by or dependent on alterations in gene expression. In contrast, proteomics, the study of the protein complement of a genome, will have a major impact on platelet biology. It offers the opportunity to comprehensively describe the proteins involved in discrete elements of platelet function, from the subsecond events following platelet activation and adhesion through to platelet aggregation and granule secretion. As the function of every protein is understood and as the mechanisms that regulate protein modifications are unravelled, we will discover a wealth of proteins that are themselves potential therapeutic agents or novel targets for the development of diagnostics and drugs. Here we review the current applications of proteomics to platelet research. We briefly describe various proteomic approaches to unravel platelet biology, including the documentation of platelet proteins, the investigation of thrombin-activated phosphotyrosine signaling networks and the analysis of the proteins that are secreted upon platelet activation. Proteomics is a young field and there are only a handful of published examples applying proteomics to platelet research. This number will increase over the next few years, as advances in analytical methods allow a more functional analysis of the platelet proteome.

Animals↗
PubMed2003

Helicobacter pylori induces cyclooxygenase-1 and cyclooxygenase-2 expression in vascular endothelial cells.

BACKGROUND: Helicobacter pylori induces cyclooxygenase activity in the stomach, although the COX isoform and cellular source are unclear. A potential source is the vascular endothelial cell, which plays a role in regulating mucosal blood flow and inflammatory cell infiltration. METHODS: We examined the effect of four strains (toxigenic and non-toxigenic) of H. pylori on COX isoform expression in vascular endothelial cells. Prostaglandin synthesis was measured by enzyme immunoassay and COX isozyme expression determined by Western blot and RT-PCR. Gene induction was examined using 5' deletion constructs of the COX-1 and COX-2 promoters coupled with luciferase. RESULTS: All H. pylori strains induced prostaglandin generation and expression of both COX-1 and COX-2 in HUVEC, although this was most pronounced with the highly toxigenic strain H. pylori 60190. Treatment of the cells with selective COX inhibitors demonstrated that COX-1 was predominantly responsible for the enhanced generation of prostacyclin induced by H. pylori 60190. Similar results were seen with H. pylori broth culture filtrates, suggesting that a secreted product was responsible. Induction of COX-2 reflected both enhanced gene expression and stabilization of the mRNA. CONCLUSIONS: H. pylori increased both COX-1 and COX-2 activity in vascular endothelial cells. This increased generation of endothelial cell prostacyclin may play a role in modulating mucosal blood flow, platelet function and inflammatory cell infiltration in response to H. pylori infection. The regulation of COX-1 at the transcriptional level by H. pylori described in this study is a novel finding and calls into question the traditional description of COX-1 as a purely constitutive, housekeeping gene.

Blotting, Western↗
PubMed2003

A novel family of hydroxamate-based acylating inhibitors of cyclooxygenase.

Aspirin irreversibly inhibits cyclooxygenase (COX) by acetylating a serine residue in the active site. We synthesized a series of novel acylating agents based on our previously reported acetylating compound, O-acetylsalicylhydroxamic acid. One of these, triacetylsalicylhydroxamic acid (TriAcSHA) was more effective than aspirin and O-acetylsalicylhydroxamic acid in inactivating both COX-1 and COX-2. Preincubation of COX-1 with inhibitor for 5 min yielded IC(50) values of 18 microM for TriAcSHA and 60 microM for acetylsalicylic acid. Inhibition was time-dependent, with complete inhibition within 10 min at a concentration of 50 microM. As with aspirin, mutation of the serine 530 of COX-1 to alanine abolished the activity of the TriAcSHA. Mutation of the alanine 119 to a glutamine markedly reduced the sensitivity to TriAcSHA, suggesting that this residue was necessary for the interaction with the enzyme. TriAcSHA was also more effective than aspirin as an inhibitor of platelet aggregation induced by arachidonic acid. The diacetylated phenylhydroxamates N-methyl-O,O-diacetylsalicylhydroxamic acid, N,O-diacetylbenzohydroxamic acid, and 2-methyl-O,N-diacetylbenzohydroxamic acid showed reduced or absent activity against COX-1. In addition, we synthesized a series of triacylsalicylhydroxamic acids with progressively longer acyl groups (three to six carbons). All of the compounds inhibited COX-1 and demonstrated progressively greater COX-1 selectivity with increasing number of carbons. Hence, salicylhydroxamic acid provides a versatile backbone for the generation of a family of acylating inhibitors of cyclooxygenase.

Acetylation↗
PubMed2002

Stimulation of adhesion molecule expression by Helicobacter pylori and increased neutrophil adhesion to human umbilical vein endothelial cells.

Helicobacter pylori upregulates endothelial adhesion molecules but the pattern is unclear. Human umbilical vein endothelial cells (HUVEC) were exposed to control medium or H. pylori 60190. Binding of monoclonal antibodies against P-selectin, E-selectin, vascular adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) was determined using enzyme-linked immunosorbent assay. Binding of polymorphonuclear leukocytes to HUVEC was determined on cells exposed as above. After 6 h exposure to H. pylori, there were 30%, 124%, 167% and 100% increases in P-selectin, E-selectin, VCAM-1 and ICAM-1 levels and a 400% increase in polymorphonuclear leukocyte adhesion in HUVEC exposed to H. pylori. Effects of incubation for other intervals between 0 and 18 h are also described. H. pylori exerts some of its effects on gastric mucosa via gastric vasculature. This study gives insight into the pattern of H. pylori-associated endothelial adhesion molecule upregulation.

Cell Adhesion↗
PubMed2002

Local circuit neurons in the striatum regulate neural and behavioral responses to dopaminergic stimulation.

Interneurons are critical for shaping neuronal circuit activity in many parts of the central nervous system. To study interneuron function in the basal ganglia, we tested and characterized an NK-1 receptor-based method for targeted ablation of specific classes of interneuron in the striatum. Our findings demonstrate that the neurotoxin SP-PE35, a substance P-Pseudomonas exotoxin conjugate, selectively targets striatal cholinergic and nitric oxide synthase/somatostatinergic interneurons when injected locally into the striatum. The effects of this selective cell targeting encompassed alterations in both behavioral and neural responses to dopaminergic stimulation, including altered patterns of early-gene response in striosomes and matrix. We conclude that NK-1-bearing local circuit neurons of the striatum regulate the differential responses of striatal projection neurons to dopamine-mediated signaling.

Animals↗
PubMed2002

The contribution of genetic factors to thrombotic and bleeding outcomes in coronary patients randomised to IIb/IIIa antagonists.

Genetic variants are risk factors for coronary disease, but their role in recurrent events and in response to treatment is less clear. We genotyped genetic variants implicated in primary coronary disease in 924 Caucasians with acute coronary syndromes participating in the OPUS-TIMI16 trial of the GPIIb/IIIa antagonist orbofiban. These were the platelet glycoprotein (GP) receptors GPIIIa, GPIa, GPIbalpha; platelet ligands beta-fibrinogen and von Willebrand Factor (vWF); interleukins (IL) IL-1RN, and IL-6; adhesion proteins E-selectin and P-selectin; and metalloproteinase MMP-9. Cox modelling of all genetic variants demonstrated no significant impact on the composite endpoint (P = 0.88), which included myocardial infarction (MI), death, recurrent ischemia, urgent revascularisation and stroke, but a significant impact on recurrent myocardial infarction alone (chi(2) = 20.4, 10 df, P = 0.04). There was a significant interaction of the polymorphisms with orbofiban treatment influencing bleeding outcomes (P = 0.004). Thus, genetic polymorphisms may be associated with subsequent myocardial infarction, and may also be associated with treatment-associated bleeding among coronary patients.

Alanine↗
PubMed2001

Genetic variation in glycoprotein IIb/IIIa (GPIIb/IIIa) as a determinant of the responses to an oral GPIIb/IIIa antagonist in patients with unstable coronary syndromes.

This study examined the influence of the Pl(A) polymorphism of glycoprotein IIIa (GPIIIa) in determining the response to an oral GPIIb/IIIa antagonist, orbofiban, in patients with unstable coronary syndromes. Genotyping for the Pl(A) polymorphism was performed in 1014 patients recruited into the OPUS-TIMI-16 (orbofiban in patients with unstable coronary syndromes-thrombolysis in myocardial infarction 16) trial, in which patients were randomized to low- or high-dose orbofiban or placebo for 1 year. The primary end point (n = 165) was a composite of death, myocardial infarction (MI), recurrent ischemia requiring rehospitalization, urgent revascularization, and stroke. Overall, orbofiban failed to reduce ischemic events when compared with placebo, but increased the rate of bleeding. In the whole population, Pl(A2) carriers had a significant increase in MI (n = 33) during follow up, with a relative risk (RR) of 2.71 (95% CI, 1.37 to 5.38; P =.004). There was a significant interaction between treatment (placebo and orbofiban) and the Pl(A) polymorphism for bleeding (n = 187; P =.05). Thus, while orbofiban increased bleeding in noncarriers (RR = 1.87, 1.29 to 2.71; P <.001) in a dose-dependent fashion, it did not increase bleeding events in Pl(A2) carriers (RR = 0.87, 0.46 to 1.64). There was no interaction between treatment (placebo and orbofiban) and the Pl(A) polymorphism for the primary end point (P =.10). However, in the patients receiving orbifiban there was a higher risk of a primary event (RR = 1.55, 1.03 to 2.34; P =.04) and MI (RR 4.27, 1.82 to 10.03; P <.001) in Pl(A2) carriers compared with noncarriers. In contrast, there was no evidence that Pl(A2) influenced the rate of recurrent events in placebo-treated patients. In patients presenting with an acute coronary syndrome, the Pl(A) polymorphism of GPIIb/IIIa may explain some of the variance in the response to an oral GPIIb/IIIa antagonist.

Aged↗
PubMed2001

A Val193Met mutation in GPIIIa results in a GPIIb/IIIa receptor with a constitutively high affinity for a small ligand.

We have identified a patient designated as (GTa) with Glanzmann's Thrombasthenia (GT) diagnosed on the basis of a prolonged bleeding time and failure of the patient's platelets to aggregate. The number of glycoprotein (GP)IIb/IIIa receptors on the platelet surface was 37% of normal and those receptors displayed a defect in soluble fibrinogen binding. Nevertheless, GTa platelets showed increased adhesion to solid-phase fibrinogen and binding affinity for the RGD-mimetic (3)H-SC52012, a non-peptide GPIIb/IIIa antagonist. Dithiothreitol (DTT) and ADP enhanced the affinity for [(3)H]-SC52012 in normal platelets, but had little effect in GTa platelets. These findings suggested that GTa platelets were locked in an altered affinity state. Genetic analysis showed that GTa was a compound heterozygote for the GPIIIa gene. One allele showed a deletion at the 3' end of exon 3 resulting in a premature stop codon. The second GPIIIa allele had a G to A transition at nucleotide 577, resulting in a Val193Met substitution. HEK 293T cells transfected with mutant GPIIb/IIIaV193M bound [(3)H]-SC52012 with a higher affinity than wild-type GPIIb/IIIa, and this was not increased by DTT. The mutant receptor distinguishes between platelet adhesion and aggregation, and demonstrates the phenotype that may be expected when platelet aggregation alone is inhibited.

Adenosine Diphosphate↗
PubMed2001

O-acetylsalicylhydroxamic acid, a novel acetylating inhibitor of prostaglandin H2 synthase: structural and functional characterization of enzyme-inhibitor interactions.

Aspirin is unique among clinically used nonsteroidal antiinflammatory drugs in that it irreversibly inactivates prostaglandin (PG) H2 synthase (PGHS) via acetylation of an active-site serine residue. We report the synthesis and characterization of a novel acetylating agent, O-acetylsalicylhydroxamic acid (AcSHA), which inhibits PGE2 synthesis in vivo and blocks the cyclooxygenase activity of PGHS in vitro. AcSHA requires the presence of the active-site residue Ser-529 to be active against human PGHS-1; the S529A mutant is resistant to inactivation by the inhibitor. Analysis of PGHS inactivation by AcSHA, coupled with the X-ray crystal structure of the complex of ovine PGHS-1 with AcSHA, confirms that the inhibitor elicits its effects via acetylation of Ser-529 in the cyclooxygenase active site. The crystal structure reveals an intact inhibitor molecule bound in the enzyme's cyclooxygenase active-site channel, hydrogen bonding with Arg-119 of the enzyme. The structure-activity profile of AcSHA can be rationalized in terms of the crystal structure of the enzyme-ligand complex. AcSHA may prove useful as a lead compound to facilitate the development of new acetylating inhibitors.

Acetylation↗
PubMed2001

Dual-function vaccine for Pseudomonas aeruginosa: characterization of chimeric exotoxin A-pilin protein.

Pseudomonas aeruginosa is the major infectious agent of concern for cystic fibrosis patients. Strategies to prevent colonization by this bacterium and/or neutralize its virulence factors are clearly needed. Here we characterize a dual-function vaccine designed to generate antibodies to reduce bacterial adherence and to neutralize the cytotoxic activity of exotoxin A. To construct the vaccine, key sequences from type IV pilin were inserted into a vector encoding a nontoxic (active-site deletion) version of exotoxin A. The chimeric protein, termed PE64Delta553pil, was expressed in Escherichia coli, refolded to a near-native conformation, and then characterized by various biochemical and immunological assays. PE64Delta553pil bound specifically to asialo-GM1, and, when injected into rabbits, produced antibodies that reduced bacterial adherence and neutralized the cell-killing activity of exotoxin A. Results support further evaluation of this chimeric protein as a vaccine to prevent Pseudomonas colonization in susceptible individuals.

ADP Ribose Transferases↗
PubMed2001

Selective inhibition of COX-2 in humans is associated with less gastrointestinal injury: a comparison of nimesulide and naproxen.

BACKGROUND: Selective inhibitors of cyclooxygenase (COX)-2 may provoke less gastric damage and platelet inhibition than conventional non-steroidal anti-inflammatory drugs. AIMS: We compared the biochemical and gastrointestinal effects of nimesulide, a potent and selective COX-2 inhibitor, with naproxen which exhibits no selectivity. SUBJECTS: Thirty six healthy volunteers were randomised to nimesulide 100 mg or naproxen 500 mg twice daily for two weeks in a double blind, crossover study with a washout between treatments. METHODS: Gastrointestinal side effects were assessed by endoscopy, and by estimation of small intestinal absorption-permeability and inflammation. Comparisons were made between variables at the end of each treatment phase. RESULTS: Nimesulide caused significantly less gastric injury using the modified Lanza score (p<0.001) as well as reduced duodenum injury (p=0.039). Nimesulide had lower visual analogue scores (VAS) for haemorrhage and erosive lesions in the stomach (p<0.001) and for mucosal injection in the duodenum (p=0.039). Naproxen increased excretion of calprotectin, a marker of intestinal inflammation (5.5 (1.2) to 12.1 (2.1) mg/l) while nimesulide had no effect (treatment difference p=0.03). Naproxen abolished platelet aggregation to arachidonic acid and suppressed serum thromboxane B(2) (TXB(2)) by 98%, indices of COX-1 activity. In contrast, nimesulide had no significant effect on platelet aggregation, although it reduced serum TXB(2) by 29%. Production of prostaglandin E(2) and prostacyclin by gastric biopsies, also COX-1 dependent, was inhibited by naproxen, but not by nimesulide. COX-2 activity, determined as endotoxin induced prostaglandin E(2) formation in plasma, was markedly suppressed by both treatments. INTERPRETATION: Nimesulide has preferential selectivity for COX-2 over COX-1 in vivo at full therapeutic doses and induces less gastrointestinal damage than that seen with naproxen in the short term.

Adolescent↗