Protective Effect of Probiotics Isolated from Traditional Fermented Tea Leaves (Miang) from Northern Thailand and Role of Synbiotics in Ameliorating Experimental Ulcerative Colitis in Mice.

This study aimed to investigate the protective effect of probiotics and synbiotics from traditional Thai fermented tea leaves (Miang) on dextran sulfate sodium (DSS)-induced colitis in mice, in comparison to sulfasalazine. C57BL/6 mice were treated with probiotics L. pentosus A14-6, CMY46 and synbiotics, L. pentosus A14-6 combined with XOS, and L. pentosus CMY46 combined with GOS for 21 days. Colitis was induced with 2% DSS administration for seven days during the last seven days of the experimental period. The positive group was treated with sulfasalazine. At the end of the experiment, clinical symptoms, pathohistological changes, intestinal barrier integrity, and inflammatory markers were analyzed. The probiotics and synbiotics from Miang ameliorated DSS-induced colitis by protecting body weight loss, decreasing disease activity index, restoring the colon length, and reducing pathohistological damages. Furthermore, treatment with probiotics and synbiotics improved intestinal barrier integrity, accompanied by lowing colonic and systemic inflammation. In addition, synbiotics CMY46 combined with GOS remarkedly elevated the expression of IL-10. These results suggested that synbiotics isolated from Miang had more effectiveness than sulfasalazine. Thereby, they could represent a novel potential natural agent against colonic inflammation.

Anti-Inflammatory Effects of Heritiera littoralis Fruits on Dextran Sulfate Sodium- (DSS-) Induced Ulcerative Colitis in Mice by Regulating Gut Microbiota and Suppressing NF-κB Pathway.

MATERIALS AND METHODS: The chemical compositions of EFH were identified using LC-ESI-MS. The mice with 3% DSS-induced UC were administered EFH (200, 400, and 800 mg/kg), sulfasalazine (SASP, 200 mg/kg), and azathioprine (AZA, 13 mg/kg) for 10 days via daily gavage. The colonic inflammation was evaluated by the disease activity index (DAI), colonic length, histological scores, and levels of inflammatory mediators. The gut microbiota was characterized by 16S rRNA gene sequencing and analysis. RESULTS: LC-ESI-MS analysis showed that EFH was rich in alkaloids and flavones. The results indicated that EFH significantly improved the DAI score, relieved colon shortening, and repaired pathological colonic variations in colitis. In addition, proteins in the NF-κB pathway were significantly inhibited by EFH. Furthermore, EFH recovered the diversity and balance of the gut microbiota. CONCLUSIONS: EFH has protective effects against DSS-induced colitis by keeping the balance of the gut microbiota and suppressing the NF-κB pathway.

Combination of probiotics with different functions alleviate DSS-induced colitis by regulating intestinal microbiota, IL-10, and barrier function.

The potential of probiotics for treating ulcerative colitis (UC) has attracted increasing attention. However, more studies are still needed to guide physicians on the proper selection and use of probiotics. Here, we propose that combination of multiple probiotics with different functions can reduce intestinal inflammation. In this study, the effects of probiotics (Lactobacillus reuteri, Bacillus coagulans, Bifidobacterium longum, and Clostridium butyricum) on the physiology and histopathology of colon were evaluated in a dextran sulfate sodium (DSS)-induced colitis mouse model. The combined species, as well as the species individually, were tested and compared with sulfasalazine (SASP) and two Chinese herbal therapies. Results show that the functions of the four probiotic strains were different in regulating intestinal immunity and barrier function. The four-species probiotic cocktail was more effective than the species individually and anti-inflammatory drugs in repairing the dysbiosis of mucosal microbial ecology and reducing intestinal inflammation. The multi-strain probiotic mixture increased the proportion of beneficial bacteria and decreased the proportion of pro-inflammatory bacteria in the colonic mucosa. In addition, probiotic mixture significantly enhanced the expression of IL-10 and intestinal barrier function. These results suggest that a combination of multiple probiotics with different functions has synergistic effects and can restore the balance of interactions between microorganisms and immunological niches.

[Acupuncture assisted by dynamic moxibustion for adult ankylosing spondylitis at early-to-mid stage].

OBJECTIVE: To observe the clinical efficacy differences between acupuncture combined with dynamic moxibustion and acupuncture alone for adult ankylosing spondylitis (AS) at early-to-mid stage based on medication. METHODS: Fifty-five cases of adult AS were randomly divided into an acupuncture-moxibustion group (28 cases) and an acupuncture group (27 cases). The two groups were treated with oral administration of sulfasalazine tablets. In addition, the acupuncture-moxibustion group was treated with acupuncture at Jiaji (EX-B 2), Shenshu (BL 23), Dachangshu (BL 25), Weizhong (BL 40) as well as dynamic moxibustion at the first line of bladder meridian of foot-taiyang and governor vessel from Dazhui (GV 14) to Yaoshu (GV 2). The acupuncture group was treated with acupuncture, the acupoints and manipulation of which were identical to acupuncture-moxibustion group. The treatment was given once a day, five days per week; one session was consisted of one-month treatment, and totally three sessions were given. The bath ankylosing spondylitis functional index (BAFI) and bath ankylosing spondylitis disease activity index (BASDAI) were compared before and after treatment in the two groups; also the clinical effective rates were compared between the two groups. RESULTS: The total effective rate was 96.4% (27/28) in the acupuncture-moxibustion group, which was superior to 88.9% (24/27) in the acupuncture group (P<0.05). Compared before treatment, the BASFI and BASDAI were reduced after treatment in the two groups (all P<0.05), which were more significant in the acupuncture-moxibustion group (both P<0.05). CONCLUSIONS: Based on medication, acupuncture combined with dynamic moxibustion could improve the clinical symptoms of AS, which is superior to simple acupuncture.

Traditional Chinese medicine versus western medicine as used in China in the management of rheumatoid arthritis: a randomized, single-blind, 24-week study.

This study is designed to compare the efficacy and safety of traditional Chinese medicine (TCM) with western medicine (WM) in the management of rheumatoid arthritis (RA). This is a 24-week, randomized, multicenter, single-blind study comparing TCM with WM (as used in China) carried out between June 2002 and December 2004 in nine research centers in China, involving 489 patients. Patients were randomized to receive TCM (n = 247), MTX and SSZ (n = 242). MTX was started at a dose of 5 mg to a final dose of 7.5-15 mg weekly. The maintenance dose was 2.5-7.5 mg weekly. The starting dose of SSZ was 0.25 g bid, increasing by 0.25 g a day once a week to a final dose of 0.5-1 g qid. The maintenance dose was 0.5 g tid to qid. Primary end point was the proportion of patients with response according to the American College of Rheumatology 20 % improvement criteria (ACR20) at weeks 24. At 24 weeks, ACR20 responses were 53.0 % in TCM group and 66.5 % in WM group, (P < 0.001) at 24 weeks. ACR 50 responses were 31.6 % of TCM group and 42.6 % in WM group, (P = 0.01). ACR70 responses were 12.6 % in TCM group and 17.4 % in WM group, (P = 0.14). Side effects were observed more frequently in WM group. In this study, ACR20, ACR50 responses at 24 weeks were significantly better in the WM treated group, by intention to treat (ITT) and per protocol analysis. The ACR 70 response showed no significant difference between the two groups. TCM, while effective in treating RA, appears to be less effective than WM in controlling symptoms, but TCM is associated with fewer side effects.

[Observation on clinical effect of ZHUANG medicine mediated thread moxibustion combined with medication for patients with ulcerative colitis].

OBJECTIVE: To observe the clinical effect and safety of Sulfasalazine (SASP) combined with ZHUANG medicine mediated thread moxibustion (ZMMTM) for patients with mild and moderate ulcerative colitis (UC). METHODS: A total of 46 UC patients were randomly and equally divided into moxibustion group (SASP combined with ZMMTM) and SASP medication group. Patients of both groups were treated by oral administration of SASP (1 g, tid) for six weeks. For patients of the moxibustion group, ZMMTM was applied to points Tianshu (ST 25), Qihai (CV 6), Guanyuan (CV 4), and Dachangshu (BL 25), once a day, for 20 times. The therapeutic effect was assessed according to Schroeder and colleagues' method (1987), scores of Baron' s endoscope scale (0 - 9 scoring standards, 1964), 0 - 3 scoring standards of activity indexes (including 4 items of diarrhea, hemorrhage, mucosal appearance and doctors' evaluation), respectively. RESULTS: Of the two 32 UC patients in the medication and moxibustion groups, 6 and 9 had a complete remission in their symptoms, 6 and 7 experienced a remarkable improvement, 5 and 6 were effective, and 6 and 1 was invalid, with the effective rates being 73.91% and 95.65%, respectively. Following the treatment, both endoscopic score and activity index in the moxibustion group were significantly lower than those of the medication group (P < 0.05). CONCLUSION: ZMMTM combined with medication is significantly superior to simple medication in relieving clinical symptoms of mild and moderate UC patients.

Conventional combination treatment versus biological treatment in methotrexate-refractory early rheumatoid arthritis: 2 year follow-up of the randomised, non-blinded, parallel-group Swefot trial.

BACKGROUND: Analysis of the Swedish Farmacotherapy (Swefot) trial at 12 months showed that the addition of an anti-tumour-necrosis-factor agent gave an improved clinical outcome compared with the addition of conventional disease-modifying antirheumatic drugs in patients with methotrexate-refractory early rheumatoid arthritis. Here we report the 2 year follow-up assessment. METHODS: In this randomised, non-blinded, parallel-group trial, we enrolled adult patients older than 18 years with rheumatoid arthritis and a symptom duration of less than 1 year from 15 rheumatology units in Sweden between December, 2002 and December, 2006. All patients were started on methotrexate. After 3-4 months, those who failed treatment were randomly assigned (1:1) to group A (conventional treatment; additional sulfasalazine and hydroxychloroquine) or group B (biological treatment; additional infliximab). Randomisation was done with a computer-generated sequence. We analysed clinical outcomes at months 18 and 24 by the response criteria of the American College of Rheumatology and the European League Against Rheumatism, and radiographs of patients' hands and feet at months 12 and 24 using the Van der Heijde modification of the Sharp score. Analysis was by intention to treat. This trial is registered with www.ClinicalTrials.gov, number NCT00764725. FINDINGS: Of 493 screened individuals, we enrolled 487, of whom 258 were randomly allocated to treatment. The proportion of patients in group B who received a EULAR-defined good response was non-significantly greater than it was in group A at 18 months (49 of 128 [38%] vs 38 of 130 [29%]) and at 24 months (49 of 128 [38%] vs 40 of 130 [31%]; p=0·204). After 24 months, radiological disease progression was greater in patients in group A than it was in those in group B (mean 7·23 [SD 12·72] vs 4·00 [10·0]; p=0·009). We recorded three serious adverse events: an extended generalised illness in group A, an extended febrile episode in group B, and a generalised illness in group B. INTERPRETATION: Additional biological treatment is a valid option for patients who fail initial methotrexate treatment. However, improved clinical outcomes after 12 months and better radiographical results after 24 months should be weighed against the absence of a convincing clinical difference at 24 months and substantially higher costs. Therefore, for many patients who fail initial methotrexate treatment, add-on treatment with disease-modifying antirheumatic drugs is an appropriate treatment option. FUNDING: Swedish Rheumatism Association, Stockholm County, and Schering-Plough/Merck Sharp and Dohme.

[Consensus Statement of the Spanish Society of Rheumatology on the management of biologic therapies in spondyloarthritis except for psoriatic arthritis]. / Documento SER de consenso sobre el uso de terapias biológicas en la espondilitis anquilosante y otras espondiloartritis, excepto la artritis psoriásica.

OBJECTIVE: Due to the amount and variability in quality regarding the use of biologic therapy (BT) in patients with spondyloarthritis (SpA), except for psoriatic arthritis (PsA) patients, the Spanish Society of Rheumatology has promoted the generation of recommendations based on the best evidence available. These recommendations should be a reference for rheumatologists and those involved in the treatment of patients with spondyloarthritis (SpA), except for psoriatic arthritis (PsA), who are using, or about to use BT. METHODS: Recommendations were developed following a nominal group methodology and based on systematic reviews. The level of evidence and grade of recommendation were classified according to the model proposed by the Center for Evidence Based Medicine at Oxford. The level of agreement was established through Delphi technique. RESULTS: We have produced recommendations on the use of BT currently available for SpA (but not PsA) in our country. These recommendations include disease assessment, treatment objectives, therapeutic scheme and switching. CONCLUSIONS: We present an update on the SER recommendations for the use of BT in patients with SpA, except for PsA.

Comparative evaluation of different doses of green tea extract alone and in combination with sulfasalazine in experimentally induced inflammatory bowel disease in rats.

BACKGROUND: The exact etiopathology of inflammatory bowel disease is still unclear. Most of the therapies present are directed towards symptomatic improvement. Surgical therapy in the form of restorative proctocolectomy is reserved for the terminal stage disease, which is unresponsive to medical therapy. The present study was conducted to evaluate the effect of green tea in experimentally induced inflammatory bowel disease. METHODS: A total of 36 animals were included in the study. The animals were divided into five groups (n = 6): Group I-Vehicle (ethanol), group II-TNBS + ethanol, group III-green tea-treated group was divided into two sub-groups on the basis of different doses: group IIIA-TNBS + green tea (35 mg/kg), group IIIB-TNBS + green tea (70 mg/kg), group IV-TNBS + sulfasalazine (360 mg/kg), group V-TNBS + sulfasalazine (360 mg/kg) + green tea (least effective dose found in group III). After completion of 2 weeks of treatment, the rats were killed under ether anesthesia by cervical dislocation for assessment of intestinal inflammation, histological analysis, myeloperoxidase assay, malondialdehyde assay, and TNF-α estimation. RESULTS: The study showed that green tea alone and in combination with sulfasalazine reduced inflammatory changes induced by tri nitro benzene sulfonic acid in rats. This reduction is associated with reduced malondialdehyde, lipid peroxidation, and TNF-α. This correlates well with both gross morphological and histopathological scores. CONCLUSIONS: The authors concluded that a combination of green tea extract with sulfasalazine showed greater efficacy than single drug treatment.

[Ozone therapy combined with sulfasalazine delivered via a colon therapy system for treatment of ulcerative colitis].

OBJECTIVE: To assess the therapeutic effect of ozone therapy combined with sulfasalazine sulfasalazine delivered via a colon therapy system in the treatment of distal ulcerative colitis. METHODS: This prospective randomized controlled clinical trial involved 54 patients with mild to moderate active distal ulcerative colitis, who were randomize into 3 groups in accordance with the inclusion criteria (n=18). Each group was given sulfasalazine at the daily dose of 2 g, and in colon therapy group and ozone therapy plus sulfasalazine therapy group, sulfasalazine was delivered via a colon therapy system on a daily basis; the control group received sulfasalazine via retention enema only. At 0, 2, and 4 weeks of the treatment, colonoscopy was performed to evaluate the disease activity, and biopsy samples were obtained at 0 and 4 weeks for histological examination. RESULTS: In comparison with colon therapy group and control group, ozone therapy plus colon therapy resulted in more rapid alleviation of the clinical symptoms and better histological improvement without any adverse effects. CONCLUSION: Ozone therapy combined with sulfasalazine delivered via a colon therapy system is feasible and effective for treatment of ulcerative colitis.

The good initial response to therapy with a combination of traditional disease-modifying antirheumatic drugs is sustained over time: the eleven-year results of the Finnish rheumatoid arthritis combination therapy trial.

OBJECTIVE: To evaluate the evolution of functional and clinical outcomes over 11 years in patients with early rheumatoid arthritis (RA) initially treated with a combination of 3 disease-modifying antirheumatic drugs (DMARDs) or with a single DMARD. METHODS: A cohort of 199 patients with early active RA were initially randomized to receive treatment with a combination of methotrexate, sulfasalazine, and hydroxychloroquine with prednisolone or treatment with a single DMARD (initially, sulfasalazine) with or without prednisolone. After 2 years, the drug treatment strategy became unrestricted, but still targeted remission. At 11 years, function was assessed with the Health Assessment Questionnaire (HAQ), and clinical outcomes were assessed with the modified Minimal Disease Activity (MDA) measure and the American College of Rheumatology (ACR) criteria for remission. RESULTS: At 11 years, 138 patients were assessed (68 in the combination-DMARD group and 70 in the single-DMARD group). The mean+/-SD HAQ scores were 0.34+/-0.54 in the combination-DMARD group and 0.38+/-0.58 in the single-DMARD group (P=0.88). Modified MDA was achieved by 63% (95% confidence interval [95% CI] 51, 77) and by 43% (95% CI 32, 55) (P=0.016) of the combination-DMARD group and the single-DMARD group, respectively, and ACR remission by 37% (95% CI 26, 49) and by 19% (95% CI 11, 29) (P=0.017), respectively. CONCLUSION: Initial therapy with a combination of DMARDs in early RA results in higher rates of patients achieving modified MDA and strict ACR remission even over the long term than initial single-DMARD therapy. Targeting remission with tight clinical controls results in good functional and clinical outcomes in most RA patients.

Differential effect on symptoms treated with traditional Chinese medicine and western combination therapy in RA patients.

OBJECTIVE: This study is designed to compare the therapeutic effects and safety of traditional Chinese medicine (CM) therapy and western combined therapy (WM) in the treatment of rheumatoid arthritis (RA). METHODS: After 24 weeks' treatment, the efficacy, safety and the improvement on symptoms of traditional Chinese medicine in 199 patients and western medicine therapy in 197 patients of RA were analyzed. CM therapy included Glucosidorum Tripterygll Totorum tablet and Yishen Juanbi Tablet. The WM therapy included voltaren extended action tablet, methotrexate and sulfasalazine. The American College of Rheumatology (ACR) 20, 50 and 70 responses were employed as primary end-point analysis and the 18 symptoms as secondary end-point analysis. All data were analyzed on SPSS11.5 statistical package. RESULTS: The ACR20 and ACR50 responses in WM were higher than in CM group, but more improvement on the symptoms and less adverse events were observed in CM therapy. The 18 CM symptoms in RA could be grouped into four symptom combinations with factor analysis method. The factor loading value difference (which reflects the degree of improvement) in responded cases was lower than in non-responded cases in the symptom combination 1. The loading value difference in both responded and non-responded cases in CM treated patients were higher than those in WM treated group in the symptom combination 2 and 3. CONCLUSIONS: WM combined therapy was more effective in the treatment of RA in ACR20 evaluation, but more improvement on CM symptoms were seen in the CM therapy.

Curcumin maintenance therapy for ulcerative colitis: randomized, multicenter, double-blind, placebo-controlled trial.

BACKGROUND & AIMS: Curcumin is a biologically active phytochemical substance present in turmeric and has pharmacologic actions that might benefit patients with ulcerative colitis (UC). The aim in this trial was to assess the efficacy of curcumin as maintenance therapy in patients with quiescent ulcerative colitis (UC). METHODS: Eighty-nine patients with quiescent UC were recruited for this randomized, double-blind, multicenter trial of curcumin in the prevention of relapse. Forty-five patients received curcumin, 1g after breakfast and 1g after the evening meal, plus sulfasalazine (SZ) or mesalamine, and 44 patients received placebo plus SZ or mesalamine for 6 months. Clinical activity index (CAI) and endoscopic index (EI) were determined at entry, every 2 months (CAI), at the conclusion of 6-month trial, and at the end of 6-month follow-up. RESULTS: Seven patients were protocol violators. Of 43 patients who received curcumin, 2 relapsed during 6 months of therapy (4.65%), whereas 8 of 39 patients (20.51%) in the placebo group relapsed (P=.040). Recurrence rates evaluated on the basis of intention to treat showed significant difference between curcumin and placebo (P=.049). Furthermore, curcumin improved both CAI (P=.038) and EI (P=.0001), thus suppressing the morbidity associated with UC. A 6-month follow-up was done during which patients in both groups were on SZ or mesalamine. Eight additional patients in the curcumin group and 6 patients in the placebo group relapsed. CONCLUSIONS: Curcumin seems to be a promising and safe medication for maintaining remission in patients with quiescent UC. Further studies on curcumin should strengthen our findings.

[Drug therapy for ulcerative colitis: salazosulfapyridine and 5-ASA].

Aminosalicylates have a wide range of anti-inflammatory and immunomodulatory effects. Oral salazosulfapyridine (SASP) and 5-aminosalicylic acid (5-ASA) are the 'first-line' therapy for induction of remission in mild to moderate active ulcerative colitis (UC). SASP, which is consisted of 5-ASA and sulfapyridine, has greater incidence of side effects. 5-ASA is a therapeutically active compound, while sulfapyridine is related to adverse effects. For this reason, 5-ASA formulas exclusive of sulfapyridine were developed and they enabled higher dose of 5-ASA administration without adverse effects. Topical treatment by 5-ASA enema or SASP suppository should be considered for the treatment of proctitis or distal type of UC. Oral aminosalicylate therapy is also effective for the maintenance of remission in UC. Therefore, aminosalicylates are key drugs for the treatment of UC.

Sulfasalazine is a potent inhibitor of the reduced folate carrier: implications for combination therapies with methotrexate in rheumatoid arthritis.

OBJECTIVE: To investigate whether interactions of sulfasalazine (SSZ) with reduced folate carrier (RFC), the dominant cell membrane transporter for natural folates and methotrexate (MTX), may limit the efficacy of combination therapy with MTX and SSZ in patients with rheumatoid arthritis. METHODS: Human RFC-(over)expressing CEM cells of T cell origin were used to analyze the effect of SSZ on the RFC-mediated cellular uptake of radiolabeled MTX and the natural folate leucovorin. Moreover, both cells with and those without acquired resistance to SSZ were used to assess the antiproliferative effects of MTX in combination with SSZ. RESULTS: Transport kinetic analyses revealed that SSZ was a potent noncompetitive inhibitor of RFC-mediated cellular uptake of MTX and leucovorin, with mean +/- SD K(i) (50% inhibitory concentration) values of 36 +/- 6 microM and 74 +/- 7 microM, respectively. Consistent with the inhibitory interaction of SSZ with RFC, a marked loss of MTX efficacy was observed when MTX was coadministered with SSZ: up to 3.5-fold for CEM cells in the presence of 0.25 mM of SSZ, and >400-fold for SSZ-resistant cells in the presence of 2.5 mM of SSZ. Importantly, along with diminished efficacy of MTX, evidence for cellular folate depletion was obtained by the demonstration of an SSZ dose-dependent decrease in leucovorin accumulation. CONCLUSION: At clinically relevant plasma concentrations, interactions of SSZ with RFC provide a biochemical rationale for 2 important clinical observations: 1) the onset of (sub)clinical folate deficiency during SSZ treatment, and 2) the lack of additivity/synergism of the combination of SSZ and MTX when these disease-modifying antirheumatic drugs are administered simultaneously. Thus, when considering use of these drugs in combination therapies, the present results provide a rationale both for the use of folate supplementation and for spacing administration of these drugs over time.

Folic acid and sulfasalazine for colorectal carcinoma chemoprevention in patients with ulcerative colitis: the old and new evidence.

BACKGROUND: The purpose of the study was to assess whether folic acid supplementation and long term therapy with sulfasalazine can reduce the risk of colorectal cancer (CRC) development in longstanding extensive ulcerative colitis. MATERIAL AND METHODS: A meta-analysis was performed including the last 10 years published and Medline indexed studies on this subject. RESULTS: 3 studies have been included concerning the protective effect of folate supplementation in development of CRC. The association of these two factors is significant (effect size r =0.124, p = 0.025). The fail-safe number of studies with an opposite result should be 4 to revert the significance. 4 studies regarding sulfasalazine's protective effect in longstanding extensive ulcerative colitis have also been evaluated. A similar significance has been obtained, r = 0.148, p = 0.0007 and a fail-safe number of studies equal to 7. The homogeneity of these studies is validated by standard tests. CONCLUSIONS: Both sulfasalazine therapy and folate supplementation have a protective effect in colorectal cancer development in a population of patients with longstanding ulcerative colitis. Randomized controlled trials are needed to explore these hypotheses.

Role of mesalazine in acute and long-term treatment of ulcerative colitis and its complications.

BACKGROUND: Sulfasalazine, consisting of 5-aminosalicylic acid bound to sulfapyridine by a diazo bond, was first used for treatment of ulcerative colitis in the early 1940s and later found effective in placebo-controlled trials for acute disease and for long-term maintenance of remission. Later studies found that the active moiety is 5-ASA (mesalazine, mesalamine) and the sulfapyridine moiety acts as a carrier molecule but causes many of the symptomatic adverse reactions. METHODS: Review of the literature. RESULTS: The finding that 5-ASA in the active motility led to the development of mesalazine prodrugs, olsalazine (Dipentum) and balsalazide (Colazide, Colazal), and targeted release mesalazine preparations, such as Asacol, Pentasa, and Salofalk, as well as enemas and suppository preparations for distal disease. Most patients with adverse effects from sulfasalazine will tolerate mesalazine. Mesalazine has been shown equivalent or superior to sulfasalazine, and superior to placebo, with a dose-response benefit, in inducing remission of acute disease. and comparable to sulfasalazine and superior to placebo for long-term maintenance of remission. Better tolerance of mesalazine and the ability to use higher doses favor its use in patients intolerant of sulfasalazine and in patients failing to respond to usual doses of sulfasalazine. Adverse effects from mesalazine are uncommon, but include idiosyncratic worsening of the colitis symptoms and renal toxicity. Mesalazine is safe to use during pregnancy and for nursing mothers. As maintenance therapy, mesalazine may reduce the risk of developing colorectal carcinoma. CONCLUSION: Mesalazine represents effective and well-tolerated first-line therapy for mildly to moderately acute disease as well as for the long-term maintenance treatment in the patient with ulcerative colitis.

Comparative absorption of 5-aminosalicylic acid (5-ASA) after administration of a 5-ASA enema and salazosulfapyridine (SASP) after an SASP suppository in Japanese volunteers.

Salazosulfapyridine (SASP) is widely used orally and rectally in the treatment of ulcerative colitis. SASP is mainly metabolized by hydrolysis and the main active metabolite, 5-aminosalicylic acid (5-ASA), has an antiinflammatory effect. In the present study, we prepared suppositories containing 6.5 mmol of SASP and an enema containing 6.5 mmol of 5-ASA. We measured the concentrations of SASP and its various metabolites, 5-ASA, sulfapyridine (SP), acetylated metabolite of SP (Ac-SP), and N-acetyl-5-ASA (Ac-5-ASA), in the serum and urine after a single administration of each preparation to healthy male volunteers. When the SASP suppository was administered, the maximum concentration (Cmax) of SASP and Ac-5-ASA was 2.5+/-0.4 and 0.5+/-0.2 microM and the time to Cmax (Tmax) was 5 and 12 h, respectively. The Cmax value of SP, which causes side effects, was one-half of that of the parent compound. No 5-ASA in the serum was observed. When the 5-ASA enema was administered, Cmax and Tmax values of 5-ASA and Ac-5-ASA were 5.8+/-2.0 and 13.3+/-3.6 microM and 1 and 7 h, respectively. The area under the serum concentration-time curve (AUC) of SASP was 27.4+/-4.8 microM x h, a finding similar to that of 5-ASA after the administration of the 5-ASA enema (29.4+/-11.1 microM x h). The percentage of urinary recovery of SASP 24 h after administration of the SASP suppository was approximately 0.2%. These results indicate that SASP administered rectally is almost completely hydrolyzed in the colon and that 5-ASA is partially absorbed from the small intestine in unchanged form. On the other hand, approximately 0.3% of 5-ASA was recovered in the urine in unchanged form after the administration of the 5-ASA enema, whereas the urinary recovery of Ac-5-ASA was more than 10%. The present findings suggest that 5-ASA has favorable absorptive properties and can be expected to have systemic action after rectal administration of a 5-ASA enema.

Bone turnover, joint damage and bone mineral density in early rheumatoid arthritis treated with combination therapy including high-dose prednisolone.

OBJECTIVES: Exploration of bone metabolism changes at different levels of disease activity, both with and without oral corticosteroid therapy, and prediction of changes in joint damage and bone density from the observed changes in markers of bone turnover. METHODS: Data analysis from a randomized clinical trial with 155 rheumatoid arthritis (RA) patients; median age 50 yr, early and active disease (diagnosis < 2 yr); one group treated with a combination of sulphasalazine (SSZ; 2000 mg/day), methotrexate (MTX; 7.5 mg/week) and prednisolone (initially 60 mg/day, tapered in six weekly steps to 7.5 mg/day), the other group with SSZ alone. Prednisolone and MTX were tapered and stopped after weeks 28 and 40, respectively, while SSZ was continued. Urine and serum samples were collected at baseline and weeks 16, 28, 40 and 56. Measurements of urinary pyridinoline (PYD) and deoxypyridinoline (DPD) and serum alkaline phosphatase (tAP) and osteocalcin (OC) were performed, as well as standard clinimetry and bone densitometry. RESULTS: Over time and in both treatment groups, bone formation and bone resorption markers showed a pattern similar to erythrocyte sedimentation rate (ESR): a significant decrease compared with baseline and a larger decrease with combined treatment at weeks 16 and 28. PYD excretion, tAP, OC, and joint damage scores were significantly lower in the combined treatment group. Changes in bone density (of spine and hips) did not significantly differ between treatment groups. Mainly cumulative ESR explained progression of joint damage. CONCLUSIONS: Prednisolone and disease-modifying anti-rheumatic drug therapy in patients with early and active RA are both independently associated with decreased levels of urinary excretion of bone collagen resorption markers PYD and DPD. Markers of bone formation and resorption closely followed changes in ESR in both treatment groups. Reduced bone resorption together with reduced bone formation-initially at a somewhat faster pace-resulted in less bone turnover and explain the observed (non-significant and partially reversible) extra bone loss in the lumbar spine associated with prednisolone (combined treatment).

Sulfasalazine, a potent suppressor of lymphoma growth by inhibition of the x(c)- cystine transporter: a new action for an old drug.

Although cyst(e)ine is nutritionally a non-essential amino acid, lymphoid cells cannot synthesize it, rendering their growth dependent on uptake of cyst(e)ine from their microenvironment. Accordingly, we previously suggested that the x(c)- plasma membrane cystine transporter provided a target for lymphoid cancer therapy. Its inhibition could lead to cyst(e)ine deficiency in lymphoma cells via reduction of both their cystine uptake and cysteine supply by somatic cells. In this study, using rat Nb2 lymphoma cultures, drugs were screened for growth arrest based on x(c)- inhibition. Sulfasalazine was fortuitously found to be a novel, potent inhibitor of the x(c)- transporter. It showed high rat lymphoma growth-inhibitory and lytic activity in vitro (IC50 = 0.16 mM), based specifically on inhibition of x(c)--mediated cystine uptake, in contrast to its colonic metabolites, sulfapyridine and 5-aminosalicylic acid. Sulfasalazine was even more effective against human non-Hodgkin's lymphoma (DoHH2) cultures. In rats (n = 13), sulfasalazine (i.p.) markedly inhibited growth of well-developed, rapidly growing rat Nb2 lymphoma transplants without apparent side-effects. Reduced, macrophage-mediated supply of cysteine was probably involved. In five rats, 90-100% tumor growth suppression, relative to controls, was obtained. The x(c)- cystine transporter represents a novel target for sulfasalazine-like drugs with high potential for application in therapy of lymphoblastic and other malignancies dependent on extracellular cyst(e)ine.