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PubMedDate not supplied

Effects of an experimentally developed adhesive resin system and CO2 laser irradiation on direct pulp capping.

This study examined the wound healing process of rat pulp directly capped with various experimentally developed adhesive resin systems and treated with CO2 laser irradiation. The experimental adhesive resins used in this study were made from Clearfil Mega Bond (MB). The adhesive resin groups were capped with a combination of the following primers and bonding agents: commercially available MB primer (MBP), experimental MB primer containing 2wt% N-methacryloyl 5-aminosalicylic acid (5-NMSA: MP3) and 5wt% 12-methacryloyloxydodecylpyridinium bromide (MDPB: ABP); and commercially available MB bonding agent (MBB), experimental MB bonding agent containing 5wt% and 10wt% hydroxyl-calcium phosphate (hydroxyapatite: MB1, MB2) and 5wt% dicalcium phosphate dihydrate (brushite: MB3) as a reparative dentin-promoter. The combination of the three primers and four bonding agents yielded the 12 adhesive resin groups used in this study. The CO2 laser group was irradiated with a laser and directly capped with MB. The CO2 laser used was an Opelaser 03S II SP, and irradiation conditions were as follows: a power output of 0.5 W, superpulse mode 1, repeat pulse mode (a cycle of 10 msec irradiation and 10 msec interval), defocused beam (approximately distance 20 mm from pulp exposure surface) and an irradiation time of three seconds, with air cooling. The control group was capped with Dycal (DY) and MB. After the direct pulp capping procedures were undertaken, all cavities were restored with Clearfil AP-X resin composite. The rats were sacrificed on the 14th post-operative day. The specimens were alternately stained with Mayer's H & E, Hucker-Conn bacterial stain and the ABC method on TGF-beta1. These stained sections were observed using light microscopy and the following parameters were evaluated: pulp tissue disorganization, inflammatory cell infiltration, reparative dentin formation and bacterial penetration. The results of this study include the following: all experimentally developed bonding agent groups showed reparative dentin formation; whereas, the MBB-capped groups showed very little reparative dentin formation. The descending order regarding the amount of reparative dentin formation was MB2 > MB3 > MB1 >>> MBB, which tended to be dependent on the concentration of the blended reparative dentin-promoter. In terms of the quality of the formed dentin, it was observed that MB1-capped teeth tended to form tubular dentin; whereas, MB2- and MB3-capped teeth formed irregular and osteodentin types of dentin. Among the primers used, the descending order regarding the amount of reparative dentin and tubular type dentin formation was MP3 > MBP > ABP. The descending order of migration of macrophages and leukocytes was ABP > MBP > MP3. The CO2 laser group showed a very irregular fibrous dentin matrix in the vicinity of the denatured and carbonized tissue but definite reparative dentin formation was not observed. The control group showed reparative dentin, which was very thick, compared with the other groups. In all the groups, pulp tissue showed almost normal morphology. Positive staining of TGF-beta1 was only observed slightly in some specimens of all groups. There was no difference in the staining of each group. Based on the results of this study, it was concluded that the combination of MP3 (containing 2wt% 5-NMSA) and MB1 (containing 5wt% hydroxyapatite) was effective in initiating an early repair process after direct pulp capping. CO2 laser irradiation is effective for field control, but a longer observation time will be required to determine findings concerning dentin bridge formation.

Acid Etching, Dental↗
PubMed1996

Nonsteroidal antiinflammatory drugs interact with horseradish peroxidase in an in vitro assay system for hydrogen peroxide scavenging.

The established horseradish peroxidase/guaiacol in an in vitro assay system was used for investigation of the reactivity of nonsteroidal antiinflammatory drugs with hydrogen peroxide. Although the drugs rapidly seemed to react in the selected conditions, difficulties were encountered in attempts to quantify the reaction and an interaction with horseradish peroxidase was suspected. A more specific assay system based on the absolute specificity of the enzyme glutathione peroxidase for glutathione was subsequently used which demonstrated that none of the investigated nonsteroidal antiinflammatory drugs was able to scavenge hydrogen peroxide. An original procedure to further evidence the interaction was developed thereafter, based on the reaction of 5-aminosalicylic acid with similar hemoproteins. This led to the demonstration that nonsteroidal antiinflammatory drugs were substrates for horseradish peroxidase and explained their reactivity in the horseradish peroxidase/guaiacol assay system. The compound 5-aminosalicylic acid showed an unusual behaviour that was attributed to its ability to both scavenge hydrogen peroxide and interact with horseradish peroxidase. It was concluded that the lack of specificity of horseradish peroxidase for its donor substrate may lead to erroneous results in assays for hydrogen peroxide scavenging of some drugs. An alternative method is however available and a simple spectroscopic assay can evidence the interaction with horseradish peroxidase.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2003

Sulphasalazine-induced leucopenia in a patient with renal dysfunction.

BACKGROUND: Sulphasalazine is used for the long-term maintenance therapy of ulcerative colitis to prevent the relapse of symptoms. However, its clinical use is often restricted by its serious adverse effects. OBJECTIVE: Leucopenia occurred in a patient with severe renal dysfunction after administration of sulphasalazine. The present study was designed to examine whether the adverse event was associated with a disability in the metabolism of sulphasalazine. SUBJECT: A 29-year-old male patient with ulcerative colitis, who underwent haemodialysis thrice a week because of severe renal dysfunction. The chief complaint was diarrhoea. METHODS: Serum concentrations of three major metabolites of sulphasalazine, (5-aminosalicylic acid, sulphapyridine and N-acetyl-sulphapyridine), were measured. The polymorphism of N-acetyltransferase 2, an enzyme that metabolizes sulphapyridine, was also determined by polymerase chain reaction. RESULTS: The trough levels of 5-aminosalicylic acid, sulphapyridine and N-acetyl-sulphapyridine were 0.77-1.45 microg/mL, 31.20-39.25 microg/mL and 14.19-15.03 microg/mL, respectively. The gene diagnosis of N-acetyltransferase 2 suggested that the type was classified as NAT2*6A/*7B, indicating that the patient was a slow acetylator. CONCLUSION: The patient was a slow acetylator, which might lead to a rise in the serum sulphapyridine concentration. Moreover, the decrease in protein binding of sulphasalazine as a result of severe renal dysfunction might have potentiated the effect because of the extremely high protein binding of this compound. Thus, it is most likely that these two factors contributed to the sulphasalazine-induced leucopenia.

Adult↗
PubMed2005

Increased expression of MIP-3alpha/CCL20 in peripheral blood mononuclear cells from patients with ulcerative colitis and its down-regulation by sulfasalazine and glucocorticoid treatment.

UNLABELLED: CCL20 expression is known to increase in the mucosal tissues of inflammatory bowel diseases (IBDs). Moreover, the discovery of Nod2 as the IBD1 susceptibility gene has underscored the significance of blood mononuclear cells in IBD pathogenesis. METHODS: This study addresses whether CCL20 expression is similarly altered in peripheral blood mononuclear cells (PBMCs) of patients with ulcerative colitis (UC), a major type of IBD in Korea. RESULTS: Expression of CCL20 was significantly up-regulated in the PBMCs of patients with UC compared with those of normal healthy controls. Interestingly, untreated UC groups expressed higher levels of CCL20 mRNA than either treated UC or normal control groups, suggesting that CCL20 could be modulated by anti-inflammatory drugs. Accordingly, a strong association between CCL20 levels and disease activity index was observed. Supporting these findings, results from a 3-month follow-up study revealed that the UC groups treated with 5-aminosalicylic acid and glucocorticoid exhibited dramatic decreases of CCL20 mRNA in PBMCs, accompanied by ameliorated disease states. Moreover, tumor necrosis factor-alpha- or interleukin-1beta-induced CCL20 secretion was greatly diminished by 5-aminosalicylic acid and/or glucocorticoid treatment of human intestinal epithelial HT-29 cells. Of note, CCR6 cell populations were significantly reduced in the blood of severe patients with UC compared with normal controls, whereas no significant changes in CCR6 cell populations were observed in the blood of patients with mild UC or acute colitis. CONCLUSIONS: Collectively, these findings suggest that CCL20 expression in blood mononuclear cells is associated with altered immune and inflammatory responses in patients with UC.

Adult↗
PubMed1980

Drug interferences with tests performed by a 12-channel autoanalyzer.

The information reported in a variety of sources on drug interferences with routine laboratory tests (serum concentrations of sodim, potassium, carbon dioxide, chloride, glucose, BUN, cholesterol, total protein, albumin, total bilirubin, alkaline phosphatase, and SGOT) performed by a 12-channal autoanalyzer was reviewed. A determination was made whether or not the information was based on an evaluation of original articles, if the study was done in vitro or in vivo, what medium was used, if the drug level causing the interference would be encountered in a patient's serum, and if the reported conclusions were clinically significant. The review narrowed considerably the list of drug interactions with laboratory tests performed by 12-channel autoanalyzer methods. Clinically significant interactions were found for (1) aminosalicylic acid and the test for serum glucose; (2) gamma globulins and cholesterol measurement; (3) sulfonamides and paramethadione and the test for albumin; (4) albumin from placental sources and alkaline phosphatas measurement; (5) erythromycin estolate and aminosalicylic acid and the determination of SGOT; and, possibly (5) medications releasing bromide ions and the measurement of serum chloride. The study showed the need to determine the relevancy of drug interactions to the specific methods used in the laboratory of each medical institution.

Autoanalysis↗
PubMed1989

Immunosuppressive drugs in inflammatory bowel disease. A review of their mechanisms of efficacy and place in therapy.

Immune effector mechanisms are central to the disease process in inflammatory bowel disease, but it is not clear whether the mucosal or systemic immunological abnormalities are primary phenomena, or are secondary to disease activity. Corticosteroid drugs remain the most effective treatment for active disease, but there is no evidence that they are useful for maintenance therapy. Some patients, however, are dependent on low-dose corticosteroids, and relapse when the drug is withdrawn. These drugs have widespread actions on the immune response, and monocytes are particularly sensitive to corticosteroids. In contrast, sulphasalazine and 5-aminosalicylic acid are effective in maintenance therapy, but do not act primarily by immunosuppressive mechanisms. They are effective in maintenance therapy of ulcerative colitis, and mild relapses of ulcerative colitis and colonic Crohn's disease. New preparations of 5-aminosalicylic acid have reduced side effects, many of which are due to sulphapyridine. Azathioprine and 6-mercaptopurine are used less widely: in Crohn's disease there is reasonable evidence for benefit in chronic active disease unresponsive to corticosteroids, and maintenance of remission. In ulcerative colitis, the position is less clearcut. Overall, trials favour an effect in chronic active disease, and there are pointers to an effect in maintenance of remission. Because of their side effects, in particular marrow suppression, these drugs should be reserved for second-line therapy. Similarly, other cytotoxic drugs are not used because of their side effects. More recently, cyclosporin A, with its selective action on interleukin-2 release and/or synthesis, and inhibition of helper T cell function, has been shown to be helpful in Crohn's disease. At present it should only be used in controlled trials, for patients with unresponsive disease in whom surgery is contraindicated. Renal toxicity may limit long term use. There is little data for cyclosporin A in ulcerative colitis. On the basis that there may be an underlying immune defect in Crohn's disease leading to mucosal inflammation, immunostimulant therapy has been used, but there is no evidence for benefit from treatment with BCG or levamisole in active disease or in maintenance therapy. 7S-Immunoglobulin, plasmapheresis or T-lymphocyte apheresis have been used in acute relapse, but evidence is anecdotal, and does not support their use except as a desperate measure to avoid surgery. Further well-designed controlled trials are needed to define the role of all these drugs, and further research into the mechanism of action on the immune response may shed light on the pathogenesis of inflammatory bowel disease.

Clinical Trials as Topic↗
PubMed1997

Aminobenzoic acid compounds as HOCl traps for activated neutrophils.

This study was designed to develop traps for hypochlorous acid (HOCl) which could be used to detect HOCl in the microenvironment of activated neutrophils. Reagent HOCl was found to react with para-aminobenzoic acid (PABA) in aqueous solution to produce a predominant metabolite detectable by high performance liquid chromatography (HPLC). Mass spectroscopy and nuclear magnetic resonance identified this metabolite as the ring addition product 3-chloro PABA. The related compound para-aminosalicylic acid (PAS) was also metabolized by HOCl to 3-chloro PAS. The formation of the 3-chloro metabolite was specific for reactions involving HOCl, since several other oxidants in chloride buffer failed to produce the metabolite. Human blood neutrophils activated by phorbol myristate acetate or zymosan in the presence of PABA (or PAS) used their HOCl to produce large amounts of the 3-chloro metabolite. The formation of 3-chloro PABA was inhibited by azide, catalase, and taurine, which is consistent with the production of the metabolite by the neutrophil myeloperoxidase (MPO) pathway. The reaction of HOCl with PABA and PAS was relatively slow as shown by competitive reactions with endogenous antioxidants like taurine, methionine, and glutathione. This was confirmed in reactions involving PABA/PAS and reagent HOCl or HOCl generated by the MPO enzyme system. In these in vitro systems, glutathione and serum completely inhibited the formation of the 3-chloro metabolite. In contrast, activated neutrophils metabolized PABA/PAS to the 3-chloro metabolite even in the presence of 1% serum. These findings demonstrate that PABA and PAS are specific trapping agents for HOCl produced by neutrophils in complex biological conditions.

4-Aminobenzoic Acid↗
PubMed1999

Beneficial effects of ropivacaine in rat experimental colitis.

Ropivacaine, a new, long-acting local anesthetic agent, has been shown to have beneficial effects in the treatment of ulcerative colitis. Treatment with this drug results in prompt symptomatic relief. The aim of this study was to examine the effects of ropivacaine on mucosal healing and to investigate whether ropivacaine can restore the decreased colonic contractility seen in the diseased state. Colitis was induced in rats by a single intrarectal administration of trinitrobenzene sulfonic acid. Mucosal healing was assessed after 1 week of therapy. The effects on colonic contractility were examined either after 1 week of treatment or by application of the drugs to untreated, inflamed rat colon segments placed in organ baths. After the induction of colitis, daily intracolonic treatment with ropivacaine for 1 week reduced morphological damage and myeloperoxidase activity. One week of treatment also restored the contractile response to acetylcholine. By adding ropivacaine directly to untreated inflamed colonic segments in organ baths, the contractile response to acetylcholine was increased compared with controls. For comparison, the effects of budesonide and 5-aminosalicylic acid were also examined. Ropivacaine improved mucosal healing and restored colonic motor activity in experimental colitis, similar to budesonide but superior to 5-aminosalicylic acid.

Acetylcholine↗
PubMed1995

Myeloperoxidase as a generator of drug free radicals.

Reactive metabolites are believed to be responsible for many types of toxicity, including idiosyncratic drug reactions. Bone marrow is a frequent target of idiosyncratic reactions, and, since these reactions have characteristics that suggest involvement of the immune system, the formation of reactive metabolites by leucocytes could also play a role in the aetiology of idiosyncratic drug reactions. The major oxidation system in neutrophils and monocytes is a combination of NADPH oxidase and myeloperoxidase. This system oxidizes primary arylamines, such as sulphonamides, to reactive metabolites and these drugs are also associated with a high incidence of agranulocytosis, generalized idiosyncratic reactions and/ or drug-induced lupus. Clozapine is oxidized by this system to a relatively stable nitrenium ion; clozapine is also associated with a high incidence of agranulocytosis. Arylamines that have an oxygen or nitrogen in the para position, such as amodiaquine, vesnarinone and 5-aminosalicylic acid, are oxidized to quinone-like reactive intermediates. Aminopyrine is oxidized to a very reactive dication. Such reactive metabolites could also inhibit neutrophil function and mediate some of the therapeutic effects of these drugs: for example, the use of dapsone for dermatitis herpetiformis and the use of 5-aminosalicylic acid for inflammatory bowel disease.

Free Radicals↗
PubMed1992

Oxidant-evoked release of acetylcholine from enteric neurons of the rat colon.

In the presence of halides, granulocytes generate hypochlorous acid and, subsequently, chlorinated amines (chloramines). These lipophilic, potent reactive oxygen metabolites may contribute to the mucosal pathophysiology associated with inflammatory bowel disease. A common symptom of inflammatory bowel disease is mucosal secretion of fluid and electrolytes, leading to diarrhea. Because acetylcholine (Ach) can stimulate colonic fluid secretion, we determined the effect of monochloramine (NH2Cl) on Ach release by mucosal/submucosal nerves. Mucosa from the rat colon was separated from outer muscle layers and minced before incubation with [14C]choline to label stores of Ach in cholinergic neurons. Release of [14C]Ach was evoked with NH2Cl in the absence and presence of 5-aminosalicylic acid, glutathione, nordihydroguaiarectic acid or the cyclooxygenase inhibitor piroxicam. NH2Cl produced concentration-related increases in [14C] Ach release into the medium; greater than 100% over base line was observed at 0.5 mM. Glutathione inhibited the NH2Cl-evoked release in a concentration-dependent fashion. Release induced by 0.1 mM NH2Cl was abolished by 5-aminosalicylic acid and significantly inhibited by nordihydroguaiarectic acid. Piroxicam also prevented the effect of NH2Cl on release of [14C] Ach. None of these agents alone had any effect on base line [14C]Ach release. Tetrodotoxin (5 microM) did not significantly inhibit the NH2Cl-evoked transmitter release. We conclude that NH2Cl, at concentrations believed to exist in inflamed tissue, causes the release of Ach from mucosal/submucosal nerves primarily through nonspecific neural membrane injury. Endogenous prostaglandins, possibly liberated as a consequence of the injury, may be involved in the Ach release process.

Acetylcholine↗
PubMed1993

NPC 15669, an inhibitor of neutrophil recruitment, is efficacious in acetic acid-induced colitis in rats.

BACKGROUND: The efficacy of the leukocyte recruitment inhibitor, N-[9H-2,7-dimethylfluoren-9-ylmethoxy)carbonyl]-L-leucine (NPC 15669) was compared with drugs used to treat inflammatory bowel diseases in a rat model, acetic acid-induced colitis. METHODS: Colonic damage assessed by visual inspection, histological quantitation of tissue injury, vascular permeability, myeloperoxidase (MPO) accumulation, and synthesis of inflammatory mediators were measured. RESULTS: Intrarectal pretreatment with NPC 15669 results in a significant reduction of all measured indices of inflammation. The median effective dose (ED50) of NPC 15669 for inhibition of MPO accumulation and vascular permeability is 13.2 mg/kg and 31 mg/kg, respectively. The active moiety of sulfasalazine, 5-aminosalicylic acid (5-ASA), the antioxidant/5-lipoxygenase inhibitor, nordihydroguaiaretic acid (NDGA) and the corticosteroids dexamethasone and hydrocortisone, yielded ED50 values (MPO accumulation) of 68 mg/kg, 95 mg/kg, 0.7 mg/kg, and 13 mg/kg, respectively. When formulated suspensions of NPC 15669, 5-ASA, or dexamethasone were used, potency was increased 10-40-fold. Furthermore, NPC 15669 (10 mg/kg) administered 7 hours after acetic acid and evaluated 24 hours after acetic acid administration significantly attenuated neutrophil influx (70% inhibition of MPO accumulation), whereas 5-ASA (100 mg/kg) displayed no therapeutic effects. CONCLUSIONS: NPC 15669 may be useful in the treatment of inflammatory disorders.

Acetates↗
PubMed1998

Management of inflammatory bowel disease.

Patients with an inflammatory bowel disease, such as ulcerative colitis or Crohn's disease, have recurrent symptoms with considerable morbidity. Patient involvement and education are necessary components of effective management. Mild disease requires only symptomatic relief and dietary manipulation. Mild to moderate disease can be managed with 5-aminosalicylic acid compounds, including olsalazine and mesalamine. Mesalamine enemas and suppositories are useful in treating proctosigmoiditis. Antibiotics such as metronidazole may be required in patients with Crohn's disease. Corticosteroids are beneficial in patients with more severe symptoms, but side effects limit their use, particularly for chronic therapy. Immunosuppressant therapy may be considered in patients with refractory disease that is not amenable to surgery. Inflammatory bowel disease in pregnant women can be managed with 5-aminosalicylic acid compounds and corticosteroids. Since longstanding inflammatory bowel disease (especially ulcerative colitis) is associated with an increased risk of colon cancer, periodic colonoscopy is warranted.

Adrenal Cortex Hormones↗
PubMed1998

Sulfasalazine: a potent and specific inhibitor of nuclear factor kappa B.

Transcription factors of the NF-kappaB/Rel family are critical for inducible expression of multiple genes involved in inflammatory responses. Sulfasalazine and its salicylate moiety 5-aminosalicylic acid are among the most effective agents for treating inflammatory bowel disease and rheumatoid arthritis. However, the mode of action of these drugs remains unclear. Here we provide evidence that the transcription factor NF-kappaB is a target of sulfasalazine-mediated immunosuppression. Treatment of SW620 colon cells with sulfasalazine inhibited TNFalpha-, LPS-, or phorbol ester- induced NF-kappaB activation. NF-kappaB-dependent transcription was inhibited by sulfasalazine at micro- to millimolar concentrations. In contrast, 5-aminosalicylic acid or sulfapyridine did not block NF-kappaB activation at all doses tested. TNFalpha-induced nuclear translocation of NF-kappaB was prevented by sulfasalazine through inhibition of IkappaBalpha degradation. When blocking proteasome-mediated degradation of IkappaBalpha, we could demonstrate that sulfasalazine interfered with IkappaBalpha phosphorylation, suggesting a direct effect on an IkappaBalpha kinase or on an upstream signal. Inhibition of NF-kappaB activation seems to be specific since other DNA-binding activities such as AP1 were not affected. These results demonstrate that sulfasalazine is a potent and specific inhibitor of NF-kappaB activation, and thus may explain some of the known biological properties of sulfasalazine.

Anti-Infective Agents↗
PubMed2003

[Comparative efficacy of mezakol and sulfasalazine in treating chronic relapsing ulcerative colitis].

This research testifies to the fact that it is more preferable to use mesacol than sulfasalazine in treatment of common forms of ulcerative colitis of light and average severity. Mesacol acts faster in arresting inflammations in proximal parts of the larger intestine. One can assume that the pH-dependent release of 5-aminosalicylic acid in these forms of the disease suffers less than the destruction of the diazo link by the anaerobic microflora, due to which a higher concentration of the preparation is formed in the large intestine. Another alternative explanation can be the dose-dependent effect. Thus, 2.4. g of mesacol correspond to 6 g of sulfasalazine. The dose of sulfasalazine was smaller in our study. Mesacol had no advantages over sulfasalazine in treatment of distal colitis, which can and must be treated with rectal introduction of corticosteroids and 5-aminosalicylic acid preparations. Thus, mesacol must be reserved for treatment of patients with common ulcerative colitis of light and average severity in case of intolerance to sulfasalazine or impossibility to increase the preparation dose over 4 g/day. Its efficiency and price make the preparation available for most patients and patient care institutions.

Adult↗
PubMed2001

[Collagenous colitis. A study of 11 cases].

BACKGROUND: Collagenous colitis (CC) is a rare large bowel inflammatory disorder. The aim of this retrospective study was to analyze extra-digestive manifestations of CC, associated systemic diseases, clinical course and response to therapeutic regimens. PATIENTS AND METHODS: Between 1989 and 1999, eleven patients were diagnosed as having CC, in two Departments of Internal Medicine and Gastroenterology, on the basis of usual criteria: chronic watery diarrhea, endoscopic examination showing normal findings and subepithelial collagen band thicker than 10 micrometer. RESULTS: Ten women and one man, age 39 to 88 years (mean: 66.6), had had their diarrhea for 1 to 240 months before diagnosis (mean: 48). Associated extra-digestive manifestations were: weight loss (3 cases out of 11), inflammatory arthralgia (4 cases), fever (2 cases), pelvispondylitis (2 cases), autoimmune thyroiditis (2 cases), and Sharp syndrome (1 cases). Laboratory abnormalities were: inflammatory syndrome (3 cases), anemia (5 cases), hypogammaglobulinemia (3 cases), and hypoalbuminemia (4 cases). Stool cultures and parasite examination were negative in all patients. Therapy used successively for CC until resolution of chronic diarrhea (uncontrolled with symptomatic treatment) was: sulfasalazine in 7 patients (beneficial (B) in 5 out of 7), 5-aminosalicylic acid in 6 (B: 2/6), corticosteroids in 2 (B: 2/2), azathioprine in 1 (B: 1/1). After a mean follow-up of 18 months (range: 1-72), resolution of CC was observed in 8 out of 11 patients. DISCUSSION: Mean characteristics of CC were: female predominance (91%), presence of extra-digestive manifestations (36%); mucosal inflammation with subepithelial collagen band and frequent association to rheumatic or autoimmune diseases suggest an immune basis for CC. Usefulness of systematic colon biopsies is underlined. Clinical course is often favorable with sulfasalazine and 5-aminosalicylate acid. Corticosteroids are rarely used.

Adult↗
PubMed2001

Sulphasalazine inhibits macrophage activation: inhibitory effects on inducible nitric oxide synthase expression, interleukin-12 production and major histocompatibility complex II expression.

The anti-inflammatory agent sulphasalazine is an important component of several treatment regimens in the therapy of ulcerative colitis, Crohn's disease and rheumatoid arthritis. Sulphasalazine has many immunomodulatory actions, including modulation of the function of a variety of cell types, such as lymphocytes, natural killer cells, epithelial cells and mast cells. However, the effect of this agent on macrophage (M phi) function has not been characterized in detail. In the present study, we investigated the effect of sulphasalazine and two related compounds - sulphapyridine and 5-aminosalicylic acid - on M phi activation induced by bacterial lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma). In J774 M phi stimulated with LPS (10 microg/ml) and IFN-gamma (100 U/ml), sulphasalazine (50-500 microM) suppressed nitric oxide (NO) production in a concentration-dependent manner. The expression of the inducible NO synthase (iNOS) was suppressed by sulphasalazine at 500 microM. Sulphasalazine inhibited the LPS/IFN-gamma-induced production of both interleukin-12 (IL-12) p40 and p70. The suppression of both NO and IL-12 production by sulphasalazine was superior to that by either sulphapyridine or 5-aminosalicylic acid. Although the combination of LPS and IFN-gamma induced a rapid expression of the active forms of p38 and p42/44 mitogen-activated protein kinases and c-Jun terminal kinase, sulphasalazine failed to interfere with the activation of any of these kinases. Finally, sulphasalazine suppressed the IFN-gamma-induced expression of major histocompatibility complex class II. These results demonstrate that the M phi is an important target of the immunosuppressive effect of sulphasalazine.

Animals↗
PubMed2004

Evaluation of biotransformation of sulphasalazine in the colon epithelial Caco-2 cells.

Sulphasalazine (salicyl-azo-sulphapiridine, SAS) is a drug commonly used in the treatment of non-specific inflammatory bowel diseases, such as ulcerative colitis and Crohn disease. Chronic inflammatory states of the colon can lead to neoplastic changes of the intestinal mucosa. There are some suggestions in the literature that the intestinal bacterial azo-reductases are involved in biotransformation of SAS into 5-aminosalicylic acid (5-ASA) and sulphapyridine (SP). For this reason, it seemed worth of investigating whether transformation of SAS could be performed by the colon epithelial cells themselves. No enzymatic systems presumably exist in Caco-2, which could be responsible for SAS metabolism, because after 72 h-incubation of cell cultures with 1 mM SAS, its metabolites i.e., 5-ASA and SP were not detected in cells, neither in culture media. SAS metabolism, therefore, seems to depend on the presence of intestinal bacterial enzymatic systems. It was confirmed that 5-ASA is converted by Caco-2 cells to N-acetyl-5-aminosalicylic acid (Ac-5-ASA), which migrates to the culture medium. The other metabolite of SAS i.e., SP, was not transformed in the human colon cancer cells at all.

Anti-Inflammatory Agents↗
PubMed2002

Calcineurin inhibitors, cyclosporin A and tacrolimus inhibit expression of inducible nitric oxide synthase in colon epithelial and macrophage cell lines.

Nitric oxide (NO) production is increased in inflammatory bowel disease and selective inducible nitric oxide synthase (iNOS) inhibitors have proved to be anti-inflammatory in experimentally induced colitis. The aim of the present study was to test if drugs used in the treatment of inflammatory bowel disease effect on NO production in colon epithelial and macrophage cell lines. We tested the effects of cyclosporin A, tacrolimus (FK-506), methotrexate, sulfasalazine, 5-aminosalicylic acid and two novel TNF-alpha antagonists etanercept and infliximab on endotoxin-induced NO production in human T84 colon epithelial cells and in murine J774 macrophages. Cyclosporin A and FK-506 inhibited iNOS expression, and subsequent NO production, in a dose-dependent manner at therapeutically achievable drug concentrations in both cell lines. The effect was most pronounced when cyclosporin A was given 1 h prior to 4 h after endotoxin, and declined thereafter, indicating that cyclosporin A does not inhibit iNOS activity. Neither cyclosporin A nor FK-506 altered the activation of nuclear factor-kappaB (NF-kappaB) that is a critical transcription factor for iNOS. Sulfasalazine inhibited NO production slightly only when given at high (100 microM) drug concentrations. Methotrexate, 5-aminosalicylic acid and TNF-alpha antagonists infliximab and etanercept were practically ineffective. Two inhibitors of phosphatase calcineurin, cyclosporin A and FK-506, inhibited iNOS expression and NO production in human T84 colon epithelial cells and in murine J774 macrophages by an NF-kappaB independent manner. These findings are implicated in the anti-inflammatory action of these compounds.

Animals↗