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We now have at our disposal several nonsteroidal immunosuppressive and anti-inflammatory agents that may be used in addition to or instead of corticosteroids to treat ocular diseases. This article discusses some of the nonsteroidal immunosuppressive and anti-inflammatory agents available to the ophthalmologist.
The oral analgesic and anti-inflammatory activity of NK(1) antagonists with species preference for the human receptor were assessed in (1) the carrageenan-induced inflammatory hyperalgesia and (2) Freund's complete adjuvant (FCA)-induced extravasation in the knee joint models of the guinea-pig, respectively. Mechanical hyperalgesia was determined by measuring the withdrawal threshold to a noxious mechanical stimulus applied to the paw and thermal hyperalgesia as the withdrawal latency to a noxious thermal stimulus applied to the plantar surface. A concentration of 1.0% carrageenan (intraplantar) reduced mechanical thresholds from 124+/-5 to 63+/-3 g and thermal latencies from 19+/-0.4 to 4.7+/-0.9 s as determined 4 h after injection. The hyperalgesia persisted for over 24 h. The NK(1) receptor antagonists, SDZ NKT 343, RPR100893 and SR140333, reduced mechanical hyperalgesia by 68, 36 and 27% at a dose of 30 mg kg(-1) p.o., respectively. No further reduction was noted at higher doses (maximum 100 mg kg(-1) p.o.). The anti-hyperalgesic effect of SDZ NKT 343 and RPR100893 peaked at 3 h while SR140333 produced maximal reversal at 1 h after oral administration. D(30) values indicated significant differences between the potency of these compounds. SDZ NKT 343 was by far the most potent anti-hyperalgesic agent (D(30): 1.1 mg kg(-1)). The D(30) values for RPR100893 and SR140333 were estimated to be 17 and >100 mg kg(-1), respectively. In thermal hyperalgesia, SDZ NKT 343 produced a significantly weaker anti-hyperalgesic effect with a peak of 25% reversal. The D(30) value for SDZ NKT 343 was 3.89 mg kg(-1). For comparison, morphine inhibited the carrageenan-induced mechanical and thermal hyperalgesia with an ED(50) of 1.85 and 2.51 mg kg(-1) s.c., respectively. When tested up to 300 mg kg(-1) p.o., aspirin reduced carrageenan-induced mechanical and thermal hyperalgesia by 55.0 and 45.2%, respectively. In addition to the anti-hyperalgesic effects of NK(1) receptor antagonists, the effects of SDZ NKT 343 and RPR100893 on plasma protein extravasation were measured in the FCA-treated knee joint of the guinea-pig. SDZ NKT 343 reversed plasma protein extravasation 2 h after administration by 60% at the oral dose of 30 mg kg(-1). RPR100893 was significantly less effective with a maximum reversal of 30% at 100 mg kg(-1). In comparison, indomethacin produced a 50% reversal at a 10 mg kg(-1) dose. These experiments indicate that the carrageenan-induced hyperalgesia in the guinea-pig may be predictive of analgesic activity of NK(1) receptor antagonists in man. NK(1) receptor antagonists are active anti-hyperalgesic drugs in both mechanical and thermal hyperalgesia in the guinea-pig. In addition they inhibit plasma protein extravasation in the same species. The variability of in vivo potency and efficacy of the NK(1) receptor antagonists in the mechanical hyperalgesia model is difficult to interpret as all compounds are highly effective at blocking the NK(1) receptor in guinea-pig tissues. Amongst several possibilities, differences in pharmacokinetics may explain discrepancies.
Modification of cellular proteins with a small protein called ubiquitin has profound effects on their activities. Ubiquitin is covalently attached to lysine residues of acceptor proteins through the concerted action of E1 ubiquitin-activating enzyme, E2 ubiquitin-carrier proteins and E3 ligases. Mammalian cells contain a large number of E3 ligases, which determine the specificity of ubiquitination reactions. Recent studies have revealed that ubiquitination can be reversed by deubiquitinating enzymes that release ubiquitin monomers from modified proteins. Signalling networks that control inflammation are tightly regulated by a multitude of ubiquitination and deubiquitination reactions. This article begins by summarising current understanding of these pathways at a molecular level, and then focuses on the importance of ubiquitination and deubiquitination during the regulation of the pro-inflammatory transcription factor NF-kappaB. Finally, the potential for ubiquitin modifications to be targeted by novel classes of anti-inflammatory drugs is discussed.
To compare the anti-inflammatory effectiveness of corticotherapy and nonsteroid anti-inflammatory drugs (NSAID), we examined 126 infertile men with infectious aetiology. Seventy-seven patients were on corticotherapy and antibiotherapy (thirty-eight patients on high-dose and thirty-nine patients on low-dose corticotherapy). Forty-nine patients had antibiotherapy and NSAID. According to our results in both the high- and low-dose groups sperm motility significantly improved, but in the high dose group more side effects were reported. In order to overcome the effects of infections on male infertility, we prefer corticotherapy instead of NSAID because it is more effective than NSAID.
1. The present study was undertaken to investigate the anti-inflammatory effects of a synthetic compound, LCY-2-CHO, on the expression of inducible nitric oxide synthase (iNOS), COX-2, and TNF-alpha in murine RAW264.7 macrophages. 2. Within 1-30 microm, LCY-2-CHO concentration-dependently inhibited lipopolysaccharide (LPS)-induced nitric oxide (NO), prostaglandin E(2) (PGE(2)), and tumor necrosis factor-alpha (TNF-alpha) formation, with IC(50) values of 2.3, 1, and 0.8 microm, respectively. Accompanying inhibition of LPS-induced iNOS, cyclooxygenase-2 (COX-2), and pro-TNF-alpha proteins was observed. 3. Reverse transcription-polymerase chain reaction (RT-PCR) and promoter analyses indicated that iNOS expression was inhibited at the transcriptional level (IC(50)=2.3 microm), that inhibition of COX-2 expression only partially depended on gene transcription (IC(50)=7.6 microm), and that TNF-alpha transcription was unaffected. 4. Transcriptional assays revealed that activation of AP-1, but not NF-kappaB, was concomitantly blocked by LCY-2-CHO. Our results showed that LCY-2-CHO was capable of interfering with post-transcriptional regulation, altering the stability of COX-2 and TNF-alpha mRNAs. 5. Since the 3'-untranslated region (3' UTR) of both COX-2 and TNF-alpha mRNA contains a p38 mitogen-activated protein kinase (MAPK)-regulated element involved in mRNA stability, we assessed the effect of LCY-2-CHO on p38 MAPK. Our data clearly indicated an inhibition (IC(50)=1.7 microm) of LPS-mediated p38 MAPK activity, but not of extracellular signal-regulated kinase (ERK) or c-Jun N-terminal kinase (JNK) activity. However, kinase assays ruled out a direct inhibition of p38 MAPK action. The selective p38 MAPK inhibitor, SB203580, inhibited the promoter activities of iNOS and COX-2 rather than that of TNF-alpha. 6. In conclusion, LCY-2-CHO downregulates inflammatory iNOS, COX-2, and TNF-alpha gene expression in macrophages through interfering with p38 MAPK and AP-1 activation.
Genetic predisposition has been suggested to play an important role in the pathogenesis of inflammatory bowel diseases (IBDs). Linkage studies have identified a Crohn's disease susceptibility locus on chromosome 14 (14q11-12; IBD4). Interleukin-25 (IL-25) is a newly identified proinflammatory cytokine that has been shown to promote Th2 responses by inducing cytokines such as IL-4, IL-5 and IL-13. The IL-25 gene is located within this susceptibility region at 14q11.2. As IBDs are characterized by an imbalance of the Th1/Th2 cytokine response, we hypothesized that genetic alterations within the IL-25 gene might contribute to IBD. First, direct sequencing of the coding regions of the IL-25 gene in 40 patients with Crohn's disease or ulcerative colitis revealed only a newly reported polymorphism (c424C/A) in exon 2. Next, the frequency of this polymorphism was further investigated in 151 patients with Crohn's disease, 111 patients with ulcerative colitis, and 119 healthy controls to determine its clinical relevance. The genotypes of the c424C/A polymorphism did not reveal any significant differences between patients with Crohn's disease or ulcerative colitis and controls. Genoytype-phenotype relations in patients with Crohn's disease showed a comparable distribution of the c424C/A polymorphism in all subgroups of the Vienna classification. In summary, our data indicate that genetic alterations in the coding regions of the IL-25 gene are unlikely to play a role in IBDs, but the c424C/A polymorphism in the IL-25 gene should be investigated for a potential association with other chronic inflammatory and inherited disorders such as autoimmune diseases.
Macrophages infiltrate tissues in response to chemoattractants including complement 5a (C5a). Infiltrating macrophages clear microorganisms but also can cause tissue damage. We hypothesized that prevention of macrophages from excessive recruitment into infected sites may underlie the anti-inflammatory effects of piperlactam S, an alkaloid isolated from Piper kadsura (Choisy) Ohwi. To test this hypothesis, chemotactic migration of RAW264.7 macrophages was induced by C5a and the effects of piperlactam S were studied. The results showed that piperlactam S (1-30 microM) concentration-dependently suppressed C5a-induced migration across a fibrinogen-coated barrier with an IC50 of 4.5 +/- 0.3 microM. At 30 microM, piperlactam S inhibited chemotaxis by more than 95 % and also decreased phagocytosis by 25 % without reducing macrophage viability and adherent capacity. Furthermore, piperlactam S treated cells adhered but failed to spread and elongate as in control cells. Finally, piperlactam S inhibited the C5a-stimulated release of tumor necrosis factor-alpha and interleukin-1beta. We conclude that retardation of macrophage recruitment by interfering with the migration process and suppression of cytokines production might underlie the potential usefulness of piperlactam S as an anti-inflammatory agent.
BACKGROUND: Health-related quality of life (HRQOL) is an important outcome-parameter in health research and care. The aim of the working group Quality of Life in the Competence Network Inflammatory Bowel Disease (IBD; in the original German: "Kompetenznetz chronisch entzündliche Darmerkrankungen") is to generate instruments for assessment of HRQOL and its implementation as standards in clinical trials, health care and research in IBD. METHODS: The Inflammatory Bowel Disease Questionnaire (IBDQ) is an international validated disease specific instrument for HRQOL-assessment. A German version of the IBDQ was elaborated and tested in 415 outpatients with Crohn's disease (CD, n = 306) and ulcerative colitis (UC, n = 109). The aim of the study was to compare the results of HRQOL-assessment (IBDQ-D) with international investigations, to correlate HRQOL results with disease activity and to preform a pretest of psychometric properties. RESULTS: International data suggest that the IBDQ-D is a suitable instrument for HRQOL-assessment in CD and UC. For both disease a statistically significant negative correlation with disease activity was found. Tested psychometric properties do not suggest that a revision of the IBDQ-D is required. The IBDQ-D offers the HRQOL-assessment as an primary or secondary outcome in clinical trials in IBD in Germany.
Inflammatory bowel disease (IBD) comprises two chronic, tissue-destructive, clinical entities Crohn disease (CD) and ulcerative colitis (UC) both apparently caused by immunological overreaction (hypersensitivity) to commensal gut bacteria. Under normal conditions the intestinal immune system shows a down-regulating tone ('oral tolerance') against dietary antigens and the indigenous microbiota. This local homeostasis is disturbed in IBD, leading to hyperactivation of T helper 1 (Th1) cells with abundant secretion of interferon-gamma and tumor necrosis factor (TNF) and production of IgG antibodies against commensal bacteria. In addition, UC includes genetically determined autoimmunity, particularly IgG1-mediated cytotoxic epithelial attack. Breaching of the epithelium is the best-defined event underlying abrogation of oral tolerance, but immune deviation caused by cytokines fiom irritated epithelial cells or subepithelial elements (for example, mast cells, natural killer cells, macrophages) may also be involved. Endogenous infection with local hypersensitivity likewise causes periodontal disease, reflecting 'frustrated' immune elimination mechanisms entertained by antigens from dental plaque. Altogether, perturbation of a tightly controlled cytokine network, with abnormal crosstalk between several cell types, apparently explains the progressive immunopathology of chronic inflammatory mucosal diseases in general. This adverse development will be influenced by numerous immunity genes, the dosage and potential pathogeniciy of commensal bacteria, general health, nutritional status, and psychological factors. Several targets for new therapy have tentatively been identified to block immunopathological mechanisms in IBD, and inhibition of TNF has a striking beneficial effect in CD, supporting a central role of this cytokine.
In this study ketoprofen has been shown to be the most potent of all anti-inflammatory drugs in inhibiting the synthesis of prostaglandins and the 'rabbit-aorta contracting substance' (RCS), using the guinea-pig lung preparation. Although there did not appear to be a close relationship between the activities of the various drugs in inhibiting prostaglandins synthesis and in their anti-inflammatory activity, the compounds were ranked in the same order in both test systems.
The case histories of three young women with ankylosing spondylitis, rheumatoid arthritis and a seronegative inflammatory polyarthritis undergoing investigations for infertility are presented. In each, non-steroidal anti-inflammatory drug (NSAID) therapy was associated with the recurrent development of luteinized unruptured ovarian follicles and normal ovulation following drug withdrawal. It is suggested that NSAID therapy may be an important and frequently overlooked cause of anovulation and infertility.
BACKGROUND AND AIMS: We examined whether use of nonsteroidal anti-inflammatory drugs (NSAIDs) in outpatients with inflammatory bowel disease was associated with increased severity of disease activity. METHODS: Outpatients with Crohn's disease (CD; n = 426) and with ulcerative colitis (UC; n = 203) were seen between November 1997 and April 2002. Patients were questioned at each visit regarding use of prescription or over-the counter NSAIDs and a clinical disease activity index (modified Harvey Bradshaw [MHB] or Lichtiger score) was obtained. RESULTS: For the Crohn's patients, for 1315 visits no NSAIDs were used, on 215 visits low-dose NSAIDs were used, and for 139 visits high-dose NSAIDs were taken. For UC patient visits, 495 used no NSAIDs, 112 low-dose NSAIDs, and 49 high-dose NSAIDs. Average MHB score was 4.07 for the no-NSAID group, 4.24 for low-dose NSAIDs (P = 0.46), and 4.78 for high-dose (P = 0.0072 versus no NSAIDs). For the ulcerative colitis patients corresponding scores were 5.64, 5.46, and 6.20, respectively (P = not significant). The probability of moderately active disease as defined by crossing a threshold MHB or Lichtiger score, however, was not significantly affected by NSAID use. Subgroup analysis indicated the increase in disease activity among CD patients taking high-dose NSAIDs was limited to patients with colonic involvement. CONCLUSIONS: Use of low-dose NSAIDs was not associated with an increase in disease activity for these outpatients with either CD or UC. Use of high-doses of NSAIDs was associated with a higher numerical disease activity index score among CD patients with colonic involvement, but this was not reflected by an increase in significant disease flares.
Anorexia, malnutrition, altered body composition and development of mesenteric obesity are well known features of inflammatory bowel disease (IBD). Recent data suggest that dysregulation of protein secretion by white adipose tissue is involved in these manifestations of patients with IBD. Adipocytes are recently recognized as endocrine cells that secrete a variety of bioactive substances known as adipocytokines. There is evidence that adipocytokines are involved in inflammatory and metabolic pathways in human beings. Overexpression of adipocytokines such as leptin, adiponectin and resistin in mesenteric adipose tissue of operated patients with Crohn's disease has recently been reported, suggesting that mesenteric adipocytes in IBD may act as immunoregulating cells. Therefore, it could be suggested that adipocytokines play an important role in the disease pathogenesis. Moreover, modulators of mesenteric adipose function have been suggested as potential therapeutic drugs in IBD. In this review, the importance of white adipose tissue function and adipocytokines, is discussed with respect to IBD.
Childhood inflammatory bowel disease (IBD) especially those with Crohn disease is commonly complicated by faltering growth and pubertal delay. Pro-inflammatory cytokines are often elevated in IBD and may affect linear growth and puberty either systemically or at the level of the growth plate. Further study of the underlying mechanisms of the deleterious effects of cytokines on the growth plate may improve management of faltering growth in childhood IBD. Well-controlled clinical studies of the respective effect of nutritional support, immunomodulatory therapy, biological agents and growth and puberty promoting agents on managing faltering growth also require further attention.
The interaction of salicylates and other non-steroidal anti-inflammatory drugs was studied in rats. Concurrent oral administration of sodium salicylate (SS) or salicylic acid (SA) and indomethacin (IND) significantly reduced the gastro-ulcerogenicity and the plasma concentrations of IND. Acetylsalicylic acid (ASA) failed to do so. IND had no significant influence on plasma concentrations of SA. Simultaneous administration of SS and IND intraperitoneally or subcutaneously showed the same pattern of interaction as for oral administration. Concurrent oral administration of SS and IND exerted similar anti-inflammatory activity as the single drugs. SS significantly antagonized the ulcerogenicity of ibuprofen and tended to antagonize the ulcerogenic activity of ASA, phenylbutazone, tolfenamic acid and naproxen. The results suggest that in rats SS and SA (but not ASA) interact with IND concerning both gastro-ulcerogenicity and plasma concentrations of IND (but not of SA) and that the interaction is systemic in nature. We propose that the ulcerogenic interaction might be explained partly by the reduced IND plasma concentrations and partly by a weaker inhibition by SS of the prostaglandin system in the rat stomach.
Macrophage inflammatory protein 1alpha (MIP-1alpha)/CCL3 prevents the development of eosinophilic pneumonia (EP) driven by a nonprotective T2-type immunity during infection with a highly virulent strain of Cryptococcus neoformans. The present study evaluated the interaction of MIP-1alpha with other innate immune system cytokines by comparing the immune responses that followed pulmonary infections with high- (C. neoformans 145A) and low (C. neoformans 52D)-virulence strains. In contrast to what was found for C. neoformans 145A infection, lack of MIP-1alpha in C. neoformans 52D infection did not cause the development of EP. C. neoformans 52D induced tumor necrosis factor alpha (TNF-alpha), gamma interferon (IFN-gamma), and MCP-1 in the lungs of infected wild-type (WT) and MIP-1alpha knockout (KO) mice by day 7 postinfection. Both WT and MIP-1alpha KO mice subsequently cleared this infection. Thus, the robust expression of early inflammatory cytokines in C. neoformans 52D-infected mice promoted the development of protective immunity even in the absence of MIP-1alpha. Alternatively, C. neoformans 145A-infected WT and MIP-1alpha KO mice had diminished TNF-alpha, IFN-gamma, and macrophage chemoattractant protein 1 (MCP-1) responses, indicating that virulent C. neoformans 145A evaded early innate host defenses. However C. neoformans 145A-infected WT mice had an early induction of MIP-1alpha and subsequently did not develop EP. In contrast, C. neoformans 145A-infected MIP-1alpha KO mice developed EP and had increased C. neoformans dissemination into the brain by day 35. We conclude that, in the absence of other innate immune response effector molecules, MIP-1alpha is crucial to prevent the development of EP and to control C. neoformans dissemination to the brain.
INTRODUCTION: The purpose of this study was to assess the diagnostic accuracy of magnetic resonance colonography (MRC) for its ability to detect and quantify inflammatory bowel disease (IBD) affecting the colon. Endoscopically obtained histopathology specimens were used as the standard of reference. MATERIALS AND METHODS: Fifteen normal subjects and 23 patients with suspected IBD of the large bowel underwent MRC. Three dimensional T1 weighted data sets were collected following rectal administration of water prior to and 75 seconds after intravenous administration of paramagnetic contrast (gadolinium-BOPTA). The presence of inflammatory changes in patients was documented based on bowel wall contrast enhancement, bowel wall thickness, presence of perifocal lymph nodes, and loss of haustral folds. All four criteria were quantified relative to data obtained from normal subjects and summarised in a single score. This MRC based score was compared with histopathological data based on conventional endoscopic findings. RESULTS: MRC correctly identified 68 of 73 segments found to reveal IBD changes by histopathology. All severely inflamed segments were correctly identified as such and there were no false positive findings. Based on the proposed composite score, MRC detected and characterised clinically relevant IBD of the large bowel with sensitivity and specificity values of 87% and 100%, respectively, for all investigated colonic segments. CONCLUSION: MRC may be considered a promising alternative to endoscopic biopsy in monitoring IBD activity or assessing therapeutic effectiveness.
BACKGROUND/AIMS: Health-related quality of life (HRQOL) is an important outcome measure in inflammatory bowel disease (IBD). The aim of our study is to validate the Greek translation of the Inflammatory Bowel Disease Questionnaire (IBDQ). For this we assessed its construct validity, discriminant ability, reliability and sensitivity to change. METHODS: One hundred and fourteen patients with IBD (69 UC, 45 CD) completed the Greek version of the IBDQ, and a Visual Analogue Scale (VAS) for general well-being. Fifty-two patients also completed the SF-36. A subgroup of 46 patients completed the Greek IBDQ for a second time. Clinical activity was assessed by Harvey-Bradshaw Index and Colitis Activity Index. RESULTS: Correlation coefficients between the four dimensional scores of the Greek IBDQ and the clinical activity indexes, VAS and the SF-36 were all reasonably high and statistically significant. The Greek IBDQ was able to discriminate well between groups of patients with either different clinical disease activity or subjective assessment of well-being. It also showed high reliability when it was repeated in patients who reported no change in their general well-being (intraclass correlation coefficient 0.940-0.998). In contrast, there was a significant difference between the baseline and the follow-up measurement in patients who reported change in their general well-being. CONCLUSIONS: The Greek IBDQ proved to be a valid and reliable instrument for assessing HRQOL, useful in the evaluation of clinical trials or health surveys as well as in the therapeutic management of IBD patients.